Journal articles
Bowtell J, Shore A, Jackman S (In Press). An appraisal of trials investigating the effects on macular pigment optical density of lutein and zeaxanthin dietary interventions: a narrative review. Nutrition Reviews
Linschoten M, Uijl A, Schut A, Jakob CEM, Roṃo LR, Bell RM, McFarlane E, Stecher M, Zondag AGM, van Iperen EPA, et al (In Press). Clinical presentation, disease course and outcome of COVID-19 in hospitalized patients with and without pre-existing cardiac disease Рa cohort study across eighteen countries.
Abstract:
Clinical presentation, disease course and outcome of COVID-19 in hospitalized patients with and without pre-existing cardiac disease – a cohort study across eighteen countries
AbstractAimsPatients with cardiac disease are considered high risk for poor outcomes following hospitalization with COVID-19. The primary aim of this study was to evaluate heterogeneity in associations between various heart disease subtypes and in-hospital mortality.Method and resultsWe used data from the CAPACITY-COVID registry and LEOSS study. Multivariable Poisson regression models were fitted to assess the association between different types of pre-existent heart disease and in-hospital mortality. 16,511 patients with COVID-19 were included (21.1% aged 66 – 75 years; 40.2% female) and 31.5% had a history of heart disease. Patients with heart disease were older, predominantly male and often had other comorbid conditions when compared to those without. Mortality was higher in patients with cardiac disease (29.7%; n=1545 versus 15.9%; n=1797). However, following multivariable adjustment this difference was not significant (adjusted risk ratio (aRR) 1.08 [95% CI 1.02 – 1.15; p-value 0.12 (corrected for multiple testing)]). Associations with in-hospital mortality by heart disease subtypes differed considerably, with the strongest association for heart failure aRR (1.19 [1.10 – 1.30]; p-value <0.018) particularly for severe NYHA III/IV) heart failure (aRR 1.41 [95% CI 1.20 – 1.64; p-value <0.018]. None of the other heart disease subtypes, including ischemic heart disease, remained significant after multivariable adjustment. Serious cardiac complications were diagnosed in <1% of patients.ConclusionConsiderable heterogeneity exists in the strength of association between heart disease subtypes and in-hospital mortality. of all patients with heart disease, those with heart failure are at greatest risk of death when hospitalized with COVID-19. Serious cardiac complications are rare.
Abstract.
Jordan A, Anning C, Wilkes L, Ball C, Pamphilon N, Clark CE, Bellenger NG, Shore AC, Sharp ASP, Valderas JM, et al (In Press). Cross-Cultural Adaptation of the Spanish MINICHAL Instrument into English for Use in the United Kingdom.
Abstract:
Cross-Cultural Adaptation of the Spanish MINICHAL Instrument into English for Use in the United Kingdom
Abstract
. Background: Hypertension is a highly prevalent condition, with optimal treatment to BP targets conferring significant gains in terms of cardiovascular outcomes. Understanding why some patients do not achieve BP targets would be enhanced through greater understanding of their health-related quality of life (HRQoL). However, the only English language disease-specific instruments for measurement of HRQoL in hypertension have not been validated in accordance with accepted standards. It is proposed that the Spanish MINICHAL instrument for the assessment of HRQoL in hypertension could be translated, adapted and validated for use in the United Kingdom. The aim of the study was therefore to complete this process, using a cohort of patients enrolled in an 18-week programme for the treatment of grade II-III hypertension. Methods: the MINICHAL authors were contacted and the original instrument obtained. This was then translated into English by two independent English-speakers, with these versions then reconciled, before back-translation and subsequent production of a 2nd reconciled version. Thereafter, a final version was produced after cognitive debriefing, for administration and psychometric analysis in the target population. Results: the final version of the instrument was administered to 30 individuals with grade II/III hypertension before and after 18 weeks’ intensive treatment. Psychometric analysis demonstrated a floor effect, though no ceiling effect. Internal consistency for both state of mind (StM) and somatic manifestations (SM) dimensions of the instrument were acceptable (Cronbach’s alpha = 0.81 and 0.75), as was test-retest reliability (ICC=0.717 and 0.961) and construct validity, which was measured through co-administration with the EQ5d5L and Bulpitt-Fletcher instruments. No significant associations were found between scores and patient characteristics known to affect HRQoL. The EQ5D5L instrument found an improvement in HRQoL following treatment, with the StM and SM dimensions of the English language MINICHAL trending to support this (d=0.32 and 0.02 respectively). Conclusions: the present study details the successful English translation and validation of the MINICHAL instrument for use in individuals with hypertension. The data reported also supports an improvement in HRQoL with rapid treatment of grade II/III hypertension, a strategy which has been recommended by contemporaneous European guidelines. Trial registration: ISRCTN registry number: 57475376 (assigned 25/06/2015).
Abstract.
Shore A, De Marinis Y (In Press). Elevated circulating follistatin associates with an increased risk of type 2 diabetes. Nature Communications
Shore A (In Press). Microstructural Characterisation of Resistance Artery Remodelling in Diabetes Mellitus. Journal of Vascular Research
Thorn CE (In Press). Microstructure and mechanics of human resistance arteries. American Journal of Physiology - Heart and Circulatory Physiology
Gooding KM, Lienczewski C, Papale M, Koivuviita N, Maziarz M, Andersson A-MD, Sharma K, Pontrelli P, Hernandez AG, Bailey J, et al (In Press). Prognostic Imaging Biomarkers for Diabetic Kidney Disease (iBEAt): Study protocol.
Abstract:
Prognostic Imaging Biomarkers for Diabetic Kidney Disease (iBEAt): Study protocol
ABSTRACTDiabetic kidney disease (DKD) is traditionally classified based on albuminuria and reduced kidney function (estimated glomerular filtration rate (eGFR)), but these have limitations as prognostic biomarkers due to the heterogeneity of DKD. Novel prognostic markers are needed to improve stratification of patients based on risk of disease progression.The iBEAT study, part of the BEAt-DKD consortium, aims to determine whether renal imaging biomarkers (magnetic resonance imaging (MRI) and ultrasound (US)) provide insight into the pathogenesis and heterogeneity of DKD (primary aim), and whether they have potential as prognostic biomarkers in DKD progression (secondary aim).iBEAT is a prospective multi-centre observational cohort study recruiting 500 patients with type 2 diabetes (T2D) and eGFR > 30ml/min/1.73m2. At baseline each participant will undergo quantitative renal MRI and US imaging with central processing for MRI images. Blood sampling, urine collection and clinical examinations will be performed and medical history obtained at baseline, and these assessments will be repeated annually for 3 years. Biological samples will be stored in a central laboratory for later biomarker and validation studies. All data will be stored in a central data depository. Data analysis will explore the potential associations between imaging biomarkers and renal function, and whether the imaging biomarkers may improve the prediction of DKD progression rates.Embedded within iBEAT are ancillary substudies that will (1) validate imaging biomarkers against renal histopathology; (2) validate MRI based renal blood flow against water-labelled positron-emission tomography (PET); (3) develop machine-learning methods for automated processing of renal MRI images; (4) examine longitudinal changes in imaging biomarkers; (5) examine whether the glycocalyx, microvascular function and structure are associated with imaging biomarkers and eGFR decline; (6) a pilot study to examine whether the findings in T2D can be extrapolated to type 1 diabetes.The iBEAT study, the largest DKD imaging study to date, will provide invaluable insights into the progression and heterogeneity of DKD, and aims to contribute to a more personalized approach to the management of DKD in patients with type 2 diabetes.
Abstract.
Casanova F, Gooding K, Shore A, Adingupu D, Mawson D, Ball C, Anning C, Aizawa K, Gates P, Strain W, et al (In Press). Weight change and sulphonylurea therapy are related to three-year change in microvascular function in people with type 2 diabetes. Diabetologia
Williams J, Gilchrist M, Strain WD, Fraser D, Shore A (2022). 24-h Glycaemic profiles in peritoneal dialysis patients and non-dialysis controls with advanced kidney disease.
Perit Dial Int,
42(5), 497-504.
Abstract:
24-h Glycaemic profiles in peritoneal dialysis patients and non-dialysis controls with advanced kidney disease.
BACKGROUND: for patients on peritoneal dialysis (PD), the deleterious effects of high concentrations of dialysate glucose on the peritoneal membrane are well-documented. Systemic effects of peritoneally absorbed glucose are more poorly defined. Using continuous glucose monitoring (CGM), we aimed to describe 24-h glycaemic profiles of PD patients without diabetes and compare with non-dialysis controls with stage 5 chronic kidney disease (CKD-5). METHODS: in this cross-sectional, case-control study, 15 patients on PD (9 automated PD (APD) and 6 continuous ambulatory PD (CAPD)) and 16 CKD-5 controls underwent 72 h of CGM and metabolic profiling. CGM was used to derive average glucose concentrations and within-participant standard deviation (SD) of glucose. Data were analysed for the whole 72-h monitoring period and as daytime (09.00 to 21.00) and night-time (21.00 to 09.00). RESULTS: Average glucose concentrations and within-participant SD of glucose for the whole monitoring period were not different between the three groups (p ≥ 0.5). Daytime average glucose concentrations were also similar across the three groups (p = 0.729). APD was associated with a significantly higher nocturnal glucose than CAPD (5.25 mmol/L ± 0.65 vs. 4.28 ± 0.5, p = 0.026). A significant drop in nocturnal glucose compared with daytime average seen in both CAPD patients and controls was absent in APD patients. CONCLUSIONS: Systematically different glycaemic patterns were observed in non-diabetic APD and CAPD patients, including an absence of physiological nocturnal glucose dipping in patients on APD. Comprehensive CGM data sets highlight subtleties not appreciated by traditional metabolic biomarkers; this has implications when choosing the most appropriate outcome measures in future research addressing the metabolic impact of PD.
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Williams J, Gilchrist M, Strain WD, Fraser D, Shore A (2022). An exploratory study of the relationship between systemic microcirculatory function and small solute transport in incident peritoneal dialysis patients.
Perit Dial Int,
42(5), 513-521.
Abstract:
An exploratory study of the relationship between systemic microcirculatory function and small solute transport in incident peritoneal dialysis patients.
BACKGROUND: the peritoneal capillary endothelium is widely considered to be the most influential structure in dictating the rate of small solute transport (SST) during peritoneal dialysis (PD). PD patients are at significant risk of systemic microcirculatory dysfunction. The relationship between peritoneal and systemic microcirculations in patients new to PD has not been well studied. We hypothesised that for patients on PD for less than 6 months, dysfunction in the systemic microcirculation would be reflected in the rate of SST. METHODS: We recruited 29 patients to a cross-sectional, observational study. Rate of SST was measured using a standard peritoneal equilibration test. Laser Doppler Flowmetry was used to measure response to physical and pharmacological challenge (post-occlusive hyperaemic response and iontophoretic application of vasodilators) in the cutaneous microcirculation. Sidestream Darkfield imaging was used to assess sublingual microvascular density, flow and endothelial barrier properties. RESULTS: We found no moderate or strong correlations between any of the measures of systemic microcirculatory function and rate of SST or albumin clearance. There was however a significant correlation between dialysate interleukin-6 concentrations and both SST (rs = 0.758 p ≤ 0.0001) and albumin clearance (rs = 0.53, p = 0.01). CONCLUSIONS: in this study, systemic microvascular dysfunction did not significantly influence the rate of SST even early in patients PD careers. In conclusion, this study demonstrates that intraperitoneal factors particularly inflammation have a far greater impact on rate of SST than systemic factors.
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Khan F, Gonçalves I, Shore AC, Natali A, Palombo C, Colhoun HM, Östling G, Casanova F, Kennbäck C, Aizawa K, et al (2022). Plaque characteristics and biomarkers predicting regression and progression of carotid atherosclerosis.
Cell Rep Med,
3(7).
Abstract:
Plaque characteristics and biomarkers predicting regression and progression of carotid atherosclerosis.
The factors that influence the atherosclerotic disease process in high-risk individuals remain poorly understood. Here, we used a combination of vascular imaging, risk factor assessment, and biomarkers to identify factors associated with 3-year change in carotid disease severity in a cohort of high-risk subjects treated with preventive therapy (n = 865). The results show that changes in intima-media thickness (IMT) are most pronounced in the carotid bulb. Progression of bulb IMT demonstrates independent associations with baseline bulb IMT, the plaque gray scale median (GSM), and the plasma level of platelet-derived growth factor (PDGF) (standardized β-coefficients and 95% confidence interval [CI] -0.14 [-0.06 to -0.02] p = 0.001, 0.15 [0.02-0.07] p = 0.001, and 0.20 [0.03-0.07] p
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Leonetti S, Tricò D, Nesti L, Baldi S, Kozakova M, Goncalves I, Nilsson J, Shore A, Khan F, Natali A, et al (2022). Soluble CD40 receptor is a biomarker of the burden of carotid artery atherosclerosis in subjects at high cardiovascular risk.
Atherosclerosis,
343, 1-9.
Abstract:
Soluble CD40 receptor is a biomarker of the burden of carotid artery atherosclerosis in subjects at high cardiovascular risk.
BACKGROUND AND AIMS: the severity of the atherosclerotic burden is hardly quantifiable in subjects at high cardiovascular (CV) risk under intensive pharmacological therapy. Several molecules have been proposed as circulating biomarkers of atherosclerosis, but none has emerged as clinically meaningful. METHODS: Circulating proteins involved in inflammation, plaque remodeling, smooth muscle cell migration, apoptosis and endothelial activity were measured by Proximity Extension Assay in the SUMMIT study cohort (n = 1500), including patients with type 2 diabetes (66%) and established CV disease (50%), who underwent ultrasound assessment of carotid atherosclerosis with total plaque area quantification. RESULTS: in patients with evidence of carotid artery atherosclerosis (n = 1174), seven biomarkers were identified as the more closely related to atherosclerosis extension. Compared with a multivariable model including major traditional CV risk factors, the percentage gain of explained variability in total plaque area was the greatest (33%) after inclusion of CD40 receptor (CD40R) ligand, followed by PDGF (30%), CD40R (26%), EGF (22%), CXCL1 (15%), HBEGF and MMP-17 (both 11%). The relationship of total plaque area with CD40R, PDGF was hyperbolic. In the whole study cohort, including subjects without carotid plaques, CD40R was the strongest predictor of the presence and extension of carotid atherosclerosis. Subjects in the third CD40R tertile had a more than two-fold greater atherosclerotic burden compared with lower CD40R tertiles, despite an only marginally higher load of CV risk factors. CONCLUSIONS: CD40R stands among an extended set of plausible atherosclerosis-related biomarkers as the most powerful predictor of carotid atherosclerosis burden in a high CV risk cohort.
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Carmichael J, Fadavi H, Ishibashi F, Shore AC, Tavakoli M (2021). Advances in Screening, Early Diagnosis and Accurate Staging of Diabetic Neuropathy.
FRONTIERS IN ENDOCRINOLOGY,
12 Author URL.
McDonagh STJ, Sheppard JP, Warren FC, Boddy K, Farmer L, Shore H, Williams P, Lewis PS, Baumber R, Fordham J, et al (2021). Arm Based on LEg blood pressures (ABLE-BP): can systolic leg blood pressure measurements predict systolic brachial blood pressure? Protocol for an individual participant data meta-analysis from the INTERPRESS-IPD Collaboration.
BMJ Open,
11(3), e040481-e040481.
Abstract:
Arm Based on LEg blood pressures (ABLE-BP): can systolic leg blood pressure measurements predict systolic brachial blood pressure? Protocol for an individual participant data meta-analysis from the INTERPRESS-IPD Collaboration
IntroductionBlood pressure (BP) is normally measured on the upper arm, and guidelines for the diagnosis and treatment of high BP are based on such measurements. Leg BP measurement can be an alternative when brachial BP measurement is impractical, due to injury or disability. Limited data exist to guide interpretation of leg BP values for hypertension management; study-level systematic review findings suggest that systolic BP (SBP) is 17 mm Hg higher in the leg than the arm. However, uncertainty remains about the applicability of this figure in clinical practice due to substantial heterogeneity.AimsTo examine the relationship between arm and leg SBP, develop and validate a multivariable model predicting arm SBP from leg SBP and investigate the prognostic association between leg SBP and cardiovascular disease and mortality.Methods and analysisIndividual participant data (IPD) meta-analyses using arm and leg SBP measurements for 33 710 individuals from 14 studies within the Inter-arm blood pressure difference IPD (INTERPRESS-IPD) Collaboration. We will explore cross-sectional relationships between arm and leg SBP using hierarchical linear regression with participants nested by study, in multivariable models. Prognostic models will be derived for all-cause and cardiovascular mortality and cardiovascular events.Ethics and disseminationData originate from studies with prior ethical approval and consent, and data sharing agreements are in place—no further approvals are required to undertake the secondary analyses proposed in this protocol. Findings will be published in peer-reviewed journal articles and presented at conferences. A comprehensive dissemination strategy is in place, integrated with patient and public involvement.PROSPERO registration numberCRD42015031227.
Abstract.
Aizawa K, Gates PE, Mawson DM, Elyas S, Casanova F, Gooding KM, Adingupu DD, Strain WD, Shore AC (2021). Carotid–femoral pulse wave velocity acquisition methods and their associations with cardiovascular risk factors and subclinical biomarkers of vascular health.
Journal of Hypertension,
40(4), 658-665.
Abstract:
Carotid–femoral pulse wave velocity acquisition methods and their associations with cardiovascular risk factors and subclinical biomarkers of vascular health
. Background:
. Different methods to measure carotid–femoral pulse wave velocity (CFPWV) may affect the measurements obtained and influence the association between CFPWV, cardiovascular risk factors and biomarkers of subclinical vascular health. The estimation of distance between the carotid and femoral artery measurement sites (the arterial path length) is particularly problematic.
.
.
. Method:
. We determined if CFPWV and equation-based estimates of CFPWV were influenced by arterial path length and if this affected the association of CFPWV with cardiovascular risk factors and subclinical vascular biomarkers. The CFPWV derived from the measurement of surface distance (CFPWV-D), arterial path length formula (CFPWV-F), and estimated CFPWV (ePWV) were obtained from 489 older adults (67.2 ±â€Š8.8 years). Macrovascular [carotid artery: lumen diameter (LD), inter-adventitial diameter (IAD), intima–media thickness (IMT) and total plaque area (TPA)] and microvascular [reactive hyperaemia index and urinary albumin-creatinine ratio (UACR)] biomarkers were also measured.
.
.
. Results:
. CFPWV-D was significantly greater than CFPWV-F [9.6 (8.0–11.2) vs. 8.9 (7.6–10.5) m/s, P < 0.001], because of estimated path length being longer in CFPWV-D than CFPWV-F (495.4 ±â€Š44.8 vs. 465.3 ±â€Š20.6 mm, P < 0.001). ePWV was significantly greater than both CFPWV-F and CFPWV-D [11.0 (10.0–12.2) m/s, P < 0.001]. The three CFPWV methods were similarly associated with LD, IAD, IMT, TPA and UACR but not with cardiovascular risk factors.
.
.
. Conclusion:
. Different methods to measure CFPWV affect the derived measurement values and the association with cardiovascular risk factors but not the association with subclinical biomarkers of vascular health. These hitherto unreported observations are important considerations in experimental design, data interpretation and of particular importance, comparison between studies where CFPWV is measured.
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Abstract.
Elyas S, Adingupu D, Aizawa K, Casanova F, Gooding K, Fulford J, Mawson D, Gates PE, Shore AC, Strain D, et al (2021). Cerebral small vessel disease, systemic vascular characteristics and potential therapeutic targets. Aging, 13(18), 22030-22039.
Östlund Papadogeorgos N, Kuhl J, Shore A, Kahan T, Jörneskog G, Kalani M (2021). Effects of exenatide on microvascular reactivity in patients with type 2 diabetes and coronary artery disease: a randomized controlled study.
Microcirculation,
28(2).
Abstract:
Effects of exenatide on microvascular reactivity in patients with type 2 diabetes and coronary artery disease: a randomized controlled study.
OBJECTIVE: We studied the effect of the GLP-1RA exenatide on skin microvascular function in patients with T2DM and CAD. METHODS: Thirty-five patients with T2DM, CAD, and HbA1C 42-86 mmol/mol were randomized to treatment with exenatide or conventional non-GLP-1-based therapy for 12 weeks. Skin microvascular function was examined in the forearm by LDF and iontophoretic application of acetyl choline and SNP, and by PORH at baseline and after 12 weeks. Blood samples for fasting plasma glucose, HbA1C, and lipid profile were collected. RESULTS: at 12 weeks, patients on exenatide showed reductions in HbA1C (from 63.5 ± 13 to 60.7 ± 14 mmol/mol, p = .065), body weight (from 92.6 ± 16 to 89 ± 16 kg, p
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Strain WD, Elyas S, Wedge N, Mounce L, Henley W, James M, Shore AC (2021). Evaluation of microalbuminuria as a prognostic indicator after a TIA or minor stroke in an outpatient setting: the prognostic role of microalbuminuria in TIA evolution (ProMOTE) study.
BMJ Open,
11(9), e043253-e043253.
Abstract:
Evaluation of microalbuminuria as a prognostic indicator after a TIA or minor stroke in an outpatient setting: the prognostic role of microalbuminuria in TIA evolution (ProMOTE) study
ObjectiveTransient ischaemic attacks (TIA) and minor strokes are important risk factors for further vascular events. We explored the role of albumin creatinine ratio (ACR) in improving risk prediction after a first event.SettingRapid access stroke clinics in the UK.Participants2202 patients attending with TIA or minor stroke diagnosed by the attending stroke physician, able to provide a urine sample to evaluate ACR using a near-patient testing device.Primary and secondary outcomesPrimary outcome was major adverse cardiac events (MACE: recurrent stroke, myocardial infarction or cardiovascular death) at 90 days. The key secondary outcome was to determine whether urinary ACR could contribute to a risk prediction tool for use in a clinic setting.Results151 MACE occurred in 144 participants within 90 days. Participants with MACE had higher ACR than those without. A composite score awarding a point each for age >80 years, previous stroke/TIA and presence of microalbuminuria identified those at low risk and high risk. 90% of patients were at low risk (scoring 0 or 1). Their 90-day risk of MACE was 5.7%. of the remaining ‘high-risk’ population (scoring 2 or 3) 12.4% experienced MACE over 90 days (p<0.001 compared with the low-risk population). The need for acute admission in the first 7 days was twofold elevated in the high-risk group compared with the low-risk group (3.23% vs 1.43%; p=0.05). These findings were validated in an independent historic sample.ConclusionA risk score comprising age, previous stroke/TIA and microalbuminuria predicts future MACE while identifying those at low risk of a recurrent event. This tool shows promise in the risk stratification of patients to avoid the admission of low-risk patients.
Abstract.
Thorn CE, Adio AO, Fox RH, Gardner AM, Winlove CP, Shore AC (2021). Intermittent compression induces transitory hypoxic stimuli, upstream vasodilation and enhanced perfusion of skin capillaries, independent of age and diabetes.
J Appl Physiol (1985),
130(4), 1072-1084.
Abstract:
Intermittent compression induces transitory hypoxic stimuli, upstream vasodilation and enhanced perfusion of skin capillaries, independent of age and diabetes.
The benefit of enhanced shear stress to the vascular endothelium has been well-documented in conduit arteries but is less understood in skin microcirculation. The aim of this study was to provide physiological evidence of the vascular changes in skin microcirculation induced by intermittent pneumatic compression (IPC) of 1 s cuff inflation (130 mmHg) every 20 s to the palm of the hand for 30 min. The oxygenation and hemodynamics of dorsal mid-phalangeal finger skin microcirculation were assessed by laser Doppler fluximetry and reflectance spectroscopy before, during, and after IPC in 15 young (18-39 years old) and 39 older (40-80 years old) controls and 32 older subjects with type 2 diabetes mellitus. Each individual cuff inflation induced: 1) brief surge in flux immediately after cuff deflation followed by 2) transitory reduction in blood oxygen for ∼4 s, and 3) a second increase in perfusion and oxygenation of the microcirculation peaking ∼11 s after cuff deflation in all subject groups. With no significant change in blood volume observed by reflectance spectroscopy, despite the increased shear stress at the observed site, this second peak in flux and blood oxygen suggests a delayed vasoactive response upstream inducing increased arterial influx in the microcirculation that was higher in older controls and subjects with diabetes compared to young controls (P < 0.001, P < 0.001, respectively) and achieving maximum capillary recruitment in all subject groups. Transitory hypoxic stimuli with conducted vasodilation may be a mechanism through which IPC enhances capillary perfusion in skin microcirculation independent of age and type 2 diabetes mellitus.NEW & NOTEWORTHY This study demonstrates that hand intermittent pneumatic compression evokes transitory hypoxic stimuli in distal finger skin microcirculation inducing vasodilation of arterial inflow vessels, enhanced perfusion, and maximum capillary recruitment in young and older subjects and older subjects with type 2 diabetes mellitus. Enhanced shear stress in the microcirculation did not appear to induce local skin vasodilation.
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Author URL.
Jordan AN, Fulford J, Gooding K, Anning C, Wilkes L, Ball C, Pamphilon N, Mawson D, Clark CE, Shore AC, et al (2021). Morphological and functional cardiac consequences of rapid hypertension treatment: a cohort study.
Journal of Cardiovascular Magnetic Resonance,
23(1).
Abstract:
Morphological and functional cardiac consequences of rapid hypertension treatment: a cohort study
Abstract
. Background
. Left ventricular (LV) hypertrophy (LVH) in uncontrolled hypertension is an independent predictor of mortality, though its regression with treatment improves outcomes. Retrospective data suggest that early control of hypertension provides a prognostic advantage and this strategy is included in the 2018 European guidelines, which recommend treating grade II/III hypertension to target blood pressure (BP) within 3 months. The earliest LVH regression to date was demonstrated by echocardiography at 24 weeks. The effect of a rapid guideline-based treatment protocol on LV remodelling, with very early BP control by 18 weeks remains controversial and previously unreported. We aimed to determine whether such rapid hypertension treatment is associated with improvements in LV structure and function through paired cardiovascular magnetic resonance (CMR) scanning at baseline and 18 weeks, utilising CMR mass and feature tracking analysis.
.
. Methods
. We recruited participants with never-treated grade II/III hypertension, initiating a guideline-based treatment protocol which aimed to achieve BP control within 18 weeks. CMR and feature tracking were used to assess myocardial morphology and function immediately before and after treatment.
.
. Results
. We acquired complete pre- and 18-week post-treatment data for 41 participants. During the interval, LV mass index reduced significantly (43.5 ± 9.8 to 37.6 ± 8.3 g/m2, p < 0.001) following treatment, accompanied by reductions in LV ejection fraction (65.6 ± 6.8 to 63.4 ± 7.1%, p = 0.03), global radial strain (46.1 ± 9.7 to 39.1 ± 10.9, p < 0.001), mid-circumferential strain (− 20.8 ± 4.9 to − 19.1 ± 3.7, p = 0.02), apical circumferential strain (− 26.0 ± 5.3 to − 23.4 ± 4.2, p = 0.003) and apical rotation (9.8 ± 5.0 to 7.5 ± 4.5, p = 0.003).
.
. Conclusions
. LVH regresses following just 18 weeks of intensive antihypertensive treatment in subjects with newly-diagnosed grade II/III hypertension. This is accompanied by potentially advantageous functional changes within the myocardium and supports the hypothesis that rapid treatment of hypertension could improve clinical outcomes.
. Trial registration: ISRCTN registry number: 57475376 (assigned 25/06/2015).
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Abstract.
Hubbard T, Dudgeon A, Ferguson D, Shore A, Stone N (2021). P100. High wavenumber Raman spectroscopy tissue differentiation for intraoperative margin analysis. European Journal of Surgical Oncology, 47(5).
Aizawa K, Casanova F, Gates PE, Mawson DM, Gooding KM, Strain WD, Östling G, Nilsson J, Khan F, Colhoun HM, et al (2021). Reservoir-Excess Pressure Parameters Independently Predict Cardiovascular Events in Individuals with Type 2 Diabetes.
Hypertension,
78(1), 40-50.
Abstract:
Reservoir-Excess Pressure Parameters Independently Predict Cardiovascular Events in Individuals with Type 2 Diabetes
. The parameters derived from reservoir-excess pressure analysis have prognostic utility in several populations. However, evidence in type 2 diabetes (T2DM) remains scarce. We determined if these parameters were associated with T2DM and whether they would predict cardiovascular events in individuals with T2DM. We studied 306 people with T2DM with cardiovascular disease (CVD; DMCVD, 70.4±7.8 years), 348 people with T2DM but without CVD (diabetes mellitus, 67.7±8.4 years), and 178 people without T2DM or CVD (control group [CTRL], 67.2±8.9 years). Reservoir-excess pressure analysis–derived parameters, including reservoir pressure integral, peak reservoir pressure, excess pressure integral, systolic rate constant, and diastolic rate constant, were obtained by radial artery tonometry. Reservoir pressure integral was lower in DMCVD and diabetes mellitus than CTRL. Peak reservoir pressure was lower, and excess pressure integral was greater in DMCVD than diabetes mellitus and CTRL. Systolic rate constant was lower in a stepwise manner among groups (DMCVD< diabetes mellitus <CTRL). Diastolic rate constant was greater in DMCVD than CTRL. In the subgroup of individuals with T2DM (n=642), 14 deaths (6 cardiovascular and 9 noncardiovascular causes), and 108 cardiovascular events occurred during a 3-year follow-up period. Logistic regression analysis revealed that reservoir pressure integral (odds ratio, 0.59 [95% CI, 0.45–0.79]) and diastolic rate constant (odds ratio, 1.60 [95% CI, 1.25–2.06]) were independent predictors of cardiovascular events during follow-up after adjusting for conventional risk factors (both
. P
. <0.001). Further adjustments for potential confounders had no influence on associations. These findings demonstrate that altered reservoir-excess pressure analysis–derived parameters are associated with T2DM. Furthermore, baseline values of reservoir pressure integral and diastolic rate constant independently predict cardiovascular events in individuals with T2DM, indicating the potential clinical utility of these parameters for risk stratification in T2DM.
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Abstract.
Shami A, Edsfeldt A, Bengtsson E, Nilsson J, Shore AC, Natali A, Khan F, Lutgens E, Goncalves I (2021). Soluble CD40 Levels in Plasma Are Associated with Cardiovascular Disease and in Carotid Plaques with a Vulnerable Phenotype.
JOURNAL OF STROKE,
23(3), 367-+.
Author URL.
Holm Nielsen S, Edsfeldt A, Tengryd C, Gustafsson H, Shore AC, Natali A, Khan F, Genovese F, Bengtsson E, Karsdal M, et al (2021). The novel collagen matrikine, endotrophin, is associated with mortality and cardiovascular events in patients with atherosclerosis.
Journal of Internal Medicine,
290(1), 179-189.
Abstract:
The novel collagen matrikine, endotrophin, is associated with mortality and cardiovascular events in patients with atherosclerosis
Background: Rupture of atherosclerotic plaques is the major cause of acute cardiovascular events. The biomarker PRO-C6 measuring Endotrophin, a matrikine of collagen type VI, may provide valuable information detecting subjects in need of intensified strategies for secondary prevention. Objective: in this study, we evaluate endotrophin in human atherosclerotic plaques and circulating levels of PRO-C6 in patients with atherosclerosis, to determine the predictive potential of the biomarker. Methods: Sections from the stenotic human carotid plaques were stained with the PRO-C6 antibody. PRO-C6 was measured in serum of patients enrolled in the Carotid Plaque Imagining Project (CPIP) (discovery cohort, n = 577) and the innovative medicines initiative surrogate markers for micro- and macrovascular hard end-points for innovative diabetes tools (IMI-SUMMIT, validation cohort, n = 1,378). Median follow-up was 43 months. Kaplan–Meier curves and log-rank tests were performed in the discovery cohort. Cox proportional hazard regression analysis (HR with 95% CI) was used in the discovery cohort and binary logistic regression (OR with 95% CI) in the validation cohort. Results: PRO-C6 was localized in the core and shoulder of the atherosclerotic plaque. In the discovery cohort, PRO-C6 independently predicted future cardiovascular events (HR 1.089 [95% CI 1.019 −1.164], p = 0.01), cardiovascular death (HR 1.118 [95% CI 1.008 −1.241], p = 0.04) and all-cause death (HR 1.087 [95% CI 1.008 −1.172], p = 0.03). In the validation cohort, PRO-C6 predicted future cardiovascular events (OR 1.063 [95% CI 1.011 −1.117], p = 0.017). Conclusion: PRO-C6 is present in the atherosclerotic plaque and associated with future cardiovascular events, cardiovascular death and all-cause mortality in two large prospective cohorts.
Abstract.
Casanova F, Wood AR, Yaghootkar H, Beaumont RN, Jones SE, Gooding KM, Aizawa K, Strain WD, Hattersley AT, Khan F, et al (2020). A Mendelian Randomization Study Provides Evidence That Adiposity and Dyslipidemia Lead to Lower Urinary Albumin-to-Creatinine Ratio, a Marker of Microvascular Function.
Diabetes,
69(5), 1072-1082.
Abstract:
A Mendelian Randomization Study Provides Evidence That Adiposity and Dyslipidemia Lead to Lower Urinary Albumin-to-Creatinine Ratio, a Marker of Microvascular Function.
Urinary albumin-to-creatinine ratio (ACR) is a marker of diabetic nephropathy and microvascular damage. Metabolic-related traits are observationally associated with ACR, but their causal role is uncertain. Here, we confirmed ACR as a marker of microvascular damage and tested whether metabolic-related traits have causal relationships with ACR. The association between ACR and microvascular function (responses to acetylcholine [ACH] and sodium nitroprusside) was tested in the SUMMIT study. Two-sample Mendelian randomization (MR) was used to infer the causal effects of 11 metabolic risk factors, including glycemic, lipid, and adiposity traits, on ACR. MR was performed in up to 440,000 UK Biobank and 54,451 CKDGen participants. ACR was robustly associated with microvascular function measures in SUMMIT. Using MR, we inferred that higher triglyceride (TG) and LDL cholesterol (LDL-C) levels caused elevated ACR. A 1 SD higher TG and LDL-C level caused a 0.062 (95% CI 0.040, 0.083) and a 0.026 (95% CI 0.008, 0.044) SD higher ACR, respectively. There was evidence that higher body fat and visceral body fat distribution caused elevated ACR, while a metabolically "favorable adiposity" phenotype lowered ACR. ACR is a valid marker for microvascular function. MR suggested that seven traits have causal effects on ACR, highlighting the role of adiposity-related traits in causing lower microvascular function.
Abstract.
Author URL.
Clark C, Warren F, Boddy K, McDonagh S, Moore S, Goddard J, Reed N, Turner M, Alzamora MT, Ramos Blanes R, et al (2020). Associations Between Systolic Interarm Differences in Blood Pressure and Cardiovascular Disease Outcomes and Mortality: Individual Participant Data Meta-Analysis, Development and Validation of a Prognostic Algorithm: the INTERPRESS-IPD Collaboration. Hypertension, n/a, 1-12.
Van Zuydam NR, Ladenvall C, Voight BF, Strawbridge RJ, Fernandez-Tajes J, Rayner NW, Robertson NR, Mahajan A, Vlachopoulou E, Goel A, et al (2020). Genetic Predisposition to Coronary Artery Disease in Type 2 Diabetes Mellitus.
Circulation: Genomic and Precision Medicine,
13(6).
Abstract:
Genetic Predisposition to Coronary Artery Disease in Type 2 Diabetes Mellitus
Background: Coronary artery disease (CAD) is accelerated in subjects with type 2 diabetes mellitus (T2D). Methods: to test whether this reflects differential genetic influences on CAD risk in subjects with T2D, we performed a systematic assessment of genetic overlap between CAD and T2D in 66 643 subjects (27 708 with CAD and 24 259 with T2D). Variants showing apparent association with CAD in stratified analyses or evidence of interaction were evaluated in a further 117 787 subjects (16 694 with CAD and 11 537 with T2D). Results: None of the previously characterized CAD loci was found to have specific effects on CAD in T2D individuals, and a genome-wide interaction analysis found no new variants for CAD that could be considered T2D specific. When we considered the overall genetic correlations between CAD and its risk factors, we found no substantial differences in these relationships by T2D background. Conclusions: This study found no evidence that the genetic architecture of CAD differs in those with T2D compared with those without T2D.
Abstract.
Williams J, Gilchrist M, Fraser D, Strain D, Shore A (2020). P1161CUTANEOUS MICROCIRCULATORY DYSFUNCTION IN PERITONEAL DIALYSIS PATIENTS. Nephrology Dialysis Transplantation, 35(Supplement_3).
Riddell A, Kirkwood J, Smallwood M, Winyard P, Knight B, Steer K, Puddicombe L, Romanczuk L, Shore A, Gilchrist M, et al (2020). P1612CAN THE URINARY NITRATE TO CREATININE RATIO BE USED AS a MARKER FOR KIDNEY TRANSPLANT REJECTION?. Nephrology Dialysis Transplantation, 35(Supplement_3).
Kozakova M, Morizzo C, Penno G, Shore AC, Nilsson J, Palombo C (2020). Plasma Homocysteine and Cardiovascular Organ Damage in a Population with a High Prevalence of Risk Factors.
J Clin Endocrinol Metab,
105(8).
Abstract:
Plasma Homocysteine and Cardiovascular Organ Damage in a Population with a High Prevalence of Risk Factors.
PURPOSE: it is unclear whether plasma homocysteine (Hcy) has a direct noxious impact on the cardiovascular (CV) system or whether its association with cardiovascular events (CVEs) is mediated by established risk factors. To explore the role of Hcy in CV impairment, the study evaluated cross-sectional relationships between plasma Hcy and indices of CV organ damage together with the associations of these indices with the history of CVEs. METHODS: in 269 patients with a high prevalence of diabetes, dyslipidemia, and hypertension, the carotid intima-media thickness, ankle-brachial index (ABI), reactive hyperemic index, carotid-femoral pulse wave velocity (cfPWV), left ventricular (LV) mass, and cardiac index were measured. RESULTS: 132 patients had carotid plaque, 31 ABIâ€
Abstract.
Author URL.
Gooding KM, Lienczewski C, Papale M, Koivuviita N, Maziarz M, Dutius Andersson A-M, Sharma K, Pontrelli P, Garcia Hernandez A, Bailey J, et al (2020). Prognostic imaging biomarkers for diabetic kidney disease (iBEAt): study protocol.
BMC Nephrology,
21(1).
Abstract:
Prognostic imaging biomarkers for diabetic kidney disease (iBEAt): study protocol
Abstract
Background
Diabetic kidney disease (DKD) remains one of the leading causes of premature death in diabetes. DKD is classified on albuminuria and reduced kidney function (estimated glomerular filtration rate (eGFR)) but these have modest value for predicting future renal status. There is an unmet need for biomarkers that can be used in clinical settings which also improve prediction of renal decline on top of routinely available data, particularly in the early stages. The iBEAt study of the BEAt-DKD project aims to determine whether renal imaging biomarkers (magnetic resonance imaging (MRI) and ultrasound (US)) provide insight into the pathogenesis and heterogeneity of DKD (primary aim) and whether they have potential as prognostic biomarkers in DKD (secondary aim).
Methods
iBEAt is a prospective multi-centre observational cohort study recruiting 500 patients with type 2 diabetes (T2D) and eGFR ≥30 ml/min/1.73m2. At baseline, blood and urine will be collected, clinical examinations will be performed, and medical history will be obtained. These assessments will be repeated annually for 3 years. At baseline each participant will also undergo quantitative renal MRI and US with central processing of MRI images. Biological samples will be stored in a central laboratory for biomarker and validation studies, and data in a central data depository. Data analysis will explore the potential associations between imaging biomarkers and renal function, and whether the imaging biomarkers improve the prediction of DKD progression. Ancillary substudies will: (1) validate imaging biomarkers against renal histopathology; (2) validate MRI based renal blood flow measurements against H2O15 positron-emission tomography (PET); (3) validate methods for (semi-)automated processing of renal MRI; (4) examine longitudinal changes in imaging biomarkers; (5) examine whether glycocalyx and microvascular measures are associated with imaging biomarkers and eGFR decline; (6) explore whether the findings in T2D can be extrapolated to type 1 diabetes.
Discussion
iBEAt is the largest DKD imaging study to date and will provide valuable insights into the progression and heterogeneity of DKD. The results may contribute to a more personalised approach to DKD management in patients with T2D.
Trial registration
Clinicaltrials.gov (NCT03716401).
Abstract.
Jordan AN, Anning C, Wilkes L, Ball C, Pamphilon N, Clark CE, Bellenger NG, Shore AC, Sharp ASP (2020). Rapid treatment of moderate to severe hypertension using a novel protocol in a single-centre, before and after interventional study.
J Hum Hypertens,
34(2), 165-175.
Abstract:
Rapid treatment of moderate to severe hypertension using a novel protocol in a single-centre, before and after interventional study.
Rapid treatment to target in hypertension may have beneficial effects on long-term outcomes. This has led to a new recommendation in the 2018 European hypertension guidelines for patients with grade II/III hypertension to be treated to target within three months. However, whether it is feasible and safe to quickly manage treatment-naïve grade II/III hypertension to target was unclear. We examined this using a single-centre before and after interventional study, treating newly diagnosed, never-treated, grade II/III hypertensive patients with a daytime average systolic ABP ≥ 150 mmHg to target within 18 weeks. The proportion at office target BP at 18 weeks was determined, together with office and ambulatory BP change from baseline to after the intervention. The protocol was designed to maximise medication adherence, including a low threshold for treatment adaptation. Safety was evaluated through close monitoring of adverse events and protocol discontinuation. Fifty-five participants were enrolled with 54 completing the protocol. 69 ± 12.3% were at office target BP at their final visit, despite a high average starting BP of 175/103 mmHg, as a consequence of significant reductions in both office and ambulatory BP. of those at office target BP, 51% were above target on ambulatory measurement. Adherence testing demonstrated that 92% of participants were adherent to treatment at their final visit. Therefore we conclude that the accelerated management of treatment-naïve grade II/III hypertension is feasible and safe to implement in routine practice and there is no evidence to suggest it causes harm. Further large-scale randomised studies of rapid, adaptive treatment, including a cost-effectiveness analysis, are required.
Abstract.
Author URL.
Williams JK, Smallwood MJ, Benjamin N, D'Souza RJ, Shore AC, Winyard PG, Gilchrist M (2020). Renal nitrate clearance in chronic kidney disease. Nitric Oxide, 97, 16-19.
Williams J, Gilchrist M, Strain D, Fraser D, Shore A (2020). The systemic microcirculation in dialysis populations.
Microcirculation,
27(5).
Abstract:
The systemic microcirculation in dialysis populations.
In a rapidly expanding population of patients with chronic kidney disease, including 2 million people requiring renal replacement therapy, cardiovascular mortality is 15 times greater than the general population. In addition to traditional cardiovascular risk factors, more poorly defined risks related to uremia and its treatments appear to contribute to this exaggerated risk. In this context, the microcirculation may play an important early role in cardiovascular disease associated with chronic kidney disease. Experimentally, the uremic environment and dialysis have been linked to multiple pathways causing microvascular dysfunction. Coronary microvascular dysfunction is reflected in remote and more easily studied vascular beds such as the skin. There is increasing evidence for a correlation between systemic microvascular dysfunction and adverse cardiovascular outcomes. Systemic microcirculatory changes have not been extensively investigated across the spectrum of chronic kidney disease. Recent advances in non-invasive techniques studying the microcirculation in vivo in man are increasing the data available particularly in patients on hemodialysis. Here, we review current knowledge of the systemic microcirculation in dialysis populations, explore whether non-invasive techniques to study its function could be used to detect early stage cardiovascular disease, address challenges faced in studying this patient cohort and identify potential future avenues for research.
Abstract.
Author URL.
Riddell A, Kirkwood J, Smallwood M, Winyard P, Knight B, Romanczuk L, Shore A, Gilchrist M (2020). Urinary nitrate concentration as a marker for kidney transplant rejection.
BMC Nephrol,
21(1).
Abstract:
Urinary nitrate concentration as a marker for kidney transplant rejection.
BACKGROUND: Early identification and treatment of kidney transplant rejection episodes is vital to limit loss of function and prolong the life of the transplanted kidney and recipient. Current practice depends on detecting a creatinine rise. A biomarker to diagnose transplant rejection at an earlier time point than current practice, or to inform earlier decision making to biopsy, could be transformative. It has previously been shown that urinary nitrate concentration is elevated in renal transplant rejection. Nitrate is a nitric oxide (NO) oxidation product. Transplant rejection upregulates NO synthesis via inducible nitric oxide synthase leading to elevations in urinary nitrate concentration. We have recently validated a urinary nitrate concentration assay which could provide results in a clinically relevant timeframe. Our aim was to determine whether urinary nitrate concentration is a useful tool to predict renal transplant rejection in the context of contemporary clinical practice. METHODS: We conducted a prospective observational study, recruiting renal transplant participants over an 18-month period. We made no alterations to the patients' clinical care including medications, immunosuppression, diet and frequency of visits. We collected urine samples from every clinical attendance. We assessed the urinary nitrate to creatinine ratio (uNCR) between patient groups: routine attendances, biopsy proven rejection, biopsy proven no rejection and other call backs. uNCR was examined over time for those with biopsy proven transplant rejection. These four groups were compared using an ANOVA test. RESULTS: a total of 2656 samples were collected. uNCR during biopsy proven rejection, n = 15 (median 49 μmol/mmol, IQR 23-61) was not significantly different from that of routine samples, n = 164 (median 55 μmol/mmol, IQR 37-82) (p = 0.55), or biopsy proven no rejection, n = 12 (median 39 μmol/mmol, IQR 21-89) (P = 0.77). Overall uNCR was highly variable with no diagnostic threshold for kidney transplant rejection. Furthermore, within-patient uNCR was highly variable over time, and thus it was not possible to produce individualised patient thresholds to identify rejection. The total taking Tacrolimus was 204 patients, with no statistical difference between the uNCR of all those on Tacrolimus, against those not, p = 0.18. CONCLUSION: the urinary nitrate to creatinine ratio is not a useful biomarker for renal transplant rejection.
Abstract.
Author URL.
To C, Rees-Lee JE, Gush RJ, Gooding KM, Cawrse NH, Shore AC, Wilson ADH (2019). "Reply: Intra-operative tissue perfusion measurement by Laser Speckle Imaging (LSI): a potential aid for reducing post-operative complications in free flap breast reconstructions.".
Plast Reconstr Surg Author URL.
Casanova F, Tyrrell J, Beaumont RN, Ji Y, Jones SE, Hattersley AT, Weedon MN, Murray A, Shore AC, Frayling TM, et al (2019). A genome-wide association study implicates multiple mechanisms influencing raised urinary albumin-creatinine ratio.
Hum Mol Genet,
28(24), 4197-4207.
Abstract:
A genome-wide association study implicates multiple mechanisms influencing raised urinary albumin-creatinine ratio.
Raised albumin-creatinine ratio (ACR) is an indicator of microvascular damage and renal disease. We aimed to identify genetic variants associated with raised ACR and study the implications of carrying multiple ACR-raising alleles with metabolic and vascular-related disease. We performed a genome-wide association study of ACR using 437 027 individuals from the UK Biobank in the discovery phase, 54 527 more than previous studies, and followed up our findings in independent studies. We identified 62 independent associations with ACR across 56 loci (P 0.8) coinciding with signals for at least 16 related metabolic and vascular traits, suggested multiple pathways leading to raised ACR levels. After excluding variants at the CUBN locus, known to alter ACR via effects on renal absorption, an ACR genetic risk score was associated with a higher risk of hypertension, and less strongly, type 2 diabetes and stroke. For some rare genotype combinations at the CUBN locus, most individuals had ACR levels above the microalbuminuria clinical threshold. Contrary to our hypothesis, individuals carrying more CUBN ACR-raising alleles, and above the clinical threshold, had a higher frequency of vascular disease. The CUBN allele effects on ACR were twice as strong in people with diabetes-a result robust to an optimization-algorithm approach to simulating interactions, validating previously reported gene-diabetes interactions (P ≤ 4 × 10-5). In conclusion, a variety of genetic mechanisms and traits contribute to variation in ACR.
Abstract.
Author URL.
Aizawa K, Ramalli A, Sbragi S, Tortoli P, Casanova F, Morizzo C, Thorn CE, Shore AC, Gates PE, Palombo C, et al (2019). Arterial wall shear rate response to reactive hyperaemia is markedly different between young and older humans.
J Physiol,
597(16), 4151-4163.
Abstract:
Arterial wall shear rate response to reactive hyperaemia is markedly different between young and older humans.
KEY POINTS: the vasodilatory response to reactive hyperaemia is impaired with advancing age, but it is unclear whether this is because of an altered wall shear rate (WSR) stimulus or an altered flow-mediated dilatation (FMD) response. Using new technology that allows detailed WSR measurement, we assessed the WSR-FMD response in healthy older people. Our data show that older people have a markedly altered and diminished WSR response to reactive hyperaemia compared to young people, but reduced WSR alone does not fully explain reduced FMD. In young people, WSR appears to be coupled to FMD but, by age ∼65 years, the arterial vasodilatory response has begun to uncouple from the WSR stimulus. These findings point to the importance and utility of comprehensively characterizing the WSR-FMD response when using reactive hyperaemia to assess vascular function, as well as giving new insight into the age-related alteration in vascular function. ABSTRACT: the vasodilatory response to reactive hyperaemia is impaired with age, but it is unknown whether this is because of an altered wall shear rate (WSR) stimulus or an altered flow-mediated dilatation (FMD) response to the WSR stimulus. Inherent difficulties in measuring blood flow velocity close to the arterial wall have prevented detailed assessment of the WSR-FMD response. Using an enhanced multigate spectral Doppler ultrasound system (ultrasound advanced open platform), we aimed to produce new data on the WSR-FMD relationship in healthy older adults. Sixty healthy people, comprising 28 young (27.5 ± 5.5 years) and 32 older (64.9 ± 3.7 years) individuals, underwent FMD assessment. Raw data were post-processed using custom-designed software to obtain WSR and diameter parameters. The data revealed that older people have a much altered and diminished WSR response to reactive hyperaemia compared to younger people [e.g. WSR peak: 622 (571-673) vs. 443 (396-491) 1/s in young and older respectively; P
Abstract.
Author URL.
Ramalli A, Aizawa K, Shore AC, Morizzo C, Palombo C, Lenge M, Tortoli P (2019). Continuous Simultaneous Recording of Brachial Artery Distension and Wall Shear Rate: a New Boost for Flow-Mediated Vasodilation.
IEEE Transactions on Ultrasonics, Ferroelectrics, and Frequency Control,
66(3), 463-471.
Abstract:
Continuous Simultaneous Recording of Brachial Artery Distension and Wall Shear Rate: a New Boost for Flow-Mediated Vasodilation
Vascular ultrasound has been extensively applied in the clinical setting to noninvasively assess the endothelial function by means of the so-called brachial artery flow mediated dilation (FMD). Despite the usefulness in large-scale epidemiological studies, this approach has revealed some pitfalls for assessing vascular physiology and health in individual subjects. Mainly, a reliable FMD examination should be based on the simultaneous and reliable measurement of both the stimulus, i.e. the wall shear rate (WSR), and the response, i.e. the diameter change. However, multiple technical, practical, and methodological challenges must be faced to meet this goal. In this work, we present the technical developments needed to implement a system to enable the extensive and reliable clinical ultrasound FMD examination. It integrates both a hardware part, i.e. an upgraded version of the ultrasound advanced open platform (ULA-OP), and a software part, i.e. a signal processing and data analysis platform. The system was applied for a two-center pilot clinical study on 35 young and healthy volunteers. Therefore, we present here the results of a statistical analysis on magnitude, time-course, and kinetic parameters of WSR and diameter trends that allowed us to accurately explore the vasodilatory response to the dynamic WSR changes. Our observations demonstrate that a direct and accurate estimation of WSR stimulus by multigate spectral Doppler allows understanding brachial artery vasodilatory response to reactive hyperemia. Drawing inferences on WSR stimulus from the diameter response along with an inaccurate estimation of WSR may cause further uncertainties for the accurate interpretation of the FMD response.
Abstract.
To C, Rees-Lee JE, Gush RJ, Gooding KM, Cawrse NH, Shore AC, Wilson ADH (2019). Intraoperative Tissue Perfusion Measurement by Laser Speckle Imaging: a Potential Aid for Reducing Postoperative Complications in Free Flap Breast Reconstruction.
Plast Reconstr Surg,
143(2), 287e-292e.
Abstract:
Intraoperative Tissue Perfusion Measurement by Laser Speckle Imaging: a Potential Aid for Reducing Postoperative Complications in Free Flap Breast Reconstruction.
Adequate tissue perfusion is essential to minimize postoperative complications following microsurgery. Intraoperative knowledge of tissue perfusion could aid surgical decision-making and result in reduced complications. Laser speckle imaging is a new, noninvasive technique for mapping tissue perfusion. This article discusses the feasibility of using laser speckle imaging during free flap breast reconstruction and its potential to identify areas of inadequate perfusion, thus reducing surgical complications. Adult patients scheduled to undergo free flap breast reconstruction were recruited into the study. Laser speckle images were obtained from the abdominal and breast areas at different stages intraoperatively. Zonal perfusion was compared with the Holm classification and clinical observations. Twenty patients scheduled to undergo free flap breast reconstruction were recruited (23 reconstructed breasts) (mean age, 50 years; range, 32 to 68 years). Flap zonal perfusion was 238 (187 to 313), 222 (120 to 265), 206 (120 to 265), and 125 (102 to 220) perfusion units for zones I, II, III, and IV, respectively (analysis of variance, p < 0.0001). Zonal area with perfusion below an arbitrary perfusion threshold were 20 (0.3 to 75), 41 (3 to 99), 49 (9 to 97), and 99 (25 to 100) percent, respectively (analysis of variance, p < 0.0001). One example is presented to illustrate potential intraoperative uses for laser speckle imaging. This study shows that laser speckle imaging is a feasible, noninvasive technique for intraoperative mapping of tissue perfusion during free flap breast reconstruction. Zonal tissue perfusion was reduced across the Holm classification. Observations indicated the potential for laser speckle imaging to provide additional information to augment surgical decision-making by detection of inadequate tissue perfusion. This highlights the opportunity for surgeons to consider additional aids for intraoperative tissue perfusion assessment to help reduce perfusion-related complications. CLINICAL QUESTION/LEVEL OF EVIDENCE:: Diagnostic, IV.
Abstract.
Author URL.
To C, Rees-Lee JE, Gush RJ, Cawrse NH, Shore AC, Wilson ADH (2019). Letter to the Editor: the use of indocyanine green angiography in postmastectomy reconstruction: Do outcomes improve over time?.
J Plast Reconstr Aesthet Surg,
72(9), 1576-1606.
Author URL.
Aung MM, Slade K, Freeman LAR, Kos K, Whatmore JL, Shore AC, Gooding KM (2019). Locally delivered GLP-1 analogues liraglutide and exenatide enhance microvascular perfusion in individuals with and without type 2 diabetes.
Diabetologia,
62(9), 1701-1711.
Abstract:
Locally delivered GLP-1 analogues liraglutide and exenatide enhance microvascular perfusion in individuals with and without type 2 diabetes.
AIMS/HYPOTHESIS: Glucagon-like peptide-1 (GLP-1) analogues reduce the risk of macrovascular disease in diabetes; however, little is known about their microvascular effects. This research examined the microvascular actions of the GLP-1 analogues liraglutide and exenatide in individuals with and without type 2 diabetes (study 1). It also explored the involvement of the GLP-1 receptor (study 2) and the nitric oxide pathway in mediating the microvascular effects of the analogues. METHODS: Trial design: Studies 1 and 2 had a randomised, controlled, double-blind study design. Study 1 participants, intervention and methods: three participant groups were recruited: individuals with well-controlled type 2 diabetes, and obese and lean individuals without diabetes (21 participants per group). Liraglutide (0.06 mg), exenatide (0.5 μg) and saline (154 mmol/l NaCl; 0.9%) control were microinjected into separate sites in the dermis (forearm) in a randomised order, blinded to operator and participant. Skin microvascular perfusion was assessed by laser Doppler perfusion imaging. Outcomes were stabilised response (mean skin perfusion between 7.5 and 10 min post microinjection) and total response (AUC, normalised for baseline perfusion). Perfusion response to GLP-1 analogues was compared with saline within each group as well as between groups. Study 2 participants, intervention and methods: in healthy individuals (N = 16), liraglutide (0.06 mg) and saline microinjected sites were pretreated with saline or the GLP-1 receptor blocker, exendin-(9,39), in a randomised order, blinded to participant and operator. Outcomes were as above (stabilised response and total perfusion response). Perfusion response to liraglutide was compared between the saline and the exendin-(9,39) pretreated sites. In vitro study: the effects of liraglutide and exenatide on nitrate levels and endothelial nitric oxide synthase phosphorylation (activation) were examined using human microvascular endothelial cells. RESULTS: Study 1 results: both analogues increased skin perfusion (stabilised response and total response) in all groups (n = 21 per group, p
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Author URL.
Natali A, Nesti L, Venturi E, Shore AC, Khan F, Gooding K, Gates PE, Looker HC, Dove F, Goncalves I, et al (2019). Metformin is the key factor in elevated plasma growth differentiation factor-15 levels in type 2 diabetes: a nested, case-control study.
Diabetes Obes Metab,
21(2), 412-416.
Abstract:
Metformin is the key factor in elevated plasma growth differentiation factor-15 levels in type 2 diabetes: a nested, case-control study.
Produced as a tissue defence response to hypoxia and inflammation, growth differentiation factor-15 (GDF-15) is elevated in people receiving metformin treatment. To gain insight into the relationship of GDF-15 with metformin and major cardiovascular risk factors, we analysed the data from the SUMMIT cohort (n = 1438), a four-centre, nested, case-control study aimed at verifying whether biomarkers of atherosclerosis differ according to the presence of type 2 diabetes and cardiovascular disease. While in univariate analysis, major cardiovascular risk factors, with the exception of gender and cholesterol, increased similarly and linearly across GDF-15 quartiles, the independent variables associated with GDF-15, both in participants with and without diabetes, were age, plasma creatinine, N-terminal pro-brain natriuretic peptide, diuretic use, smoking exposure and glycated haemoglobin. In participants with diabetes, metformin treatment was associated with a 40% rise in GDF-15 level, which was independent of the other major factors, and largely explained their elevated GDF-15 levels. The relatively high GDF-15 bioavailability might partly explain the protective cardiovascular effects of metformin.
Abstract.
Author URL.
Hubbard TJE, Shore A, Stone N (2019). Raman spectroscopy for rapid intra-operative margin analysis of surgically excised tumour specimens.
Analyst,
144(22), 6479-6496.
Abstract:
Raman spectroscopy for rapid intra-operative margin analysis of surgically excised tumour specimens.
Raman spectroscopy, a form of vibrational spectroscopy, has the ability to provide sensitive and specific biochemical analysis of tissue. This review article provides an in-depth analysis of the suitability of different Raman spectroscopy techniques in providing intra-operative margin analysis in a range of solid tumour pathologies. Surgical excision remains the primary treatment of a number of solid organ cancers. Incomplete excision of a tumour and positive margins on histopathological analysis is associated with a worse prognosis, the need for adjuvant therapies with significant side effects and a resulting financial burden. The provision of intra-operative margin analysis of surgically excised tumour specimens would be beneficial for a number of pathologies, as there are no widely adopted and accurate methods of margin analysis, beyond histopathology. The limitations of Raman spectroscopic studies to date are discussed and future work necessary to enable translation to clinical use is identified. We conclude that, although there remain a number of challenges in translating current techniques into a clinically effective tool, studies so far demonstrate that Raman Spectroscopy has the attributes to successfully perform highly accurate intra-operative margin analysis in a clinically relevant environment.
Abstract.
Author URL.
To C, Rees-Lee JE, Gush RJ, Gooding KM, Cawrse NH, Shore AC, Wilson ADH (2019). Reply: Intraoperative Tissue Perfusion Measurement by Laser Speckle Imaging: a Potential Aid for Reducing Postoperative Complications in Free Flap Breast Reconstruction.
Plast Reconstr Surg,
144(5), 935e-936e.
Author URL.
Chapman DP, Gooding KM, McDonald TJ, Shore AC (2019). Stability of urinary albumin and creatinine after 12 months storage at -20 °C and -80 °C.
Pract Lab Med,
15Abstract:
Stability of urinary albumin and creatinine after 12 months storage at -20 °C and -80 °C.
BACKGROUND: Increasing albumin to creatinine ratio (ACR) within the normal range is a risk factor for cardiovascular disease in the general population. Clinical and epidemiological studies often store urine samples for long durations prior to ACR assessment. The stability of ACR at the lowest urinary albumin concentrations during prolonged storage has not been previously studied because routine clinical assays can't quantify very low concentrations of albumin. AIM: to determine the stability of urinary albumin and creatinine over 12 months in samples stored at -20 °C and -80 °C using an assay which enables assessment of previously undetectable levels of albumin and to investigate if additives can be used to prevent urinary albumin degradation. METHOD: ACR was measured in 30 urine samples from healthy subjects on the day of collection. Each sample was divided into 5 portions, each receiving a different treatment; alkalisation, protease inhibiter, boric acid, low protein binding tubes and no treatment (control). Samples were stored at -20 °C and -80 °C and ACR was analysed again after 12 months. RESULTS: Mean (95% CI) percent change in ACR was -34.3% (-47.2 to -21.4; p 
Abstract.
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van Zuydam NR, Ahlqvist E, Sandholm N, Deshmukh H, Rayner NW, Abdalla M, Ladenvall C, Ziemek D, Fauman E, Robertson NR, et al (2018). A Genome-Wide Association Study of Diabetic Kidney Disease in Subjects with Type 2 Diabetes.
Diabetes,
67(7), 1414-1427.
Abstract:
A Genome-Wide Association Study of Diabetic Kidney Disease in Subjects with Type 2 Diabetes.
Identification of sequence variants robustly associated with predisposition to diabetic kidney disease (DKD) has the potential to provide insights into the pathophysiological mechanisms responsible. We conducted a genome-wide association study (GWAS) of DKD in type 2 diabetes (T2D) using eight complementary dichotomous and quantitative DKD phenotypes: the principal dichotomous analysis involved 5,717 T2D subjects, 3,345 with DKD. Promising association signals were evaluated in up to 26,827 subjects with T2D (12,710 with DKD). A combined T1D+T2D GWAS was performed using complementary data available for subjects with T1D, which, with replication samples, involved up to 40,340 subjects with diabetes (18,582 with DKD). Analysis of specific DKD phenotypes identified a novel signal near GABRR1 (rs9942471, P = 4.5 × 10-8) associated with microalbuminuria in European T2D case subjects. However, no replication of this signal was observed in Asian subjects with T2D or in the equivalent T1D analysis. There was only limited support, in this substantially enlarged analysis, for association at previously reported DKD signals, except for those at UMOD and PRKAG2, both associated with estimated glomerular filtration rate. We conclude that, despite challenges in addressing phenotypic heterogeneity, access to increased sample sizes will continue to provide more robust inference regarding risk variant discovery for DKD.
Abstract.
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Old O, Lloyd G, Isabelle M, Almond LM, Kendall C, Baxter K, Shepherd N, Shore A, Stone N, Barr H, et al (2018). Automated cytological detection of Barrett's neoplasia with infrared spectroscopy.
J Gastroenterol,
53(2), 227-235.
Abstract:
Automated cytological detection of Barrett's neoplasia with infrared spectroscopy.
BACKGROUND: Development of a nonendoscopic test for Barrett's esophagus would revolutionize population screening and surveillance for patients with Barrett's esophagus. Swallowed cell collection devices have recently been developed to obtain cytology brushings from the esophagus: automated detection of neoplasia in such samples would enable large-scale screening and surveillance. METHODS: Fourier transform infrared (FTIR) spectroscopy was used to develop an automated tool for detection of Barrett's esophagus and Barrett's neoplasia in esophageal cell samples. Cytology brushings were collected at endoscopy, cytospun onto slides and FTIR images were measured. An automated cell recognition program was developed to identify individual cells on the slide. RESULTS: Cytology review and contemporaneous histology was used to inform a training dataset containing 141 cells from 17 patients. A classification model was constructed by principal component analysis fed linear discriminant analysis, then tested by leave-one-sample-out cross validation. With application of this training model to whole slide samples, a threshold voting system was used to classify samples according to their constituent cells. Across the entire dataset of 115 FTIR maps from 66 patients, whole samples were classified with sensitivity and specificity respectively as follows: normal squamous cells 79.0% and 81.1%, nondysplastic Barrett's esophagus cells 31.3% and 100%, and neoplastic Barrett's esophagus cells 83.3% and 62.7%. CONCLUSIONS: Analysis of esophageal cell samples can be performed with FTIR spectroscopy with reasonable sensitivity for Barrett's neoplasia, but with poor specificity with the current technique.
Abstract.
Author URL.
Aizawa K, Sbragi S, Ramalli A, Tortoli P, Casanova F, Morizzo C, Thorn CE, Shore AC, Gates PE, Palombo C, et al (2018). Brachial artery vasodilatory response and wall shear rate determined by multigate Doppler in a healthy young cohort.
J Appl Physiol (1985),
124(1), 150-159.
Abstract:
Brachial artery vasodilatory response and wall shear rate determined by multigate Doppler in a healthy young cohort.
Wall shear rate (WSR) is an important stimulus for the brachial artery flow-mediated dilation (FMD) response. However, WSR estimation near the arterial wall by conventional Doppler is inherently difficult. To overcome this limitation, we utilized multigate Doppler to accurately determine the WSR stimulus near the vessel wall simultaneously with the FMD response using an integrated FMD system [Ultrasound Advanced Open Platform (ULA-OP)]. Using the system, we aimed to perform a detailed analysis of WSR-FMD response and establish novel WSR parameters in a healthy young population. Data from 33 young healthy individuals (27.5 ± 4.9 yr, 19 females) were analyzed. FMD was assessed with reactive hyperemia using ULA-OP. All acquired raw data were postprocessed using custom-designed software to obtain WSR and diameter parameters. The acquired velocity data revealed that nonparabolic flow profiles within the cardiac cycle and under different flow states, with heterogeneity between participants. We also identified seven WSR magnitude and four WSR time-course parameters. Among them, WSR area under the curve until its return to baseline was the strongest predictor of the absolute ( R2 = 0.25) and percent ( R2 = 0.31) diameter changes in response to reactive hyperemia. For the first time, we identified mono- and biphasic WSR stimulus patterns within our cohort that produced different magnitudes of FMD response [absolute diameter change: 0.24 ± 0.10 mm (monophasic) vs. 0.17 ± 0.09 mm (biphasic), P < 0.05]. We concluded that accurate and detailed measurement of the WSR stimulus is important to comprehensively understand the FMD response and that this advance in current FMD technology could be important to better understand vascular physiology and pathology. NEW & NOTEWORTHY an estimation of wall shear rate (WSR) near the arterial wall by conventional Doppler ultrasound is inherently difficult. Using a recently developed integrated flow-mediated dilation ultrasound system, we were able to accurately estimate WSR near the wall and identified a number of novel WSR variables that may prove to be useful in the measurement of endothelial function, an important biomarker of vascular physiology and disease.
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Author URL.
Weir-McCall JR, Brown L, Summersgill J, Talarczyk P, Bonnici-Mallia M, Chin SC, Khan F, Struthers AD, Sullivan F, Colhoun HM, et al (2018). Development and Validation of a Path Length Calculation for Carotid-Femoral Pulse Wave Velocity Measurement: a TASCFORCE, SUMMIT, and Caerphilly Collaborative Venture.
Hypertension,
71(5), 937-945.
Abstract:
Development and Validation of a Path Length Calculation for Carotid-Femoral Pulse Wave Velocity Measurement: a TASCFORCE, SUMMIT, and Caerphilly Collaborative Venture.
Current distance measurement techniques for pulse wave velocity (PWV) calculation are susceptible to intercenter variability. The aim of this study was to derive and validate a formula for this distance measurement. Based on carotid femoral distance in 1183 whole-body magnetic resonance angiograms, a formula was derived for calculating distance. This was compared with distance measurements in 128 whole-body magnetic resonance angiograms from a second study. The effects of recalculation of PWV using the new formula on association with risk factors, disease discrimination, and prediction of major adverse cardiovascular events were examined within 1242 participants from the multicenter SUMMIT study (Surrogate Markers of Micro- and Macrovascular Hard End-Points for Innovative Diabetes Tools) and 825 participants from the Caerphilly Prospective Study. The distance formula yielded a mean error of 7.8 mm (limits of agreement =-41.1 to 56.7 mm; P
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Gates PE, Gurung A, Mazzaro L, Aizawa K, Elyas S, Strain WD, Shore AC, Shandas R (2018). Measurement of Wall Shear Stress Exerted by Flowing Blood in the Human Carotid Artery: Ultrasound Doppler Velocimetry and Echo Particle Image Velocimetry.
Ultrasound Med Biol,
44(7), 1392-1401.
Abstract:
Measurement of Wall Shear Stress Exerted by Flowing Blood in the Human Carotid Artery: Ultrasound Doppler Velocimetry and Echo Particle Image Velocimetry.
Vascular endothelial cells lining the arteries are sensitive to wall shear stress (WSS) exerted by flowing blood. An important component of the pathophysiology of vascular diseases, WSS is commonly estimated by centerline ultrasound Doppler velocimetry (UDV). However, the accuracy of this method is uncertain. We have previously validated the use of a novel, ultrasound-based, particle image velocimetry technique (echo PIV) to compute 2-D velocity vector fields, which can easily be converted into WSS data. We compared WSS data derived from UDV and echo PIV in the common carotid artery of 27 healthy participants. Compared with echo PIV, time-averaged WSS was lower using UDV (28 ± 35%). Echo PIV revealed that this was due to considerable spatiotemporal variation in the flow velocity profile, contrary to the assumption that flow is steady and the velocity profile is parabolic throughout the cardiac cycle. The largest WSS underestimation by UDV was found during peak systole (118 ± 16%) and the smallest during mid-diastole (4.3± 46%). The UDV method underestimated WSS for the accelerating and decelerating systolic measurements (68 ± 30% and 24 ± 51%), whereas WSS was overestimated for end-diastolic measurements (-44 ± 55%). Our data indicate that UDV estimates of WSS provided limited and largely inaccurate information about WSS and that the complex spatiotemporal flow patterns do not fit well with traditional assumptions about blood flow in arteries. Echo PIV-derived WSS provides detailed information about this important but poorly understood stimulus that influences vascular endothelial pathophysiology.
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Author URL.
Shore AC, Colhoun HM, Natali A, Palombo C, Khan F, Östling G, Aizawa K, Kennbäck C, Casanova F, Persson M, et al (2018). Use of Vascular Assessments and Novel Biomarkers to Predict Cardiovascular Events in Type 2 Diabetes: the SUMMIT VIP Study.
Diabetes Care,
41(10), 2212-2219.
Abstract:
Use of Vascular Assessments and Novel Biomarkers to Predict Cardiovascular Events in Type 2 Diabetes: the SUMMIT VIP Study.
OBJECTIVE: Cardiovascular disease (CVD) risk prediction represents an increasing clinical challenge in the treatment of diabetes. We used a panel of vascular imaging, functional assessments, and biomarkers reflecting different disease mechanisms to identify clinically useful markers of risk for cardiovascular (CV) events in subjects with type 2 diabetes (T2D) with or without manifest CVD. RESEARCH DESIGN AND METHODS: the study cohort consisted of 936 subjects with T2D recruited at four European centers. Carotid intima-media thickness and plaque area, ankle-brachial pressure index, arterial stiffness, endothelial function, and circulating biomarkers were analyzed at baseline, and CV events were monitored during a 3-year follow-up period. RESULTS: the CV event rate in subjects with T2D was higher in those with (n = 440) than in those without (n = 496) manifest CVD at baseline (5.53 vs. 2.15/100 life-years, P < 0.0001). New CV events in subjects with T2D with manifest CVD were associated with higher baseline levels of inflammatory biomarkers (interleukin 6, chemokine ligand 3, pentraxin 3, and hs-CRP) and endothelial mitogens (hepatocyte growth factor and vascular endothelial growth factor A), whereas CV events in subjects with T2D without manifest CVD were associated with more severe baseline atherosclerosis (median carotid plaque area 30.4 mm2 [16.1-92.2] vs. 19.5 mm2 [9.5-40.5], P = 0.01). Conventional risk factors, as well as measurements of arterial stiffness and endothelial reactivity, were not associated with CV events. CONCLUSIONS: Our observations demonstrate that markers of inflammation and endothelial stress reflect CV risk in subjects with T2D with manifest CVD, whereas the risk for CV events in subjects with T2D without manifest CVD is primarily related to the severity of atherosclerosis.
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Thorn CE, Knight B, Pastel E, McCulloch LJ, Patel B, Shore AC, Kos K (2017). Adipose tissue is influenced by hypoxia of obstructive sleep apnea syndrome independent of obesity.
Diabetes Metab,
43(3), 240-247.
Abstract:
Adipose tissue is influenced by hypoxia of obstructive sleep apnea syndrome independent of obesity.
AIMS: Obstructive sleep apnea syndrome (OSAS) is associated with increased cardiovascular risk and diabetes independent of obesity. We investigated whether adipose tissue dysfunction is exacerbated due to increased tissue hypoxia. METHODS: Adipose tissue (AT) oxygenation was measured with a Clarke-type electrode (pATO2) in 16 men with OSAS before and after 4 months of continuous positive airway pressure therapy (CPAP) and in BMI-matched controls. Oxygenation was simultaneously monitored in arterial blood by pulse oximetry (SaO2); mixed blood in AT microcirculation by reflectance spectroscopy (SATO2) along with blood flow. Markers of hypoxia, adipo- and angiogenesis, inflammation and fibrosis were analysed in AT and serum. RESULTS: OSAS subjects were more insulin resistant. Despite lower arterial SaO2 (95.4±1.3% vs. 97.1±1.6%, P=0.013) in subjects with OSAS, there was no difference in the oxygen content of AT microcirculation (61.6±18.4 vs. 72.2±7.0%, P=0.07) or pATO2 (49.2±7.5 vs. 50.4±14.7mmHg, P=0.83) between groups. Resting AT blood flow was higher in OSAS compared to controls (108.5±22.7 vs. 78.9±24.9au, P
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Author URL.
Clark CE, Boddy K, Warren FC, Taylor RS, Aboyans V, Cloutier L, McManus RJ, Shore AC, Campbell JL (2017). Associations between interarm differences in blood pressure and cardiovascular disease outcomes: protocol for an individual patient data meta-analysis and development of a prognostic algorithm.
BMJ Open,
7(6).
Abstract:
Associations between interarm differences in blood pressure and cardiovascular disease outcomes: protocol for an individual patient data meta-analysis and development of a prognostic algorithm.
INTRODUCTION: Individual cohort studies in various populations and study-level meta-analyses have shown interarm differences (IAD) in blood pressure to be associated with increased cardiovascular and all-cause mortality. However, key questions remain, such as follows: (1) What is the additional contribution of IAD to prognostic risk estimation for cardiovascular and all-cause mortality? (2) What is the minimum cut-off value for IAD that defines elevated risk? (3) is there a prognostic value of IAD and do different methods of IAD measurement impact on the prognostic value of IAD? We aim to address these questions by conducting an individual patient data (IPD) meta-analysis. METHODS AND ANALYSIS: This study will identify prospective cohort studies that measured blood pressure in both arms during recruitment, and invite authors to contribute IPD datasets to this collaboration. All patient data received will be combined into a single dataset. Using one-stage meta-analysis, we will undertake multivariable time-to-event regression modelling, with the aim of developing a new prognostic model for cardiovascular risk estimation that includes IAD. We will explore variations in risk contribution of IAD across predefined population subgroups (eg, hypertensives, diabetics), establish the lower limit of IAD that is associated with additional cardiovascular risk and assess the impact of different methods of IAD measurement on risk prediction. ETHICS AND DISSEMINATION: This study will not include any patient identifiable data. Included datasets will already have ethical approval and consent from their sponsors. Findings will be presented to international conferences and published in peer reviewed journals, and we have a comprehensive dissemination strategy in place with integrated patient and public involvement. PROSPERO REGISTRATION NUMBER: CRD42015031227.
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Petrie JR, Chaturvedi N, Ford I, Brouwers MCGJ, Greenlaw N, Tillin T, Hramiak I, Hughes AD, Jenkins AJ, Klein BEK, et al (2017). Cardiovascular and metabolic effects of metformin in patients with type 1 diabetes (REMOVAL): a double-blind, randomised, placebo-controlled trial. The Lancet Diabetes & Endocrinology, 5(8), 597-609.
Gurung A, Gates PE, Mazzaro L, Fulford J, Zhang F, Barker AJ, Hertzberg J, Aizawa K, Strain WD, Elyas S, et al (2017). Echo Particle Image Velocimetry for Estimation of Carotid Artery Wall Shear Stress: Repeatability, Reproducibility and Comparison with Phase-Contrast Magnetic Resonance Imaging.
Ultrasound Med Biol,
43(8), 1618-1627.
Abstract:
Echo Particle Image Velocimetry for Estimation of Carotid Artery Wall Shear Stress: Repeatability, Reproducibility and Comparison with Phase-Contrast Magnetic Resonance Imaging.
Measurement of hemodynamic wall shear stress (WSS) is important in investigating the role of WSS in the initiation and progression of atherosclerosis. Echo particle image velocimetry (echo PIV) is a novel ultrasound-based technique for measuring WSS in vivo that has previously been validated in vitro using the standard optical PIV technique. We evaluated the repeatability and reproducibility of echo PIV for measuring WSS in the human common carotid artery. We measured WSS in 28 healthy participants (18 males and 10 females, mean age: 56 ± 12 y). Echo PIV was highly repeatable, with an intra-observer variability of 1.0 ± 0.1 dyn/cm2 for peak systolic (maximum), 0.9 dyn/cm2 for mean and 0.5 dyn/cm2 for end-diastolic (minimum) WSS measurements. Likewise, echo PIV was reproducible, with a low inter-observer variability (max: 2.0 ± 0.2 dyn/cm2, mean: 1.3 ± 0.1 dyn/cm2, end-diastolic: 0.7 dyn/cm2) and more variable inter-scan (test-retest) variability (max: 7.1 ± 2.3 dyn/cm2, mean: 2.9 ± 0.4 dyn/cm2, min: 1.5 ± 0.1 dyn/cm2). We compared echo PIV with the reference method, phase-contrast magnetic resonance imaging (PC-MRI); echo PIV-based WSS measurements agreed qualitatively with PC-MRI measurements (r = 0.89, p
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Pastel E, McCulloch LJ, Ward R, Joshi S, Gooding KM, Shore AC, Kos K (2017). GLP-1 analogue-induced weight loss does not improve obesity-induced AT dysfunction.
Clin Sci (Lond),
131(5), 343-353.
Abstract:
GLP-1 analogue-induced weight loss does not improve obesity-induced AT dysfunction.
Glucagon-like peptide-1 (GLP-1) analogues aid weight loss that improves obesity-associated adipose tissue (AT) dysfunction. GLP-1 treatment may however also directly influence AT that expresses the GLP-1 receptor (GLP-1R). The present study aimed to assess the impact of GLP-1 analogue treatment on subcutaneous AT (SCAT) inflammatory and fibrotic responses, compared with weight loss by calorie reduction (control). Among the 39 participants with Type 2 diabetes recruited, 30 age-matched participants were randomized to 4 months treatment with Liraglutide (n=22) or calorie restriction based on dietetic counselling (n=8). Assessments included clinical characteristics and repeated subcutaneous abdominal AT biopsies. Liraglutide resulted in weight loss in most participants (-3.12±1.72 kg, P=0.007) and significant reduction in visceral AT (VAT). It was more effective in lowering fasting glucose, in comparison with weight loss by dieting. However, tumour necrosis factor-α (TNFA) AT-expression (P=0.0005), macrophage chemoattractant protein-1 (MCP-1) expression (P=0.027) and its serum levels (P=0.048) increased with Liraglutide, suggestive of an inflammatory response unlike in the diet arm in which a trend of lower cluster of differentiation 14 (CD14) expression (P=0.09) was found. Liraglutide treatment also increased expression of factors involved in extracellular matrix (ECM) deposition, transforming growth factor-β (TGFB) and collagen type 1 alpha 1 chain (COL1A1) (TGFB1: before 0.73±0.09 arbitrary units (AU), after 1.00±0.13 AU, P=0.006; COL1A1: 0.84±0.09 AU compared with 1.49±0.26 AU, P=0.026). Liraglutide thus appears to induce an inflammatory response in AT and influences ECM remodelling. Despite its superior effect on glycaemia, Liraglutide does not improve obesity-associated AT dysfunction in subcutaneous tissue. It is yet unclear whether this limits AT storage capacity for lipids. This may be of importance in patients being re-exposed to positive energy balance such as post GLP-1 discontinuation.
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Gilchrist M, Shore A (2017). Inorganic Nitrate: Marker or Mediator of Mortality?.
J Am Heart Assoc,
6(11).
Author URL.
Petrie JR, Chaturvedi N, Ford I, Hramiak I, Hughes AD, Jenkins AJ, E. Klein B, Klein R, Ooi TC, Rossing P, et al (2017). Metformin in adults with type 1 diabetes: Design and methods of REducing with MetfOrmin Vascular Adverse Lesions (REMOVAL): an international multicentre trial. Diabetes, Obesity and Metabolism, 19(4), 509-516.
Frost J, Ludeman L, Hillaby K, Gornall R, Lloyd G, Kendall C, Shore AC, Stone N (2017). Raman spectroscopy and multivariate analysis for the non invasive diagnosis of clinically inconclusive vulval lichen sclerosus.
Analyst,
142(8), 1200-1206.
Abstract:
Raman spectroscopy and multivariate analysis for the non invasive diagnosis of clinically inconclusive vulval lichen sclerosus.
Vulval lichen sclerosus (LS) is a common inflammatory condition associated with an increased risk of developing vulval carcinoma. Diagnosis is usually clinical although biopsy is necessary if the diagnosis is uncertain or if there is a failure to respond to adequate initial treatment. Raman spectroscopy has the potential to be applied in vivo for near real time objective non-invasive optical diagnosis, avoiding the need for invasive tissue biopsies. The aim of this study was to evaluate the diagnostic performance of Raman spectroscopy for differentiating LS from other vulval conditions in fresh vulval biopsies. Biopsies were analysed from 27 women with suspected LS in whom the attending gynaecologist could not establish the diagnosis on clinical presentation alone. Spectral variance was explored using principal component analysis and in conjunction with the histological diagnoses was used to develop and test a multivariate linear discriminant classification model. This model was validated with leave one sample out cross validation and the diagnostic performance of the technique assessed in comparison with the pathology gold standard. After cross validation the technique was able to correctly differentiate LS from other inflammatory vulval conditions with a sensitivity of 91% and specificity of 80%. This study demonstrates Raman spectroscopy has potential as a technique for in vivo non-invasive diagnosis of vulval skin conditions. Applied in the clinical setting this technique may reduce the need for invasive tissue biopsy. Further in vivo study is needed to assess the ability of Raman spectroscopy to diagnose other vulval conditions before clinical application.
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Old OJ, Lloyd GR, Nallala J, Isabelle M, Almond LM, Shepherd NA, Kendall CA, Shore AC, Barr H, Stone N, et al (2017). Rapid infrared mapping for highly accurate automated histology in Barrett's oesophagus.
ANALYST,
142(8), 1227-1234.
Author URL.
Old OJ, Lloyd GR, Nallala J, Isabelle M, Almond LM, Shepherd NA, Kendall CA, Shore AC, Barr H, Stone N, et al (2017). Rapid infrared mapping for highly accurate automated histology in Barrett's oesophagus.
Analyst,
142(8), 1227-1234.
Abstract:
Rapid infrared mapping for highly accurate automated histology in Barrett's oesophagus.
Barrett's oesophagus (BE) is a premalignant condition that can progress to oesophageal adenocarcinoma. Endoscopic surveillance aims to identify potential progression at an early, treatable stage, but generates large numbers of tissue biopsies. Fourier transform infrared (FTIR) mapping was used to develop an automated histology tool for detection of BE and Barrett's neoplasia in tissue biopsies. 22 oesophageal tissue samples were collected from 19 patients. Contiguous frozen tissue sections were taken for pathology review and FTIR imaging. 45 mid-IR images were measured on an Agilent 620 FTIR microscope with an Agilent 670 spectrometer. Each image covering a 140 μm × 140 μm region was measured in 5 minutes, using a 1.1 μm2 pixel size and 64 scans per pixel. Principal component fed linear discriminant analysis was used to build classification models based on spectral differences, which were then tested using leave-one-sample-out cross validation. Key biochemical differences were identified by their spectral signatures: high glycogen content was seen in normal squamous (NSQ) tissue, high glycoprotein content was observed in glandular BE tissue, and high DNA content in dysplasia/adenocarcinoma samples. Classification of normal squamous samples versus 'abnormal' samples (any stage of Barrett's) was performed with 100% sensitivity and specificity. Neoplastic Barrett's (dysplasia or adenocarcinoma) was identified with 95.6% sensitivity and 86.4% specificity. Highly accurate pathology classification can be achieved with FTIR measurement of frozen tissue sections in a clinically applicable timeframe.
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Smallwood MJ, Ble A, Melzer D, Winyard PG, Benjamin N, Shore AC, Gilchrist M (2017). Relationship Between Urinary Nitrate Excretion and Blood Pressure in the InChianti Cohort.
Am J Hypertens,
30(7), 707-712.
Abstract:
Relationship Between Urinary Nitrate Excretion and Blood Pressure in the InChianti Cohort.
BACKGROUND: Inorganic nitrate from the oxidation of endogenously synthesized nitric oxide (NO) or consumed in the diet can be reduced to NO via a complex enterosalivary circulation pathway. The relationship between total nitrate exposure by measured urinary nitrate excretion and blood pressure in a large population sample has not been assessed previously. METHODS: for this cross-sectional study, 24-hour urinary nitrate excretion was measured by spectrophotometry in the 919 participants from the InChianti cohort at baseline and blood pressure measured with a mercury sphygmomanometer. RESULTS: After adjusting for age and sex only, diastolic blood pressure was 1.9 mm Hg lower in subjects with ≥2 mmol urinary nitrate excretion compared with those excreting
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Casanova F, Adingupu DD, Adams F, Gooding KM, Looker HC, Aizawa K, Dove F, Elyas S, Belch JJF, Gates PE, et al (2017). The impact of cardiovascular co-morbidities and duration of diabetes on the association between microvascular function and glycaemic control.
Cardiovasc Diabetol,
16(1).
Abstract:
The impact of cardiovascular co-morbidities and duration of diabetes on the association between microvascular function and glycaemic control.
BACKGROUND: Good glycaemic control in type 2 diabetes (T2DM) protects the microcirculation. Current guidelines suggest glycaemic targets be relaxed in advanced diabetes. We explored whether disease duration or pre-existing macrovascular complications attenuated the association between hyperglycaemia and microvascular function. METHODS: 743 participants with T2DM (n = 222), cardiovascular disease (CVD = 183), both (n = 177) or neither (controls = 161) from two centres in the UK, underwent standard clinical measures and endothelial dependent (ACh) and independent (SNP) microvascular function assessment using laser Doppler imaging. RESULTS: People with T2DM and CVD had attenuated ACh and SNP responses compared to controls. This was additive in those with both (ANOVA p
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Gonçalves I, Edsfeldt A, Colhoun HM, Shore AC, Palombo C, Natali A, Fredrikson GN, Björkbacka H, Wigren M, Bengtsson E, et al (2016). Association between renin and atherosclerotic burden in subjects with and without type 2 diabetes.
BMC Cardiovasc Disord,
16(1).
Abstract:
Association between renin and atherosclerotic burden in subjects with and without type 2 diabetes.
BACKGROUND: Activation of the renin-angiotensin-aldosterone-system (RAAS) has been proposed to contribute to development of vascular complications in type 2 diabetes (T2D). The aim of the present study was to determine if plasma renin levels are associated with the severity of vascular changes in subjects with and without T2D. METHODS: Renin was analyzed by the Proximity Extension Assay in subjects with (n = 985) and without (n = 515) T2D participating in the SUMMIT (SUrrogate markers for Micro- and Macro-vascular hard endpoints for Innovative diabetes Tools) study and in 205 carotid endarterectomy patients. Vascular changes were assessed by determining ankle-brachial pressure index (ABPI), carotid intima-media thickness (IMT), carotid plaque area, pulse wave velocity (PWV) and the reactivity hyperemia index (RHI). RESULTS: Plasma renin was elevated in subjects with T2D and demonstrated risk factor-independent association with prevalent cardiovascular disease both in subjects with and without T2D. Renin levels increased with age, body mass index, HbA1c and correlated inversely with HDL. Subjects with T2D had more severe carotid disease, increased arterial stiffness, and impaired endothelial function. Risk factor-independent associations between renin and APBI, bulb IMT, carotid plaque area were observed in both T2D and non-T2D subjects. These associations were independent of treatment with RAAS inhibitors. Only weak associations existed between plasma renin and the expression of pro-inflammatory and fibrous components in plaques from 205 endarterectomy patients. CONCLUSIONS: Our findings provide clinical evidence for associations between systemic RAAS activation and atherosclerotic burden and suggest that this association is of particular importance in T2D.
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Iyengar SS, Morgan-Hughes G, Ukoumunne O, Clayton B, Davies EJ, Nikolaou V, Hyde CJ, Shore AC, Roobottom CA (2016). Diagnostic accuracy of high-definition CT coronary angiography in high-risk patients.
Clin Radiol,
71(2), 151-158.
Abstract:
Diagnostic accuracy of high-definition CT coronary angiography in high-risk patients.
AIM: to assess the diagnostic accuracy of computed tomography coronary angiography (CTCA) using a combination of high-definition CT (HD-CTCA) and high level of reader experience, with invasive coronary angiography (ICA) as the reference standard, in high-risk patients for the investigation of coronary artery disease (CAD). MATERIALS AND METHODS: Three hundred high-risk patients underwent HD-CTCA and ICA. Independent experts evaluated the images for the presence of significant CAD, defined primarily as the presence of moderate (≥ 50%) stenosis and secondarily as the presence of severe (≥ 70%) stenosis in at least one coronary segment, in a blinded fashion. HD-CTCA was compared to ICA as the reference standard. RESULTS: No patients were excluded. Two hundred and six patients (69%) had moderate and 178 (59%) had severe stenosis in at least one vessel at ICA. The sensitivity, specificity, positive predictive value, and negative predictive value were 97.1%, 97.9%, 99% and 93.9% for moderate stenosis, and 98.9%, 93.4%, 95.7% and 98.3%, for severe stenosis, on a per-patient basis. CONCLUSION: the combination of HD-CTCA and experienced readers applied to a high-risk population, results in high diagnostic accuracy comparable to ICA. Modern generation CT systems in experienced hands might be considered for an expanded role.
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Aizawa K, Elyas S, Adingupu DD, Casanova F, Gooding KM, Shore AC, Strain WD, Gates PE (2016). Echogenicity of the Common Carotid Artery Intima-Media Complex in Stroke.
Ultrasound Med Biol,
42(5), 1130-1137.
Abstract:
Echogenicity of the Common Carotid Artery Intima-Media Complex in Stroke.
The grey-scale median of the common carotid artery intima-media complex (IM-GSM) characterizes arterial wall composition, and a low IM-GSM is associated with increased cardiovascular mortality in the elderly. We aimed to determine differences in the IM-GSM between a cohort with cerebrovascular disease and a healthy cohort. Eighty-two healthy individuals (control group: 63.2 ± 8.7 y) and 96 patients with either stroke or transient ischemic attacks (CRVD group: 68.6 ± 9.8 y) were studied. Common carotid artery intima-media thickness and IM-GSM obtained by ultrasound were analyzed using semi-automated edge-detection software. The IM-GSM was significantly lower in the CRVD group than in the control group (106 ± 24 vs. 124 ± 27 au, p < 0.001). The IM-GSM was similar for the infarct and non-infarct sides in CRVD. In the pooled cohort of all participants, the lower the quartile of IM-GSM, the greater were the carotid artery intima-media thickness and carotid artery remodeling. These results suggest the presence of an altered atherosclerotic phenotype in the intima-media complex of CRVD patients that can be detected by ultrasound.
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Shepherd AI, Wilkerson DP, Fulford J, Winyard PG, Benjamin N, Shore AC, Gilchrist M (2016). Effect of nitrate supplementation on hepatic blood flow and glucose homeostasis: a double-blind, placebo-controlled, randomized control trial.
Am J Physiol Gastrointest Liver Physiol,
311(3), G356-G364.
Abstract:
Effect of nitrate supplementation on hepatic blood flow and glucose homeostasis: a double-blind, placebo-controlled, randomized control trial.
Nitric oxide alters gastric blood flow, improves vascular function, and mediates glucose uptake within the intestines and skeletal muscle. Dietary nitrate, acting as a source of nitric oxide, appears to be a potential low-cost therapy that may help maintain glucose homeostasis. In a randomized, double-blind, placebo-controlled crossover study, 31 young and older adult participants had a standardized breakfast, supplemented with either nitrate-rich beetroot juice (11.91 mmol nitrate) or nitrate-depleted beetroot juice as placebo (0.01 mmol nitrate). MRI was used to assess apparent diffusion coefficient (ADC), portal vein flux, and velocity. Plasma glucose, incretin, and C-peptide concentrations and blood pressure were assessed. Outcome variables were measured at baseline and hourly for 3 h. Compared with a placebo, beetroot juice resulted in a significant elevation in plasma nitrate and plasma nitrite concentration. No differences were seen for the young or older adult cohorts between placebo and beetroot juice for ADC, or portal vein flux. There was an interaction effect in the young adults between visits for portal vein velocity. Nitrate supplementation did not reduce plasma glucose, active GLP-1, total GLP-1, or plasma C-peptide concentrations for the young or older adult cohorts. Despite a significant elevation in plasma nitrite concentration following an acute dose of (11.91 mmol) nitrate, there was no effect on hepatic blood flow, plasma glucose, C-peptide, or incretin concentration in healthy adults.
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Frost J, Ludeman L, Hillaby K, Gornall R, Lloyd G, Kendall C, Shore AC, Stone N (2016). Identification of cancer associated molecular changes in histologically benign vulval disease found in association with vulval squamous cell carcinoma using Fourier transform infrared spectroscopy.
Analytical Methods,
8(48), 8452-8460.
Abstract:
Identification of cancer associated molecular changes in histologically benign vulval disease found in association with vulval squamous cell carcinoma using Fourier transform infrared spectroscopy
This study evaluates the capability of Fourier transform infrared spectroscopy (FTIR-S) in the differentiation of molecular changes in vulval intraepithelial neoplasia (VIN) and lichen sclerosus (LS) found in association with vulval squamous cell carcinoma (SCC), compared with VIN and LS found in isolation. 48 sections of vulval epithelium with features of VIN (n = 24) or LS (n = 24) underwent FTIR-S micro-spectroscopic mapping. Spectra from each section were correlated with the pathological diagnoses and the presence of concurrent SCC. Spectral variance was explored using principal component analysis and a multivariate linear discriminant classification model was developed and validated with leave one sample out cross validation. The discriminant model was able to correctly identify FTIR-S spectra taken from samples of VIN and LS found in association with SCC from those found in isolation with a sensitivity of 82% and specificity of 93% for LS and sensitivity of 75% and specificity of 94% for VIN. The discriminant model was adjusted to maximise sensitivity whilst conceding specificity on a per patient basis and could differentiate LS associated with SCC with a sensitivity of 100% and specificity of 84% and VIN associated with SCC sensitivity of 100% and specificity 58%. In distinguishing VIN and LS found in association with SCC from that found in isolation FTIR-S offers a potential technique for the assessment of molecular changes in the vulva that predispose to the development of SCC. Further study is needed to assess the ability of FTIR-S to risk stratify patients with VIN or LS.
Abstract.
Clark CE, Taylor RS, Butcher I, Stewart MC, Price J, Fowkes FGR, Shore AC, Campbell JL (2016). Inter-arm blood pressure difference and mortality: a cohort study in an asymptomatic primary care population at elevated cardiovascular risk.
Br J Gen Pract,
66(646), e297-e308.
Abstract:
Inter-arm blood pressure difference and mortality: a cohort study in an asymptomatic primary care population at elevated cardiovascular risk.
BACKGROUND: Differences in blood pressure between arms are associated with increased cardiovascular mortality in cohorts with established vascular disease or substantially elevated cardiovascular risk. AIM: to explore the association of inter-arm difference (IAD) with mortality in a community-dwelling cohort that is free of cardiovascular disease. DESIGN AND SETTING: Cohort analysis of a randomised controlled trial in central Scotland, from April 1998 to October 2008. METHOD: Volunteers from Lanarkshire, Glasgow, and Edinburgh, free of pre-existing vascular disease and with an ankle-brachial index ≤0.95, had systolic blood pressure measured in both arms at recruitment. Inter-arm blood pressure differences were calculated and examined for cross-sectional associations and differences in prospective survival. Outcome measures were cardiovascular events and all-cause mortality during mean follow-up of 8.2 years. RESULTS: Based on a single pair of measurements, 60% of 3350 participants had a systolic IAD ≥5 mmHg and 38% ≥10 mmHg. An IAD ≥5 mmHg was associated with increased cardiovascular mortality (adjusted hazard ratio [HR] 1.91, 95% confidence interval [CI] = 1.19 to 3.07) and all-cause mortality (adjusted HR 1.44, 95% CI = 1.15 to 1.79). Within the subgroup of 764 participants who had hypertension, IADs of ≥5 mmHg or ≥10 mmHg were associated with both cardiovascular mortality (adjusted HR 2.63, 95% CI = 0.97 to 7.02, and adjusted HR 2.96, 95% CI = 1.27 to 6.88, respectively) and all-cause mortality (adjusted HR 1.67, 95% CI = 1.05 to 2.66, and adjusted HR 1.63, 95% CI = 1.06 to 2.50, respectively). IADs ≥15 mmHg were not associated with survival differences in this population. CONCLUSION: Systolic IADs in blood pressure are associated with increased risk of cardiovascular events, including mortality, in a large cohort of people free of pre-existing vascular disease.
Abstract.
Author URL.
Elyas S, Shore AC, Kingwell H, Keenan S, Boxall L, Stewart J, James MA, Strain WD (2016). Microalbuminuria could improve risk stratification in patients with TIA and minor stroke.
Ann Clin Transl Neurol,
3(9), 678-683.
Abstract:
Microalbuminuria could improve risk stratification in patients with TIA and minor stroke.
OBJECTIVE: Transient ischemic attacks (TIA) and minor strokes are important risk factors for recurrent strokes. Current stroke risk prediction scores such as ABCD2, although widely used, lack optimal sensitivity and specificity. Elevated urinary albumin excretion predicts cardiovascular disease, stroke, and mortality. We explored the role of microalbuminuria (using albumin creatinine ratio (ACR)) in predicting recurrence risk in patients with TIA and minor stroke. METHODS: Urinary ACR was measured on a spot sample in 150 patients attending a daily stroke clinic with TIA or minor stroke. Patients were followed up at day 7, 30, and 90 to determine recurrent stroke, cardiovascular events, or death. Eligible patients had a carotid ultrasound Doppler investigation. High-risk patients were defined as those who had an event within 90 days or had >50% internal carotid artery (ICA) stenosis. RESULTS: Fourteen (9.8%) recurrent events were reported by day 90 including two deaths. Fifteen patients had severe ICA stenosis. In total, 26 patients were identified as high risk. These patients had a higher frequency of previous stroke or hypercholesterolemia compared to low-risk patients (P = 0.04). ACR was higher in high-risk patients (3.4 [95% CI 2.2-5.2] vs. 1.7 [1.5-2.1] mg/mmol, P = 0.004), independent of age, sex, blood pressure, diabetes, and previous stroke. An ACR greater than 1.5 mg/mmol predicted high-risk patients (Cox proportional hazard ratio 3.5 (95% CI 1.3-9.5, P = 0.01). INTERPRETATION: After TIA or minor stroke, a higher ACR predicted recurrent events and significant ICA stenosis. Incorporation of urinary ACR from a spot sample in the acute setting could improve risk stratification in patients with TIA and minor stroke.
Abstract.
Author URL.
Clark CE, Taylor RS, Shore AC, Campbell JL (2016). Prevalence of systolic inter-arm differences in blood pressure for different primary care populations: systematic review and meta-analysis.
Br J Gen Pract,
66(652), e838-e847.
Abstract:
Prevalence of systolic inter-arm differences in blood pressure for different primary care populations: systematic review and meta-analysis.
BACKGROUND: Various prevalence figures have been reported for inter-arm differences in blood pressure (IAD); variation may be explained by differing population vascular risk and by measurement method. AIM: to review the literature to derive robust estimates of IAD prevalence relevant to community populations. DESIGN AND SETTING: Systematic review and meta-analysis. METHOD: MEDLINE, Embase, and CINAHL were searched for cross-sectional studies likely to represent general or primary care populations, reporting prevalence of IAD and employing a simultaneous method of measurement. Using study-level data, pooled estimates of mean prevalence of systolic IADs were calculated and compared using a random effects model. RESULTS: Eighty IAD studies were identified. Sixteen met inclusion criteria: pooled estimates of prevalence for systolic IAD ≥10 mmHg were 11.2% (95% confidence interval [CI] = 9.1 to 13.6) in hypertension, 7.4% (95% CI = 5.8 to 9.2) in diabetes, and 3.6% (95% CI = 2.3 to 5.0) for a general adult population (P
Abstract.
Author URL.
Aizawa K, Elyas S, Adingupu DD, Casanova F, Gooding KM, Strain WD, Shore AC, Gates PE (2016). Reactivity to low-flow as a potential determinant for brachial artery flow-mediated vasodilatation.
Physiol Rep,
4(12).
Abstract:
Reactivity to low-flow as a potential determinant for brachial artery flow-mediated vasodilatation.
Previous studies have reported a vasoconstrictor response in the radial artery during a cuff-induced low-flow condition, but a similar low-flow condition in the brachial artery results in nonuniform reactivity. This variable reactivity to low-flow influences the subsequent flow-mediated dilatation (FMD) response following cuff-release. However, it is uncertain whether reactivity to low-flow is important in data interpretation in clinical populations and older adults. This study aimed to determine the influence of reactivity to low-flow on the magnitude of brachial artery FMD response in middle-aged and older individuals with diverse cardiovascular risk profiles. Data were analyzed from 165 individuals, divided into increased cardiovascular risk (CVR: n = 115, 85M, 67.0 ± 8.8 years) and healthy control (CTRL: n = 50, 30M, 63.2 ± 7.2 years) groups. Brachial artery diameter and blood velocity data obtained from Doppler ultrasound were used to calculate FMD, reactivity to low-flow and estimated shear rate (SR) using semiautomated edge-detection software. There was a significant association between reactivity to low-flow and FMD in overall (r = 0.261), CTRL (r = 0.410) and CVR (r = 0.189, all P
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Author URL.
Bokori-Brown M, Petrov PG, Khafaji MA, Mughal MK, Naylor CE, Shore AC, Gooding KM, Casanova F, Mitchell TJ, Titball RW, et al (2016). Red Blood Cell Susceptibility to Pneumolysin: CORRELATION WITH MEMBRANE BIOCHEMICAL AND PHYSICAL PROPERTIES.
J Biol Chem,
291(19), 10210-10227.
Abstract:
Red Blood Cell Susceptibility to Pneumolysin: CORRELATION WITH MEMBRANE BIOCHEMICAL AND PHYSICAL PROPERTIES.
This study investigated the effect of the biochemical and biophysical properties of the plasma membrane as well as membrane morphology on the susceptibility of human red blood cells to the cholesterol-dependent cytolysin pneumolysin, a key virulence factor of Streptococcus pneumoniae, using single cell studies. We show a correlation between the physical properties of the membrane (bending rigidity and surface and dipole electrostatic potentials) and the susceptibility of red blood cells to pneumolysin-induced hemolysis. We demonstrate that biochemical modifications of the membrane induced by oxidative stress, lipid scrambling, and artificial cell aging modulate the cell response to the toxin. We provide evidence that the diversity of response to pneumolysin in diabetic red blood cells correlates with levels of glycated hemoglobin and that the mechanical properties of the red blood cell plasma membrane are altered in diabetes. Finally, we show that diabetic red blood cells are more resistant to pneumolysin and the related toxin perfringolysin O relative to healthy red blood cells. Taken together, these studies indicate that the diversity of cell response to pneumolysin within a population of human red blood cells is influenced by the biophysical and biochemical status of the plasma membrane and the chemical and/or oxidative stress pre-history of the cell.
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Author URL.
Thorn CE, Shore AC (2016). The role of perfusion in the oxygen extraction capability of skin and skeletal muscle.
Am J Physiol Heart Circ Physiol,
310(10), H1277-H1284.
Abstract:
The role of perfusion in the oxygen extraction capability of skin and skeletal muscle.
Oxygen extraction (OE) by all cells is dependent on an adequate supply of oxygen in proximal blood vessels and the cell's need and ability to uptake that oxygen. Here the role of blood flow in regulating OE in skin and skeletal muscle was investigated in lean and obese men. OE was derived by two optical reflectance spectroscopy techniques: 1) from the rate of fall in mean blood saturation during a 4 min below knee arterial occlusion, and thus no blood flow, in calf skin and skeletal muscle and 2) in perfused, unperturbed skin, using the spontaneous falls in mean blood saturation induced by vasomotion in calf and forearm skin of 24 subjects, 12 lean and 12 obese. OE in perfused skin was significantly higher in lean compared with obese subjects in forearm (Mann-Whitney, P < 0.004) and calf (P < 0.001) and did not correlate with OE in unperfused skin (ρ = -0.01, P = 0.48). With arterial occlusion and thus no blood flow, skin OE in lean and obese subjects no longer differed (P = 0.23, not significant). In contrast in skeletal muscle with arterial occlusion and no blood flow, the difference in OE between lean and obese subjects occurred, with obese subjects exhibiting significantly higher OE (P < 0.012). The classic model of metabolic blood flow regulation to support oxygen extraction is evident in perfused skin; OE is perturbed without blood flow and reduced in obesity. In resting skeletal muscle other mechanism(s), independent of blood flow, are implicated in oxygen extraction.
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Author URL.
Clark C, Shore A, Taylor R, Campbell J (2015). 1C.08: THE INTER-ARM DIFFERENCE IN BLOOD PRESSURE AND MORTALITY: SYSTEMATIC REVIEW AND META-ANALYSIS.
J Hypertens,
33 Suppl 1Abstract:
1C.08: THE INTER-ARM DIFFERENCE IN BLOOD PRESSURE AND MORTALITY: SYSTEMATIC REVIEW AND META-ANALYSIS.
OBJECTIVE: We previously reported the association of inter-arm differences in blood pressure measurements (IAD) with increased cardiovascular and all-cause mortality. Several new large cohorts have been reported since our 2012 meta-analysis. We have therefore updated our meta-analyses to take account of these new data. DESIGN AND METHOD: Systematic review and meta-analysis: Medline, Embase and CINAHL were searched for studies reporting survival data in association with IAD. Study level hazard ratios (HR) were extracted for systolic IADs >=10mmHg and >=15mmHg, and pooled using generic inverse variance in a random effects model. Statistical heterogeneity was assessed using the I statistic. RESULTS: Searches to 12th November 2014 identified 3514 unique citations. Eighty full texts were assessed, and 13 studies (reporting data for 14 unique cohorts) contributed to the analyses, Median follow up ranged from 3 to 13 years. Five cohorts employed a simultaneous method of IAD measurement; the remainder used sequential measurements. Ten cohorts were recruited from community populations, including one hypertensive and one diabetic cohort. Four were selected hospital cohorts at increased vascular risk.Cardiovascular mortality was greater with an IAD >=10mmHg (HR 1.9 (95%CI 1.3 to 2.6; 7 cohorts, 13815 participants; I = 45%) and an IAD >=15mmHg (HR 1.7 (1.2 to 2.4; 9 cohorts; 18241 participants; I = 30%). For all-cause mortality HRs were 1.4 (1.2 to 1.8; 10 cohorts, 17709 participants; I = 62%) for IAD >=10mmHg and 1.4 (1.1 to 1.7; 12 cohorts, 18714 participants; I = 46%) for IAD >=15mmHg. Heterogeneity between studies could be accounted for by stratification according to underlying population cardiovascular risk, with higher HRs seen in populations at elevated risk; cardiovascular mortality with an IAD >=10mmHg: HR 1.4 (1.1 to 1.8; I = 0%) for community based cohorts compared to 3.8 (2.2 to 6.6; I = 0%) for those at elevated cardiovascular risk (p = 0.001; Figure).(Figure is included in full-text article.) CONCLUSIONS: : New studies confirming the association of an IAD with increased cardiovascular and all-cause mortality are consistent with previously published findings. Risks associated with an IAD rise in association with the underlying vascular risk of the population studied.
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Author URL.
Siervo M, Lara J, Jajja A, Sutyarjoko A, Ashor AW, Brandt K, Qadir O, Mathers JC, Benjamin N, Winyard PG, et al (2015). Ageing modifies the effects of beetroot juice supplementation on 24-hour blood pressure variability: an individual participant meta-analysis.
Nitric Oxide,
47, 97-105.
Abstract:
Ageing modifies the effects of beetroot juice supplementation on 24-hour blood pressure variability: an individual participant meta-analysis.
OBJECTIVES: Abnormal circadian oscillations of blood pressure (BP) and nocturnal-diurnal BP differences (i.e. dipping) increase cardiovascular risk. Whether inorganic nitrate supplementation influences 24-hr BP variability is currently unknown. We studied the effects of high-nitrate beetroot juice supplementation on BP variability measured by 24-hr ambulatory BP monitoring (24-hr ABPM) in older subjects. METHODS: Data from four independent randomised clinical trials were collated. Eighty-five older participants (age range: 55-76 years) were included in the final database. Two trials had an open-label, parallel design and two trials had a cross-over, double-blind design. Participants were randomised to either beetroot juice or placebo. Changes in 24-hr ABPM (daily, diurnal, nocturnal), variability (weighted-SDs), night-dipping, morning surge for systolic and diastolic BP were measured. Meta-analysis was conducted to obtain pooled estimates of the effect size for each BP outcome. Sub-group analyses were conducted to evaluate the influence of age, BMI, gender, BP status and changes in nitrite concentrations on the effect size. RESULTS: the pooled effect of beetroot juice on all BP outcomes was not significant. Beetroot juice ingestion determined a significant decrease in nocturnal systolic BP variability in subjects aged less than 65 y (2.8 mmHg, -4.5 -1.0, p = 0.002) compared to the older group (≥ 65 y; 1.0 mmHg, -2.2 4.2, p = 0.54). A greater change in NO2(-) concentrations after beetroot supplementation was associated with significant differences for nocturnal mean (-3.4 mmHg, -0.6 -2.4, p = 0.02) and variability (-0.8 mmHg, -1.5 -0.06, p = 0.03) of systolic BP. CONCLUSIONS: the vascular responsiveness to inorganic nitrate may be modified by mechanisms of vascular ageing influencing the reducing capacity to convert inorganic nitrate into nitrite and tissue-specific responses to dietary nitrate supplementation.
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Author URL.
Adingupu DD, Thorn CE, Casanova F, Elyas S, Gooding K, Gilchrist M, Aizawa K, Gates PE, Shore AC, Strain DW, et al (2015). Blood Oxygen Saturation After Ischemia is Altered with Abnormal Microvascular Reperfusion.
Microcirculation,
22(4), 294-305.
Abstract:
Blood Oxygen Saturation After Ischemia is Altered with Abnormal Microvascular Reperfusion.
OBJECTIVE: We have previously described a distinct abnormality in the cutaneous microcirculation that is characterized by an abnormal reperfusion response following an ischemic stimulus. We investigated the physiological significance of this abnormality; by measuring microvascular perfusion and blood oxygen saturation in groups stratified by three distinct reperfusion responses. METHODS: Cutaneous microvascular reperfusion after four minutes of arterial occlusion above the ankle was measured on the foot using laser Doppler fluximetry and optical reflectance spectroscopy in almost 400 adults. Individuals were stratified into three groups according to the microvascular reperfusion response: normal and two abnormal patterns (DEP and NDEP). RESULTS: Our main findings were that abnormal microvascular reperfusion responses (DEP and NDEP) had a higher baseline oxygen saturation (p = 0.005), a lower plateau in oxygen saturation (p < 0.0001 and
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Author URL.
Elyas S, Adingupu D, Aizawa K, Shore AC, Strain WD, Gates PE (2015). Cerebral hemodynamics in patients with large vessel disease stroke and lacunar stroke.
INTERNATIONAL JOURNAL OF STROKE,
10, 368-368.
Author URL.
Shepherd AI, Gilchrist M, Winyard PG, Jones AM, Hallmann E, Kazimierczak R, Rembialkowska E, Benjamin N, Shore AC, Wilkerson DP, et al (2015). Effects of dietary nitrate supplementation on the oxygen cost of exercise and walking performance in individuals with type 2 diabetes: a randomized, double-blind, placebo-controlled crossover trial.
Free Radic Biol Med,
86, 200-208.
Abstract:
Effects of dietary nitrate supplementation on the oxygen cost of exercise and walking performance in individuals with type 2 diabetes: a randomized, double-blind, placebo-controlled crossover trial.
Dietary nitrate supplementation has been shown to reduce the oxygen (O2) cost of exercise and enhance exercise tolerance in healthy individuals. This study assessed whether similar effects could be observed in individuals with type 2 diabetes (T2DM). In a randomized, double-blind, placebo-controlled crossover study, 48 participants with T2DM supplemented their diet for 4 days with either nitrate-rich beetroot juice (70ml/day, 6.43mmol nitrate/day) or nitrate-depleted beetroot juice as placebo (70ml/day, 0.07mmol nitrate/day). After each intervention period, resting plasma nitrate and nitrite concentrations were measured subsequent to participants completing moderate-paced walking. Pulmonary gas exchange was measured to assess the O2 cost of walking. After a rest period, participants performed the 6-min walk test (6MWT). Relative to placebo, beetroot juice resulted in a significant increase in plasma nitrate (placebo, 57±66 vs beetroot, 319±110µM; P < 0.001) and plasma nitrite concentration (placebo, 680±256 vs beetroot, 1065±607nM; P < 0.001). There were no differences between placebo juice and beetroot juice for the O2 cost of walking (946±221 vs 939±223ml/min, respectively; P = 0.59) and distance covered in the 6MWT (550±83 vs 554±90m, respectively; P = 0.17). Nitrate supplementation did not affect the O2 cost of moderate-paced walking or improve performance in the 6MWT. These findings indicate that dietary nitrate supplementation does not modulate the response to exercise in individuals with T2DM.
Abstract.
Author URL.
Goncalves I, Bengtsson E, Colhoun HM, Shore AC, Palombo C, Natali A, Edsfeldt A, Dunér P, Fredrikson GN, Björkbacka H, et al (2015). Elevated Plasma Levels of MMP-12 Are Associated with Atherosclerotic Burden and Symptomatic Cardiovascular Disease in Subjects with Type 2 Diabetes.
Arterioscler Thromb Vasc Biol,
35(7), 1723-1731.
Abstract:
Elevated Plasma Levels of MMP-12 Are Associated with Atherosclerotic Burden and Symptomatic Cardiovascular Disease in Subjects with Type 2 Diabetes.
OBJECTIVE: Matrix metalloproteinases (MMPs) degrade extracellular matrix proteins and play important roles in development and tissue repair. They have also been shown to have both protective and pathogenic effects in atherosclerosis, and experimental studies have suggested that MMP-12 contributes to plaque growth and destabilization. The objective of this study was to investigate the associations between circulating MMPs, atherosclerosis burden, and incidence of cardiovascular disease with a particular focus on type 2 diabetes mellitus. APPROACH AND RESULTS: Plasma levels of MMP-1, -3, -7, -10, and -12 were analyzed by the Proximity Extension Assay technology in 1500 subjects participating in the SUMMIT (surrogate markers for micro- and macrovascular hard end points for innovative diabetes tools) study, 384 incident coronary cases, and 409 matched controls in the Malmö Diet and Cancer study and in 205 carotid endarterectomy patients. Plasma MMP-7 and -12 were higher in subjects with type 2 diabetes mellitus, increased with age and impaired renal function, and was independently associated with prevalent cardiovascular disease, atherosclerotic burden (as assessed by carotid intima-media thickness and ankle-brachial pressure index), arterial stiffness, and plaque inflammation. Baseline MMP-7 and -12 levels were increased in Malmö Diet and Cancer subjects who had a coronary event during follow-up. CONCLUSIONS: the plasma level of MMP-7 and -12 are elevated in type 2 diabetes mellitus, associated with more severe atherosclerosis and an increased incidence of coronary events. These observations provide clinical support to previous experimental studies, demonstrating a role for these MMPs in plaque development, and suggest that they are potential biomarkers of atherosclerosis burden and cardiovascular disease risk.
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Author URL.
Lewandowski AJ, Davis EF, Yu G, Digby JE, Boardman H, Whitworth P, Singhal A, Lucas A, Mccormick K, Shore AC, et al (2015). Elevated blood pressure in preterm-born offspring associates with a distinct antiangiogenic state and microvascular abnormalities in adult life.
Hypertension,
65(3), 607-614.
Abstract:
Elevated blood pressure in preterm-born offspring associates with a distinct antiangiogenic state and microvascular abnormalities in adult life
Supplemental Digital Content is available in the text. Preterm-born individuals have elevated blood pressure. We tested the hypothesis that this associates with an enhanced antiangiogenic circulating profile and that this association is mediated by variations in capillary density. We studied 204 adults aged 25 years (range, 20-30 years), of which 102 had been followed up prospectively since very preterm birth (mean gestational age, 30.3±2.5 weeks) and 102 were born term to uncomplicated pregnancies. A panel of circulating biomarkers, including soluble endoglin and soluble fms-like tyrosine kinase-1, were compared between groups and related to perinatal history and adult cardiovascular risk. Associations with cardiovascular phenotype were studied in 90 individuals who had undergone detailed assessment of microvascular, macrovascular, and cardiac structure and function. Preterm-born individuals had elevations in soluble endoglin (5.64±1.03 versus 4.06±0.85 ng/mL; P
Abstract.
Shore AC, Colhoun HM, Natali A, Palombo C, Östling G, Aizawa K, Kennbäck C, Casanova F, Persson M, Gooding K, et al (2015). Measures of atherosclerotic burden are associated with clinically manifest cardiovascular disease in type 2 diabetes: a European cross-sectional study.
Journal of Internal Medicine,
278(3), 291-302.
Abstract:
Measures of atherosclerotic burden are associated with clinically manifest cardiovascular disease in type 2 diabetes: a European cross-sectional study
Background: There is a need to develop and validate surrogate markers of cardiovascular disease (CVD) in subjects with diabetes. The macrovascular changes associated with diabetes include aggravated atherosclerosis, increased arterial stiffness and endothelial dysfunction. The aim of this study was to determine which of these factors is most strongly associated with clinically manifest cardiovascular events. Methods: Vascular changes were measured in a cohort of 458 subjects with type 2 diabetes (T2D) and CVD (myocardial infarction, stroke or lower extremity arterial disease), 527 subjects with T2D but without clinically manifest CVD and 515 subjects without T2D and with or without CVD. Results: Carotid intima-media thickness (IMT) and ankle-brachial pressure index were independently associated with the presence of CVD in subjects with T2D, whereas pulse wave velocity and endothelial function provided limited independent additive information. Measurement of IMT in the carotid bulb provided better discrimination of the presence of CVD in subjects with T2D than measurement of IMT in the common carotid artery. The factors most significantly associated with increased carotid IMT in T2D were age, disease duration, systolic blood pressure, impaired renal function and increased arterial stiffness, whereas there were no or weak independent associations with metabolic factors and endothelial dysfunction. Conclusions: Measures of atherosclerotic burden are associated with clinically manifest CVD in subjects with T2D. In addition, vascular changes that are not directly related to known metabolic risk factors are important in the development of both atherosclerosis and CVD in T2D. A better understanding of the mechanisms involved is crucial for enabling better identification of CVD risk in T2D.
Abstract.
Shore AC, Colhoun HM, Natali A, Palombo C, Östling G, Aizawa K, Kennbäck C, Casanova F, Persson M, Gooding K, et al (2015). Measures of atherosclerotic burden are associated with clinically manifest cardiovascular disease in type 2 diabetes: a European cross-sectional study.
J Intern Med,
278(3), 291-302.
Abstract:
Measures of atherosclerotic burden are associated with clinically manifest cardiovascular disease in type 2 diabetes: a European cross-sectional study.
BACKGROUND: There is a need to develop and validate surrogate markers of cardiovascular disease (CVD) in subjects with diabetes. The macrovascular changes associated with diabetes include aggravated atherosclerosis, increased arterial stiffness and endothelial dysfunction. The aim of this study was to determine which of these factors is most strongly associated with clinically manifest cardiovascular events. METHODS: Vascular changes were measured in a cohort of 458 subjects with type 2 diabetes (T2D) and CVD (myocardial infarction, stroke or lower extremity arterial disease), 527 subjects with T2D but without clinically manifest CVD and 515 subjects without T2D and with or without CVD. RESULTS: Carotid intima-media thickness (IMT) and ankle-brachial pressure index were independently associated with the presence of CVD in subjects with T2D, whereas pulse wave velocity and endothelial function provided limited independent additive information. Measurement of IMT in the carotid bulb provided better discrimination of the presence of CVD in subjects with T2D than measurement of IMT in the common carotid artery. The factors most significantly associated with increased carotid IMT in T2D were age, disease duration, systolic blood pressure, impaired renal function and increased arterial stiffness, whereas there were no or weak independent associations with metabolic factors and endothelial dysfunction. CONCLUSIONS: Measures of atherosclerotic burden are associated with clinically manifest CVD in subjects with T2D. In addition, vascular changes that are not directly related to known metabolic risk factors are important in the development of both atherosclerosis and CVD in T2D. A better understanding of the mechanisms involved is crucial for enabling better identification of CVD risk in T2D.
Abstract.
Author URL.
Shepherd AI, Wilkerson DP, Dobson L, Kelly J, Winyard PG, Jones AM, Benjamin N, Shore AC, Gilchrist M (2015). The effect of dietary nitrate supplementation on the oxygen cost of cycling, walking performance and resting blood pressure in individuals with chronic obstructive pulmonary disease: a double blind placebo controlled, randomised control trial.
Nitric Oxide,
48, 31-37.
Abstract:
The effect of dietary nitrate supplementation on the oxygen cost of cycling, walking performance and resting blood pressure in individuals with chronic obstructive pulmonary disease: a double blind placebo controlled, randomised control trial.
BACKGROUND: Chronic obstructive pulmonary disease (COPD) results in exercise intolerance. Dietary nitrate supplementation has been shown to lower blood pressure (BP), reduce the oxygen cost of exercise, and enhance exercise tolerance in healthy volunteers. This study assessed the effects of dietary nitrate on the oxygen cost of cycling, walking performance and BP in individuals with mild-moderate COPD. METHODS: Thirteen patients with mild-moderate COPD were recruited. Participants consumed 70 ml of either nitrate-rich (6.77 mmol nitrate; beetroot juice) or nitrate-depleted beetroot juice (0.002 mmol nitrate; placebo) twice a day for 2.5 days, with the final supplement ~3 hours before testing. BP was measured before completing two bouts of moderate-intensity cycling, where pulmonary gas exchange was measured throughout. The six-minute walk test (6 MWT) was completed 30 minutes subsequent to the second cycling bout. RESULTS: Plasma nitrate concentration was significantly elevated following beetroot juice vs. placebo (placebo; 48 ± 86 vs. beetroot juice; 215 ± 84 µM, P = 0.002). No significant differences were observed between placebo vs. beetroot juice for oxygen cost of exercise (933 ± 323 vs. 939 ± 302 ml: min(-1); P = 0.88), distance covered in the 6 MWT (456 ± 86 vs. 449 ± 79 m; P = 0.37), systolic BP (123 ± 14 vs. 123 ± 14 mmHg; P = 0.91), or diastolic BP (77 ± 9 vs. 79 ± 9 mmHg; P = 0.27). CONCLUSION: Despite a large rise in plasma nitrate concentration, two days of nitrate supplementation did not reduce the oxygen cost of moderate intensity cycling, increase distance covered in the 6 MWT, or lower BP.
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Author URL.
Gilchrist M, Winyard PG, Fulford J, Anning C, Shore AC, Benjamin N (2014). Dietary nitrate supplementation improves reaction time in type 2 diabetes: development and application of a novel nitrate-depleted beetroot juice placebo.
Nitric Oxide,
40, 67-74.
Abstract:
Dietary nitrate supplementation improves reaction time in type 2 diabetes: development and application of a novel nitrate-depleted beetroot juice placebo.
BACKGROUND: in this substudy of the effect of dietary nitrate on blood pressure, endothelial function, and insulin sensitivity in type 2 diabetes, we report the development of a novel nitrate depleted beetroot juice for use clinical trials and determine if dietary nitrate supplementation improved cognitive function in patients with type 2 diabetes mellitus. METHODS: Beetroot juice was treated with the anion exchange resin Purolite A520e. UV-vis-spectrophotometry, and a blind taste test were performed along with determination of sugar content, measurement of ascorbate and dehydroascorbate, the ionic composition of juice and Proton NMR. Subsequently, 27 patients, age 67.2±4.9 years, (18 male) were recruited for a double blind, randomised, placebo-controlled crossover trial. Participants were randomised to begin in either order beetroot juice (nitrate content 7.5 mmol per 250 ml) or placebo (nitrate depleted beetroot juice nitrate content 0.002 mmol per 250 ml). At the end of each 2 week supplementation period cognitive function was assessed using E-prime, E-Studio software with 5 separate tests being performed. The tests utilised in the present study have been adapted from the Cambridge Neuropsychological Test Automated Battery (CANTAB). RESULTS: the differences in the UV-vis spectra were comparable to the natural variation found in differing cultivars. There were no discernable differences in taste, sugar content, or Proton NMR. Ascorbate and dehydroascorbate were undetectable in either juice. After 2 weeks of beetroot juice simple reaction time was significantly quicker in the active arm at 327±40 ms versus 341.8±52.7 ms in the placebo arm, mean difference 13.9±25.6 ms (95% CI 3.8-24.0 ms), p=0.009. No other measures of cognitive function differed between treatment arms. CONCLUSION: We have developed an effective placebo beetroot juice for use in trials of supplementation of dietary nitrate. Two weeks supplementation of the diet with 7.5 mmol of nitrate per day caused a significant improvement in simple reaction time in individuals with T2DM.
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Author URL.
Pienaar PR, Micklesfield LK, Gill JMR, Shore AC, Gooding KM, Levitt NS, Lambert EV (2014). Ethnic differences in microvascular function in apparently healthy South African men and women.
Experimental Physiology,
99(7), 985-994.
Abstract:
Ethnic differences in microvascular function in apparently healthy South African men and women
Microvascular dysfunction precedes the clinical manifestations of cardiovascular disease. Given the ethnic disparities in cardiovascular disease, we aimed to investigate ethnic differences in microvascular endothelial function in a group of young (18-33 years old), apparently healthy individuals (n = 33, nine Black African, 12 mixed ancestry and 12 Caucasian). Microvascular endothelium-dependent and -independent function was assessed by laser Doppler imagery and iontophoresis of ACh and sodium nitroprusside (SNP), respectively, adjusting for skin resistance. Microvascular reactivity was expressed as maximum absolute perfusion, percentage change from baseline and area under the curve (AUC). Skin resistance was significantly lower in the Caucasian group in response to ACh (Caucasian, mean 0.16 ± 0.03 Ω versus Black, 0.21 ± 0.04 Ω and mixed ancestry, 0.20 ± 0.02 Ω, P < 0.01) and SNP (Caucasian, 0.08 ± 0.01 Ω versus Black, 0.11 ± 0.02 Ω and mixed ancestry, 0.12 ± 0.01 Ω, P < 0.01). Microvascular function in response to ACh was significantly higher in the Caucasian group compared with the other two groups; however, after adjusting for skin resistance these differences were no longer significant. Conversely, the microvascular SNP response remained significantly higher in the Caucasian group, even after adjusting for skin resistance (P < 0.01). Diastolic blood pressure was inversely associated with the AUC of ACh (r = -0.4) and all SNP responses (r = -0.3 to -0.6). Skin resistance was inversely associated with AUC and maximum absolute ACh response (r = -0.59 and -0.64, respectively) and all SNP responses (r = -0.37 to -0.79). Ethnic differences in endothelium-independent microvascular function may contribute to ethnic disparities in cardiovascular disease. Moreover, skin resistance plays a significant role in the interpretation of the microvascular response to outcomes of iontophoresis in a multiethnic group. © 2014 the Physiological Society.
Abstract.
Pienaar PR, Micklesfield LK, Gill JMR, Shore AC, Gooding KM, Levitt NS, Lambert EV (2014). Ethnic differences in microvascular function in apparently healthy South African men and women.
Exp Physiol,
99(7), 985-994.
Abstract:
Ethnic differences in microvascular function in apparently healthy South African men and women.
Microvascular dysfunction precedes the clinical manifestations of cardiovascular disease. Given the ethnic disparities in cardiovascular disease, we aimed to investigate ethnic differences in microvascular endothelial function in a group of young (18-33 years old), apparently healthy individuals (n = 33, nine Black African, 12 mixed ancestry and 12 Caucasian). Microvascular endothelium-dependent and -independent function was assessed by laser Doppler imagery and iontophoresis of ACh and sodium nitroprusside (SNP), respectively, adjusting for skin resistance. Microvascular reactivity was expressed as maximum absolute perfusion, percentage change from baseline and area under the curve (AUC). Skin resistance was significantly lower in the Caucasian group in response to ACh (Caucasian, mean 0.16 ± 0.03 Ω versus Black, 0.21 ± 0.04 Ω and mixed ancestry, 0.20 ± 0.02 Ω, P
Abstract.
Author URL.
Pienaar PR, Micklesfield LK, Levitt NS, Gooding K, Shore AC, Goedecke JH, Gill JMR, Lambert EV (2014). Insulin Resistance is Associated with Lower Acetylcholine-Induced Microvascular Reactivity in Nondiabetic Women.
Metabolic Syndrome and Related Disorders,
12(3), 178-184.
Abstract:
Insulin Resistance is Associated with Lower Acetylcholine-Induced Microvascular Reactivity in Nondiabetic Women
Background: the association between insulin resistance and microvascular dysfunction is well established in obese individuals with type 2 diabetes. It is unclear whether this relationship is dependent on obesity and body fat in insulin-resistant persons. This study investigated acetylcholine (ACh)-induced microvascular reactivity in apparently healthy women (n=37, 20-45 years), with and without insulin resistance. Methods: Body fat mass (dual X-ray absorptiometry), waist circumference (WC), blood pressure, fasting glucose, insulin, and free fatty acid concentrations were measured. Insulin resistance was estimated using homeostasis model assessment of insulin resistance (HOMA-IR), and subjects were divided into insulin-resistant (IR, n=16) and insulin-sensitive (IS, n=21) groups. ACh-induced forearm microvascular reactivity was measured by laser Doppler imagery using iontophoresis of ACh and compared between groups adjusting for WC and skin resistance (SR). Results: the IR group had a higher body mass index (BMI) (30.7±6.4 vs. 22.9±7.3 kg/m2, P
Abstract.
Clark CE, Steele AM, Taylor RS, Shore AC, Ukoumunne OC, Campbell JL (2014). Interarm Blood Pressure Difference in People with Diabetes: Measurement and Vascular and Mortality Implications a Cohort Study.
DIABETES CARE,
37(6), 1613-1620.
Author URL.
Ripley DP, Kannoly S, Gosling OE, Hossain E, Chawner RR, Moore J, Shore AC, Bellenger NG (2014). Safety and feasibility of dobutamine stress cardiac magnetic resonance for cardiovascular assessment prior to renal transplantation.
J Cardiovasc Med (Hagerstown),
15(4), 288-294.
Abstract:
Safety and feasibility of dobutamine stress cardiac magnetic resonance for cardiovascular assessment prior to renal transplantation.
AIMS: Current guidelines recommend cardiovascular risk assessment prior to renal transplantation. There is currently no evidence for the role of cardiovascular magnetic resonance (CMR) in this population, despite an established evidence base in the non-chronic kidney disease (CKD) population. Our aim is to determine the feasibility and safety of dobutamine stress CMR (DSCMR) imaging in the risk stratification of CKD patients awaiting renal transplantation. METHODS: CKD patients who were deemed at high risk for coronary artery disease (CAD) and awaiting renal transplantation underwent DSCMR. RESULTS: Forty-one patients whose median age was 56 years (range 28–73 years) underwent DSCMR. Nineteen were undergoing haemodialysis, 10 peritoneal dialysis and 12 pre-dialysis. The aetiology of the renal failure was diabetes mellitus in 29%, glomerulonephritis in 24%, hypertension in 22% and autosomal dominant polycystic kidney disease in 10%. Thirty-eight patients (93%) achieved the end point, either positive for ischaemia or negative, achieving at least 85% of age-predicted heart rate. Two of them did not achieve target heart rate and one was discontinued because of severe headache. of the 38 patients who achieved the end point, 35 (92%) were negative for inducible wall motion abnormalities and four (10%) were positive. There were no serious adverse effects. CONCLUSION: DSCMR is a well tolerated and viable investigation for the cardiovascular risk stratification of high-risk CKD patients prior to renal transplantation. DSCMR already has an established evidence base in the non-CKD population with superiority over other noninvasive techniques. Larger studies with outcome data are now required to define its true utility in the CKD population.
Abstract.
Author URL.
Ripley DP, Gosling OE, Bhatia L, Peebles CR, Shore AC, Curzen N, Bellenger NG (2014). The relationship between the contralateral collateral supply and myocardial viability on cardiovascular magnetic resonance: can the angiogram predict functional recovery?.
International Journal of Cardiology,
177(2), 362-367.
Abstract:
The relationship between the contralateral collateral supply and myocardial viability on cardiovascular magnetic resonance: can the angiogram predict functional recovery?
Background: a collateral circulation which supplies a myocardial territory, subtended by a chronic total occlusion (CTO), may be observed at invasive coronary angiography. The prognostic and protective role of such collateralisation is well demonstrated suggesting that a good collateral circulation may be a predictor of myocardial viability, but current evidence is discrepant. The aim of this study is to assess the relationship between collateralisation from the contralateral epicardial vessels and myocardial viability by cardiovascular magnetic resonance (CMR).
Abstract.
Ripley DP, Gosling OE, Bhatia L, Peebles CR, Shore AC, Curzen N, Bellenger NG (2014). The relationship between the contralateral collateral supply and myocardial viability on cardiovascular magnetic resonance: can the angiogram predict functional recovery?. International Journal of Cardiology
Strain WD, Hughes AD, Mayet J, Wright AR, Kooner J, Chaturvedi N, Shore AC (2013). Attenuated systemic microvascular function in men with coronary artery disease is associated with angina but not explained by atherosclerosis.
Microcirculation,
20(7), 670-677.
Abstract:
Attenuated systemic microvascular function in men with coronary artery disease is associated with angina but not explained by atherosclerosis.
INTRODUCTION: Refractory angina is the occurrence of clinical symptoms despite maximal therapy. We investigated associations between microvascular function, atherosclerotic burden, and clinical symptoms in subjects with CAD. METHODS: Skin microvascular response to heating and ischemia was assessed in 167 male volunteers by laser Doppler fluximetry; 82 with CAD on maximal therapy and 85 with no known CAD (noCAD). CAC scores, carotid IMT, and femoral IMT were measured and symptoms were scored using the Rose angina questionnaire. RESULTS: Patients with CAD had poorer microvascular response to heating (114[95% CI 106-122]au CAD vs. 143[134-153]au no CAD; p < 0.0001) and ischemia (42[38-46]au CAD vs. 53[78-58]au. noCAD; p = 0.001). Thirty-eight percent of the noCAD group had elevated CAC scores. There were no associations between markers of atherosclerosis and microvascular function. Forty-two percent of the CAD group had refractory angina. This was associated with impaired microvascular function compared to those with elevated CAC scores but no symptoms (109 [95-124]au vs. 131[122-140]au; p = 0.008). CONCLUSIONS: Men with symptomatic CAD have poorer microvascular function compared to individuals without CAD. Microvascular function does not correlate with atherosclerosis, but is impaired in individuals with refractory angina. Microvascular dysfunction may play a role in the symptomatology of angina.
Abstract.
Author URL.
Gosling O, Morgan-Hughes G, Iyengar S, Strain W, Loader R, Shore A, Roobottom C (2013). Computed tomography to diagnose coronary artery disease: a reduction in radiation dose increases applicability.
Clinical Radiology,
68(4), 340-345.
Abstract:
Computed tomography to diagnose coronary artery disease: a reduction in radiation dose increases applicability
Aim: to assess the effects of dose-saving algorithms on the radiation dose in an established computed tomography coronary angiography (CTCA) clinical service. Materials and methods: a 3 year retrospective analysis of all patients attending for a clinically indicated CTCA was performed. The effective dose was calculated using a cardiac-specific conversion factor [0.028 mSv(mGy·cm)-1]. Patients were stratified by the advent of new scanning technology and dose-saving protocols. Results: Between September 2007 and August 2010, 1736 examinations were performed. In the first 6 months, 150 examinations were performed with a mean effective dose of 29.6 mSv (99% CI 26.6-33 mSv). In March 2008 prospective electrocardiogram (ECG) gating was installed; reducing the effective dose to 13.6 mSv (99% CI 12.5-14.9 mSv). In March 2009, the scanner parameters were set to a minimal exposure time and 100 kV in patients with a body mass index (BMI) of
Abstract.
Gosling O, Morgan-Hughes G, Iyengar S, Strain W, Loader R, Shore A, Roobottom C (2013). Computed tomography to diagnose coronary artery disease: a reduction in radiation dose increases applicability.
Clin Radiol,
68(4), 340-345.
Abstract:
Computed tomography to diagnose coronary artery disease: a reduction in radiation dose increases applicability.
AIM: to assess the effects of dose-saving algorithms on the radiation dose in an established computed tomography coronary angiography (CTCA) clinical service. MATERIALS AND METHODS: a 3 year retrospective analysis of all patients attending for a clinically indicated CTCA was performed. The effective dose was calculated using a cardiac-specific conversion factor [0.028 mSv(mGy·cm)(-1)]. Patients were stratified by the advent of new scanning technology and dose-saving protocols. RESULTS: Between September 2007 and August 2010, 1736 examinations were performed. In the first 6 months, 150 examinations were performed with a mean effective dose of 29.6 mSv (99% CI 26.6-33 mSv). In March 2008 prospective electrocardiogram (ECG) gating was installed; reducing the effective dose to 13.6 mSv (99% CI 12.5-14.9 mSv). In March 2009, the scanner parameters were set to a minimal exposure time and 100 kV in patients with a body mass index (BMI) of
Abstract.
Author URL.
Blake E, Allen J, Thorn C, Shore A, Curnow A (2013). Effect of an oxygen pressure injection (OPI) device on the oxygen saturation of patients during dermatological methyl aminolevulinate photodynamic therapy.
Lasers in Medical Science,
28(3), 997-1005.
Abstract:
Effect of an oxygen pressure injection (OPI) device on the oxygen saturation of patients during dermatological methyl aminolevulinate photodynamic therapy
Methyl aminolevulinate photodynamic therapy (MAL-PDT) (a topical treatment used for a number of precancerous skin conditions) utilizes the combined interaction of a photosensitizer (protoporphyrin IX (PpIX)), light of the appropriate wavelength, and molecular oxygen to produce singlet oxygen and other reactive oxygen species which induce cell death. During treatment, localized oxygen depletion occurs and is thought to contribute to decreased efficacy. The aim of this study was to investigate whether an oxygen pressure injection (OPI) device had an effect on localized oxygen saturation levels and/or PpIX fluorescence of skin lesions during MAL-PDT. This study employed an OPI device to apply oxygen under pressure to the skin lesions of patients undergoing standard MAL-PDT. Optical reflectance spectrometry and fluorescence imaging were used to noninvasively monitor the localized oxygen saturation and PpIX fluorescence of the treatment area, respectively. No significant changes in oxygen saturation were observed when these data were combined for the group with OPI and compared to the group that received standard MAL-PDT without OPI. Additionally, no significant difference in PpIX photobleaching or clinical outcome at 3 months between the groups of patients was observed, although the group that received standard MAL-PDT demonstrated a significant increase (p < 0.05) in PpIX fluorescence initially and both groups produced a significant decrease (p < 0.05) after light irradiation. In conclusion, with this sample size, this OPI device was not found to be an effective method with which to improve tissue oxygenation during MAL-PDT. Further investigation is therefore required to find a more effective method of MAL-PDT enhancement. © 2012 Springer-Verlag London Ltd.
Abstract.
Blake E, Allen J, Thorn C, Shore A, Curnow A (2013). Effect of an oxygen pressure injection (OPI) device on the oxygen saturation of patients during dermatological methyl aminolevulinate photodynamic therapy.
Lasers Med Sci,
28(3), 997-1005.
Abstract:
Effect of an oxygen pressure injection (OPI) device on the oxygen saturation of patients during dermatological methyl aminolevulinate photodynamic therapy.
Methyl aminolevulinate photodynamic therapy (MAL-PDT) (a topical treatment used for a number of precancerous skin conditions) utilizes the combined interaction of a photosensitizer (protoporphyrin IX (PpIX)), light of the appropriate wavelength, and molecular oxygen to produce singlet oxygen and other reactive oxygen species which induce cell death. During treatment, localized oxygen depletion occurs and is thought to contribute to decreased efficacy. The aim of this study was to investigate whether an oxygen pressure injection (OPI) device had an effect on localized oxygen saturation levels and/or PpIX fluorescence of skin lesions during MAL-PDT. This study employed an OPI device to apply oxygen under pressure to the skin lesions of patients undergoing standard MAL-PDT. Optical reflectance spectrometry and fluorescence imaging were used to noninvasively monitor the localized oxygen saturation and PpIX fluorescence of the treatment area, respectively. No significant changes in oxygen saturation were observed when these data were combined for the group with OPI and compared to the group that received standard MAL-PDT without OPI. Additionally, no significant difference in PpIX photobleaching or clinical outcome at 3 months between the groups of patients was observed, although the group that received standard MAL-PDT demonstrated a significant increase (p
Abstract.
Author URL.
Gilchrist M, Winyard PG, Aizawa K, Anning C, Shore A, Benjamin N (2013). Effect of dietary nitrate on blood pressure, endothelial function, and insulin sensitivity in type 2 diabetes.
Free Radic Biol Med,
60, 89-97.
Abstract:
Effect of dietary nitrate on blood pressure, endothelial function, and insulin sensitivity in type 2 diabetes.
Diets rich in green, leafy vegetables have been shown to lower blood pressure (BP) and reduce the risk of cardiovascular disease. Green, leafy vegetables and beetroot are particularly rich in inorganic nitrate. Dietary nitrate supplementation, via sequential reduction to nitrite and NO, has previously been shown to lower BP and improve endothelial function in healthy humans. We sought to determine if supplementing dietary nitrate with beetroot juice, a rich source of nitrate, will lower BP and improve endothelial function and insulin sensitivity in individuals with type 2 diabetes (T2DM). Twenty-seven patients, age 67.2±4.9 years (18 male), were recruited for a double-blind, randomized, placebo-controlled crossover trial. Participants were randomized to begin, in either order, a 2-week period of supplementation with 250ml beetroot juice daily (active) or 250ml nitrate-depleted beetroot juice (placebo). At the conclusion of each intervention period 24-h ambulatory blood pressure monitoring, tests of macro- and microvascular endothelial function, and a hyperinsulinemic isoglycemic clamp were performed. After 2 weeks administration of beetroot juice mean ambulatory systolic BP was unchanged: 134.6±8.4mmHg versus 135.1±7.8mmHg (mean±SD), placebo vs active-mean difference of -0.5mmHg (placebo-active), p=0.737 (95% CI -3.9 to 2.8). There were no changes in macrovascular or microvascular endothelial function or insulin sensitivity. Supplementation of the diet with 7.5mmol of nitrate per day for 2 weeks caused an increase in plasma nitrite and nitrate concentration, but did not lower BP, improve endothelial function, or improve insulin sensitivity in individuals with T2DM.
Abstract.
Author URL.
Alkhouli N, Mansfield J, Green E, Bell J, Knight B, Liversedge N, Tham JC, Welbourn R, Shore AC, Kos K, et al (2013). The mechanical properties of human adipose tissues and their relationships to the structure and composition of the extracellular matrix.
Am J Physiol Endocrinol Metab,
305(12), E1427-E1435.
Abstract:
The mechanical properties of human adipose tissues and their relationships to the structure and composition of the extracellular matrix.
Adipose tissue (AT) expansion in obesity is characterized by cellular growth and continuous extracellular matrix (ECM) remodeling with increased fibrillar collagen deposition. It is hypothesized that the matrix can inhibit cellular expansion and lipid storage. Therefore, it is important to fully characterize the ECM's biomechanical properties and its interactions with cells. In this study, we characterize and compare the mechanical properties of human subcutaneous and omental tissues, which have different physiological functions. AT was obtained from 44 subjects undergoing surgery. Force/extension and stress/relaxation data were obtained. The effects of osmotic challenge were measured to investigate the cellular contribution to tissue mechanics. Tissue structure and its response to tensile strain were determined using nonlinear microscopy. AT showed nonlinear stress/strain characteristics of up to a 30% strain. Comparing paired subcutaneous and omental samples (n = 19), the moduli were lower in subcutaneous: initial 1.6 ± 0.8 (means ± SD) and 2.9 ± 1.5 kPa (P = 0.001), final 11.7 ± 6.4 and 32 ± 15.6 kPa (P < 0.001), respectively. The energy dissipation density was lower in subcutaneous AT (n = 13): 0.1 ± 0.1 and 0.3 ± 0.2 kPa, respectively (P = 0.006). Stress/relaxation followed a two-exponential time course. When the incubation medium was exchanged for deionized water in specimens held at 30% strain, force decreased by 31%, and the final modulus increased significantly. Nonlinear microscopy revealed collagen and elastin networks in close proximity to adipocytes and a larger-scale network of larger fiber bundles. There was considerable microscale heterogeneity in the response to strain in both cells and matrix fibers. These results suggest that subcutaneous AT has greater capacity for expansion and recovery from mechanical deformation than omental AT.
Abstract.
Author URL.
Gooding KM, Shore AC, von Lany H, Ling R, Mitra M, Ball CI, Mawson D, Tooke JE (2012). Are features of the metabolic syndrome associated with macular thickness in individuals without diabetes mellitus?. Clinical and Experimental Ophthalmology, 3, 7-7.
Campbell J, Clark CE, Taylor RS, Shore AC, Ukoumunne OC (2012). Association of a difference in systolic blood pressure between arms with vascular disease and mortality: a systematic review and meta analysis. Lancet
Clark CE, Taylor RS, Shore AC, Ukoumunne OC, Campbell JL (2012). Association of a difference in systolic blood pressure between arms with vascular disease and mortality: a systematic review and meta-analysis (vol 379, pg 905, 2012).
LANCET,
380(9838), 218-218.
Author URL.
Vink H, Hubble S, Wijnands KA, Thorn C, Mawson D, Roos S, Poeze M, Shore A (2012). CLINICAL ASSESSMENT OF THE ENDOTHELIAL GLYCOCALYX TO MONITOR VASCULAR DYSFUNCTION IN SEPTIC SHOCK PATIENTS.
INTENSIVE CARE MEDICINE,
38, S227-S227.
Author URL.
Clark CE, Taylor RS, Shore AC, Ukoumunne OC, Campbell JL (2012). Erratum: Association of a diff erence in systolic blood pressure between arms with vascular disease and mortality: a systematic review and meta-analysis (The Lancet (2012) 379 (905-914). The Lancet, 380(9838).
Mahadavan L, Loktionov A, Daniels IR, Shore A, Cotter D, Llewelyn AH, Hamilton W (2012). Exfoliated colonocyte DNA levels and clinical features in the diagnosis of colorectal cancer: a cohort study in patients referred for investigation.
Colorectal Dis,
14(3), 306-313.
Abstract:
Exfoliated colonocyte DNA levels and clinical features in the diagnosis of colorectal cancer: a cohort study in patients referred for investigation.
AIM: Selection of patients for investigation of suspected colorectal cancer is difficult. One possible improvement may be to measure DNA isolated from exfoliated cells collected from the rectum. METHOD: This was a cohort study in a surgical clinic. Participants were aged ≥40 years and referred for investigation of suspected colorectal cancer. Exclusion criteria were inflammatory bowel disease, previous gastrointestinal malignancy, or recent investigation. A sample of the mucocellular layer of the rectum was taken with an adapted proctoscope (the Colonix system). Haemoglobin, mean cell volume, ferritin, carcino-embryonic antigen and faecal occult bloods were tested. Analysis was by logistic regression. RESULTS: Participation was offered to 828 patients, of whom 717 completed the investigations. Three were lost to follow up. Seventy-two (10%) had colorectal cancer. Exfoliated cell DNA was higher (P
Abstract.
Author URL.
Park C, Bathula R, Shore AC, Tillin T, Strain WD, Chaturvedi N, Hughes AD (2012). Impaired post-ischaemic microvascular hyperaemia in Indian Asians is unexplained by diabetes or other cardiovascular risk factors.
Atherosclerosis,
221(2), 503-507.
Abstract:
Impaired post-ischaemic microvascular hyperaemia in Indian Asians is unexplained by diabetes or other cardiovascular risk factors.
OBJECTIVE: People of Indian Asian descent have an increased risk of cardiovascular disease (CVD) that cannot be explained by diabetes and other established CVD risk factors. We investigated if microcirculatory function was impaired in a population-based sample of people of Indian Asian descent compared with Europeans in the UK and whether any differences could be accounted for by diabetes or other CVD risk factors. RESEARCH DESIGN AND METHODS: Cutaneous microvascular function was assessed using laser Doppler fluximetry in response to heating to 42 °C (maximum hyperaemia) and 3 min arterial occlusion (post occlusive reactive hyperaemia: PORH) in 148 Indian Asians and 147 Europeans. Blood pressure, anthropometry and fasting bloods were also measured. RESULTS: Maximum hyperaemia and minimum resistance did not differ significantly by ethnicity. Resting flux and PORH were lower in Indian Asians and time to peak of PORH was prolonged. Diabetes was associated with reduced maximum hyperaemia and PORH. Adjustment for diabetes accounted for differences in resting flux and time to peak but not differences in PORH (Europeans = 45.0 (40.3, 50.1)au, Indian Asians = 35.6 (31.9, 39.7)au, mean (95% confidence interval); p = 0.008 after adjustment). Differences in conventional CVD risk factors did not account for interethnic differences in microvascular responses. CONCLUSIONS: People of Indian Asian descent have impaired post-occlusive reactive hyperaemia unexplained by diabetes, dysglycaemia or other CVD risk factors. Abnormal microvascular function in response to ischaemia could represent a novel mechanism contributing to the elevated risk of CVD in Indian Asians.
Abstract.
Author URL.
Clark CE, Taylor RS, Shore AC, Ukoumunne OC, Campbell JL (2012). Interarm blood pressure difference and vascular disease Reply.
LANCET,
380(9836), 24-25.
Author URL.
Strain WD, Adingupu DD, Shore AC (2012). Microcirculation on a large scale: techniques, tactics and relevance of studying the microcirculation in larger population samples.
Microcirculation,
19(1), 37-46.
Abstract:
Microcirculation on a large scale: techniques, tactics and relevance of studying the microcirculation in larger population samples.
The role of microcirculatory dysfunction is increasingly being recognized in the etiopathogenesis of cardiovascular disease. Whilst the importance of detailed mechanistic studies to determine the exact nature of these disturbances is without question, it was large-scale population-based studies that first identified the associations between deranged microvascular perfusion, autoregulation or structure, and subsequent target organ damage. This is the subject of considerable studies to establish whether there is a causal effect in either direction, or simply represents shared risk factors, although it is most likely to be a complex combination of bidirectional interactions. The techniques for investigating microcirculatory function have evolved almost exponentially over the last 75 years: So too have the strategies for investigation. Current epidemiological studies are focusing on attempting to untangle the inter-relationship between risk factors and pathological mechanisms to attempt to determine whether these represent therapeutic targets or simple markers of unmeasured risk. We plan to review the techniques used for these population-based studies, the advances made, and the clinical implications derived.
Abstract.
Author URL.
Lazdam M, de la Horra A, Diesch J, Francis J, Kenworthy Y, Shore A, Neubauer S, Kharbanda R, Alp N, Redman C, et al (2012). PP032. Unique features of long-term cardiovascular phenotype in young women with early-onset pre-eclampsia.
Pregnancy Hypertens,
2(3), 259-260.
Abstract:
PP032. Unique features of long-term cardiovascular phenotype in young women with early-onset pre-eclampsia.
INTRODUCTION: Early-onset preeclampsia is associated with a greater risk of cardiovascular disease than late-onset preeclampsia. OBJECTIVES: We tested the hypothesis that young women, with previous early-onset preeclampsia, have unique differences in long term cardiovascular phenotype compared to late-onset preeclampsia or normal pregnancy. METHODS: 140 women (mean age 40 yrs) were followed up 6-13years following pregnancy. 90 had had preeclampsia (45 early onset (before 34 weeks of gestation), 45 late onset) and 50 had normotensive uncomplicated pregnancies. Women with cardiovascular risk factors present before pregnancy were excluded. Fasting lipids, glucose, insulin and circulating cytokines were measured. Central blood pressure (BP) and arterial stiffness (pulse wave velocity (PWV)/augmentation index (AI)) were assessed by applanation tonometry, common carotid intima media thickness (cIMT) by ultrasound and cutaneous capillary density by intravital microscopy. 46 women returned for assessment of cardiac structure and function by magnetic resonance and echocardiography as well as ambulatory blood pressure monitoring. RESULTS: all women with a previous history of preeclampsia had 5-10mmHg higher peripheral and central BP (P
Abstract.
Author URL.
Veeramootoo D, Shore AC, Wajed SA (2012). Randomized controlled trial of laparoscopic gastric ischemic conditioning prior to minimally invasive esophagectomy, the LOGIC trial.
Surg Endosc,
26(7), 1822-1829.
Abstract:
Randomized controlled trial of laparoscopic gastric ischemic conditioning prior to minimally invasive esophagectomy, the LOGIC trial.
INTRODUCTION: Minimally invasive esophagectomy (MIE) is a viable alternative to open resection for the management of esophagogastric cancer. However, the technique may relate to a higher incidence of ischemia-related gastric conduit complications. Laparoscopic ischemic conditioning (LIC) by ligating the left gastric vessels 2 weeks before MIE may have a protective role, possibly through an improvement of conduit perfusion. This project was designed to evaluate whether LIC influenced ultimate conduit perfusion. METHODS: a randomized controlled trial was designed to compare MIE with LIC (L) against MIE without (N). The project began in May 2009 and was offered to consecutive patients with the objective of recruiting 22 in each arm. Sample size calculations were based on data from previous clinical series. The main outcome measure was perfusion recorded by validated laser Doppler fluximetry, at the fundus (F) and greater curve (G); performed at routine staging laparoscopy and every stage of an MIE. A perfusion coefficient measured as ratio at stage of MIE over baseline was used for statistical analysis. RESULTS: Sixteen patients were recruited before an interim analysis of the trial data. At staging laparoscopy perfusion at F was higher than at G (p = 0.016). In the L cohort, an apparent rise in perfusion at G is observed post intervention (p = 0.176). At MIE, baseline perfusion is comparable for both arms; however, a significant drop is observed at both locations once the stomach is mobilized and exteriorized (p = 0.001). Once delivered at the neck, perfusion coefficient is approximately 38% of baseline levels. However, there was no discernible difference between the L (38.3 ± 12) and N (37.7 ± 16.8) cohorts (p = 0.798). CONCLUSIONS: LIC does not translate into an improved perfusion of the gastric conduit tip. The benefits reported from published clinical series suggest that the resistance of the conduit to ischemia occurs through alternative possibly microcellular mechanisms.
Abstract.
Author URL.
Chaturvedi N, Bathula R, Shore AC, Panerai R, Potter J, Kooner J, Chambers J, Hughes AD (2012). South Asians Have Elevated Postexercise Blood Pressure and Myocardial Oxygen Consumption Compared to Europeans Despite Equivalent Resting Pressure.
JOURNAL OF THE AMERICAN HEART ASSOCIATION,
1(5).
Author URL.
Clark CE, Taylor RS, Shore AC, Campbell JL (2012). The difference in blood pressure readings between arms and survival: primary care cohort study.
BMJ,
344Abstract:
The difference in blood pressure readings between arms and survival: primary care cohort study.
To determine whether a difference in systolic blood pressure readings between arms can predict a reduced event free survival after 10 years.
Abstract.
Author URL.
Lazdam M, De La Horra A, Diesch J, Kenworthy Y, Davis E, Lewandowski AJ, Szmigielski C, Shore A, MacKillop L, Kharbanda R, et al (2012). Unique blood pressure characteristics in mother and offspring after early onset preeclampsia.
Hypertension,
60(5), 1338-1345.
Abstract:
Unique blood pressure characteristics in mother and offspring after early onset preeclampsia
Risk of hypertension in mother and offspring after preeclampsia is greater if preeclampsia develops early in pregnancy. We investigated whether those who develop early onset disease have unique adverse blood pressure characteristics. One hundred forty women were studied 6 to 13 years either after a pregnancy complicated by preeclampsia (45 women with early onset preeclampsia before 34 weeks gestation and 45 women with late-onset preeclampsia) or after a normotensive pregnancy (50 women). Forty-seven offspring from these pregnancies also participated. Data on maternal antenatal and postnatal blood pressures were extracted from maternity records and related to peripheral, central, and ambulatory blood pressure measurements in later life. Compared with late-onset preeclampsia, early onset preeclampsia was associated with higher diastolic blood pressure 6 weeks postnatally (86.25±13.46 versus 75.00±5.00 mm Hg, P
Abstract.
Wajed SA, Veeramootoo D, Shore AC (2012). Video. Surgical optimisation of the gastric conduit for minimally invasive oesophagectomy.
Surg Endosc,
26(1), 271-276.
Abstract:
Video. Surgical optimisation of the gastric conduit for minimally invasive oesophagectomy.
BACKGROUND: Total minimally invasive oesophagectomy (MIO) is a valid alternative to open surgery for the management of oesophagogastric cancer and may lead to a more rapid restoration of health-related quality of life post surgery. However, a high incidence of gastric conduit failure (GCF) has also been observed which could be detrimental to any potential benefits of this approach. Technical modifications have been introduced in an attempt to reduce conduit morbidity, and the aim of this study was to evaluate their efficacy. METHODS: Minimally invasive oesophagectomy has been the procedure of choice in our unit since April 2004. Data on patient and surgical variables are entered onto a prospective database. Laparoscopic ischaemic conditioning (LIC) by ligation of the left gastric vessels 2 weeks prior to MIO was introduced in April 2006. Extracorporeal formation of the gastric conduit through a minilaparotomy was offered to patients since January 2008. Where present, GCF was characterised as one of three types: I, simple anastomotic leak; II, conduit tip necrosis; and III, whole conduit necrosis. RESULTS: As of January 2010, 131 patients had undergone an MIO and GCF was observed in 21 patients (16.0%). Sixty-seven patients had LIC and 9 of them (13.4%) developed GCF (I, 10.4%; II, 0%; III, 3.0%) compared to 12 (18.8%) of 64 patients who did not have LIC (I, 6.3%; II, 7.8%; III, 4.7%). A total of 43 patients had an extracorporeally fashioned conduit and 6 (14.0%) developed GCF (I, 11.6%; II, 0%; III, 2.3%), whilst 88 had an intracorporeal conduit with 15 (17.0%) developing GCF (I, 6.8%; II, 5.7%; III, 4.5%). GCF can be reduced with the incorporation of LIC and an extracorporeally fashioned conduit, with possible elimination of type II conduit tip necrosis. CONCLUSIONS: Surgical modification of a three-stage minimally invasive oesophagectomy technique, with the further incorporation of laparoscopic ischaemic conditioning and extracorporeal conduit formation, reduces gastric conduit morbidity, allowing the potential benefits of this approach to be realised.
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Author URL.
Thorn CE, Kyte H, Slaff DW, Shore AC (2011). An association between vasomotion and oxygen extraction.
Am J Physiol Heart Circ Physiol,
301(2), H442-H449.
Abstract:
An association between vasomotion and oxygen extraction.
Vasomotion is defined as a spontaneous local oscillation in vascular tone whose function is unclear but may have a beneficial effect on tissue oxygenation. Optical reflectance spectroscopy and laser Doppler fluximetry provide unique insights into the possible mechanisms of vasomotion in the cutaneous microcirculation through the simultaneous measurement of changes in concentration of oxyhemoglobin ([HbO(2)]), deoxyhemoglobin ([Hb]), and mean blood saturation (S(mb)O(2)) along with blood volume and flux. The effect of vasomotion at frequencies 29.3°C (X(2) = 6.19, P < 0.02). A consistent minimum threshold in S(mb)O(2) (mean: 39.4%, range: 24.0-50.6%) was seen to precede a sudden transient surge in flux, inducing a fast rise in S(mb)O(2). The integral increase in flux correlated with the integral increase in [HbO(2)] (Pearson's correlation r(2) = 0.50, P < 0.001) and with little change in blood volume suggests vasodilation upstream, responding to a low S(mb)O(2) downstream. This transient surge in flux was followed by a sustained period where blood volume and flux remained relatively constant and a steady decrease in [HbO(2)] and equal and opposite increase in [Hb] was considered to provide a measure of oxygen extraction. A measure of this oxygen extraction has been approximated by the mean half-life of the decay in S(mb)O(2) during this period. A comparison of the mean half-life in the 8 normal subjects [body mass index (BMI) 29.5 kg/m(2)) of 18.8 s was statistically significant (Mann Whitney, P < 0.004). The S(mb)O(2) fluctuated spontaneously in this saw tooth manner by an average of 9.0% (range 4.0-16.2%) from mean S(mb)O(2) values ranging from 30 to 52%. These observations support the hypothesis that red blood cells may act as sensors of local tissue hypoxia, through the oxygenation status of the hemoglobin, and initiate improved local perfusion to the tissue through hypoxic vasodilation.
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Aizawa K, Gates PE, Strain WD, Gosling OE, Mazzaro L, Zhang F, Barker AJ, Fulford J, Shore AC, Bellenger NG, et al (2011). Arterial Wall Shear Stress Measurement in Vivo Using Echo Particle Image Velocimetry (Echo PIV).
MEDICINE AND SCIENCE IN SPORTS AND EXERCISE,
43(5), 743-744.
Author URL.
Zhang F, Lanning C, Mazzaro L, Barker AJ, Gates PE, Strain WD, Fulford J, Gosling OE, Shore AC, Bellenger NG, et al (2011). In vitro and preliminary in vivo validation of echo particle image velocimetry in carotid vascular imaging.
Ultrasound Med Biol,
37(3), 450-464.
Abstract:
In vitro and preliminary in vivo validation of echo particle image velocimetry in carotid vascular imaging.
Noninvasive, easy-to-use and accurate measurements of wall shear stress (WSS) in human blood vessels have always been challenging in clinical applications. Echo particle image velocimetry (Echo PIV) has shown promise for clinical measurements of local hemodynamics and wall shear rate. Thus far, however, the method has only been validated under simple flow conditions. In this study, we validated Echo PIV under in vitro and in vivo conditions. For in vitro validation, we used an anatomically correct, compliant carotid bifurcation flow phantom with pulsatile flow conditions, using optical particle image velocimetry (optical PIV) as the reference standard. For in vivo validation, we compared Echo PIV-derived 2-D velocity fields obtained at the carotid bifurcation in five normal subjects against phase-contrast magnetic resonance imaging (PC-MRI)-derived velocity measurements obtained at the same locations. For both studies, time-dependent, 2-D, two-component velocity vectors; peak/centerline velocity, flow rate and wall shear rate (WSR) waveforms at the common carotid artery (CCA), carotid bifurcation and distal internal carotid artery (ICA) were examined. Linear regression, correlation analysis and Bland-Altman analysis were used to quantify the agreement of different waveforms measured by the two techniques. In vitro results showed that Echo PIV produced good images of time-dependent velocity vector maps over the cardiac cycle with excellent temporal (up to 0.7 ms) and spatial (∼0.5 mm) resolutions and quality, comparable with optical PIV results. Further, good agreement was found between Echo PIV and optical PIV results for velocity and WSR measurements. In vivo results also showed good agreement between Echo PIV velocities and phase contrast MRI velocities. We conclude that Echo PIV provides accurate velocity vector and WSR measurements in the carotid bifurcation and has significant potential as a clinical tool for cardiovascular hemodynamics evaluation.
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Author URL.
Gilchrist M, Shore AC, Benjamin N (2011). Inorganic nitrate and nitrite and control of blood pressure.
Cardiovasc Res,
89(3), 492-498.
Abstract:
Inorganic nitrate and nitrite and control of blood pressure.
Continual nitric oxide (NO) synthesis is important in the regulation of vascular tone and thus blood pressure. Whereas classically NO is provided by the enzymatic oxidation of l-arginine via endothelial NO synthase, it is now clear that NO can also be generated in mammals from the reduction of nitrite and nitrate. Thus inorganic nitrate derived either from NO oxidation or from dietary sources may be an important storage form of reactive nitrogen oxides which can be reduced back to nitrite and NO when physiologically required or in pathological conditions. The very short half-life of NO and the ready availability of stored nitrite and nitrate make for a very sensitive and responsive blood pressure control system. This review will examine processes by which these storage forms are produced and how augmentation of dietary nitrate intake may have a beneficial effect on blood pressure and other vascular function in humans.
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Wilkerson DP, Poole DC, Jones AM, Fulford J, Mawson DM, Ball CI, Shore AC (2011). Older type 2 diabetic males do not exhibit abnormal pulmonary oxygen uptake and muscle oxygen utilization dynamics during submaximal cycling exercise.
Am J Physiol Regul Integr Comp Physiol,
300(3), R685-R692.
Abstract:
Older type 2 diabetic males do not exhibit abnormal pulmonary oxygen uptake and muscle oxygen utilization dynamics during submaximal cycling exercise.
There are reports of abnormal pulmonary oxygen uptake (Vo(2)) and deoxygenated hemoglobin ([HHb]) kinetics in individuals with Type 2 diabetes (T2D) below 50 yr of age with disease durations of
Abstract.
Bathula R, Hughes AD, Panerai RB, Potter JF, McG Thom SA, Tillin T, Shore AC, Hale R, Chambers J, Kooner J, et al (2011). South Asians have adverse cerebrovascular haemodynamics, despite equivalent blood pressure, compared with Europeans. This is due to their greater hyperglycaemia.
Int J Epidemiol,
40(6), 1490-1498.
Abstract:
South Asians have adverse cerebrovascular haemodynamics, despite equivalent blood pressure, compared with Europeans. This is due to their greater hyperglycaemia.
BACKGROUND: South Asians have a 1.5-fold increased stroke mortality compared with Europeans, despite similar blood pressures (BP). We hypothesized that it is the greater hyperglycaemia in South Asians that increases stroke risk, by adversely affecting cerebrovascular haemodynamics. METHODS: a population-based sample of 149 Europeans and 151 South Asians underwent metabolic profiling and concurrent measurement of finger BP using a Finapres and middle cerebral artery (MCA) blood flow velocity using transcranial Doppler ultrasound. Cerebrovascular autoregulation, cerebrovascular resistance [resistive index (RI) and pulsatility index (PI)] were calculated. Means of cerebrovascular haemodynamic measures were compared by ethnicity, with the introduction of explanatory variables to a regression model to determine which variable could best account for ethnic differences. RESULTS: Cerebrovascular resistance (RI) was 12.9 × 10(3) (0.9-24.8, P = 0.04) greater in South Asians than Europeans. Systolic, diastolic and mean MCA velocities were also higher in South Asians (mean velocity 41.4 ± 8.0 cm/s vs 38.0 ± 8.0 cm/s, respectively, P = 0.001). Low frequency gain, a measure of autoregulation, was worse in South Asians compared with Europeans (0.50 ± 0.01 cm/s mm/Hg vs 0.45 ± 0.01 cm/s mm/Hg, P = 0.01). RI positively correlated with HbA(1c) (r = 0.184; P < 0.01). Adjustment for BP could not explain the higher RI in South Asians, but adjustment for HbA(1c) abolished the ethnic difference in RI (5.8 × 10(3) (-6.5 to 18.1, P = 0.4). CONCLUSIONS: Cerebrovascular resistance and autoregulation are worse in South Asians than in Europeans, despite equivalent resting BP. The greater hyperglycaemia in South Asians accounts for their adverse cerebrovascular resistance. This could explain excess stroke in South Asians but requires testing in longitudinal studies.
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Author URL.
Whiteman M, Gooding KM, Whatmore JL, Ball CI, Mawson D, Skinner K, Tooke JE, Shore AC (2010). Adiposity is a major determinant of plasma levels of the novel vasodilator hydrogen sulphide.
Diabetologia,
53(8), 1722-1726.
Abstract:
Adiposity is a major determinant of plasma levels of the novel vasodilator hydrogen sulphide.
AIMS/HYPOTHESIS: Hydrogen sulphide is a recently identified endogenous endothelium-dependent vasodilator. Animal models of diabetes have shown that low plasma H(2)S levels are associated with marked endothelial dysfunction and insulin resistance. However, human studies on H(2)S and vascular function in health and disease are lacking. METHODS: Plasma was obtained from male patients with type 2 diabetes (n = 11), overweight (n = 16) and lean (n = 11) volunteers. H(2)S levels were determined by zinc trap spectrophotometry. Anthropometric measurements (BMI/waist:hip ratio), lipid profile, systemic blood pressure, biochemical indices of diabetes (fasting glucose, insulin sensitivity, Hb(1Ac)) and microvascular function (minimum vascular resistance) were determined. RESULTS: Median plasma H(2)S levels (25th, 75th percentiles) in age-matched lean, overweight and type 2 diabetes individuals were 38.9 (29.7, 45.1) micromol/l, 22.0 (18.6, 26.7) micromol/l and 10.5 (4.8, 22.0) micromol/l, respectively. Median plasma H(2)S levels were significantly lower in patients with type 2 diabetes compared with lean (p = 0.001, Mann-Whitney) and overweight participants (p = 0.008). Median plasma H(2)S levels in overweight participants were significantly lower than in lean controls (p = 0.003). Waist circumference was an independent predictor of plasma H(2)S (R (2) = 0.423, standardised beta: -0.650, p < 0.001). This relationship was independent of diabetes, which only contributed a further 5% to the model (R (2) = 0.477). Waist circumference or other measures of adiposity (waist:hip ratio/BMI) remained independent predictors of plasma H(2)S after adjustment for systolic blood pressure, microvascular function, insulin sensitivity, glycaemic control and lipid profile. CONCLUSIONS/INTERPRETATION: Plasma H(2)S levels are reduced in overweight participants and patients with type 2 diabetes. Increasing adiposity is a major determinant of plasma H(2)S levels.
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Author URL.
Strain WD, Elyas S, Gates PE, Shore AC (2010). Age-related change in endothelial and microvessel function and therapeutic consequences.
Reviews in Clinical Gerontology,
20(3), 161-170.
Abstract:
Age-related change in endothelial and microvessel function and therapeutic consequences
As the absolute numbers and proportion of older adults increases across most of the developed world, a greater understanding of the aetiopathogenic mechanisms of the increased vascular risk and their therapeutic implications becomes essential to all clinicians assessing and managing the geriatric patient. The role of endothelial function and the microcirculation is increasingly recognized in the maintenance of adequate perfusion, and their dysfunction is thought to be an early and potentially reversible mechanism by which age acts to increase cardiovascular risk. Here we review evidence that altered microvascular function appears before other recognized predictors of vascular disease, and progresses from childhood to late adult life, preceding fulminant atherosclerotic or arteriosclerotic disease. Low birth-weight babies have reduced endothelial function in skin microvessels at 3 months, and by age ten brachial artery endothelial function is reduced in comparison with normal birth-weight babies. In overweight/obese adolescent children with clustering of traditional cardiovascular disease risk factors, endothelial function is lower compared with normal weight children and this appears to persist into early adulthood. Adult ageing is associated with impaired microvessel endothelial function and an increase in capillary blood pressure, independent of brachial artery blood pressure. Biological and lifestyle factors that influence microvessel function include body fat and visceral adiposity, sex hormone status, diet and physical activity. Exploration of the therapeutic implications for management of endothelial dysfunction remains in embryonic state. The use of ACE-inhibitors, angiotensin receptor blockers and direct renin inhibitors in patients with evidence of microvascular damage such as retinopathy and microalbuminuria has been established; however, in the general older population the benefit has yet to be established. Therefore current recommendations are to screen for microvascular damage and if present target treatments after control of other vascular risk factors such as hypertension. Copyright © 2010 Cambridge University Press.
Abstract.
Strain WD, Shore AC, Melzer D (2010). Albumin:creatinine ratio predicts mortality after stroke: analysis of the Third National Health and Nutrition Examination Survey.
J Am Geriatr Soc,
58(12), 2434-2435.
Author URL.
Strain WD, Chaturvedi N, Hughes A, Nihoyannopoulos P, Bulpitt CJ, Rajkumar C, Shore AC (2010). Associations between cardiac target organ damage and microvascular dysfunction: the role of blood pressure.
J Hypertens,
28(5), 952-958.
Abstract:
Associations between cardiac target organ damage and microvascular dysfunction: the role of blood pressure.
BACKGROUND: Microvascular dysfunction may be an early precursor of cardiovascular disease (CVD). Increased left ventricular mass (LVM), concentric left ventricular remodelling and increased left atrial size are the factors that could predict future CVD. We investigated whether microvascular dysfunction was associated with these cardiac measures. METHODS AND RESULTS: Laser Doppler fluximetry of skin vessels was used to study associations with risk factors and echocardiographic measurements of LVM, relative wall thickness (RWT), and left atrial size in 305 people (aged 40-65 years; 117 with type 2 diabetes). Flow in response to a 3-min arterial occlusion was measured. Postischaemic peak flow responses were categorized into three distinct groups: slow rise to peak (normal), nondominant early peak group (mildly abnormal) and a dominant early peak (abnormal). Those with a dominant early peak had higher blood pressure (P = 0.001), weight (P = 0.001), fasting glucose (P = 0.001) and prevalence of diabetes (P = 0.02). LVM (P = 0.01), RWT (P < 0.001) and left atrial size (P < 0.001) were greater with worsening postischaemic peak flow responses. Differences in LVM between postischaemic response groups were accounted for by blood pressure (BP). However, differences in BP and other CVD risk factors did not account for the greater RWT and left atrial size observed in the more adverse peak response groups [geometric mean of RWT [95% confidence interval (CI)] 0.40 (0.38-0.41) vs. 0.41 (0.40-0.42) vs. 0.43 (0.41-0.45), P = 0.007; left atrial size 36.1 (35.4-36.1) vs. 37.4 (36.8-38.0) vs. 38.7 (37.5-40.0), P = 0.002 for normal vs. mildly abnormal vs. abnormal respectively]. CONCLUSION: an abnormal microcirculatory cutaneous peak flow response following ischaemia is associated with adverse cardiac remodelling, independent of CVD risk factors including blood pressure.
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Strain WD, Hughes AD, Mayet J, Wright AR, Kooner J, Chaturvedi N, Shore AC (2010). Attenuation of microvascular function in those with cardiovascular disease is similar in patients of Indian Asian and European descent.
BMC Cardiovasc Disord,
10Abstract:
Attenuation of microvascular function in those with cardiovascular disease is similar in patients of Indian Asian and European descent.
BACKGROUND: Indian Asians are at increased risk of cardiovascular death which does not appear to be explained by conventional risk factors. As microvascular disease is also more prevalent in Indian Asians, and as it is thought to play a role in the development of macrovascular disease, we decided to determine whether impaired microcirculation could contribute to this increased cardiovascular risk in Indian Asians. METHODS: Forearm skin laser Doppler fluximetry in response to heating and ischaemia was assessed in 83 Europeans (41 with angiographically confirmed atherosclerotic coronary artery disease (CAD) and 42 from the general population) and 84 Indian Asians (41 with CAD). Explanations for differences in microvascular function were sought using multivariate analysis including conventional cardiovascular risk factors. RESULTS: Compared to ethnically matched control populations both Europeans and Indian Asians with CAD had poorer microvascular responses to heating than those without (117(95% CI 105-131) vs. 142(130-162) arbitrary units, (au) for Europeans and 111(101-122) vs. 141(131-153)au for Indian Asians) and to ischaemia (44(38-50) vs. 57(49-67)au & 39(34-45) vs. 49(43-56)au respectively). These differences were not accounted for by conventional cardiovascular risk factors. There was no ethnic difference in the attenuation of microvascular function associated with CAD. CONCLUSION: Patients of European and Indian Asian descent with symptomatic CAD have poorer microvascular maximal tissue perfusion and reactive hyperaemia in the skin compared to ethnically matched asymptomatic control populations. Despite the increased cardiovascular risk in Indian Asians, the attenuation of microvascular function associated with CAD was equivalent in the ethic groups. This suggests that in Indian Asians microcirculation does not explain the increased susceptibility to CAD.
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Author URL.
Gooding KM, Tooke JE, von Lany H, Mitra M, Ling R, Ball CI, Mawson D, Skinner K, Shore AC (2010). Capillary pressure may predict preclinical changes in the eye.
Diabetologia,
53(9), 2029-2035.
Abstract:
Capillary pressure may predict preclinical changes in the eye.
AIMS/HYPOTHESIS: Microvascular dysfunction is associated with end-organ damage. Macular oedema is an important component of diabetic retinopathy. Macular thickness can be accurately quantified by optical coherence tomography (OCT), enabling accurate assessment of the macular prior to clinically apparent abnormalities. We investigated whether macular (fovea) thickness in non-diabetic individuals is related to the microvascular variables controlling fluid filtration across a blood vessel wall, in particular capillary pressure and the microvascular filtration capacity (Kf). METHODS: We recruited 50 non-diabetic individuals (25 men, 25 women; age range: 26-78 years; BMI range: 20-46 kg/m(2)). Fovea thickness was assessed by OCT. Microvascular assessments included: finger nailfold capillary pressure; Kf; microvascular structural assessments, i.e. skin vasodilatory capacity, minimum vascular resistance (MVR) and microvascular distensibility; and endothelial function. RESULTS: at 214.6 (19.9) microm (mean [SD]), fovea thickness was within normal range. Capillary pressure, adjusted for BMI, was associated with fovea thickness (standardised beta 0.573, p = 0.006, linear regression). Fovea thickness was not associated with Kf, microvascular structural assessments or endothelial function. Capillary pressure was still associated with fovea thickness when adjusted for microvascular variables (Kf, vasodilatory capacity, MVR, microvascular distensibility or endothelial function), or for risk factors for diabetes (systemic blood pressure, insulin sensitivity, inflammation, glycaemic status and lipids) and age. CONCLUSIONS/INTERPRETATION: Capillary pressure, a key determinant of movement of fluid across a blood vessel wall, is associated with fovea thickness in non-diabetic individuals. This suggests that with regard to potential preventative or therapeutic targets, attention should be directed at the mechanisms determining retinal microvascular pressure.
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Whiteman M, Haigh R, Tarr JM, Gooding KM, Shore AC, Winyard PG (2010). Detection of hydrogen sulfide in plasma and knee-joint synovial fluid from rheumatoid arthritis patients: relation to clinical and laboratory measures of inflammation.
Ann N Y Acad Sci,
1203, 146-150.
Abstract:
Detection of hydrogen sulfide in plasma and knee-joint synovial fluid from rheumatoid arthritis patients: relation to clinical and laboratory measures of inflammation.
Blood concentrations of hydrogen sulfide (H(2)S) are markedly elevated in several animal models of inflammation. Pharmacological inhibition of H(2)S synthesis reduces inflammation and swelling, suggesting that H(2)S is a potential inflammatory mediator. However, it is currently unknown whether H(2)S synthesis is perturbed in human inflammatory conditions or whether H(2)S is present in synovial fluid. We analyzed paired plasma and synovial fluid (SF) aspirates from rheumatoid arthritis (RA; n= 20) and osteoarthritis (OA; n= 4) patients and plasma from age matched healthy volunteers (n= 20). Median plasma H(2)S concentrations from healthy volunteers and RA and OA patients were 37.6, 36.6, and 37.6 microM, respectively. In RA patients, median synovial fluid H(2)S levels (62.4 microM) were significantly higher than paired plasma (P= 0.002) and significantly higher than in synovial fluid from OA patients (25.1 microM; P= 0.009). SF H(2)S levels correlated with clinical indices of disease activity (tender joint count, r= 0.651; P < 0.05) and markers of chronic inflammation; Europhile count (r=-0.566; P < 0.01) and total white cell count (r=-0.703; P < 0.01). Our study shows for the first time that H(2)S is present in synovial fluid and levels correlated with inflammatory and clinical indices in RA patients.
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Author URL.
Bathula R, Hughes AD, Panerai R, Potter J, McG. Thom SA, Francis DP, Shore AC, Kooner J, Chaturvedi N (2010). Indian Asians have poorer cardiovascular autonomic function than Europeans: This is due to greater hyperglycaemia and may contribute to their greater risk of heart disease.
Diabetologia,
53(10), 2120-2128.
Abstract:
Indian Asians have poorer cardiovascular autonomic function than Europeans: This is due to greater hyperglycaemia and may contribute to their greater risk of heart disease
Aims/hypothesis a high prevalence of diabetes contributes to excess CHD in Indian Asians, but the underlying mechanisms are unclear. Heart rate, heart rate variability (HRV) and baroreflex sensitivity (BRS) are measures of cardiac autonomic function that are disturbed by hyperglycaemia and predict CHD. We compared these measures in Indian Asians and Europeans, and sought explanations for the observed differences. Methods a representative sample of 149 Europeans and 151 Indian Asians was recruited from primary care, 66% of them men (aged 35-75 years), 34% women (aged 55-75 years). Heart rate HRV, BRS and cardio-metabolic profiles were measured over four successive 5 min periods with continuous ECG and blood pressure monitoring. Results Indian Asians were hyperglycaemic compared with Europeans (HbA1c (mean ± SD) 6.5±1.2% vs 5.9±1.0%, p= 0.001). They had shorter mean RR intervals ((mean ± SE) 969±13 vs 1,022±12 ms, p=0.002), lower total RR interval power ((geometric mean, 95% CI) 925 [796-1075] vs 1,224 [1,064-1,422] ms2, p=0.008) and lower BRS ((mean ± SE) 5.7±1.0 vs 6.6±1.0 ms/mmHg, p=0.01). All measures of cardiac autonomic dysfunction were significantly associated with hyperglycaemia (mean RR interval vs HbA1c r=-0.22; p
Abstract.
Veeramootoo D, Shore AC, Shields B, Krishnadas R, Cooper M, Berrisford RG, Wajed SA (2010). Ischemic conditioning shows a time-dependant influence on the fate of the gastric conduit after minimally invasive esophagectomy.
Surg Endosc,
24(5), 1126-1131.
Abstract:
Ischemic conditioning shows a time-dependant influence on the fate of the gastric conduit after minimally invasive esophagectomy.
BACKGROUND: Minimally invasive esophagectomy (MIO) is now established as a valid alternative to open surgery for the management of esophagogastric cancers. However, a high incidence of ischemia-related gastric conduit failure (ICF) is observed, which is detrimental to any potential benefits of this approach. METHODS: Since April 2004, MIO has been the procedure of choice for esophagogastric resection in the authors' unit. Data relating to the surgical technique were collected, with a focus on ischemic conditioning by laparoscopic ligation of the left gastric artery (LIC) 2 weeks or 5 days before resection. RESULTS: a total of 97 patients underwent a planned MIO. Four in-patient deaths (4.1%) occurred, none of which were conduit related, and overall, 20 patients experienced ICF (20.6%). In four patients, ICF was recognized and dealt with at the initial surgery. The remaining 16 patients experienced this complication postoperatively, with 9 (9.3%) of them requiring further surgery. of the 97 patients, 55 did not undergo ischemic conditioning, and conduit failure was observed in 11 (20%). Thirty-five patients had LIC at 2 weeks, and 2 (5.7%) experienced ICF. All seven patients (100%) who had LIC at 5 days experienced ICF. Timing of ischemic conditioning (p < 0.0001) had a definite impact on the conduit failure rate, and the benefit of ischemic conditioning at 2 weeks compared with no conditioning neared significance (p = 0.07). CONCLUSIONS: Ischemic failure of the gastric conduit significantly impairs recovery after MIO. Ischemic conditioning 2 weeks before surgery may reduce this complication and allow the benefits of this approach to be realized.
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Author URL.
Gates PE, Strain WD, Shore AC (2009). Human endothelial function and microvascular ageing.
Exp Physiol,
94(3), 311-316.
Abstract:
Human endothelial function and microvascular ageing.
Age is a primary risk factor for cardiovascular disease, and this is an increasingly important public health concern because of an increase in the absolute number and proportion of the population at an older age in many countries. A key component of cardiovascular ageing is reduced function of the vascular endothelium, and this probably contributes to the impaired microvessel function observed with ageing in multiple vascular beds. In turn, impaired microvessel function is thought to contribute to the pathophysiology of cardiovascular and metabolic diseases. Here we review evidence that the first signs of altered endothelial and microvessel function can appear in childhood and at all stages of the human lifespan; low-birth-weight babies have reduced endothelial function in skin microvessels at 3 months, and by age 10 years their brachial artery endothelial function is reduced in comparison with normal-birth-weight babies. In overweight/obese adolescent children with clustering of traditional cardiovascular disease risk factors, endothelial function is reduced compared with normal-weight children, and this appears to persist into early adulthood. Adult ageing is associated with impaired microvessel endothelial function and an increase in capillary blood pressure. Biological and lifestyle factors that influence microvessel function include body fat and visceral adiposity, sex hormone status, diet and physical activity. The mechanisms underlying age-associated changes in microvessel function are uncertain but may involve alterations in nitric oxide, prostanoid, endothelium-derived hyperpolarizing factor(s) and endothelin-1 pathways.
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Author URL.
Thorn CE, Matcher SJ, Meglinski IV, Shore AC (2009). Is mean blood saturation a useful marker of tissue oxygenation?.
AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY,
296(5), H1289-H1295.
Author URL.
Hubble SMA, Kyte HL, Gooding K, Shore AC (2009). Variability in sublingual microvessel density and flow measurements in healthy volunteers.
Microcirculation,
16(2), 183-191.
Abstract:
Variability in sublingual microvessel density and flow measurements in healthy volunteers.
OBJECTIVES: As sublingual microvascular indices are increasingly heralded as new resuscitation end-points, better population data are required to power clinical studies. This paper describes improved methods to quantify sublingual microvessel flow and density in images obtained by sidestream dark field (SDF) technology in healthy volunteers, including vessels under 10 microm in diameter. MATERIALS AND METHODS: Measurements of sublingual capillary density and flow were obtained by recording three 15-second images in 20 healthy volunteers over three days. Two independent observers quantified capillary density by using two methods: total vessel length (mm/mm2) and counting (number/mm). Both intraoral and temporal variabilities within subject and observer reproducibilities were determined by using coefficients of variability and reproducibility indices. RESULTS: for small (1-10 microm), medium (11-20 microm), and large (21-50 microm) diameter, mean vessel density with standard deviations (SDs) in volunteers was 21.3(+/- 4.9), 5.2 (+/- 1.2), and 2.7 (+/- 0.9) mm/mm2, respectively. Also, 94.0 +/- 1.4% of small vessels, 94.5 +/- 1.4% of medium vessels, and 94.5+/- 4.0% of large vessels had continuous perfusion. Within subjects, the means of all measurements over three days varied less than 13, 22, and 35% in small, medium, and large vessels, respectively. Interobserver reproducibility was good, especially for capillary (1-10 microm) density and flow measurements. CONCLUSIONS: Our methods of microvessel flow and density quantification have low observer variability and confirm the stability of microcirculatory measurements over time. These results facilitate the development of SDF-acquired sublingual microvascular indices as feasible microperfusion markers in shock resuscitation.
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Author URL.
McHarg S, Shore AC, Whatmore JL (2008). Heterogeneity of phospholipase D activation by angiotensin II, lysophosphatidylcholine, and insulin in human endothelial cells.
Endothelium,
15(4), 213-218.
Abstract:
Heterogeneity of phospholipase D activation by angiotensin II, lysophosphatidylcholine, and insulin in human endothelial cells.
Human endothelial cells (ECs) are heterogeneous, although little is known regarding regional variations in their regulation of vascular tone. This study compares activation of the key enzyme phospholipase D (PLD) by the vasoconstrictors angiotensin II (AII) and lysophosphatidylcholine (lysoPC), and the vasodilator insulin, in primary human microvascular endothelial cells (HMVECs) and human umbilical vein endothelial cells (HUVECs). PLD activity was measured by [(3)H]phosphatidylethanol production in cells labeled with [(3)H]myristic acid. AII maximally activated PLD in both cell types at 1 nmol/L. AII also significantly activated PLD at 100 pmol/L in HUVECS but not in HMVECs. LysoPC dose dependently activated PLD in both cell types, although HUVECs were more sensitive to the agonist; being significantly activated by 10 micromol/L lysoPC and displaying an approximately sevenfold greater PLD activity with 20 micromol/L lysoPC compared to HMVECs. Insulin significantly increased PLD activity in both cell types with maximum activation at 1 nmol/L. Again differential sensitivity was observed; 10 nmol/L insulin significantly stimulated PLD in HUVECs but not HMVECs. Differential sensitivity of PLD activation in human endothelial cells from different vascular beds in response to vasoactive agents was observed, with the HUVECs displaying greater sensitivity to vasoconstricting agents than HMVECs.
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Lonnen KF, Powell RJ, Taylor D, Shore AC, MacLeod KM (2008). Road traffic accidents and diabetes: insulin use does not determine risk.
Diabet Med,
25(5), 578-584.
Abstract:
Road traffic accidents and diabetes: insulin use does not determine risk.
AIMS: Progressive restrictions placed on insulin-treated patients with diabetes exclude them from driving group 2 and class C1 and D1 vehicles. This reflects an assumption that an increased risk of hypoglycaemia in these patients will cause road traffic accidents. These restrictions have been implemented without any consistent evidence that this is the case. The aim of the study was therefore to investigate whether the rate of road traffic collisions in insulin-treated patients was higher than that of the non-diabetic population using a population register-based study. METHODS: a historical cohort study combined information from the Devon and Cornwall Constabulary database on road traffic collisions with the district wide retinal screening database, to provide an anonymized matched database of road traffic collisions in the diabetic population. Accident rates were calculated in the diabetic population and compared to rates in the non-diabetic population using relative risks. RESULTS: the estimated overall annual accident rate for the non-diabetic population was 1469 per 100,000 vs. 856 per 100,000 for the diabetic population as a whole (Chi-squared, P < 0.001). On stratification of the groups by age, within the insulin-treated group there was no significant difference in the accident rate compared to the non-diabetic population, with relative risks between 0.51 [confidence interval (CI) 0.25-1.05] and 1.13 (CI 0.88-1.46). CONCLUSIONS: Our findings suggest that insulin-treated patients as a group do not pose an increased risk to road safety. They reiterate the need for an individualized risk-based assessment when considering driving restrictions.
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Tillin T, Dhutia H, Chambers J, Malik I, Coady E, Mayet J, Wright AR, Kooner J, Shore A, Thom S, et al (2008). South Asian men have different patterns of coronary artery disease when compared with European men.
Int J Cardiol,
129(3), 406-413.
Abstract:
South Asian men have different patterns of coronary artery disease when compared with European men.
BACKGROUND: to compare patterns of coronary artery disease in British South Asian and White European men. METHODS: 41 South Asian and 42 European men (mean age 64+/-9 years) with coronary artery disease were studied. All had similar symptoms. Vessel reference diameter and degree of stenosis were calculated using quantitative coronary angiography. Extent of atherosclerotic disease in the LAD was assessed using calcification scores (CAC) measured by multislice Computed Tomography. Fasting bloods and blood pressure were measured. The LAD was subdivided into four 2.5 cm segments for analysis. RESULTS: Most atherosclerosis occurred in the proximal LAD segment, South Asian men had more proximal LAD stenosis than European men (50% vs. 37%, p=0.036), but CAC scores were similar. South Asians with CAC scores in the lowest tertile (0-22 HU), had significantly narrower LAD diameters than Europeans (2.8 mm vs. 3.8 mm, p=0.004, adjusted for body surface area and age). This ethnic difference was not explained by measured risk factors, including diabetes. In contrast, ethnic differences in LAD diameter were abolished in the upper tertiles of CAC scores (23-2416 HU) (South Asians: 3.0 mm, Europeans: 3.1 mm, p=0.6). Calcification scores were negatively correlated with LAD diameter in Europeans (rho=-0.38, p=0.016) but not in South Asians (rho=-0.06, p=0.72). CONCLUSIONS: Increased LAD stenosis, despite equivalent levels of calcified disease, in South Asians is attributable to narrower arteries. Reduced LAD diameter is associated with advanced disease in Europeans but not in South Asians, indicative of ethnic differences in vascular remodelling.
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Chaturvedi N, Coady E, Mayet J, Wright AR, Shore AC, Byrd S, McG Thom SA, Kooner JS, Schalkwijk CG, Hughes AD, et al (2007). Indian Asian men have less peripheral arterial disease than European men for equivalent levels of coronary disease.
Atherosclerosis,
193(1), 204-212.
Abstract:
Indian Asian men have less peripheral arterial disease than European men for equivalent levels of coronary disease.
OBJECTIVES: Indian Asians have high rates of heart disease and stroke, but risks of peripheral arterial disease appear to be low. This paradox, and reasons for it, have not been explored. We compared ethnic differences in peripheral arterial disease for a given level of coronary disease. METHODS: We studied 83 European and 84 Indian Asian men with a range of coronary disease. Extent of coronary atheroma was quantified by coronary artery calcification score on multislice CT. Femoral intima-media thickness (IMT) was measured by ultrasound. RESULTS: Femoral IMT was 1.58, 2.06, 2.12, and 2.69 mm in Europeans, and 0.61, 1.41, 1.81 and 2.29 in Indian Asians by increasing categories of coronary atheroma (p=0.003 for ethnic difference, adjusted for age and lumen diameter). Adjustment for smoking and systolic blood pressure, the only risk factors adversely distributed in Europeans, only partly accounted for this ethnic difference (p=0.05). Other risk factors, including lipids, obesity, insulin and glycaemic status, more adversely distributed in Indian Asians, could not account for ethnic differences. Prevalence of abnormal ankle brachial index and lower limb atherosclerotic plaque was also greater in Europeans. CONCLUSIONS: for a given level of coronary disease, Indian Asians have less lower limb atherosclerosis than Europeans, unexplained by established risk factors. Further study of these populations would help tease out relative contributions of risk factors to atherosclerosis in different vessel beds.
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Tillin T, Chambers J, Malik I, Coady E, Byrd S, Mayet J, Wright AR, Kooner J, Shore A, Thom S, et al (2007). Measurement of pulse wave velocity: site matters.
J Hypertens,
25(2), 383-389.
Abstract:
Measurement of pulse wave velocity: site matters.
BACKGROUND: Aortic pulse wave velocity (PWV) predicts mortality from cardiovascular disease, ischaemic heart disease and stroke. However, a comparison of associations between PWV measured at different sites and atherosclerosis in coronary, carotid and femoral arteries has not been made. METHODS: in 159 men (ages 45-82 years) with and without known coronary artery disease, PWV measurements were made between carotid-femoral, carotid-radial and femoral-posterior tibial sites, using an ultrasound technique. Coronary artery calcification (CAC) scores were measured by multislice computed tomography. Carotid and femoral intima-media thickness (IMT) and presence of plaque were determined by ultrasound. Known coronary artery disease was confirmed by angiography. Participants were grouped into four categories of CAC score: 0-10, 11-100, 101-400, > 400 Hounsfield Units (HU). Measurements of blood pressure, heart rate and fasting bloods were made in all individuals. RESULTS: Carotid-femoral PWV correlated positively with CAC score and increased with incremental coronary calcification category (median carotid-femoral PWV 16.8 m/s in those with CAC score > 400 HU and 13.8 m/s in those with CAC score < 10 HU; P = 0.003). Carotid-femoral PWV also correlated with carotid and femoral IMT (P < 0.001, P = 0.004, respectively) and with carotid and femoral plaque (P = 0.001, P = 0.038, respectively). Increased carotid-femoral PWV also correlated with increasing age (P < 0.001), systolic blood pressure (P < 0.001), mean arterial pressure and pulse pressure (P < 0.001). Carotid-radial and femoral-posterior tibial PWV were not significantly associated with CAC score, carotid or femoral IMT or carotid plaque. CONCLUSIONS: Carotid-femoral PWV is a better indicator of atherosclerosis than either carotid-radial or femoral-posterior tibial PWV, and should be used preferentially in studies of atherosclerosis and in stratifying risk in clinical settings.
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Dotsenko O, Chaturvedi N, Thom SAM, Wright AR, Mayet J, Shore A, Schalkwijk C, Hughes AD (2007). Platelet and leukocyte activation, atherosclerosis and inflammation in European and South Asian men.
J Thromb Haemost,
5(10), 2036-2042.
Abstract:
Platelet and leukocyte activation, atherosclerosis and inflammation in European and South Asian men.
BACKGROUND: Increased platelet activation occurs in ischemic heart disease (IHD), but increased platelet activation is also seen in cerebrovascular atherosclerosis and peripheral artery disease. It is not clear therefore whether platelet activation is an indicator of IHD or a marker of generalized atherosclerosis and inflammation. South Asian subjects are at high risk of IHD, but little is known regarding differences in platelet and leukocyte function between European and South Asian subjects. METHODS: Fifty-four male subjects (age 49-79 years) had coronary artery calcification measured by multislice computed tomography (CT), aortic atherosclerosis assessed by measurement of carotid-femoral pulse wave velocity (aortic PWV), and femoral and carotid atherosclerosis measured by B-mode ultrasound. Platelet and leukocyte activation was assessed by flow cytometry of platelet-monocyte complexes (PMC), platelet expression of PAC-1 binding site and CD62P, and expression of L-selectin on leukocytes. RESULTS: Elevated circulating PMC correlated significantly with elevated aortic PWV and PMC were higher in subjects with femoral plaques. In contrast PMC did not differ by increasing coronary artery calcification category or presence of carotid plaques. Higher numbers of PMC were independently related to elevated levels of C-reactive protein (CRP), higher aortic PWV, hypertension and smoking in a multivariate model. Markers of platelet and leukocyte activation did not differ significantly by ethnicity. CONCLUSIONS: Increased PMC are related to the extent of aortic and femoral atherosclerosis rather than coronary or carotid atherosclerosis. The association between elevated CRP and increased PMC suggests that inflammation in relation to generalized atherosclerosis may play an important role in PMC activation.
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Hughes AD, Coady E, Raynor S, Mayet J, Wright AR, Shore AC, Kooner JS, Thom SAM, Chaturvedi N (2007). Reduced endothelial progenitor cells in European and South Asian men with atherosclerosis.
Eur J Clin Invest,
37(1), 35-41.
Abstract:
Reduced endothelial progenitor cells in European and South Asian men with atherosclerosis.
BACKGROUND: Circulating endothelial progenitor cells (EPCs) play a role in the repair and regeneration of the endothelium and may represent a novel cardiovascular risk factor. South Asian subjects have an increased risk of cardiovascular disease which is not fully explained by known risk factors. This study examined associations of EPCs with atherosclerosis and possible ethnic differences in EPCs. MATERIALS AND METHODS: a population sample of 58 European and South Asian adult men was enriched with the recruitment of an additional 59 European and South Asian men with known coronary disease. The coronary artery calcification score was measured by multi-slice computerized tomography (CT), carotid and femoral intima-media thickness (IMT), and femoral plaques were measured by ultrasound. The subjects were further subdivided into three categories of coronary artery disease on the basis of coronary artery calcification score and clinical history. Total EPCs and non-senescent EPCs (ns-EPCs) were quantified after 5 days cell culture and the number of late outgrowth colonies was measured over a 6-week test period. Circulating CD34+ haematopoietic precursor cells were measured by flow cytometry. RESULTS: Individuals with femoral plaques had reduced total and ns-EPCs. The number of ns-EPCs were reduced in individuals with the most coronary atheroma and were inversely related to the coronary calcification score and femoral IMT. These relationships persisted after multivariate adjustment for other risk factors. The numbers of late outgrowth colonies or circulating CD34+ cells were unrelated to the presence of atherosclerosis. There were no differences in the number of EPCs between European and South Asian subjects. CONCLUSION: the number of EPCs are reduced in subjects with atherosclerosis independent of other risk factors. Reduction in EPC numbers may be an independent risk factor for atherosclerosis but does not explain ethnic differences in cardiovascular risk.
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Johnson P, Shore A, Potter J, Panerai R, James M (2006). Baroreflex sensitivity measured by spectral and sequence analysis in cerebrovascular disease : methodological considerations.
Clin Auton Res,
16(4), 270-275.
Abstract:
Baroreflex sensitivity measured by spectral and sequence analysis in cerebrovascular disease : methodological considerations.
Baroreflex sensitivity (BRS) is impaired and of prognostic value in cerebrovascular disease. However, no studies to date have been published on the reproducibility of current methods of measuring BRS in this group. The reproducibility of sequence and spectral analysis methods were therefore assessed in subjects with cerebrovascular disease. A total of 14 subjects were assessed on 2 separate occasions at least 2 weeks apart, and beat-to-beat blood pressure (BP) and ECG trace were recorded for three 5-minute periods. These traces were then analyzed by spectral analysis using Fast Fourier Transform and sequence analysis. Reproducibility was calculated as the coefficient of variation (CV) and reproducibility coefficient (RC). There were no significant differences in heart rate, BP or BRS derived by either method between visits. Reproducibility was CV 22.2%, RC 6.04 ms/mmHg with spectral analysis, and CV 26.3%, RC 7.48 ms/mmHg for sequence analysis. There was close agreement between sequence and spectral derived BRS (r = 0.90). We have demonstrated that the use of spectral and sequence analysis to measure BRS is reproducible in subjects with cerebrovascular disease. These techniques are suitable for follow-up and intervention studies of BRS in this patient group.
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DREAM (Diabetes REduction Assessment with ramipril and rosiglitazone Medication) Trial Investigators, Gerstein HC, Yusuf S, Bosch J, Pogue J, Sheridan P, Dinccag N, Hanefeld M, Hoogwerf B, Laakso M, et al (2006). Effect of rosiglitazone on the frequency of diabetes in patients with impaired glucose tolerance or impaired fasting glucose: a randomised controlled trial.
Lancet,
368(9541), 1096-1105.
Abstract:
Effect of rosiglitazone on the frequency of diabetes in patients with impaired glucose tolerance or impaired fasting glucose: a randomised controlled trial.
BACKGROUND: Rosiglitazone is a thiazolidinedione that reduces insulin resistance and might preserve insulin secretion. The aim of this study was to assess prospectively the drug's ability to prevent type 2 diabetes in individuals at high risk of developing the condition. METHODS: 5269 adults aged 30 years or more with impaired fasting glucose or impaired glucose tolerance, or both, and no previous cardiovascular disease were recruited from 191 sites in 21 countries and randomly assigned to receive rosiglitazone (8 mg daily; n=2365) or placebo (2634) and followed for a median of 3 years. The primary outcome was a composite of incident diabetes or death. Analyses were done by intention to treat. This trial is registered at ClinicalTrials.gov, number NCT00095654. FINDINGS: at the end of study, 59 individuals had dropped out from the rosiglitazone group and 46 from the placebo group. 306 (11.6%) individuals given rosiglitazone and 686 (26.0%) given placebo developed the composite primary outcome (hazard ratio 0.40, 95% CI 0.35-0.46; p
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AShore, Hemsley A, James M, Tullet J (2006). Effects of Aging and Hypertension on the Microcirculation. Hypertension, 47(5), 968-974.
James MA, Tullett J, Hemsley AG, Shore AC (2006). Effects of aging and hypertension on the microcirculation.
Hypertension,
47(5), 968-974.
Abstract:
Effects of aging and hypertension on the microcirculation.
Alterations of structure and function of the microcirculation in hypertension in the elderly and changes with normotensive aging have not been fully clarified. We studied capillary pressure, density, and skin microvascular function in 46 subjects in 3 groups: elderly subjects (aged >60 years) with untreated hypertension (n=16), elderly normotensive subjects (n=16), and young normotensive subjects (age
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Strain D, Chaturvedi N, Dockery F, Shiff R (2006). Increased arterial stiffness in Europeans and African Caribbeans with type 2 diabetes cannot be accounted for by conventional cardiovascular risk factors. American Journal of Hypertension, 19(9), 889-896.
Whatmore JL, Konopatskaya O, Shore AC (2006). Lysophosphatidylcholine stimulation of CGMP production in human endothelial cells involves tyrosine kinases, heterotrimeric GTP binding proteins, phosphatidylinositol 3-kinase and protein kinase C. Vascular Pharmacology, 45(3), e142-e143.
Gooding KM, Hannemann MM, Tooke JE, Clough GF, Shore AC (2006). Maximum skin hyperaemia induced by local heating: possible mechanisms.
J Vasc Res,
43(3), 270-277.
Abstract:
Maximum skin hyperaemia induced by local heating: possible mechanisms.
BACKGROUND: Maximum skin hyperaemia (MH) induced by heating skin to > or = 42 degrees C is impaired in individuals at risk of diabetes and cardiovascular disease. Interpretation of these findings is hampered by the lack of clarity of the mechanisms involved in the attainment of MH. METHODS: MH was achieved by local heating of skin to 42-43 degrees C for 30 min, and assessed by laser Doppler fluximetry. Using double-blind, randomized, placebo-controlled crossover study designs, the roles of prostaglandins were investigated by inhibiting their production with aspirin and histamine, with the H1 receptor antagonist cetirizine. The nitric oxide (NO) pathway was blocked by the NO synthase inhibitor, NG-nitro-L-arginine methyl esther (L-NAME), and enhanced by sildenafil (prevents breakdown of cGMP). RESULTS: MH was not altered by aspirin, cetirizine or sildenafil, but was reduced by L-NAME: median placebo 4.48 V (25th, 75th centiles: 3.71, 4.70) versus L-NAME 3.25 V (3.10, 3.80) (p = 0.008, Wilcoxon signed rank test). Inhibition of NO production (L-NAME) resulted in a more rapid reduction in hyperaemia after heating (p = 0.011), whereas hyperaemia was prolonged in the presence of sildenafil (p = 0.003). The increase in skin blood flow was largely confined to the directly heated area, suggesting that the role of heat-induced activation of the axon reflex was small. CONCLUSION: NO, but not prostaglandins, histamine or an axon reflex, contributes to the increase in blood flow on heating and NO is also a component of the resolution of MH after heating.
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Middlebrooke AR, Elston LM, Macleod KM, Mawson DM, Ball CI, Shore AC, Tooke JE (2006). Six months of aerobic exercise does not improve microvascular function in type 2 diabetes mellitus.
Diabetologia,
49(10), 2263-2271.
Abstract:
Six months of aerobic exercise does not improve microvascular function in type 2 diabetes mellitus.
AIMS/HYPOTHESIS: Adults with type 2 diabetes mellitus have impaired microvascular function. It has been hypothesised that microvascular function may be restored through regular exercise. The aim of this study was to investigate whether 6 months of regular aerobic exercise would improve microvascular function in adults with type 2 diabetes. MATERIALS AND METHODS: Fifty-nine patients with type 2 diabetes (32 males, age 62.9+/-7.6 years, HbA(1c) 6.8+/-0.9%) were randomised to either a 6-month aerobic exercise programme (30 min, three times a week, 70-80% of maximal heart rate) or a 'standard care' control group. Before and after the intervention period, microvascular function was assessed as the maximum skin hyperaemia to local heating and endothelial and non-endothelial responsiveness following the iontophoretic application of acetylcholine and sodium nitroprusside. Maximal oxygen uptake, as an index of aerobic fitness, was assessed using a maximal exercise test. RESULTS: No significant improvement was seen in the exercise group compared with the control group for any of the variables measured: maximal oxygen uptake (control pre: 1.73+/-0.53 [means+/-SD] vs post: 1.67+/-0.40; exercise pre: 1.75+/-0.56 vs post: 1.87+/-0.62 l/min, p=0.10); insulin sensitivity (insulin tolerance test) (control pre: -0.17+/-0.06 vs post: -0.17+/-0.06; exercise pre: -0.16+/-0.1 vs post: -0.17+/-0.07 mmol l(-1) min(-1), p=0.97); maximal hyperaemia (control pre: 1.49+/-0.43 vs post: 1.52+/-0.57; exercise pre: 1.42+/-0.36 vs post: 1.47+/-0.33 V, p=0.85); peak response to acetylcholine (control pre: 1.37+/-0.47 vs post: 1.28+/-0.37; exercise pre: 1.27+/-0.44 vs post: 1.44+/-0.23 V, p=0.19) or to sodium nitroprusside (control pre: 1.09+/-0.50 vs post: 1.10+/-0.39; exercise pre: 1.12+/-0.28 vs post: 1.13+/-0.40 V, p=0.98). CONCLUSIONS/INTERPRETATION: in this group of type 2 diabetic patients with good glycaemic control a 6-month aerobic exercise programme did not improve microvascular function or aerobic fitness.
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Tooke JE, Elston LM, Gooding KM, Ball CI, Mawson DM, Piper J, Sriraman R, Urquhart R, Shore AC (2006). The insulin sensitiser pioglitazone does not influence skin microcirculatory function in patients with type 2 diabetes treated with insulin.
Diabetologia,
49(5), 1064-1070.
Abstract:
The insulin sensitiser pioglitazone does not influence skin microcirculatory function in patients with type 2 diabetes treated with insulin.
AIMS/HYPOTHESIS: Insulin resistance is associated with abnormal microvascular function. Treatment with insulin sensitisers may provoke oedema, suggesting microvascular effects. The mechanisms underlying the peripheral oedema observed during glucose-lowering treatment with thiazolidinediones are unclear. Therefore we examined the effect of pioglitazone on microvascular variables involved in oedema formation. METHODS: Subjects (40-80 years) with type 2 diabetes and on insulin were randomised to 9 weeks of pioglitazone therapy (30 mg/day; n=14) or placebo (n=15). The following assessments were performed at baseline and 9 weeks: microvascular filtration capacity; isovolumetric venous pressure; capillary pressure; capillary recruitment following venous or arterial occlusion; postural vasoconstriction; and maximum blood flow. A number of haematological variables were also measured including vascular endothelium growth factor (VEGF), IL-6 and C-reactive protein (CRP). RESULTS: Pioglitazone did not significantly influence any microcirculatory variable as compared with placebo (analysis of covariance [ANCOVA] for microvascular filtration capacity for the two groups, p=0.26). Mean VEGF increased with pioglitazone (61.1 pg/ml), but not significantly more than placebo (9.76 pg/ml, p=0.94). HbA(1c) levels and the inflammatory markers IL-6 and CRP decreased with pioglitazone compared with placebo (ANCOVA: p=0.009, p=0.001 and p=0.004, respectively). CONCLUSIONS/INTERPRETATION: Pioglitazone improved glycaemic control and inflammatory markers over 9 weeks but had no effect on microcirculatory variables associated with oedema or insulin resistance in type 2 diabetic patients treated with insulin.
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Konopatskaya O, Shore AC, Tooke JE, Whatmore JL (2005). A role for heterotrimeric GTP-binding proteins and ERK1/2 in insulin-mediated, nitric-oxide-dependent, cyclic GMP production in human umbilical vein endothelial cells.
Diabetologia,
48(3), 595-604.
Abstract:
A role for heterotrimeric GTP-binding proteins and ERK1/2 in insulin-mediated, nitric-oxide-dependent, cyclic GMP production in human umbilical vein endothelial cells.
AIMS/HYPOTHESIS: Insulin is known to stimulate endothelial nitric oxide synthesis, although much remains unknown about the intracellular mechanisms involved. This study aims to examine, in human endothelial cells, the specific contribution of heterotrimeric Gi proteins and extracellular signal-regulated protein kinases 1/2 (ERK1/2) in insulin signalling upstream of nitric-oxide-dependent cyclic GMP production. METHODS: Human umbilical vein endothelial cells were treated with 1 nmol/l insulin in the presence or absence of inhibitors of tyrosine kinases (erbstatin), Gi proteins (pertussis toxin) or ERK1/2 (PD098059 or U0126), and nitric oxide production was examined by quantification of intracellular cyclic GMP. Activation/phosphorylation of ERK1/2 by insulin was examined by immunoblotting with specific antibodies, and direct association of the insulin receptor with Gi proteins was examined by immunoprecipitation. RESULTS: Treatment of cells with a physiological concentration of insulin (1 nmol/l) for 5 min increased nitric-oxide-dependent cyclic GMP accumulation by 3.3-fold, and this was significantly inhibited by erbstatin. Insulin-stimulated cyclic GMP production was significantly reduced by pertussis toxin and by the inhibitors of ERK1/2, PD098059 and U0126. Immunoblotting indicated that insulin stimulated the phosphorylation of ERK1/2 after 5 min and 1 h, and that this was completely abolished by pertussis toxin, but insensitive to the nitric oxide synthase inhibitor L-NAME. No direct interaction of the insulin receptor beta with Gialpha2 could be demonstrated by immunoprecipitation. CONCLUSIONS/INTERPRETATION: This study demonstrates, for the first time, that nitric oxide production induced by physiologically relevant concentrations of insulin, is mediated by the post-receptor activation of a pertussis-sensitive GTP-binding protein and subsequent downstream activation of the ERK1/2 cascade.
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Strain WD, Chaturvedi N, Bulpitt CJ, Rajkumar C, Shore AC (2005). Albumin excretion rate and cardiovascular risk: could the association be explained by early microvascular dysfunction?.
Diabetes,
54(6), 1816-1822.
Abstract:
Albumin excretion rate and cardiovascular risk: could the association be explained by early microvascular dysfunction?
Elevated albumin excretion rate (AER) independently predicts total and cardiovascular mortality in a variety of conditions, although the exact mechanisms are unknown. Laser Doppler fluximetry was used to study associations with risk factors and renal damage (AER calculated from a timed overnight urine collection) in 188 people without diabetes and 117 individuals with diabetes. Skin flow (flux) in response to arterial occlusion (ischemia) was measured. Three distinct patterns of postischemic peak flow were observed: 1) gradual rise to peak (normal), 2) nondominant early peak, and 3) dominant early peak. Those with a dominant early peak were more likely to have diabetes (P = 0.01), hypertension (P = 0.001), and obesity (P < 0.001) and had a higher AER (12.6 microg/min [95% CI 7.8-20.2] vs. 7.2 [5.5-9.5] nondominant early peak group and 3.7 [3.2-4.1] normal group; P < 0.001 for trend). This could not be accounted for by conventional cardiovascular risk factors (P < 0.001 after adjustment). A rapid peak flow response after ischemia is associated with an elevated AER and increased cardiovascular risk. This may represent shared mechanistic pathways and causative or con-sequential changes in the microvasculature and supports the hypothesis that microvascular dysfunction may contribute to large vessel pathophysiology.
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Strain D, Bulpitt C, Chaturvedi N, Nihoyannopoulos P (2005). Differences in the association between type 2 diabetes and impaired microvascular function among Europeans and African Caribbeans. Diabetologia, 48(11), 2269-2277.
Middlebrooke AR, Armstrong N, Welsman JR, Shore AC, Clark P, MacLeod KM (2005). Does aerobic fitness influence microvascular function in healthy adults at risk of developing Type 2 diabetes?.
Diabet Med,
22(4), 483-489.
Abstract:
Does aerobic fitness influence microvascular function in healthy adults at risk of developing Type 2 diabetes?
AIM: to investigate whether aerobic fitness is associated with skin microvascular function in healthy adults with an increased risk of developing Type 2 diabetes. METHODS: Twenty-seven healthy normal glucose-tolerant humans with either a previous diagnosis of gestational diabetes or having two parents with Type 2 diabetes and 27 healthy adults who had no history of diabetes were recruited. Maximal oxygen uptake was assessed using an incremental exercise test to exhaustion. Skin microvascular function was assessed using laser Doppler techniques as the maximum skin hyperaemic response to a thermal stimulus (maximum hyperaemia) and the forearm skin blood flow response to the iontophoretic application of acetylcholine (ACh) and sodium nitroprusside. RESULTS: Maximal oxygen uptake was not significantly different in the 'at-risk' group compared with healthy controls. Maximum hyperaemia was reduced in those 'at risk' (1.29 +/- 0.30 vs. 1.46 +/- 0.33 V, P = 0.047); however, the peak response to acetylcholine or sodium nitroprusside did not differ in the two groups. A significant positive correlation was demonstrated between maximal oxygen uptake and maximum hyperaemia (r = 0.52, P = 0.006 l/min and r = 0.60, P = 0.001 ml/kg/min) and peak ACh response (r = 0.40, P = 0.04 l/min and r = 0.47, P = 0.013 ml/kg/min) in the 'at-risk' group when expressed in absolute (l/min) or body mass-related (ml/kg/min) terms. No significant correlations were found in the control group. CONCLUSIONS: in this 'at-risk' group with skin microvascular dysfunction maximal oxygen uptake was not reduced compared with healthy controls. However, in the 'at-risk' group alone, individuals with higher levels of aerobic fitness also had better microvascular and endothelial responsiveness.
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Strain WD, Chaturvedi N, Shore A, Cruickshank JK, Heagerty AM (2005). Ethnic differences in microvascular structure and function [3] (multiple letters). Journal of Hypertension, 23(7), 1434-1436.
Strain D, Chaturvedi N, Leggetter S, Nihoyannopoulos P (2005). Ethnic differences in skin microvascular function and their relation to cardiac target-organ damage. Journal of Hypertension, 23(1), 133-140.
Gooding KM, MacLeod KM, Spyer G, Ewings P, Tooke JE, Shore AC (2005). Impact of hormone replacement therapy on microvascular function in healthy and Type 2 diabetic postmenopausal women.
Diabet Med,
22(5), 536-542.
Abstract:
Impact of hormone replacement therapy on microvascular function in healthy and Type 2 diabetic postmenopausal women.
AIMS: Hormone replacement therapy (HRT) has been previously reported to modulate vascular function and cardiovascular risk. Its impact on the macrocirculation has previously been explored, however, little data is available on its impact on the microcirculation. This study aimed to determine the impact of HRT on microvascular function in healthy and Type 2 diabetic postmenopausal women (n=20 and 17, respectively). METHODS: Microvascular function was assessed by skin maximum hyperaemia, skin hyperaemic response to iontophoretically applied acetylcholine (endothelial-dependent vasodilator) and sodium nitroprusside (endothelial-independent vasodilator), capillary pressure and the microvascular filtration capacity. Microvascular assessments were carried out at baseline and repeated following 6 months' oral hormone replacement therapy (1 mg oestradiol/0.5 mg norethisterone or 1 mg unopposed oestradiol for hysterectomized women). RESULTS: Following 6 months' therapy there were no significant changes in microvascular assessments in the healthy women. In the diabetic women there was a reduction in the skin hyperaemic response to acetylcholine [median pretreatment peak response: 1.95 (25th, 75th centiles: 1.54, 2.30) V vs. post-treatment peak response: 1.53 (1.30, 1.91) V (P=0.011, Wilcoxon's signed rank test)] and sodium nitroprusside [median peak response 1.59 (1.37, 1.99) vs. 1.35 (0.92, 1.63) V (P=0.011)] with HRT, but no other changes. CONCLUSION: These data suggests that HRT does not affect microvascular function in healthy women, but adversely affects it in diabetic women. These findings may help to explain why HRT fails to provide the predicted cardiovascular protection, and raises the possibility that HRT influences microangiopathy progression in diabetic women.
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Hannemann M, Mawson D, Shore A (2005). Letter to the editor. Diabetes and Vascular Disease Research, 2(2), 94-95.
Fegan PG, Shore AC, Mawson D, Tooke JE, MacLeod KM (2005). Microvascular endothelial function in subjects with Type 2 diabetes and the effect of lipid-lowering therapy.
Diabet Med,
22(12), 1670-1676.
Abstract:
Microvascular endothelial function in subjects with Type 2 diabetes and the effect of lipid-lowering therapy.
AIMS: Abnormalities of microvascular and endothelial function are present in subjects with Type 2 diabetes. Although statin therapy improves cardiovascular risk in diabetes, dyslipidaemia in diabetes may be more responsive to combined statin and fibrate therapy. We examined the effect of cerivastatin and fenofibrate on microvascular function in subjects with Type 2 diabetes with no clinical evidence of cardiovascular disease and near normal lipid levels. METHODS: Age-, sex-, lipid- and blood pressure-matched subjects with Type 2 diabetes were randomized in double-blind fashion to one of four treatment groups: group 1 placebo/placebo (n=12), group 2 fenofibrate/placebo (n=10), group 3 cerivastatin/placebo (n=20) and group 4 cerivastatin/fenofibrate (n=11). The subjects were recruited from the Lipid in Diabetes Study. Microvascular function was assessed by skin blood flow response to iontophoresis of acetylcholine and sodium nitroprusside and by skin maximum hyperaemia to local heating. Measurements were carried out at baseline and 3 months later. RESULTS: Although all lipid parameters improved in groups 2-4 after 3 months' therapy, no difference was detected in skin blood flow to iontophoresis or maximum hyperaemia in any of the groups. Highly sensitive c-reactive protein (Hs-CRP) did not change with therapy. CONCLUSIONS: in conclusion, we were unable to demonstrate any improvement in microvascular endothelial function in non-hyperlipidaemic Type 2 diabetic subjects treated with single or combination lipid-lowering therapy.
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Moger J, Winlove, C.P. Matcher, S.J. (2005). The Effect of Multiple Scattering upon Velocity Profiles Measured using Doppler OCT. Journal of Physics D: Applied Physics, 38(15), 2597-2605.
Moger J, Winlove CP, Shore AC, Matcher SJ (2005). The effect of multiple scattering upon velocity profiles measured using doppler OCT.
Progress in Biomedical Optics and Imaging - Proceedings of SPIE,
5861, 1-12.
Abstract:
The effect of multiple scattering upon velocity profiles measured using doppler OCT
We investigate the effect of multiple scattering upon Doppler optical coherence tomography images of model blood vessels immersed in a fluuid with similar optical properties to those of the human dermis. Furthermore, we quantify the deviation of the acquired velocity profiles from that known to exist within the glass capillary at various depths within the scattering media. A flow phantom consisting of a glass tube containing whole blood flowing under laminar conditions submerged in a variable depth of Intralipid was used to simulate a blood vessel within the cutaneous microcirculation. Doppler optical coherence tomography images and velocity profiles of the tube acquired at various depths within the Intralipid are compared to those obtained from the same tube in a non-scattering media with the same refractive index. © 2005 SPIE and OSA.
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Shore A (2004). Book Review Diabetes and Cardiovascular Disease: Integrating Science and Clinical Medicine Edited by Steven P. Marso and David M. Stern. 527 pp. illustrated. Philadelphia, Lippincott Williams & Wilkins, 2004. $99.95. 0-7817-4053-3.
N Engl J Med,
351(18), 1918-1919.
Abstract:
Book Review Diabetes and Cardiovascular Disease: Integrating Science and Clinical Medicine Edited by Steven P. Marso and David M. Stern. 527 pp. illustrated. Philadelphia, Lippincott Williams & Wilkins, 2004. $99.95. 0-7817-4053-3.
This extremely useful book describes the potential mechanisms underlying the macrovascular and microvascular complications of diabetes, the clinical manifestations of such abnormalities, and effective strategies for treatment. The information in its 500-plus pages is densely packed into two sections, one dealing with basic science (including 150 pages on vascular biology) and a larger section on clinical topics. In general, the chapters start with a brief introduction to a topic but rapidly move into very detailed descriptions of the subject at hand - for example, biochemical pathways. Each chapter succeeds in putting the basic-science aspect of the information into the context. .
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Irving RJ, Shore AC, Belton NR, Elton RA, Webb DJ, Walker BR (2004). Low birth weight predicts higher blood pressure but not dermal capillary density in two populations.
Hypertension,
43(3), 610-613.
Abstract:
Low birth weight predicts higher blood pressure but not dermal capillary density in two populations.
The association between low birth weight and high blood pressure is well established, but underlying mechanisms remain undefined. Vascular rarefaction, which may elevate peripheral vascular resistance, has been observed in capillaries of young men at risk for hypertension and men who had low birth weight. We looked for evidence that capillary rarefaction explains the association of low birth weight with high blood pressure in two cohorts. Participants in study 1 included 107 healthy boys aged 6 to 16 years recruited at random from a single school. Study 2 included 61 members of a cohort recruited at birth and studied at age 24 years. Measurements included indices of current size, blood pressure by automated sphygmomanometer, and dermal capillary density by video capillaroscopy of dorsal index finger skin after 10 minutes of venous occlusion. Lower birth weight predicted higher systolic blood pressure in both studies: in study 1, 3.57 mm Hg/kg birth weight (after adjustment for current height, 95% confidence interval 0.38 to 6.75, P
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Moger J, Matcher SJ, Winlove CP, Shore A (2004). Measuring red blood cell flow dynamics in a glass capillary using Doppler optical coherence tomography and Doppler amplitude optical coherence tomography.
J Biomed Opt,
9(5), 982-994.
Abstract:
Measuring red blood cell flow dynamics in a glass capillary using Doppler optical coherence tomography and Doppler amplitude optical coherence tomography.
Blood, being a suspension of deformable red cells suspended in plasma, displays flow dynamics considerably more complicated than those of an ideal Newtonian fluid. Flow dynamics in blood capillaries of a few hundred micrometers in diameter are investigated using Doppler optical coherence tomography (DOCT) and Doppler amplitude optical coherence tomography (DAOCT), a novel extension of DOCT. Velocity profiles and concentration distributions of normal and rigidified in vitro red blood cell suspensions are shown to vary as functions of mean flow velocity, cell concentration, and cell rigidity. Deviation from the parabolic velocity profile expected for Pouseille flow is observed for both rigid and normal cells at low flow rates. Axial red cell migration both toward and away from the tube axis is observed for both rigid and normal cells as a function of flow velocity. Good agreement is found between our measurements, and theoretical expectations.
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Barker AL, Konopatskaya O, Neal CR, Macpherson JV, Whatmore JL, Winlove CP, Unwin PR, Shore AC (2004). Observation and characterisation of the glycocalyx of viable human endothelial cells using confocal laser scanning microscopy.
Physical Chemistry Chemical Physics, 1006-1011.
Abstract:
Observation and characterisation of the glycocalyx of viable human endothelial cells using confocal laser scanning microscopy
This paper describes the use of confocal laser scanning microscopy (CLSM) to observe and characterise the fully hydrated glycocalyx of human umbilical vein endothelial cells (HUVECs). Viable HUVECs in primary culture were studied at room temperature in HEPES-buffered, phenol red- and serum-free CS-C cell culture medium. A fluorescein isothiocyanate-linked wheat germ agglutinin (WGA-FITC)(2 µg ml-1, 30 min) was used to detect N-acetylneuraminic (sialic) acid, which is a significant component of the endothelial glycocalyx. Single confocal sections, less than 1.3 µm thick, were collected at intervals of 0.5 µm, scanning through the entire z-axis of a series of cells. Cell-surface associated staining was observed, which enabled the glycocalyx thickness to be deduced as 2.5 ± 0.5 µm. This dimension is significantly greater than that measured by electron microscopy, for glutaraldehyde-fixed cells (0.10 ± 0.04 µm). The specificity of WGA-FITC staining was demonstrated by treatments with several enzymes, known to degrade glycocalyx (heparatinase, chondroitinase, hyaluronidase and neuraminidase), of which neuraminidase (1 U ml-1, 30-60 min) was the most effective, removing up to 78 ± 2% of WGA-FITC binding to HUVECs. Cell viability was assessed simultaneously with ethidium homodimer-1 staining and confirmed by standard colorimetric 3-[4,5]dimethylthiazol-2,5diphenyltetrazolium bromide (MTT) test. CLSM thus provides a useful approach for in situ visualisation and characterisation of the endothelial glycocalyx in viable preparations, revealing a thickness that is an order of magnitude greater than found in ex situ measurements on fixed cells. © the Owner Societies.
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Hahn M, Jünger M, Shore AC (2004). The effect of prostaglandin E1 on nailfold capillary blood pressure and red blood cell velocity in humans.
Clin Hemorheol Microcirc,
31(3), 227-234.
Abstract:
The effect of prostaglandin E1 on nailfold capillary blood pressure and red blood cell velocity in humans.
PGE(1) or PGI(2) acutely increase total skin perfusion in healthy volunteers. This study investigated whether skin nutritive perfusion and capillary pressure were increased by acute infusion of PGE(1). In a double blind randomised placebo controlled study the effect of Alprostadil (PGE(1), Prostavasin, intra-venous, infusion rate: 0.38 microg/h/kg,) on skin nailfold capillary blood pressure (CP) and capillary red blood cell velocity (CBV) was investigated in 16 healthy volunteers (placebo: 5 male, 3 female, age: 27.7, range: 22-29 years; Alprostadil: 5 m, 3 f, age 27.1, 22-38 y), using the electrical impedance servo nulling technique and spatial shift alignment method, respectively. Initial finger tip temperature, systemic blood pressure, heart rate, CP, capillary pulse pressure amplitude (CPPA) and CBV showed no significant differences between the two groups (placebo: 23.6 +/- 3.0 degrees C, 123 +/- 13/83 +/- 5 mmHg, 63 +/- 11 beats/min, 15.6 +/- 3.9 mmHg, 1.5 +/- 1.8 mmHg, and 425 microm/s (290-800); Alprostadil: 23.4 +/- 2.7 degrees C, 121 +/- 9/82 +/- 10 mmHg, 65 +/- 9 beats/min, 14.4 +/- 3.7 mmHg, 1.8 +/- 1.3 mmHg, and 680 (140-1090 microm/s)). Twenty minute infusion with either Alprostadil or placebo had no significant effect on any of the parameters measured. Thus, in healthy volunteers, skin capillary blood pressure, capillary pulse pressure amplitude and capillary blood velocity are unaltered by acute administration of PGE(1) at ambient temperatures.
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Fegan PG, Tooke JE, Gooding KM, Tullett JM, MacLeod KM, Shore AC (2003). Capillary pressure in subjects with type 2 diabetes and hypertension and the effect of antihypertensive therapy.
Hypertension,
41(5), 1111-1117.
Abstract:
Capillary pressure in subjects with type 2 diabetes and hypertension and the effect of antihypertensive therapy.
Raised capillary pressure has been implicated in the formation of diabetic microangiopathy in type I diabetes, in which it is elevated in those with the earliest signs of diabetic kidney disease but remains normal in those without complications. In subjects with type 2 diabetes without complications, capillary pressure is normal, although alterations in the pressure waveforms suggested enhanced wave reflections. The nature of skin capillary pressure in subjects with type 2 diabetes and hypertension remains to be elucidated, as does the effect of blood pressure-lowering therapy on capillary pressure in these subjects. Three studies were performed in well-matched groups. First, capillary pressure was elevated in hypertensive subjects with type 2 diabetes compared with normotensive subjects with type 2 diabetes (20.2 [17.4 to 22.7] mm Hg versus 17.7 [16.1 to 18.9] mm Hg, respectively, P
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Paisley KE, Beaman M, Tooke JE, Mohamed-Ali V, Lowe GDO, Shore AC (2003). Endothelial dysfunction and inflammation in asymptomatic proteinuria.
Kidney Int,
63(2), 624-633.
Abstract:
Endothelial dysfunction and inflammation in asymptomatic proteinuria.
BACKGROUND: Proteinuria is associated with vascular risk and a systemic increase in vascular permeability. Endothelial dysfunction occurs early in atherosclerosis and modulates vascular permeability. Vascular risk and chronic inflammation are associated. This study investigates whether the increased vascular permeability in proteinuria reflects systemic endothelial dysfunction and chronic inflammation. METHODS: Twenty-one patients with asymptomatic proteinuria (1.29 g/24 h; range 0.18 to 3.17) and 21 matched controls were studied. Microvascular endothelial function was assessed using acetylcholine iontophoresis. Maximum microvascular hyperemia (MMH) was assessed by flux response to local skin heating. Macrovascular endothelial function was assessed by flow-associated dilation (FAD) in the brachial artery using ultrasound. von Willebrand factor (vWF) was measured as a marker of endothelial activation. Low-grade inflammation was assessed by measurement of circulating C-reactive protein (CRP) values using a high sensitivity assay. RESULTS: FAD was impaired in proteinuric subjects (AP) compared to controls [1.8 (0.2 to 5.3) AP vs. 3.8 (1.5 to 6.2) C %; P = 0.014]. There was no significant difference between groups in MMH or in the response to acetylcholine iontophoresis. The AP group had a higher CRP [4.0 (0.5 to 39.0) AP vs. 0.2 (0.1 to 21.3) C mg/L; P < 0.001] and tendency to higher vWF [101.5 (67.0 to 197.0) AP vs. 77.5 (45.0 to 185.0) C IU/dL; P = 0.046] compared to controls. In the AP, but not control, group there was an inverse correlation between CRP and microvascular function as determined by acetylcholine iontophoresis (r = -0.509; P = 0.018). CONCLUSIONS: in AP subjects there is evidence of macrovascular endothelial dysfunction remote from the kidney and of low-grade inflammation that is associated with microvascular endothelial dysfunction.
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Konopatskaya O, Whatmore JL, Tooke JE, Shore AC (2003). Insulin and lysophosphatidylcholine synergistically stimulate NO-dependent cGMP production in human endothelial cells.
Diabet Med,
20(10), 838-845.
Abstract:
Insulin and lysophosphatidylcholine synergistically stimulate NO-dependent cGMP production in human endothelial cells.
AIMS: Nitric oxide (NO) is an important regulator of cardiovascular homeostasis. Lysophosphatidylcholine (lyso-PC), a major constituent of oxidized low density lipoproteins (oxLDL), has been reported to impair nitric oxide-dependent vasodilatation. This study investigated the possible mechanism of the lyso-PC effect on insulin-stimulated NO-dependent of cyclic guanosine 3',5'-monophosphate (cGMP) generation in human endothelial cells. METHODS: the intracellular concentration of cGMP in cultured human umbilical vein endothelial cells (HUVECs) was used to estimate NO production. The levels of endothelial nitric oxide synthase (eNOS) protein expression were assessed by Western blotting analyses. RESULTS: Both insulin, at physiological concentration, and lyso-PC stimulated rapid and prolonged intracellular of cGMP production, and together induced a marked synergistic response (for short-term stimulation: 1185 +/- 285.9% over control level (100%) compared with insulin and lyso-PC alone (384.8 +/- 67.4% and 357 +/- 205%, respectively; P < 0.001), for long-term stimulation: 3495 +/- 1377%, compared with insulin and lyso-PC alone (663 +/- 131% and 487 +/- 250%, P = 0.002)). Stimulated levels of cGMP accumulation were completely abrogated by NOS inhibitor, indicating NO involvement in the effects of insulin and lyso-PC. Stimulated NO synthesis was not associated with altered eNOS protein expression. Cell subfractionation studies demonstrate that insulin and lyso-PC each alone induced translocation of eNOS from the membrane to the cytosolic compartment and together caused a synergistic translocation. CONCLUSIONS: the presented data suggest that insulin and lyso-PC synergistically upregulate endothelial NO production via eNOS translocation from the membrane fraction to the cytosol. This study raises the possibility that an interplay between various factors accompanying diabetes can lead to endothelial NO overproduction or desensitization of NO-dependent responses. Appropriate rather than necessarily high levels of nitric oxide is the determinant of vascular health.
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Shore AC, Evans JC, Frayling TM, Clark PM, Lee BC, Horikawa Y, Hattersley AT, Tooke JE (2002). Association of calpain-10 gene with microvascular function.
Diabetologia,
45(6), 899-904.
Abstract:
Association of calpain-10 gene with microvascular function.
AIMS/HYPOTHESIS: Genotype could influence vascular function. In some populations, Calpain 10 gene polymorphisms increase susceptibility to diabetes or insulin resistance. Alterations in microvascular function could contribute to insulin resistance. This study investigated whether polymorphisms in the Calpain-10 gene influence microvascular function. METHODS: Skin maximum microvascular hyperaemia to local heating on the dorsum of the foot (30 min at 43 degrees C) was measured by Laser Doppler Fluximetry in 37 healthy volunteers. All were normoglycaemic according to World Health Organisation criteria, normotensive and not on any medication. Four polymorphisms in the calpain-10 gene were typed: SNP-44, SNP-43, SNP-19, SNP-63. The SNP common to all the described high risk haplotypes is the G-allele at SNP-43. This intron 3 polymorphism appears to influence gene expression. Microvascular function was examined in relation to polymorphisms at this site alone as well as the effects of the known extended high risk haplotypes using the SNP's above. RESULTS: Maximum microvascular hyperaemia was increased in the 21 subjects with G/G genotypes at SNP-43 compared to the combined group of subjects ( G/ a genotype at SNP-43 ( n=12) + A/ a genotype at SNP-43 ( n=4)), and the minimum microvascular resistance was reduced 49.4 (39.6-94.2) vs 67.5 (39.1-107.3) mmHg/V, p=0.007). Haplotype analysis of the hyperaemic response revealed no significant differences between haplotypes. The two groups did not differ in terms of anthropometric measures, blood pressure, insulin resistance or glucose. CONCLUSIONS/INTERPRETATION: the polymorphism that confers susceptibility to Type II (non-insulin-dependent) diabetes mellitus in some populations is associated in United Kingdom Caucasians with enhanced microvascular function in the presence of normoglycaemia.
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Irving RJ, Walker BR, Noon JP, Watt GCM, Webb DJ, Shore AC (2002). Microvascular correlates of blood pressure, plasma glucose, and insulin resistance in health.
Cardiovasc Res,
53(1), 271-276.
Abstract:
Microvascular correlates of blood pressure, plasma glucose, and insulin resistance in health.
OBJECTIVES: the associations between hypertension, insulin resistance and glucose intolerance are poorly understood. Altered microvascular structure and function could contribute by increasing peripheral vascular resistance and decreasing tissue delivery of glucose. We addressed this hypothesis in a sample of healthy men. METHODS: We studied 105 healthy young men aged 23-33 years. Insulin resistance was calculated using the Homeostasis Model Assessment (HOMA). Video capillaroscopy was used on the dorsum of the finger to measure skin capillary density, and in nailfold capillaries to measure capillary blood velocity. Skin vasodilatation was measured with laser Doppler fluximetry on the forearm following heating and iontophoresis of acetylcholine. RESULTS: Higher systolic blood pressure was associated with insulin resistance (r=0.31, P
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Walker BR, Shore AC (2002). Reply to letter to the editor.
CARDIOVASCULAR RESEARCH,
55(2), 420-421.
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Shore AC (2002). The microvasculature in type 1 diabetes.
Semin Vasc Med,
2(1), 9-20.
Abstract:
The microvasculature in type 1 diabetes.
Alterations in the microvasculature seen early in type 1 diabetes appear to be related to glycemic control. The later abnormalities occur primarily in patients with incipient or overt nephropathy and are likely to represent a more generalized vascular dysfunction as indicated by the increased cardiovascular risk in these groups. The mechanisms involved may be related to genetic susceptibility in combination with impaired hemorheology, dyslipidemia, hypertension, or the toxic effects of hyperglycemia. Many of these effects may relate to a common final pathway such as activation of PKC or increased oxidative stress. Therapeutic interventions to inhibit either PKC effects or decrease oxidative stress have been effective in reducing microangiopathy in diabetic animals. Vitamin C or E supplementation may improve vascular function in type 1 diabetes. The results of ongoing trials of PKC inhibitors are awaited with interest. Whether such interventions will influence the course of microangiopathy remains to be determined.
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Hannemann MM, Liddell WG, Shore AC, Clark PM, Tooke JE (2002). Vascular function in women with previous gestational diabetes mellitus.
J Vasc Res,
39(4), 311-319.
Abstract:
Vascular function in women with previous gestational diabetes mellitus.
It is hypothesised that vascular dysfunction, which characterises type 2 diabetes, may predate development of hyperglycaemia. 17 women with previous gestational diabetes mellitus, and thus at risk of developing type 2 diabetes, were matched with normal controls for body mass index, menstrual phase, smoking, age, blood pressure, and lipid profiles. All had normal glucose tolerance. Tests of microvascular and macrovascular function, including endothelium-dependent and -independent vasodilatation, were performed. Laser Doppler fluximetry of maximum skin microvascular hyperaemia in response to local heating of the dorsum of the foot to 42 degrees C for 30 min was impaired in subjects compared to controls [subjects = 1.15 (0.73-1.73) V median (range) versus controls = 1.50 (0.95-2.29) V, p = 0.008]. There were no differences in laser Doppler perfusion imaging of responses to forearm skin iontophoresis of acetylcholine [subjects = 1.59 (0.32-2.55) V median (range) versus controls = 1.79 (0.72-2.06) V; p = 0.81] and sodium nitroprusside [subjects = 1.39 (0.8-3.14) V versus controls = 1.41 (0.34-2.19) V; p = 0.68], ultrasound estimation of brachial artery flow-mediated dilatation [subjects = 1.65 (-0.5-9.07)% versus controls = 2.77 (0.63-6.6)%; p = 0.42] and glyceryl trinitrate-induced dilatation [subjects = 15.20 (6.64-20.91)% versus controls = 15.92 (3.94-22.09)%; p = 0.48]. Microvascular maximum hyperaemia was impaired in the index group, suggesting the presence of a defect in vascular function. This defect was not explained by those aspects of endothelial function measured by the other techniques.
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Fegan PG, Macleod KM, Tooke JE, Shore AC (2002). n-3 NEFA: vascular implications.
Eur Heart J,
23(3), 185-187.
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Goh KL, Shore AC, Quinn M, Tooke JE (2001). Impaired microvascular vasodilatory function in 3-month-old infants of low birth weight.
Diabetes Care,
24(6), 1102-1107.
Abstract:
Impaired microvascular vasodilatory function in 3-month-old infants of low birth weight.
OBJECTIVE: Low birth weight has been linked to an increased risk of type 2 diabetes and cardiovascular disease in adult life. The fetal insulin hypothesis proposed that a genetic predisposition to insulin resistance may also influence vascular development. Therefore, impaired vascular function may be an intrinsic abnormality in low-birth weight infants that antedates clinical features of the insulin resistance syndrome. RESEARCH DESIGN AND METHODS: Two groups of 3-month-old term infants were included in the study: 17 infants of lowest quartile birth weight (LQBW) and 21 infants of highest quartile birth weight (HQBW). Three aspects of skin microvascular function were examined; response to local heating, response to acetylcholine iontophoresis, and capillary density. RESULTS: Median (interquartile ranges) birth weights of the LQBW and HQBW infants were 3,140 g (2,738-3,254) and 3,920 g (3,750-4,020), respectively. Skin maximal hyperemic response to local heating was 2.14 V (1.68-2.30) in the LQBW group vs. 2.44 V (1.96-2.90) in the HQBW group (P = 0.020), and the endothelium-dependent vasodilatory response was 1.03 V (0.62-1.32) in the LQBW group vs. 0.78 V (0.45-1.32) in the HQBW group (P = 0.297). Capillary density in the LQBW and HQBW groups were 46.3 mm(-2) (40.1-53.7) and 44.1 mm(-2) (41.7-56.0), respectively (P = 0.736). CONCLUSIONS: Skin maximal hyperemic response was lower in LQBW infants, although no reduction in capillary density or defect in endothelium-dependent vasodilatation was observed. Such a lower maximal hyperemic response in early life in LQBW subjects who are at risk for type 2 diabetes and cardiovascular disease supports the hypothesis that impaired microvascular function is an early antecedent to diabetes in later life.
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Lee BC, Shore AC, Humphreys JM, Lowe GD, Rumley A, Clark PM, Hattersley AT, Tooke JE (2001). Skin microvascular vasodilatory capacity in offspring of two parents with Type 2 diabetes.
Diabet Med,
18(7), 541-545.
Abstract:
Skin microvascular vasodilatory capacity in offspring of two parents with Type 2 diabetes.
AIMS: Microvascular dysfunction occurs in Type 2 diabetes and in subjects with fasting hyperglycaemia. It is unclear whether this dysfunction relates to dysglycaemia. This study investigated in normogylcaemic individuals whether a genetic predisposition to diabetes, or indices of insulin resistance including endothelial markers, were associated with impaired microvascular function. METHODS: Maximum microvascular hyperaemia to local heating of the skin was measured using laser Doppler flowmetry in 21 normoglycaemic subjects with no family history of diabetes (Group 1) and 21 normoglycaemic age, sex and body mass index-matched offspring of two parents with Type 2 diabetes (Group 2). RESULTS: Although Group 2 had normal fasting plasma glucose and glucose tolerance tests, the 120-min glucose values were significantly higher at 6.4 (5.3-6.6) mmol/l (median (25th - 75th centile)) than the control group at 4.9 (4.6-5.9) mmol/l (P = 0.005) and the insulinogenic index was lower at 97.1 (60.9-130.8) vs. 124.0 (97.2-177.7) (P = 0.027). Skin maximum microvascular hyperaemia (Group 1: 1.56 (1.39-1.80) vs. Group 2: 1.53 (1.30-1.98) V, P = 0.99) and minimum microvascular resistance which normalizes the hyperaemia data for blood pressure (Group 1: 52.0 (43.2-67.4) vs. Group 2: 56.0 (43.7-69.6) mmHg/V, P = 0.70) did not differ in the two groups. Significant positive associations occurred between minimum microvascular resistance and indices of the insulin resistance syndrome; plasminogen activator inhibitor type 1 (R(s) = 0.46, P = 0.003), t-PA (R(s) = 0.36, P = 0.03), total cholesterol (R(s) = 0.35, P = 0.02), and triglyceride concentration (R(s) = 0.35, P = 0.02), and an inverse association with insulin sensitivity (R(s) = -0.33, P = 0.03). CONCLUSIONS: in normoglycaemic adults cutaneous microvascular vasodilatory capacity is associated with features of insulin resistance syndrome, particularly with plasminogen activator inhibitor type 1. A strong family history of Type 2 diabetes alone does not result in impairment in the maximum hyperaemic response. Diabet. Med. 18, 541-545 (2001)
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Shore AC (2000). Capillaroscopy and the measurement of capillary pressure.
Br J Clin Pharmacol,
50(6), 501-513.
Abstract:
Capillaroscopy and the measurement of capillary pressure.
Capillaries play a critical role in cardiovascular function as the point of exchange of nutrients and waste products between the tissues and circulation. Studies of capillary function in man are limited by access to the vascular bed. However, skin capillaries can readily be studied by the technique of capillaroscopy which enables the investigator to assess morphology, density and blood flow velocity. It is also possible to estimate capillary pressure by direct cannulation using glass micropipettes. This review will describe the techniques used to make these assessments and will outline some of the changes that are seen in health and disease.
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Kernick DP, Shore AC (2000). Characteristics of laser Doppler perfusion imaging in vitro and in vivo.
Physiol Meas,
21(2), 333-340.
Abstract:
Characteristics of laser Doppler perfusion imaging in vitro and in vivo.
Traditional laser Doppler flowmetry (LDF) employs continuous recording of perfusion at one point with time. In order to eliminate the large spatial and temporal fluctuations that occur in the microcirculation, laser Doppler perfusion imaging (LDI) integrates flow readings over a large area. This paper describes a number of experiments to identify some of the characteristics of the LDI, its relationship to flow and no-flow conditions and to compare it with LDF. We undertook experiments to establish the effect of scanner head height, avascular skin thickness and haematocrit on LDI output. We also investigated the contribution of the biological zero signal (the signal obtained from skin when flow is arrested) to the LDI output. LDI output increased with scanner height in vitro and in vivo. Increasing avascular skin thickness reduced the LDI output although linear output characteristics with flow were maintained over the flow range studied. Increasing the haematocrit resulted in a loss of linearity of output with flow at lower velocities. The biological zero signal contributes a similar proportion of the output signal in LDF and LDI. We have presented a series of experiments that will contribute to the understanding of the characteristics of laser Doppler perfusion imaging, its comparison to laser Doppler flowmetry and its relationship to flow and no flow situations. However, our experiments were restricted to one machine, and may not necessarily be applicable to other instruments.
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Hamid S, Klaentschi K, Shore AC, Tooke JE (1999). A modified diffusion chamber to study the effect of hydrostatic pressure on fluid permeability.
JOURNAL OF VASCULAR RESEARCH,
36(4), 336-337.
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Lee BC, Appleton M, Shore AC, Tooke JE, Hattersley AT (1999). Impaired maximum microvascular hyperaemia in patients with MODY 3 (hepatocyte nuclear factor-1alpha gene mutations).
Diabet Med,
16(9), 731-735.
Abstract:
Impaired maximum microvascular hyperaemia in patients with MODY 3 (hepatocyte nuclear factor-1alpha gene mutations).
AIMS: Functional abnormalities of blood flow and capillary pressure may be involved in the pathogenesis of diabetic microangiopathy. Important differences in microvascular behaviour are observed between Type 1 and Type 2 diabetes mellitus, raising the possibility that the pathogenesis of microangiopathy may differ between these. MODY3 patients have hyperglycaemia as a result of genetic defect of beta-cell function rather than increased insulin resistance and are susceptible to microvascular complications and offer an opportunity to examine microvascular behaviour in this setting. METHODS: the maximum microvascular hyperaemic response to local heating of the skin was studied in 12 MODY3 patients and age and sex-matched control subjects using laser Doppler fluximetry. RESULTS: Maximum hyperaemia was reduced in MODY3 patients (median 1.17 (range 0.88-1.92)V vs. 1.70 (1.07-2.19)V normal control subjects; P=0.03) and thus was negatively associated with duration of diabetes (r(s)=-0.79; P = 0.002). CONCLUSIONS: the results suggest that the duration of diabetes is a determinant of impaired microvascular hyperaemia in MODY3 patients. The pattern of vasodilatory impairment is similar to that observed in Type 1 diabetes mellitus and differs from that seen in Type 2 diabetes. This provides support for the concept that beta cell dysfunction and insulin resistance may have differing effects on microvascular behaviour.
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Klaentschi K, Shore AC, Tooke JE, Brown JA (1999). Pressure-permeability relationships in crosslinked basement membranes.
Microvasc Res,
58(3), 329-332.
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Kernick DP, Tooke JE, Shore AC (1999). The biological zero signal in laser Doppler fluximetry - origins and practical implications.
Pflugers Arch,
437(4), 624-631.
Abstract:
The biological zero signal in laser Doppler fluximetry - origins and practical implications.
This study seeks to identify the origin of the signal, known as biological zero, that is obtained using laser Doppler fluximetry when flow is arrested. It makes specific recommendations on how this signal should be measured and handled when undertaking flow studies. The experiments undertaken using flow models, animal and human tissue, organ preparations and human subjects showed that, although there may be contributions to the no-flow laser Doppler signal from vasomotion, Brownian motion from within the vascular compartment and the effects of cuff compression, the predominant contribution is from Brownian motion arising from the interstitial compartment. The biological zero signal is additive to the flow signal providing conditions within the interstitium remain constant with changes in blood flow. It is thus concluded that the biological zero signal arises from Brownian motion of the macro molecules within the interstitium. This signal should be obtained following 3-5 min of cuff occlusion with inflation applied rapidly with the smallest cuff that is compatible with flow arrest. Biological zero should be measured under each experimental condition and subtracted from the flow signal.
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Taylor RS, Stockman J, Kernick D, Reinhold D, Shore AC, Tooke JE (1998). Ambulatory blood pressure monitoring for hypertension in general practice.
J R Soc Med,
91(6), 301-304.
Abstract:
Ambulatory blood pressure monitoring for hypertension in general practice.
Ambulatory blood pressure monitoring (ABPM) is being increasingly used in general practice. There is at present little published evidence regarding the clinical utility of ABPM in the care of patients with established hypertension in this setting. We examined this issue by undertaking ABPM in a group of patients with established hypertension. 40 patients (aged 33-60 years) currently being treated for hypertension were randomly selected from a general practice list and underwent a single 24-hour ABPM study. ABPM values were compared with clinic blood pressure (CBP) values obtained on the day of monitoring together with previous readings taken by the general practitioner (GP). In the case of mean arterial pressure, 24-hour, awake and asleep ABPM values were found to underestimate CBP values by 14 mmHg (95% confidence interval 11-16 mmHg), 9 mmHg (95% C16-12 mmHg) and 24 mmHg (95% CI 21-27 mmHg), respectively. When used to classify blood pressure control, ABPM values produced equivalent results to CBP except by the criterion of BP load, for which 24-hour ABPM showed a higher rate of unsatisfactory control. 5 patients classified by CBP to have satisfactory BP control according to current international guidelines were found to have unsatisfactory BP control by ABPM. This study demonstrates the potential value of ABPM in patients with essential hypertension in a general practice setting. ABPM provided information over and above that obtained by CBP in a substantial proportion of patients.
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Mawson DM, Shore AC (1998). Comparison of CapiFlow and frame by frame analysis for the assessment of capillary red blood cell velocity.
J Med Eng Technol,
22(2), 53-63.
Abstract:
Comparison of CapiFlow and frame by frame analysis for the assessment of capillary red blood cell velocity.
CapiFlow (CF), a new fully computerized system for the measurement of capillary blood velocity (CBV) was compared to manual frame by frame analysis (a) in a model system, and (b) in finger nailfold capillaries recorded on video tape. In the model the overall agreement between the two methods was very good (figure 1), with no significant differences being noted between the two sets of results and the calculated velocities. However, when comparing frame by frame and CapiFlow directly, CapiFlow read on average 4.50 +/- 5.21% higher than frame by frame analysis (figure 2). The in vivo results obtained by the two methods showed similar dynamic changes although some differences between the overall mean CBVs were noted (capillary 1, manual 0.13 +/- 0.59 mm s-1 versus CF 0.12 +/- 0.02 mm s-1, (mean +/- SD), p = 0.354; capillary 2, manual 0.66 +/- 0.23 mm s-1 versus CF 0.47 +/- 0.09 mm s-1, p < 0.001; capillary 3, manual 2.53 +/- 0.73 mm s-1 versus CF 2.35 +/- 0.34 mm s-1, p = 0.062). Further analyses established the optimum settings of delta limit and cross correlation. Investigations into the effects of changes in window size, window distance or video settings on CBV results obtained by CapiFlow, indicated that only settings radically different from the optimum had a significant effect on the results obtained.
Abstract.
Author URL.
Klaentschi K, Tooke JE, Shore AC (1998). Effect of increased pressure on microvascular endothelial cell growth.
JOURNAL OF VASCULAR RESEARCH,
35(3), 226-227.
Author URL.
Turner RC, Holman RR, Cull CA, Stratton IM, Matthews DR, Frighi V, Manley SE, Neil A, McElroy K, Wright D, et al (1998). Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33).
LANCET,
352(9131), 837-853.
Author URL.
Klaentschi K, Brown JA, Niblett PG, Shore AC, Tooke JE (1998). Pressure-permeability relationships in basement membrane: Effects of static and dynamic pressures.
American Journal of Physiology - Heart and Circulatory Physiology,
274(4 43-4).
Abstract:
Pressure-permeability relationships in basement membrane: Effects of static and dynamic pressures
The glomerular basement membrane (GBM) is an important component of the filtration barrier that is the glomerular capillary wall. Previously GBM permeability has been investigated only under static pressures and often within a supraphysiological range. We used Matrigel as a model of GBM and formed membranes at the base of a filtration chamber. We measured membrane permeability under static and dynamic pressures. Matrigel membranes were size and charge selective toward neutrally and negatively charged dextrans. Their permeability (as measured by hydraulic conductivity) was found to decrease from 1.61 ± 0.06 to 0.75 ± 0.07 x 10-6cm·s-1·cmH2O-1as static pressure increased from 6 to 78 cmH2O, an effect attributed to membrane compression. In comparison to static pressure, sinusoidal pressure waves with a mean pressure of 50 cmH2O decreased membrane permeability, e.g. fluid flux was reduced by a maximum of 2% to a value of 5.47 ± 0.38 x 10-5cm/s; albumin clearance was reduced by a maximum of 5.2% to a value of 9.63 ± 1.06 x 10-6ml·cm-2·s-1. Such changes were affected by the frequency of pressure wave application and could be attributed to a switching on and off of the membrane compression effect.
Abstract.
Klaentschi K, Brown JA, Niblett PG, Shore AC, Tooke JE (1998). Pressure-permeability relationships in basement membrane: effects of static and dynamic pressures.
Am J Physiol,
274(4), H1327-H1334.
Abstract:
Pressure-permeability relationships in basement membrane: effects of static and dynamic pressures.
The glomerular basement membrane (GBM) is an important component of the filtration barrier that is the glomerular capillary wall. Previously GBM permeability has been investigated only under static pressures and often within a supraphysiological range. We used Matrigel as a model of GBM and formed membranes at the base of filtration chamber. We measured membrane permeability under static and dynamic pressures. Matrigel membranes were size and charge selective toward neutrally and negatively charged dextrans. Their permeability (as measured by hydraulic conductivity) was found to decrease from 1.61 +/- 0.06 to 0.75 +/- 0.07 x 10(-6) cm.s-1.cmH2O-1 as static pressure increased from 6 to 78 cmH2O, an effect attributed to membrane compression. In comparison to static pressure, sinusoidal pressure waves with a mean pressure of 50 cmH2O decreased membrane permeability, e.g. fluid flux was reduced by a maximum of 2% to a value of 5.47 +/- 0.38 x 10(-5) cm/s; albumin clearance was reduced by a maximum of 5.2% to a value of 9.63 +/- 1.06 x 10(-6) ml.cm-2.s-1. Such changes were affected by the frequency of pressure wave application and could be attributed to a switching on and off of the membrane compression effect.
Abstract.
Author URL.
Lewis DM, Bradwell AR, Shore AC, Beaman M, Tooke JE (1997). Capillary filtration coefficient and urinary albumin leak at altitude.
Eur J Clin Invest,
27(1), 64-68.
Abstract:
Capillary filtration coefficient and urinary albumin leak at altitude.
Rapid ascent to altitude risks the development of acute mountain sickness. This study demonstrates changes in peripheral capillary filtration coefficient and renal protein loss in subjects suffering from various degrees of mountain sickness after passive ascent to 4559 m. Capillary filtration coefficient of the calf capillary bed, measured by computer-based multistep strain gauge plethysmography, increased significantly after 23.5 h at altitude when symptoms were most severe: 4.45 (2.76-6.03) to 6.31 (3.86-11.07) ml min(-1) per 100 g of tissue mmHg(-1), median (range) (P < 0.02). Urinary albumin excretion was increased after one night at altitude from 1.1 (0.6-1.5) to 2.45 (1.0-6-8) mg of albumin per mmol of creatinine (P < 0.05). These results demonstrate simultaneous leakage of a peripheral capillary bed to fluid measured by strain gauge plethysmography, and renal albumin leak, and suggest a systemic process of increased capillary leakage for different-sized molecules caused by rapid exposure to hypobaric hypoxia.
Abstract.
Author URL.
Kunzek S, Quinn MW, Shore AC (1997). Does change in skin perfusion provide a good index to monitor the sympathetic response to a noxious stimulus in preterm newborns?.
Early Hum Dev,
49(2), 81-89.
Abstract:
Does change in skin perfusion provide a good index to monitor the sympathetic response to a noxious stimulus in preterm newborns?
Skin perfusion was measured using laser Doppler fluximetry (LDF) in 16 preterm babies undergoing a standardised heel prick procedure. Although there was a significant reduction in skin blood flow following the heel prick, this was variable and dependent on basal skin blood flow. This, together with loss of data due to movement artefact, makes this technique unreliable in quantifying the sympathetic response to a noxious stimulus in preterm infants.
Abstract.
Author URL.
Noon JP, Walker BR, Webb DJ, Shore AC, Holton DW, Edwards HV, Watt GC (1997). Impaired microvascular dilatation and capillary rarefaction in young adults with a predisposition to high blood pressure.
J Clin Invest,
99(8), 1873-1879.
Abstract:
Impaired microvascular dilatation and capillary rarefaction in young adults with a predisposition to high blood pressure.
Increased vascular resistance in essential hypertension occurs mainly in microvessels with luminal diameters < 100 microm. It is not known whether abnormalities in these vessels are a cause or consequence of high blood pressure (BP). We studied 105 men (aged 23-33 yr) in whom predisposition to high blood pressure has been characterized by both their own BP and those of their parents. Factors that are secondary to high BP correlate with offspring BP irrespective of parental BP, but factors that are components of the familial predisposition to high BP are more closely associated with higher BP in offspring whose parents also have high BP. Offspring with high BP whose parents also have high BP had impaired dermal vasodilatation in the forearm following ischemia and heating (289+/-27 [n = 25] versus 529+/-40 [n = 26], 476+/-38 [n = 30], and 539+/-41 flux units [n = 24] in other groups; P < 0.0001) and fewer capillaries on the dorsum of the finger (23+/-0.8 capillaries/0.25 mm2 versus 26+/-0.8 in all other groups; P < 0.003). Except for BP, other hemodynamic indices (including cardiac output and forearm vascular resistance) were not different. The dermal vessels of men who express a familial predisposition to high BP exhibit increased minimum resistance and capillary rarefaction. Defective angiogenesis may be an etiological component in the inheritance of high BP.
Abstract.
Author URL.
Jaap AJ, Shore AC, Tooke JE (1997). Relationship of insulin resistance to microvascular dysfunction in subjects with fasting hyperglycaemia.
Diabetologia,
40(2), 238-243.
Abstract:
Relationship of insulin resistance to microvascular dysfunction in subjects with fasting hyperglycaemia.
Microvascular hyperaemia is decreased in subjects at risk of developing non-insulin-dependent diabetes mellitus (NIDDM) who have fasting hyperglycaemia. Such microvascular abnormalities may be involved in the pathogenesis of diabetic microangiopathy. To investigate the relationship of reduced microvascular hyperaemia to metabolic and blood pressure abnormalities associated with the prediabetic state, we studied 24 subjects with fasting hyperglycaemia and 24 age- and sex-matched control subjects. The microvascular hyperaemic response to local heating of the skin on the dorsum of the foot measured by laser Doppler fluximetry was reduced in the subjects with fasting hyperglycaemia (1.18 [0.87-1.83] volts vs 1.51 [1.30-2.14] volts normal subjects; p = 0.0002) and was negatively correlated with fasting plasma insulin concentration (Rs = 0.70; p = 0.001) and positively related to insulin sensitivity determined by continuous infusion of glucose with model assessment (CIGMA) (Rs = 0.52; p = 0.01), but showed no association with fasting plasma glucose, beta-cell function 24 h ambulatory blood pressure profiles or serum lipid concentrations. These results suggests that hyperinsulinaemia, as a result of insulin resistance, may have a detrimental effect on microvascular function in the prediabetic state.
Abstract.
Author URL.
Tooke JE, Shore AC, Cohen RA, Kluft C (1996). Diabetic angiopathy: tracking down the culprits.
J Diabetes Complications,
10(3), 173-181.
Author URL.
Jaap AJ, Shore AC, Tooke JE (1996). Differences in microvascular fluid permeability between long-duration type I (insulin-dependent) diabetic patients with and without significant microangiopathy.
Clin Sci (Lond),
90(2), 113-117.
Abstract:
Differences in microvascular fluid permeability between long-duration type I (insulin-dependent) diabetic patients with and without significant microangiopathy.
1. To further investigate the role of microvascular functional changes in the pathogenesis of diabetic microangiopathy in type 1 diabetes, microvascular fluid permeability was measured in nine patients with a long disease duration and no or minimal (background retinopathy alone) microangiopathy, nine age-, sex- and duration-matched patients with microalbuminuria and nine control subjects. Microvascular fluid permeability was assessed by determination of the forearm capillary filtration coefficient using a sensitive strain-gauge plethysmographic technique. 2. Microvascular fluid permeability was significantly higher in the patients with microalbuminuria [8.5 (6.8-15.2) x 10(-3)ml min-1 100g-1 of tissue mmHg-1; median (range)] than in the patients with no or minimal complications [5.2 (3.6-7.0) x 10(-3) ml min-1 100g-1 of tissue mmHg-1, P < 0.001]. There was, however, no significant difference in microvascular fluid permeability between the patients with no or minimal complications and control subjects [4.5 (3.2-5.7) x 10(-3) ml min-1 100g-1 of tissue mmHg-1, P = 0.31]. Blood pressure and glycaemic control were similar in the two groups of diabetic patients. 3. These results provide further evidence that changes in microvascular permeability are found in other vascular beds in patients with incipient nephropathy, whereas no such changes are found in patients with a long disease duration and little evidence of microangiopathy.
Abstract.
Author URL.
Mahy IR, Lewis DM, Shore AC, Penney MD, Smith LD, Tooke JE (1996). Disturbance of peripheral microvascular fluid permeability by the onset of atrioventricular asynchrony in patients with programmable pacemakers.
Heart,
75(5), 509-512.
Abstract:
Disturbance of peripheral microvascular fluid permeability by the onset of atrioventricular asynchrony in patients with programmable pacemakers.
BACKGROUND: in vitro and in vivo evidence suggests that atrial natriuretic peptide can enhance fluid flux from intravascular to extravascular compartments. The relevance of this to human pathophysiology remains unclear. OBJECTIVES: to determine whether a central haemodynamic change associated with increased plasma concentrations of atrial natriuretic peptide produces detectable change in the capillary filtration coefficient in a peripheral microvascular bed. PATIENTS: 12 patients with programmable dual chamber permanent pacemakers. METHODS: Calf capillary filtration coefficient (using a modified plethysmographic technique) and plasma atrial natriuretic peptide concentrations were measured during atrioventricular synchronous and ventricular pacing. RESULTS: Atrioventricular asynchrony was associated with higher mean (SD) concentrations of atrial natriuretic peptide (231.9 (123.1) v 53.5 (38.8) pg/ml) and an increased mean (SD) calf capillary filtration coefficient (4.2 (1.1) v 3.6 (1.1) ml/min.mm Hg.100 ml x 10(-3)), but there was no correlation between the magnitude of the change in these variables in individual patients. CONCLUSIONS: the peripheral capillary filtration coefficient may change in response to altered central haemodynamics. Atrial natriuretic peptide remains one potential candidate mechanism, but other factors are also likely to be involved.
Abstract.
Author URL.
Noon JP, Haynes WG, Webb DJ, Shore AC (1996). Local inhibition of nitric oxide generation in man reduces blood flow in finger pulp but not in hand dorsum skin.
J Physiol,
490 ( Pt 2)(Pt 2), 501-508.
Abstract:
Local inhibition of nitric oxide generation in man reduces blood flow in finger pulp but not in hand dorsum skin.
1. Nitric oxide generation is important in the regulation of resistance vessel tone. Until now, however, there has been no evidence of such a role for basal generation of nitric oxide in the skin microcirculation of humans. 2. To investigate this, L-NG-monomethylarginine (L-NMMA), a competitive inhibitor of nitric oxide synthase, was administered at 1, 2 and 4 mumol min-1 (each for 10 min), via the brachial artery, in six healthy male subjects. 3. At each dose, using laser Doppler fluximetry, red blood cell flux was measured as an index of blood flow in the pulp of the thumb, an area rich in arteriovenous anastomoses, and on the dorsal surface of the hand, where arteriovenous anastomoses are rare. Finger nailfold capillary blood velocity was monitored at each dose using videomicroscopy. Forearm blood flow was measured by venous occlusion plethysmography, before, and 8 min after, completing infusion of L-NMMA. All data were obtained from both the infused and control arms. 4. L-NMMA reduced blood flow in the infused forearm by 37% (P = 0.005). In contrast, dorsum red cell flux, capillary blood velocity, and skin temperature were unchanged. There was, however, a significant reduction in thumb red cell flux (ANOVA, P = 0.0001), reaching a maximum reduction of 33% with 4 mumol min-1 L-NMMA. There were no effects apparent in the opposite arm. 5. These results suggest that endogenous nitric oxide production may be more important in regulating microvascular skin blood flow in regions rich in arteriovenous anastomoses than in areas containing mainly nutritive vessels.
Abstract.
Author URL.
Hahn M, Klyscz T, Shore AC, Jünger M (1996). Newly developed software for capillary blood pressure analysis in microcirculatory research.
Int J Microcirc Clin Exp,
16(3), 129-136.
Abstract:
Newly developed software for capillary blood pressure analysis in microcirculatory research.
The introduction of the servonulling technique by Wiederhielm in 1963 allowed for the first time continuous and dynamic recording of capillary blood pressure (CP). In 1979 Mahler used this technique for the first measurements in humans. Data analysis was limited to manual analysis of chart recordings. Nowadays fast analog-digital converters with ay high sampling frequency are used for data recordings, and consequently there is a need for an easy-to-use software for data analysis of CP data. The presented newly developed computer software allows analysis of mean CP, taking into account the zero pressure measured before and after capillary cannulation. The simultaneously recorded electrocardiogram R wave is used as a marker for the calculation of the mean capillary pulse pressure waves and of their characteristic data. This may help determine the significance of the capillary pulse waveform for microvascular function. Changes in the pulse waveform may be the only detectable difference between patients and healthy controls. Analysis of simultaneously recorded temperature, the display of markers for valid readings, and the possibility of excluding nonvalid data or artefacts from analysis are additional features.
Abstract.
Author URL.
Morris SJ, Shore AC (1996). Skin blood flow responses to the iontophoresis of acetylcholine and sodium nitroprusside in man: possible mechanisms.
J Physiol,
496 ( Pt 2)(Pt 2), 531-542.
Abstract:
Skin blood flow responses to the iontophoresis of acetylcholine and sodium nitroprusside in man: possible mechanisms.
1. The mechanisms involved in the human skin blood flow responses to iontophoretic application of acetylcholine (ACH; delivered using an anodal charge) or sodium nitroprusside (SNP; administered with a cathodal charge) are unclear. The aims of this study were to investigate possible contributions of prostaglandin production to the increase in skin blood flow induced following the iontophoresis of ACh and to investigate possible contributions from local sensory nerves to the perfusion responses induced by ACh, SNP and their vehicles. 2. The contribution of prostaglandins to the ACh response was determined in a randomized double-blind study of eight healthy subjects, who were studied on two occasions. Basal responses to ACh were measured before the oral administration of 600 mg soluble aspirin in diluted orange juice (1 occasion or orange juice (1 occasion) and again 30 min after the drink. The contribution of local sensory nerve activation to the responses to ACh and ACh vehicle (8 subjects) and to SNP and SNP vehicle (7 subjects) was assessed. EMLA (5%) (a eutectic mixture of lignocaine and prilocaine) and placebo cream were applied to two separate areas on the forearm in a double-blind randomized manner 2 h before drug responses were measured. In all studies the skin microcirculation responses to iontophoretically applied drug vehicle (1 site) and drug (2 sites) were recorded by laser Doppler perfusion imaging. 3. The increase in forearm skin perfusion (P < 0.001) in response to the iontophoresis of ACh minus the response to ACh vehicle was not significantly different following placebo or aspirin administration. The increase in forearm skin red blood cell flux (P < 0.001) in response to the iontophoresis of ACh minus the response to ACh vehicle was not significantly different at the placebo-compared with the EMLA-treated site. THe small increase in perfusion (P < 0.001) in response to the iontophoresis of ACh vehicle was significantly inhibited at the EMLA-compared with the placebo-treated site (P < 0.05). The marked increase in perfusion (P < 0.001) in response to the iontophoresis of SNP vehicle was significantly inhibited at the EMLA-compared with the placebo-treated site (P < 0.01). 4. These data suggest that in healthy volunteers: (1) mechanisms other than prostaglandin production and local sensory nerve activation may be involved in the increase in skin perfusion observed following the iontophoretic application of ACh; and (2) stimulation of local sensory nerves may be responsible for the increase in tissue perfusion observed following the iontophoretic application of either ACh vehicle or SNP vehicle.
Abstract.
Author URL.
Jaap AJ, Shore AC, Stockman AJ, Tooke JE (1996). Skin capillary density in subjects with impaired glucose tolerance and patients with type 2 diabetes.
Diabet Med,
13(2), 160-164.
Abstract:
Skin capillary density in subjects with impaired glucose tolerance and patients with type 2 diabetes.
In view of recent interest in the role of impaired early development and the pathogenesis of cardiovascular disease and carbohydrate intolerance in adults, this study examines whether reduced skin capillary density contributes to the limited microvascular hyperaemic responses observed in patients with Type 2 diabetes and subjects with impaired glucose tolerance (IGT). Fifteen patients with Type 2 diabetes, 15 subjects with IGT and 15 matched non-diabetic control subjects were studied. Capillary videomicroscopy was used to record images of the skin capillaries on the dorsum of the middle phalanx of the left middle finger before and after 10 min venous occlusion at 35 mmHg. There were no significant differences between the three groups in either basal capillary density (112 (71-144) caps mm-2 Type 2 patients (median and range) vs 107 (76-140) caps mm-2 IGT subjects vs 112 (76-138) caps mm-2 control subjects; p = 0.9, Kruskal Wallis), or following venous occlusion (122 (87-157) caps mm-2 vs 121 (90-143) caps mm-2 vs 123 (81-147) caps mm-1; p = 0.9). In addition there were no differences in blood pressure, BMI or skin temperature. These results do not support the concept of impaired early development of the skin microcirculation in patients with Type 2 diabetes or IGT and suggest that mechanisms other than reduced capillary density are involved in limiting microvascular vasodilation.
Abstract.
Author URL.
Morris SJ, Kunzek S, Shore AC (1996). The effect of acetylcholine on finger capillary pressure and capillary flow in healthy volunteers.
J Physiol,
494 ( Pt 1)(Pt 1), 307-313.
Abstract:
The effect of acetylcholine on finger capillary pressure and capillary flow in healthy volunteers.
1. Constitutive nitric oxide (NO) synthase has been demonstrated in human skin microvascular endothelial cells; however, the physiological significance of this finding is not known. The aim of this study was to investigate the effects of acetylcholine (ACh), which stimulates the release of NO from endothelial cells, on skin capillary pressure, capillary pulse pressure amplitude (CPPA) and capillary red blood cell velocity (CBV) in healthy volunteers. 2. Finger nailfold capillary pressure was measured in five healthy volunteers. CBV was measured in capillaries of the dorsal middle phalangeal area of the finger in six subjects using a recently developed capillary anemometer. In each case the responses to ionophoretically applied ACh and vehicle were measured on two separate fingers on the left hand. 3. Application of vehicle did not significantly change either capillary pressure, CPPA or CBV. ACh significantly increased capillary pressure (from 15.8 +/- 2.2 mmHg under basal conditions to 27.7 +/- 3.8 mmHg at the plateau of the ACh response; P < 0.008), CPPA (from 2.4 +/- 2.4 mmHg at baseline to 8.4 +/- 2.4 mmHg at the plateau of the drug response; P < 0.013) and CBV (from 0.54 +/- 0.22 mm s-1 at baseline to 2.46 +/- 1.12 mm s-1 after ACh; P < 0.008). 4. The increases in capillary pressure, CPPA and CBV following the application of ACh suggest that the overall effect of ACh was to induce a reduction in the pre- to postcapillary resistance ratio.
Abstract.
Author URL.
Mahy IR, Tooke JE, Shore AC (1995). Capillary pressure during and after incremental venous pressure elevation in man.
J Physiol,
485 ( Pt 1)(Pt 1), 213-219.
Abstract:
Capillary pressure during and after incremental venous pressure elevation in man.
1. The relationship between capillary pressure and venous pressure was investigated during incremental venous pressure elevation in seven healthy volunteers. Pressure was measured simultaneously at the apex of finger nailfold capillaries and in the dorsal vein of the ipsilateral hand. Elevation of venous pressure was accomplished by inflation of a sphygmomanometer cuff around the upper arm. 2. As venous pressure rose, apical capillary pressure (Pc) approached venous pressure (Pv). For changes in Pv greater than 20 mmHg, the increment in Pc was invariably less than the increment in Pv. 3. Above a cuff pressure of 20 mmHg, capillary pulse pressure amplitude (CPPA) tended to decline. At 50 mmHg cuff pressure, CPPA was lower than at baseline for all subjects. At baseline, CPPA was 4.2 +/- 2.0 mmHg (mean +/- S.D.) and at 50 mmHg it was 2.3 +/- 1.1 mmHg (P = 0.02). 4. In the period between 1 and 6 min following cuff release, both Pc and CPPA were lower than at baseline. (At baseline, Pc was 16.1 +/- 2.3 mmHg and following cuff release it was 11.2 +/- 1.5 mmHg (P = 0.02). At baseline, CPPA was 4.2 +/- 2.0 mmHg and following cuff release it was 1.8 +/- 1.1 mmHg (P = 0.03).) 5. Estimated changes in the ratio of pre- to postcapillary resistance (Ra/Rv), using arterial blood pressure (Pa) measured in the contralateral arm, and taking (Pa-Pc)/(Pc-Pv) to approximate to Ra/Rv, closely mirrored changes in CPPA.(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract.
Author URL.
Shore AC, Sandeman DD, Tooke JE (1995). Capillary pressure, pulse pressure amplitude, and pressure waveform in healthy volunteers.
Am J Physiol,
268(1 Pt 2), H147-H154.
Abstract:
Capillary pressure, pulse pressure amplitude, and pressure waveform in healthy volunteers.
The influence of gender, local temperature, and systemic blood pressure on human capillary pressure is unknown. Finger nail fold capillary pressure was therefore directly measured in 74 healthy supine volunteers (40 female) at midaxillary level. Capillary pressure was lower in women than in men (15.9 +/- 3.0 vs. 18.2 +/- 2.3 mmHg; P = 0.001), particularly in premenopausal women, but was not related to systolic, diastolic, or mean blood pressure. Capillary pulse pressure amplitude was related to skin temperature, an effect more marked in women (P = 0.003). There was a significant association between skin temperature and the time taken for the systolic pressure rise to reach the capillary, in women only (r = -0.69, P < 0.001). Increasing age reduced the high-frequency waves in the pressure waveform [2nd harmonic percentage of fundamental: r = -0.52 and P = 0.002 (women), r = -0.52 and P = 0.004 (men)]. Thus mean capillary pressure and the pressure waveform may be influenced by gender, age, and skin temperature, illustrating the necessity to adequately match control groups during assessments of capillary pressure pathophysiology.
Abstract.
Author URL.
Mahy IR, Shore AC, Smith LD, Tooke JE (1995). Disturbance of peripheral microvascular function in congestive heart failure secondary to idiopathic dilated cardiomyopathy.
Cardiovasc Res,
30(6), 939-944.
Abstract:
Disturbance of peripheral microvascular function in congestive heart failure secondary to idiopathic dilated cardiomyopathy.
OBJECTIVES: Previous studies of peripheral microvascular function in human heart failure have concentrated on changes in flow, and there is little information concerning the impact of heart failure on the principal determinants of transcapillary fluid exchange. This study investigated whether alterations in capillary pressure and microvascular fluid permeability can be detected in subjects with idiopathic dilated cardiomyopathy. METHODS: Finger nailfold capillary pressure and calf capillary filtration coefficient (CFC) were measured in parallel studies of two overlapping groups of 12 non-oedematous subjects with idiopathic dilated cardiomyopathy and mild to moderate heart failure and in age- and sex-matched healthy controls. Capillary pressure was measured by direct cannulation using an electronic resistance feedback servonulling technique, and CFC by mercury-in-silastic strain gauge plethysmography using a modification of the technique which avoids assumptions concerning isovolumetric venous pressure. RESULTS: Following correction for differences in skin temperature, capillary pressure was lower in the subjects with heart failure (P = 0.02). Both CFC and isovolumetric venous pressure were greater in the subjects with heart failure than in controls (3.4 +/- 0.9 vs. 2.6 +/- 0.7 ml.min-1.mmHg-1.100 ml-1, P = 0.03; 27.1 +/- 8.4 vs. 17.2 +/- 7.2 mmHg, P = 0.01). CONCLUSIONS: These data suggest that factors other than changes in arterial inflow and venous outflow pressures are likely to play an important role in the disruption of microvascular homeostasis which occurs in heart failure. Changes in capillary hydraulic conductance may contribute to the pathogenesis of oedema.
Abstract.
Author URL.
Jaap AJ, Pym CA, Seamark C, Shore AC, Tooke JE (1995). Microvascular function in type 2 (non-insulin-dependent) diabetes: improved vasodilation after one year of good glycaemic control.
Diabet Med,
12(12), 1086-1091.
Abstract:
Microvascular function in type 2 (non-insulin-dependent) diabetes: improved vasodilation after one year of good glycaemic control.
Abnormalities of microvascular function may be important in the development of diabetic microangiopathy. The major functional abnormality identified in patients with Type 2 diabetes has been a marked limitation of microvascular vasodilation, which is present from the time of diagnosis. The effects of sustained improvements in glycaemic control on vasodilator capacity in Type 2 diabetes are unknown. Twelve Type 2 diabetic patients were studied prospectively for 1 year after diagnosis. The reduced maximum hyperaemic response to local heating of the foot skin present at the time of diagnosis remained unchanged after 3 months of improved glycaemic control (1.12 +/- 0.56 V at diagnosis vs 1.21 +/- 0.69 V at 3 months, mean +/- SD; p = 0.25), but was improved after 1 year (1.42 +/- 0.91 V; p = 0.04 vs 3 months). The percentage increase in maximum hyperaemia correlated with the percentage decrease in HbA1c (rs = 0.53, p = 0.04). These results suggest that the early microvascular abnormalities demonstrated in Type 2 diabetes are potentially reversible and provide a further reason for striving for optimal glycaemic control in this patient group.
Abstract.
Author URL.
Mahy IR, Shore AC, Smith LD, Tooke JE (1995). Postural vasoconstrictor response in human heart failure.
Int J Microcirc Clin Exp,
15(3), 137-142.
Abstract:
Postural vasoconstrictor response in human heart failure.
In order to study whether posturally induced vasoconstriction is impaired in subjects with heart failure, laser Doppler fluximetry was used to measure blood flow in the cutaneous microvascular bed of the foot at rest and during passive lowering of the extremity below heart level, in subjects with idiopathic dilated cardiomyopathy and in healthy controls. Two sites were studied: the toe pulp where arteriovenous anastomoses are numerous and the dorsum of the foot where such anastomoses are absent. Despite demonstrating a marked reduction in cutaneous blood flow at rest at each site [dorsum 3.0 AU (1.8-4.5) [median (range)] in heart failure patients vs 4.5 AU (1.8-31.6) in controls; toe 8.7 AU (3.1-33.5) in heart failure vs. 44.7 AU (5.2-280.0) in controls, p < 0.01], the results suggest that in non-oedematous subjects with severe left ventricular dysfunction there is no major disturbance of the postural vasoconstrictor response, either at a site rich in highly innervated anastomoses [43.6% (14.5-89.4) vs. 43.7% (15.6-91.1)] or in a site with few such anastomoses [79.7% (39.6-92.3) vs 69.6% (10.1-94.9)].
Abstract.
Author URL.
Morris SJ, Shore AC, Tooke JE (1995). Responses of the skin microcirculation to acetylcholine and sodium nitroprusside in patients with NIDDM.
Diabetologia,
38(11), 1337-1344.
Abstract:
Responses of the skin microcirculation to acetylcholine and sodium nitroprusside in patients with NIDDM.
The mechanisms involved in the pathogenesis of microangiopathy occurring in non-insulin-dependent diabetes mellitus (NIDDM) are unclear. In the present study, blood flow responses to the vasodilators acetylcholine (which acts via the endothelium) and sodium nitroprusside (a smooth muscle relaxant) were evaluated in this patient group. In 14 male patients with NIDDM, treated with either diet alone (n = 6) or diet plus insulin, (mean age 59 years) and 14 age-pair-matched control subjects, forearm skin perfusion following multiple doses of iontophoretically applied 1% acetylcholine and 0.01% sodium nitroprusside was recorded by laser Doppler perfusion imaging. Basal skin blood flow was not significantly different in the diabetic group compared with the control group. The following results are expressed as drug-minus-vehicle response. Acetylcholine significantly increased forearm skin perfusion (p < 0.001, analysis of variance) in all subjects, but the vasodilatation was attenuated in the patient group compared with control subjects (0.86 +/- 0.09 vs 1.36 +/- 0.14 arbitrary units of volts (V) respectively, at the fifth measurement point, mean +/- SEM, p < 0.01). Skin perfusion significantly increased following sodium nitroprusside (p < 0.001) but was lower in patients than control subjects (0.12 +/- 0.05 vs 0.45 +/- 0.11 V, respectively, at the fifth measurement point, p < 0.01). These data suggest that endothelial and/or smooth muscle function may be impaired in the skin microcirculation of patients with NIDDM.
Abstract.
Author URL.
Jaap AJ, Shore AC, Gamble J, Gartside IB, Tooke JE (1994). Capillary filtration coefficient in type II (non-insulin-dependent) diabetes.
J Diabetes Complications,
8(2), 111-116.
Abstract:
Capillary filtration coefficient in type II (non-insulin-dependent) diabetes.
Changes in microvascular permeability may be important in the pathogenesis of diabetic microangiopathy. In order to assess microvascular fluid permeability, the capillary filtration coefficient was determined in the forearm of 24 normotensive type II diabetic patients with minimal evidence of microangiopathy and satisfactory glycemic control, and 24 age- and sex-matched control subjects, using a sensitive strain gauge plethysmographic system. The median capillary filtration coefficient was not significantly different in the type II diabetic patients and control subjects [5.3 (3.2 - 9.1) x 10(-3) mL.min-1.100 g tissue-1.mm Hg-1 versus 5.4 (3.5 - 8.0) x 10(-3) mL.min-1.100 g tissue-1.mm Hg-1, p = 0.98)]. There were no correlations between capillary filtration coefficient and age, blood pressure, body mass index, duration of diabetes, glycemic control, or the presence of microvascular complications. These findings contrast with type I diabetes, where capillary filtration coefficient is elevated at an early stage in the disease, and lend support to the theory that there are differences in early microvascular functional abnormalities between type I and type II diabetes.
Abstract.
Author URL.
Shore AC, Jaap AJ, Tooke JE (1994). Capillary pressure in patients with NIDDM.
Diabetes,
43(10), 1198-1202.
Abstract:
Capillary pressure in patients with NIDDM.
The hemodynamic hypothesis suggests that raised capillary pressure may play a role in the pathogenesis of diabetic microangiopathy. Although patients with non-insulin-dependent diabetes mellitus (NIDDM) and insulin-dependent diabetes NIDDM) develop a similar range of microvascular complications, differences in their expression and prevalence suggest that different pathogenic mechanisms may be operational. Capillary pressure is elevated in IDDM; the aim of this study was to assess whether capillary pressure was also elevated in NIDDM. Twenty-one patients with NIDDM (15 men) and 21 healthy control subjects matched for age, sex, and skin temperature were investigated supine with the hand at heart level. Finger nailfold capillary pressure was measured after direct cannulation at the summit of the capillary loops using glass micropipettes. The groups were matched for skin temperature (30.4 [24.2-33.8] degrees C, median [95% confidence interval], NIDDM patients vs. 30.0 [23.4-33.6] degrees C control subjects), age (62.0 [39.4-72.7] years NIDDM patients vs. 62.0 [39.4-72.0] years control subjects), and both systolic (sBP) and diastolic (dBP) blood pressures (133.0 [111.0-167.3]/78.0 [57.0-89.5] mmHg NIDDM patients vs. 133.0 [114.1-158.9]/80.0 [68.2-88.9] mmHg control subjects). Capillary pressure did not differ in the two groups (17.6 [13.1-21.2] mmHg NIDDM patients vs. 19.1 [14.1-23.6] mmHg control subjects [NS]). There was no correlation of capillary pressure with either HbA1c or glucose; however, there was a negative association between capillary pressure and diabetes duration (Rs = -0.50, P = 0.020).(ABSTRACT TRUNCATED AT 250 WORDS)
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Mahy IR, Shore AC, Smith LD, Tooke JE (1994). Capillary pulse waveform in aortic stenosis.
Int J Microcirc Clin Exp,
14(5), 257-261.
Abstract:
Capillary pulse waveform in aortic stenosis.
The importance of the dynamic nature of perfusion pressure within the peripheral microcirculation is increasingly recognised. Capillary pressure is determined not only by arterial inflow pressure, but is also subject to a variety of local and systemic influences which have been shown to affect both mean pressure and the capillary pulse waveform. To what extent changes in central pulse waveform influence capillary pressure has yet to be determined. By using a dynamic technique of capillary pressure measurement in human subjects with aortic stenosis, we have been able to show that the characteristics of the pulse waveform typically associated with large vessels in this condition are also readily detectable at a capillary level despite local influences. However, changes in the rate of pulse wave transmission described in large arteries were not apparent at a microvascular level. Unlike mean capillary pressure and capillary pulse pressure, pulse waveform in the capillary mimics central haemodynamics.
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Author URL.
Shore AC, Tooke JE (1994). Microvascular function in human essential hypertension.
J Hypertens,
12(7), 717-728.
Author URL.
Flynn MD, Shore AC, Sandeman DE, Mawson D, Donohoe M, Tooke JE (1994). Oedema in patients with Addison's disease on replacement therapy: glucocorticoid excess and mineralocorticoid deficiency?.
QJM,
87(7), 437-441.
Abstract:
Oedema in patients with Addison's disease on replacement therapy: glucocorticoid excess and mineralocorticoid deficiency?
Steroid hormones influence mechanisms related to oedema formation, including postural vasoconstriction and vascular tone. We studied fifteen patients (7 male, 8 female) with primary adrenal failure on clinically optimal replacement therapy. Five patients, all female, had clinically detectable oedema. Patients with oedema had evidence of mineralocorticoid deficiency, with increased supine and erect plasma renin activity and greater postural fall in blood pressure. Mean morning plasma cortisol levels were significantly higher in the group with oedema, suggesting they were receiving insufficient mineralocorticoid and a possible relative excess of glucocorticoid. There were no significant differences between patients with and without oedema in lower-limb cutaneous blood flow or in postural vasoconstrictor responses measured by laser Doppler flowmetry. The mechanism of oedema formation is unclear, but appears not to be modulated by haemodynamic mechanisms with expansion of intravascular volume or, in contrast to the known effects of sex hormones, by impairment of postural vasoconstriction. Theoretically, excess glucocorticoid replacement may result in oedema formation, by direct action on vascular tone, by altering capillary permeability, or by influencing other factors such as atrial natriuretic peptide. Measurement of plasma renin activity in conjunction with plasma cortisol profiles may be useful in adjusting replacement therapy in patients with Addison's disease and oedema.
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Shore AC, Price KJ, Sandeman DD, Tripp JH, Tooke JE (1994). Posturally induced vasoconstriction in diabetes mellitus.
Arch Dis Child,
70(1), 22-26.
Abstract:
Posturally induced vasoconstriction in diabetes mellitus.
In healthy subjects, standing elicits a reduction in blood flow to the skin of the foot. In adults with insulin dependent diabetes this posturally induced response is deficient, resulting in capillary hypertension when the foot is in the dependent position (that is, below heart level). Such functional abnormalities of the microcirculation in diabetes may precede any evidence of clinically detectable microangiopathy. This study investigates the posturally induced change in blood flow to the skin of the foot in prepubertal and postpubertal patients with insulin dependent diabetes. Laser Doppler fluximetry was used to assess the postural change in blood flow at the pulp of the great toe. Postural vasoconstriction (dependent flux value/supine flux value x 100) was greater after puberty in normal subjects (median (range) 60.4 (7.0-164.9)% prepubertal v 20.5 (5.9-101.0)% postpubertal). Prepubertal children with diabetes did not differ from their healthy peers (69.8 (7.2-192.7)% with diabetes v 60.4 (7.0-164.9)% controls); however postpubertal children with diabetes had a significantly impaired postural vasoconstriction (40.6 (7.9-140.2)% with diabetes v 20.5 (5.9-101.7)% controls). Abnormalities in the normal reduction of blood flow on standing occurred in young postpubertal children with diabetes, most of whom were free of complications.
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Jaap AJ, Hammersley MS, Shore AC, Tooke JE (1994). Reduced microvascular hyperaemia in subjects at risk of developing type 2 (non-insulin-dependent) diabetes mellitus.
Diabetologia,
37(2), 214-216.
Abstract:
Reduced microvascular hyperaemia in subjects at risk of developing type 2 (non-insulin-dependent) diabetes mellitus.
Abnormalities of microvascular function may be important in the pathogenesis of diabetic microangiopathy. As such changes are already present at diagnosis in patients with Type 2 (non-insulin-dependent) diabetes mellitus, subjects at risk of developing the disease, who had elevated fasting plasma glucose concentrations below the diabetic range, were studied. The maximal microvascular hyperaemic response to local heating was determined in the feet of 11 subjects with fasting hyperglycaemia and 11 age- and sex-matched control subjects. There was reduced maximal hyperaemia in the subjects with fasting hyperglycaemia (1.01 [0.71-1.57]V, median and range), when compared to control subjects (1.41 [1.32-2.13]V, p < 0.001). It is unlikely that this limited vasodilation is a result of the mild degree of hyperglycaemia observed in the subjects included in this study. Further studies are therefore required to address the possible mechanisms of limited microvascular reactivity in subjects at risk of developing Type 2 diabetes.
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Hahn M, Shore AC (1994). The effect of rapid local cooling on human finger nailfold capillary blood pressure and blood cell velocity.
J Physiol,
478 ( Pt 1)(Pt 1), 109-114.
Abstract:
The effect of rapid local cooling on human finger nailfold capillary blood pressure and blood cell velocity.
1. The effect of a rapid local reduction in finger temperature on finger nailfold capillary blood pressure and blood cell velocity was investigated in healthy subjects. 2. Cooling was achieved by placing the finger into an adjustable copper cylindrical finger holder, which incorporated a Peltier element within its base; thus the entire finger from just distal to the nailfold to the interphalangeal joint was cooled. The Peltier element was cooled to 8 degrees C for 5 min. 3. Finger tip temperature was reduced to 76 +/- 12% of its resting value during cooling (28.8 +/- 4.8 degrees C (mean +/- S.D.) baseline versus 22.1 +/- 6.4 degrees C in the fifth minute of cooling, P = 0.012); this was accompanied by a reduction in capillary blood cell velocity similar to that described previously in cooling experiments using cold air (baseline median, 671 microns s-1 (range, 29-4421 microns s-1) versus median during cooling, 221 microns s-1 (range, 6.7-2579 microns s-1), P = 0.012). 4. The magnitude and timing of the capillary pressure response to cooling and recovery varied between individuals. In the group as a whole, there was no significant fall in capillary pressure during cooling (basal before cooling, 16.7 +/- 3.7 mmHg versus minimum during cooling, 15.1 +/- 3.5 mmHg, P = 0.12), whereas capillary pulse pressure amplitude was reduced (basal before cooling, 5.3 +/- 3.1 mmHg versus minimum during cooling, 3.7 +/- 2.6 mmHg, P = 0.028). 5. During the recovery phase, post cooling, both capillary pressure and capillary pulse pressure amplitude were markedly elevated compared to baseline or the cooling phase.(ABSTRACT TRUNCATED AT 250 WORDS)
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Jaap AJ, Shore AC, Tooke JE (1994). The influence of hypertension on microvascular blood flow and resistance to flow in the skin of patients with type 2 (non-insulin-dependent) diabetes.
Diabet Med,
11(9), 883-887.
Abstract:
The influence of hypertension on microvascular blood flow and resistance to flow in the skin of patients with type 2 (non-insulin-dependent) diabetes.
Maximum microvascular blood flow and resistance to flow were determined in the skin of nine hypertensive and nine normotensive Type 2 (non-insulin-dependent) diabetic patients and nine control subjects to determine the influence of hypertension on these variables. Maximum blood flow was reduced in both the hypertensive (1.05 (0.70-1.42) V) and normotensive (1.04 (0.79-1.63) V) Type 2 diabetic patients when compared with control subjects (1.40 (1.26-2.13) V, p < 0.01 for hypertensive and p < 0.05 for normotensive patients, respectively); however, maximum blood flow was similar in both groups of diabetic patients (p = 0.82). In contrast, resistance to flow was significantly greater in the diabetic patients with hypertension (127.2 (87.5-181.3) mmHg V-1 vs 84.7 (61.9-123.0) mmHg V-1 normotensive diabetic patients, p < 0.02). In addition, R was greater in the normotensive Type 2 diabetic patients than in control subjects (70.7 (44.7-79.9) mmHg V-1, p < 0.05). These results suggest that hypertension is associated with an additional rise in pre-capillary vascular resistance in Type 2 diabetes which, while protecting the microcirculation from the effects of increased arterial pressure, may further diminish protective hyperaemic responses.
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Mahy IR, Shore AC, Smith LD, Tooke JE (1994). The peripheral microcirculation in atrial fibrillation: preservation of capillary pressure and filtration coefficient.
Cardiovasc Res,
28(10), 1555-1558.
Abstract:
The peripheral microcirculation in atrial fibrillation: preservation of capillary pressure and filtration coefficient.
OBJECTIVE: the aim was to assess whether atrial fibrillation results in disturbances of capillary pressure and capillary filtration coefficient in man. METHODS: Finger nailfold capillary pressure and calf capillary filtration coefficient were measured in subjects in atrial fibrillation and in matched healthy controls in sinus rhythm. Capillary pressure was measured by direct cannulation using an electronic resistance feedback servonulling technique, and capillary filtration coefficient by mercury-in-Silastic strain gauge plethysmography using a technique believed not to invoke the venoarteriolar response. RESULTS: Mean capillary pressure did not differ significantly between subjects in atrial fibrillation and those in sinus rhythm [18.4(SD 5.1) mm Hg in atrial fibrillation v 18.0(2.9) mm Hg in sinus rhythm]. In a subgroup of patients restored to sinus rhythm (n = 7) by dc cardioversion there was no significant alteration in capillary pressure [15.3(4.2) mm Hg v 16.6(2.8) mm Hg]. Capillary filtration coefficient was also similar in subjects in atrial fibrillation to that in healthy controls in sinus rhythm [2.81(0.65) kfu in atrial fibrillation v 2.87(0.69) kfu in sinus rhythm]. CONCLUSIONS: These data would suggest that under resting conditions autoregulatory mechanisms are able to preserve microvascular homeostasis despite the central changes associated with atrial fibrillation.
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YOUMBISSI TJ, SELLARS L, SHORE AC, WILKINSON R (1993). BLOOD-PRESSURE, CHRONIC AMBULATORY PERITONEAL-DIALYSIS, AND HEMODIALYSIS - RELATIONSHIPS WITH SODIUM LOAD, PLASMA-RENIN ACTIVITY, AND ALDOSTERONE.
SEMAINE DES HOPITAUX,
69(9), 243-247.
Author URL.
Shore AC, Sandeman DD, Tooke JE (1993). Effect of an increase in systemic blood pressure on nailfold capillary pressure in humans.
Am J Physiol,
265(3 Pt 2), H820-H823.
Abstract:
Effect of an increase in systemic blood pressure on nailfold capillary pressure in humans.
Moderate autoregulation of capillary pressure occurs during changes in arterial and/or venous pressure in animals. Whether an increase in systemic blood pressure is transmitted to capillaries in humans is unknown. Eight healthy volunteers performed isometric handgrip exercise (30% of maximum) while nailfold capillary pressure (CP) and digital arterial blood pressure (DBP) were measured in the contralateral hand. CP was measured for 40 s before exercise and 40-100 s during exercise. Only experiments with no change in pipette position and no artifactual changes in flow were accepted. Basal DBP was stable [91.5 +/- 12.7 mmHg (-40 to -20 s basal) and 91.3 +/- 11.8 mmHg (-20 to 0 s basal)], and isometric exercise increased DBP [100.4 +/- 13.9 mmHg (0-20 s exercise) and 103.1 +/- 15.3 mmHg (20-40 s exercise); P < 0.05]. CP was unchanged during the first 40 s of exercise [18.9 +/- 4.9 mmHg (-40 to 20 s basal), 18.9 +/- 5.2 mmHg (-20 to 0 s basal), 18.4 +/- 4.7 mmHg (0-20 s exercise), and 18.3 +/- 5.3 mmHg (20-40 s exercise)] and remained unchanged for up to 100 s (n = 5), despite a continued elevation of DBP. These data suggest that protective mechanisms minimize the transmission of increases in systemic blood pressure to the capillary bed in humans.
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Jaap AJ, Shore AC, Gartside IB, Gamble J, Tooke JE (1993). Increased microvascular fluid permeability in young type 1 (insulin-dependent) diabetic patients.
Diabetologia,
36(7), 648-652.
Abstract:
Increased microvascular fluid permeability in young type 1 (insulin-dependent) diabetic patients.
Microvascular fluid permeability was assessed by determination of the capillary filtration coefficient in the forearm of ten young Type 1 (insulin-dependent) diabetic patients with a short duration of diabetes, satisfactory glycaemic control and minimal evidence of microangiopathy, and ten age- and sex-matched control subjects. A strain gauge plethysmographic method with a computer based logging and analysis system was used. This enabled differentiation between the volume filling and fluid filtration components of the response to venous pressure elevation. The median capillary filtration coefficient was found to be significantly higher in the young diabetic patients in comparison with control subjects (9.2 x 10(-3) ml.min-1.100 g tissue-1.mmHg-1 vs 3.8 x 10(-3) ml.min-1.100 g tissue-1.mmHg-1, p < 0.001). There were no significant correlations between capillary filtration coefficient and either plasma glucose concentration, haemoglobin A1c or duration of diabetes. As there is no evidence from other studies to support an increase in capillary surface area in the forearms of young Type 1 diabetic patients, these results may reflect a primary change in microvascular fluid permeability.
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Spiegel M, Vesti B, Shore A, Franzeck UK, Becker F, Bollinger A (1992). Pressure of lymphatic capillaries in human skin.
Am J Physiol,
262(4 Pt 2), H1208-H1210.
Abstract:
Pressure of lymphatic capillaries in human skin.
The network of lymphatic capillaries of the human skin was depicted at the distal part of the tibial plateau by fluorescence microlymphography (fluorescein isothiocyanate-dextran 150,000). Intralymphatic pressure was determined in 28 lymphatic capillaries of 21 healthy volunteers (mean diameter 56.0 +/- 10.0 microns) by a servo-nulling pressure system. It averaged 4.0 +/- 4.5 mmHg (range: -6.8 to +10.7 mmHg). These are the first measurements of pressure in the initial lymphatics of human skin and form a basis with which to compare measurements made in patients with different forms of edema.
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Sandeman DD, Shore AC, Tooke JE (1992). Relation of skin capillary pressure in patients with insulin-dependent diabetes mellitus to complications and metabolic control.
N Engl J Med,
327(11), 760-764.
Abstract:
Relation of skin capillary pressure in patients with insulin-dependent diabetes mellitus to complications and metabolic control.
BACKGROUND: Microvascular disease is a major problem in patients with diabetes mellitus. It has been suggested that diabetic microangiopathy may result from an increase in capillary blood flow and capillary hypertension, but direct evidence of capillary hypertension in such patients is lacking. METHODS: We measured capillary pressure at the summit of the capillary loop by direct microcannulation of skin nail-fold capillaries and a dynamic method of pressure measurement in 29 patients with insulin-dependent (Type I) diabetes and 29 normal subjects matched for age and sex. Among the diabetic patients, 7 had had diabetes for less than one year, 12 had incipient nephropathy (albumin excretion, 20 to 200 micrograms per minute), and 10 had overt nephropathy (albumin excretion, greater than 200 micrograms per minute). In addition, seven patients with no evidence of nephropathy were studied before and after three months of improved glycemic control. RESULTS: the median capillary pressure in the diabetic patients was 20.4 mm Hg (range, 13.6 to 25.3), as compared with 16.7 mm Hg (range, 12.8 to 22.8; P less than 0.001) in the normal subjects. The values were higher in each subgroup of diabetic patients than in the corresponding group of normal subjects, but the values did not differ among the three subgroups of diabetic patients. In the seven patients who were studied before and after three months of improved glycemic control, the median capillary pressure fell from 20.0 mm Hg (range, 18.5 to 21.7) to 17.8 mm Hg (range, 14.1 to 20.3; P = 0.02). CONCLUSIONS: Nail-fold capillary hypertension may develop early in the course of diabetes, before the emergence of microvascular disease, and may be influenced by changes in metabolic control.
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Flynn MD, Sandeman DD, Mawson DM, Shore AC, Tooke JE (1991). Cyclical hypothermia: successful treatment with ephedrine.
J R Soc Med,
84(12), 752-753.
Author URL.
Shore AC, Price KJ, Sandeman DD, Green EM, Tripp JH, Tooke JE (1991). Impaired microvascular hyperaemic response in children with diabetes mellitus.
Diabet Med,
8(7), 619-623.
Abstract:
Impaired microvascular hyperaemic response in children with diabetes mellitus.
Clinically detectable microvascular complications of diabetes are uncommon in children with diabetes especially in the prepubertal group. It is unclear whether subtle functional abnormalities of the microcirculation occur in children without evidence of clinical microangiopathy and in particular whether abnormalities can be demonstrated in children before puberty. The maximum hyperaemic response to direct local heating (44 degrees C) of the foot skin was measured by laser Doppler fluximetry in 50 diabetic and 50 non-diabetic children. An impaired hyperaemic response occurred in the diabetic children compared with control children (diabetic 1.25 (95% CI 1.13-1.37) V; control 1.74 (1.60-1.88) V; p less than 0.001) and was significantly related to duration of diabetes but not to long-term blood glucose control. The impaired response was also present in prepubertal diabetic children (diabetic 1.37 (1.16-1.58) V; control 1.89 (1.67-2.12) V; p less than 0.001). Systolic and diastolic blood pressure were significantly raised in the prepubertal diabetic children. These data suggest that a functional abnormality of the microcirculation occurs in children with diabetes in the absence of clinically detectable microangiopathy, and even before puberty.
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Sandeman DD, Pym CA, Green EM, Seamark C, Shore AC, Tooke JE (1991). Microvascular vasodilatation in feet of newly diagnosed non-insulin dependent diabetic patients.
BMJ,
302(6785), 1122-1123.
Author URL.
Shore AC, Markandu ND, MacGregor GA (1988). A randomized crossover study to compare the blood pressure response to sodium loading with and without chloride in patients with essential hypertension.
J Hypertens,
6(8), 613-617.
Abstract:
A randomized crossover study to compare the blood pressure response to sodium loading with and without chloride in patients with essential hypertension.
Six patients with essential hypertension underwent a randomized cross over design study to investigate the effect of supplementing a 10 mmol/day sodium diet for a period of 5 days with either 120 mmol sodium chloride (Slow Sodium, Ciba, Horsham, UK) or 122 mmol sodium in the presence of other anions, mainly phosphate (Phosphate, Sandoz, Feltham, UK). With both sodium salts, urinary sodium excretion was increased. The calculated amount of sodium retained was similar for both the sodium chloride and sodium phosphate periods. However, with the addition of sodium chloride to the low-salt diet, there were increases in supine mean blood pressure whereas with the addition of sodium phosphate no change in mean blood pressure occurred. The supine mean blood pressure after supplementation with sodium chloride (119.8 +/- 4.3 mmHg) was significantly greater than that after sodium phosphate (113.3 +/- 4.5 mmHg), similarly, the standing mean blood pressure was greater after addition of sodium chloride than of sodium phosphate (122.3 +/- 4.20 versus 115.4 +/- 3.0 mmHg). With both salts there were similar but non-significant increases in weight and reductions in plasma renin activity (PRA) and plasma aldosterone (PA).
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Walter SJ, Shore AC, Shirley DG (1988). Effect of potassium depletion on renal tubular function in the rat.
Clin Sci (Lond),
75(6), 621-628.
Abstract:
Effect of potassium depletion on renal tubular function in the rat.
1. In order to investigate the effects of K+ depletion on renal function, micropuncture studies were performed on anaesthetized rats which had been kept on a K+-deficient diet for 2 weeks; results were compared with those from control animals. 2. In the K+-depleted animals, values for total glomerular filtration rate and single-nephron filtration rate were significantly lower than in controls. Urine osmolality was also reduced; this was associated with reductions in the osmolality, Na+ concentration and K+ concentration of papillary interstitial fluid. No significant difference between urine and papillary osmolality was observed. 3. Fractional reabsorption by the proximal convoluted tubule was enhanced in the K+-depleted animals; end-proximal fluid delivery was markedly reduced. 4. Absolute, but not fractional, delivery of K+ to the beginning of the distal tubule was reduced in the K+-depleted animals. In contrast to observations in control rats, no net secretion of K+ into the distal tubule occurred and there was indirect evidence of K+ reabsorption in the collecting duct. 5. K+ depletion was associated with reductions in the delivery of Na+ and water to early and late regions of the distal tubule, whereas excretion rates of Na+ and water were unaffected. 6. It is suggested that the reduction in Na+ delivery to the loop of Henle (arising from the changes in filtration rate and proximal tubular reabsorption) might contribute to the reduced medullary osmotic concentration observed during K+ depletion. Reductions in fractional reabsorption of Na+ and water in the collecting duct might result from lowered plasma aldosterone levels and the reduced medullary osmolality.
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Shore AC, Markandu ND, Sagnella GA, Singer DR, Forsling ML, Buckley MG, Sugden AL, MacGregor GA (1988). Endocrine and renal response to water loading and water restriction in normal man.
Clin Sci (Lond),
75(2), 171-177.
Abstract:
Endocrine and renal response to water loading and water restriction in normal man.
1. Nine normal subjects (eight male, one female) on a fixed daily intake of 150 mmol of sodium and 80 mmol of potassium, were randomized to receive either 3 days of 1.0 litre total water intake/24 h (food + fluid) or 4 days of 6.8 litres total water intake/24 h, and were then crossed over after a 3 day control period (2.7 litres water/24 h). 2. During water restriction, urine volume fell from 1.94 litres/24 h to less than 1 litre/24 h by the first day and was 0.77 litre/24 h on the final day. Plasma atrial natriuretic peptide levels were unchanged from baseline despite a large increase in plasma vasopressin and plasma and urine osmolality. Urinary sodium was unaltered throughout, while urinary potassium was increased on the final 2 days of water restriction. 3. During water loading, urine volume increased from 1.85 litres/24 h to 5.44 litres/24 h on the first day and remained at approximately 6 litres/24 h for the final 3 days. Plasma atrial natriuretic peptide showed no change. Plasma vasopressin and plasma and urine osmolality were reduced. Urinary sodium and potassium output were unchanged from baseline. 4. These results suggest that changes in plasma atrial natriuretic peptide are unlikely to be involved in the normal homoeostatic response to changes in water balance in man.
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Sagnella GA, Markandu ND, Buckley MG, Shore AC, Sugden AL, Singer DR, MacGregor GA (1988). Plasma atrial natriuretic peptide in essential hypertension. Comparison with normotensive subjects and effects of changes in dietary sodium intake.
Am J Hypertens,
1(2), 112-118.
Abstract:
Plasma atrial natriuretic peptide in essential hypertension. Comparison with normotensive subjects and effects of changes in dietary sodium intake.
Plasma levels of atrial natriuretic peptide (ANP) in 106 patients with essential hypertension with a supine mean blood pressure (mean +/- SEM) of 128.9 +/- 1.6 mmHg and not on treatment were significantly higher than those in 47 normotensive subjects (supine mean blood pressure 93.9 +/- 1.2 mmHg) with mean values of 17.2 +/- 1.1 and 8.6 +/- 0.6 pg/ml, respectively (P less than 0.001). Similar results were found in a subgroup of 35 hypertensive patients identically matched in terms of age, sex, and race with 35 normotensive subjects. Plasma levels of ANP were correlated significantly with age in normotensive subjects and with age and blood pressure in the hypertensive patients. In 12 hypertensive patients studied on a low (10 mmol sodium/day), on their usual sodium intake (around 120 mmol sodium/24 hr) and on a high (350 mmol sodium/day) intake, plasma ANP increased approximately twofold by the fifth day of the high sodium intake, but there was no significant difference between the plasma levels on their usual sodium intake and those on the fifth day of the low sodium intake. Supine mean blood pressure on the patients' usual sodium intake was 119.3 +/- 2.7 mmHg and was reduced to 110.0 +/- 3 mmHg by the fifth day of the low sodium intake (P less than 0.005). However, there was no significant difference between the blood pressure levels on their usual and high sodium intake (118.3 +/- 3.0 mmHg).(ABSTRACT TRUNCATED AT 250 WORDS)
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Cappuccio FP, Markandu ND, Tucker FA, Shore AC, MacGregor GA (1987). A double-blind study of the blood pressure lowering effect of a thiazide diuretic in hypertensive patients already on nifedipine and a beta-blocker.
J Hypertens,
5(6), 733-738.
Abstract:
A double-blind study of the blood pressure lowering effect of a thiazide diuretic in hypertensive patients already on nifedipine and a beta-blocker.
Twelve hypertensive patients who were already on treatment with atenolol (100 mg once daily) and nifedipine as tablets (20 mg twice daily) were entered into a double-blind, randomized crossover study of the addition of 1 month's treatment with either bendrofluazide (5 mg once daily) or a matching placebo. The addition of bendrofluazide to the combination of atenolol and nifedipine did not cause any statistically significant fall in the blood pressure 2 h after the last dose of nifedipine compared to treatment with placebo [bendrofluazide: 135.2 +/- 5.1/89.8 +/- 2.5 (mean +/- s.e.), versus placebo: 132.1 +/- 4.6/89.9 +/- 3.1 mmHg; P = NS]. However, 12 hours after the last dose of nifedipine blood pressure tended to be lower whilst on bendrofluazide compared with placebo. Plasma urate levels were significantly higher on the diuretic compared to placebo (461 +/- 27 versus 396 +/- 21 mumol P less than 0.001). Plasma potassium was lower on the diuretic compared to placebo (3.59 +/- 0.12 vs 3.76 +/- 0.10) but this difference just failed to reach statistical significance. The results of this study suggest that a thiazide diuretic has little additive effect on blood pressure in patients already on treatment with atenolol and nifedipine, particularly when nifedipine is maximally effective. However, the addition of a diuretic does have potentially deleterious metabolic effects.
Abstract.
Author URL.
Cappuccio FP, Markandu ND, Buckley MG, Sagnella GA, Shore AC, MacGregor GA (1987). Atrial natriuretic peptides and mineralocorticoid escape in man. Journal of Hypertension, 5(SUPPL. 5).
Singer DR, Markandu ND, Shore AC, MacGregor GA (1987). Captopril and nifedipine in combination for moderate to severe essential hypertension.
Hypertension,
9(6), 629-633.
Abstract:
Captopril and nifedipine in combination for moderate to severe essential hypertension.
The effects of the addition of a calcium entry antagonist, nifedipine (20-mg tablet twice a day), to an angiotensin converting enzyme inhibitor, captopril (25 mg three times a day), and the addition of captopril to nifedipine were observed in two separate studies in patients with essential hypertension. After 4 weeks of captopril therapy alone, mean arterial pressure fell by 12 mm Hg, and with the addition of nifedipine to captopril for a further month, blood pressure fell by an additional 10 mm Hg. In a separate group of patients treated with the same doses, mean arterial pressure fell by 17 mm Hg with nifedipine treatment alone; when captopril was added to the nifedipine therapy for an additional month, mean arterial pressure fell by a further 11 mm Hg. These blood pressures were measured 2 hours after the last dose; however, there was less of a fall in blood pressure when it was measured 12 hours after the last dose. This study confirms that captopril and nifedipine have a marked additive effect on blood pressure in whichever order they are given, but it shows that the combination is relatively short-acting.
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Cappuccio FP, Markandu ND, Buckley MG, Sagnella GA, Shore AC, MacGregor GA (1987). Changes in the plasma levels of atrial natriuretic peptides during mineralocorticoid escape in man.
Clin Sci (Lond),
72(5), 531-539.
Abstract:
Changes in the plasma levels of atrial natriuretic peptides during mineralocorticoid escape in man.
Plasma levels of atrial natriuretic peptide (ANP) were measured by radioimmunoassay in eight normal healthy volunteers before and during mineralocorticoid escape. Mean plasma ANP on a fixed sodium intake before fludrocortisone was 6.5 +/- SEM 1.1 pg/ml. Within 24 h of fludrocortisone administration there was a significant increase in plasma ANP which continued to increase daily reaching a plateau by day 4 (14.9 +/- 2.4 pg/ml) to day 7 (15.1 +/- 2.6 pg/ml). The rise in plasma ANP was closely related to the amount of sodium retained during the fludrocortisone treatment and the sodium 'escape' occurred by days 4 to 7. These results support the concept that ANP could play an important hormonal role in over-coming the sodium-retaining effects of mineralocorticoids in man.
Abstract.
Author URL.
Singer DR, Shore AC, Markandu ND, Buckley MG, Sagnella GA, MacGregor GA (1987). Dissociation between plasma atrial natriuretic peptide levels and urinary sodium excretion after intravenous saline infusion in normal man.
Clin Sci (Lond),
73(3), 285-289.
Abstract:
Dissociation between plasma atrial natriuretic peptide levels and urinary sodium excretion after intravenous saline infusion in normal man.
1. Plasma immunoreactive atrial natriuretic peptide (ANP) and urinary sodium excretion were measured in six normal male subjects before, during and for 195 min after a 60 min infusion of 2 litres of saline (0.9% NaCl, 308 mmol of Na+). 2. During the saline infusion, there was a significant increase in plasma ANP and urinary sodium excretion and a significant decrease in plasma renin activity, aldosterone, albumin, creatinine and packed cell volume. 3. The maximal rise in mean plasma ANP occurred 15 min after stopping the infusion and the maximal rise in mean urinary sodium excretion in the collection period 30 min later. 4. Plasma ANP then decreased so that by the end of the study the level was the same as before the saline infusion. However, at this time, 195 min after the saline infusion was stopped, there was still a net positive sodium balance of 220 mmol and urinary sodium excretion remained significantly elevated. 5. Our results are compatible with the concept that increased ANP secretion may play a role in the immediate increase in sodium excretion after a saline load. However, they also suggest that other mechanisms may be more important for the longer term increase in sodium excretion.
Abstract.
Author URL.
Cappuccio FP, Markandu ND, Singer DR, Smith SJ, Shore AC, MacGregor GA (1987). Does oral calcium supplementation lower high blood pressure? a double blind study.
J Hypertens,
5(1), 67-71.
Abstract:
Does oral calcium supplementation lower high blood pressure? a double blind study.
Eighteen unselected patients with untreated mild to moderate essential hypertension, whose average supine blood pressure after 2 months' observation on no treatment was 154/103 mmHg, were entered into a double-blind randomized crossover study of 1 month's treatment with calcium lactate gluconate (40 mmol of elemental calcium/day) and treatment with placebo for a further month. Despite a significant increase in total plasma calcium (P less than 0.01) and in 24-h urinary excretion of calcium (P less than 0.025) while taking calcium lactate gluconate, there was no fall in blood pressure with calcium supplementation compared to treatment with placebo.
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Author URL.
MacGregor GA, Markandu ND, Singer DR, Cappuccio FP, Shore AC, Sagnella GA (1987). Moderate sodium restriction with angiotensin converting enzyme inhibitor in essential hypertension: a double blind study.
Br Med J (Clin Res Ed),
294(6571), 531-534.
Abstract:
Moderate sodium restriction with angiotensin converting enzyme inhibitor in essential hypertension: a double blind study.
Fifteen unselected patients who had essential hypertension and whose average supine blood pressure when they were not receiving any treatment and their usual sodium intake was 162/107 mm Hg were treated with captopril 50 mg twice daily. After one month's treatment their supine blood pressure had decreased to 149/94 mm Hg. They were then instructed to reduce their sodium intake to about 80 mmol(mEq)/day. After two weeks of moderate sodium restriction they were entered into a double blind randomised crossover study comparing the effect of 10 Slow Sodium tablets (100 mmol sodium chloride) with matching placebo tablets while continuing to take captopril and restrict sodium in their diet. After one month of taking placebo their mean supine blood pressure was 137/88 mm Hg with a urinary sodium excretion of 83 mmol/24 h, while after one month of taking Slow Sodium tablets their mean supine blood pressure was 150/97 mm Hg (p less than 0.001) with a sodium excretion of 183 mmol/24 h. The mean supine blood pressure during moderate sodium restriction therefore decreased by 9% and correlated significantly with the reduction in urinary sodium excretion. These results suggest that the combination of treatment with a moderate but practical reduction in sodium intake and an angiotensin converting enzyme inhibitor is effective in decreasing the blood pressure in patients with essential hypertension. This combined approach overcomes some of the objections that have been made to salt restriction alone and to converting enzyme inhibitors alone.
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Singer DR, Markandu ND, Shore AC, MacGregor GA (1987). Nifedipine and acebutolol in combination for the treatment of moderate to severe essential hypertension.
J Hum Hypertens,
1(1), 31-37.
Abstract:
Nifedipine and acebutolol in combination for the treatment of moderate to severe essential hypertension.
In a randomised, crossover study of patients with moderate to severe essential hypertension, the effects of the calcium entry antagonist nifedipine and the beta-receptor blocking drug acebutolol were studied on their own, and in combination. After 4 weeks of nifedipine tablets 20 mg twice daily (Adalat, Bayer), mean supine blood pressure (BP) fell by 20 mmHg and after 4 weeks of acebutolol 200 mg twice a day (Sectral, May & Baker) by 11 mmHg. When nifedipine and acebutolol were given in combination in the above doses for 4 weeks, there was a significantly greater fall in BP than with either agent alone, supine mean arterial pressure falling by 27 mmHg. The above BPs were measured 2 h after the last dose of tablets. Measurements 12 h after the last dose showed smaller falls in BP, with a significantly greater fall with combination treatment than with acebutolol alone. The fall in BP 12 h after the last dose of the combination was greater than with nifedipine alone but this difference was not statistically significant. This randomised, controlled study showed that nifedipine and acebutolol have a marked additive effect on BP which is sustained for at least 12 h after treatment.
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Author URL.
Sagnella GA, Markandu ND, Buckley MG, Singer DR, Sugden AL, Shore AC, MacGregor GA (1987). Plasma atrial natriuretic peptide in essential hypertension: effects of changes in dietary sodium.
Br Med J (Clin Res Ed),
295(6595), 417-418.
Author URL.
Sagnella GA, Markandu ND, Shore AC, Forsling ML, MacGregor GA (1987). Plasma atrial natriuretic peptide: its relationship to changes in sodium intake, plasma renin activity and aldosterone in man.
Clin Sci (Lond),
72(1), 25-30.
Abstract:
Plasma atrial natriuretic peptide: its relationship to changes in sodium intake, plasma renin activity and aldosterone in man.
Plasma levels of immunoreactive atrial natriuretic peptide (IrANP), plasma renin activity, aldosterone and vasopressin were measured in 11 normotensive subjects on a low (10 mmol/day), a normal (150 mmol/day) and a high (350 mmol/day) sodium intake. Plasma levels of IrANP increased significantly with increasing dietary sodium intake with levels (means +/- SD) of 3.9 +/- 2.1 pg/ml on the fifth day of the low sodium diet, 6.1 +/- 3.4 pg/ml on the fifth day of the normal sodium diet and 11.4 +/- 4.6 pg/ml on the fifth day of the high sodium diet. Plasma renin activity and aldosterone decreased significantly with increasing sodium intake whereas plasma vasopressin was highest on the high sodium intake. These results suggest that the atrial peptides may be a new and important component in the overall control of sodium and water balance during increased sodium intake.
Abstract.
Author URL.
Sagnella GA, Markandu ND, Shore AC, MacGregor GA (1987). Plasma immunoreactive atrial natriuretic peptide and changes in dietary sodium intake in man.
Life Sci,
40(2), 139-143.
Abstract:
Plasma immunoreactive atrial natriuretic peptide and changes in dietary sodium intake in man.
Plasma levels of immunoreactive atrial natriuretic peptides (IrANP) have been measured in 8 normotensive subjects during alterations in dietary sodium intake. Subjects were studied on their normal sodium intake (2 days) then on a low sodium intake (7 days, 10 mmols Na+/day) and subsequently on a high sodium intake (14 days, 350 mmols Na+/day with the diets being given in a fixed order. Plasma levels (mean +/- S.E.M.) of IrANP on a normal sodium diet were 7.3 +/- 0.9 pg/ml; 4.5 +/- 0.8 on the 7th day of a low sodium intake and 10.8 +/- 1.3; 16.6 +/- 3.3; 15.5 +/- 4.2; 15.6 +/- 2.3 pg/ml respectively or the 1st, 3rd, 10th and 14th day on the high sodium intake. Changes in plasma IrANP were closely associated with changes in urinary sodium excretion. These results suggest that in normal subjects the atrial natriuretic peptides may play an important role in the adaptation to increases in dietary sodium intake both on a short and on a longer term basis.
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Author URL.
Shore AC, Booker J, Sagnella GA, Markandu ND, MacGregor GA (1987). Serum ionized calcium and pH: effects of blood storage, some physiological influences and a comparison between normotensive and hypertensive subjects.
J Hypertens,
5(4), 499-505.
Abstract:
Serum ionized calcium and pH: effects of blood storage, some physiological influences and a comparison between normotensive and hypertensive subjects.
The effects on serum ionized calcium (ICa) and pH of different storage conditions of blood or serum, and of physiological influences such as over-ventilation, food intake and dietary sodium intake have been investigated. Temperature and time-related changes in ICa occurred with storage and were minimized by immediate separation of serum and storage at 4 degrees C, (6 h or less). Elevation of serum ICa and a fall in pH accompanied increased salt intake; over-ventilation induced an elevation of serum pH and a reduction in ICa. Day-to-day intra-individual variation of ICa was 0.93%. We proceeded to examine a group of age-, sex- and race-matched hypertensive and normotensive subjects under standardized conditions designed to minimize such technical and physiological artefacts. ICa was not significantly different in the two groups; however, serum pH was significantly elevated in the hypertensive group. In the combined group of normotensive and hypertensive subjects, serum pH was significantly correlated with blood pressure. Exclusion of the black subjects from the analysis did not alter the findings.
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Innes JA, Mills CJ, Noble MI, Murphy K, Pugh S, Shore AC, Guz A (1987). Validation of beat by beat pulsed Doppler measurements of ascending aortic blood velocity in man.
Cardiovasc Res,
21(1), 72-80.
Abstract:
Validation of beat by beat pulsed Doppler measurements of ascending aortic blood velocity in man.
The volume, velocity, and acceleration of ascending aortic blood were measured in man using a pulsed Doppler ultrasound instrument, with online spectral analysis and offline computer processing of velocity data. This system was firstly validated in a test rig capable of generating pulsatile flow of talc particles in water at physiological velocities and accelerations in a model aorta. Doppler measurements correlated well (r greater than or equal to 0.90) with simultaneous electromagnetic measurements of stroke volume, peak ejection velocity, and maximum acceleration in this rig. In vivo validation was performed firstly by comparing simultaneous Doppler and thermodilution cardiac output (Q) measurements; this yielded the following regression equation: Doppler Q = 0.90 X thermodilution Q + 0.03 litre.min-1, r = 0.92; n = 38. Beat by beat measurements were then validated against simultaneous invasive aortic blood velocity measurements made using a Mills electromagnetic cathetertip probe. When paced single beats of different size were compared within subjects the correlation coefficients between Doppler and electromagnetic measurements averaged 0.89 for stroke volume, 0.91 for peak ejection velocity, and 0.79 for maximum acceleration in five subjects. The absolute values for velocity and acceleration from the Doppler system differed significantly from the absolute values given by the electromagnetic system and this difference was not consistent between subjects. It is concluded that the Doppler system can non-invasively record relative changes in left ventricular ejection in man.
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Katoh Y, Kurosawa T, Takeda S, Kurokawa S, Sakamotom H, Marumo F, Kikawada R, Singer DRJ, Shore AC, Markandu ND, et al (1986). ATRIAL NATRIURETIC PEPTIDE LEVELS IN TREATED CONGESTIVE HEART FAILURE. The Lancet, 327(8485).
Cappuccio FP, Markandu ND, Beynon GW, Shore AC, MacGregor GA (1986). Effect of increasing calcium intake on urinary sodium excretion in normotensive subjects.
Clin Sci (Lond),
71(4), 453-456.
Abstract:
Effect of increasing calcium intake on urinary sodium excretion in normotensive subjects.
Eight normotensive subjects were studied in a randomized crossover trial of a high calcium diet (1800 mg of calcium/day) for a week against a low calcium diet (200 mg of calcium/day) for a further week. The subjects were placed on a diet containing 200 mg of calcium/day throughout the study and the high calcium diet was achieved by supplementing the low calcium diet with calcium glubionate and galactogluconate. Sodium and potassium intake were kept constant throughout the study. Twenty-four hour urinary sodium, potassium, calcium and phosphate were measured daily. In spite of a highly significant increase in calcium excretion from the low to the high calcium diet (P less than 0.0001), there was no increase in sodium or change in potassium excretion with the increased calcium intake. A transient but significant fall in urinary sodium excretion was observed up to the fourth day of the high calcium diet (P = 0.021). Twenty-four hour urinary phosphate excretion fell significantly on the high calcium diet (P less than 0.0001). Body weight, blood pressure, plasma renin activity, aldosterone, plasma creatinine and serum ionized calcium did not change. These results suggest that a short-term increase in calcium intake in normotensive subjects does not increase urinary sodium and potassium excretion.
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Sagnella GA, Jones JC, Shore AC, Markandu ND, MacGregor GA (1986). Evidence for increased levels of a circulating ouabainlike factor in essential hypertension.
Hypertension,
8(5), 433-437.
Abstract:
Evidence for increased levels of a circulating ouabainlike factor in essential hypertension.
The effect of plasma from normotensive and hypertensive subjects on the binding of [3H]ouabain on human erythrocytes was investigated. The binding of [3H]ouabain on human erythrocytes was saturable and highly specific; linear Scatchard plots indicated the presence of a single type of binding site. Human plasma decreased the binding of [3H]ouabain on its receptor to a greater extent than could be accounted for by the plasma potassium concentration. The level of this circulating ouabainlike factor (or factors) was quantitated using a radioreceptor assay. Plasma from 22 hypertensive subjects (systolic blood pressure greater than 160 mm Hg or diastolic blood pressure greater than 90 mm Hg) displayed higher levels than that from 24 normotensive subjects; furthermore there was a positive and significant correlation (r = 0.42, n = 46, p less than 0.004) between the ouabainlike content and the individual subject's systolic blood pressure. The receptor assay described is relatively simple and should be useful for further work on the nature and clinical importance of the endogenous ouabainlike factor.
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Author URL.
Sagnella GA, Markandu ND, Shore AC, MacGregor GA (1986). Raised circulating levels of atrial natriuretic peptides in essential hypertension.
Lancet,
1(8474), 179-181.
Abstract:
Raised circulating levels of atrial natriuretic peptides in essential hypertension.
Plasma levels (mean +/- SD) of immunoreactive atrial natriuretic peptides (ANP) were significantly higher in 28 hypertensive subjects (17.1 +/- 13.8 pg/ml) than in 24 normotensive subjects (8.4 +/- 3.7 pg/ml) matched as far as possible for age, sex, and race. All subjects were studied on their normal dietary sodium intake. In the normotensive subjects ANP levels were significantly correlated with age but not with blood pressure, whereas in the hypertensive subjects ANP levels were significantly correlated with systolic blood pressure but not with age. These findings may indicate a compensatory reaction to a diminished renal capacity for sodium excretion, in response to increasing age in normotensive subjects and to higher blood pressure in hypertensive subjects.
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Sagnella GA, Markandu ND, Shore AC, MacGregor GA (1985). Effects of changes in dietary sodium intake and saline infusion on immunoreactive atrial natriuretic peptide in human plasma.
Lancet,
2(8466), 1208-1211.
Abstract:
Effects of changes in dietary sodium intake and saline infusion on immunoreactive atrial natriuretic peptide in human plasma.
Plasma levels of immunoreactive atrial natriuretic peptide (IrANP) were measured in healthy normotensive subjects before and after saline infusion and changes in dietary salt intakes. When 2 litres of 0.9% saline (308 mmol Na+) were infused over 1 h, plasma levels (mean +/- SD) of IrANP increased from 5.8 +/- 2.8 pg/ml to 15.8 +/- 12.5 pg/ml. Plasma levels on the fifth day of a low sodium diet (10 mmol/day) were 3.8 +/- 2.4 pg/ml, a normal sodium intake (150 mmol/day) 6.4 +/- 2.9 pg/ml, and a high salt intake (350 mmol/day) 12.7 +/- 6 pg/ml. These results suggest that atrial natriuretic peptides could be important hormones in the control of sodium balance in normal man.
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Sagnella GA, Nolan DA, Shore AC, MacGregor GA (1985). Effects of synthetic atrial natriuretic peptides on sodium-potassium transport in human erythrocytes.
Clin Sci (Lond),
69(2), 223-226.
Abstract:
Effects of synthetic atrial natriuretic peptides on sodium-potassium transport in human erythrocytes.
The effects of synthetic human and rat atrial peptides on sodium and potassium ion transport has been investigated in intact human erythrocytes. The effects of these peptides have been tested on the active, sodium pump-dependent (ouabain-sensitive) and on the sodium-potassium cotransport system (bumetanide-sensitive) with 86Rb used as a tracer. Human (alpha-ANP, 28 amino acids) or rat (atriopeptin III) atrial peptides, over a wide range of concentrations, did not influence the uptake of 86Rb in either the ouabain-sensitive or the bumetanide-sensitive transport system. These results suggest that the natriuretic effect of the atrial peptides is not mediated through inhibition of the sodium pump or the loop-diuretic-sensitive Na-K cotransport.
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Author URL.
Cappuccio FP, Markandu ND, Beynon GW, Shore AC, Sampson B, MacGregor GA (1985). Lack of effect of oral magnesium on high blood pressure: a double blind study.
Br Med J (Clin Res Ed),
291(6490), 235-238.
Abstract:
Lack of effect of oral magnesium on high blood pressure: a double blind study.
Seventeen unselected patients with mild to moderate essential hypertension and whose average supine blood pressure after two months' observation with no treatment was 154/100 mm Hg were entered into a double blind randomised crossover study of one month's treatment with magnesium aspartate (15 mmol magnesium/day) and treatment with placebo for a further month. This preparation of magnesium was well tolerated and did not cause diarrhoea. Despite a significant increase in plasma magnesium concentration and a significant increase in urinary excretion of magnesium while taking magnesium aspartate there was no fall in blood pressure compared with either treatment with placebo or values before treatment. The results provide no evidence for a role of dietary magnesium in the regulation of high blood pressure and are contrary to recent speculations.
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Author URL.
Shore AC, Beynon GW, Jones JC, Markandu ND, Sagnella GA, MacGregor GA (1985). Mononuclear leucocyte intracellular free calcium--does it correlate with blood pressure?.
J Hypertens,
3(2), 183-188.
Abstract:
Mononuclear leucocyte intracellular free calcium--does it correlate with blood pressure?
Abnormalities of calcium binding and calcium transport in cells from hypertensive subjects or animals have been previously described. Total cell sodium is reported to be increased in white blood cells from hypertensive subjects; thus by analogy with Blaustein's proposal for the vascular smooth muscle cell, mononuclear leucocyte cytosolic calcium might be increased via a reduction of the Na-Ca exchange. Using the fluorescent calcium indicator, quin 2, cytosolic calcium was measured in mononuclear leucocytes from 22 hypertensive and 19 normotensive subjects. There was no significant difference between the mononuclear leucocyte cytosolic calcium level in the two groups. Incubation of the cells with 10(-4) M ouabain reduced 86 rubidium (86Rb) uptake by 80% of the control value but failed to alter cytosolic calcium. These findings are consistent with a minimal role of the Na-Ca exchange in the mononuclear leucocyte and may explain why the cytosolic calcium was not increased in hypertension despite the previous reports of increased total cell sodium in white blood cells.
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Sellars L, Shore AC, Wilkinson R (1985). Renal vein renin studies in renovascular hypertension--do they really help?.
J Hypertens,
3(2), 177-181.
Abstract:
Renal vein renin studies in renovascular hypertension--do they really help?
Measurement of the renal vein renin ratio (RVRR) is commonly used to predict the response of blood pressure to surgery in hypertensive patients with unilateral renovascular disease. We have reviewed our experience in 37 such patients in whom renal vein renin levels were measured basally and after stimulation of renin secretion with intravenous diazoxide or tilting. Twenty-four patients were cured or improved. When a basal ratio of greater than or equal to 1.5 (diseased: normal kidney) was taken as a positive test the false positive rate was 39% and the false negative rate 71%, there being little difference in outcome between those with ratios above or below 1.5. No other threshold value of RVRR identified those responding to surgery, and acute stimulation of renin secretion did not increase the value of the test. We conclude that the RVRR is of no prognostic value in the surgical treatment of hypertension due to unilateral renovascular disease.
Abstract.
Author URL.
Sellars L, Shore AC, Wilkinson R (1985). Reply by author's. Journal of Hypertension, 3(6), 659-660.
Sellars L, Shore AC, Mott V, Wilkinson R (1985). The renin-angiotensin-aldosterone system in decompensated cirrhosis: its activity in relation to sodium balance.
Q J Med,
56(220), 485-496.
Abstract:
The renin-angiotensin-aldosterone system in decompensated cirrhosis: its activity in relation to sodium balance.
Plasma renin activity (PRA), plasma renin concentration (PRC), plasma angiotensin II concentration (AII), plasma and urinary aldosterone (PA, UA) and urinary sodium excretion (UNaV) were measured in 51 normal controls, 16 patients with decompensated cirrhosis (i.e. ascites and/or oedema present) in sodium equilibrium (Group 1) and 13 patients with decompensated cirrhosis in a phase of active sodium retention (Group 2). In Group 1 the mean supine and erect values, although lower, were not significantly different from controls. In Group 2 the mean values were significantly elevated, but several individual values were within the normal range; there were significant direct relationships between plasma renin activity and plasma renin concentration (r = 0.85, p less than 0.001 erect), plasma renin concentration and plasma angiotensin II concentration (r = 0.86, p less than 0.001 erect), and plasma angiotensin II concentration and plasma aldosterone (r = 0.70, p less than 0.01 erect). In Group 2 there was an inverse correlation between urinary sodium excretion and both urinary aldosterone (r = -0.50) and erect plasma aldosterone (r = -0.36) but, perhaps because of the narrow range of sodium excretion rates, significance was not reached. The normal values in Group 1 indicate that hyperaldosteronism is not essential for the maintenance of established ascites, but do not exclude a role for aldosterone in the control of sodium excretion if it is accepted that renal tubular sensitivity to aldosterone is increased in these patients. In Group 2, the raised mean plasma and urinary aldosterone levels and the trend towards an inverse relationship with urinary sodium excretion suggests a role for aldosterone in the active retention of sodium. It appears that stimulation of the renin-angiotensin system is the major factor in the elevation of plasma aldosterone; there was no relationship between plasma aldosterone and either plasma sodium or potassium levels. The mechanism of renin hypersecretion is unclear but this may represent part of a sympathetically mediated response in order to maintain blood pressure. The close relationship between plasma renin activity and plasma renin concentration indicates that the former is a valid measure of circulating renin levels in cirrhosis, despite low renin-substrate levels.
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Author URL.
Sellars L, Shore AC, Wilkinson R, James OF, Robson V (1981). Sodium status and the renin-angiotensin-aldosterone system in compensated liver disease.
Eur J Clin Invest,
11(4), 299-304.
Abstract:
Sodium status and the renin-angiotensin-aldosterone system in compensated liver disease.
Exchangeable sodium, plasma renin activity, plasma angiotensin II and plasma aldosterone were measured in forty-six control subjects, nineteen patients with chronic non-cirrhotic liver disease and twenty patients with compensated cirrhosis (i.e. without ascites or oedema). In the three groups respectively, mean exchangeable sodium (mmol/kg lean body mass) was 53 (SD = 3), 50 (SD = 5) and 52 (SD = 8). Mean plasma renin activity (pmol l(-1) min(-1)) was 3.2, 3.1 and 3.0 supine and 6.2, 6.2 and 5.1 erect. Mean plasma angiotensin II (pmol l(-1) was 7.3, 5.8 and 6.6 supine and 10.6, 7.9 and 9.0 erect. Mean plasma aldosterone (pmol l(-1)) was 82, 64 and 77 supine and 188, 133 and 121 erect. There were no significant differences among the mean values of any of these variables. These findings indicate that, on the basis of exchangeable sodium measurements, sodium retention is not present in compensated liver disease and that the renin--angiotensin--aldosterone system is essentially normal.
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Author URL.
Irving RJ, Walker BR, Noon JP, Webb DJ, Watt GCM, Shore AC (1971). Microvascular correlates of blood pressure, plasma glucose, and insulin resistance in health.
Cardiovascular Research,
5(SUPP1), 271-276.
Abstract:
Microvascular correlates of blood pressure, plasma glucose, and insulin resistance in health
Objectives: the associations between hypertension, insulin resistance and glucose intolerance are poorly understood. Altered microvascular structure and function could contribute by increasing peripheral vascular resistance and decreasing tissue delivery of glucose. We addressed this hypothesis in a sample of healthy men. Methods: We studied 105 healthy young men aged 23-33 years. Insulin resistance was calculated using the Homeostasis Model Assessment (HOMA). Video capillaroscopy was used on the dorsum of the finger to measure skin capillary density, and in nailfold capillaries to measure capillary blood velocity. Skin vasodilatation was measured with laser Doppler fluximetry on the forearm following heating and iontophoresis of acetylcholine. Results: Higher systolic blood pressure was associated with insulin resistance (r=0.31, P
Abstract.
Mahy IR, Shore AC, Tooke JE, Smith LD (1969). Disturbance of peripheral microvascular function in congestive heart failure secondary to idiopathic dilated cardiomyopathy.
Cardiovascular Research,
3(4), 939-944.
Abstract:
Disturbance of peripheral microvascular function in congestive heart failure secondary to idiopathic dilated cardiomyopathy
Objectives: Previous studies of peripheral microvascular function in human heart failure have concentrated on changes in flow, and there is little information concerning the impact of heart failure on the principal determinants of transcapillary fluid exchange. This study investigated whether alterations in capillary pressure and microvascular fluid permeability can be detected in subjects with idiopathic dilated cardiomyopathy. Methods: Finger nailfold capillary pressure and calf capillary filtration coefficient (CFC) were measured in parallel studies of two overlapping groups of 12 non-oedematous subjects with idiopathic dilated cardiomyopathy and mild to moderate heart failure and in age- and sex-matched healthy controls. Capillary pressure was measured by direct cannulation using an electronic resistance feedback servonulling technique, and CFC by mercury-in-silastic strain gauge plethysmography using a modification of the technique which avoids assumptions concerning isovolumetric venous pressure. Results: Following correction for differences in skin temperature, capillary pressure was lower in the subjects with heart failure (P = 0.02). Both CFC and isovolumetric venous pressure were greater in the subjects with heart failure than in controls (3.4 ± 0.9 vs. 2.6 ± 0.7 ml · min
. · mmHg
. · 100 ml
. P = 0.03; 27.1 ± 8.4 vs. 17.2 ± 7.2 mmHg, P = 0.01). Conclusions: These data suggest that factors other than changes in arterial inflow and venous outflow pressures are likely to play an important role in the disruption of microvascular homeostasis which occurs in heart failure. Changes in capillary hydraulic conductance may contribute to the pathogenesis of oedema.
Abstract.
