Journal articles
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
Dwivedi OP, Barreiro K, Käräjämäki A, Valo E, Giri AK, Prasad RB, Roy RD, Thorn LM, Rannikko A, Holthöfer H, et al (2023). Genome-wide mRNA profiling in urinary extracellular vesicles reveals stress gene signature for diabetic kidney disease. iScience, 26(5).
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
Abstract.
Author URL.
Aizawa K, Hughes AD, Casanova F, Gates PE, Mawson DM, Gooding KM, Gilchrist M, Goncalves I, Nilsson J, Khan F, et al (2022). Reservoir Pressure Integral is Independently Associated with the Reduction in Renal Function in Older Adults.
Hypertension,
79(10), 2364-2372.
Abstract:
Reservoir Pressure Integral is Independently Associated with the Reduction in Renal Function in Older Adults.
BACKGROUND: Arterial hemodynamic parameters derived from reservoir-excess pressure analysis exhibit prognostic utility. Reservoir-excess pressure analysis may provide useful information about an influence of altered hemodynamics on target organ such as the kidneys. We determined whether the parameters derived from the reservoir-excess pressure analysis were associated with the reduction in estimated glomerular filtration rate in 542 older adults (69.4±7.9 years, 194 females) at baseline and after 3 years. METHODS: Reservoir-excess pressure parameters, including reservoir pressure integral, excess pressure integral, systolic, and diastolic rate constants, were obtained by radial artery tonometry. RESULTS: After 3 years, and in a group of 94 individuals (72.4±7.6 years, 26 females), there was an estimated glomerular filtration rate reduction of >5% per year (median reduction of 20.5% over 3 years). A multivariable logistic regression analysis revealed that higher baseline reservoir pressure integral was independently associated with a smaller reduction in estimated glomerular filtration rate after accounting for conventional cardiovascular risk factors and study centers (odds ratio: 0.660 [95% CIs, 0.494-0.883]; P=0.005). The association remained unchanged after further adjustments for potential confounders and baseline renal function (odds ratio: 0.528 [95% CIs, 0.351-0.794]; P=0.002). No other reservoir-excess pressure parameters exhibited associations with the reduction in renal function. CONCLUSIONS: This study demonstrates that baseline reservoir pressure integral was associated with the decline in renal function in older adults at 3-year follow-up, independently of conventional cardiovascular risk factors. This suggests that reservoir pressure integral may play a role in the functional decline of the kidneys.
Abstract.
Author URL.
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 ± 8.8 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 ± 44.8 vs. 465.3 ± 20.6 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.
.
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.
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).
.
Abstract.
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.
.
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.
Aizawa K, Casanova F, Mawson D, Gooding K, Elyas S, Adingupu D, Strain D, Gates P, Shore A (2020). P17 Comparisons of Carotid-femoral Pulse Wave Velocity Obtained from the Surface-distance Measurement and from the Population-derived Distance Formula: Associations with Macro- and Microvascular Alterations in Older Adults. Artery Research, 25(Supplement 1).
Gooding KM, Lienczewski C, Papale M, Koivuviita N, Maziarz M, Andersson A-MD, Sharma K, Pontrelli P, Hernandez AG, Bailey J, et al (2020). 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.
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.
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.
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.
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
Abstract.
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.
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.
Author URL.
Aizawa K, Casanova F, Mawson DM, Gooding KM, Strain WD, Gates PE, Östling G, Khan F, Colhoun HM, Palombo C, et al (2018). Reservoir pressure integral is independently associated with the reduction in renal function in an older population. Artery Research, 24(C), 72-73.
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.
Abstract.
Author URL.
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.
Abstract.
Author URL.
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
Abstract.
Author URL.
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.
Abstract.
Author URL.
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.
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
Abstract.
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.
Abstract.
Author URL.
Aizawa K, Casanova F, Mawson D, Elyas S, Adingupu DD, Gooding KM, Strain WD, Park CM, Parker KH, Gates PE, et al (2016). [PP.11.05] RESERVOIR-PRESSURE ANALYSIS IN TYPE 2 DIABETES INDIVIDUALS WITH CARDIOVASCULAR DISEASE. Journal of Hypertension, 34(Supplement 2), e178-e178.
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
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.
Abstract.
Author URL.
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.
Aizawa. K, Casanova F, Mawson D, Elyas S, Adingupu D, Gooding K, Strain D, Shore A, Gates P (2015). P3.5 TYPE 2 DIABETES EXACERBATES CAROTID ARTERY ECHOGENICITY AND CENTRAL ARTERY STIFFNESS IN MIDDLE-AGED AND OLDER INDIVIDUALS. Artery Research, 12(C), 11-11.
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.
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.
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.
Abstract.
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.
Abstract.
Author URL.
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.
Abstract.
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.
Abstract.
Author URL.
Gooding KM, Spyer G, Tooke JE, MacLeod KM (2007). Alteration of oestradiol, testosterone, gonadotrophins and SHBG by type 2 diabetes in postmenopausal women: Clinical implications for the incidence of breast cancer, and cardiovascular risk in diabetic women?.
Practical Diabetes International,
24(9), 465-470.
Abstract:
Alteration of oestradiol, testosterone, gonadotrophins and SHBG by type 2 diabetes in postmenopausal women: Clinical implications for the incidence of breast cancer, and cardiovascular risk in diabetic women?
Sex hormones influence cardiovascular risk and bone mineral density. Total oestradiol is Increased in postmenopausal women with type 2 diabetes, whereas its impact on androgens, sex hormone binding globulin (SHBG) and gonadotrophins in postmenopausal women is not so clearly understood. This study aims to clarify the impact of type 2 diabetes on sex hormone levels in Caucasian postmenopausal women. Type 2 diabetic (n=42) and non-diabetic (n=45) postmenopausal women were recruited. Venous blood samples were drawn and, assayed for total testosterone, luteinising hormone (LH, follicle stimulating hormone (FSH) and SHBG. Ratio of total testosterone to SHBO was used as an index of free, testosterone(FT). Total oestradiol and FT were significantly higher in diabetic subjects compared to controls - oestradiol median: 59.5(25th, 75th centiles: 41.5, 74.5) vs 42.5(37.0, 59.8)pmol/L, p=0.009) Mann-Whitney test; and FT 0.038(0.021, 0.070) vs 0.022(0.012, 0.036), p=0.003. SHBG, FSH and LH were lower in diabetic subjects compared to controls - SHBG: 32(23.3,47.3) vs 55(37,70)nmol/L, p
Abstract.
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.
Abstract.
Author URL.
JTooke, Ball C, Elston L, Gooding K (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.
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.
Abstract.
Author URL.
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.
Abstract.
Author URL.
Gooding KM, Whatmore JL, Warland D, Hannemann MM, Middlebrooke AR, Paisley K, Liddell W, Lee B, Tooke JE, Shore AC, et al (2004). PC21 PREDICTORS OF SKIN MINIMUM VASCULAR RESISTANCE IN WOMEN. Microcirculation, 11(6), 545-546.
Stride A, Pearson ER, Brown A, Gooding K, Castleden HAJ, Hattersley AT (2004). Serum amino acids in patients with mutations in the hepatocyte nuclear factor-1 alpha gene.
Diabet Med,
21(8), 928-930.
Abstract:
Serum amino acids in patients with mutations in the hepatocyte nuclear factor-1 alpha gene.
AIMS: Knockout mice lacking both copies of the hepatocyte nuclear factor 1 (HNF1) gene have altered serum levels of amino acids and generalized aminoaciduria. The aim of our study was to test whether alterations in serum amino acid levels were found in patients with mutations in the hepatocyte nuclear factor-1 alpha (HNF-1alpha) gene compared with controls. METHODS: Fasting serum from 20 patients with HNF-1alpha mutations and 20 age, sex and body mass index-matched controls was analysed for 16 amino acids. Means were compared between the two groups and Z scores calculated. RESULTS: There was no significant difference between patients with HNF-1alpha mutations and controls in serum levels of phenylalanine, arginine, citrulline or lysine as suggested by knockout mice models. Although serum levels of eight amino acids were different in the two groups, these were not significant after Bonferroni correction. CONCLUSIONS: the alterations in serum amino acid levels seen in mice models are not seen in patients with mutations in the HNF-1alpha gene. This suggests differences in mouse and man in the regulation of amino acid transport and has not provided us with a phenotypic marker to use before confirmatory genetic testing.
Abstract.
Author URL.
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
Abstract.
Author URL.
