Km Gooding

Adiposity is a major determinant of plasma levels of the novel vasodilator hydrogen sulphide

Aims/hypothesisHydrogen sulphide is a recently identified endogenous endothelium-dependent vasodilator. Animal models of diabetes have shown that low plasma H2S levels are associated with marked endothelial dysfunction and insulin resistance. However, human studies on H2S and vascular function in health and disease are lacking.MethodsPlasma was obtained from male patients with type 2 diabetes (n = 11), overweight (n = 16) and lean (n = 11) volunteers. H2S 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, Hb1Ac) and microvascular function (minimum vascular resistance) were determined.ResultsMedian plasma H2S levels (25th, 75th percentiles) in age-matched lean, overweight and type 2 diabetes individuals were 38.9 (29.7, 45.1) µmol/l, 22.0 (18.6, 26.7) µmol/l and 10.5 (4.8, 22.0) µmol/l, respectively. Median plasma H2S 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 H2S levels in overweight participants were significantly lower than in lean controls (p = 0.003). Waist circumference was an independent predictor of plasma H2S (R2 = 0.423, standardised beta: −0.650, p < 0.001). This relationship was independent of diabetes, which only contributed a further 5% to the model (R2 = 0.477). Waist circumference or other measures of adiposity (waist:hip ratio/BMI) remained independent predictors of plasma H2S after adjustment for systolic blood pressure, microvascular function, insulin sensitivity, glycaemic control and lipid profile.Conclusions/interpretationPlasma H2S levels are reduced in overweight participants and patients with type 2 diabetes. Increasing adiposity is a major determinant of plasma H2S levels.

Maximum Skin Hyperaemia Induced by Local Heating: Possible Mechanisms

Background: Maximum skin hyperaemia (MH) induced by heating skin to ≧42°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°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.

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 (H2S) are markedly elevated in several animal models of inflammation. Pharmacological inhibition of H2S synthesis reduces inflammation and swelling, suggesting that H2S is a potential inflammatory mediator. However, it is currently unknown whether H2S synthesis is perturbed in human inflammatory conditions or whether H2S 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 H2S concentrations from healthy volunteers and RA and OA patients were 37.6, 36.6, and 37.6 μM, respectively. In RA patients, median synovial fluid H2S levels (62.4 μM) were significantly higher than paired plasma (P= 0.002) and significantly higher than in synovial fluid from OA patients (25.1 μM; P= 0.009). SF H2S 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 H2S is present in synovial fluid and levels correlated with inflammatory and clinical indices in RA patients.

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.

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 μm in diameter.

Capillary Pressure in Subjects With Type 2 Diabetes and Hypertension and the Effect of Antihypertensive Therapy

Abstract—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 <0.03, Mann-Whitney U test). Second, no significant difference was detected between hypertensive subjects with type 2 diabetes and hypertensive subjects without type 2 diabetes (19.4 [15.8 to 21.3] mm Hg versus 17.2 [15.1 to 19.8] mm Hg, respectively, P =0.5, Mann-Whitney U test). Finally, patients with type 2 diabetes were recruited to a case-control study. Seven subjects received blood pressure–lowering therapy and 8 did not. Therapy reduced capillary pressure from 18.2 [15.8 to 20.1] mm Hg to 15.9 [15.4 to 17.0] mm Hg (P =0.024 ANOVA), in contrast to the lack of effect of time alone. Mean arterial pressure was reduced from 110 [102 to 115] mm Hg to 105 [101 to 111] mm Hg (P =0.006, ANOVA). These findings provide a plausible mechanism by which reducing arterial hypertension may reduce the risk of microangiopathy in type 2 diabetes.

Association between renin and atherosclerotic burden in subjects with and without type 2 diabetes

BackgroundActivation 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.MethodsRenin 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).ResultsPlasma 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.ConclusionsOur findings provide clinical evidence for associations between systemic RAAS activation and atherosclerotic burden and suggest that this association is of particular importance in T2D.

Measures of atherosclerotic burden are associated with clinically manifest cardiovascular disease in type 2 diabetes: a European cross-sectional study

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.

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).

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.