Angela C. Shore

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.

RESPONSES OF THE SKIN MICROCIRCULATION TO ACETYLCHOLINE AND SODIUM-NITROPRUSSIDE IN PATIENTS WITH NIDDM

SummaryThe 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.

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.

Association of a difference in systolic blood pressure between arms with vascular disease and mortality: a systematic review and meta-analysis

BACKGROUND Differences in systolic blood pressure (SBP) of 10 mm Hg or more or 15 mm Hg or more between arms have been associated with peripheral vascular disease and attributed to subclavian stenosis. We investigated whether an association exists between this difference and central or peripheral vascular disease, and mortality. METHODS We searched Medline, Embase, Cumulative Index to Nursing and Allied Health Literature, Cochrane, and Medline In Process databases for studies published before July, 2011, showing differences in SBP between arms, with data for subclavian stenosis, peripheral vascular disease, cerebrovascular disease, cardiovascular disease, or survival. We used random effects meta-analysis to combine estimates of the association between differences in SBP between arms and each outcome. FINDINGS We identified 28 eligible studies for review, 20 of which were included in our meta-analyses. In five invasive studies using angiography, mean difference in SBP between arms was 36·9 mm Hg (95% CI 35·4-38·4) for proven subclavian stenosis (>50% occlusion), and a difference of 10 mm Hg or more was strongly associated with subclavian stenosis (risk ratio [RR] 8·8, 95% CI 3·6-21·2). In non-invasive studies, pooled findings showed that a difference of 15 mm Hg or more was associated with peripheral vascular disease (nine cohorts; RR 2·5, 95% CI 1·6-3·8; sensitivity 15%, 9-23; specificity 96%, 94-98); pre-existing cerebrovascular disease (five cohorts; RR 1·6, 1·1-2·4; sensitivity 8%, 2-26; specificity 93%, 86-97); and increased cardiovascular mortality (four cohorts; hazard ratio [HR] 1·7, 95% CI 1·1-2·5) and all-cause mortality (HR 1·6, 1·1-2·3). A difference of 10 mm Hg or higher was associated with peripheral vascular disease (five studies; RR 2·4, 1·5-3·9; sensitivity 32%, 23-41; specificity 91%, 86-94). INTERPRETATION A difference in SBP of 10 mm Hg or more, or of 15 mm Hg or more, between arms might help to identify patients who need further vascular assessment. A difference of 15 mm Hg or more could be a useful indicator of risk of vascular disease and death. FUNDING Royal College of General Practitioners, South West GP Trust, and Peninsula Collaboration for Leadership in Applied Health Research and Care.

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.

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.

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.

Relationship of insulin resistance to microvascular dysfunction in subjects with fasting hyperglycaemia

Summary 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 suggest that hyperinsulinaemia, as a result of insulin resistance, may have a detrimental effect on microvascular function in the prediabetic state. [Diabetologia (1997) 40: 238–243]

Reduced microvascular hyperaemia in subjects at risk of developing Type 2 (non-insulin-dependent) diabetes mellitus

SummaryAbnormalities 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.

The biological zero signal in laser doppler fluximetry – origins and practical implications

Abstract 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.