Erik H. Serné

Impaired Microvascular Function in Obesity Implications for Obesity-Associated Microangiopathy, Hypertension, and Insulin Resistance

Background—Obesity is associated with an increased risk of developing microangiopathy, hypertension, and insulin resistance. We hypothesized that obesity is a primary cause of microvascular dysfunction, which may contribute to the development of these obesity-related disorders. Methods and Results—We examined microvascular function in 16 lean (body mass index <24 kg/m2) and 12 obese (body mass index >30 kg/m2) healthy women (mean age, 38.9±6.7 years) in the basal state and during physiological systemic hyperinsulinemia. We determined skin capillary recruitment after arterial occlusion with capillaroscopy and skin endothelium–(in)dependent vasodilation by iontophoresis of acetylcholine and sodium nitroprusside. Obese women, compared with lean women, had higher systolic blood pressure (P <0.05), impaired insulin sensitivity (P <0.01), impaired capillary recruitment in the basal state (P <0.05) and during hyperinsulinemia (P <0.05), and impaired acetylcholine-mediated vasodilation in the basal state (P <0.05) and during hyperinsulinemia (P <0.01). Sodium nitroprusside–mediated vasodilation was similar in lean and obese women. Capillary recruitment and acetylcholine-mediated vasodilation were positively correlated with insulin sensitivity (r =0.58, P <0.01 and r =0.55, P <0.01, respectively) and negatively with blood pressure (r =−0.64, P <0.001 and r =−0.42, P <0.05, respectively) in both lean and obese women. Conclusions—Obesity is characterized by impaired microvascular function in the basal state and during hyperinsulinemia and, in both lean and obese women, microvascular dysfunction is associated with increased blood pressure and decreased insulin sensitivity. These findings are consistent with a contribution of impaired microvascular function to the development of obesity-related microangiopathy, hypertension, and insulin resistance.

Microvascular function relates to insulin sensitivity and blood pressure in normal subjects.

BACKGROUND A strong but presently unexplained inverse association between blood pressure and insulin sensitivity has been reported. Microvascular vasodilator capacity may be a common antecedent linking insulin sensitivity to blood pressure. To test this hypothesis, we studied 18 normotensive and glucose-tolerant subjects showing a wide range in insulin sensitivity as assessed with the hyperinsulinemic, euglycemic clamp technique. METHODS AND RESULTS Blood pressure was measured by 24-hour ambulatory blood pressure monitoring. Videomicroscopy was used to measure skin capillary density and capillary recruitment after arterial occlusion. Skin blood flow responses after iontophoresis of acetylcholine and sodium nitroprusside were evaluated by laser Doppler flowmetry. Insulin sensitivity correlated with 24-hour systolic blood pressure (24-hour SBP; r=-0.50, P<0.05). Capillary recruitment and acetylcholine-mediated vasodilatation were strongly and positively related to insulin sensitivity (r=0.84, P<0.001; r=0.78, P<0.001, respectively), and capillary recruitment was inversely related to 24-hour SBP (r=-0.53, P<0.05). Waist-to-hip ratio showed strong associations with insulin sensitivity, blood pressure, and the measures of microvascular function but did not confound the associations between these variables. Subsequent regression analysis showed that the association between insulin sensitivity and blood pressure was not independent of the estimates of microvascular function, and part of the variation in both blood pressure (R2=38%) and insulin sensitivity (R2=71%) could be explained by microvascular function. CONCLUSIONS Insulin sensitivity and blood pressure are associated well within the physiological range. Microvascular function strongly relates to both, consistent with a central role in linking these variables.

Rapid Decrease in Delivery of Chemotherapy to Tumors after Anti-VEGF Therapy: Implications for Scheduling of Anti-Angiogenic Drugs

Current strategies combining anti-angiogenic drugs with chemotherapy provide clinical benefit in cancer patients. It is assumed that anti-angiogenic drugs, such as bevacizumab, transiently normalize abnormal tumor vasculature and contribute to improved delivery of subsequent chemotherapy. To investigate this concept, a study was performed in non-small cell lung cancer (NSCLC) patients using positron emission tomography (PET) and radiolabeled docetaxel ([(11)C]docetaxel). In NSCLC, bevacizumab reduced both perfusion and net influx rate of [(11)C]docetaxel within 5 hr. These effects persisted after 4 days. The clinical relevance of these findings is notable, as there was no evidence for a substantial improvement in drug delivery to tumors. These findings highlight the importance of drug scheduling and advocate further studies to optimize scheduling of anti-angiogenic drugs.

Individuals at increased coronary heart disease risk are characterized by an impaired microvascular function in skin.

Background To investigate whether microvascular function in skin is a valid model to study the relationships between cardiovascular risk factors and microvascular function, we investigated skin microvascular function in individuals with increased coronary heart disease (CHD) risk.

Impaired skin capillary recruitment in essential hypertension is caused by both functional and structural capillary rarefaction

Capillary rarefaction occurs in many tissues in patients with essential hypertension and may contribute to an increased vascular resistance and impaired muscle metabolism. Rarefaction may be caused by a structural (anatomic) absence of capillaries, functional nonperfusion, or both. The aim of this study was to assess the extent of structural versus functional capillary rarefaction in the skin of subjects with essential hypertension. We examined skin capillary density with video microscopy before and during maximization of the number of perfused capillaries by venous congestion (structural capillary number) and before and during postocclusive reactive hyperemia (capillary recruitment, which may have a structural and/or functional basis). The study group was composed of 26 patients with never-treated essential hypertension and 26 normotensive control subjects. In both groups, intermittently perfused capillaries in the resting state were an important functional reserve for recruitment during postocclusive hyperemia. Recruitment of perfused capillaries during postocclusive reactive hyperemia was decreased in the hypertensive subjects compared with normotensive control subjects (47.9±6.8 versus 55.3±8.2 capillaries/mm2, respectively;P <0.01). During venous occlusion, maximal capillary density was significantly lower in the hypertensive subjects than in the control subjects (52.5±6.6 versus 57.2±8.6 capillaries/mm2, respectively;P <0.05), suggesting structural rarefaction. However, in the hypertensive subjects compared with the normotensive subjects, a smaller proportion of the maximal number of capillaries was perfused during postocclusive hyperemia (91.6±7.5% versus 97.2±2.7%, respectively;P <0.05), suggesting an additional functional impairment of capillary recruitment. If the difference in capillary numbers during venous congestion (≈4.6 capillaries/mm2) truly reflects the structural difference between the normotensive and hypertensive subjects, then, at most, 62% (4.6/7.4×100%) of the difference in capillary numbers during postocclusive hyperemia (≈7.4 capillaries/mm2) can be explained by structural defects, and at least 38% can be explained by functional defects. In conclusion, in patients with essential hypertension, recruitment of perfused capillaries is impaired, which can be explained by both functional and structural rarefaction.

Microvascular Dysfunction: A Potential Pathophysiological Role in the Metabolic Syndrome

Obesity and a central body fat distribution, hypertension, insulin resistance, glucose intolerance, dyslipidemia, and proinflammatory and prothrombotic factors are all part of the metabolic syndrome. The metabolic syndrome defines a clustering of metabolic risk factors which confers an increased risk for type 2 diabetes and cardiovascular disease.1 In the past years a large amount of research has been aimed at elucidating the pathophysiology underlying this clustering of risk factors, because a better understanding may lead to new therapeutic approaches that specifically target underlying causes of the metabolic syndrome. Recently, it has become clear that microvascular dysfunction, by affecting both pressure and flow patterns, may have consequences not only for peripheral vascular resistance, but also for insulin-mediated changes in muscle perfusion and glucose metabolism, providing a novel pathophysiological framework for understanding the association between hypertension, obesity, and impaired insulin-mediated glucose disposal.2–4 The present article examines recent data concerning the role of microvascular dysfunction as an explanation for the associations among hypertension, obesity, and impaired insulin-mediated glucose disposal. Description of the Microcirculation An exact definition of the microcirculation is elusive. Morphologically, the microcirculation is widely taken to encompass vessels 150 m in diameter. It therefore includes arterioles, capillaries, and venules. Alternatively, a definition based on arterial vessel physiology rather than diameter or structure has been proposed. 3 By this definition, all arterial vessels that respond to increasing pressure by a myogenic reduction in lumen diameter are included in the microcirculation. Such a definition would include the smallest arteries and arterioles in the microcirculation in addition to capillaries and venules. Small arterial and arteriolar components should, therefore, be considered a continuum rather than distinct sites of resistance control. A primary function of the microcirculation is to optimize nutrient and oxygen supply within the tissue in response to variations in demand. A second important function is to avoid large fluctuations in hydrostatic pressure at the level of the capillaries causing disturbances in capillary exchange. Finally, it is at the level of the microcirculation that a substantial proportion of the drop in hydrostatic pressure occurs. The microcirculation is therefore extremely important in determining overall peripheral vascular resistance.

Regulation of Vascular Function and Insulin Sensitivity by Adipose Tissue: Focus on Perivascular Adipose Tissue

ABSTRACT

Capillary recruitment is impaired in essential hypertension and relates to insulin's metabolic and vascular actions

OBJECTIVE In patients with essential hypertension, defects in both the metabolic and vascular actions of insulin have been described. Impaired microvascular function, a well-established abnormality in essential hypertension, may explain part of these defects. In the present study we investigated whether microvascular function is impaired in essential hypertension and relates to insulins metabolic and vasodilatatory actions. METHODS We measured 24-h ambulatory blood pressure, capillary recruitment after arterial occlusion, and skin blood flow responses to iontophoresis of acetylcholine and sodium nitroprusside in 18 subjects with untreated essential hypertension and in 18 control subjects. Whole body insulin sensitivity and leg insulin-mediated vasodilatation were assessed with the hyperinsulinaemic clamp technique and plethysmography. RESULTS Hypertensive, as compared to normotensive, subjects had a decreased insulin sensitivity (0.8+/-0.3 vs. 1.7+/-0. 6 mgkg(-1)min(-1) per pmoll(-1); P<0.001), capillary recruitment after arterial occlusion (21.5+/-5.8 vs. 45.9+/-10.4%; P<0.001), acetylcholine-mediated vasodilatation (331+/-84 vs. 688+/-192%; P<0. 001), and insulin-mediated vasodilatation (median 29.3 vs. 47.2%; P<0.05). Correlation analyses with adjustment for sex, age, body mass index and waist-to-hip ratio showed significant relationships of capillary recruitment after arterial occlusion with blood pressure (r=-0.68; P<0.01), insulin sensitivity (r=+0.55; P<0.01) and insulin-mediated vasodilatation (r=+0.51; P<0.05), which extended from the normotensive to the hypertensive range. CONCLUSION Skin microvascular function is associated with blood pressure and insulins metabolic and vasodilatatory actions, both in normotensive and hypertensive subjects. These findings offer a potential mechanistic explanation of the links among insulin resistance, impaired insulin-mediated vasodilatation and hypertension.

Cigarette smoking is associated with an acute impairment of microvascular function in humans.

An effect on microvascular function has been proposed as a possible mechanism explaining the association of acute smoking with increased blood pressure and decreased insulin sensitivity. However, the effects of smoking on microvascular function have not been studied. We have investigated the acute effects of smoking on microvascular function in 12 healthy smokers. Before and after smoking a cigarette, we measured heart rate, blood pressure and capillary recruitment during peak reactive hyperaemia. We also measured endothelium-dependent and endothelium-independent vasodilatation of the skin microcirculation with iontophoresis of acetylcholine and sodium nitroprusside respectively combined with laser Doppler fluxmetry. To exclude non-specific changes, a control study with sham smoking was performed. The smoking and sham smoking studies were conducted in a randomized order. Compared with sham smoking, acute smoking caused increases in heart rate (smoking, 9.3+/-4.1 beats/min; sham, -1.3+/-3.0 beats/min; P < 0.001) and systolic blood pressure (smoking, 6.3+/-8.8 mmHg; sham, 0.8+/-4.4 mmHg; P < 0.05); decreases in absolute (smoking, -4.9+/-6.9 per mm(2); sham, 0.8+/-2.1 per mm(2); P = 0.01) and relative (smoking, -13.8+/-21.4%; sham, 1.9+/-6.9%; P = 0.02) capillary recruitment during peak reactive hyperaemia; and decreases in absolute [smoking, -62.4+/-47.7 perfusion units (PU); sham, -30.8+/-32.6 PU; P = 0.04] and relative (smoking, -147+/-163%; sham, 32+/-225%; P = 0.07) vasodilatation caused by acetylcholine. Absolute (smoking, -31.6+/-58.5 PU; sham, -8.4+/-44.0 PU; P = 0.3) and relative (smoking, -50.2+/-219.0%; sham, -17.1+/-139%; P = 0.7) vasodilatation caused by sodium nitroprusside were not affected. Thus acute smoking is associated with impaired capillary recruitment during peak reactive hyperaemia and impaired microvascular endothelium-dependent vasodilatation. These findings may explain the increased blood pressure and decreased insulin sensitivity that have been observed after acute smoking.

Signs of accelerated preclinical atherosclerosis in patients with ankylosing spondylitis.

Objective. Preliminary evidence suggests that ankylosing spondylitis (AS) is associated with an increased cardiovascular (CV) risk. We investigated subclinical atherosclerosis and arterial stiffness in patients with AS compared with controls, and identified CV and AS related risk factors for atherosclerotic disease. Methods. A total of 59 patients with AS who were scheduled for etanercept treatment according to the ASsessments in Ankylosing Spondylitis guidelines and 30 healthy controls were recruited. Subclinical atherosclerosis was assessed as the average intima-media thickness (IMT) of the common carotid artery. Arterial stiffness was determined by distensibility, compliance, and Young’s elastic modulus of the carotid artery. Results. AS patients had a greater IMT (0.62 ± 0.09 mm vs 0.57 ± 0.09 mm in controls; p = 0.02), a difference that remained after adjustment for traditional CV risk factors. AS was associated with higher carotid pulse pressure (47 ± 7 mm Hg vs 44 ± 8 mm Hg in controls; p = 0.04), but this was not due to local vessel wall properties. Among AS patients, age and body mass index (BMI) were determinants of IMT. Age, BMI, total cholesterol, triglycerides, and disease duration were identified as determinants of stiffness indices. No relationship was found between large-vessel properties and higher Bath AS disease indices or C-reactive protein values. Conclusion. AS was associated with subclinical atherosclerosis and arterial stiffness, supporting epidemiological evidence of an increased CV risk in these patients. Whether these differences are due to AS or to a higher prevalence of CV risk factors in patients with AS remains to be determined.