Microvascular endothelial dysfunction in skin is associated with higher risk of heart failure with preserved ejection fraction in women with type 2 diabetes: the Hoorn Diabetes Care System Cohort.

BACKGROUND: Microvascular dysfunction plays a crucial role in complications of type 2 diabetes and might contribute to heart failure with preserved ejection fraction (HFpEF), a disease that disproportionally affects women. We aimed to investigate if presence and degree of microvascular dysfunction (MVD) in skin relates to markers of left ventricular diastolic dysfunction (LVDD) and HFpEF risk in adults with type 2 diabetes, and whether sex modifies this association. METHODS: We recruited 154 participants (50% women) from the Hoorn Diabetes Care System Cohort, a prospective cohort study, for in vivo evaluation of skin MVD, echocardiography and blood sampling. MVD was assessed by laser speckle contrast analysis combined with iontophoresis of insulin, acetylcholine and sodium nitroprusside (SNP). We performed a cross-sectional analysis of the association between perfusion responses and echocardiographic and clinical markers of LVDD and the H2FPEF score by multivariable linear regression analysis adjusted for confounders. Sex was evaluated as a potential effect modifier and the analysis was stratified. RESULTS: Mean age was 67 ± 6y, mean HbA1c 7.6 ± 1.3%. Women were more frequently obese (54.5 vs. 35.1%), had higher NT-proBNP plasma levels (80, IQR:34-165 vs. 46, 27-117 pg/ml) and E/E'(13.3 ± 4.3 vs. 11.4 ± 3.0) than men. Eleven women and three men were diagnosed with HFpEF, and showed lower perfusion response to insulin than those without HFpEF. A lower perfusion response to insulin and acetylcholine was associated with higher HFpEF risk in women, but not men (10% decreased perfusion response was associated with 5.8% [95%CI: 2.3;9.4%] and 5.9% [1.7;10.1%] increase of the H2FPEF score, respectively). A lower perfusion response to SNP was associated with higher pulmonary arterial systolic pressure in men while a lower perfusion response to acetylcholine associated with higher LV mass index in women and with worse LV longitudinal strain in the total population. No significant associations were found between perfusion responses and conventional LVDD markers. CONCLUSIONS: Impaired microvascular responses to insulin and acetylcholine in skin confers a higher risk of HFpEF in women with type 2 diabetes. In vivo measures of systemic MVD could represent novel risk markers for HFpEF, opening new avenues for the prevention of HFpEF in type 2 diabetes.

Reduced Microvascular Blood Volume as a Driver of Coronary Microvascular Disease in Patients With Non-obstructive Coronary Artery Disease: Rationale and Design of the MICORDIS Study.

Background: Ischemia with non-obstructive coronary arteries (INOCA) is part of the ischemic heart disease spectrum, and is particularly observed in women. INOCA has various mechanisms, such as coronary vasospasm and coronary microvascular dysfunction (CMD). A decreased coronary flow reserve (CFR) and-or increased myocardial resistance (MR) are commonly used to diagnose CMD. However, CFR and MR do not describe all pathophysiological mechanisms underlying CMD. Increased myocardial oxygen consumption (MVO2) normally increases myocardial blood volume (MBV), independently from myocardial blood flow (MBF). In addition insulin enhances MBV in healthy skeletal muscle, and this effect is impaired in INOCA-related conditions such as diabetes and obesity. Therefore, we propose that MBV is reduced in INOCA patients. Aim: To assess whether myocardial blood volume (MBV) is decreased in INOCA patients, at baseline, during hyperinsulinemia and during stress. Design: The MICORDIS-study is a single-center observational cross-sectional cohort study (identifier NTR7515). The primary outcome is MBV, compared between INOCA patients and matched healthy controls. The patient group will undergo coronary function testing using a Doppler guidewire, intracoronary adenosine and acetylcholine to measure CFR and coronary vasospasm. Both the patient- and the control group will undergo myocardial contrast echocardiography (MCE) to determine MBV at baseline, during hyperinsulinemia and during stress. Subsequently, cardiac magnetic resonance (CMR) will be evaluated as a new and noninvasive diagnostic tool for CMD in INOCA patients. Microvascular endothelial function is a determinant of MBV and will be evaluated by non-invasive microvascular function testing using EndoPAT and by measuring NO production in circulating endothelial cells (ECFCs).

Hyperoxia does not directly affect vascular tone in isolated arteries from mice.

Hospitalized patients often receive oxygen supplementation, which can lead to a supraphysiological oxygen tension (hyperoxia). Hyperoxia can have hemodynamic effects, including an increase in systemic vascular resistance. This increase suggests hyperoxia-induced vasoconstriction, yet reported direct effects of hyperoxia on vessel tone have been inconsistent. Furthermore, hyperoxia-induced changes in vessel diameter have not been studied in mice, currently the most used mammal model of disease. In this study we set out to develop a pressure-myograph model using isolated vessels from mice for investigation of pathways involved in hyperoxic vasoconstriction. Isolated conduit and resistance arteries (femoral artery and gracilis arteriole, respectively) from C57BL/6 mice were exposed to normoxia (PO2 of 80 mmHg) and three levels of hyperoxia (PO2 of 215, 375 and 665 mmHg) in a no-flow pressure myograph setup. Under the different PO2 levels, dose-response agonist induced endothelium-dependent vasodilation (acetylcholine, arachidonic acid), endothelium-independent vasodilation (s-nitroprusside), as well as vasoconstriction (norepinephrine, prostaglandin F2α) were examined. The investigated arteries did not respond to oxygen by a change in vascular tone. In the dose-response studies, maximal responses and EC50 values to any of the aforementioned agonists were not affected by hyperoxia either. We conclude that arteries and arterioles from healthy mice are not intrinsically sensitive to hyperoxic conditions. The present ex-vivo model is therefore not suitable for further research into mechanisms of hyperoxic vasoconstriction.

Do grape polyphenols improve metabolic syndrome components? A systematic review.

BACKGROUND/OBJECTIVES: Epidemiological, in vitro and animal studies suggest that grape polyphenols, such as those present in wine, have favorable effects on the metabolic syndrome. However, controversy remains whether treatment with grape polyphenols is effective in humans. Here, we aimed to systemically review the effects of grape polyphenols on metabolic syndrome components in humans. SUBJECTS/METHODS: We systematically searched Medline, EMBASE and the Cochrane database for all clinical trials assessing the effects of grape polyphenols on insulin sensitivity, glycemia, blood pressure or lipid levels. We screened all titles and reviewed abstracts of potentially relevant studies. Full papers were assessed for eligibility and quality-rated according to the Jadad scale by two independent assessors. RESULTS: Thirty-nine studies met the eligibility criteria. In individuals without component criteria of the metabolic syndrome, only low- and medium-quality studies were found with primarily neutral results. In individuals with the metabolic syndrome or related conditions, one of two high-quality studies suggested improvement in insulin sensitivity. Glycemia was improved in 2 of 11 lower-quality studies and 2 of 4 high-quality studies. Seven of 22 studies demonstrated a significant decrease in blood pressure, but only one was of high quality. Two of four high-quality studies pointed towards effects on total cholesterol while other lipidemic parameters were not affected. CONCLUSIONS: No compelling data exist that grape polyphenols can positively influence glycemia, blood pressure or lipid levels in individuals with or without the metabolic syndrome. Limited evidence suggests that grape polyphenols may improve insulin sensitivity.

Exercise effects on perivascular adipose tissue: endocrine and paracrine determinants of vascular function.

Obesity is a global epidemic, accompanied by increased risk of type 2 diabetes and cardiovascular disease. Adipose tissue hypertrophy is associated with adipose tissue inflammation, which alters the secretion of adipose tissue-derived bioactive products, known as adipokines. Adipokines determine vessel wall properties such as smooth muscle tone and vessel wall inflammation. Exercise is a mainstay of prevention of chronic, non-communicable diseases, type 2 diabetes and cardiovascular disease in particular. Aside from reducing adipose tissue mass, exercise has been shown to reduce inflammatory activity in this tissue. Mechanistically, contracting muscles release bioactive molecules known as myokines, which alter the metabolic phenotype of adipose tissue. In adipose tissue, myokines induce browning, enhance fatty acid oxidation and improve insulin sensitivity. In the past years, the perivascular adipose tissue (PVAT) which surrounds the vasculature, has been shown to control vascular tone and inflammation through local release of adipokines. In obesity, an increase in mass and inflammation of PVAT culminate in dysregulation of adipokine secretion, which contributes to vascular dysfunction. This review describes our current understanding of the mechanisms by which active muscles interact with adipose tissue and improve vascular function. Aside from the exercise-dependent regulation of canonical adipose tissue function, we will focus on the interactions between skeletal muscle and PVAT and the role of novel myokines, such as IL-15, FGF21 and irisin, in these interactions. LINKED ARTICLES: This article is part of a themed section on Molecular Mechanisms Regulating Perivascular Adipose Tissue - Potential Pharmacological Targets? To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.20/issuetoc.

Insulin's microvascular vasodilatory effects are inversely related to peripheral vascular resistance in overweight, but insulin-sensitive subjects.

OBJECTIVE: The mechanisms underlying obesity-related hypertension are incompletely understood. Microvascular dysfunction might play a role by increasing peripheral vascular resistance (PVR). Metabolic and microvascular effects of insulin are impaired in obesity, but how these impairments contribute to disturbed blood pressure homeostasis is unclear. Specifically, it is unknown whether local microvascular vasoactive effects of insulin play a role in determining systemic vascular resistance. The aim of this study was to investigate the association between PVR and local microvascular effects of insulin. DESIGN AND METHODS: Thirty-seven healthy, overweight subjects (age 25-55 years, BMI 25-30 kg/m(2) ) were cross-sectionally studied. Local insulin-mediated vasodilation was measured using skin laser Doppler fluxmetry combined with transcutaneous iontophoresis of insulin. For comparison, local vasodilatory effects of acetylcholine and sodium nitroprusside were measured. PVR was calculated from mean arterial pressure and cardiac output, assessed by pulse-dye densitometry. RESULTS: PVR was inversely correlated with insulin-mediated vasodilation (r = -0.50; P < 0.01). This finding was maintained after adjustment for age, sex, blood pressure, and smoking. PVR was not associated with local microvascular effects of acetylcholine. CONCLUSIONS: Our study in overweight subjects suggests that insulin's role in the microvasculature may contribute to blood pressure control.

Perivascular Fat and the Microcirculation: Relevance to Insulin Resistance, Diabetes, and Cardiovascular Disease.

Type 2 diabetes and its major risk factor, obesity, are a growing burden for public health. The mechanisms that connect obesity and its related disorders, such as insulin resistance, type 2 diabetes, and hypertension, are still undefined. Microvascular dysfunction may be a pathophysiologic link between insulin resistance and hypertension in obesity. Many studies have shown that adipose tissue-derived substances (adipokines) interact with (micro)vascular function and influence insulin sensitivity. In the past, research focused on adipokines from perivascular adipose tissue (PVAT). In this review, we focus on the interactions between adipokines, predominantly from PVAT, and microvascular function in relation to the development of insulin resistance, diabetes, and cardiovascular disease.

Thrombin-induced endothelial barrier disruption in intact microvessels: role of RhoA/Rho kinase-myosin phosphatase axis.

Endothelial hyperpermeability is regulated by a myosin light chain-2 (MLC2) phosphorylation-dependent contractile mechanism. Thrombin is a potent inducer of hyperpermeability of cultured monolayers of endothelial cells (ECs) via Rho kinase-mediated MLC2-phosphorylation. The aim of the present study was to investigate the effects of thrombin on in situ endothelial morphology and barrier integrity. Cytoskeletal dynamics, regions of paracellular flux, and MLC2-phosphorylation of ECs were visualized by digital three-dimensional imaging microscopy of pressurized rat kidney arterioles. Myosin phosphatase targeting subunit (MYPT1)-phosphorylation was used as a surrogate marker for Rho kinase activity. Thrombin induced the formation of F-actin filaments in ECs in situ and rounding of the ECs in the absence of obvious formation of gaps between ECs. These changes were accompanied by an increase in MLC2 phosphorylation and a decrease in barrier integrity. In vitro analysis revealed that Rho kinase activity on F-actin filaments was associated with a contractile response that enhanced opening of the barrier. Rho kinase activity was not detectable on F-actin filaments induced by histamine, an inducer of a more transient hyperpermeability response. Inhibition of the myosin phosphatase mimicked the effects of thrombin on barrier function. The thrombin-induced changes in in situ MLC2 phosphorylation and barrier function were Rho kinase dependent. These data demonstrate a direct effect of thrombin on EC morphology and barrier integrity in intact microvessels. Furthermore, they establish an important contribution of enhanced Rho kinase activity to the development of prolonged but not transient types of endothelial barrier dysfunction.

Preglomerular and postglomerular basal diameter changes and reactivity to angiotensin II in obese rats.

AIM AND METHODS: Obesity in humans is associated with proteinuria and an increased glomerular filtration, possibly related to an increase in glomerular capillary pressure. We investigated in obese and lean Zucker rats (10-12 weeks old) whether this might be related to alterations in the diameter of preglomerular and postglomerular microvessels and their reactivity to the resistance regulator angiotensin II (AngII), using the hydronephrotic kidney model. RESULTS: The obese rats exhibited a hyperinsulinaemic, euglycaemic state and hypertension. Urinary protein concentration and fluid intake were both increased threefold. Basal diameters of distal interlobular arteries (ILAs) and afferent arterioles (AAs) were larger in the obese rat than in the lean rat (ILA: 25.7 +/- 0.3 vs. 23.0 +/- 0.4 microm and AA: 18.8 +/- 0.3 vs. 16.7 +/- 0.5 microm, respectively; p