Microvascular Function In Type Research Articles

The additive effects of obesity on myocardial microcirculation in diabetic individuals: a cardiac magnetic resonance first-pass perfusion study

BackgroundThe microvascular effects of obesity should be considered in diabetic individuals for elucidating underlying mechanisms and developing targeted therapies. This study aims to determine the effect of obesity on myocardial microvascular function in type 2 diabetes mellitus (T2DM) patients using cardiac magnetic resonance (CMR) first-pass perfusion imaging and assessed significant risk factors for microvascular dysfunction.Materials and methodsBetween September 2016 and May 2018, 120 patients with T2DM (45.8% women [55 of 120]; mean age, 56.45 ± 11.97 years) and 79 controls (44.3% women [35 of 79]; mean age, 54.50 ± 7.79 years) with different body mass index (BMI) scales were prospectively enrolled and underwent CMR examination. CMR-derived perfusion parameters, including upslope, time to maximum signal intensity (TTM), maximum signal intensity (MaxSI), MaxSI (-baseline), and SI (baseline), and T2DM related risk factors were analyzed among groups/subgroups both in T2DM patients and controls. Univariable and multivariable linear and logistic regression analyses were performed to assess the potential additive effect of obesity on microvascular dysfunction in diabetic individuals.ResultsCompared with controls with comparable BMIs, patients with T2DM showed reduced upslope and MaxSI and increased TTM. For both T2DM and control subgroups, perfusion function gradually declined with increasing BMI, which was confirmed by all perfusion parameters, except for TTM (all P < 0.01). In multivariable linear regression analysis, BMI (β = − 0.516; 95% confidence interval [CI], − 0.632 to − 0.357; P < 0.001), female sex (β = 0.372; 95% CI, 0.215 to 0.475; P < 0.001), diabetes duration (β = − 0.169; 95% CI, − 0.319 to − 0.025; P = 0.022) and glycated haemoglobin (β = − 0.184; 95% CI, − 0.281 to − 0.039; P = 0.010) were significantly associated with global upslope in the T2DM group. Multivariable logistic regression analysis indicated that T2DM was an independent predictor of microvascular dysfunction in normal-weight (odds ratio[OR], 6.46; 95% CI, 2.08 to 20.10; P = 0.001), overweight (OR, 7.19; 95% CI, 1.67 to 31.07; P = 0.008) and obese participants (OR, 11.21; 95% CI, 2.38 to 52.75; P = 0.002).ConclusionsMyocardial microvascular function gradually declined with increasing BMI in both diabetes and non-diabetes status. T2DM was associated with an increased risk of microvascular dysfunction, and obesity exacerbated the adverse effect of T2DM.

Skin microvascular reactivity correlates to clinical microangiopathy in type 1 diabetes: A pilot study.

Aim:The aim of this study was to investigate the correlation between skin microvascular reactivity and clinical microangiopathy in patients with type 1 diabetes.Methods:We included 61 patients with type 1 diabetes, that is, 31 patients with and 30 without clinical microangiopathy, and 31 healthy controls. A microangiopathy scoring system was introduced for comparison of data between patients with microangiopathy. Responses to iontophoresis of acetylcholine and sodium nitroprusside were assessed by laser Doppler imaging.Results:Patients with microangiopathy had reduced acetylcholine- and sodium nitroprusside-mediated flux in forearm skin microcirculation compared to healthy controls (p = 0.03 and p < 0.001, respectively, repeated measures analysis of variance), whereas no significant differences were found between patients without microangiopathy and controls. Skin reactivity was reduced in patients with microangiopathy compared to patients without microangiopathy: 1.43 ± 0.38 versus 1.59 ± 0.39 arbitrary units for acetylcholine-mediated peak flux and 1.44 ± 0.46 versus 1.74 ± 0.34 arbitrary units for sodium nitroprusside-mediated peak flux (p < 0.05 for both). A tendency of gradual decrease in acetylcholine and sodium nitroprusside responses was found in patients with increasing microangiopathy scores.Conclusion:We conclude that skin microvascular reactivity is associated with clinical microangiopathy in patients with type 1 diabetes. Impaired skin microvascular function in type 1 diabetes seems to be multifactorial and involves both endothelial-dependent and endothelial-independent pathways. We introduce a novel microangiopathy score that could easily be used in a clinical setting for comparison of patients with various degrees of microangiopathy.

Relation of cardiac adipose tissue to coronary calcification and myocardial microvascular function in type 1 and type 2 diabetes

BackgroundCardiac adipose tissue may have local paracrine effects on epicardial arteries and the underlying myocardium, promoting calcification and affecting myocardial microcirculation. We explored whether the total amount of cardiac adipose tissue was associated with coronary artery calcium score (CAC) and myocardial flow reserve in persons with type 1 or type 2 diabetes and healthy controls.MethodsWe studied three groups: (1) 30 controls, (2) 60 persons with type 1 diabetes and (3) 60 persons with type 2 diabetes. The three groups were matched for sex and age. The three groups derived from retrospective analysis of two clinical studies. All underwent cardiac 82Rb positron emission tomography/computed tomography (PET/CT) scanning. Cardiac adipose tissue volume (the sum of epicardial and pericardial fat), CAC, and myocardial flow reserve (ratio of pharmacological stress flow and rest flow) were evaluated using semiautomatic software. We applied linear regression to assess the association between cardiac adipose tissue, CAC and myocardial flow reserve.ResultsMean (SD) cardiac adipose tissue volume was 99 (61) mL in the control group, 106 (78) mL in the type 1 diabetes group and 228 (97) mL in the type 2 diabetes group. Cardiac adipose tissue was positively associated with body mass index in all three groups (p ≤ 0.02). In the controls, cardiac adipose tissue was positively associated with CAC score (p = 0.008) and negatively associated with myocardial flow reserve (p = 0.005). However, cardiac adipose tissue was not associated with CAC or myocardial flow reserve in the groups including persons with type 1 or type 2 diabetes (p ≥ 0.50).ConclusionsIn contrast to what was found in healthy controls, we could not establish a relation between cardiac adipose tissue and coronary calcification or myocardial microvascular function in person with type 1 or type 2 diabetes. The role of cardiac adipose tissue in cardiovascular disease in diabetes remains unclear.

Vasodilator Stress Echocardiography in the Assessment of Early Coronary Microvascular Function in Type II Diabetic Mice

Vasodilator Stress Echocardiography in the Assessment of Early Coronary Microvascular Function in Type II Diabetic Mice

Diabetes and Microvascular Dysfunction

Microvascular reactivity is an important mechanism that regulates local blood flow and therefore tissue perfusion. The reactivity (vasorelaxation and vasoconstriction) of microvessels is mainly regulated by mechanical factors (shear stress for relaxation and blood pressure for myogenic tone, which is a vasoconstriction of microvessels in response to increase in intraluminal blood pressure) and neurohormones. We previously showed that epidermal growth factor receptor tyrosine kinase (EGFRtk) is an important factor in the regulation of myogenic tone in microvessels. In fact, pressure-induced myogenic tone in resistance arteries is regulated by the mechanism that involves metalloproteinases 2 and 9 activation with subsequent Heparin-BindingEGF release and EGFRtk transactivation [1]. This mechanism appears to be specific to myogenic tone, since the contractions to angiotensin and KCl are independent of EGFRtk transactivation. We previously reported that diabetes is associated with microvascular dysfunction [1,2]. We observed reduced microvascular endothelium-dependent relaxation and aberrant increase in pressure-induced myogenic tone in type 2 diabetes [3,4]. The impairment in microvascular function in type 2 diabetes is, in part, caused by the enhanced EGFRtk activity. In a murine model of type 2 diabetic mice, we found an increase of EGFRtk phosphorylation in microvessels. Interestingly, the inhibition of EGFRtk improves vascular function in type 2 diabetes independently of the diabetes and obesity [4]. We also demonstrated that advanced glycation end products cause microvascular dysfunction in type 2 diabetes through the enhance in oxidative stress [3]. In another study, we demonstrated an increase in poly (ADP-ribose) polymerase 1 (PARP1) and nuclear factor-κB activity in microvessels isolated from type 2 diabetic compared to control [2,5,6]. Interestingly, the inhibition of PARP-1 and NFκB pathways improves microvascular function in type 2 diabetic mice [2,6] indicating that PARP-1 and NFκB are important factors in microvascular dysfunction in type 2 diabetes. The aberrant increase in PARP-1 and NFκB activity is caused by the augmented EGFRtk activity [2,7]. Thus, we determined that the inhibition of EGFRtk activity improved microvascular function by PARP-1 and NFκB-dependent mechanism [2,7] suggesting that EGFRtk is up stream to PARP-1 and NFκB signaling. The aberrant increase in NFκB and PARP-1 activity impairs microvascular function in type 2 diabetes by Sp-1 and COX-2-dependent mechanism. In summary, our studies delineated the mechanism of type 2 diabetes induced microvascular dysfunction. Therefore, the EGFRtk, oxidative stress, NFκB and PARP1 pathways could be potential targets for novel therapeutic strategies to overcome diabetes-induced microvascular dysfunction.

Direct Evidence for Intrarenal Chymase-Dependent Angiotensin II Formation on the Diabetic Renal Microvasculature

Our previous work supports a major role for angiotensin-converting enzyme (ACE)-independent intrarenal angiotensin (ANG) II formation on microvascular function in type 2 diabetes mellitus. We tested the hypothesis that there is a switch from renal vascular ACE-dependent to chymase-dependent ANGII formation in diabetes mellitus. The in vitro juxtamedullary afferent arteriole (AA) contractile responses to the intrarenal conversion of the ACE-specific, chymase-resistant ANGI peptide ([Pro(10)]ANGI) to ANGII were significantly reduced in kidneys of diabetic (db/db) compared with control (db/m) mice. AA responses to the intrarenal conversion of the chymase-specific, ACE-resistant ANGI peptide ([Pro(11), D-Ala(12)]ANGI) to ANGII were significantly enhanced in kidneys of diabetic compared with control mice. AA diameters were significantly reduced by 9 ± 2, 15 ± 3, and 24 ± 3% of baseline in diabetic kidneys in response to 10, 100, and 1000 nmol/L [Pro(11), D-Ala(12)]ANGI, respectively, and the responses were significantly attenuated by angiotensin type 1 receptor or chymase-specific (JNJ-18054478) inhibition. [Pro(11), D-Ala(12)]ANGI did not produce a significant AA vasoconstriction in control kidneys. Chymase inhibition significantly attenuated ANGI-induced AA vasoconstriction in diabetic, but not control kidneys. Renal vascular mouse mast cell protease-4 or chymase/β-actin mRNA expression was significantly augmented by 5.1 ± 1.4 fold; while ACE/β-actin mRNA expression was significantly attenuated by 0.42 ± 0.08 fold in diabetic compared with control tissues. In summary, intrarenal formation of ANGII occurs primarily via ACE in the control, but via chymase in the diabetic vasculature. In conclusion, chymase-dependent mechanisms may contribute to the progression of diabetic kidney disease.

Flow-mediated dilatation of the brachial artery is a poorly reproducible indicator of microvascular function in Type I diabetes mellitus

Flow-mediated dilatation (FMD) of the brachial artery is commonly measured as a surrogate marker of endothelial function. Its measurement is, however, technically demanding and reports regarding its reproducibility have not always been favourable. Two Type I diabetes and control group comparator studies were conducted to assess the reproducibility of FMD and to analyse blood flow data normally discarded during FMD measurement. The studies were sequential and differed only with regard to operator and ultrasound machine. Seventy-two subjects with diabetes and 71 controls were studied in total. Subjects had FMD measured conventionally. Blood velocity waveforms were averaged over 10 pulses post forearm ischaemia and their component frequencies analysed using the wavelet transform, a mathematical tool for waveform analysis. The component frequencies were grouped into 11 bands to facilitate analysis. Subjects were well-matched between studies. In Study 1, FMD was significantly impaired in subjects with Type I diabetes vs. controls (median 4.35%, interquartile range 3.10-4.80 vs. 6.50, 4.79-9.42, P < 0.001). No differences were detected between groups in Study 2, however. However, analysis of blood velocity waveforms yielded significant differences between groups in two frequency bands in each study. This report highlights concerns over the reproducibility of FMD measures. Further work is required to fully elucidate the role of analysing velocity waveforms after forearm ischaemia.

Arginase inhibition restores in vivo coronary microvascular function in type 2 diabetic rats

Nitric oxide (NO) is crucial for maintaining normal endothelial function and vascular integrity. Increased arginase activity in diabetes might compete with NO synthase (NOS) for their common substrate arginine, resulting in diminished production of NO. The aim of this study was to evaluate coronary microvascular function in type 2 diabetic Goto-Kakizaki (GK) rats using in vivo coronary flow velocity reserve (CFVR) and the effect of arginase inhibition to restore vascular function. Different groups of GK and Wistar rats were given vehicle, the arginase inhibitor N(ω)-hydroxy-nor-l-arginine (nor-NOHA), l-arginine, and the NOS inhibitor N(G)-monomethyl -l-arginine (l-NMMA). GK rats had impaired CFVR compared with Wistar rats (1.31 ± 0.09 vs. 1.87 ± 0.05, P < 0.001). CFVR was restored by nor-NOHA treatment compared with vehicle in GK rats (1.71 ± 0.13 vs. 1.23 ± 0.12, P < 0.05) but remained unchanged in Wistar rats (1.88 ± 0.10 vs. 1.79 ± 0.16). The beneficial effect of nor-NOHA in GK rats was abolished after NOS inhibition. CFVR was not affected by arginine compared with vehicle. Arginase II expression was increased in the aorta and myocardium from GK rats compared with Wistar rats. Citrulline-to-ornithine and citrulline-to-arginine ratios measured in plasma increased significantly more in GK rats than in Wistar rats after nor-NOHA treatment, suggesting a shift of arginine utilization from arginase to NOS. In conclusion, coronary artery microvascular function is impaired in the type 2 diabetic GK rat. Treatment with nor-NOHA restores the microvascular function by a mechanism related to increased utilization of arginine by NOS and increased NO availability.

Pleiotropic effects of rosuvastatin on microvascular function in type 2 diabetes

Rosuvastatin is known to reduce low-density lipoprotein (LDL)-cholesterol and improve endothelial function. In addition to lipid-lowering, statins may exert pleiotropic (nonlipid lowering) effects on microvascular function. We compared the neurophysiological and vascular responses of dietary control and treatment with 10 mg of rosuvastatin in 16 subjects with neuropathy and established type 2 diabetes. Skin blood flow (SkBF) measurements were measured at baseline, after 18 weeks of diet, and after 18 weeks of diet and treatment with rosuvastatin in response to local warming and ischemia reperfusion. The study results show that total cholesterol (196.50 ± 8.02 to 134.88 ± 10.86 mg/dL) and LDL-cholesterol (114 ± 10.4 to 63.4 ± 8.48 mg/dL) decreased significantly after 18 weeks of rosuvastatin, but not after 18 weeks of diet. Neuropathy scores decreased from 8.34 ± 1.26 at baseline to 6.00 ± 0.90 after rosuvastatin treatment. Basal SkBF was significantly different from baseline, 6.81 ± 0.42 to 9.92 ± 0.78 after rosuvastatin treatment (P ≤ 0.001). These results indicate that rosuvastatin therapy positively changed basal SkBF and measures of neurovascular function. Although there was a profound lipid lowering, it is not clear that this mediated the increases in SkBF and decreases in neuropathy scores.

Effect of chronic and selective endothelin receptor antagonism on microvascular function in Type 2 diabetes

Vascular dysfunction, which presents either as an increased response to vasoconstrictors or an impaired relaxation to dilator agents, results in worsened cardiovascular outcomes in diabetes. We have established that the mesenteric circulation in Type 2 diabetes is hyperreactive to the potent vasoconstrictor endothelin-1 (ET-1) and displays increased nitric oxide-dependent vasodilation. The current study examined the individual and/or the relative roles of the ET receptors governing vascular function in the Goto-Kakizaki rat, a mildly hyperglycemic, normotensive, and nonobese model of Type 2 diabetes. Diabetic and control rats received an antagonist to either the ET type A (ETA; atrasentan; 5 mg x kg(-1) x day(-1)) or type B (ET(B); A-192621; 15 or 30 mg x kg(-1) x day(-1)) receptors for 4 wk. Third-order mesenteric arteries were isolated, and vascular function was assessed with a wire myograph. Maximum response to ET-1 was increased in diabetes and attenuated by ETA antagonism. ETB blockade with 15 mg/kg A-192621 augmented vasoconstriction in controls, whereas it had no further effect on ET-1 hyperreactivity in diabetes. The higher dose of A-192621 showed an ETA-like effect and decreased vasoconstriction in diabetes. Maximum relaxation to acetylcholine (ACh) was similar across groups and treatments. ETB antagonism at either dose had no effect on vasorelaxation in control rats, whereas in diabetes the dose-response curve to ACh was shifted to the right, indicating a decreased relaxation at 15 mg/kg A-192621. These results suggest that ETA receptor blockade attenuates vascular dysfunction and that ETB receptor antagonism exhibits differential effects depending on the dose of the antagonists and the disease state.

Six months of aerobic exercise does not improve microvascular function in type 2 diabetes mellitus

Adults with type 2 diabetes mellitus have impaired microvascular function. It has been hypothesised that microvascular function may be restored through regular exercise. The aim of this study was to investigate whether 6 months of regular aerobic exercise would improve microvascular function in adults with type 2 diabetes. Fifty-nine patients with type 2 diabetes (32 males, age 62.9+/-7.6 years, HbA(1c) 6.8+/-0.9%) were randomised to either a 6-month aerobic exercise programme (30 min, three times a week, 70-80% of maximal heart rate) or a 'standard care' control group. Before and after the intervention period, microvascular function was assessed as the maximum skin hyperaemia to local heating and endothelial and non-endothelial responsiveness following the iontophoretic application of acetylcholine and sodium nitroprusside. Maximal oxygen uptake, as an index of aerobic fitness, was assessed using a maximal exercise test. No significant improvement was seen in the exercise group compared with the control group for any of the variables measured: maximal oxygen uptake (control pre: 1.73+/-0.53 [means+/-SD] vs post: 1.67+/-0.40; exercise pre: 1.75+/-0.56 vs post: 1.87+/-0.62 l/min, p=0.10); insulin sensitivity (insulin tolerance test) (control pre: -0.17+/-0.06 vs post: -0.17+/-0.06; exercise pre: -0.16+/-0.1 vs post: -0.17+/-0.07 mmol l(-1) min(-1), p=0.97); maximal hyperaemia (control pre: 1.49+/-0.43 vs post: 1.52+/-0.57; exercise pre: 1.42+/-0.36 vs post: 1.47+/-0.33 V, p=0.85); peak response to acetylcholine (control pre: 1.37+/-0.47 vs post: 1.28+/-0.37; exercise pre: 1.27+/-0.44 vs post: 1.44+/-0.23 V, p=0.19) or to sodium nitroprusside (control pre: 1.09+/-0.50 vs post: 1.10+/-0.39; exercise pre: 1.12+/-0.28 vs post: 1.13+/-0.40 V, p=0.98). In this group of type 2 diabetic patients with good glycaemic control a 6-month aerobic exercise programme did not improve microvascular function or aerobic fitness.

Influence of Glucose Control and Improvement of Insulin Resistance on Microvascular Blood Flow and Endothelial Function in Patients with Diabetes Mellitus Type 2

The study was performed to investigate the effect of improving metabolic control with pioglitazone in comparison to glimepiride on microvascular function in patients with diabetes mellitus type 2. A total of 179 patients were recruited and randomly assigned to one treatment group. Metabolic control (HbA1c), insulin resistance (HOMA index), and microvascular function (laser Doppler fluxmetry) were observed at baseline and after 3 and 6 months. HbA1c improved in both treatment arms (pioglitazone: 7.52 +/- 0.85% to 6.71 +/- 0.89%, p < .0001; glimepiride: 7.44 +/- 0.89% to 6.83 +/- 0.85%, p < .0001). Insulin-resistance decreased significantly in the pioglitazone group (6.15 +/- 4.05 to 3.85 +/- 1.92, p < .0001) and remained unchanged in the glimepiride group. The microvascular response to heat significantly improved in both treatment groups (pioglitazone 48.5 [15.2; 91.8] to 88.8 [57.6; 124.1] arbitrary units [AU], p < .0001; glimepiride 53.7 [14.1; 91.9] to 87.9 [52.9, 131.0] AU, p < .0001, median [lower and upper quartile]). Endothelial function as measured with the acetylcholine response improved in the pioglitazone group (38.5 [22.2; 68.0] to 60.2 [36.9; 82.8], p = .0427) and remained unchanged in the glimepiride group. Improving metabolic control has beneficial effects in microvascular function in type 2 diabetic patients. Treatment of type 2 diabetic patients with pioglitazone exerts additional effects on endothelial function beyond metabolic control.

Acute, local effects of iontophoresed insulin and C-peptide on cutaneous microvascular function in Type 1 diabetes mellitus.

The aim of the present study was to demonstrate acute, local vasodilatatory effects of insulin and C-peptide on cutaneous microvascular function in Type 1 diabetic subjects. There are no published data available examining physiological effects of C-peptide delivered in this way. The study included 20 participants with C-peptide-deficient Type 1 diabetes mellitus. Cutaneous microvascular function was assessed on the forearm using laser Doppler velocimetry. Insulin, C-peptide, acetylcholine (ACh), sodium nitroprusside (SNP) and saline were delivered through the skin using iontophoresis. The response was measured as percentage increase in flux above baseline. C-peptide delivered by iontophoresis produced a vasodilatatory response greater than the response to saline (289.5 +/- 265.9% vs. 105.1 +/- 163.6%, P = 0.003). The response to C-peptide was also shown to be dose dependent. Further, the size of the response to C-peptide correlated well with the size of the response to the endothelium-dependent vasodilatator ACh (r = 0.666, P = 0.001) but not with the size of the response to the endothelium-independent vasodilator SNP (r = 0.345, P > 0.05). Physiological effects of C-peptide on cutaneous microvascular function could be demonstrated in individuals with Type 1 diabetes. The results support both physiological activity of C-peptide and an endothelium-dependent mechanism similar to that of ACh. The technique reported may be useful in investigating vasoactive actions of C-peptide in a safe and non-invasive way.

Microvascular Function in Type 2 (Non‐insulin‐dependent) Diabetes: Improved Vasodilation After One Year of Good Glycaemic Control

Abnormalities of microvascular function may be important in the development of diabetic microangiopathy. The major functional abnormality identified in patients with Type 2 diabetes has been a marked limitation of microvascular vasodilation, which is present from the time of diagnosis. The effects of sustained improvements in glycaemic control on vasodilator capacity in Type 2 diabetes are unknown. Twelve Type 2 diabetic patients were studied prospectively for 1 year after diagnosis. The reduced maximum hyperaemic response to local heating of the foot skin present at the time of diagnosis remained unchanged after 3 months of improved glycaemic control (1.12 +/- 0.56 V at diagnosis vs 1.21 +/- 0.69 V at 3 months, mean +/- SD; p = 0.25), but was improved after 1 year (1.42 +/- 0.91 V; p = 0.04 vs 3 months). The percentage increase in maximum hyperaemia correlated with the percentage decrease in HbA1c (rs = 0.53, p = 0.04). These results suggest that the early microvascular abnormalities demonstrated in Type 2 diabetes are potentially reversible and provide a further reason for striving for optimal glycaemic control in this patient group.