Nitric Oxide-mediated Cutaneous Microvascular Function is not Altered in Young Adults Following Mild-to-Moderate SARS CoV-2 Infection.

Vascular dysfunction has been reported in adults who have recovered from COVID-19. To date, no studies have investigated the underlying mechanisms of persistent COVID-19-associated vascular dysfunction. PURPOSE: To quantify nitric oxide (NO)-mediated vasodilation in healthy adults who have recovered from SARS-CoV-2 infection. We hypothesized that COVID-19-recovered adults would have impaired NO-mediated vasodilation compared to adults who have not had COVID-19. METHODS: We performed a cross-sectional study including: 10 (5M/5W, 24 ± 4yrs) healthy control (HC) adults who were unvaccinated for COVID-19, 11 (4M/7W, 25 ± 6yrs) healthy vaccinated (HV) adults, and 12 (5M/7W, 22 ± 3yrs) post-COVID-19 (PC, 19 ± 14wks) adults. COVID-19 symptoms severity (survey) were assessed. A standardized 39°C local heating protocol was used to assess NO-dependent vasodilation via perfusion (intradermal microdialysis) of 15 mM NG-nitro-l-arginine methyl ester during the plateau of the heating response. Red blood cell flux was measured (laser-Doppler flowmetry) and cutaneous vascular conductance (CVC = flux/mmHg) was expressed as a percentage of maximum (28mM sodium nitroprusside + 43°C). RESULTS: The local heating plateau (HC: 61 ± 20%, HV: 60 ± 19%, PC: 67 ± 19%, p=0.80) and NO-dependent vasodilation (HC: 77 ± 9%, HV: 71 ± 7%, PC: 70 ± 10%, p=0.36) were not different among groups. Neither symptom severity (25 ± 12 AU) nor time since diagnosis correlated with the NO-dependent vasodilation (r=0.46, p=0.13; r=0.41, p=0.19, respectively). CONCLUSION: Healthy adults who have had mild-to-moderate COVID-19 do not have altered NO-mediated cutaneous microvascular function.

High Frequency of Microvascular Dysfunction in US Outpatient Clinics: A Sign of High Residual Risk? Data from 7,105 Patients

Previous studies have linked peripheral microvascular dysfunction measured by arterial tonometry to high residual risk in on-statin patients. Digital thermal monitoring (DTM) of microvascular function is a new and simplified technique based on fingertip temperature measurements that has been correlated with the burden of atherosclerosis and its risk factors. Here, we report analyses of DTM data from two large US registries: Registry-I (6,084 cases) and Registry-II (1,021 cases) across 49 US outpatient clinics. DTM tests were performed using a VENDYS device during a 5-minute arm-cuff reactive hyperemia. Fingertip temperature falls during cuff inflation and rebounds after deflation. Adjusted maximum temperature rebound was reported as vascular reactivity index (VRI). VRI distributions were similar in both registries, with mean ± SD of 1.58 ± 0.53 in Registry-I and 1.52 ± 0.43 in Registry-II. In the combined dataset, only 18% had optimal VRI (≥2.0) and 82% were either poor (<1.0) or intermediate (1.0-2.0). Women had slightly higher VRI than men ( 1.62 ± 0.56 vs. 1.54 ± 0.47 , p < 0.001 ). VRI was inversely but mildly correlated with age ( r = − 0.19 , p < 0.001 ). Suboptimal VRI was found in 72% of patients <50 years, 82% of 50-70 years, and 86% of ≥70 years. Blood pressure was not correlated with VRI. In this largest registry of peripheral microvascular function measurements, suboptimal scores were highly frequent among on-treatment patients, possibly suggesting a significant residual risk. Prospective studies are warranted to validate microvascular dysfunction as an indicator of residual risk.

Invasive Assessment of Coronary Microvascular Function

The critical role of the coronary microvascular compartment and its invasive functional assessment has become apparent in light of the significant proportion of patients presenting signs and symptoms of myocardial ischemia, despite the absence of epicardial disease, or after the adequate treatment of it. However, coronary microvascular dysfunction (CMD) represents a diagnostic challenge because of the small dimensions of the coronary microvasculature, which prevents direct angiographic visualization. Several diagnostic tools are now available for the invasive assessment of the coronary microvascular function, which, in association with the physiological indices used to investigate the epicardial department, may provide a comprehensive evaluation of the coronary circulation as a whole. Recent evidence suggests that the physiology-guided management of CMD, although apparently costly and time-consuming, may offer a net clinical benefit in terms of symptom improvement among patients with angina and ischemic heart disease. However, despite the results of several observational studies, the prognostic effect of the physiology-driven management of CMD within this population is currently a matter of debate, and therefore represents an unmet clinical need that urgently deserves further investigation.

Contributions of Endothelin-1 and L-arginine to Blunted Cutaneous Microvascular Function in Young, Black Women

Non-Hispanic black (BL) individuals have the greatest prevalence of cardiovascular disease (CVD), relative to other racial/ethnic groups (e.g., non-Hispanic white population; WH) which may be secondary to blunted vascular function. While women typically present with reduced CVD relative to men of the same racial/ethnic group, the prevalence is similar between BL women and men though the mechanisms differ. This study hypothesized that reduced microvascular function in young, BL women is associated with endothelin-1 (ET-1) overactivity or insufficient L-arginine bioavailability. Nine BL and 9 WH women participated (age: 20 ± 2 vs. 22 ± 2 y). Cutaneous microvascular function was assessed during 39°C local heating, while Lactated Ringer's (control), BQ-123 (ET-1 receptor type A antagonist), BQ-788 (ET-1 receptor type B antagonist), or L-arginine was infused via intradermal microdialysis to modify cutaneous vascular conductance (CVC). Subsequent infusion of Nω-nitro-L-arginine methyl ester allowed for quantification of the nitric oxide (NO) contribution to vasodilation, while combined sodium nitroprusside and 43°C heating allowed for normalization to maximal CVC (%CVCmax). BL women had blunted %CVCmax and NO contribution to dilation during the 39°C plateau (P < 0.027 for both). BQ-123 improved thisresponse through augmented NO-mediated dilation (P < 0.048 for both). BQ-788 and L-arginine, did not alter the CVC responses (P > 0.835 for both) or the NO contribution (P > 0.371 for both). Cutaneous microvascular function is reduced in BL women, and ET-1 receptor type A may contribute to this reduced function. Further research is needed to better characterize these mechanisms in young, BL women.

Nitric Oxide-Dependent Micro-and Macro-Vascular Dysfunction Occurs Early in Adolescents with Type 1 Diabetes

Background: Arterial stiffness and endothelial dysfunction are both reported in children with type 1 diabetes (DM1) and may predict future cardiovascular events. In health, nitric-oxide (NO) relaxes arteries and increases microvascular perfusion. The relationships between NO-dependent macro- and microvascular functional responses and arterial stiffness have not been studied in adolescents with DM1. Here we assessed macro- and microvascular function in DM1 adolescents and aged-matched controls at baseline and during an oral glucose challenge (OGTT). Methods: DM1 adolescents (n=16) and controls (n=14) were studied before and during an OGTT. At baseline we measured: A) large artery stiffness using both aortic augmentation index (AI) and carotid-femoral pulse wave velocity (cfPWV); B) brachial flow-mediated dilation (FMD) and forearm endothelial function using post-ischemic flow velocity (PIFV); and C) forearm muscle microvascular blood volume (MBV) using contrast-enhanced ultrasound. Following OGTT, AI, cfPWV and MBV were reassessed at 60 min and MBV again at 120 min. Within individual and between-group comparisons were made by paired and unpaired t-tests or repeated measures ANOVA. Results: Baseline FMD was lower (p=0.02) in DM1. PWV at 0 and 60 min did not differ between groups. Baseline AI did not differ between groups but declined with OGTT only in controls (p=0.02) and was lower than DM1 at 60 min (p<0.03). Baseline MBV was comparable in DM1 and control groups, but declined in DM1 at 120 min (p=0.01) and was lower than the control group (p<0.03). There was an inverse correlation between plasma glucose and MBV at 120 min (r= -0.523, p<0.01). No differences were noted between groups for VO2max (ml/min/kg), body fat (%), or BMI. Conclusions: NO-dependent macro- and microvascular function, including FMD and AI, and microvascular perfusion respectively are impaired early in the course of DM1, precede increases of arterial stiffness, and may provide an early indicator of vascular risk.

Effects of Clopidogrel, Prasugrel and Ticagrelor on Microvascular Function and Platelet Reactivity in Patients With Acute Coronary Syndrome Undergoing Coronary Artery Stenting. A Randomized, Blinded, Parallel Group Trial

Aims: In this pre-specified analysis of the “endothelium, stent and antiplatelet therapy” study, we investigate the impact of antiplatelet therapies on microvascular function in patients undergoing stenting for an acute coronary syndrome.Methods and Results: Fifty-six patients [age: 63(55–67) years, males, 10 diabetics, 27 non-ST-elevation myocardial infarction] were randomized to receive clopidogrel, ticagrelor or prasugrel in form of oral loading 2 h before stenting followed by oral therapy. Investigators were blinded to the allocation. Laser-Doppler microvascular function and ADP-induced platelet aggregation capacity were measured at baseline, 2 h after oral antiplatelet loading, and 1 day, 1 week and 1 month after stenting during chronic therapy with the same antiplatelet agent. Platelet aggregation decreased in all groups 2 h after oral loading, with a significantly larger effect in the prasugrel group (P = 0.009). Similarly, prasugrel and ticagrelor loading was followed by an increase in microvascular reactive hyperemia (P = 0.007 and P = 0.042 compared to clopidogrel). This effect disappeared one day after coronary intervention, with a significant decrease in the prasugrel group (P = 0.026). Similarly, analysis of microvascular conductance showed a larger increase in the prasugrel group 2 h after loading (P = 0.022 among groups), and a decrease in all groups after stenting.Conclusions: Oral loading with prasugrel (and less consistently ticagrelor) is associated with improved microvascular function and stronger platelet inhibition in acute coronary syndrome patients. The microvascular effect was however lost 1 day after stenting and during subsequent follow-up. Further studies are necessary to clarify the the long-term effects and potential benefits of P2Y12 inhibitors on microvascular damage.ClINICALTRIALS.gov N°: NCT01700322EUDRACT-N°: 2011-005305-73.

389 Microvascular dysfunction in patients with Type II diabetes mellitus: invasive assessment of absolute coronary blood flow and microvascular resistance reserve

Aims Coronary microvascular dysfunction (CMD) is an early feature of diabetic cardiomyopathy, which usually precedes the onset of diastolic and systolic dysfunction. Continuous intracoronary thermodilution allows an accurate and reproducible assessment of absolute coronary blood flow and microvascular resistance thus allowing the evaluation of coronary flow reserve (CFR) and Microvascular Resistance Reserve (MRR), a novel index specific for microvascular function, which is independent from the myocardial mass. In the present study we compared absolute coronary flow and resistance, CFR and MRR assessed by continuous intracoronary thermodilution in diabetic vs. non-diabetic patients. Left atrial reservoir strain (LASr), an early marker of diastolic dysfunction was compared between the two groups. Methods In this observational retrospective study, 108 patients with suspected angina and non-obstructive coronary artery disease (NOCAD) consecutively undergoing elective coronary angiography (CAG) from September 2018 to June 2021 were enrolled. The invasive functional assessment of microvascular function was performed in the left anterior descending artery (LAD) with intracoronary continuous thermodilution. Patients were classified according to the presence of DM. Absolute resting and hyperaemic coronary blood flow (in mL/min) and resistance (in WU) were compared between the two cohorts. FFR was measured to assess coronary epicardial lesions, while CFR and MRR were calculated to assess microvascular function. LAS, assessed by speckle tracking echocardiography, was used to detect early myocardial structural changes potentially associated with microvascular dysfunction. Results The median FFR value was 0.83 (0.79–0.87) without any significant difference between the two groups. Absolute resting and hyperaemic flow in the left anterior descending coronary were similar between diabetic and non-diabetic patients. Similarly, resting and hyperaemic resistances did not change significantly between the two groups. In the DM cohort the CFR and MRR were significantly lower compared to the control group [CFR = 2.38 ± 0.61 and 2.88 ± 0.82; MRR = 2.79 ± 0.87 and 3.48 ± 1.02 for diabetic and non-diabetic patients respectively, (P &lt; 0.05 for both)]. Likewise, diabetic patients had a significantly lower reservoir, contractile and conductive LAS (all P &lt; 0.05). Conclusions Compared with non-diabetic patients, CFR and MRR were lower in patients with DM and non-obstructive epicardial coronary arteries, while both resting and hyperaemic coronary flow and resistance were similar. LASr was lower in diabetic patients, confirming the presence of a subclinical diastolic dysfunction associated to the microcirculatory impairment. Continuous intracoronary thermodilution-derived indexes provide a reliable and operator-independent assessment of coronary macro- and microvasculature and might potentially facilitate widespread clinical adoption of invasive physiologic assessment of suspected microvascular disease.