Microvascular Function In Patients Research Articles

The effcacy of short-term tetrahydrobiopterin administration to improve locomotor muscle microvascular function in heart failure with preserved ejection fraction

Background: Patients with heart failure with preserved ejection fraction (HFpEF) exhibit locomotor muscle microvascular dysfunction due partly to reduced nitric oxide (NO) bioavailability. Tetrahydrobiopterin (BH4) is a requisite cofactor for the enzymatic production of NO by NO synthase (NOS). BH4 insuffciency promotes NOS uncoupling, which reduces NO production and augments cellular oxidative stress. Given the potential of BH4 to improve NO bioavailability, we tested the hypothesis that short-term BH4 administration would improve locomotor muscle microvascular function in patients with HFpEF. Methods: Eight patients with HFpEF (74±7 years; 31.3±4.9 kg/m2) participated in a randomized, double-blind, crossover study, having consumed either BH4 (Sapropterin, 10 mg/kg) or placebo for 10 days, separated by a 14-day washout period. Locomotor muscle microvascular function was assessed as leg blood flow (LBF) and leg vascular conductance (LVC) responses to passive leg movement (PLM) before (pre) and after (post) each treatment. PLM-induced LBF and LVC responses were expressed as peak change (Δpeak) or total hyperemic response (area under the curve above baseline; AUC). Results: LBFΔpeak did not change following BH4 (267 ± 136 mL/min vs. 250 ± 101 mL/min) or placebo (317 ± 119 mL/min vs. 269 ± 97 mL/min) administration (pre vs. post; p>0.05). Similarly, LVCΔpeak was unchanged following either BH4 (396 ± 165 mL/min/100mmHg vs. 465 ± 180 mL/min/100mmHg) or placebo (579 ± 238 mL/min/100mmHg vs. 496 ± 185 mL/min/100mmHg) administration (pre vs. post; p>0.05). The changes in LBFAUC and LVCAUC were not affected by either treatment (LBFAUC; BH4: Δ91 ± 103 mL vs. Δ82 ± 69 mL; placebo: Δ148 ± 119 mL vs. Δ87 ± 81 mL; LVCAUC; BH4: Δ65 ± 55 mL/100mmHg vs. Δ98 ± 78 mL/100mnHg; placebo: Δ182 ± 127 mL/100mmHg vs. Δ105 ± 94 mL/100mmHg) (pre vs. post; p>0.05). Conclusion: Short-term BH4 administration did not improve locomotor muscle microvascular function in patients with HFpEF. This project was funded, in part, by the National Institutes of Health (HL118313, D.W.W.; T32HL139451, K.B.; the U.S. Department of Veterans Affairs (I01RX001311, D.W.W.; IK2RX003670, to K.B.), and the American Heart Association (18POST33960192; K.B.). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Ranolazine for improving coronary microvascular function in patients with nonobstructive coronary artery disease: a systematic review and meta-analysis with a trial sequential analysis of randomized controlled trials.

Microvascular dysfunction in patients with nonobstructive coronary artery disease is increasingly being recognized as an important health issue. This systematic review and meta-analysis evaluated the effectiveness of ranolazine, an antianginal agent, in improving coronary microvascular function. We conducted a comprehensive literature search of the Cochrane Library, PubMed, Embase, China National Knowledge Infrastructure, the Chinese BioMedical Literature Database, and gray literature databases until September 30, 2023. The included studies were randomized controlled trials (RCTs) published in the English or Chinese languages that screened for eligibility using two independent investigators. Risk of bias was evaluated with the Cochrane Collaboration tool. Subgroup and sensitivity analyses were used to identify sources of heterogeneity. Meta-analysis was performed using RevMan version 5.4 (Cochrane) and Stata version 16.0 (StataCorp). From 1,470 citations, 8 RCTs involving 379 participants were included in this analysis. Our findings showed that ranolazine increased coronary flow reserve (CFR) over an 8 to 12-week follow-up period [standardized mean difference =1.16; 95% confidence interval (CI): 0.4-1.89; P=0.002]. Ranolazine increased the global myocardial perfusion reserve index (MPRI) [weighted mean difference (WMD) =0.18; 95% CI: 0.07-0.29; P=0.002] and the midsubendocardial MPRI (WMD =0.10; 95% CI: 0.02-0.19; P=0.02). Moreover, ranolazine improved 3 of the 5 Seattle Angina Questionnaire scores, namely, physical functioning (WMD =4.89; 95% CI: 0.14 to 9.64; P=0.04), angina stability (WMD =17.31; 95% CI: 7.13-27.49; P=0.0009), and quality of life (WMD =10.11; 95% CI: 3.57-16.65; P=0.0003). Trial sequential analysis showed that the meta-analysis of angina stability and quality of life scores had a sufficient sample size and statistical power. Our analysis suggests that ranolazine is associated with improvements in CFR, myocardial perfusion, and the Seattle Angina Questionnaire scores in patients with nonobstructive coronary artery disease. However, further large-scale RCTs with long-term follow-up are recommended to validate these findings and provide a more comprehensive understanding of the effects of ranolazine on coronary microvascular function.

Role of Protein Kinase C in Metabolic Regulation of Coronary Endothelial Small Conductance Calcium-Activated Potassium Channels.

Small conductance calcium-activated potassium (SK) channels are largely responsible for endothelium-dependent coronary arteriolar relaxation. Endothelial SK channels are downregulated by the reduced form of nicotinamide adenine dinucleotide (NADH), which is increased in the setting of diabetes, yet the mechanisms of these changes are unclear. PKC (protein kinase C) is an important mediator of diabetes-induced coronary endothelial dysfunction. Thus, we aimed to determine whether NADH signaling downregulates endothelial SK channel function via PKC. SK channel currents of human coronary artery endothelial cells were measured by whole cell patch clamp method in the presence/absence of NADH, PKC activator phorbol 12-myristate 13-acetate, PKC inhibitors, or endothelial PKCα/PKCβ knockdown by using small interfering RNA. Human coronary arteriolar reactivity in response to the selective SK activator NS309 was measured by vessel myography in the presence of NADH and PKCβ inhibitor LY333531. NADH (30-300 μmol/L) or PKC activator phorbol 12-myristate 13-acetate (30-300 nmol/L) reduced endothelial SK current density, whereas the selective PKCᵦ inhibitor LY333531 significantly reversed the NADH-induced SK channel inhibition. PKCβ small interfering RNA, but not PKCα small interfering RNA, significantly prevented the NADH- and phorbol 12-myristate 13-acetate-induced SK inhibition. Incubation of human coronary artery endothelial cells with NADH significantly increased endothelial PKC activity and PKCβ expression and activation. Treating vessels with NADH decreased coronary arteriolar relaxation in response to the selective SK activator NS309, and this inhibitive effect was blocked by coadministration with PKCβ inhibitor LY333531. NADH-induced inhibition of endothelial SK channel function is mediated via PKCβ. These findings may provide insight into novel therapeutic strategies to preserve coronary microvascular function in patients with metabolic syndrome and coronary disease.

Rethinking False Positive Exercise Electrocardiographic Stress Tests by Assessing Coronary Microvascular Function

BackgroundExercise electrocardiographic stress testing (EST) has historically been validated against the demonstration of obstructive coronary artery disease. However, myocardial ischemia can occur because of coronary microvascular dysfunction (CMD) in the absence of obstructive coronary artery disease. ObjectivesThe aim of this study was to assess the specificity of EST to detect an ischemic substrate against the reference standard of coronary endothelium-independent and endothelium-dependent microvascular function in patients with angina with nonobstructive coronary arteries (ANOCA). MethodsPatients with ANOCA underwent invasive coronary physiological assessment using adenosine and acetylcholine. CMD was defined as impaired endothelium-independent and/or endothelium-dependent function. EST was performed using a standard Bruce treadmill protocol, with ischemia defined as the appearance of ≥0.1-mV ST-segment depression 80 ms from the J-point on electrocardiography. The study was powered to detect specificity of ≥91%. ResultsA total of 102 patients were enrolled (65% women, mean age 60 ± 8 years). Thirty-two patients developed ischemia (ischemic group) during EST, whereas 70 patients did not (nonischemic group); both groups were phenotypically similar. Ischemia during EST was 100% specific for CMD. Acetylcholine flow reserve was the strongest predictor of ischemia during exercise. Using endothelium-independent and endothelium-dependent microvascular dysfunction as the reference standard, the false positive rate of EST dropped to 0%. ConclusionsIn patients with ANOCA, ischemia on EST was highly specific of an underlying ischemic substrate. These findings challenge the traditional belief that EST has a high false positive rate.

Sex differences of sequential changes in coronary blood flow and microvascular function in patients with suspected angina.

This study evaluated the sex differences of sequential changes in coronary blood flows and microvascular function in patients with suspected angina but with no obstructed coronary arteries. A total of 202 consecutive patients who experienced chest pain but had no significant coronary artery stenosis and who underwent adenosine stress echocardiography were included in the study. Coronary blood flow (CBF) velocities were measured at 1, 2, and 3min after adenosine infusion. The mean age was 61years, and 138 (68%) were women. Approximately 40% of patients had coronary microvascular dysfunction (CMD, coronary flow velocity reserve < 2.3), with women exhibiting higher CMD prevalence. The left ventricular (LV) mass index was similar between men and women, while women exhibited higher baseline rate pressure products (RPP). At baseline, coronary blood flow velocities were similar between the sexes. However, CBF velocities in women gradually increased during the examination; and in men, the increase was abrupt and steep during the early stages of examination (p = 0.015 for interaction between time and sex), even with similar RPP in stress. Coronary flow velocity reserve was steadily lower in women compared to men (1min, 2.09 ± 0.86 vs 2.44 ± 0.87; 2min, 2.39 ± 0.72 vs 2.63 ± 0.85; 3min, 2.45 ± 0.70 vs 2.68 ± 0.73). In patients with suspected angina but with no obstructed coronary arteries, CMD was especially prevalent among women. Women exhibited higher oxygen consumption, while exhibiting slower and gradual increases in CBF velocities. Conversely, men exhibited faster and steeper increases in CBF velocities even with similar RPP in stress.

Impaired retinal micro-vascular function in patients with atrial fibrillation

BackgroundCardiovascular (CV) risk factors and CV diseases, in particular heart failure, are strongly associated with impaired microvascular retinal endothelial function. Whether atrial fibrillation (AF) contributes to vascular dysfunction is not clear. Therefore, the aim of this study was to investigate the impact of AF on retinal microvascular function. MethodsIn this study, vascular function was measured non-invasively with flicker-light induced vasodilatation of retinal arterioles (FIDart%). Patients with a history of AF and risk factors for heart failure (HF) or heart failure (n = 69; age 67.9 ± 9.2 years, 71% male, 35% HFrEF, 56% paroxysmal, 25% persistent, 19% permanent AF), as well as age, sex and ejection fraction matched patients with absent history of AF (n = 66; age 63.4 ± 10.6 years, 67% male, 47% HFrEF) were included. Patients with AF were further divided into those with paroxysmal AF (in sinus rhythm – AFSR: n = 38, age 71.4 ± 9.2, 73% male), and those with AF at the time of the study visit. ResultsRetinal microvascular function was impaired in patients with AF compared to patients without AF (FIDart% 1.1% [0.3–2.8] vs. 2.7% [1.3–5.1], p < 0.001). Patients currently in AF have poorer retinal microvascular function (FIDart% 0.8% [0.1–1.9) compared to patients with a history of AF but currently in SR at the time of retinal function measurement (1.5% [0.6–4.9] p = 0.017). In patients with AF, impaired retinal vascular function was independently associated with larger left atrial volume (mean 49.8 ± 18.4), even after correction for confounding factors in different models (SCR = -0. 251 to −0.256, p = 0.035–0.01). ConclusionsAF in patients with heart failure is associated with impaired vascular function, even if currently in sinus rhythm. The association of retinal microvascular dysfunction with left atrial volume, a surrogate for elevated cardiac filling pressures, may further highlight the important interplay between the vasculature and elevated filling pressures in the development of AF.

Increased Coronary Contraction to Thromboxane A2 in Cardiac Surgery Patients With Poorly Controlled Hypertension

IntroductionCardioplegia and cardiopulmonary bypass (CP/CPB) alters coronary arteriolar response to thromboxane A2 (TXA2) in patients undergoing cardiac surgery. Comorbidities, including hypertension (HTN), can further alter coronary vasomotor tone. This study investigates the effects of HTN on coronary arteriolar response to TXA2 pre and post-CP/CPB and cardiac surgery. Materials and methodsCoronary arterioles pre and post-CP/CPB were dissected from atrial tissue samples in patients with no HTN (NH, n = 9), well-controlled HTN (WC, n = 12), or uncontrolled HTN (UC, n = 12). In-vitro coronary microvascular reactivity was examined in the presence of TXA2 analog U46619 (10−9-10−4M). Protein expression of TXA2 receptor in the harvested right atrial tissue samples were measured by immunoblotting. ResultsTXA2 analog U46619 induced dose-dependent contractile responses of coronary arterioles in all groups. Pre-CPB contractile responses to U46619 were significantly increased in microvessels in the UC group compared to the NH group (P < 0.05). The pre-CP/CPB contractile responses of coronary arterioles were significantly diminished post-CP/CPB among the three groups (P < 0.05), but there remained an increased contractile response in the microvessels of the UC group compared to the WC and NH groups (P < 0.05). There were no significant differences in U46619-induced vasomotor tone between patients in the NH and WC groups (P > 0.05). There were no differences in expression of TXA2R among groups. ConclusionsPoorly controlled HTN is associated with increased contractile response of coronary arterioles to TXA2. This alteration may contribute to worsened recovery of coronary microvascular function in patients with poorly controlled HTN after CP/CPB and cardiac surgery.

TCT-204 Effectiveness of Coronary Sinus Reducer Implantation on Coronary Microvascular Function in Patients With Angina and Nonobstructive Coronary Artery Disease

TCT-204 Effectiveness of Coronary Sinus Reducer Implantation on Coronary Microvascular Function in Patients With Angina and Nonobstructive Coronary Artery Disease

Effects of a Mitochondrial Targeted Ubiquinol (MitoQ) on Vascular Function and Exercise Capacity in Chronic Kidney Disease: A Randomized Controlled Pilot Study.

Mitochondrial derived oxidative stress is implicated in vascular and skeletal muscle abnormalities in chronic kidney disease (CKD). The purpose of this study was to investigate the effects of a mitochondrial targeted ubiquinol (MitoQ) on vascular function and exercise capacity in CKD. In this randomized controlled trial, 18 patients with CKD (Mean±SEM: Age, 62±3years; eGFR, 45±3ml/min/1.732) received 4 weeks of 20mg/day MitoQ (MTQ) or placebo (PLB). Outcomes assessed at baseline and follow up included macrovascular function measured by flow mediated dilation; microvascular function assessed by laser Doppler flowmetry combined with intradermal microdialysis; aortic hemodynamics assessed by oscillometery; and exercise capacity by cardiopulmonary exercise testing. Compared to PLB, MTQ improved flow mediated dilation (baseline vs follow up: MTQ, 2.4±0.3 vs. 4.0±0.9%; PLB, 4.2±1.0 vs. 2.5±1.0%; p=0.04). MTQ improved microvascular function (DCVC: MTQ, 4.50 ± 2.57 vs. PLB -2.22 ± 2.67%; p=0.053). Central aortic systolic and pulse pressures were unchanged, however, MTQ prevented increases in augmentation pressures that were observed in the PLB group (p=0.026). MTQ did not affect exercise capacity. This study demonstrates potential for a mitochondrial targeted ubiquinol to improve vascular function in CKD. The findings hold promise for future investigations of mitochondrial targeted therapies in CKD.

Assessment of hemodynamic indices of conjunctival microvascular function in patients with coronary microvascular dysfunction.

Coronary microvascular dysfunction (CMD) is a cause of ischaemia with non-obstructive coronary arteries (INOCA). It is notoriously underdiagnosed due to the need for invasive microvascular function testing. We hypothesized that systemic microvascular dysfunction could be demonstrated non-invasively in the microcirculation of the bulbar conjunctiva in patients with CMD. Patients undergoing coronary angiography for the investigation of chest pain or dyspnoea, with physiologically insignificant epicardial disease (fractional flow reserve ≥0.80) were recruited. All patients underwent invasive coronary microvascular function testing. We compared a cohort of patients with evidence of CMD (IMR ≥25 or CFR <2.0); to a group of controls (IMR <25 and CFR ≥2.0). Conjunctival imaging was performed using a previously validated combination of a smartphone and slit-lamp biomicroscope. This technique allows measurement of vessel diameter and other indices of microvascular function by tracking erythrocyte motion. A total of 111 patients were included (43 CMD and 68 controls). There were no differences in baseline demographics, co-morbidities or epicardial coronary disease severity. The mean number of vessel segments analysed per patient was 21.0±12.8 (3.2±3.5 arterioles and 14.8±10.8 venules). In the CMD cohort, significant reductions were observed in axial/cross-sectional velocity, blood flow, wall shear rate and stress. The changes in microvascular function linked to CMD can be observed non-invasively in the bulbar conjunctiva. Conjunctival vascular imaging may have utility as a non-invasive tool to both diagnose CMD and augment conventional cardiovascular risk assessment.

Moderate dose of dietary nitrate improves skeletal muscle microvascular function in patients with peripheral artery disease.

Peripheral artery disease (PAD) is an atherosclerotic disease characterized by compromised lower-extremity blood flow that impairs walking ability. We showed that a moderate dose of dietary nitrate in the form of beetroot juice (BRJ, 0.11mmol/kg) can improve macrovascular function and maximal walking distance in patients with PAD. However, its impacts on the microcirculation and autonomic nervous system have not been examined. Therefore, we investigated the impacts of this dose of dietary nitrate on skeletal muscle microvascular function and autonomic nervous system function and further related these measurements to 6-min walking distance, pain-free walking distance, and exercise recovery in patients with PAD. Patients with PAD (n=10) ingested either BRJ or placebo in a randomized crossover design. Heart rate variability, skeletal muscle microvascular function, and 6-min walking distance were performed pre- and post-BRJ and placebo. There were significant group×time interactions (P<0.05) for skeletal muscle microvascular function, 6-min walking distance, and exercise recovery, but no changes (P>0.05) in heart rate variability or pain-free walking distance were noted. The BRJ group demonstrated improved skeletal muscle microvascular function (∆ 22.1±7.5%·min-1), longer 6-min walking distance (Δ 37.5±9.1m), and faster recovery post-exercise (Δ -15.3±4.2s). Furthermore, changes in skeletal muscle microvascular function were positively associated with changes in 6-min walking distance (r=0.5) and pain-free walking distance (r=0.6). These results suggest that a moderate dose of dietary nitrate may support microvascular function, which is related to improvements in walking distance and claudication in patients with PAD.

Gut microbiota-derived metabolite trimethylamine N-oxide and biomarkers of inflammation are linked to endothelial and coronary microvascular function in patients with inflammatory bowel disease.

Inflammatory bowel disease (IBD), which is an umbrella term used for ulcerative colitis (UC) and Crohn's disease (CD), is associated with an increased risk for atherosclerotic cardiovascular disease (CVD). We aimed to investigate the association of local and systemic biomarkers of inflammation and gut microbiota-derived metabolite trimethylamine N-oxide (TMAO) with endothelial and coronary microvascular dysfunction in IBD. A total of 56 patients with IBD (20 with UC and 36 with CD) and 34 age and gender matched controls were included. For all participants, samples were collected to analyze faecal calprotectin, and TMAO concentrations. Ultrasound-based examinations were done to measure flow-mediated vasodilatation (FMD) and coronary flow velocity reserve (CFVR). Patients with IBD had lower CFVR (2.07 (1.82-2.40)) and FMD (8.7±3.7) as compared to controls (2.30 (2.07-2.74), p=0.005 and 11.9±6.8, p=0.03). In patients with IBD, TMAO concentration (r=-0.30, p=0.03), C-reactive protein (r=-0.29, p=0.03) and WBC count (r=-0.37, p=0.006) had a significant negative correlation with CFVR, and TMAO (β=-0.27, 95% CI: -0.23 to -0.02) and WBC count (β=-0.31, 95% CI: -0.56 to -0.06) were significant predictors of CFVR after multivariate adjustment. None of the biomarkers of inflammation or TMAO showed significant correlations with FMD. In patients with UC, TMAO showed a significant correlation with both CFVR (r=-0.55, p=0.01) and FMD (r=-0.60, p=0.005) while only WBC count had a statistically significant correlation with CFVR (r=-0.49, p=0.004) in patients with CD. Gut microbiota-derived metabolite TMAO and biomarkers of systemic inflammation are associated with measures of endothelial/coronary microvascular dysfunction in patients with IBD.

Assessment of Indices of Conjunctival Microvascular Function in Patients With and Without Obstructive Coronary Artery Disease

BackgroundAtherosclerotic heart disease often remains asymptomatic until presentation with a major adverse cardiovascular event. Primary preventive therapies improve outcomes, but conventional screening often misattributes risk. Vascular imaging can be utilised to detect atherosclerosis, but often involves ionising radiation. The conjunctiva is a readily accessible vascular network allowing non-invasive hemodynamic evaluation. AimTo compare conjunctival microcirculatory function in patients with and without obstructive coronary artery disease. MethodsWe compared the conjunctival microcirculation of myocardial infarction patients (MI-cohort) to controls with no obstructive coronary artery disease (NO-CAD cohort). Conjunctival imaging was performed using a smartphone and slit-lamp biomicroscope combination. Microvascular indices of axial (Va) and cross-sectional (Vcs) velocity; blood flow rate (Q); and wall shear rate (WSR) were compared in all conjunctival vessels between 5 and 45 μm in diameter. ResultsA total of 127 patients were recruited (66 MI vs 61 NO-CAD) and 3602 conjunctival vessels analysed (2414 MI vs 1188 NO-CAD). Mean Va, Vcs and Q were significantly lower in the MI vs NO-CAD cohort (Va 0.50 ± 0.17 mm/s vs 0.55 ± 0.15 mm/s, p < 0.001; Vcs 0.35 ± 0.12 mm/s vs 0.38 ± 0.10 mm/s, p < 0.001; Q 154 ± 116 pl/s vs 198 ± 130 pl/s, p < 0.001). To correct for differences in mean vessel diameter, WSR was compared in 10–36 μm vessels (3268/3602 vessels) and was lower in the MI-cohort (134 ± 64 s−1 vs 140 ± 63 s−1, p = 0.002). ConclusionsConjunctival microcirculatory alterations can be observed in patients with obstructive coronary artery disease. The conjunctival microvasculature merits further evaluation in cardiovascular risk screening.

Abstract 13551: Non-Invasive Assessment of Systemic Microvascular Function in Patients With Severe Aortic Stenosis Pre- and Post- Transcatheter Aortic Valve Intervention

Background: Aortic stenosis (AS) is associated with pathophysiological changes in both left ventricular and coronary microvascular structure and function. The treatment of AS with transcatheter aortic valve replacement (TAVR) has been associated with improvements in invasive indices of coronary microvascular function. This study sought to address whether systemic microvascular dysfunction was present in patients with AS and if microvascular function was altered by treatment of aortic stenosis with TAVR. The conjunctival microcirculation was used as the site for the non-invasive assessment of systemic microvascular function. Methods: Patients undergoing TAVR for the treatment of severe AS were compared to a cohort of age- and sex-matched controls without valvular heart disease. Conjunctival vascular imaging was performed in all subjects using a previously validated combination of a smartphone and slit-lamp biomicroscope. This technique allowed measurement of vessel diameter and other indices of microvascular function by tracking erythrocyte motion. Conjunctival hemodynamics were compared pre- and post-TAVR, in addition to between the severe AS and control cohorts. Results: A total of 165 patients were included (90 severe AS and 75 controls). Baseline characteristics were well matched between groups. In comparison to the control cohort, arteriole axial (Va) and cross-sectional velocity (Vcs) were significantly lower in females with AS (Va severe AS 0.53 ± 0.11mm/s vs control 0.59 ± 0.12mm/s, p=0.047; Vcs severe AS 0.38 ± 0.07mm/s vs control 0.41 ± 0.08mm/s, p=0.043), but not in males (Va severe AS 0.61 ± 0.11mm/s vs control 0.58 ± 0.10mm/s, p=0.19; Vcs severe AS 0.43 ± 0.08mm/s vs control 0.41 ± 0.07mm/s, p=0.20). Arteriole Va and Vcs significantly increased following TAVR in females (Va Pre-TAVR 0.52 ± 0.16mm/s vs post-TAVR 0.59 ± 0.15mm/s, p&lt;0.001; Vcs Pre-TAVR 0.37 ± 0.11mm/s vs post-TAVR 0.42 ± 0.11mm/s, p&lt;0.001). Conclusion: This study highlights sex-specific differences in conjunctival microvascular function in patients with severe AS. In this study TAVR resulted in significant improvements in conjunctival arteriolar V a and V cs . These findings are consistent with severe AS being a reversible cause of systemic microvascular dysfunction.

Assessment of microvascular function using a novel technique Flow Mediated Skin Fluorescence (FMSF) in patients with diabetic kidney disease: A preliminary study.

Diabetic kidney disease (DKD) plays an important role in morbidity and mortality in patients with diabetes mellitus. The pathogenesis of this microangiopathy is mainly due to impaired vascular endothelial function. The Flow Mediated Skin Fluorescence (FMSF) method is an innovative, non-invasive tool for assessing the microcirculation function (especially microcirculatory response to hypoxia), also in patients with complications of diabetes mellitus (DM). The study was conducted at the Medical University of Lodz, Poland. Total of 84 volunteers including 30 patients with DKD, 33 patients with DM without complications, and 21 healthy subjects underwent microvascular function assessments using FMSF. This technique measures changes in the intensity of nicotinamide adenine dinucleotide (NADH) fluorescence from the skin on the forearm as a function of time, in response to blocking and releasing blood flow in the forearm. In this study we asses two key parameters: Reactive Hyperemia Response (RHR) and Hypoxia Sensitivity [log(HS)] to characterize vascular circulation in patients with DKD and their response to transient ischemia. The patients with low reactive hyperemic response (the RHR parameter) had a significantly higher sCr than patients with moderate and high RHR value (p<0.001, p<0.05, respectively) and a significantly lower eGFR than the patients with moderate and high RHR parameter (p<0.001, p<0.01, respectively). The patients with very low and low log(HS) values had a significantly higher sCr than the patients with high log(HS) (p<0.001, p<0.01, respectively), and a significantly lower eGFR than the patients with high log(HS) parameter (p<0.001, p<0.01, respectively). The patients with very low log(HS) had a significantly higher sCr and a significantly lower eGFR than the patients with moderate (p<0.05, p<0.01, respectively). The mean value of the RHR parameter was significantly lower in DKD patients (18.31±5.06%) compared to both healthy subjects (34.37±8.18%, p<0.001) and DM without complications subgroup (28.75±7.12%, p<0.001). Similar trends were noted with the mean value of log(HS) parameter in DKD subgroup (1.03±0.5) vs. healthy subjects (1.59±0.53, p<0.001), and vs. DM without complications subgroup (1.73±0.52, p<0.001). We observed a significant inverse correlation between the RHR parameter and serum creatinine (sCr) and a significant positive correlations with eGFR (R= -0.3; p<0.05, R=0.61; p<0.001, respectively). We found also a significant negative correlations of the log(HS) measure with sCr and a significant positive correlations with eGFR (R=-0.33; p<0.01, R=0.55; p<0.001, respectively). We observed also a significant inverse correlation between the RHR and log(HS) parameters and advanced glycation end products (AGEs) (R=-0.6; p<0.001, R=-0.32; p<0.01, respectively). The AGEs parameter was also a significantly higher in patients with low RHR parameter than in patients with moderate (p<0.01) and high (p<0.001). The FMSF technique makes it possible to identify impairments of the microvascular function in patients with DKD. This study confirms that the simple two-parametric approach diagnostic tool perfectly characterizes the state of the microvascular system in diabetic patients with impaired renal function. These preliminary results require further validation in a larger patients cohort.

Combining body mass index with waist circumference to assess coronary microvascular function in patients with non-obstructive coronary artery disease

BackgroundCoronary microvascular dysfunction (CMD) may precede clinically overt coronary artery disease (CAD). Overall and central obesity (CO) are major risk factors for CAD. This study sought to investigate the subclinical significance of body adiposity patterns based on the CMD risk. MethodsA total of 128 patients with non-obstructive CAD were prospectively enrolled. Patients were categorized into 4 anthropometric groups: normal weight and non-CO (NWNCO, n = 41), normal weight and CO (NWCO, n = 20), excess weight and non-CO (EWNCO, n = 26), and excess weight and CO (EWCO, n = 41). Patients underwent rest/stress electrocardiography-gated 13N-ammonia positron emission tomography to measure absolute myocardial blood flow (MBF), myocardial flow reserve (MFR), hemodynamic parameters, and cardiac function. ResultsResting MBF did not differ between groups (P = .36). Compared with the NWNCO group, hyperemic MBF and MFR were significantly lower in the NWCO and EWCO groups. Notably, patients with NWCO presented the lowest hyperemic MBF and MFR and the highest incidence of CMD. Waist circumference was an independent risk factor for CMD (OR 1.05, 95% CI 1.01 to 1.10, P = .02). ConclusionIn patients with non-obstructive CAD, CO may be associated with an increased risk of CMD to better fit the study findings which did not assess management or monitoring of MBF and MFR.

PATIENTS WITH PSORIASIS PRESENT IMPAIRED MICROVASCULAR REACTIVITY INDEPENDENTLY OF TRADITIONAL CARDIOVASCULAR RISK FACTORS

Objective: Psoriasis is associated with increased rates of cardiovascular complications. Altered microvascular responses in divergent vascular beds are considered as an early precursor of cardiovascular disease and have been well-described in patients with cardiovascular risk factors and chronic inflammatory diseases. Laser Speckle Contrast Imaging (LSCI) has emerged as a novel, non-invasive and highly reproducible technique for the in vivo, real-time evaluation of microvascular perfusion. Design and method: We aimed to assess real-time skin microvascular function in patients with psoriasis free from established cardiovascular disease, in comparison with controls matched for cardiovascular risk factors. Microvascular function was evaluated dynamically using LSCI coupled with a post-occlusive reactive hyperaemia (PORH) protocol. Well-established markers of arterial stiffness, i.e. pulse wave velocity (PWV) and augmentation index (AIx), were assessed as surrogate markers of cardiovascular disease through a whole 24 h period using the Mobil-O-Graph device. Results: We studied 90 patients with psoriasis and 45 control individuals. Traditional cardiovascular risk factors and surrogate markers of cardiovascular disease did not differ between groups. By contrast, several indices of microvascular responses assessed with LSCI were found impaired in patients with psoriasis compared to controls, specifically baseline flux [45.7 (11.7) vs 36.2 (7.5) LSPUs, p &lt; 0.001], occlusion flux [11.6 (7.1) vs 7.4 (4.6) LSPUs, p &lt; 0.001], peak-to-baseline magnitude [128.9 (46.4) vs 179.0 (62.0) %, p &lt; 0.001], and baseline cutaneous vascular conductance (0.50 ± 0.13 vs 0.39 ± 0.10 LSPUs/mmHg, p &lt; 0.001). 24 h PWV significantly correlated with nearly all LSCI parameters, including time-to-peak flux, baseline perfusion, occlusion flux, peak flux, peak-to-baseline magnitude, and baseline cutaneous vascular conductance (p &lt; 0.05 for all). 24 h AIx significantly correlated only with occlusion flux (r = 0.223, p = 0.011). The latter was significantly associated with psoriasis duration (r = 0.300, p = 0.015). Conclusions: Our study shows for the first-time impaired microcirculation dynamics in patients with psoriasis using LSCI, in the absence of established cardiovascular disease and regardless of cardiovascular risk factors. A cross-talk between micro-macrovascular dysfunction apparently exists even at these early stages, before the establishment of clinically evident cardiovascular manifestations.

Association Between Insulin Resistance, Oxidative Stress, Sympathetic Activity and Coronary Microvascular Function in Patients With Early Stage Impaired Glucose Metabolism.

Although acute hyperglycemia and insulin resistance (IR) are risk factors for atherosclerosis development through oxidative stress and sympathetic activation in diabetes mellitus, the association of these factors with coronary microvascular function in the early diabetic stage remains controversial.Methods and Results: Using transthoracic echocardiography, coronary flow velocity (CFV) and its reserve (CFVR) as parameters of coronary microvascular function were measured before and 1 h after an oral glucose tolerance test (OGTT) in 40 patients (aged 59±12 years) without diagnosed diabetes mellitus or coronary artery disease. Plasma glucose, insulin and thiobarbituric acid reactive substance (TBARS; an oxidative stress marker) were measured during the OGTT. IR was evaluated as homeostasis model assessment of IR (HOMA-R). Sympathetic activity was evaluated by using plasma catecholamines after OGTT. CFVR decreased after an OGTT (P<0.0001) mainly because of an increased baseline CFV (P<0.0001). Although the change in CFVR was not associated with the change in TBARS and catecholamines, it was independently associated with HOMA-R on the multivariate regression analysis (β=-0.40, P=0.01). Another multivariate regression analysis revealed that change in baseline CFV was independently associated with HOMA-R (β=0.35, P=0.03). IR, rather than oxidative stress and sympathetic activity, was associated with an increase in baseline CFV and a decline in CFVR during acute hyperglycemia. IR might play an important role in increased myocardial oxygen demand and coronary microvascular dysfunction.

Impaired Microvascular Function in Patients With Critical COVID-19.

OBJECTIVES:Severe coronavirus disease 2019 is characterized by infected microvascular endothelial cells. The primary aim of this study was to investigate microvascular function in patients with critical coronavirus disease 2019.DESIGN:A prospective observational study was conducted in which patients with critical and severe COVID-19 were investigated during acute disease phase and at least 3 months after disease onset.SETTING:Single-center study at Danderyd University Hospital.PATIENTS:Twenty-three patients with critical coronavirus disease 2019 treated with noninvasive or invasive mechanical ventilation, seven patients with severe COVID-19 with dyspnea or need of oxygen supply up to 8 L/min, and 15 noncoronavirus disease controls.INTERVENTIONS:None.MEASUREMENTS:Skin perfusion was investigated through laser speckle contrast imaging before and after iontophoresis of acetylcholine and sodium nitroprusside for determination of the endothelial-dependent and the endothelial-independent vasodilation, respectively.MAIN RESULTS:Patients with critical COVID-19 had higher basal skin perfusion during both the acute (34 ± 9 perfusion unit; p = 0.0003) and the postinfectious phase (29 ± 8 perfusion unit; p = 0.04), compared with noncoronavirus disease controls (23 ± 7 perfusion unit). In addition, endothelial-dependent and endothelial-independent vasodilation were reduced in patients with critical COVID-19 during the acute disease phase (p < 0.001 for both), whereas no significant differences between patients and controls were found during the postinfectious phase. In patients with severe COVID-19, basal skin perfusion and endothelial-dependent vasodilatation were not significantly changed, whereas endothelial-independent vasodilatation was reduced (p = 0.02) compared with controls.CONCLUSIONS:Changes in skin microcirculation in patients with critical COVID-19 indicate that the infection induces a systemic microvascular impairment with persisting long-term effects on the microvascular function.

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.