Microvascular Responses Research Articles

Macrovascular blood flow and microvascular cerebrovascular reactivity are regionally coupled in adolescence

Cerebrovascular imaging assessments are particularly challenging in adolescent cohorts, where not all modalities are appropriate, and rapid brain maturation alters hemodynamics at both macro- and microvascular scales. In a preliminary sample of healthy adolescents (n = 12, 8–25 years), we investigated relationships between 4D flow MRI-derived blood velocity and blood flow in bilateral anterior, middle, and posterior cerebral arteries and BOLD cerebrovascular reactivity (CVR) in associated vascular territories. As hypothesized, higher velocities in large arteries are associated with an earlier response to a vasodilatory stimulus (cerebrovascular reactivity delay) in the downstream territory. Higher blood flow through these arteries is associated with a larger BOLD response to a vasodilatory stimulus (cerebrovascular reactivity amplitude) in the associated territory. These trends are consistent in a case study of adult moyamoya disease. In our small adolescent cohort, macrovascular-microvascular relationships for velocity/delay and flow/CVR change with age, though underlying mechanisms are unclear. Our work emphasizes the need to better characterize this key stage of human brain development, when cerebrovascular hemodynamics are changing, and standard imaging methods offer limited insight into these processes. We provide important normative data for future comparisons in pathology, where combining macro- and microvascular assessments may better help us prevent, stratify, and treat cerebrovascular disease.

Pressure‐Induced Microvascular Reactivity With Whole Foot Loading Is Unique Across the Human Foot Sole

ABSTRACTBackgroundFoot sole plantar pressure generates transient but habitual cutaneous ischemia, which is even more exacerbated in atypical gait patterns. Thus, adequate post‐occlusive reactive hyperaemia (PORH) is necessary to maintain skin health. Plantar pressure regional variance during daily tasks potentially generates region‐specific PORH, crucial for ischemic defence.AimsThe current work investigated regional PORH across the human foot sole resulting from stance‐like loading.Materials & MethodsA loading device equipped with an in‐line laser speckle contrast imager measured blood flux before, during, and after whole‐foot loading for 2 and 10 min durations at 15% and 50% body weight. Flux was compared between six regions: the heel, lateral arch, medial arch, and fifth, third, and first metatarsals (MT).ResultsBaseline flux was significantly greater in the 1MT and 3MT than all other regions. Loading occluded the heel, 5MT and 3MT more than all other regions. Regional PORH peak, time to peak, area under the curve, and recovery rate were ranked between regions.DiscussionThe 3MT, followed by 5MT, overall had the strongest PORH response, suggesting a heightened protection against ischemia compared to other regions.ConclusionThis work highlights regional variations within a healthy foot, providing a framework for future ulcer risk assessments and interventions to preserve foot health.

Correlation between maternal microvascular reactivity assessed by laser speckle contrast imaging and first trimester placental biomarkers

Correlation between maternal microvascular reactivity assessed by laser speckle contrast imaging and first trimester placental biomarkers

Evaluation of maternal skin microvascular reactivity by laser speckle contrast imaging in pregnancies complicated by preeclampsia and foetal growth restriction

Evaluation of maternal skin microvascular reactivity by laser speckle contrast imaging in pregnancies complicated by preeclampsia and foetal growth restriction

The Effect of Overweight/Obesity on Cutaneous Microvascular Reactivity as Measured by Laser-Doppler Fluxmetry: A Systematic Review

Introduction: We sought to determine by systematic review the independent effect of overweight/obesity on cutaneous microvascular reactivity in adults as measured by laser-Doppler fluxmetry. Methods: CINAHL Complete, SPORTSDiscus, Embase, Medline, and Cochrane Library were searched until March 2024 to identify studies investigating cutaneous microvascular reactivity in an overweight/obese but otherwise healthy group versus a lean/healthy weight. Reporting is consistent with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Quality appraisal of included studies was performed using the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) checklist. Results: Nineteen eligible articles reported on 1847 participants. Most articles reported impaired cutaneous microvascular reactivity in cohorts with overweight/obesity compared to cohorts with lean/healthy weight. Investigating reactivity via post-occlusive reactive hyperaemia (PORH) and iontophoresis of acetylcholine (ACh) has shown significance. No significant differences were reported between groups in response to local heating or to iontophoresis of methacholine or insulin, while findings of the effect of obesity on iontophoresis of sodium nitroprusside (SNP) were mixed. Conclusions: The pathophysiology of impaired cutaneous microvascular reactivity in overweight/obesity requires further investigation; however, impaired function of vasoactive substances, endothelial dysfunction, sensory nerves, and calcium-activated potassium channels may be implicated. Identifying these impaired microvascular responses should inform possible therapy targets in overweight and obesity.activated potassium channels may be implicated. Identifying these impaired microvascular responses should inform possible therapy targets in overweight and obesity.

Female patients exhibit altered vasopressin-induced coronary microvascular contractile response and molecular signaling following cardiac surgery

BackgroundEmerging data suggest women have worse outcomes than men following cardioplegia and cardiopulmonary bypass (CP/CPB). Altered coronary microvascular function affecting myocardial perfusion may contribute, but human translational studies are lacking. MethodsViable coronary microvessels (<200 μ m) were dissected from human atrial samples collected before and after CP/CPB from a subset of 108 patients enrolled. Ex vivo contractile responses to vasopressin were assessed using video microscopy. RNA deep-sequencing and immunoblotting were used to quantify gene and protein expression, respectively. ResultsCoronary microvessels exhibited increased vasopressin-induced contractile responses post-CP/CPB in males and females (p ​< ​0.0001). Females exhibited a decrease in microvascular contractile response versus males pre- (p ​= ​0.1) and post-CP/CPB (p ​= ​0.09) which approached significance. Myocardial vasopressin 1a receptor levels were increased in females versus males (p ​= ​0.001). Vasopressin-induced vasoconstriction predicted postoperative cardiac index. ConclusionsImpaired coronary microvascular contractile responses in females jeopardizing myocardial perfusion may underlie worse outcomes following cardiac surgery.

Peculiarities of the body component composition and microcirculation of qualified divers

One of the important aspects of improving the effectiveness of training qualified divers is understanding the peculiarities of body component composition and the state of microcirculation. The aim of this study was to investigate the component body composition and microcirculation peculiarities of qualified divers diving from different types of gymnastic equipment. The study sample included 30 qualified divers, consisting of 17 girls and 13 boys aged 13 to 18 years. Body composition was assessed using bioimpedance analysis, and the functional state of the microcirculatory system was evaluated through laser Doppler flowmetry. The results indicated that divers who utilized the 10-meter tower exhibited a statistically significant decrease in adipose tissue content and an increase in fat-free mass and relative muscle mass compared to athletes in other diving disciplines. Additionally, a high level of tissue perfusion and microvascular reactivity was observed among the athletes. These findings are crucial for assessing and enhancing the training effectiveness of qualified diving athletes.

Coronary microvascular dysfunction in heart failure: observations from the MICRO registry

Abstract Background Heart failure (HF) is one of the leading causes of hospitalization in the elderly. Coronary microvascular dysfunction (CMD), among other risk factors, is linked to the pathogenesis and clinical manifestations of HF. Purpose This abstract aims to summarize key findings from a comprehensive analysis of CMD in subgroups of HF, shedding light on its association with hemodynamic parameters. Methods Patients experiencing recurrent angina (CCS II-IV) and no relevant epicardial stenosis were enrolled in a prospective registry (MICRO). Epicardial and microvascular responses (pressure, resistance and flow) were assessed at rest and during adenosine and acetylcholine testing. The impact of an elevated left ventricular end-diastolic pressure (LVEDP) in the absence of clinical signs of HF was also investigated. Results Overall, 188 patients (63% (118) women, mean age 65±11 years) with angina and no epicardial stenosis were enrolled. Patients with HF (n=26) displayed lower hyperemic flow in response to endothelium-independent adenosine (5.2±3.1 vs. 7.3±4.4; P=0.004), lower coronary flow reserve (2.9±1.5 vs. 4.4±1.1; P&amp;lt;0.001) and microvascular resistance reserve (3.3±2.1 vs. 5.2±2.7; P&amp;lt;0.001), and increased microvascular resistance during adenosine-induced hyperemia (25±21 vs. 17±11; P=0.045). An increased LVEDP without clinical signs of HF was not associated with a lower coronary flow reserve (4.3±1.9 vs. 2.6±1.2; P=0.006) or microvascular resistance reserve (4.9±2.1 vs. 2.8±1.7; P=0.004). Microvascular resistance during acetylcholine (endothelium-dependent)-induced hyperemia was lower in HF patients (36.2±23.5 vs. 57.4±37.8; P=0.018). Conclusion(s) Patients with heart failure displayed signs of impaired microvascular endothelium-independent responses while endothelium-dependent reactivity appears to be maintained. An elevated LVEDP without clinical HF was not associated with impaired coronary microvascular function.

The interplay between coronary microvascular resistance, arterial reservoir function and coronary flow reserve: unravelling the significance of high microvascular resistance

Abstract Background Beyond the observation that patients with low CFR indicating presence of coronary microvascular dysfunction (CMD) have an unfavourable prognosis compared to patients with preserved CFR, recent large multicentre trials [1-2] have shown that increased minimal hyperaemic microvascular resistance (HMR or IMR) ,neither on top of the low CFR nor alone, does not play a role as a prognostic factor for ischemia in nonobstructive coronary artery disease (INOCA) patients. Purpose This study investigates the pathophysiological interactive processes in CMD and no-CMD groups with high and low HMR taking into account potential adaptive mechanisms that alter arterial reservoir function [3] associated with microvascular resistance and systemic vasomotor response in INOCA patients. Methods Analysis was conducted on 312 unique unobstructed vessels (FFR&amp;gt;0.80) from 258 patients (73% male) enrolled in the DEFINE-FLOW [4] study. CFR and HMR were quantified using intracoronary Doppler and pressure measurements. Vessels were categorized into four groups based on high and low CFR and HMR using the best available cut-off values (2.5 for both). Arterial reservoir capacity (ARC) and related parameters [3] were quantified using reservoir-excess pressure (Preservoir and Pexcess) analysis of averaged aortic and distal coronary pressure waveforms in CMD (CFR&amp;lt;2.5) and no-CMD (CFR≥2.5) subgroups. (Figure 1-2) Results Compared to vessels without CMD, functional and structural CMD have increased Pexcess (p:0.007) and a rapid decline in diastolic pressure (DRCcoronary p&amp;lt;0.001, DRCaortic, p&amp;lt;0.05), indicating the ongoing systemic hemodynamic superfluous state despite locally suppressed resting blood flow in the structural CMD. Higher baseline microvascular resistance (BMR) was associated with increased reservoir pressure (r:0.302, p&amp;lt;0.001). The vessels with preserved CFR despite high HMR are characterised by uniquely increased ARC (p:0.014), effectively diminished Pexcess (p:0.010), which parallels the local (highest BMR p&amp;lt;0.001) and global (lowest DRCaortic, p&amp;lt;0.05) vasomotor response, that normalizes the systemic and local hyperperfusion, and ultimately regains an adequate flow reserve (CFR) (p&amp;lt;0.001). The high HMR in this group was mainly due to increased resting tonus unlike structural CMD, evident by the highest RRR (BMR/HMR).(p&amp;lt;0.001) (Figure 1-2) Conclusion(s) The high HMR despite preserved CFR vessels form a unique-adaptive group, characterised by substantially increased arterial reservoir capacity and effectively diminished Pexcess, by means of an adaptive vasomotor response which manifests locally in the coronary bed as pronouncedly augmented BMR &amp; RRR, and globally as reduced DRC in the aortic pressure waveform. This adaptive myogenic response normalising resting flow and ongoing systemic and local hyperperfusion ultimately regains an adequate flow reserve (CFR).Figure 1.Methods and Main FindingsFigure 2.Visual Abstract

Combined effect of sprint interval training and post-exercise blood flow restriction on muscle deoxygenation responses during ramp incremental cycling.

This study investigated the effect of sprint-interval training combined with post-exercise blood flow restriction (i.e., SIT + BFR) on pulmonary gas exchange and microvascular deoxygenation responses during ramp incremental (RI) cycling. Nineteen healthy, untrained males (mean ± SD age: 24 ± 5years; height: 178 ± 6cm; body mass: 77.0 ± 10.7kg) were assigned to receive 4weeks of SIT or SIT + BFR. Before and after the intervention period, each participant completed a RI cycling test for determination of peak oxygen uptake ( ) and the gas exchange threshold (GET) with deoxygenated heme (Δdeoxy[heme]) and tissue oxygenation index (TOI) measured by near-infrared spectroscopy (NIRS) in vastus lateralis (VL) muscle. Relative increased by 7% following both interventions (P ≤ 0.03). SIT + BFR increased peak Δdeoxy[heme] when normalized relative to leg arterial occlusion (PRE: 57.3 ± 13.0 vs. POST: 62.0 ± 13.2%; P = 0.009) whereas there was no significant difference following SIT (PRE: 64.9 ± 14.3 vs. POST: 71.4 ± 11.7%; P = 0.17). Likewise, TOI nadir decreased at exhaustion following SIT + BFR (PRE: 56.9 ± 9.1 vs. POST: 51.4 ± 9.2%; P = 0.002) but not after SIT (PRE: 58.5 ± 7.1 vs. POST: 56.3 ± 8.2%; P = 0.29). The absolute cycling power at the GET increased following SIT + BFR (PRE: 108 ± 13 vs. POST: 125 ± 17 W, P = 0.001) but was not significantly different following SIT (PRE: 112 ± 7 VS. POST: 116 ± 11 W, P = 0.54). The addition of post-exercise BFR to SIT alters the mechanism underlying the enhancement in by increasing the peak rate of muscle fractional O2 extraction in previously untrained males.

Increased fatigability and impaired skeletal muscle microvascular reactivity in adults with obstructive sleep apnea: a cross-sectional study

BackgroundSympathetic nervous system hyperactivity and chronic intermittent nocturnal hypoxia in individuals with obstructive sleep apnea (OSA) predispose them to microvascular impairment, which may contribute to increased daytime muscle fatigue. This study aimed to assess microvascular reactivity of the skeletal muscle, examine fatigability, and determine the relationship between fatigability and microvascular reactivity in adults with OSA.MethodsTwenty-six participants were allocated into two groups—those with OSA and those without i.e. non-OSA. Each group comprised of 13 individuals who underwent an arterial occlusion test on their non-dominant leg. The percentage change of maximal hyperemic response (MHR) and the time to achieve MHR (tM) of both the total myoglobin/hemoglobin (∆[Hbtot]) and the oxygenated myoglobin/hemoglobin (∆[HbO2]) signals from near-infrared spectroscopy were calculated to examine microvascular reactivity. In addition, a 10-min walk test was performed to assess performance and perceived fatigability.ResultsThe OSA group demonstrated a reduced in ∆[Hbtot]MHR (150.9 ± 16.2% vs. 235.8 ± 72.7%, p = 0.006), ∆[HbO2]MHR (131.4 ± 8% vs. 161.7 ± 10.6%, p = 0.001) and increased ∆[Hbtot]tM (80.5 ± 13.1 s vs. 47.7 ± 9.9 s, p < 0.001), ∆[HbO2]tM (85.2 ± 22.4 s vs. 52.1 ± 5.9 s, p = 0.001) compared to the non-OSA group. In addition, participants in the OSA group experienced greater perceived (6 ± 1 vs. 2.8 ± 0.1, p = 0.001) and performance fatigability (1.1 ± 0.1 vs. 0.9 ± 0.1, p = 0.001) compared to adults in the non-OSA group. Moreover, both performance and perceived fatigability were significantly associated with microvascular reactivity parameters (all p < 0.05).ConclusionMicrovascular dysfunction, as determined by an attenuated post-occlusive reactive hyperemia, is observed in individuals with OSA that may contribute to increased fatigability in these individuals.

Retinal and cerebral hemodynamics redistribute to favor thermoregulation in response to passive environmental heating and heated exercise in humans

ABSTRACT Core temperature (TC) changes, alongside exercise, affect hemodynamic responses across different conduit and microvascular beds. This study investigated impacts of ecologically valid environmental heat and exercise exposures on cerebral, skin and retinal vascular responses by combining physiological assessments alongside computational fluid dynamics (CFD) modeling. Young, healthy participants (n = 12) were exposed to environmental passive heating (PH), and heated exercise (HE) (ergometer cycling), in climate-controlled conditions (50 mins, 40°C, 50% relative humidity) while maintaining upright posture. Blood flow responses in the common carotid (CCA), internal carotid (ICA) and central retinal (CRA) arteries were assessed using Duplex ultrasound, while forearm skin microvascular blood flow responses were measured using optical coherence tomography angiography. Three-dimensional retinal hemodynamics (flow and pressure) were calculated via CFD simulation, enabling assessment of wall shear stress (WSS). TC rose following PH (+0.2°C, p = 0.004) and HE (+1.4°C, p < 0.001). PH increased skin microvascular blood flow (p < 0.001), whereas microvascular CRA flow decreased (p = 0.038), despite unchanged ICA flow. HE exacerbated these differences, with increased CCA flow (p = 0.007), unchanging ICA flow and decreased CRA flow (p < 0.001), and interactions between vascular (CCA vs. ICA p = 0.018; CCA vs. CRA p = 0.004) and microvascular (skin vs. retinal arteriolar p < 0.001) territories. Simulations revealed patterns of WSS and lumen pressure that uniformly decreased following HE. Under ecologically valid thermal challenge, different responses occur in distinct conduit and microvascular territories, with blood flow distribution favoring systemic thermoregulation, while flow may redistribute within the brain.

L-Arginine and Taurisolo® Effects on Brain Hypoperfusion-Reperfusion Damage in Hypertensive Rats.

Acute and chronic hypertension causes cerebral vasculopathy, increasing the risk of ischemia and stroke. Our study aimed to compare the effects of arterial pressure reduction on the pial microvascular responses induced by hypoperfusion and reperfusion in spontaneously hypertensive Wistar rats, desamethasone-induced hypertensive Wistar rats and age-matched normotensive Wistar rats fed for 3 months with a normal diet or normal diet supplemented with L-arginine or Taurisolo® or L-arginine plus Taurisolo®. At the end of treatments, the rats were submitted to bilateral occlusion of common carotid arteries for 30 min and reperfusion. The microvascular parameters investigated in vivo through a cranial window were: arteriolar diameter changes, permeability increase, leukocyte adhesion to venular walls and percentage of capillaries perfused. Hypoperfusion-reperfusion caused in all rats marked microvascular changes. L-arginine treatment was effective in reducing arterial blood pressure causing vasodilation but did not significantly reduce the damage induced by hypoperfusion-reperfusion. Taurisolo® treatment was less effective in reducing blood pressure but prevented microvascular damage from hypoperfusion-reperfusion. L-arginine plus Taurisolo® maintained blood pressure levels within the physiological range and protected the pial microcirculation from hypoperfusion-reperfusion-induced microvascular injuries. Therefore, the blood pressure reduction is not the only fundamental aspect to protect the cerebral circulation from hypoperfusion-reperfusion damage.

A novel GWAS locus influences microvascular response to mental stress and predicts adverse cardiovascular events.

Excessive peripheral microvascular constriction during acute psychologicalstress reflects similar changes in coronary blood flow and is a predictor of adverse cardiovascular outcomes. Among individuals with coronary artery disease (CAD), we sought to determine if genetic factors contribute to the degree of microvascular constriction during mental stress. A total of 580 stable CAD individuals from two prospective cohort studies underwent mental stress testing. Digital pulse wave amplitude was continuously measured and the stress/rest (sPAT) ratio of pulse wave amplitude was calculated. Race stratified genome-wide association studies (GWAS) of sPAT-ratio were conducted using linear regression of additive genetic models. A trans-ethnic meta-analysis integrated the four sets of GWAS results. Participants were followed for the outcome of recurrent cardiovascular events (myocardial infarction, heart failure, revascularization, and CV death) for a median of 5years. We used Wei-Lin-Weissfeld (WLW) model to assess the association between sPAT-ratio with recurrent events. Mean age was 63 ± 9. We identified three SNPs in linkage disequilibrium, closely related to chr7:111,666,943T > C (rs6466396) that were associated with sPAT-ratio (p = 6.68E-09). Participants homozygous for the T allele had 80% higher risk of incident adverse events (HR 1.8, 95% CI, 1.4-2.2). Also, participants with a lower sPAT-ratio (< median) had a higher adverse event rate, hazard ratio (HR) = 1.3, [95%confidence interval (CI), 1.1-1.6]. However, adjustment for the genotypes did not substantially alter the impact of sPAT ratio on adverse outcome rate.In conclusion,we have identified a genetic basis for stress-induced vasomotion. The 3 linked variants modulate vasoconstriction during mental stress may have a prognostic importance.

Macrovascular blood flow and microvascular cerebrovascular reactivity are regionally coupled in adolescence.

Cerebrovascular imaging assessments are particularly challenging in adolescent cohorts, where not all modalities are appropriate, and rapid brain maturation alters hemodynamics at both macro- and microvascular scales. In a preliminary sample of healthy adolescents (n=12, 8-25 years), we investigated relationships between 4D flow MRI-derived blood velocity and blood flow in bilateral anterior, middle, and posterior cerebral arteries and BOLD cerebrovascular reactivity in associated vascular territories. As hypothesized, higher velocities in large arteries are associated with an earlier response to a vasodilatory stimulus (cerebrovascular reactivity delay) in the downstream territory. Higher blood flow through these arteries is associated with a larger BOLD response to a vasodilatory stimulus (cerebrovascular reactivity amplitude) in the associated territory. These trends are consistent in a case study of adult moyamoya disease. In our small adolescent cohort, macrovascular-microvascular relationships for velocity/delay and flow/CVR change with age, though underlying mechanisms are unclear. Our work emphasizes the need to better characterize this key stage of human brain development, when cerebrovascular hemodynamics are changing, and standard imaging methods offer limited insight into these processes. We provide important normative data for future comparisons in pathology, where combining macro- and microvascular assessments may better help us prevent, stratify, and treat cerebrovascular disease.

Statin therapy improves locomotor muscle microvascular reactivity in patients with heart failure with preserved ejection fraction.

Peripheral microvascular dysfunction has been documented in patients with heart failure with preserved ejection fraction (HFpEF), which may be related to elevated levels of inflammation and oxidative stress. Unfortunately, few strategies have been identified to effectively ameliorate this disease-related derangement. Thus, using a parallel, double-blind, placebo-controlled design, this study evaluated the efficacy of 30-day atorvastatin administration (10 mg daily) on lower limb microvascular reactivity, functional capacity, and biomarkers of inflammation and oxidative stress in patients with HFpEF (statin, n = 8, 76 ± 6 yr; placebo, n = 8, 68 ± 9 yr). The passive limb movement (PLM)-induced hyperemic response and 6-min walk test (6MWT) distance were evaluated to assess ambulatory muscle microvascular function and functional capacity, respectively. Circulating biomarkers were also measured to assess the contribution of changes in inflammation and redox balance to these outcomes. The total hyperemic response to PLM, assessed as leg blood flow area under the curve (LBFAUC), increased following the statin intervention (pre, 60 ± 68 mL; post, 164 ± 90 mL; P < 0.01), whereas these variables were unchanged in the placebo group (P = 0.99). There were no significant differences in 6MWT distance following statin or placebo intervention. Malondialdehyde (MDA), a marker of lipid peroxidation, was significantly reduced following the statin intervention (pre, 0.68 ± 0.10; post, 0.51 ± 0.11; P < 0.01) while other circulating biomarkers were unchanged. Together, these data provide new evidence for the efficacy of low-dose statin administration to improve locomotor muscle microvascular reactivity in patients with HFpEF, which may be due, in part, to a diminution in oxidative stress.NEW & NOTEWORTHY This was the first study to investigate the impact of statin administration on locomotor muscle microvascular function in patients with HFpEF. In support of our hypothesis, the total hyperemic response to PLM, assessed as leg blood flow area under the curve, increased, and malondialdehyde, a marker of oxidative damage, was reduced following the statin intervention. Together, these data provide new evidence for the efficacy of statin administration to improve locomotor muscle microvascular reactivity in patients with HFpEF, which may be due, in part, to reduced oxidative stress.

Aptamer BT200 is protective against myocardial ischemia-reperfusion injury in mice

BackgroundMyocardial ischemia-reperfusion (MI/R) injury tends to affect cardiac function and leads to poor patient prognosis, and there is still no effectively targeted drug to develop anti–von Willebrand factor (VWF) aptamer in acute coronary heart disease. However, the newly anti-VWF aptamer BT200 is applied for not only stroke and hemophilia but also antithrombolism function in clinical development. The role of BT200 in acute myocardial injury during MI/R is still unknown. ObjectivesTo investigate the cardioprotective effect of aptamer BT200 in an experiment mouse model of MI/R. MethodsC57BL/6 mice were subjected to 30-minute ischemia and 24-hour reperfusion to establish MI/R model. Mice were treated with intravenous injection of cy3-labeled BT200 and were observed by an in vivo imaging system at different time points. Then, mice were sampled and evaluated by echocardiography, Evans triphenyltetrazolium chloride staining, histopathologic, western blotting, and real-time quantitative polymerase chain reaction assays to detect cardiac injury and inflammation response after 24-hour reperfusion. ResultsBT200 aptamer can enter and infiltrate into the ischemic myocardium after 24-hour reperfusion. BT200 was shown to inhibit VWF A1 activity and prolong bleeding time in MI/R mice. Moreover, BT200-treated mice had a significant reduction in infarct size and an improvement in cardiac function post-MI/R. BT200 treatment can also alleviate MI/R-induced microvascular obstruction, inflammation response, and cardiomyocyte apoptosis. ConclusionPharmacologic targeting of VWF with BT200 alleviates acute MI/R injury in a murine model and may be a novel therapy strategy for acute myocardial infarction.

Impaired microvascular insulin-dependent dilation in women with a history of gestational diabetes.

Women with a history of gestational diabetes mellitus (GDM) have a significantly greater lifetime risk of developing cardiovascular disease and type 2 diabetes compared with women who had an uncomplicated pregnancy (HC). Microvascular endothelial dysfunction, mediated via reduced nitric oxide (NO)-dependent dilation secondary to increases in oxidative stress, persists after pregnancy complicated by GDM. We examined whether this microvascular dysfunction reduces insulin-mediated vascular responses in women with a history of GDM. We assessed in vivo microvascular endothelium-dependent vasodilator function by measuring cutaneous vascular conductance responses to graded infusions of acetylcholine (10-10-10-1 M) and insulin (10-8-10-4 M) in control sites and sites treated with 15 mM l-NAME [NG-nitro-l-arginine methyl ester; NO-synthase (NOS) inhibitor] or 5 mM l-ascorbate. We also measured protein expression of total endothelial NOS (eNOS), insulin-mediated eNOS phosphorylation, and endothelial nitrotyrosine in isolated endothelial cells from GDM and HC. Women with a history of GDM had reduced acetylcholine (P < 0.001)- and insulin (P < 0.001)-mediated dilation, and the NO-dependent responses to both acetylcholine (P = 0.006) and insulin (P = 0.006) were reduced in GDM compared with HC. Insulin stimulation increased phosphorylated eNOS content in HC (P = 0.009) but had no effect in GDM (P = 0.306). Ascorbate treatment increased acetylcholine (P < 0.001)- and insulin (P < 0.001)-mediated dilation in GDM, and endothelial cell nitrotyrosine expression was higher in GDM compared with HC (P = 0.014). Women with a history of GDM have attenuated microvascular vasodilation responses to insulin, and this attenuation is mediated, in part, by reduced NO-dependent mechanisms. Our findings further implicate increased endothelial oxidative stress in this microvascular insulin resistance.NEW & NOTEWORTHY Women who have gestational diabetes during pregnancy are at a greater risk for cardiovascular disease and type 2 diabetes in the decade following pregnancy. The mechanisms mediating this increased risk are unclear. Herein, we demonstrate that insulin-dependent microvascular responses are reduced in women who had gestational diabetes, despite the remission of glucose intolerance. This reduced microvascular sensitivity to insulin may contribute to increased cardiovascular disease and type 2 diabetes risk in these women.

Dietary Protein in a Challenge Meal Does Not Alleviate Postprandial Impairments in Vascular Endothelial Function in Healthy Older Adults with Cardiometabolic Risk: A Randomized Crossover-Controlled Trial

BackgroundPostprandial vascular endothelial dysfunction is an early marker of atherosclerosis. Meal protein has been reported to reduce endothelial dysfunction in adults, and the effect could be mediated by the amino acid content. ObjectivesThis trial aims to assess the effect of a specifically designed plant-protein blend that contains high leucine, arginine, and cysteine on postprandial endothelial function in the elderly. MethodsIn a randomized, double-blind, 3-period crossover (2-wk washout), controlled trial, we compared the vascular effects of 3 high-saturated-fat high-sucrose (HFHS) meals based on either our specific plant-protein blend, milk protein, or without added protein. The trial was conducted on 29 healthy adults aged >65 y presenting ≥2 cardiometabolic risk factors. Postprandial vascular function was evaluated at fasting, 3 h, and 5 h postprandially, using brachial flow-mediated dilation (FMD), hand microvascular reactivity (using Flowmetry Laser Doppler, FLD), and finger reactive hyperemia index (using Peripheral Arterial Tonometry, RHI). Immune cell count and gene expression in peripheral blood mononuclear cells (PBMCs) were also assessed postprandially. Data were analyzed using mixed linear models with repeated measurements on participants for meal composition and time of sampling. This trial was registered at clinicaltrials.gov as NCT04923555. ResultsFMD incremental AUC value decreased after meals (time effect P < 0.01), with no significant differences between meals. RHI also decreased with time (P < 0.01). PBMC count and monocyte chemoattractant protein-1, IL-1b, and IL-6 expression increased after meals showing postprandial endothelial activation (P < 0.05). Overall, meal composition had no effect on any of the postprandial changes (Ps>0.10). ConclusionsIn healthy adults aged >65 y presenting cardiometabolic risk, adding protein to an HFHS challenge meal does not mitigate postprandial impairments in vascular endothelial function and inflammatory activation. Further studies are needed to explore the potential differences with younger adults.

Effects of coffee intake on skeletal muscle microvascular reactivity at rest and oxygen extraction during exercise: a randomized cross-over trial.

The effects of coffee ingestion on skeletal muscle microvascular function are not well understood. This study aimed to investigate the acute effects of coffee intake with varying levels of caffeine on skeletal muscle microvascular reactivity at rest and oxygen extraction during maximal incremental exercise in physically active individuals. Twenty healthy young male participants were administered coffee with low caffeine (3 mg/kg body weight; LC), high caffeine (6 mg/kg body weight; HC), and placebo (decaf) in different sessions. Skeletal muscle reactivity indexes, including tissue saturation index 10s slope (TSI10) and TSI half time recovery (TSI ½) following 5-minute ischemia were measured at rest and were measured at baseline and post-coffee consumption using near-infrared spectroscopy (NIRS). Post-coffee intake, NIRS was also used to measure microvascular oxygen extraction during exercise via maximal incremental exercise. Peak oxygen consumption and peak power output (Wpeak) were simultaneously evaluated. Post-coffee consumption, TSI10 was significantly higher in the LC condition compared to placebo (p = 0.001) and significantly higher in the HC condition compared to placebo (p < 0.001). However, no difference was detected between LC and HC conditions (p = 0.527). HC condition also showed significant less TSI ½ compared to placebo (p = 0.005). However, no difference was detected for microvascular oxygen extraction during exercise, despite the greater Wpeak found for HC condition (p < 0.001) compared to placebo. Coffee ingestion with high caffeine level (6 mg/kg body weight) significantly enhanced skeletal muscle reactivity at rest. However, the improvement of exercise performance with coffee intake is not accompanied by alterations in muscle oxygen extraction.