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Introduction We evaluated the incidence of change in serial 12-lead electrocardiogram (ECG) diagnostic classifications in patients resuscitated from out-of-hospital (OH) cardiac arrest (OHCA) comparing OH to emergency department (ED) ECGs. Methods This retrospective case series included: 1) adults (≥ 18 years old), 2) resuscitated from OHCA, 3) ≥ 1 OH and 1 ED ECG/patient, and 4) emergency medical services (EMS) transport to the study hospital. OH and ED ECGs were classified as: 1) STEMI (ST-segment Elevation Myocardial Infarction), 2) Ischemic, and 3) Non-ischemic. Two ED physicians and one cardiologist independently classified all ECGs, then generated a consensus opinion classification for each ECG based on American Heart Association’s 2018 Expert Consensus criteria. The most ischemic OH ECG classification was compared with the last ED ECG classification. Results From 7/27/12 to 7/18/19, 176 patients were entered with a mean age of 61.2 ± 16.6 years; 102/176 (58%) were male. Overall, 504 OH and ED 12-lead ECGs were acquired (2.9 ECGs/patient). ECG classification inter-rater reliability kappa score was 0.63 ± 0.02 (substantial agreement). Overall, 86/176 (49%) changed ECG classification from the OH to ED setting; 69/86 (80%) of these ECGs changed from more to less ischemic classifications. Of 49 OH STEMI ECG classifications, 33/49 (67%) changed to a less ischemic (non-STEMI) ED ECG classification. Conclusions Change in 12-lead ECG classification from OH to ED setting in patients resuscitated from OHCA was common (49%). The OH STEMI classification changed to a less ischemic (non-STEMI) ED classification in 67% of cases.

Microvascular dysfunction predicts adverse cardiovascular events despite absence of large vessel disease. A shift in the mediator of flow-mediated dilatation (FMD) from nitric oxide (NO) to mitochondrial-derived hydrogen peroxide (H

Sedentary behavior is associated with cardiovascular disease (CVD) and mortality, independent of physical activity. The biological mechanisms underlying these associations are largely unknown. We hypothesized that obese subjects with sedentary desk jobs, when assigned a sit–stand desk, will reduce daily sedentary time, and show improvement in arterial flow-mediated dilation (FMD), an early indicator of CVD. Overweight and obese subjects without known CVD were recruited at our institution and given an adjustable sit–stand desk at work. Activities were quantified with an accelerometer for 7 days at baseline and during the intervention. FMD of the brachial and superficial femoral arteries, fasting lipids, insulin and glucose labs, and anthropometrics were measured at baseline, and 12 and 24 weeks. Repeated one-way ANOVA tests were used to compare measurements over time. Fifteen participants were enrolled (93% female, mean age 40 ± 5 years, mean body mass index [BMI] 33 ± 5). Mean daily sedentary time at work decreased by 90 minutes from baseline (385 ± 49 minutes) to 12 weeks (297 ± 80 minutes, p = 0.002) and 24 weeks (295 ± 127 minutes, p = 0.015). Femoral FMD increased from baseline (4.9 ± 1.7%) to 12 weeks (6.4 ± 2.3%, p = 0.043) and further to 24 weeks (8.1 ± 3.2%, p = 0.009). Significant improvement in fasting triglycerides and insulin resistance occurred. There was no change in brachial FMD, exercise activity, step counts, weight, or BMI. A significant reduction in sedentary time during working hours was identified with utilization of a sit–stand desk and sustained over 24 weeks. Improvements in FMD, triglycerides, and insulin resistance provide insight into mechanisms of adverse health risks associated with sedentary behavior.

BACKGROUND: Impaired endothelium-dependent vasodilation has been suggested to be a key component of coronary microvascular dysfunction (CMD). A better understanding of endothelial pathways involved in vasodilation in human arterioles may provide new insight into the mechanisms of CMD. OBJECTIVE: To investigate the role of TRPV4, NOX4, and their interaction in human arterioles and examine the underlying mechanisms. METHODS AND RESULTS: Arterioles were freshly isolated from adipose and heart tissues obtained from 71 patients without coronary artery disease, and vascular reactivity was studied by videomicroscopy. In human adipose arterioles (HAA), ACh-induced dilation was significantly reduced by TRPV4 inhibitor HC067047 and by NOX 1/4 inhibitor GKT137831, but GKT137831 did not further affect the dilation in the presence of TRPV4 inhibitors. GKT137831 also inhibited TRPV4 agonist GSK1016790A-induced dilation in HAA and human coronary arterioles (HCA). NOX4 transcripts and proteins were detected in endothelial cells of HAA and HCA. Using fura-2 imaging, GKT137831 significantly reduced GSK1016790A-induced Ca(2+) influx in the primary culture of endothelial cells and TRPV4-WT-overexpressing human coronary artery endothelial cells (HCAEC). However, GKT137831 did not affect TRPV4-mediated Ca(2+) influx in non-phosphorylatable TRPV4-S823A/S824A-overexpressing HCAEC. In addition, treatment of HCAEC with GKT137831 decreased the phosphorylation level of Ser824 in TRPV4. Finally, proximity ligation assay (PLA) revealed co-localization of NOX4 and TRPV4 proteins. CONCLUSION: Both TRPV4 and NOX4 contribute to ACh-induced dilation in human arterioles from patients without coronary artery disease. NOX4 increases TRPV4 phosphorylation in endothelial cells, which in turn enhances TRPV4-mediated Ca(2+) entry and subsequent endothelium-dependent dilation in human arterioles.

Background: Chronic stroke survivors have impaired conduit artery endothelial function, but little is known about peripheral microvascular function post-stroke. Near infrared spectroscopy (NIRS) can non-invasively measure tissue oxygen saturation (StO 2 ) of skeletal muscle, and when combined with a dynamic challenge like a vascular occlusion, can indirectly evaluate tissue oxygen utilization during the occlusion period and microvascular function during the post-occlusive hyperemic period. We hypothesized that microvascular function would be impaired in the tibialis anterior (TA) muscle of the affected leg of chronic stroke survivors compared to the non-affected leg as evidenced by a slower oxygen resaturation rate post-cuff release. Methods: Fifteen chronic stroke survivors completed this study. The mean age was 57±12 years, 10 were female, and the mean time since stroke was 12±10 years. After resting for fifteen minutes a NIRS sensor was placed over either the affected or non-affected TA. The opposite leg was tested one week later. After recording five minutes of baseline StO 2 , a cuff was placed around the proximal thigh and inflated to 225 mmHg for five minutes. StO 2 was continuously measured during cuff inflation and for five minutes post-cuff release. The rate of change in StO 2 was calculated during the five-minute cuff occlusion and the first 12 seconds post-cuff release. Results: There was no difference in baseline StO 2 between the affected and non-affected TA (68±11% vs. 67±6%, respectively; p=0.60). There was also no difference in the change in StO 2 during the occlusion period (affected ΔStO 2 = -31±12 % vs. non-affected -35±19%; p=0.76), or the rate of oxygen desaturation (affected -0.15±0.11 %·s -1 vs non-affected -0.10±0.04 %·s -1 ; p=0.39). After cuff release, there was a greater oxygen resaturation rate in the non-affected leg compared to the affected leg (3.13±2.08 %·s -1 vs. 1.60±1.11 %·s -1 , respectively; p=0.01). Conclusion: There was no difference in oxygen utilization between the affected and non-affected TA during the cuff occlusion period. The oxygen resaturation response in the affected TA post-cuff release was slower compared to the non-affected TA, suggesting microvascular function is impaired in the affected muscle.

Recent strides in anti-cancer therapeutics have improved longevity and led to a growing population of cancer survivors, who are increasingly likely to die of other causes. Treatment-induced cardiotoxicity is a complication of several therapeutic agents with acute and long-term consequences for cancer patients. Vascular endothelial dysfunction is a precursor and hallmark of ischemic coronary disease and may play a role in anti-cancer therapy-induced cardiotoxicity. This review summarizes clinical evidence for endothelial dysfunction following anti-cancer therapy and extends the discussion to include the impact of therapeutic agents on conduit arteries and the microcirculation. We highlight the role of innate immune system activation and cross-talk between inflammation and oxidative stress as pathogenic mechanisms underlying anti-cancer therapy-induced vascular toxicity. Understanding the impact of anti-cancer agents on the vascular endothelium will inform therapeutic approaches to prevent or reverse treatment-induced cardiotoxicity and may serve as an important tool to predict, monitor, and prevent adverse cardiovascular outcomes in patients undergoing treatment.

Female athletes display a high prevalence of hypothalamic amenorrhea as a result of energy imbalance. In these athletes with amenorrhea, decreased luteinizing hormone/follicule-stimulating hormone secretion leads to deficiency in endogenous estrogen. The severe estrogen deficiency in these athletes may increase cardiovascular risk similar to that in postmenopausal women. This review discusses the potential cardiovascular risk factors in athletes with amenorrhea as a result of hypoestrogenism, which include endothelial dysfunction and unfavorable lipid profiles. We also consider the potential to reverse the cardiovascular risk by restoring energy or hormonal imbalance along the reproductive axis in athletes with amenorrhea.

AIMS Cardiac contractility modulation (CCM) improves symptoms and exercise tolerance and reduces heart failure (HF) hospitalizations over 6-month follow-up in patients with New York Heart Association (NYHA) class III or IV symptoms, QRS

The vascular endothelium plays a crucial role to regulate vascular tone. Severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2) infection is known to cause vascular endothelial dysfunction. However, the long‐term effects of SARS‐CoV‐2 in resistance vessels remains unknown. This study is designed to test whether endothelium‐dependent vasodilation in human arterioles remains impaired after clearance of SARS‐CoV‐2 virus. Fresh human adipose tissues were obtained as discarded surgical specimens from control subjects (n=15, no SARS‐CoV‐2 exposure, 46.7±4 years) and previously SARS‐CoV‐2 positive subjects (PSPSs: n=8, 35.8±3.8 years). Among PSPSs, the time between positive and negative SARS‐CoV‐2 test results was ≤3 months (n=6) or 8 months (n=2). Isolated arterioles (100‐200 µm) were cannulated under 60 mmHg and examined for diameter changes to acetylcholine (ACh; 10−9 to 10−5 M) and sodium nitroprusside (SNP: 10−9 to 10−4 M) using videomicroscopy. Flow‐mediated dilation (FMD) was recorded at steady‐state during graded increases in intraluminal pressure gradients (5‐100 cm H2O). Dilation to ACh and FMD in arterioles from PSPSs was significantly reduced (ACh max. dilation at 10−5 M: 60±6% vs. 92.8±3.9% in control, n=7‐8, P

Objective: Coronary artery disease (CAD) is associated with a compensatory switch in mechanism of flow-mediated dilation (FMD) from nitric oxide (NO) to H 2 O 2 . The underlying mechanism responsible for the pathological shift is not well understood, and recent reports directly implicate telomerase and indirectly support a role for autophagy. We hypothesize that autophagy is critical for shear stress–induced release of NO and is a crucial component of for the pathway by which telomerase regulates FMD. Approach and Results: Human left ventricular, atrial, and adipose resistance arterioles were collected for videomicroscopy and immunoblotting. FMD and autophagic flux were measured in arterioles treated with autophagy modulators alone, and in tandem with telomerase-activity modulators. LC3B II/I was higher in left ventricular tissue from patients with CAD compared with non-CAD (2.8±0.2 versus 1.0±0.2-fold change; P 2 O 2 , while activation of autophagy restored NO-mediated vasodilation in CAD arterioles. In the presence of an autophagy activator, telomerase inhibitor prevented the expected switch (Control: 82±4%; NG-Nitro-l-arginine methyl ester: 36±5%; polyethylene glycol catalase: 80±3). Telomerase activation was unable to restore NO-mediated FMD in the presence of autophagy inhibition in CAD arterioles (control: 72±7%; NG-Nitro-l-arginine methyl ester: 79±7%; polyethylene glycol catalase: 38±9%). Conclusions: We provide novel evidence that autophagy is responsible for the pathological switch in dilator mechanism in CAD arterioles, demonstrating that autophagy acts downstream of telomerase as a common denominator in determining the mechanism of FMD.

Traditionally thought of primarily as the predominant regulator of myocardial perfusion, it is becoming more accepted that the human coronary microvasculature also exerts a more direct influence on the surrounding myocardium. Coronary microvascular dysfunction (CMD) not only precedes large artery atherosclerosis, but is associated with other cardiovascular diseases such as heart failure with preserved ejection fraction and hypertrophic cardiomyopathy. It is also highly predictive of cardiovascular events in patients with or without atherosclerotic cardiovascular disease. This review focuses on this recent paradigm shift and delves into the clinical consequences of CMD. Concepts of how resistance arterioles contribute to disease will be discussed, highlighting how the microvasculature may serve as a potential target for novel therapies and interventions. Finally, both invasive and non-invasive methods with which to assess the coronary microvasculature both for diagnostic and risk stratification purposes will be reviewed.

Although microvascular dysfunction (MVD) has been well characterized in individual organs as different disease entities, clinical evidence is mounting in support of an underlying systemic process. To address this hypothesis, we systematically searched PubMed and Medline for studies in adults published between 2014 and 2019 that measured blood biomarkers of MVD in three vital organs i.e. brain, heart, and the kidney. Of the 9706 unique articles 321 met the criteria, reporting 49 biomarkers of which 16 were common to the three organs. Endothelial dysfunction, inflammation including reactive oxidation, immune activation, and coagulation were the commonly recognized pathways. Triglyceride, C-reactive protein, Cystatin C, homocysteine, uric acid, IL-6, NT-proBNP, thrombomodulin, von Willebrand Factor, and uric acid were increased in MVD of all three organs. In contrast, vitamin D was decreased. Adiponectin, asymmetric dimethylarginine, total cholesterol, high-density and low-density cholesterol were found to be variably increased or decreased in studies. We review the pathways underlying MVD in the three organs and summarize evidence supporting its systemic nature. This scoping review informs clinicians and researchers in the multi-system manifestation of MVD. Future work should focus on longitudinal investigations to evaluate the multi-system involvement of this disease.

Introduction: Femoral artery atrophy and reduced endothelial function in the peripheral arteries of the affected lower limb contribute to reduced hyperemic blood flow in response to muscle contractions in chronic stroke survivors. These impairments could contribute to increased muscle weakness and exacerbate neuromuscular fatigue in stroke survivors. The time-course of these changes to the peripheral vasculature post-stroke have not been examined. Hypothesis: Superficial femoral artery atrophy and reduced blood flow to the affected limb occur in the subacute stroke period. Methods: This was a prospective, observational study which enrolled subacute stroke survivors admitted to inpatient rehabilitation at a single site. Maximum voluntary contractions (MVCs) of the paretic and non-paretic knee extensor muscles were assessed using a Biodex dynamometer. The superficial femoral artery was imaged in both legs using ultrasonography and arterial diameter was measured off-line with Brachial Analyzer software. Superficial femoral artery resting and hyperemic blood flow following MVCs was also quantified using ultrasonography. Results: Twelve subacute stroke survivors were enrolled in this study (7 men, 5 women). The mean age of all study participants was 65±10 years and the mean time since stroke was 12±6 days. Superficial femoral artery diameter was smaller in the affected leg compared to the non-affected leg (5.9±0.9 mm vs. 6.3±0.9 mm, respectively; p=0.006 paired t-test). Resting blood flow to the affected leg was also lower compared to the non-affected leg (164±68 ml/min vs. 205±105 ml/min, respectively; p=0.031 paired t-test). The MVC of the knee extensor muscles of the affected leg was less than the non-affected leg (103±63 Nm vs. 152±58 Nm, respectively; p=0.027, Wilcoxon signed rank test) and hyperemic blood flow was also reduced in the affected limb (248±94 ml/min vs. 428±203 ml/min, respectively; p2 =0.47, p=0.014). Conclusions: Superficial femoral artery atrophy and reduced limb blood flow occur in stroke survivors in the first weeks post-stroke and may contribute to limb weakness.

Heart failure (HF) is responsible for substantial morbidity and mortality and is increasing in prevalence. Although there has been remarkable progress in the treatment of HF with reduced ejection fraction (HFrEF), morbidity and mortality are still substantial. Cardiac contractility modulation (CCM) signals, consisting of biphasic high-voltage bipolar signals delivered to the right ventricular septum during the absolute refractory period, have been shown to improve symptoms, exercise tolerance and quality of life and reduce the rate of HF hospitalizations in patients with ejection fractions (EF) between 25% and 45%. CCM therapy is currently approved in the European Union, China, India, Australia and Brazil for use in symptomatic HFrEF patients with normal or slightly prolonged QRS duration. CCM is particularly beneficial in patients with baseline EF between 35% and 45%, which includes half the range of HF patients with mid-range EFs (HFmrEF). At the cellular level, CCM has been shown in HFrEF patients to improve calcium handling, to reverse the foetal myocyte gene programme associated with HF, and to facilitate reverse remodelling. This review highlights the preclinical and clinical literature related to CCM in HFrEF and HFmrEF and outlines the potential of CCM for HF with preserved EF, concluding that CCM may fill an important unmet need in the therapeutic approach to HF across the range of EFs.

Background and purpose NO produces arteriolar flow-induced dilation (FID) in healthy subjects but is replaced by mitochondria-derived hydrogen peroxide (mtH2 O2 ) in patients with coronary artery disease (CAD). Lysophosphatidic acid (LPA) is elevated in patients with risk factors for CAD, but its functional effect in arterioles is unknown. We tested whether elevated LPA changes the mediator of FID from NO to mtH2 O2 in human visceral and subcutaneous adipose arterioles. Experimental approach Arterioles were cannulated on glass micropipettes and pressurized to 60 mmHg. We recorded lumen diameter after graded increases in flow in the presence of either NOS inhibition (L-NAME) or H2 O2 scavenging (Peg-Cat) ± LPA (10 μM, 30 min), ±LPA1 /LPA3 receptor antagonist (Ki16425) or LPA2 receptor antagonist (H2L5186303). We analysed LPA receptor RNA and protein levels in human arterioles and human cultured endothelial cells. Key results FID was inhibited by L-NAME but not Peg-Cat in untreated vessels. In vessels treated with LPA, FID was of similar magnitude but inhibited by Peg-Cat while L-NAME had no effect. Rotenone attenuated FID in vessels treated with LPA indicating mitochondria as a source of ROS. RNA transcripts from LPA1 and LPA2 but not LPA3 receptors were detected in arterioles. LPA1 but not LPA3 receptor protein was detected by Western blot. Pretreatment of vessels with an LPA1 /LPA3 , but not LPA2 , receptor antagonist prior to LPA preserved NO-mediated dilation. Conclusions and implications These findings suggest an LPA1 receptor-dependent pathway by which LPA increases arteriolar release of mtH2 O2 as a mediator of FMD.

Mitochondria contribute to key processes of cellular function, while mitochondrial dysfunction is implicated in metabolic disorders, neurodegenerative diseases, and cardiovascular diseases, in which angiogenesis - the formation of new blood capillaries - is dysregulated. The Hippo signaling transducer, Yes-associated protein (YAP1) binds to the TEA domain (TEAD1) transcription factor and controls angiogenesis. YAP1 also regulates glucose metabolism through peroxisome proliferator-activated receptor gamma co-activator 1-alpha (PGC1α), a major player controlling mitochondrial biogenesis. However, the role of YAP1-TEAD1-PGC1α signaling in mitochondrial structure, cellular metabolism, and angiogenesis in endothelial cells (ECs) remains unclear. We now find that knockdown of TEAD1 decreases the expression of PGC1α and suppresses mitochondrial biogenesis, glycolysis, and oxygen consumption in ECs. A YAP1 mutant construct, YAP1S127A, which stimulates binding of YAP1 to TEAD1, upregulates the expression of PGC1α, induces mitochondrial biogenesis, and increases oxygen consumption and glycolytic flux in ECs; in contrast, YAP1S94A, which fails to bind to TEAD1, attenuates these effects. PGC1α knockdown inhibits YAP1S127A-induced EC sprouting in vitro and vascular morphogenesis in the fibrin gel subcutaneously implanted on mice, while overexpression of PGC1α reverses vascular morphogenesis suppressed by YAP1S94A. These results suggest that YAP1-TEAD1 signaling induces mitochondrial biogenesis in ECs and stimulates angiogenesis through PGC1α. Modulation of YAP1-TEAD1-PGC1α signaling in ECs may provide a novel intervention for angiogenesis-related diseases.

A rise in reactive oxygen species (ROS) may contribute to cardiovascular disease by reducing nitric oxide (NO) levels, leading to loss of NO’s vasodilator and anti-inflammatory effects. Although primarily studied in larger conduit arteries, excess ROS release and a corresponding loss of NO also occur in smaller resistance arteries of the microcirculation, but the underlying mechanisms and therapeutic targets have not been fully characterized. We examined whether either of the two subunits of telomerase, telomerase reverse transcriptase (TERT) or telomerase RNA component (TERC), affect microvascular ROS production and peak vasodilation at baseline and in response to in vivo administration to angiotensin II (ANG II). We report that genetic loss of TERT [maximal dilation: 52.0 ± 6.1% with vehicle, 60.4 ± 12.9% with Nω-nitro-l-arginine methyl ester (l-NAME), and 32.2 ± 12.2% with polyethylene glycol-catalase (PEG-Cat) ( P < 0.05), means ± SD, n = 9–19] but not TERC [maximal dilation: 79 ± 5% with vehicle, 10.7 ± 9.8% with l-NAME ( P < 0.05), and 86.4 ± 8.4% with PEG-Cat, n = 4–7] promotes flow-induced ROS formation. Moreover, TERT knockout exacerbates the microvascular dysfunction resulting from in vivo ANG II treatment, whereas TERT overexpression is protective [maximal dilation: 88.22 ± 4.6% with vehicle vs. 74.0 ± 7.3% with ANG II (1,000 ng·kg−1·min−1) ( P = not significant), n = 4]. Therefore, loss of TERT but not TERC may be a key contributor to the elevated microvascular ROS levels and reduced peak dilation observed in several cardiovascular disease pathologies. NEW & NOTEWORTHY This study identifies telomerase reverse transcriptase (TERT) but not telomerase RNA component as a key factor regulating endothelium-dependent dilation in the microcirculation. Loss of TERT activity leads to microvascular dysfunction but not conduit vessel dysfunction in first-generation mice. In contrast, TERT is protective in the microcirculation in the presence of prolonged vascular stress. Understanding the mechanism of how TERT protects against vascular stress represents a novel target for the treatment of vascular disorders.

BACKGROUND Sedentary behavior and obesity are major risk factors for cardiovascular disease. Regular physical activity has independent protective effects on the cardiovascular system, but the mechanisms responsible remain elusive. Recent studies suggest that the protein peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) participates in the response to exercise training. We hypothesized that the arterioles of athletes maintain dilation to flow despite combined inhibition of multiple vasodilators, but loss of PGC-1α renders these vessels susceptible to inhibition of a single vasodilator pathway. In addition, arterioles from overweight and obese individuals will display an an exercise-like phenotype when PGC-1α is activated. METHODS Isolated arterioles from exercise-trained (ET) and from mildly overweight or obese subjects (body mass index >25) were cannulated, and changes in lumen diameter in response to graded increases in flow were recorded in the absence and presence of compounds that inhibit various endothelium-dependent vasodilators. RESULTS Microvessels of ET subjects displayed robust dilation that could not be inhibited through targeting the combination of nitric oxide, prostaglandins, and hydrogen peroxide, but were inhibited via interference with membrane hyperpolarization. Loss of PGC-1α (siRNA) in the microcirculation of ET subjects eliminates this vasodilatory robustness rendering vessels susceptible to blockade of H2O2 alone. Pharmacological activation of PGC-1α with alpha-lipoic acid in isolated microvessels from sedentary, overweight, and obese subjects increases arteriolar resistance to vasodilator blockade and protects against acute increases in intraluminal pressure. CONCLUSIONS These findings suggest that the microvascular adaptations to exercise training, and the exercise-induced protection against acute vascular stress in overweight/obese subjects, are mediated by PGC-1α.

Blood flow through healthy human vessels releases NO to produce vasodilation, whereas in patients with coronary artery disease (CAD), the mediator of dilation transitions to mitochondria-derived hydrogen peroxide ( mt H 2 O 2 ). Excessive mt H 2 O 2 production contributes to a proatherosclerotic vascular milieu. Loss of PGC-1α (peroxisome proliferator–activated receptor γ coactivator 1α) is implicated in the pathogenesis of CAD. We hypothesized that PGC-1α suppresses mt H 2 O 2 production to reestablish NO-mediated dilation in isolated vessels from patients with CAD. Isolated human adipose arterioles were cannulated, and changes in lumen diameter in response to graded increases in flow were recorded in the presence of PEG (polyethylene glycol)–catalase (H 2 O 2 scavenger) or L-NAME ( N G -nitro- l -arginine methyl ester; NOS inhibitor). In contrast to the exclusively NO- or H 2 O 2 -mediated dilation seen in either non-CAD or CAD conditions, respectively, flow-mediated dilation in CAD vessels was sensitive to both L-NAME and PEG-catalase after PGC-1α upregulation using ZLN005 and α-lipoic acid. PGC-1α overexpression in CAD vessels protected against the vascular dysfunction induced by an acute increase in intraluminal pressure. In contrast, downregulation of PGC-1α in non-CAD vessels produces a CAD-like phenotype characterized by mt H 2 O 2 -mediated dilation (no contribution of NO). Loss of PGC-1α may contribute to the shift toward the mt H 2 O 2 -mediated dilation observed in vessels from subjects with CAD. Strategies to boost PGC-1α levels may provide a therapeutic option in patients with CAD by shifting away from mt H 2 O 2 -mediated dilation, increasing NO bioavailability, and reducing levels of mt H 2 O 2 . Furthermore, increased expression of PGC-1α allows for simultaneous contributions of both NO and H 2 O 2 to flow-mediated dilation.

Purpose: The purpose of this study was to determine whether increased intraluminal pressure is the damaging factor that reduces flow-mediated dilation (FMD) in young, healthy subjects after resistance exercise to maximal exertion. Hypothesis: Attenuating the rise in brachial artery pressure during weight lifting by placing a blood pressure cuff on the upper arm prevents postexercise impairment of brachial artery FMD in sedentary individuals. Methods: Nine sedentary individuals who exercise once a week or less and six exercise-trained individuals who exercise three times a week or more performed leg press exercise to maximal exertion on two separate occasions. During one visit, a blood pressure cuff, proximal to the site of brachial artery measurement, was inflated to 100 mm Hg to protect the distal vasculature from the rise in intraluminal pressure, which occurs during resistance exercise. Brachial artery FMD was determined using ultrasonography before and 30 min after weight lifting. Results: Without the protective cuff, brachial artery FMD in sedentary individuals was reduced after weight lifting (9.0% ± 1.2% prelift vs 6.6% ± 0.8% postlift; P = 0.005), whereas in exercise-trained individuals, FMD was unchanged (7.4% ± 0.7% prelift vs 8.0% ± 0.9% postlift; P = 0.543). With the protective cuff, FMD no longer decreased but rather increased in sedentary individuals (8.7% ± 1.2% prelift vs 10.5% ± 1.0% postlift, P = 0.025). An increase in FMD was also seen in exercise-trained subjects when the cuff was present (6.6% ± 0.7% prelift vs 10.9% ± 1.5% postlift, P < 0.001). Conclusion: Protecting the brachial artery from exercise-induced hypertension enhances FMD in sedentary and exercise-trained individuals. These results indicate that increased intraluminal pressure in the artery contributes to the reduced FMD after heavy resistance exercise in sedentary individuals.

The microcirculation maintains tissue homeostasis through local regulation of blood flow and oxygen delivery. Perturbations in microvascular function are characteristic of several diseases and may be early indicators of pathological changes in the cardiovascular system and in parenchymal tissue function. These changes are often mediated by various reactive oxygen species and linked to disruptions in pathways such as vasodilation or angiogenesis. This overview compiles recent advances relating to redox regulation of the microcirculation by adopting both cellular and functional perspectives. Findings from a variety of vascular beds and models are integrated to describe common effects of different reactive species on microvascular function. Gaps in understanding and areas for further research are outlined. © 2020 American Physiological Society. Compr Physiol 10:229-260, 2020.

Homeostasis is maintained within organisms through the physiological recycling process of autophagy, a catabolic process that is intricately involved in the mobilization of nutrients during starvation, recycling of cellular cargo, as well as initiation of cellular death pathways. Specific to the cardiovascular system, autophagy responds to both chemical (e.g. free radicals) and mechanical stressors (e.g. shear stress). It is imperative to note that autophagy is not a static process, and measurement of autophagic flux provides a more comprehensive investigation into the role of autophagy. The overarching themes emerging from decades of autophagy research are that basal levels of autophagic flux are critical, physiological stressors may increase or decrease autophagic flux, and more importantly, aberrant deviations from basal autophagy may elicit detrimental effects. Autophagy has predominantly been examined within cardiac or vascular smooth muscle tissue within the context of disease development and progression. Autophagic flux within the endothelium holds an important role in maintaining vascular function, demonstrated by the necessary role for intact autophagic flux for shear-induced release of nitric oxide however the underlying mechanisms have yet to be elucidated. Within this review, we theorize that autophagy itself does not solely control vascular homeostasis, rather, it works in concert with mitochondria, telomerase, and lipids to maintain physiological function. The primary emphasis of this review is on the role of autophagy within the human vasculature, and the integrative effects with physiological processes and diseases as they relate to the vascular structure and function.

Background Elevated levels of ceramide, a sphingolipid known to cause a transition from nitric oxide (NO)– to hydrogen peroxide–dependent flow‐induced dilation ( FID ) in human arterioles, correlate with adverse cardiac events. However, elevations of ceramide are associated with changed concentrations of other sphingolipid metabolites. The effects of sphingolipid metabolites generated through manipulation of this lipid pathway on microvascular function are unknown. We examined the hypothesis that inhibition or activation of the ceramide pathway would determine the mediator of FID . Methods and Results Using videomicroscopy, internal diameter changes were measured in human arterioles collected from discarded adipose tissue during surgery. Inhibition of neutral ceramidase, an enzyme responsible for the hydrolysis of ceramide, favored hydrogen peroxide–dependent FID in arterioles from healthy patients. Using adenoviral technology, overexpression of neutral ceramidase in microvessels from diseased patients resulted in restoration of NO ‐dependent FID . Exogenous sphingosine‐1‐phosphate, a sphingolipid with opposing effects of ceramide, also restored NO as the mediator of FID in diseased arterioles. Likewise, exogenous adiponectin, a known activator of neutral ceramidase, or, activation of adiponectin receptors, favored NO ‐dependent dilation in arterioles collected from patients with coronary artery disease. Conclusions Sphingolipid metabolites play a critical role in determining the mediator of FID in human resistance arterioles. Manipulating the sphingolipid balance towards ceramide versus sphingosine‐1‐phosphate favors microvascular dysfunction versus restoration of NO ‐mediated FID , respectively. Multiple targets exist within this biolipid pathway to treat microvascular dysfunction and potentially improve patient outcomes.

Background: Preeclampsia (PreE) is a significant global health burden which impacts 10 million pregnancies annually resulting in over a half million lost lives. Mitochondrial damage has previously been demonstrated to be present in PreE. A novel relationship may exist between preeclampsia and mitochondrial damage via the release of cell-free mitochondrial DNA (cf-mtDNA). Previous work in models of systemic hypertension shows cf-mtDNA mediated activation of TLR9 to be a key part of disease development. We aim to evaluate the level of TLR9 activation and ROS production in patients with and without PreE. Methods: To investigate whether PreE plasma contains increased levels of cell free DNA that can activate TLR9, HEK-Blue TM -hTLR9 reporter cell line (Invivogen) was treated with 3% plasma from either control or PreE patients. The TLR9 activator ODN2006 served as positive control (Fig.1, A&B). To investigate whether PreE plasma can stimulate production of ROS, HUVECs were treated in similar fashion and ROS was evaluated using Mitosox TM (Fig. 1, C&D). Results: Cells treated with PreE plasma demonstrated a 1.7-fold increase in TLR9 activation vs control (p=0.005, Fig. 1A&B). In addition, Mitosox TM signal indicated a 1.8-fold increase in ROS in PreE vs. control (p=0.066, Fig. 1C&D). Conclusion: We conclude that plasma from PreE patients contains higher levels of cf-mtDNA that stimulates inflammation response via TLR9 that promotes mitochondrial ROS production. This mechanism may present a novel target for treatment of Pre-E.

Chemotherapy (CT) is a necessary treatment to prevent the growth and survival of cancer cells. However, CT has a well-established adverse impact on the cardiovascular (CV) system, even years after cessation of treatment. The effects of CT drugs on tumor vasculature have been the focus of much research, but little evidence exists showing the effects on the host microcirculation. Microvascular (MV) dysfunction is an early indicator of numerous CV disease phenotypes, including heart failure. The goal of this study was to evaluate the direct effect of doxorubicin (Dox) on human coronary MV function. To study the effect of CT on the cardiac MV function, flow-mediated dilation (FMD), pharmacologically-induced endothelial dependent dilation to acetylcholine (ACh), and smooth muscle-dependent dilation to papaverine were investigated. Vessels were freshly isolated from atrial appendages of adult patients undergoing cardiopulmonary bypass surgery or from cardiac tissue of pediatric patients, collected at the time of surgery to repair congenital heart defects. Isolated vessels were incubated in endothelial culture medium containing vehicle or Dox (100 nm, 15–20 h) and used to measure dilator function by video microscopy. Ex vivo treatment of adult human coronary microvessels with Dox significantly impaired flow-mediated dilation (FMD). Conversely, in pediatric coronary microvessels, Dox-induced impairment of FMD was significantly reduced in comparison with adult subjects. In both adult and pediatric coronary microvessels, ACh-induced constriction was reversed into dilation in the presence of Dox. Smooth muscle-dependent dilation remained unchanged in all groups tested. In vessels from adult subjects, acute treatment with Dox in clinically relevant doses caused significant impairment of coronary arteriolar function, whereas vessels from pediatric subjects showed only marginal impairment to the same stressor. This interesting finding might explain the delayed onset of future adverse CV events in children compared with adults after anthracycline therapy. NEW & NOTEWORTHY We have characterized, for the first time, human microvascular responses to acute ex vivo exposure to doxorubicin in coronary vessels from patients without cancer. Our data show an augmented impairment of endothelial function in vessels from adult subjects compared with pediatric samples.

Background We developed a new left ventricular hypertrophy ( LVH ) criterion using a machine‐learning technique called Bayesian Additive Regression Trees ( BART ). Methods and Results This analysis included 4714 participants from MESA (Multi‐Ethnic Study of Atherosclerosis) free of clinically apparent cardiovascular disease at enrollment. We used BART to predict LV mass from ECG and participant characteristics using cardiac magnetic resonance imaging as the standard. Participants were randomly divided into a training set (n=3774) and a validation set (n=940). We compared the diagnostic/prognostic performance of our new BART ‐ LVH criteria with traditional ECG ‐ LVH criteria and cardiac magnetic resonance imaging– LVH . In the validation set, BART ‐ LVH showed the highest sensitivity (29.0%; 95% CI , 18.3%–39.7%), followed by Sokolow‐Lyon‐ LVH (21.7%; 95% CI , 12.0%–31.5%), Peguero–Lo Presti (14.5%; 95% CI , 6.2%–22.8%), Cornell voltage product (10.1%; 95% CI , 3.0%–17.3%), and Cornell voltage (5.8%; 95% CI , 0.3%–11.3%). The specificity was >93% for all criteria. During a median follow‐up of 12.3 years, 591 deaths, 492 cardiovascular disease events, and 332 coronary heart disease events were observed. In adjusted Cox models, both BART ‐ LVH and cardiac magnetic resonance imaging– LVH were associated with mortality (hazard ratio [95% CI ], 1.88 [1.45–2.44] and 2.21 [1.74–2.81], respectively), cardiovascular disease events (hazard ratio [95% CI ], 1.46 [1.08–1.98] and 1.91 [1.46–2.51], respectively), and coronary heart disease events (hazard ratio [95% CI ], 1.72 [1.20–2.47] and 1.96 [1.41–2.73], respectively). These associations were stronger than associations observed with traditional ECG ‐ LVH criteria. Conclusions Our new BART ‐ LVH criteria have superior diagnostic/prognostic ability to traditional ECG ‐ LVH criteria and similar performance to cardiac magnetic resonance imaging– LVH for predicting events.

Obesity is associated with microvascular dysfunction. While low-fat diet improves cardiovascular risk, its contributions on microvascular function, independent of weight loss, is unknown. We tested the hypothesis that nitric oxide (NO)-dependent vasodilation in microvessels is improved by low-fat diets designed for weight loss (LFWL) compared to low-fat weight maintenance (LFWM) diet. Obese adults were randomly assigned to either a LFWL diet (n = 11) or LFWM diet (n = 10) for six weeks. Microvessels were obtained from gluteal subcutaneous fat biopsies before and after the intervention for vascular reactivity measurements to acetylcholine (Ach) and flow, with and without L-NAME or indomethacin. Vascular and serum NO and C-reactive protein (CRP) were also measured. LFWL diet increased flow-induced (FID) and ACh-induced dilation (AChID), an effect that was inhibited by L-NAME. Conversely, LFWM diet did not affect FID or AChID. Indomethacin improved FID and AChID in the baseline and this effect was minimized in response to both diets. Serum NO or CRP did not change in response to either diet. In conclusion, LFWL diet improves microvascular reactivity compared to LFWM diet and increased vascular NO contribution to the improved microvascular dilation. These data suggest that weight reduction on low fat diet is critical for microvascular health.

Angiogenesis - the growth of new blood capillaries- is impaired in aging animals. Biophysical factors such as changes in cell size control endothelial cell (EC) proliferation and differentiation. However, the effects of aging on EC size and the mechanism by which changes in cell size control age-dependent decline in EC proliferation are largely unknown. Here, we have demonstrated that aged ECs are larger than young ECs and that age-dependent increases in EC size control EC proliferation and senescence through CDC42-Yes-associated protein (YAP1) signaling. Reduction of aged EC size by culturing on single-cell sized fibronectin-coated smaller islands decreases CDC42 activity, stimulates YAP1 nuclear translocation and attenuates EC senescence. Stimulation of YAP1 or inhibition of CDC42 activity in aged ECs also restores blood vessel formation. Age-dependent changes in EC size and/or CDC42 and YAP1 activity may be the key control point of age-related decline in angiogenesis.

Introduction: Brachial artery flow mediated dilation (FMD) is a well-established measure of vascular endothelial health and is pathologically low in chronic stroke survivors. Ischemic conditioning (IC) is a cardioprotective stimulus and has been shown to improve FMD and enhance motor function in healthy humans. We recently showed that IC can improve paretic muscle strength and increase self-selected walking speed in stroke survivors. These improvements could be, in part, mediated by improved peripheral vascular function and increased blood flow to the exercising muscle. The effects of IC on vascular endothelial function post-stroke have not been investigated. Hypothesis: Two weeks of IC on the paretic leg of chronic stroke survivors will improve FMD in the non-paretic brachial artery. Methods: This was a prospective, randomized, blinded and controlled pilot study. Twenty chronic stroke survivors (>1-year post-stroke) received either IC (cuff inflation on the paretic leg for five minutes to 225 mmHg) or Sham IC (cuff inflation to 10 mmHg) every other day for two weeks (five on-off cycles per session). Brachial artery FMD was assessed using ultrasonography within 48 hours of the beginning and end of the intervention period. Results: Eight men and twelve women participated in this study. The mean age was 59 ± 16 years and the mean time post-stroke was 9 ± 9 years. Brachial artery FMD increased in the IC group from 6.2 ± 4.9% to 8.9 ± 3.9% (n=10; p=0.023, 2-way Repeated Measures ANOVA) while no change was observed in the Sham IC group (pre- vs. post = 3.8 ± 3.9% vs. 2.7 ± 3.1%, respectively; p=0.32, n=10). Expressed as the mean change in FMD, IC increased FMD by 2.8 ± 3.7% while no change was observed in the Sham IC group (delta FMD = -1.1 ± 3.4%; p=0.024 IC vs. IC Sham, unpaired t-test). Conclusions: Two weeks of IC increases brachial artery FMD in chronic stroke survivors. Taken together with our previous work that shows IC increases paretic muscle strength and walking speed in chronic stroke survivors, IC has the potential to improve both motor and cardiovascular function post-stroke. Future larger studies are needed to evaluate the efficacy of IC to improve stroke recovery and to identify the pathways involved which confer benefit to both the nervous and cardiovascular systems.

Background Impaired microvascular function leads to a poor outcome in a variety of medical conditions. Our aim was to determine whether vasodilator responses to acetylcholine (Ach) are impaired in human omental arterioles from patients with severe trauma. Materials and methods Patients with massive blood loss and severe shock requiring damage control procedures were included. Tissues were collected at the first (FEL) and the second explorative laparotomy (SEL). Control tissues were collected from nontrauma patients. Freshly isolated 50–200-μm-diameter omental arterioles were analysed using videomicroscopy. Dihydroethidine and DCF-DA fluorescence were used to assess reactive oxygen species (ROS) production. MnTBAP was used to determine the contribution of excess vascular superoxide contribution to endothelial dysfunction. Results After constriction (30–50%) with endothelin-1, dilation to graded doses of Ach (10−9–10−4 M) was greater in control vessels compared to FEL and SEL (max dilation at 10−4 M (MD) = 25 ± 3%, n = 8; and 59 ± 8%, n = 8, respectively, and controls MD = 93 ± 10%, n = 6, P < 0·05). Fluorescence imaging of ROS production showed significant increases in superoxide (225·46 ± 12·86; 215·77 ± 10·75 vs. 133·75 ± 7·26, arbitrary units; P < 0·05) and peroxide-related ROS (240·8 ± 20·42; 234·59 ± 28·86, vs. 150·78 ± 15·65, arbitrary units; P < 0·05), in FEL and SEL microvessels compared to control, respectively. FEL pretreated with MnTBAP demonstrated significant improvement in Ach-induced vasodilation (25·5 ± 3·0% vs. 79·5 ± 8·2%; P < 0·05). Conclusions Severe shock associated with microvascular endothelial dysfunction enhances production of ROS in human omental tissues. The altered flow regulation may contribute to a mismatch between local blood supply and demand, exacerbating abnormal tissue perfusion and function.

Objective— This study examined vascular actions of angiotensin 1–7 (ANG 1–7) in human atrial and adipose arterioles. Approach and Results— The endothelium-derived hyperpolarizing factor of flow-mediated dilation (FMD) switches from antiproliferative nitric oxide (NO) to proatherosclerotic hydrogen peroxide in arterioles from humans with coronary artery disease (CAD). Given the known vasoprotective properties of ANG 1–7, we tested the hypothesis that overnight ANG 1–7 treatment restores the NO component of FMD in arterioles from patients with CAD. Endothelial telomerase activity is essential for preserving the NO component of vasodilation in the human microcirculation; thus, we also tested whether telomerase activity was necessary for ANG 1–7–mediated vasoprotection by treating separate arterioles with ANG 1–7±the telomerase inhibitor 2-[[(2E)-3-(2-naphthalenyl)-1-oxo-2-butenyl1-yl]amino]benzoic acid. ANG 1–7 dilated arterioles from patients without CAD, whereas dilation was significantly reduced in arterioles from patients with CAD. In atrial arterioles from patients with CAD incubated with ANG 1–7 overnight, the NO synthase inhibitor NG-nitro- l -arginine methyl ester abolished FMD, whereas the hydrogen peroxide scavenger polyethylene glycol catalase had no effect. Conversely, in vessels incubated with ANG 1–7+2-[[(2E)-3-(2-naphthalenyl)-1-oxo-2-butenyl1-yl]amino]benzoic acid, NG-nitro- l -arginine methyl ester had no effect on FMD, but polyethylene glycol catalase abolished dilation. In cultured human coronary artery endothelial cells, ANG 1–7 significantly increased telomerase activity. These results indicate that ANG 1–7 dilates human microvessels, and dilation is abrogated in the presence of CAD. Furthermore, ANG 1–7 treatment is sufficient to restore the NO component of FMD in arterioles from patients with CAD in a telomerase-dependent manner. Conclusions— ANG 1–7 exerts vasoprotection in the human microvasculature via modulation of telomerase activity.