Coronary Artery Endothelial Function Research Articles

Urocortin2 attenuates diabetic coronary microvascular dysfunction by regulating macrophage extracellular vesicles

Diabetic patients develop coronary microvascular dysfunction (CMD) and exhibit high mortality of coronary artery disease. Methylglyoxal (MGO) largely accumulates in the circulation due to diabetes. We addressed whether macrophages exposed to MGO exhibited damaging effect on the coronary artery and whether urocortin2 (UCN2) serve as protecting factors against such diabetes-associated complication. Type 2 diabetes was induced by high-fat diet and a single low-dose streptozotocin in mice. Small extracellular vesicles (sEV) derived from MGO-treated macrophages (MGO-sEV) were used to produce diabetes-like CMD. UCN2 was examined for a protective role against CMD. The involvement of arginase1 and IL-33 was tested by pharmacological inhibitor and IL-33-/- mice. MGO-sEV was capable of causing coronary artery endothelial dysfunction similar to that by diabetes. Immunocytochemistry studies of diabetic coronary arteries supported the transfer of arginase1 from macrophages to endothelial cells. Mechanism studies revealed arginase1 contributed to the impaired endothelium-dependent relaxation of coronary arteries in diabetic and MGO-sEV-treated mice. UCN2 significantly improved coronary artery endothelial function, and prevented MGO elevation in diabetic mice or enrichment of arginase1 in MGO-sEV. Diabetes caused a reduction of IL-33, which was also reversed by UCN2. IL-33-/- mice showed impaired endothelium-dependent relaxation of coronary arteries, which can be mitigated by arginase1 inhibition but can’t be improved by UCN2 anymore, indicating the importance of restoring IL-33 for the protection against diabetic CMD by UCN2. Our data suggest that MGO-sEV induces CMD via shuttling arginase1 to coronary arteries. UCN2 is able to protect against diabetic CMD via modulating MGO-altered macrophage sEV cargoes.

Coronary artery endothelial function and aging in people with HIV and HIV-negative individuals.

Coronary artery disease (CAD) is a common comorbidity in people with human immunodeficiency virus (HIV) (PWH) and impaired coronary endothelial function (CEF) plays a central role in the pathogenesis of CAD. Age-related impaired CEF among PWH, however, is not well characterized. We investigated the association between CEF and age in males and females with and without HIV using 3-T magnetic resonance imaging (MRI). We measured the changes in coronary cross-sectional area (CSA) and coronary blood flow during isometric handgrip exercise (IHE), an established endothelial-dependent stressor with smaller increases in CSA and coronary blood flow indicative of impaired CEF. We included 106 PWH and 82 individuals without HIV. Differences in demographic and clinical characteristics between PWH and individuals without HIV were explored using Pearson's χ2 test for categorical variables and Welch's t test for continuous variables. Linear regression models were used to examine the association between CEF and age. CEF was significantly lower in PWH as compared with individuals without HIV. Coronary endothelial dysfunction was also present at younger ages in PWH than in the individuals without HIV and there were significant differences in CEF between the PWH and individuals without HIV across age groups. Among the individuals without HIV, the percent changes in CSA were inversely related to age in unadjusted and adjusted models. There was no significant association between CEF and age in PWH. To the best of our knowledge, this is the first study to examine the relationship between age and CEF in PWH, and our results suggest that factors other than age significantly impair CEF in PWH across the life span.NEW & NOTEWORTHY This is the first study to examine the relationship between age and coronary endothelial function (CEF) in people with human immunodeficiency virus (HIV) (PWH). CEF was assessed using magnetic resonance imaging (MRI) in people with and without HIV. Although age and CEF were significantly inversely related in individuals without HIV, there was no association between age and CEF in PWH.

GYY4137, a hydrogen sulfide donor, protects against endothelial dysfunction in porcine coronary arteries exposed to myeloperoxidase and hypochlorous acid

Background and aimsMyeloperoxidase (MPO) and its principal reaction product hypochlorous acid (HOCl) are part of the innate immune response but are also associated with endothelial dysfunction, thought to involve a reduction in nitric oxide (NO) bioavailability. We aimed to investigate the effect of MPO and HOCl on vasorelaxation of coronary arteries and to assess directly the involvement of NO. In addition, we hypothesised that the slow release hydrogen sulfide (H2S) donor GYY4137 would salvage coronary artery endothelial function in the presence of MPO and HOCl. Methods and resultsContractility of porcine coronary artery segments was measured using isometric tension recording. Incubation with MPO (50 ng/ml) plus hydrogen peroxide (H2O2) (30 μM; substrate for MPO) impaired endothelium-dependent vasorelaxation to bradykinin in coronary arteries. HOCl (10–500 μM) also impaired endothelium-dependent relaxations. There was no effect of MPO plus H2O2, or HOCl, on endothelium-independent relaxations to 5′-N-ethylcarboxamidoadenosine and sodium nitroprusside. L-NAME (300 μM), a NO synthase inhibitor, attenuated bradykinin relaxations, leaving L-NAME-resistant relaxations to bradykinin mediated by endothelium-dependent hyperpolarization. In the presence of L-NAME, MPO plus H2O2 largely failed to impair endothelium-dependent relaxations to bradykinin. Similarly, HOCl failed to inhibit endothelium-dependent relaxations to bradykinin in the presence of L-NAME. GYY4137 (1–100 μM) protected endothelium-dependent relaxations to bradykinin from dysfunction caused by MPO plus H2O2, and HOCl, with no effect alone on bradykinin relaxation responses. The specific MPO inhibitor aminobenzoic acid hydrazide (ABAH) (1 and 10 μM) also protected against MPO plus H2O2-induced endothelial dysfunction (at 10 μM ABAH), but was less potent than GYY4137. ConclusionsMPO plus H2O2, and HOCl, impair coronary artery endothelium-dependent vasorelaxation via inhibition of NO. GYY4137 protects against endothelial dysfunction in arteries exposed to MPO plus H2O2, and HOCl. H2S donors such as GYY4137 are possible therapeutic options to control excessive MPO activity in cardiovascular diseases.

Endothelial and Hemodynamic Function in a Large Animal Model in Relation to Different Extracorporeal Membrane Oxygenation Cannulation Strategies and Intra-Aortic Balloon Pumping.

The use of simultaneous veno-arterial extracorporeal membrane oxygenation (ECMO) with or without an Intra-Aortic Balloon Pump (IABP) is a widely used tool for mechanical hemodynamic support. Endothelial function, especially in relation to different cannulation techniques, is rarely investigated in the setting of extracorporeal life support (ECLS). In this study, we analyzed endothelial function in relation to hemodynamic and laboratory parameters for central and peripheral ECMO, with or without concomitant IABP support in a large animal model to gain a better understanding of the underlying basic mechanisms. In this large animal model, healthy female pigs with preserved ejection fraction were divided into the following groups related to cannulation strategy for ECMO and simultaneous IBAP support: control (no ECMO, no IABP), peripheral ECMO (pECMO), central ECMO (cECMO), pECMO and IABP or cECMO and IABP. During the experimental setting, the blood flow in the ascending aorta, left coronary artery and arteria carotis was measured. Afterwards, endothelial function was investigated after harvesting the right coronary artery, arteria carotis and renal artery. In addition, laboratory markers, such as creatine kinase (CK), creatine kinase muscle-brain (CK-MB), troponin, creatinine and endothelin were analyzed. The blood flow in the ascending aorta and the left coronary artery was significantly lower in all discussed experimental settings compared to the control group. Of note, the cECMO cannulation strategy generated favorable hemodynamic circumstances with higher blood flow in the coronary arteries than pECMO regardless of flow circumstances in the ascending aorta. The concomitant usage of IABP did not result in an improvement of the coronary blood flow, but partially showed a negative impact on the endothelial function of coronary arteries in comparison to the control. These findings correlate to higher CK/CK-MB levels in the setting of cECMO + IABP and pECMO + IABP. The usage of mechanical circulatory support with concomitant ECMO and IABP in a large animal model might have an influence on the endothelial function of coronary arteries while not improving the coronary artery perfusion in healthy hearts with preserved ejection.

Coronary Endothelial Dysfunction in People Living With HIV Is Related to Body Fat Distribution.

People living with HIV (PLWH) on antiretroviral therapy (ART) are at increased risk of atherosclerotic disease. Abnormal adipose distribution is common in PLWH and may contribute to atherosclerosis. Because coronary artery endothelial function (CEF) is impaired in early atherosclerosis, predicts future cardiovascular events, and is reduced in PLWH, we investigated associations between body fat distribution and CEF in PLWH. Prospective cohort study. PLWH on stable ART underwent MRI to quantify CEF, measured as change in coronary cross-sectional area from rest to that during isometric handgrip exercise, an endothelial-dependent stressor. Abdominal visceral and subcutaneous fat area (axial L4 level) and liver fat fraction were quantified using MRI. Linear regression was used to determine associations between CEF and independent variables. Among 84 PLWH (52 ± 11 years; 33% women), mean cross-sectional area change was 0.74 ± 11.7%, indicating impaired CEF. On univariable regression analysis, CEF was inversely related to waist circumference (R = -0.31, P = 0.014), hip circumference (R = -0.27, P = 0.037), and subcutaneous fat area (R = -0.25, P = 0.031). We did not observe significant relationships between CEF and liver fat fraction, waist/hip ratio, or visceral fat area. On multivariable regression adjusted for age, sex, and race, CEF was associated with waist circumference, hip circumference, subcutaneous fat, and liver fat fraction. Waist and hip circumference and subcutaneous fat area are associated with impaired CEF, an established metric of abnormal vascular health in PLWH on stable ART, and may contribute to the increased rate of heart disease in this population.

Prenatal Hypoxia is Associated with Coronary Artery Endothelial Dysfunction in Male and Female Offspring

IntroductionFetal hypoxia is a common consequence of complicated pregnancies and is linked to the development of cardiovascular (CV) dysfunction in the offspring. We showed an impaired cardiac function in adult prenatal hypoxia offspring, however, the mechanisms are not known. Coronary artery endothelial dysfunction has been shown to contribute to the development of cardiac dysfunction, however, whether endothelial function is impaired in coronary arteries of prenatal hypoxia offspring is unknown. We hypothesize that prenatal hypoxia leads to impaired coronary artery endothelial function in adult male and female offspring.MethodsPregnant Sprague‐Dawley rats were exposed to normoxia (21% O2) or hypoxia (11% O2; p‐Hyp) on gestational days 15‐21 (term=22 days). Male and female offspring were aged to 9‐9.5 months. Left anterior descending coronary arteries were isolated (n=5‐7/group), and endothelium‐dependent vasodilation to methylcholine (MCh) and endothelium‐independent vasodilation to the nitric oxide (NO) donor sodium nitroprusside (SNP) were assessed by wire myography. To assess the contribution of endothelial vasodilation pathways, MCh‐curves were performed in the presence/absence of inhibitors of nitric oxide synthase (L‐NAME), prostaglandin H synthase ([PGHS]; meclofenamate), or small‐ and intermediate‐conductance Ca2+‐activated potassium channels (apamin and TRAM‐34, respectively). Data were summarized as Emax (maximum vasodilation response), pEC50 (concentration required to produce 50% of Emax) or Area Under the Curve (AUC). Data were compared by two‐way ANOVA (Sidak's post hoc test); p<0.05 was significant.ResultsMch‐induced vasodilation (Emax) was decreased in p‐Hyp males (p=0.006) and females (p=0.032) compared to normoxia offspring. L‐NAME completely inhibited vasodilation (AUC) in normoxia and p‐Hyp males (p<0.0001). In the female offspring, incubation with L‐NAME completely inhibited vasodilation in the normoxia group (p<0.0001), but to a lesser extent (Emax ~15%) in the p‐Hyp offspring (p<0.0001). In contrast, meclofenamate did not alter MCh‐induced vasodilation (AUC) in males, while in females, meclofenamate increased vasodilation to MCh in the p‐Hyp group only (p=0.04). Apamin and TRAM‐34 did not alter responses to MCh in any of the groups. SNP sensitivity (pEC50) was decreased in p‐Hyp females compared to normoxia controls (p=0.012), without changes in males.ConclusionsOur data suggest that prenatal hypoxia leads to coronary artery endothelial dysfunction in male and female offspring. In prenatal hypoxia males, NO contribution to endothelium‐mediated vasodilation was reduced. In females, prenatal hypoxia increased PGHS‐dependent vasoconstriction and decreased smooth muscle sensitivity to NO. Understanding the mechanistic pathways involved in programming of CV disease may allow for the development of future prenatal and postnatal therapeutic interventions.

Features of endothelial function and autonomic regulation of heart rhytm in patients with vasospastic angina

BACKGROUND: The clinical features of vasospastic angina are well known, but pathogenesis remains a subject of discussion. Changes in the autonomic regulation of coronary artery tone and endothelial function that contribute to the development of vasospasm are not well understood. The data on the subject from the published studies are contradictory.
 AIM: To evaluate features of endothelial function and autonomic regulation of heart rhythm in patients with vasospastic angina.
 MATERIALS AND METHODS: The study included 16 patients with proven vasospastic angina. All the patients have been evaluated for the heart rate variability at rest and vegetative tests (deep breathing, and active standing tests). Endothelial function has been assessed in terms of reactive hyperemia index by peripheral arterial tonometry using an Endo-PAT 2000 device.
 RESULTS: The baseline of the total heart rate variability was borderline with the normal parameters SDNN 50 (32.5; 50) ms in the patients with vasospastic angina. There were 14 patients who have demonstrated an imbalance of the autonomic nervous system at rest, mainly due to an increase of parasympathetic influences. The appropriate reaction of the autonomic nervous system, characterized by an increase of vagal influences, has been determined in 13 patients in the deep-breathing test. A paradoxical reaction, characterized by an increase of vagal influences on the heart rhythm, has been registered in 13 patients in the active standing tests. Endothelial dysfunction has been observed in half of the studied patients. Furthermore, a combination of both pathophysiological mechanisms, i.e., endothelial and autonomic dysfunctions have been observed in all the patients with a reduced reactive hyperemia index.
 CONCLUSIONS: According to the results of our study, the parasympathetic influences of the autonomic nervous system on the heart rhythm were predominant in the patients with vasospastic angina, which is not typical for coronary heart disease. All the patients had autonomic or endothelial dysfunction. A combination of both pathophysiological mechanisms has been observed in half of the examined patients.

Characteristics of coronary flow velocity reserve on transthoracic Doppler echocardiography in patients with a history of Kawasaki disease.

The coronary flow velocity reserve of the left anterior descending artery was examined by transthoracic Doppler echocardiography in 189 patients (male 125, female 64) with a history of Kawasaki disease and 10 volunteers (control). Their ages ranged from 6 to 40 years (median 22 years). The patients were divided into nine groups based on the left anterior descending artery lesions. The coronary flow velocity reserve was measured by intravenous administration of adenosine triphosphate (0.15 mg/kg/minute) while fasting. The coronary flow velocity reserve was calculated as the ratio of hyperaemic to basal mean diastolic flow velocities. The respective groups were as follows: control, no coronary artery lesions (n = 39), no coronary artery lesions in the right coronary artery (n = 29), regression (n = 11), aneurysm at the bifurcation of the left coronary artery (n = 26), aneurysm of the left anterior descending artery (n = 15), localised stenosis <75% (n = 12), localised stenosis ≥75% (n = 17), segmental stenosis (n = 5) and coronary artery bypass grafting (n = 36). One-factor ANOVA followed by Tukey's test was used to compare the coronary flow velocity reserve among the groups. The coronary flow velocity reserve was significantly lower in the localised stenosis ≥75%, segmental stenosis and coronary artery grafting groups than in the other groups (p < 0.05). The endothelial function in the epicoronary artery was preserved in patients with a history of Kawasaki disease and dilated coronary artery lesions.

4. HYPERTENSION RISK ASSOCIATION TO CORONARY HEART DISEASES IN OBESITY PATIENTS AT PUBLIC HOSPITALS OF THE CHRISTIAN UNIVERSITY OF INDONESIA FOR THE YEAR 2019

Background: Modern developments have influenced various fields. Especially changes in lifestyle to diet. Modern lifestyle and diet are starting to appear to increase the risk of cardiovascular disease, one of which is coronary heart disease. According to the World Health Organization (WHO), in 2012 Coronary Heart Disease (CHD) is one of the most common cardiovascular diseases and is a cause of death globally with a high enough figure, scoring 7.4 million and increasing every day. In Indonesia, the prevalence of CHD cases is quite high for cardiovascular disease, amounting to 1.5% in 2013. According to age groups, CHD occurs mostly in age groups. 65-74 years (3.6%) age group 75 years and over (3.2%), age group 55-64 years (2.1%) and age group 35-44 years (1.3%). Obesity is one of the risk factors in the increased incidence of CHD. According to Jean Vaguen, there is a close relationship between differences in body morphology or distribution of body fat with health problems related to obesity risk factors. Obesity caused by excessive fat accumulation. Heart and Blood Vessel Disease which is caused by the accumulation of fat in the central part of the body. Another risk factor is hypertension. Hypertension can cause atherosclerosis in the coronary blood vessels in various ways, affecting the force of blood flow, coronary artery endothelial function, permeability of blood vessel walls, adhesiveness of platelets, and remodeling of blood vessels Objective: To study the association of hypertension risk factors in patients with coronary heart disease and obesity at the Hospital of the Faculty of Medicine, Christian University of Indonesia, Jakarta. Method: This type of research is an observational study. This study only made observations to patients and did not provide any treatment to patients. The research design used was cross sectional. Research Location: General Hospital of Christian University of Indonesia, Time of study: April to June 2020 The target population in this study were patients with coronary heart disease, both outpatient and inpatient. The sample selection used purposive sampling method. Conclusion: There is a significant relationship between hypertension, hypercholesterolemia, and diabetes on CHD in obese patients at the General Hospital of the Christian University of Indonesia, Jakarta for the period 2019.

Endothelial Function in Coronary Arteries from Pneumonia-Infected Pigs

This study investigated whether pneumonia is accompanied with endothelial dysfunction in coronary arteries. The lungs and hearts of normal and Mycoplasma hyopneumoniae-infected pigs (6-month-old females and castrated males) were obtained from a local abattoir, and left anterior descending coronary arteries were isolated from the hearts. Lymphocyte infiltration was observed in the lung tissue of pneumonia-infected pigs (PP). However, the histopathological images of coronary arteries in PP were not different from the images in normal pigs (NP). In organ chamber experiments, endothelium-dependent relaxation of coronary arteries by bradykinin (0.1 nM–0.1 μM) and A23187 (1 nM–1 μM) were identical between PP and NP; the relaxant responses were not different even in the presence of L-NAME (100 μM, nitric oxide synthase inhibitor) alone or in combination with indomethacin (10 μM, cyclooxygenase inhibitor). In addition, the relaxant responses to nitric oxide [sodium nitroprusside (1 nM–10 μM)], hydrogen peroxide (10 μM–1 mM), and 11, 12-epoxyeicosatrienoic acids (30 nM–3 μM), all of which function as endothelium-derived relaxing factors in pig coronary arteries, were also identical between PP and NP. These findings suggest that mycoplasma pneumonia in pigs is not a risk factor for endothelial dysfunction in coronary arteries.

Endothelial Dysfunction and Coronary Vasoreactivity - A Review of the History, Physiology, Diagnostic Techniques, and Clinical Relevance.

The fervency for advancement and evolution in percutaneous coronary intervention has revolutionised the treatment of coronary artery disease. Historically, the focus of the interventional cardiologist was directed at the restoration of luminal patency of the major epicardial coronary arteries, yet whilst this approach is evolving with much greater utilisation of physiological assessment, it often neglects consideration of the role of the coronary microcirculation, which has been shown to clearly influence prognosis. In this review, we explore the narrative of the coronary circulation as more than just a simple conduit for blood but an organ with functional significance. We review organisation and physiology of the coronary circulation, as well as the current methods and techniques used to examine it. We discuss the studies exploring coronary artery endothelial function, appreciating that coronary artery disease occurs on a spectrum of disorder and that percutaneous coronary intervention has a latent effect on the coronary circulation with long-term consequences. It is concluded that greater recognition of the coronary artery endothelium and mechanisms of the coronary circulation should further guide revascularisation strategies.

Abstract 13062: Epicardial Fat Associates With Endothelial Dysfunction, but Not With Coronary Calcium Score: From the Elsa-brasil Cohort Study

Introduction: Epicardial fat has been related to coronary artery disease (CAD) independent of visceral or subcutaneous fat. The mechanism responsible for this association has not yet been elucidated. Our objective was to evaluate the association between automatically measured epicardial fat volume (EFV), cardiovascular risk factors, coronary artery calcium (CAC) and endothelial function in participants of ELSA-Brasil. Methods and Results: The sample comprised 470 (mean age 55± 8y, 52.3% men) participants from ELSA-MG, one of the Investigation Centers of the cohort, who had valid computed tomography scans and endothelial function evaluated by peripheral arterial tonometry (PAT). The mean EFV was 111 (IQ 86-144) mL. CAC=0 was detected in 55% of participants. In the multivariable analyses between cardiovascular risk factors and EFV, the following associations were observed with higher EFV: female sex; and increased age, waist circumference and triglycerides (p &lt;0.001 for all). In multivariable analyses, higher EFV remained associated with worse endothelial function - basal pulse amplitude (q2=1.22, CI95% 1.07-1.40, p=0.004; q3=1.50, CI95% 1.30-1.74, p&lt;0.001; q4=1.50, CI95% 1.28-1.79, p&lt;0.001) and PAT ratio (q2=0.87, CI95% 0.81-0.95, p&lt;0.001; q3=0.86, CI95% 0.79-0.94, p&lt;0.001; q4=0.80, CI95% 0.73-0.89, p&lt;0.001), but not with CAC. Conclusions: Higher EFV was associated with impaired endothelial function, but not with higher CAC. Our results suggest that the mechanism by which epicardial fat deposits relates to CAD may be different from the pathway of CAC, which relates to calcified plaques. A possible mechanism may be through the enhancement of endothelial dysfunction, microvascular disease and predominantly lipidic non-calcified plaques.

Effect of Continuous‐Flow Left Ventricular Assist Device Support on Coronary Artery Endothelial Function in Ischemic and Non‐Ischemic Cardiomyopathy

The coronary vasculature encounters a reduction in pulsatility after implementing durable continuous‐flow left ventricular assist device (CF‐LVAD) circulatory support. Evidence exists that appropriate pulsatility is required to maintain endothelial cell homeostasis. We hypothesized that coronary artery endothelial function would be impaired after CF‐LVAD intervention. Coronary arteries from patients with end‐stage heart failure caused by ischemic (ICM, n=16) or non‐ischemic (NICM, n=22) cardiomyopathy were isolated from the LV apical core which was removed for the CF‐LVAD implantation. In 11 of these patients, paired coronary arteries were obtained from an adjacent region of myocardium after the CF‐LVAD intervention (n = 6 ICM, 5 NICM). Vascular function was assessed ex vivo using isometric tension procedures in these patients and in 7 non‐failing donor controls. Maximal endothelium‐dependent vasorelaxation to bradykinin (BK, 10−6 to 10−10 M) was blunted (p&lt;0.05) in arteries from patients with ICM compared to NICM and donor controls, whereas responses to sodium nitroprusside (SNP, 10−4 to 10−9 M) were similar among the groups. Contrary to our hypothesis, vasorelaxation responses to BK and SNP were similar before and 219±37 days after CF‐LVAD support. Of these patients, an exploratory subgroup analysis revealed that BK‐induced coronary artery vasorelaxation was greater (p&lt;0.05) after (87±6%) vs. before (54±14%) CF‐LVAD intervention in ICM patients, while SNP‐evoked responses were similar. Coronary artery endothelial function is not impaired by durable CF‐LVAD support, and in ICM patients appears to be improved. Investigating coronary endothelial function using in vivo approaches in a larger patient population is warranted.Support or Funding InformationJDS (AHA16GRNT31050004, NIH RO3AGO52848, NHLBI RO1 HL141540); LD, ND, TB (University of Utah Undergraduate Research Opportunities Program); JMC (University of Utah Graduate Research Fellowship); SGD (AHA Heart Failure Strategically Focused Research Network 16SFRN29020000, NHLBI RO1 HL135121, NHLBI RO1 HL132067).

Coronary vasomotion and exercise-induced adaptations in coronary artery disease patients: A systematic review and meta-analysis.

Background:Exercise can improve coronary blood flow in a healthy heart, but the vascular response of patients with coronary artery disease (CAD) is different. The aim of this study was to systematically review the chronic effects of exercise on coronary arterial function in CAD patients.Materials and Methods:Six electronic databases (PubMed, ScienceDirect, “Scopus,” Web of Science, EMBASE, and Google Scholar) covering publications from 1986 to 2019 were systematically searched with related keywords. Studies were included if they investigated changes in blood flow and coronary artery diameter in response to chronic exercise training in patients with CAD. A total of 5421 studies were assessed for quality and outcomes, and finally five studies met criteria for inclusion. For metaanalysis, the results of the studies were pooled using the randomeffects model. The heterogeneity between the studies was checked using I2 index.Results:The total sample population consisted of 108 CAD patients. According to the findings of this study, coronary artery function in adaptation with exercise showed that a period of exercise leads to statistically significant improvement in coronary flow velocity reserve (z = 3.15, P = 0.002; standardized mean difference [SMD] =2.33, 95% confidence interval [CI]: 0.88–3.78) (containing six trials). In addition, vasodilatory response of coronary arteries in response to endothelium-independent vasodilator nitroglycerin was investigated in three studies (containing four trials). A meta-analysis showed that performing chronic aerobic exercises did not make a significant change in the endothelium-independent vasodilator (z = 0.83, P = 0.40; SMD = −0.36, 95% CI: −1.21–0.49).Conclusion:Based on the results of the present study, aerobic exercises improve the endothelial function of coronary arteries and thereby the vascular vasomotion function, while the results of this meta-analysis showed no change in arterial smooth muscle's function by chronic aerobic exercises. This study reflects the lack of high- and medium-quality reports about the chronic effects of anaerobic and resistance exercises and the various methods of aerobic exercise on cardiovascular function.

Effect of Continuous-Flow Left Ventricular Assist Device Support on Coronary Artery Endothelial Function in Ischemic and Nonischemic Cardiomyopathy.

The coronary vasculature encounters a reduction in pulsatility after implementing durable continuous-flow left ventricular assist device (CF-LVAD) circulatory support. Evidence exists that appropriate pulsatility is required to maintain endothelial cell homeostasis. We hypothesized that coronary artery endothelial function would be impaired after CF-LVAD intervention. Coronary arteries from patients with end-stage heart failure caused by ischemic cardiomyopathy (ICM; n=16) or non-ICM (n=22) cardiomyopathy were isolated from the left ventricular apical core, which was removed for the CF-LVAD implantation. In 11 of these patients, paired coronary arteries were obtained from an adjacent region of myocardium after the CF-LVAD intervention (n=6 ICM, 5 non-ICM). Vascular function was assessed ex vivo using isometric tension procedures in these patients and in 7 nonfailing donor controls. Maximal endothelium-dependent vasorelaxation to BK (bradykinin; 10-6-10-10 M) was blunted (P<0.05) in arteries from patients with ICM compared with non-ICM and donor controls, whereas responses to sodium nitroprusside (10-4-10-9 M) were similar among the groups. Contrary to our hypothesis, vasorelaxation responses to BK and sodium nitroprusside were similar before and 219±37 days after CF-LVAD support. Of these patients, an exploratory subgroup analysis revealed that BK-induced coronary artery vasorelaxation was greater (P<0.05) after (87±6%) versus before (54±14%) CF-LVAD intervention in ICM patients, whereas sodium nitroprusside-evoked responses were similar. Coronary artery endothelial function is not impaired by durable CF-LVAD support and in ICM patients appears to be improved. Investigating coronary endothelial function using in vivo approaches in a larger patient population is warranted.

Expert consensus and evidence-based recommendations for the assessment of flow-mediated dilation in humans.

Endothelial dysfunction is involved in the development of atherosclerosis, which precedes asymptomatic structural vascular alterations as well as clinical manifestations of cardiovascular disease (CVD). Endothelial function can be assessed non-invasively using the flow-mediated dilation (FMD) technique. Flow-mediated dilation represents an endothelium-dependent, largely nitric oxide (NO)-mediated dilatation of conduit arteries in response to an imposed increase in blood flow and shear stress. Flow-mediated dilation is affected by cardiovascular (CV) risk factors, relates to coronary artery endothelial function, and independently predicts CVD outcome. Accordingly, FMD is a tool for examining the pathophysiology of CVD and possibly identifying subjects at increased risk for future CV events. Moreover, it has merit in examining the acute and long-term impact of physiological and pharmacological interventions in humans. Despite concerns about its reproducibility, the available evidence shows that highly reliable FMD measurements can be achieved when specialized laboratories follow standardized protocols. For this purpose, updated expert consensus guidelines for the performance of FMD are presented, which are based on critical appraisal of novel technical approaches, development of analysis software, and studies exploring the physiological principles underlying the technique. Uniformity in FMD performance will (i) improve comparability between studies, (ii) contribute to construction of reference values, and (iii) offer an easy accessible and early marker of atherosclerosis that could complement clinical symptoms of structural arterial disease and facilitate early diagnosis and prediction of CVD outcomes.

Metformin Prevents High Glucose Induced Disruption of Coronary Artery Endothelial Barrier Function and Accelerates Wound Healing Via Regulating Junctional Protein, VE‐Cadherin

Despite the great strides have been made in treating diabetes induced vascular endothelial barrier dysfunction, current treatments have shown limited success in reversing vascular pathologies. Increase in endothelial permeability via modification of endothelial junctional proteins, such as vascular endothelial cadherin (VE‐Cadherin), leads to the formation of minute inter‐endothelial gaps, and the infiltration of protein‐rich fluid in the interstitial space. If remained unchecked, the persistent buildup of edema underlying the endothelial lining sets the stage for the serious life‐threatening complications. Hyperglycemia‐induced endothelial dysfunction contributes vascular complications of diabetes. Moreover, wound healing impairment is also increasingly recognized to be a consequence of hyperglycemia‐induced dysfunction of endothelial in type 2 diabetes mellitus (T2DM). Metformin, an oral anti‐hyperglycemic agent, is the first‐line drug in the clinic for patients with T2DM. Clinical studies suggested that the beneficial effect of metformin on the incidence of diabetes complications was not only related to its action on blood glucose normalization. We hypothesized that the metformin prevents high glucose‐induced endothelial barrier dysfunction and accelerates wound healing process in human coronary endothelial cells (HCAE) via preventing the destabilization of VE‐cadherin. Endothelial permeability was evaluated by using Electric Cell‐substrate Impedance Sensing (ECIS) mechanism, a measure of trans‐endothelial electrical resistance (TEER) across the endothelial monolayers using TEER electrodes. Wound healing assay was performed by employing electric signals to both wound and monitor the healing process in endothelial monolayer. Our data show that 25mM glucose concentration increased endothelial permeability and abrogated the wound healing process. Metformin at the dose of 10mM significantly prevented alteration of endothelial barrier function and enhances wound healing process in the presence of high glucose concentration. To investigate the signaling mechanism involved in the protection offered by metformin, we found that metformin prevented myosin light chain kinase (MYLK) phosphorylation and increased in VE‐cadherin expression, suggesting abrogation of increase endothelial contractility and dismantling the junctional proteins in presence of high glucose concentration. In conclusion, our study shows that metformin maintained endothelial barrier function and improved the process of wound healing in endothelial cells exposed to high glucose. Thus, metformin is emerging as a potential therapeutics in improving coronary endothelial barrier function in diabetes mellitus.Support or Funding InformationThis work was supported by funding from CTRE SEED Grant Award to Mohammad Tauseef.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Secreted Klotho Protects Against Aging‐associated Coronary Endothelial Dysfunction via SIRT1 Activation

Background and ObjectiveCoronary heart disease (CHD) is the leading cause of death in the world. Endothelial dysfunction is an initial step in the development of CHD and may be a critical early target for the prevention of CHD. Klotho, originally identified as an aging‐suppressor gene, is predominately expressed in kidneys. Klotho protein is secreted into the circulation. The objective of this study is to investigate whether secreted Klotho protein protects against aging‐associated coronary endothelial dysfunction and CHD.Methods and ResultsWe found that aging‐associated coronary endothelial dysfunction assessed by endothelium‐dependent vasodilation and coronary blood flow was accompanied by a reduction in serum level of secreted Klotho (sKL) protein. Using klotho‐hypomorphic (KL (−/−)) mice, we confirmed that Klotho deficiency caused coronary endothelial dysfunction. Interestingly, the impaired endothelium‐dependent vasorelaxation and coronary flow were remarkably improved by in vivo delivery of exogenous sKL protein in aged mice and KL (−/−) mice, suggesting that sKL rescued aging‐induced coronary artery endothelial dysfunction. In addition, sKL treatment protected against aging‐associated and Klotho deficiency‐induced cardiac dysfunction, as evidenced by restoration of stroke volume and cardiac output in aged and KL (−/−) mice. sKL treatment also enhanced coronary endothelial nitric oxide bioavailability and attenuated oxidative stress and apoptosis. Mechanistically, aging via Klotho deficiency suppressed SIRT1‐AMPKα‐eNOS pathway in the coronary endothelial cell through activation of transcription repressor HIC‐1. Furthermore, pharmacological activation of SIRT1 by SRT 1720 protected against Klotho deficiency‐induced coronary artery endothelial dysfunction and cardiac dysfunction.ConclusionKlotho regulates coronary artery endothelial function via SIRT1 activation. Supplement of exogenous Klotho protein represents a promising therapeutic strategy for the treatment of aging‐associated coronary heart disease.Support or Funding InformationAG049780, HL118558This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Tetramethylpyrazine suppresses angiotensin II-induced soluble epoxide hydrolase expression in coronary endothelium via anti-ER stress mechanism

Activation of soluble epoxide hydrolase (sEH) is associated with endothelial dysfunction in hypertension, though the underlying mechanisms are inadequately understood and the role of endoplasmic reticulum (ER) stress is yet to be studied in detail. Tetramethylpyrazine (TMP), a major bioactive ingredient of Chinese herb Chuanxiong, is well-known for its cardiovascular benefits. Nevertheless, whether TMP may protect vascular endothelium from ER stress and whether regulation of sEH is involved remain unknown. This study aimed at investigating the role of ER stress in angiotensin-II (Ang-II)-induced sEH dysregulation and elucidating the significance of ER stress regulation in the vasoprotective effect of TMP. Porcine primary coronary artery endothelial cells (PCECs) were used for western blot, ELISA, and reverse-transcription PCR analysis. Porcine coronary arteries were assessed in a myograph for endothelial dilator function. Ang-II induced expression of ER stress molecules in PCECs meanwhile enhanced sEH expression and decreased 11,12-EET. Exposure of PCECs to the chemical ER stress inducer tunicamycin also increased sEH expression. Inhibition of ER stress suppressed sEH upregulation, resulting in an increase of 11,12-EET. The impairment of endothelium-dependent vasorelaxation induced by Ang-II or tunicamycin was ameliorated by inhibitors of ER stress or sEH. TMP showed comparable inhibitory effect to ER stress inhibitors on the expression of ER stress molecules, the dysregulation of sEH/EET, and the impairment of endothelial dilator function. We demonstrated that ER stress mediates Ang-II-induced sEH upregulation in coronary endothelium. TMP has potent anti-ER stress capacity through which TMP normalizes sEH expression and confers protective effect against Ang-II on endothelial function of coronary arteries.

Lipid Emulsions Containing Medium Chain Triacylglycerols Blunt Bradykinin-Induced Endothelium-Dependent Relaxation in Porcine Coronary Artery Rings.

Lipid emulsions for parenteral nutrition are used to provide calories and essential fatty acids for patients. They have been associated with hypertriglyceridemia, hypercholesterolemia, and metabolic stress, which may promote the development of endothelial dysfunction in patients. The aim of the present study was to determine whether five different industrial lipid emulsions may affect the endothelial function of coronary arteries. Porcine coronary artery rings were incubated with lipid emulsions 0.5, 1, or 2% (v/v) for 30min before the determination of vascular reactivity in organ chambers and the level of oxidative stress using electron paramagnetic resonance. Incubation of coronary artery rings with either Lipidem®, Medialipid® containing long- and medium-chain triacylglycerols (LCT/MCT), or SMOFlipid® containing LCT, MCT, omega-9, and -3, significantly reduced the bradykinin-induced endothelium-dependent relaxation, affecting both the nitric oxide (NO) and endothelium-dependent hyperpolarization (EDH) components, whereas, Intralipid® containing LCT (soybean oil) and ClinOleic® containing LCT (soybean and olive oil) did not have such an effect. The endothelial dysfunction induced by Lipidem® was significantly improved by indomethacin, a cyclooxygenase (COX) inhibitor, inhibitors of oxidative stress (N-acetylcysteine, superoxide dismutase, catalase) and transition metal chelating agents (neocuproine, tetrathiomolybdate, deferoxamine and L-histidine). Lipidem® significantly increased the arterial level of oxidative stress. The present findings indicate that lipid emulsions containing LCT/MCT induce endothelial dysfunction in coronary artery rings by blunting both NO- and EDH-mediated relaxations. The Lipidem®-induced endothelial dysfunction is associated with increased vascular oxidative stress and the formation of COX-derived vasoconstrictor prostanoids.