Coronary Endothelial Function Research Articles

Evaluation of changes in the global longitudinal strain for left ventricular function before and after eight weeks of taking high dose of atorvastatin in patients with coronary slow flow phenomenon

BackgroundCoronary Slow Flow Phenomenon (CSFP) is a well-recognized clinical entity characterized by delayed opacification of coronary arteries in the presence of a normal coronary angiogram. The objective of this study was determined and compared left ventricle (LV)strain in patients with CSFP before and after receiving a high-dose atorvastatin.Materials and methodsThis cross-sectional study was conducted on 51 patients with CSFP from the beginning of 2021 to the end of September 2022. Trans-thoracic Echocardiogram (TTE) was performed by an echocardiography specialist. Thereafter, the patient’s basic information was entered into the researcher’s checklist after treatment with atorvastatin 40 mg daily for eight consecutive weeks. After eight weeks, the patients were subjected again to TTE. The data were analyzed in SPSS statistical software.ResultsThe mean LV-GLS before taking atorvastatin was − 16.53%±3.63%. The mean LV-GLS after taking atorvastatin was 17.57%±3.53% (P.value = 0.01). The mean LV function before taking atorvastatin was 48.82%±9.19%. Meanwhile, the mean LV function after taking atorvastatin was 50.59%±7.91% (P = 0.01). There was no significantly change in left atrium volume (49.88 ± 0.68 vs. 49.9 + 0.67) after 8 weeks taking atorvastatin (P = 0.884).ConclusionThe plasma ET-1 levels are elevated in CSFP patients, and atorvastatin improves coronary flow and endothelial function. As evidenced by the results of this study, the daily intake of 40 mg of oral atorvastatin during eight consecutive weeks in patients with CSFP significantly improved LV strain and LV function, however atorvastatin does not have a significant effect on improving the right ventricular function and pulmonary artery systolic pressure.

Endothelial Dysfunction in Youth-Onset Type 2 Diabetes: A Clinical Translational Study.

Youth-onset type 2 diabetes (Y-T2D) is associated with increased risk for coronary atherosclerotic disease, but the timing of the earliest pathological features and evidence of cardiac endothelial dysfunction have not been evaluated in this population. Endothelial function magnetic resonance imaging may detect early and direct endothelial dysfunction in the absence of classical risk factors (severe hyperglycemia, hypertension, and hyperlipidemia). Using endothelial function magnetic resonance imaging, we evaluated peripheral and coronary artery structure and endothelial function in young adults with Y-T2D diagnosed ≤5 years compared with age-matched healthy peers. We isolated and characterized plasma-derived small extracellular vesicles and evaluated their effects on inflammatory and signaling biomarkers in healthy human coronary artery endothelial cells to validate the imaging findings. Right coronary wall thickness, coronary artery flow-mediated dilation, and brachial artery flow-mediated dilation were measured at baseline and during isometric handgrip exercise using a 3.0T magnetic resonance imaging. Human coronary artery endothelial cells were treated with Y-T2D plasma-derived small extracellular vesicles. Protein expression was measured by Western blot analysis, oxidative stress was measured using the redox-sensitive probe dihydroethidium, and nitric oxide levels were measured by 4-amino-5-methylamino-2',7'-difluororescein diacetate. Y-T2D (n=20) had higher hemoglobin A1c and high-sensitivity C-reactive protein, but similar total and LDL (low-density lipoprotein)-cholesterol compared with healthy peers (n=16). Y-T2D had greater coronary wall thickness (1.33±0.13 versus 1.22±0.13 mm; P=0.04) and impaired endothelial function: lower coronary artery flow-mediated dilation (-3.1±15.5 versus 15.9±17.3%; P<0.01) and brachial artery flow-mediated dilation (6.7±14.7 versus 26.4±15.2%; P=0.001). Y-T2D plasma-derived small extracellular vesicles reduced phosphorylated endothelial nitric oxide synthase expression and nitric oxide levels, increased reactive oxygen species production, and elevated ICAM (intercellular adhesion molecule)-mediated inflammatory pathways in human coronary artery endothelial cells. Coronary and brachial endothelial dysfunction was evident in Y-T2D who were within 5 years of diagnosis and did not have severe hyperglycemia or dyslipidemia. Plasma-derived small extracellular vesicles induced markers of endothelial dysfunction, which corroborated accelerated subclinical coronary atherosclerosis as an early feature in Y-T2D. URL: https://www.clinicaltrials.gov; Unique identifier: NCT02830308 and NCT01399385.

Methylglyoxal induces endothelial cell apoptosis and coronary microvascular dysfunction through regulating AR-cPLA2 signaling

ObjectiveSince diabetic patients with coronary microvascular dysfunction (CMD) exhibit high cardiac mortality and women have higher prevalence of non-obstructive coronary artery disease than men, we tried to expand the limited understanding about the etiology and the sex difference of diabetic CMD. Approach and resultsAccumulated methylglyoxal (MGO) due to diabetes promotes vascular damage and it was used for mimicking diabetic status. Flow cytometry analysis and isometric tension measurement were performed to evaluate coronary artery endothelial injury. MGO induced apoptosis of coronary endothelial cells, accompanied by downregulation of androgen receptor (AR). Lentivirus-mediated stable expression of AR in coronary endothelial cells increased anti-apoptotic Bcl-2 expression and attenuated MGO-induced cell apoptosis. cPLA2 activation was the downstream of AR downregulation by MGO treatment. Moreover, MGO also activated cPLA2 rapidly to impair endothelium-dependent vasodilation of coronary arteries from mice. Reactive oxygen species (ROS) overproduction was demonstrated to account for MGO-mediated cPLA2 activation and endothelial dysfunction. Importantly, AR blockade increased endothelial ROS production whereas AR activation protected coronary artery endothelial vasodilatory function from the MGO-induced injury. Although galectin-3 upregulation was confirmed by siRNA knockdown in endothelial cells not to participate in MGO-induced endothelial apoptosis, pharmacological inhibitor of galectin-3 further enhanced MGO-triggered ROS generation and coronary artery endothelial impairment. ConclusionsOur data proposed the AR downregulation-ROS overproduction-cPLA2 activation pathway as one of the mechanisms underlying diabetic CMD and postulated a possible reason for the sex difference of CMD-related angina. Meanwhile, MGO-induced galectin-3 activation played a compensatory role against coronary endothelial dysfunction.

Innovative Treatments to Counteract Endothelial Dysfunction in Chronic Kidney Disease Patients.

In chronic kidney disease (CKD) patients, several risk factors contribute to the development of endothelial dysfunction (ED), which can be described as an alteration in the cell structure or in the function of the endothelium. Among the well-known CKD-related risk factors capable of altering the production of endothelium-derived relaxing factors, we include asymmetric dimethylarginine increase, reduced dimethylarginine dimethylamine hydrolase enzyme activity, low-grade chronic systemic inflammation, hyperhomocysteinemia, oxidative stress, insulin resistance, alteration of calcium phosphorus metabolism, and early aging. In this review, we also examined the most important techniques useful for studying ED in humans, which are divided into indirect and direct methods. The direct study of coronary endothelial function is considered the gold standard technique to evaluate if ED is present. In addition to the discussion of the main pharmacological treatments useful to counteract ED in CKD patients (namely sodium-glucose cotransporter 2 inhibitors and mineralocorticoid receptor antagonist), we elucidate innovative non-pharmacological treatments that are successful in accompanying the pharmacological ones. Among them, the most important are the consumption of extra virgin olive oil with high intake of minor polar compounds, adherence to a plant-dominant, low-protein diet (LPD), an adaptive physical activity program and, finally, ketoanalogue administration in combination with the LPD or the very low-protein diet.

Patients With Coronary Microvascular Dysfunction Have Less Circulating α-Klotho.

Coronary microvascular dysfunction (CMD) represents an early functional characteristic of coronary vascular aging. Klotho (α-klotho) is a circulating protein inversely linked to physiological aging. We examined low klotho as a potential marker for vascular aging in patients with CMD and no coronary artery disease. Patients undergoing nonurgent angiogram for chest pain who had no coronary artery disease underwent invasive coronary microvascular and endothelial function testing. CMD was defined by ≤50% increase in coronary blood flow (percentage change in coronary blood flow) in response to intracoronary acetylcholine or coronary flow reserve ≤2. Fresh arterial whole blood was used to analyze circulating endothelial progenitor cells with flow cytometry. Stored arterial plasma was used for klotho analysis by ELISA. Participants with CMD (n=62) were compared with those without CMD (n=36). Those with CMD were age 55±10 years (versus 51±11 years; P=0.07) and 73% women (versus 81%; P=0.38). Traditional risk factors for coronary artery disease were similar between groups. Patients with CMD had less klotho (0.88±1.50 versus 1.75±2.38 ng/mL; P=0.03), and the odds of low klotho in CMD were significant in a logistic regression model after adjusting for traditional cardiovascular risk factors (odds ratio [OR], 0.80 [95% CI, 0.636-0.996]; P=0.05). Higher klotho was associated with higher numbers of endothelial progenitor cells with vascular regenerative potential (CD34+ and CD34+CD133+KDR+). Among a subgroup of patients with atherosclerotic cardiovascular disease risk <5% (n=58), CMD remained associated with lower klotho (OR, 0.80 [95% CI, 0.636-0.996]; P=0.047). Klotho may be a biomarker for CMD and may be a therapeutic target for groups of patients without significant traditional cardiovascular risk.

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 microvascular function in male physicians with burnout and job stress: an observational study

BackgroundAs a professional group, physicians are at increased risk of burnout and job stress, both of which are associated with an increased risk of coronary heart disease that is at least as high as that of other professionals. This study aimed to examine the association of burnout and job stress with coronary microvascular function, a predictor of major adverse cardiovascular events.MethodsThirty male physicians with clinical burnout and 30 controls without burnout were included. Burnout was assessed with the Maslach Burnout Inventory and job stress with the effort-reward imbalance and overcommitment questionnaire. All participants underwent myocardial perfusion positron emission tomography to quantify endothelium-dependent (cold pressor test) and endothelium-independent (adenosine challenge) coronary microvascular function. Burnout and job stress were regressed on coronary flow reserve (primary outcome) and two additional measures of coronary microvascular function in the same model while adjusting for age and body mass index.ResultsBurnout and job stress were significantly and independently associated with endothelium-dependent microvascular function. Burnout was positively associated with coronary flow reserve, myocardial blood flow response, and hyperemic myocardial blood flow (r partial = 0.28 to 0.35; p-value = 0.008 to 0.035). Effort-reward ratio (r partial = − 0.32 to − 0.38; p-value = 0.004 to 0.015) and overcommitment (r partial = − 0.30 to − 0.37; p-value = 0.005 to 0.022) showed inverse associations with these measures.ConclusionsIn male physicians, burnout and high job stress showed opposite associations with coronary microvascular endothelial function. Longitudinal studies are needed to show potential clinical implications and temporal relationships between work-related variables and coronary microvascular function. Future studies should include burnout and job stress for a more nuanced understanding of their potential role in cardiovascular health.

Abstract 17343: Coronary Microvascular Function in Physician Burnout and Job Stress

Background: As a professional group, physicians are at increased risk of burnout and job stress, both of which are associated with an increased risk of coronary heart disease that seems more prevalent among male than female physicians. Aim: This study aimed to examine the association of burnout and job stress with coronary microvascular function, a predictor of major adverse cardiovascular events. Methods: Thirty male physicians with clinical burnout and 30 controls without burnout were included. Burnout was assessed with the Maslach Burnout Inventory and job stress with the effort-reward imbalance and overcommitment questionnaire. All participants underwent myocardial perfusion positron emission tomography to quantify endothelium-dependent (cold pressor test) and endothelium-independent (adenosine challenge) coronary microvascular function. Burnout and job stress were regressed on measures of coronary microvascular function in the same model while adjusting for age and body mass index. Results: Burnout and job stress had significant and independent effects on endothelium-dependent microvascular function. Burnout was positively associated with coronary flow reserve, myocardial blood flow (MBF) response, and hyperemic MBF (r partial: 0.29 to 0.35; p-value: 0.008 to 0.027). Effort-reward ratio (r partial: -0.32 to -0.34; p-value: 0.009 to 0.017) and overcommitment (r partial: -0.29 to -0.35; p-value: 0.008 to 0.027) showed inverse associations with these measures. Conclusions: In male physicians, burnout and high job stress showed opposite effects on coronary microvascular endothelial function. Longitudinal studies are needed to show potential clinical implications. Future studies should include burnout and job stress for a more nuanced understanding of their potential impact on cardiovascular health.

Rapid Improvement of Coronary Endothelial Function With PCSK9 Inhibition in People With HIV Is Associated With Reduced Lipoprotein (a) and Not LDL-cholesterol.

Rapid Improvement of Coronary Endothelial Function With PCSK9 Inhibition in People With HIV Is Associated With Reduced Lipoprotein (a) and Not LDL-cholesterol.

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.

Acute protein kinase C beta inhibition preserves coronary endothelial function after cardioplegic hypoxia/reoxygenation

ObjectiveProtein kinase C (PKC) influences myocardial contractility and susceptibility to long-term cardiac dysfunction after ischemia–reperfusion injury. In diabetes, PKC inhibition has a protective effect in terms of microvascular dysfunction. SK-channel dysfunction also influences endothelial dysfunction in cardioplegic hypoxia–reoxygenation (CP-H/R). Here, we examine whether acute inhibition of PKC beta protects against CP-H/R–induced coronary endothelial and SK channel dysfunction. MethodsIsolated mouse coronary arterioles, half pretreated with selective PKC inhibitor ruboxistaurin (RBX), were subjected to hyperkalemic, cardioplegic hypoxia (1 hour), and reoxygenation (1 hour) with Krebs buffer. Sham control vessels were continuously perfused with oxygenated Krebs buffer without CP-H/R. After 1 hour of reoxygenation, responses to the endothelium-dependent vasodilator adenosine-diphosphate (ADP) and the SK-channel activator NS309 were examined. Endothelial SK-specific potassium currents from mouse heart endothelial cells were examined using whole-cell path clamp configurations in response to NS309 and SK channel blockers apamin and TRAM34. ResultsCP-H/R significantly decreased coronary relaxation responses to ADP (P = .006) and NS309 (P = .0001) compared with the sham control group. Treatment with selective PKC beta inhibitor RBX significantly increased recovery of coronary relaxation responses to ADP (P = .031) and NS309 (P = .004) after CP-H/R. Treatment with RBX significantly increased NS309-mediated potassium currents following CP-H/R (P = .0415). Apamin and TRAM34 sensitive currents were significantly greater in CP-H/R + RBX versus CP-H/R mouse heart endothelial cells (P = .0027). ConclusionsAcute inhibition of PKC beta significantly protected mouse coronary endothelial function after CP-H/R injury. This suggests that acute PKC beta inhibition may be a novel approach for preventing microvascular dysfunction during CP-H/R.

Evaluation of Coronary Microvascular and Endothelial Function in the Cardiac Catheterization Laboratory

Evaluation of Coronary Microvascular and Endothelial Function in the Cardiac Catheterization Laboratory

Sex differences in the development of coronary microvascular diseases in type-2 diabetes: possible role of gap junction protein connexin-40

Type-2 diabetes (T2D) increases the risk of cardiovascular diseases 2-4 folds in both sexes compared to non-diabetic individuals. However, more than 50% of female patients who experience chest pain have coronary microvascular disease (CMD) instead of obstructive CAD. On the other hand, 20% of men with chest pain have CMD. CMD is characterized by reduced coronary flow reserve, and coronary flow is regulated by the change in capillary density and vessel diameter. Gap junction protein connexin-40 (Cx40) plays a significant role in coronary microvascular function by controlling endothelium-dependent relaxation (EDR), cardiac endothelial cell (CEC) migration and capillary density. We hypothesized that T2D differentially affects the CX-40 expression and function in male and female coronary artery (CA) and causes CMD. The objective of this study is to identify the molecular mechanisms underlining the development of T2D-induced CMD in male and female mice.T2D mice were generated by a combination of high-fat diet feeding and a low-dose of streptozotocin (75 mg/kg, i.p.). The oral glucose tolerance was conducted at 4-, 8-, 12-, and 16 weeks after diabetes induction. Coronary flow velocity reserve (CFVR) was used to assess coronary microvascular function in mice. Coronary endothelial function was determined by 1) capillary density measurement in the left ventricle and 2) isometric tension experiment in small CAs (3rd order). CECs from male and female mice were isolated to conduct molecular biological experiments.There was no significant difference in CFVR and capillary density between control male and female mice. However, T2D mice of both sexes showed significant differences in the properties of EDR, CFVR and capillary density. T2D male mice exhibited a significant attenuation of EDR accompanied by impaired endothelium-derived nitric oxide(EDNO)-dependent relaxation and endothelium-dependent hyperpolarization (EDH)-mediated relaxation. On the contrary, there is no difference in EDR between control and diabetic female mice. Capillary density was reduced in T2D mice of both sexes compared to the respective controls. Our RNA sequencing data in CECs revealed that Cx40 is one of the genes which contributes to diabetes-mediated CMD. Systemic Cx40-KO male mice showed reduced EDR, EDH-mediated relaxation and capillary density compared to wild type control. T2D reduced the expression of Cx40 and overexpression of Cx40 restored EDR in CAs and increased capillary density in T2D male mice.T2D impaired coronary microvascular function in both sexes. However, the cause of reduced CFVR was different between diabetic male and female mice. In T2D females, capillary rarefaction was a primary cause of reduced CFVR. In contrast, attenuated EDNO- and EDH-mediated relaxation, reduced capillary density and downregulation of Cx40 contributed to decreased CFVR in T2D male mice. Future studies are required to establish the role of Cx40 in the development of CMD in T2D females. Supported by NIH R01HL142214 and DOD W81XWH2110472 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

The role of HIV as a risk modifier for coronary endothelial function in young adults.

People living with HIV have an increased risk of cardiovascular disease (CVD). Although coronary endothelial function (CEF) is an early direct indicator of CVD, only a few studies have been able to interrogate CEF directly. Most studies have examined vascular endothelial function through indirect assessment of brachial flow-mediated dilatation (FMD). However, peripheral arteries are significantly larger and manifest atherogenesis differently from the coronary arteries, and so produce conflicting results. Additionally, none of these studies focused on young adults who acquired HIV perinatally or in early childhood. The present study investigates CEF in a unique population of young adults with lifelong HIV using direct magnetic resonance imaging (MRI) of coronary FMD (corFMD) with an in-house developed MRI-integrated isometric handgrip exercise system with continuous feedback and monitoring mechanisms (fmIHE). Young adults who acquired HIV perinatally or in early childhood (n = 23) and group-matched healthy participants (n = 12) completed corFMD-MRI with fmIHE. CorFMD was measured as the coronary cross-sectional area response to the fmIHE. In univariable and multivariable regression analysis, HIV status was a significant risk modifier. CD8+ T-cell count and smoking pack-years and their interaction with HIV status were independently associated with impaired coronary artery response to fmIHE. In people living with HIV, corFMD was significantly inversely correlated with CD8+ T-cells and smoking pack-years. In a multivariable regression analysis adjusted for age and body mass index, CD8+ T-cells and smoking and their interaction with HIV status remained significant independent predictors of coronary endothelial dysfunction. In this unique population of young adults, HIV status was a significant risk modifier, and immune activation and smoking were associated with decreased CEF, directly measured from the coronary vascular response to fmIHE. Management of CVD risk factors such as smoking and developing strategies that target immune activation in people living with HIV are warranted.

Glycated Hemoglobin and Waist-Hip Ratio Are Important Metabolic Factors Associated With Coronary Endothelial Cell Function in Patients With Non-Obstructive Coronary Artery Disease

Glycated Hemoglobin and Waist-Hip Ratio Are Important Metabolic Factors Associated With Coronary Endothelial Cell Function in Patients With Non-Obstructive Coronary Artery Disease

Effect of Sex on Coronary Endothelial Dysfunction in People Living With HIV.

Background Impaired coronary endothelial function (CEF) predicts cardiovascular events and occurs in people living with HIV (PLWH). Women compared with men living with HIV have worse cardiovascular outcomes, but prior CEF studies included few women. The authors aimed to compare CEF in women with HIV versus without HIV, investigate sex differences in CEF and PCSK9 (proprotein convertase subtilisin/kexin type 9) (a proinflammatory biomarker), and evaluate whether increased serum levels of PCSK9 are associated with CEF in PLWH. Methods and Results Magnetic resonance imaging was performed to measure CEF (as percent change in coronary cross-sectional area and coronary blood flow during isometric handgrip exercise, an endothelial-dependent stressor) and serum PCSK9 levels were measured in 106 PLWH and 76 people without HIV. CEF was significantly reduced in women with versus without HIV (cross-sectional area change -0.5%±9.7 versus 9.5%±3.2, respectively). After adjustment for age, body mass index, and menopausal status, women with HIV still had reduced CEF (percentageof cross-sectional area: ß -8.3 [-13 to -3.6], P=0.001) compared with women without HIV. PCSK9 was elevated in women living with HIV versus without (306 ng/mL [200-412 ng/mL] versus 180 ng/mL [154-223 ng/mL], P<0.001), and no sex differences in either CEF or PCSK9 were detected in PLWH. Elevated PCSK9 was associated with impaired CEF in PLWH; however, no significant sex differences in the association were detected. Conclusions Among PLWH, coronary endothelial dysfunction is present in women and comparable to men. PCSK9 is higher in women with versus without HIV and a significant inverse relationship between PCSK9 and CEF was shown. Future studies should determine whether PLWH would benefit from interventions to improve endothelial function.

Depot-specific adipose tissue modulation by SGLT2 inhibitors and GLP1 agonists mediates their cardioprotective effects in metabolic disease.

Sodium-glucose transporter-2 inhibitors (SGLT-2i) and glucagon-like peptide 1 (GLP-1) receptor agonists are newer antidiabetic drug classes, which were recently shown to decrease cardiovascular (CV) morbidity and mortality in diabetic patients. CV benefits of these drugs could not be directly attributed to their blood glucose lowering capacity possibly implicating a pleotropic effect as a mediator of their impact on cardiovascular disease (CVD). Particularly, preclinical and clinical studies indicate that SGLT-2i(s) and GLP-1 receptor agonists are capable of differentially modulating distinct adipose pools reducing the accumulation of fat in some depots, promoting the healthy expansion of others, and/or enhancing their browning, leading to the suppression of the metabolically induced inflammatory processes. These changes are accompanied with improvements in markers of cardiac structure and injury, coronary and vascular endothelial healing and function, vascular remodeling, as well as reduction of atherogenesis. Here, through a summary of the available evidence, we bring forth our view that the observed CV benefit in response to SGLT-2i or GLP-1 agonists therapy might be driven by their ameliorative impact on adipose tissue inflammation.

Abstract 13094: Extracellular Vesicles Associate With Cardio-Metabolic Status and Endothelial Dysfunction in a Cohort of African-American Women

Extracellular vesicles (EVs) are emerging as promising biomarkers for cardiovascular disease (CVD) and contributors to CVD pathogenesis. Plasma EVs access the endothelium from various vascular beds allowing them to impact endothelial function and inform on the global particulate secretome produced by parenchymal, vascular and immune cells. In this study we examined associations between plasma EVs and biochemical and physiological parameters in a cohort of African American (AA) women at risk for CVD. We also examined EV effect on coronary endothelial function. This study will serve as baseline data for a longitudinal study aimed to determine the effects of exercise on EVs and endothelial function in a similar cohort.A cohort of 24 AA women between 22-71 yrs, with BMI between 26-47 kg/m 2 and ASCVD risk scores between 2.3-22.1 were included in the study. EVs were isolated from fasted heparinized plasma using size exclusion chromatography. EV size and numbers were determined using nanoparticle tracking analysis. Lipids, inflammatory cytokines, and metabolic panels were measured at the time of blood draw. Human coronary endothelial cells were treated with EVs from participants and endothelial barrier function and migration were measured using ECIS technology. Associations were determined using multivariable linear regression analysis, adjusted for BMI and ASCVD risk.We found a negative association (beta=-0.712, p&lt;0.01) between total triglycerides (TG), TG rich lipoprotein (Lp), and EV size; EV concentration was positively associated (beta= 0.51-0.61, p&lt;0.01) with TG rich Lp, LDL cholesterol and TNFa. Reduced endothelial barrier function due to EVs was positively associated with monocyte counts (beta=0.42, p&lt;0.05). EVs effect on increased endothelial migration was strongly and negatively associated with monocyte counts (beta=-0.85, p&lt;0.001), IL8 and CXCl10 (beta=-0.56-0.46, p&lt;0.05).Collectively these data show that EVs number and size strongly associate with circulating lipids, while EV impact on endothelial dysfunction is associated with inflammatory markers. EVs are therefore promising indicators of endothelial dysfunction that associate with inflammatory and metabolic markers even after adjusting for BMI and ASCVD risk.

Abstract 15087: Chronic Inhibition of NADPH Oxidase Improves Coronary Endothelial Function in Mice With Diabetes

Introduction:: Endothelial dysfunction is the leading cause for diabetes (DM) related coronary heart disease. Diabetes is associated with NADPH Oxidase (Nox) overproduction and related ROS amplification in endothelial cells and coronary vasculature, which may contribute to coronary endothelial dysfunction. Small conductance calcium-activated-potassium (SK) channels also play a key role in diabetes-induced coronary endothelial dysfunction . Hypothesis: Chronic inhibition of Nox may improve coronary endothelial function/coronary arteriolar relaxation, and SK activator-induced vasodilation in mice with or without diabetes. Methods: Wild type (control), non-diabetic (ND) mice and genetically modified, obesity/type-2 diabetic mice (BKS.Cg- Dock7 m +/+ Lepr db /J) with or with treatment with Nox inhibitor apocynin (n = 4-6/group) were used in the study. In the Nox inhibitor treated group, apocynin (30mg/kg/day, i.p) was applied to the diabetic mice for 4 weeks. Small coronary arteries (70-120μM) isolated for harvested hearts were pre-contracted and examined in the presence or absence of the vasodilatory agents, SNP, ADP, and NS309, respectively. Results: After 4-week treatment with apocynin, endothelium-NO-dependent relaxation responses to ADP, and endothelium-dependent, SK channel activator NS309 in the diabetic mice were significantly increased when compared with that in untreated diabetic mice, respectively (# p&lt;0.05 vs ND Figure ). There were no significant differences in responses to the endothelium-independent vasodilator SNP (P&gt;0.05) among the three groups. Conclusions: Chronic inhibition of Nox appears to improve coronary endothelial function/coronary relaxation and SK channel activity in mice with diabetes.