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Abstract Normal endothelial cell dependent vascular smooth muscle cell function is mediated by nitric oxide (NO), which stimulates soluble guanylyl cyclase (sGC) production of the second messenger cyclic guanosine monophosphate (cGMP) leading to increased protein kinase G (PKG) activity and vascular smooth muscle relaxation. NO bioavailability is impaired in high glucose (HG). We tested the hypothesis that the sGC sensitizer vericiguat reverses HG-mediated decreased sGC activity in two experimental models, human aortic vascular smooth muscle cells (HVSMCs) and isolated mouse aortic rings. HVSMCs were exposed to normal glucose (NG) or to HG with or without 1 μm vericiguat for 24 h and cGMP and PKG activity were measured. Murine aortic rings were incubated in NG or HG for 24 h. Following incubation, the aortic rings were placed in an organ chamber bath containing the same NG or HG concentration used during the incubation. Dose-response curves to increasing concentrations of acetylcholine (ACh) and sodium nitroprusside were constructed for four groups: control (NG), NG + vericiguat, HG, and HG + vericiguat. As compared with the results in the NG group, cGMP production and PKG activity were significantly impaired in the HG cells incubated without, but not in those incubated with, vericiguat. In isolated aortic rings, ACh-mediated relaxation was impaired following treatment with HG, but not when a HG group was treated with vericiguat. The findings suggest clinical studies are warranted to investigate the potential of sGC sensitization as a therapeutic intervention to improve vascular NO-cGMP signaling endothelium -dependent function that is impaired in HG settings such as diabetes and the metabolic syndrome.

Background HIV‐associated cardiovascular disease (CVD) is increasing in prevalence. The mechanisms underlying the heightened cardiovascular risk faced by people with HIV (PWH), however, remain poorly defined. Recent studies indicate an important role of lipoprotein(a) (Lp[a]) in predicting CVD risk in the general population, but little is known regarding its role in HIV‐associated CVD. Thus, we sought to evaluate whether Lp(a) is elevated in PWH and if it is associated with impaired coronary endothelial function (CEF), a known mediator of CVD in PWH. Methods and Results In this cross‐sectional study, cardiac magnetic resonance imaging with isometric handgrip exercise, an endothelial dependent stressor, was performed to assess CEF in 65 PWH and 52 controls without HIV. Percent changes in coronary cross‐sectional area and coronary blood flow from rest to stress were used to quantify CEF. Lp(a) levels were assessed by immunoturbidimetric assay at the time of magnetic resonance imaging. Lp(a) levels were higher in PWH compared with controls (78 nmol/L [39–137 nmol/L] versus 45.5 nmol/L [18–102.5 nmol/L], P

Objective: Assess the yield of genetic testing for pathogenic variants in ABCG5, ABCG8, LIPA, and APOE in individuals with personal and family histories suggestive of familial hypercholesterolemia. Methods: Retrospective review of patients seen in the Advanced Lipid Disorders Clinic at Johns Hopkins Results: In the lipid clinic at a single center during the years 2015–2023, 607 patients underwent genetic testing for familial hypercholesterolemia, of which 263 underwent the expanded genetic testing for sitosterolemia. Eighty-eight patients had genetic testing which included APOE, and 22 patients had testing which included LIPA. Among these, one patient was identified to have a pathogenic variant in APOE and another patient with a pathogenic variant in ABCG5 (0.7 % yield). The frequency of a positive result was double that of a variant of uncertain significance. Conclusion: These data suggest in rare cases expanded testing can provide answers for patients and families with a minimal likelihood of a variant of uncertain significance.

Objective: Elevated lipoprotein(a) [Lp(a)] is associated with atherosclerotic cardiovascular disease, yet little is known about Lp(a) testing patterns in real-world practice. The objective of this analysis was to determine how Lp(a) testing is used in clinical practice in comparison with low density lipoprotein cholesterol (LDL-C) testing alone, and to determine whether elevated Lp(a) level is associated with subsequent initiation of lipid-lowering therapy (LLT) and incident cardiovascular (CV) events. Methods: This is an observational cohort study, based on lab tests administered between Jan 1, 2015 and Dec 31, 2019. We used electronic health record (EHR) data from 11 United States health systems participating in the National Patient-Centered Clinical Research Network (PCORnet). We created two cohorts for comparison: 1) the Lp(a) cohort, of adults with an Lp(a) test and 2) the LDL-C cohort, of 4:1 date- and site-matched adults with an LDL-C test, but no Lp(a) test. The primary exposure was the presence of an Lp(a) or LDL-C test result. In the Lp(a) cohort, we used logistic regression to assess the relationship between Lp(a) results in mass units (< 50, 50-100, and > 100mg/dL) and molar units ( 250nmol/L) and initiation of LLT within 3 months. We used multivariable adjusted Cox proportional hazards regression to evaluate these Lp(a) levels and time to composite CV hospitalization, including hospitalization for myocardial infarction, revascularization and ischemic stroke. Results: Overall, 20,551 patients had Lp(a) test results and 2,584,773 patients had LDL-C test results (82,204 included in the matched LDL-C cohort). Compared with the LDL-C cohort, the Lp(a) cohort more frequently had prevalent ASCVD (24.3% vs. 8.5%) and multiple prior CV events (8.6% vs. 2.6%). Elevated Lp(a) was associated with greater odds of subsequent LLT initiation. Elevated Lp(a) reported in mass units was also associated with subsequent composite CV hospitalization [aHR (95% CI): Lp(a) 50-100mg/dL 1.25 (1.02-1.53), p 100mg/dL 1.23 (1.08-1.40), p

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 (percentage of 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

BackgroundProprotein convertase subtilisin/kexin type 9 (PCSK9) is a serine protease that is a mediator of the immune response to sepsis. PCSK9 is also highly expressed in pneumocytes and pulmonary endothelial cells. We hypothesized that serum PCSK9 levels would be associated with death and ICU outcomes in patients with ARDS.MethodsUsing data and plasma samples from the NIH BioLINCC data repository, we assembled a cohort of 1,577 patients with the acute respiratory distress syndrome (ARDS) enrolled in two previously completed clinical trials, EDEN and SAILS. We measured PCSK9 levels in plasma within 24 h of intubation using commercially available ELISA kits (R&D Systems). We assessed the association of PCSK9 with mortality using Cox proportional hazard models. We also assessed clinical factors associated with PCSK9 level and the association of PCSK9 with the number of days free of mechanical ventilation and days free of ICU care.ResultsIn 1,577 ARDS patients, median age was 53 years (IQR 42–65 years) and median APACHE III score 91 (72–111) connoting moderate critical illness. PCSK9 levels were 339.3 ng/mL (IQR 248.0–481.0). In multivariable models, race, cause of ARDS, body mass index, pre-existing liver disease, body temperature, sodium, white blood cell count and platelet count were associated with PCSK9 level. Presence of sepsis, use of vasopressors and ventilator parameters were not associated with PCSK9 level. PCSK9 levels were not associated with in-hospital mortality (HR per IQR 0.96, 95% CI 0.84–1.08, P = 0.47). Higher PCSK9 levels were associated with fewer ICU and ventilator free days.ConclusionsPlasma PCSK9 is not associated with mortality in ARDS, however higher PCSK9 levels are associated with secondary outcomes of fewer ICU free and ventilator free days. Clinical factors associated with PCSK9 in ARDS are largely unmodifiable. Further research to define the mechanism of this association is warranted.

Background Sex differences in the trends for control of cardiovascular disease (CVD) risk factors have been described, but temporal trends in the age at which CVD and its risk factors are diagnosed and sex‐specific differences in these trends are unknown. Methods and Results We used the Medical Expenditure Panel Survey 2008 to 2017, a nationally representative sample of the US population. Individuals ≥18 years, with a diagnosis of hypercholesterolemia, hypertension, coronary heart disease, or stroke, and who reported the age when these conditions were diagnosed, were included. We included 100 709 participants (50.2% women), representing 91.9 million US adults with above conditions. For coronary heart disease and hypercholesterolemia, mean age at diagnosis was 1.06 and 0.92 years older for women, compared with men, respectively (both P

Inflammation constitutes a complex, highly conserved cascade of molecular and cellular events. Inflammation has been labeled as “the fire within,” is highly regulated, and is critical to host defense and tissue repair. In general, inflammation is beneficial and has evolved to promote survival. However, inflammation can also be maladaptive when chronically activated and sustained, leading to progressive tissue injury and reduced survival. Examples of a maladaptive response include rheumatologic disease and atherosclerosis. Despite evidence gathered by Virchow over 100 years ago showing that inflammatory white cells play a role in atherogenesis, atherosclerosis was until recently viewed as a disease of passive cholesterol accumulation in the subendothelial space. This view has been supplanted by considerable basic scientific and clinical evidence demonstrating that every step of atherogenesis, from the development of endothelial cell dysfunction to foam cell formation, plaque formation and progression, and ultimately plaque rupture stemming from architectural instability, is driven by the cytokines, interleukins, and cellular constituents of the inflammatory response. Herein we provide an overview of the role of inflammation in atherosclerotic cardiovascular disease, discuss the predictive value of various biomarkers involved in inflammation, and summarize recent clinical trials that evaluated the capacity of various pharmacologic interventions to attenuate the intensity of inflammation and impact risk for acute cardiovascular events.

Background PCSK9 (proprotein convertase subtilisin/kexin type 9) is well recognized for its important role in cholesterol metabolism. Elevated levels are associated with increased cardiovascular risk and inhibition with PCSK9 antibodies (PCSK9i) lowers cardiovascular events in patients with coronary artery disease. PCSK9 levels are also elevated in people living with HIV (PLWH) and those with dyslipidemia. Because increased PCSK9 in PLWH is associated with impaired coronary endothelial function, a barometer of coronary vascular health, we tested the hypothesis that PCSK9i improves impaired coronary endothelial function in dyslipidemia without coronary artery disease and in PLWH with nearly optimal/above goal low‐density lipoprotein cholesterol levels. Methods and Results We performed a single‐center study in 19 PLWH and 11 with dyslipidemia to evaluate the effects of the PCSK9i evolocumab on coronary endothelial function using cine 3T MRI to noninvasively measure coronary endothelial function, assessed as the changes in coronary cross‐sectional area and coronary blood flow from rest to that during isometric handgrip exercise, a known endothelial‐dependent vasodilator. Before evolocumab, there was a decrease or no coronary vasodilation and no increase in coronary blood flow (the normal responses) to isometric handgrip exercise in either group. Following 6 weeks of evolocumab, 480 mg q4 weeks, the % cross‐sectional area changes from rest to isometric handgrip exercise were +5.6±5.5% and +4.5±3.1% in the PLWH and dyslipidemia groups, respectively, both P

Background HIV+ people are at increased risk of coronary artery disease, but the responsible mechanisms are incompletely understood. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is traditionally recognized for its importance in cholesterol metabolism; however, recent data suggest an additional, low‐density lipoprotein receptor–independent adverse effect on endothelial cell inflammation and function. We tested the hypotheses that PCSK9 levels are increased and that abnormal coronary endothelial function is related to PCSK9 serum levels in HIV+ individuals. Methods and Results Forty‐eight HIV+ participants receiving antiretroviral therapy with suppressed viral replication, without coronary artery disease, and 15 age‐ and low‐density lipoprotein cholesterol–matched healthy HIV− subjects underwent magnetic resonance imaging to measure coronary endothelial function, quantified as percentage change in coronary artery cross‐sectional area during isometric handgrip exercise, an endothelial‐dependent stressor; and blood was obtained for serum PCSK9 and systemic vascular biomarkers. Data are presented as mean±SD. Mean serum PCSK9 was 65% higher in the HIV+ subjects (302±146 ng/mL) than in the HIV− controls (183±52 ng/mL, P

Positron emission tomography/computed tomography (PET/CT) applied with positron-emitting flow tracers such as 13N-ammonia and 82Rubidium enables the quantification of both myocardial perfusion and myocardial blood flow (MBF) in milliliters per gram per minute for coronary artery disease (CAD) detection and characterization. The detection of a regional myocardial perfusion defect during vasomotor stress commonly identifies the culprit lesion or most severe epicardial narrowing, whereas adding regional hyperemic MBFs, myocardial flow reserve (MFR), and/or longitudinal flow decrease may also signify less severe but flow-limiting stenosis in multivessel CAD. The addition of regional hyperemic flow parameters, therefore, may afford a comprehensive identification and characterization of flow-limiting effects of multivessel CAD. The non-specific origin of decreases in hyperemic MBFs and MFR, however, prompts an evaluation and interpretation of regional flow in the appropriate context with the presence of obstructive CAD. Conversely, initial results of the assessment of a longitudinal hyperemic flow gradient suggest this novel flow parameter to be specifically related to increases in CAD caused epicardial resistance. The concurrent assessment of myocardial perfusion and several hyperemic flow parameters with PET/CT may indeed open novel avenues of precision medicine to guide coronary revascularization procedures that may potentially lead to a further improvement in cardiovascular outcomes in CAD patients.

Most studies of the heart focus on cardiomyocytes (CM) at the exclusion of other cell types such as myocardial endothelial cells (EC). Such mono-cellular approaches propagate the presumption that EC provide a mere passive lining or supportive role. In fact, EC contribute to a dynamic network regulating vascular tone, cardiac development, and repair. Two distinct EC types, vascular EC and epicardial EC, possess important structural and signaling properties within both the healthy and diseased myocardium. In this review, we address EC-CM interactions in mature, healthy myocardium, followed by a discussion of diseases characterized by EC dysfunction. Finally, we consider strategies to reverse EC-CM miscommunication to improve patients’ outcomes in various cardiovascular diseases.

Severe coronavirus disease-19 (COVID-19) is characterized by vascular inflammation and thrombosis. We and others have proposed that the inflammatory response to coronavirus infection activates endothelial cells, leading to endothelial release of pro-thrombotic proteins. These mediators can trigger obstruction of the pulmonary microvasculature, leading to worsening oxygenation, acute respiratory distress syndrome, and death. In the current study, we tested the hypothesis that higher levels of biomarkers released from endothelial cells are associated with worse oxygenation in patients with COVID-19. We studied 83 participants aged 18-84 years with COVID-19 admitted to a single center. The severity of pulmonary disease was classified by oxygen requirement, including no oxygen requirement, low-flow oxygen, high-flow nasal cannula oxygen, mechanical ventilation, and death. We measured plasma levels of two proteins released by activated endothelial cells, von Willebrand Factor (VWF) antigen and soluble P-Selectin (sP-Sel), and a biomarker of systemic thrombosis, D-dimer. Additionally, we explored the association of endothelial biomarker levels with the levels of pro-inflammatory cytokine and chemokines, and vascular inflammation biomarkers. We found that levels of VWF, sP-sel, and D-dimer were increased in individuals with more severe COVID-19 pulmonary disease. Biomarkers of endothelial cell activation were also correlated with proinflammatory cytokines and chemokines. Taken together, our data demonstrate increased levels of VWF and sP-selectin are linked to the severity of lung disease in COVID-19 and correlated with biomarkers of inflammation and vascular inflammation. Our data support the concept that COVID-19 is a vascular disease which involves endothelial injury in the context of an inflammatory state.

Endothelial-myocardial interactions may be critically important for ischemia/reperfusion injury. Tetrahydrobiopterin (BH4) is a required cofactor for nitric oxide (NO) production by endothelial NO synthase (eNOS). Hyperglycemia (HG) leads to significant increases in oxidative stress, oxidizing BH4 to enzymatically incompetent dihydrobiopterin. How alterations in endothelial BH4 content impact myocardial ischemia/reperfusion injury remains elusive. The aim of this study was to examine the effect of endothelial-myocardial interaction on ischemia/reperfusion injury, with an emphasis on the role of endothelial BH4 content. Langendorff-perfused mouse hearts were treated by triton X-100 to produce endothelial dysfunction and subsequently subjected to 30 min of ischemia followed by 2 h of reperfusion. The recovery of left ventricular systolic and diastolic function during reperfusion was impaired in triton X-100 treated hearts compared with vehicle-treated hearts. Cardiomyocytes (CMs) were co-cultured with endothelial cells (ECs) and subsequently subjected to 2 h of hypoxia followed by 2 h of reoxygenation. Addition of ECs to CMs at a ratio of 1∶3 significantly increased NO production and decreased lactate dehydrogenase activity compared with CMs alone. This EC-derived protection was abolished by HG. The addition of 100 µM sepiapterin (a BH4 precursor) or overexpression of GTP cyclohydrolase 1 (the rate-limiting enzyme for BH4 biosynthesis) in ECs by gene trasfer enhanced endothelial BH4 levels, the ratio of eNOS dimer/monomer, eNOS phosphorylation, and NO production and decreased lactate dehydrogenase activity in the presence of HG. These results demonstrate that increased BH4 content in ECs by either pharmacological or genetic approaches reduces myocardial damage during hypoxia/reoxygenation in the presence of HG. Maintaining sufficient endothelial BH4 is crucial for cardioprotection against hypoxia/reoxygenation injury.