Long-Term Mortality in Patients With Severe Hypercholesterolemia Phenotype From a Racial and Ethnically Diverse US Cohort.

BACKGROUND: Tools for mortality prediction in patients with the severe hypercholesterolemia phenotype (low-density lipoprotein cholesterol ≥190 mg/dL) are limited and restricted to specific racial and ethnic cohorts. We sought to evaluate the predictors of long-term mortality in a large racially and ethnically diverse US patient cohort with low-density lipoprotein cholesterol ≥190 mg/dL. METHODS: We conducted a retrospective analysis of all patients with a low-density lipoprotein cholesterol ≥190 mg/dL seeking care at Montefiore from 2010 through 2020. Patients <18 years of age or with previous malignancy were excluded. The primary end point was all-cause mortality. Analyses were stratified by age, sex, and race and ethnicity. Patients were stratified by primary and secondary prevention. Cox regression analyses were used to adjust for demographic, clinical, and treatment variables. RESULTS: A total of 18 740 patients were included (37% non-Hispanic Black, 30% Hispanic, 12% non-Hispanic White, and 2% non-Hispanic Asian patients). The mean age was 53.9 years, and median follow-up was 5.2 years. Both high-density lipoprotein cholesterol and body mass index extremes were associated with higher mortality in univariate analyses. In adjusted models, higher low-density lipoprotein cholesterol and triglyceride levels were associated with an increased 9-year mortality risk (adjusted hazard ratio [HR], 1.08 [95% CI, 1.05-1.11] and 1.04 [95% CI, 1.02-1.06] per 20-mg/dL increase, respectively). Clinical factors associated with higher mortality included male sex (adjusted HR, 1.31 [95% CI, 1.08-1.58]), older age (adjusted HR, 1.19 per 5-year increase [95% CI, 1.15-1.23]), hypertension (adjusted HR, 2.01 [95% CI, 1.57-2.57]), chronic kidney disease (adjusted HR, 1.68 [95% CI, 1.36-2.09]), diabetes (adjusted HR, 1.79 [95% CI, 1.50-2.15]), heart failure (adjusted HR, 1.51 [95% CI, 1.16-1.95]), myocardial infarction (adjusted HR, 1.41 [95% CI, 1.05-1.90]), and body mass index <20 kg/m2 (adjusted HR, 3.36 [95% CI, 2.29-4.93]). A significant survival benefit was conferred by lipid-lowering therapy (adjusted HR, 0.57 [95% CI, 0.42-0.77]). In the primary prevention group, high-density lipoprotein cholesterol <40 mg/dL was independently associated with higher mortality (adjusted HR, 1.49 [95% CI, 1.06-2.09]). Temporal trend analyses showed a reduction in statin use over time (P<0.001). In the most recent time period (2019-2020), 56% of patients on primary prevention and 85% of those on secondary prevention were on statin therapy. CONCLUSIONS: In a large, diverse cohort of US patients with the severe hypercholesterolemia phenotype, we identified several patient characteristics associated with increased 9-year all-cause mortality and observed a decrease in statin use over time, in particular for primary prevention. Our results support efforts geared toward early recognition and consistent treatment for patients with severe hypercholesterolemia.

Experimentally Induced Peripheral Venous Congestion Exacerbates Inflammation, Oxidative Stress, and Neurohormonal and Endothelial Cell Activation in Patients With Systolic Heart Failure.

BACKGROUND: Venous congestion (VC) is a hallmark of symptomatic heart failure (HF) requiring hospitalization; however, its role in the pathogenesis of HF progression remains unclear. We investigated whether peripheral VC exacerbates inflammation, oxidative stress and neurohormonal and endothelial cell (EC) activation in patients with HF with reduced ejection fraction (HFrEF). METHODS AND RESULTS: Two matched groups of patients with HFrEF and with no peripheral VC vs without recent HF hospitalization were studied. We modeled peripheral VC by inflating a cuff around the dominant arm, targeting ∼ 30 mmHg increase in venous pressure (venous stress test [VST]). Blood and ECs were sampled before and after 90 minutes of VST. We studied 44 patients (age 53 ± 12 years, 32% female). Circulating endothelin-1, tumor necrosis factor-α, interleukin-6, isoprostane, angiotensin II (ang-2), angiopoietin-2, vascular cell adhesion molecule-1, and CD146 significantly increased after the VST. Enhanced endothelin-1 and angiopoietin-2 responses to the VST were present in patients with vs without recent hospitalization and were prospectively associated with incident HF-related events; 6698 messenger ribonucleic acid (mRNA probe sets were differentially expressed in ECs after VST. CONCLUSIONS: Experimental VC exacerbates inflammation, oxidative stress, neurohormonal and EC activation and promotes unfavorable transcriptome remodeling in ECs of patients with HFrEF. A distinct biological sensitivity to VC appears to be associated with high risk for HF progression.

Thermal Shift Assay as a Tool to Evaluate the Release of Breakdown Peptides from Cowpea ß-Vignin during Seed Germination.

The present work aimed to characterize the molecular relationships between structure and function of the seed storage protein ß-vignin, the vicilin storage protein of cowpea (Vigna unguiculata, l. Walp) seeds. The molecular characterization of ß-vignin was carried out firstly by assessing its thermal stability, under different conditions of pH and ionic strength, by thermal shift assay (TSA) using SYPRO Orange fluorescent dye. Secondly, its aggregation propensity was evaluated using a combination of chromatographic and electrophoretic techniques. Two forms of ß-vignin were considered: the native form purified from mature quiescent seeds, and a stable breakdown intermediate of 27 kDa produced while seeds germinate. TSA is a useful tool for determining and following over time the structural changes that occur to the protein during germination. The main result was the molecular characterization of the 27 kDa intermediate breakdown polypeptide, which, to the best of our knowledge, has never been described before. ß-vignin seems to retain its trimeric conformation despite the evident degradation of its polypeptides.

SARS-COV-2 infection presenting as ST-elevationmyocardial infarction.

We describe a patient presenting with chest discomfort, anterolateral ST elevation, and developing acute cardiogenic shock secondary to SARS-COV-2infection-patient zero presenting to our institution's cardiac catheterization laboratory. The emergent presentation with limited clinical information led to exposure of personnel. The diagnosis was complicated by two negative tests for SARS-COV-2, and high-clinical suspicion from the patient's occupational history led to additional testing in order to confirm the diagnosis.

The Unique Blood Pressures and Pulsatility of LVAD Patients: Current Challenges and Future Opportunities.

An increasing number of end-stage heart failure patients are now implanted with continuous-flow left ventricular assist devices (CF-LVADs). Although this therapeutic approach is associated with improved clinical outcomes, continuous flow physiology reduces arterial pulse pressure and pulsatility to an extent that is unique to this population. Recent data suggest that high blood pressure (BP) contributes to life-threatening complications such as pump thrombosis and stroke of CF-LVAD patients. However, limited understanding of the distinct hemodynamics of these pumps makes measurement and, consequently, medical management of BP quite challenging. Here, we review the evolution of LVAD design, the impact of CF-LVAD flow, and "artificial pulse" technology on hemodynamics and BP measurement, as well as suggest new approaches for the assessment and interpretation of the unique physiology of modern LVADs.

Hypertension and Stroke in Patients with Left Ventricular Assist Devices (LVADs).

Stroke is one of the most dreaded complications of left ventricular assist device therapy in patients with end-stage congestive heart failure. There is strong evidence linking anticoagulation and infection with ischemic and hemorrhagic strokes, though recent data has emerged regarding the importance of elevated blood pressure. In the recently completed Heartware Ventricular Assist Device studies, a mean arterial pressure greater than 90 mmHg was associated with greater stroke risk, particularly the hemorrhagic subtype. In this review, we discuss recent evidence regarding deleterious effects of uncontrolled hypertension in patients with left ventricular devices, and propose measurement and management strategies.

Use of Extracorporeal Membrane Oxygenation for Primary Graft Dysfunction After Cardiac Transplantation: Results of an A Priori Ventless Approach.

Primary graft dysfunction (PGD) after cardiac transplantation is a devastating complication with increasing frequency lately in the setting of donation after circulatory death (DCD). Severe PGD is commonly treated with extracorporeal membrane oxygenation (ECMO) using central or peripheral cannulation. We retrospectively reviewed the outcomes of PGD after cardiac transplantation requiring ECMO support at our center from 2015 to 2020, focused on our now preferential approach using peripheral cannulation without a priori venting. During the study period, 255 patients underwent heart transplantation at our center and 26 (10.2%) of them required ECMO for PGD. Of 24 patients cannulated peripherally 19 (79%) were alive at 30 days and 17 (71%) 1 year after transplant; two additional patients underwent central ECMO cannulation due to unfavorable size of femoral vessels and concern for limb ischemia. Successful decannulation with full graft function recovery occurred in 22 of 24 (92%) patients cannulated peripherally. Six of them had an indwelling intra-aortic balloon pump placed before the transplantation. None of the other 18 patients received a ventricular vent. In conclusion, the use of an a priori peripheral and ventless ECMO approach in patients with PGD after heart transplant is an effective strategy associated with high rates of graft recovery and survival.

Association of cardiometabolic and vascular atherosclerosis phenotypes on non-contrast chest CT with incident heart failure in patients with severe hypercholesterolemia.

BACKGROUND: Coronary artery calcium (CAC), thoracic aorta calcification (TAC), non-alcoholic fatty liver disease (NAFLD), and epicardial adipose tissue (EAT) are associated with atherosclerotic cardiovascular disease (ASCVD) and heart failure (HF). OBJECTIVES: We aimed to determine whether these cardiometabolic and atherosclerotic risk factors identified by non-contrast chest computed tomography (CT) are associated with HF hospitalizations in patients with LDL-C≥ 190 mg/dL. METHODS: We conducted a retrospective cohort analysis of patients with LDL-C ≥190 mg/dL, aged ≥40 years without established ASCVD or HF, who had a non-contrast chest CT within 3 years of LDL-C measurement. Ordinal CAC, ordinal TAC, EAT, and NAFLD were measured. Kaplan-Meier curves and multivariable Cox regression models were built to ascertain the association with HF hospitalization. RESULTS: We included 762 patients with median age 60 (53-68) years, 68% (n=520) female, and median LDL-C level of 203 (194-216) mg/dL. Patients were followed for 4.7 (interquartile range 2.75-6.16) years, and 107 (14%) had a HF hospitalization. Overall, 355 (47%) patients had CAC=0, 210 (28%) had TAC=0, 116 (15%) had NAFLD, and median EAT was 79 mL (49-114). Moderate-Severe CAC (log-rank p<0.001) and TAC (log-rank p=0.006) groups were associated with increased HF hospitalizations. This association persisted when considering myocardial infarction (MI) as a competing risk. NAFLD and EAT volume were not associated with HF. CONCLUSIONS: In patients without established ASCVD and LDL-C≥190 mg/dL, CAC was independently associated with increased HF hospitalizations while TAC, NAFLD, and EAT were not.

Predicting Hemodynamic Changes During Intra-Aortic Balloon Pump Support With a Longitudinal Evaluation.

The use of intra-aortic balloon pump (IABP) has decreased in recent years due to negative outcome studies in cardiogenic shock complicating acute myocardial infarction, despite its favorable adverse-event profile. Acute hemodynamic response studies have identified potential super-responders with immediate improvements in cardiac index (CI) in heart failure patients. This single-center retrospective study aimed to predict CI and mean arterial pressure (MAP) changes throughout the entire duration of IABP support. The study analyzed 336 patients who received IABP between 2016 and 2022. Linear mixed-effect regression models were used to predict CI and MAP improvement during IABP support. The results showed that CI and MAP increases during the first days of support, and changes during IABP support varied with time and were associated with baseline parameters. Longitudinal CI change was associated with body surface area, baseline CI, baseline pulmonary artery pulsatility index, baseline need for pressors, and diabetes. Longitudinal MAP change was associated with baseline MAP, baseline heart rate, need for pressors, or inotropes. The study recommends considering these parameters when deciding if IABP is the most appropriate form of support for a specific patient. Further prospective studies are needed to validate the findings.

Global Longitudinal Strain Is Associated with Mortality in Patients with Multiple Myeloma.

Patients with multiple myeloma (MM) are at a high risk for developing cardiovascular complications. Global longitudinal strain (GLS) can detect early functional impairment before structural abnormalities develop. It remains unknown if reduced GLS is associated with reduced survival in patients with MM. We conducted a retrospective cohort analysis of patients diagnosed with MM between 1 January 2000 and 31 December 2017 at our institution. Patients with a 2D transthoracic echocardiogram completed within 1 year of MM diagnosis, left ventricular ejection fraction (LVEF) greater than 40%, and no history of myocardial infarction prior to MM diagnosis were included. GLS was measured using an artificial-intelligence-powered software (EchoGo Core), with reduced GLS defined as an absolute value of <18%. The primary outcome of interest was overall survival since myeloma diagnosis. Our cohort included 242 patients with a median follow up of 4.28 years. Fifty-two (21.5%) patients had reduced average GLS. Patients with reduced GLS were more likely to have an IVSd ≥ 1.2cm, E/E' > 9.6, LVEF/GLS > 4.1, higher LV mass index, and low-voltage ECG. A Total of 126 (52.1%) deaths occurred during follow-up. Overall survival was lower among patients with reduced GLS (adjusted HR: 1.81, CI: 1.07-3.05).

Pulsatility and flow patterns across macro- and microcirculatory arteries of continuous-flow left ventricular assist device patients.

BACKGROUND: Reduced arterial pulsatility in continuous-flow left ventricular assist devices (CF-LVAD) patients has been implicated in clinical complications. Consequently, recent improvements in clinical outcomes have been attributed to the "artificial pulse" technology inherent to the HeartMate3 (HM3) LVAD. However, the effect of the "artificial pulse" on arterial flow, transmission of pulsatility into the microcirculation and its association with LVAD pump parameters is not known. METHODS: The local flow oscillation (pulsatility index, PI) of common carotid arteries (CCAs), middle cerebral arteries (MCAs) and central retinal arteries (CRAs-representing the microcirculation) were quantified by 2D-aligned, angle-corrected Doppler ultrasound in 148 participants: healthy controls, n = 32; heart failure (HF), n = 43; HeartMate II (HMII), n = 32; HM3, n = 41. RESULTS: In HM3 patients, 2D-Doppler PI in beats with "artificial pulse" and beats with "continuous-flow" was similar to that of HMII patients across the macro- and microcirculation. Additionally, peak systolic velocity did not differ between HM3 and HMII patients. Transmission of PI into the microcirculation was higher in both HM3 (during the beats with "artificial pulse") and in HMII patients compared with HF patients. LVAD pump speed was inversely associated with microvascular PI in HMII and HM3 (HMII, r2 = 0.51, p < 0.0001; HM3 "continuous-flow," r2 = 0.32, p = 0.0009; HM3 "artificial pulse," r2 = 0.23, p = 0.007), while LVAD pump PI was only associated with microcirculatory PI in HMII patients. CONCLUSIONS: The "artificial pulse" of the HM3 is detectable in the macro- and microcirculation but without creating a significant alteration in PI compared with HMII patients. Increased transmission of pulsatility and the association between pump speed and PI in the microcirculation indicate that the future clinical care of HM3 patients may involve individualized pump settings according to the microcirculatory PI in specific end-organs.

The analysis of COVID-19 in-hospital mortality: A competing risk approach or a cure model?

Competing risk analyses have been widely used for the analysis of in-hospital mortality in which hospital discharge is considered as a competing event. The competing risk model assumes that more than one cause of failure is possible, but there is only one outcome of interest and all others serve as competing events. However, hospital discharge and in-hospital death are two outcomes resulting from the same disease process and patients whose disease conditions were stabilized so that inpatient care was no longer needed were discharged. We therefore propose to use cure models, in which hospital discharge is treated as an observed "cure" of the disease. We consider both the mixture cure model and the promotion time cure model and extend the models to allow cure status to be known for those who were discharged from the hospital. An EM algorithm is developed for the mixture cure model. We also show that the competing risk model, which treats hospital discharge as a competing event, is equivalent to a promotion time cure model. Both cure models were examined in simulation studies and were applied to a recent cohort of COVID-19 in-hospital patients with diabetes. The promotion time model shows that statin use improved the overall survival; the mixture cure model shows that while statin use reduced the in-hospital mortality rate among the susceptible, it improved the cure probability only for older but not younger patients. Both cure models show that treatment was more beneficial among older patients.

Incidence of new-onset atrial fibrillation in COVID-19 is associated with increased epicardial adipose tissue.

PURPOSE: Coronary artery calcium (CAC) and epicardial adipose tissue (EAT) can predict AF in the general population. We aimed to determine if CAC and EAT measured by computed tomographic (CT) scanning can predict new-onset AF in patients admitted with COVID-19 disease. METHODS: We performed a retrospective, post hoc analysis of all patients admitted to Montefiore Medical Center with a confirmed COVID-19 diagnosis from March 1st to June 23rd, 2020, who had a non-contrast CT of the chest within 5 years prior to admission. We determined ordinal CAC scores and quantified the EAT volume and examined their relationship with inpatient mortality. RESULTS: A total of 379 patients were analyzed. There were 16 events of new-onset AF (4.22%). Patients who developed AF during the index admission were more likely to be male (75 vs 47%, p < 0.001) and had higher EAT (129.5 [76.3-197.3] vs 91.0 [60.0-129.0] ml, p = 0.049). There were no differences on age (68 [56-71] vs 68 [58-76] years; p = 0.712), BMI (28.5 [25.3-30.8] vs 26.9 [23.1-31.8] kg/m2; p = 0.283), ordinal CAC score (3 [1-6] vs 2 [0-4]; p = 0.482), or prevalence of diabetes (56.3 vs 60.1%; p = 0.761), hypertension (75.0 vs 87.3%, p = 0.153), or coronary artery disease (50.0 vs 39.4%, p = 0.396). Patients with new-onset AF had worse clinical outcomes (death/intubation/vasopressors) (87.5 vs 44.1%; p = 0.001). CONCLUSION: Increased EAT measured by non-contrast chest CT identifies patients hospitalized with COVID-19 at higher risk of developing new-onset AF. Patients with new-onset AF have worse clinical outcomes.

Visual Coronary and Aortic Calcium Scoring on Chest Computed Tomography Predict Mortality in Patients With Low-Density Lipoprotein-Cholesterol ≥190 mg/dL.

BACKGROUND: Current guidelines recommend coronary artery calcium (CAC) scoring for stratification of atherosclerotic cardiovascular disease risk only in patients with borderline to intermediate risk score by the pooled cohort equation with low-density lipoprotein-cholesterol (LDL-C) of 70 to 190 mg/dL. It remains unknown if CAC or thoracic aorta calcification (TAC), detected on routine chest computed tomography, can provide further risk stratification in patients with LDL-C≥190 mg/dL. METHODS: From a multisite medical center, we retrospectively identified all patients from March 2005 to June 2021 age ≥40 years, without established atherosclerotic cardiovascular disease and LDL-C≥190 mg/dL who had non-gated non-contrast chest computed tomography within 3 years of LDL-C measurement. Ordinal CAC and TAC scores were measured by visual inspection. Kaplan-Meier curves and multivariable Cox-regression models were built to ascertain the association of CAC and TAC scores with all-cause mortality. RESULTS: We included 811 patients with median age 59 (53-68) years, 262 (32.3%) were male, and LDL-C median level was 203 (194-217) mg/dL. Patients were followed for 6.2 (3.29-9.81) years, and 109 (13.4%) died. Overall, 376 (46.4%) of patients had CAC=0 and 226 (27.9%) had TAC=0. All-cause mortality increased with any CAC and moderate to severe TAC. In a multivariate model, patients with CAC had a significantly higher mortality compared with those without CAC: mild hazard ratio (HR), 1.71 (1.03-2.83), moderate HR, 2.12 (1.14-3.94), and severe HR, 3.49 (1.94-6.27). Patients with moderate TAC (HR, 2.34 [1.19-4.59]) and those with severe TAC (HR, 3.02 [1.36-6.74]) had higher mortality than those without TAC. CONCLUSIONS: In patients without history of atherosclerotic cardiovascular disease and LDL-C≥190 mg/dL, the presence and severity of CAC and TAC are independently associated with all-cause mortality.

Hospital bed occupancy rate is an independent risk factor for COVID-19 inpatient mortality: a pandemic epicentre cohort study.

INTRODUCTION: COVID-19 first struck New York City in the spring of 2020, resulting in an unprecedented strain on our healthcare system and triggering multiple changes in public health policy governing hospital operations as well as therapeutic approaches to COVID-19. We examined inpatient mortality at our centre throughout the course of the pandemic. METHODS: This is a retrospective chart review of clinical characteristics, treatments and outcome data of all patients admitted with COVID-19 from 1 March 2020 to 28 February 2021. Patients were grouped into 3-month quartiles. Hospital strain was assessed as per cent of occupied beds based on a normal bed capacity of 1491. RESULTS: Inpatient mortality decreased from 25.0% in spring to 10.8% over the course of the year. During this time, use of remdesivir, steroids and anticoagulants increased; use of hydroxychloroquine and other antibiotics decreased. Daily bed occupancy ranged from 62% to 118%. In a multivariate model with all year's data controlling for demographics, comorbidities and acuity of illness, percentage of bed occupancy was associated with increased 30-day in-hospital mortality of patients with COVID-19 (0.7% mortality increase for each 1% increase in bed occupancy; HR 1.007, CI 1.001 to 1.013, p=0.004) CONCLUSION: Inpatient mortality from COVID-19 was associated with bed occupancy. Early reduction in epicentre hospital bed occupancy to accommodate acutely ill and resource-intensive patients should be a critical component in the strategic planning for future pandemics.

Twenty-four-hour blood pressure and heart rate variability are reduced in patients on left ventricular assist device support.

BACKGROUND: Limited data exist on the circadian blood pressure (BP) and heart rate (HR) variations that occur in heart failure (HF) patients on left ventricular assist device (LVAD) support. METHODS: We prospectively recorded clinic and 24-hour ambulatory BP and HR data in patients on HeartMate II LVAD support. Results were compared to HF patients with ejection fraction ≤30% and controls with no history of cardiovascular disease. Physiologic nocturnal BP and HR dipping was defined as a ≥10% decline compared to daytime values. RESULT: Twenty-nine LVAD patients (age 59 ± 15 years, 76% male, 38% ischemic etiology), 25 HF patients (age 64 ± 13 years, 84% male, 32% ischemic etiology) and 26 controls (age 56 ± 9 years, 62% male) were studied. Normal nocturnal BP dipping was less frequent in LVAD patients (10%) than in HF patients (28%) and controls (62%) and reversed BP dipping (BP increase at night) was more common in LVAD patients (24%), compared to HF (16%) and controls (8%), (p < 0.001, for all comparisons). Physiologic HR reduction was less frequent in LVAD patients (14%), compared to HF (16%) and controls (59%) (p < 0.001, for all comparisons). Among LVAD patients, 36% exhibited sustained hypertension over the 24-hours and 25% had white-coat hypertension. CONCLUSIONS: Treatment of advanced HF with an LVAD does not restore physiologic circadian variability of BP and HR; additionally, BP was not adequately controlled in more than a third of LVAD patients, and a quarter of them exhibited white-coat hypertension. Future studies are warranted to confirm these findings and investigate prognostic and management implications in this population.

Severity of Functional Mitral Regurgitation on Admission for Acute Decompensated Heart Failure Predicts Long-Term Risk of Rehospitalization and Death.

Background Functional mitral regurgitation (FMR) has emerged as a therapeutic target in patients with chronic heart failure and left ventricular systolic dysfunction. The significance of FMR in acute decompensated heart failure remains obscure. We systematically investigated the prevalence and clinical significance of FMR on admission in patients admitted with acute decompensated heart failure and left ventricular systolic dysfunction. Methods and Results The study was a single-center, retrospective review of patients admitted with acute decompensated heart failure and left ventricular systolic dysfunction between 2012 and 2017. Patients were divided into 3 groups of FMR: none/mild, moderate, and moderate-to-severe/severe FMR. The primary outcome was 1-year post-discharge all-cause mortality. We also compared these groups for 6-month heart failure hospitalization rates. Of 2303 patients, 39% (896) were women. Median left ventricular ejection fraction was 25%. Four hundred and fifty-three (20%) patients had moderate-to-severe/severe FMR, which was independently associated with 1-year all-cause mortality. Moderate or worse FMR was found in 1210 (53%) patients and was independently associated with 6-month heart failure hospitalization. Female sex was independently associated with higher severity of FMR. Conclusions More than half of patients hospitalized with acute decompensated heart failure and left ventricular systolic dysfunction had at least moderate FMR, which was associated with increased readmission rates and mortality. Intensified post-discharge follow-up should be undertaken to eliminate FMR amenable to pharmacological therapy and enable timely and appropriate intervention for persistent FMR. Further studies are needed to examine sex-related disparities in FMR.

Complement promotes endothelial von Willebrand factor and angiopoietin-2 release in obstructive sleep apnea.

STUDY OBJECTIVE: Obstructive sleep apnea (OSA) is highly prevalent and triples vascular thromboembolic risk. Intermittent hypoxia (IH) during transient cessation of breathing in OSA impairs endothelial protection against complement. Complement activation stimulates the endothelial release of a pro-thrombotic von Willebrand factor (vWF). We investigated whether increased complement activity in OSA promotes the endothelial release of vWF and pro-inflammatory angiopoietin-2. We further investigated whether improving complement protection with statins reverses these changes. METHODS: Using endothelial cells (ECs) and blood collected from OSA patients (n = 109) and controls (n = 67), we assessed whether altered cellular localization of complement inhibitor CD59 in OSA modulates exocytosis of Weibel-Palade bodies (WPB), secretory granules that store vWF and angiopoietin-2. These interactions were also assessed in vitro in ECs exposed to normoxia or IH with or without recombinant complement C9 and with or without atorvastatin. RESULTS: Circulating levels of angiopoietin-2 were greater in OSA than controls and levels of vWF cleavage products correlated with OSA severity. In cultured ECs, IH enhanced complement-stimulated angiopoietin-2 and vWF release by reducing EC surface and increasing intracellular expression of complement inhibitor CD59. Intracellular CD59 co-localized with WPB in OSA. IH increased binding of intracellular CD59 to syntaxin-3, which dissociated syntaxin-3 from voltage-sensitive calcium channel Cav1.2, and activated WPB exocytosis in a calcium-dependent manner. Atorvastatin reversed IH-enhanced endothelial release of vWF and angiopoietin-2. CONCLUSIONS: IH promotes the complement-mediated release of vWF and angiopoietin-2, which may contribute to pro-thrombotic and pro-inflammatory conditions in OSA. Statin reversed these effects, suggesting a potential approach to reduce cardiovascular risk in OSA.

Coronary artery calcification and epicardial adipose tissue as independent predictors of mortality in COVID-19.

Recent epidemiological studies have demonstrated that common cardiovascular risk factors are strongly associated with adverse outcomes in COVID-19. Coronary artery calcium (CAC) and epicardial fat (EAT) have shown to outperform traditional risk factors in predicting cardiovascular events in the general population. We aim to determine if CAC and EAT determined by Computed Tomographic (CT) scanning can predict all-cause mortality in patients admitted with COVID-19 disease. We performed a retrospective, post-hoc analysis of all patients admitted to Montefiore Medical Center with a confirmed COVID-19 diagnosis from March 1st, 2020 to May 2nd, 2020 who had a non-contrast CT of the chest within 5 years prior to admission. We determined ordinal CAC scores and quantified the epicardial (EAT) and thoracic (TAT) fat volume and examined their relationship with inpatient mortality. A total of 493 patients were analyzed. There were 197 deaths (39.95%). Patients who died during the index admission had higher age (72, [64-80] vs 68, [57-76]; p < 0.001), CAC score (3, [0-6] vs 1, [0-4]; p < 0.001) and EAT (107, [70-152] vs 94, [64-129]; p = 0.023). On a competing risk analysis regression model, CAC ≥ 4 and EAT ≥ median (98 ml) were independent predictors of mortality with increased mortality of 63% (p = 0.003) and 43% (p = 0.032), respectively. As a composite, the group with a combination of CAC ≥ 4 and EAT ≥ 98 ml had the highest mortality. CAC and EAT measured from chest CT are strong independent predictors of inpatient mortality from COVID-19 in this high-risk cohort.