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Abstract Elevation in soluble urokinase receptor (suPAR) and proteinuria are common signs in patients with moderate to severe coronavirus disease 2019 (COVID-19). Here we characterize a new type of proteinuria originating as part of a viral response. Inoculation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes increased suPAR levels and glomerulopathy in African green monkeys. Using an engineered mouse model with high suPAR expression, inhaled variants of SARS-CoV-2 spike S1 protein elicite proteinuria that could be blocked by either suPAR antibody or SARS-CoV-2 vaccination. In a cohort of 1991 COVID-19 patients, suPAR levels exhibit a stepwise association with proteinuria in non-Omicron, but not in Omicron infections, supporting our findings of biophysical and functional differences between variants of SARS-CoV-2 spike S1 protein and their binding to podocyte integrins. These insights are not limited to SARS-CoV-2 and define viral response proteinuria (VRP) as an innate immune mechanism and co-activation of podocyte integrins.

Abstract We sought to determine whether the biomarkers of chronic inflammation predict cognitive decline in a prospective observational study. We measured baseline serum soluble urokinase plasminogen activator receptor (suPAR) and high sensitivity C‐reactive protein (hs‐CRP) levels in 282 participants of the University of Michigan Memory and Aging Project. Cognitive function was measured using the Montreal Cognitive Assessment (MoCA) and the Clinical Dementia Rating (CDR) scale for up to five time points. SuPAR and hs‐CRP levels were not significantly higher in participants with mild cognitive impairment (n = 97) or dementia (n = 59), compared to those with normal cognitive function (n = 126). Overall, 14% of participants experienced significant cognitive decline over the study period. The change in MoCA or CDR scores over time did not differ significantly according to baseline suPAR or hs‐CRP levels. Chronic systemic inflammation, as measured by serum suPAR or hs‐CRP levels, is unlikely to contribute significantly to cognitive decline.

Background Evidence guiding the pre‐hematopoietic stem cell transplantation (HSCT) cardiovascular evaluation is limited. We sought to derive and validate a pre‐HSCT score for the cardiovascular risk stratification of HSCT candidates. Methods and Results We leveraged the CARE‐BMT (Cardiovascular Registry in Bone Marrow Transplantation) study, a contemporary multicenter observational study of adult patients who underwent autologous or allogeneic HSCT between 2008 and 2019 (N=2435; mean age at transplant of 55 years; 4.9% Black). We identified the subset of variables most predictive of post‐HSCT cardiovascular events, defined as a composite of cardiovascular death, myocardial infarction, heart failure, stroke, atrial fibrillation or flutter, and sustained ventricular tachycardia. We then developed a point‐based risk score using the hazard ratios obtained from Cox proportional hazards modeling. The score was externally validated in a separate cohort of 919 HSCT recipients (mean age at transplant 54 years; 20.4% Black). The risk score included age, transplant type, race, coronary artery disease, heart failure, peripheral artery disease, creatinine, triglycerides, and prior anthracycline dose. Risk scores were grouped as low‐, intermediate‐, and high‐risk, with the 5‐year cumulative incidence of cardiovascular events being 4.0%, 10.3%, and 22.4%, respectively. The area under the receiver operating curves for predicting cardiovascular events at 100 days, 5 and 10 years post‐HSCT were 0.65 (95% CI, 0.59–0.70), 0.73 (95% CI, 0.69–0.76), and 0.76 (95% CI, 0.69–0.81), respectively. The model performed equally well in autologous and allogeneic recipients, as well as in the validation cohort. Conclusions The CARE‐BMT risk score is easy to calculate and could help guide referrals of high‐risk HSCT recipients to cardiovascular specialists before transplant and guide long‐term monitoring.

Background Literature suggests a bidirectional association between advanced hepatic fibrosis (AHF) and coronary artery disease (CAD). We evaluated the association of AHF with immune activation, systemic inflammation, and adverse outcomes in patients with CAD. Methods and Results A fibrosis‐4 index cutoff value ≥2.67 was used to define AHF. Circulating levels of soluble urokinase plasminogen activator receptor and hsCRP (high‐sensitivity C‐reactive protein) were measured as markers for immune activation and systemic inflammation, respectively. The relationship of AHF with soluble urokinase plasminogen activator receptor, hsCRP, and adverse cardiovascular outcomes was evaluated. Among 3406 participants with CAD, 479 had AHF. Participants with AHF were older; were less likely to be Black individuals; and had a lower body mass index, worse renal function, and a prior history of heart failure. In multivariable linear regression models adjusted for clinical and demographic confounders, participants with AHF had 15.6% higher soluble urokinase plasminogen activator receptor and 24.0% higher hsCRP levels. They were more likely to experience the following adverse outcomes: all‐cause death (adjusted hazard ratio [HR], 1.57 ([95% CI, 1.29–1.92]; P

Abstract Background Cardiac metastasis of melanoma is rare and typically diagnosed post‐mortem. Here we perform a retrospective cohort study and systematic review of patients with metastatic melanoma to characterize prevalence, clinical characteristics, and outcomes of cardiac metastasis. Methods We reviewed the electronic medical records of all outpatients with metastatic melanoma who underwent evaluation at the University of Michigan in Ann Arbor from January 2009 to January 2022, identifying patients with a clinical or histopathologic diagnosis of cardiac metastasis. We performed a systematic review of the literature to summarize the clinical characteristics and outcomes of patients with melanoma and cardiac metastasis. Results Overall, 23 of 1254 (1.8%) patients with metastatic melanoma were diagnosed with cardiac metastasis. Cardiac metastasis was reported in the right ventricle (65%), left ventricle (35%), and right atrium (35%). A total of 11 (48%) patients experienced at least one cardiovascular complication after the diagnosis of cardiac metastasis, the most common being arrhythmia (30%), heart failure (22%), and pericardial effusion (17%). Immunotherapy was more commonly used in patients with cardiac metastasis (80% vs 65%; p = 0.005). Mortality at 2‐years post‐diagnosis was higher for patients with cardiac metastasis compared to those without (59% vs 37%; p = 0.034). Progression of malignancy was the underlying cause of death of all patients. Conclusions Cardiac metastasis occurs in

Background: Data regarding outcomes among patients with cancer and co-morbid cardiovascular disease (CVD)/cardiovascular risk factors (CVRF) after SARS-CoV-2 infection are limited. Objectives: To compare Coronavirus disease 2019 (COVID-19) related complications among cancer patients with and without co-morbid CVD/CVRF. Methods: Retrospective cohort study of patients with cancer and laboratory-confirmed SARS-CoV-2, reported to the COVID-19 and Cancer Consortium (CCC19) registry from 03/17/2020 to 12/31/2021. CVD/CVRF was defined as established CVD or no established CVD, male ≥ 55 or female ≥ 60 years, and one additional CVRF. The primary endpoint was an ordinal COVID-19 severity outcome including need for hospitalization, supplemental oxygen, intensive care unit (ICU), mechanical ventilation, ICU or mechanical ventilation plus vasopressors, and death. Secondary endpoints included incident adverse CV events. Ordinal logistic regression models estimated associations of CVD/CVRF with COVID-19 severity. Effect modification by recent cancer therapy was evaluated. Results: Among 10,876 SARS-CoV-2 infected patients with cancer (median age 65 [IQR 54–74] years, 53% female, 52% White), 6253 patients (57%) had co-morbid CVD/CVRF. Co-morbid CVD/CVRF was associated with higher COVID-19 severity (adjusted OR: 1.25 [95% CI 1.11–1.40]). Adverse CV events were significantly higher in patients with CVD/CVRF (all p

Acute kidney injury (AKI) secondary to sepsis results in poor outcomes and conventional kidney function indicators lack diagnostic value. Soluble urokinase plasminogen activator receptor (suPAR) is an innate immune–derived molecule implicated in inflammatory organ damage. We characterized the diagnostic ability of longitudinal serum suPAR levels to discriminate severity and course of sepsis-induced AKI (SI-AKI) in 200 critically ill patients meeting Sepsis-3 criteria. The pathophysiologic relevance of varying suPAR levels in SI-AKI was explored in a polymicrobial sepsis model in WT, (s)uPAR-knockout, and transgenic suPAR-overexpressing mice. At all time points studied, suPAR provided a robust classification of SI-AKI disease severity, with improved prediction of renal replacement therapy (RRT) and mortality compared with established kidney biomarkers. Patients with suPAR levels of greater than 12.7 ng/mL were at highest risk for RRT or death, with an adjusted odds ratio of 7.48 (95% CI, 3.00–18.63). suPAR deficiency protected mice against SI-AKI. suPAR-overexpressing mice exhibited greater kidney damage and poorer survival through inflamed kidneys, accompanied by local upregulation of potent chemoattractants and pronounced kidney T cell infiltration. Hence, suPAR allows for an innate immune–derived and kidney function–independent staging of SI-AKI and offers improved longitudinal risk stratification. suPAR promotes T cell–based kidney inflammation, while suPAR deficiency improves SI-AKI.

Background: Elevated cardiac troponin (cTn) levels in patients with COVID-19 has been associated with worse outcomes. Guidelines on best practices of those patients remain uncertain. Methods: We included patients with COVID-19 and cTn above the assay-specific upper limit of normal (ULN) enrolled in the American Heart Association's COVID-19 registry between March 2020–January 2021. Site-level variability in invasive coronary angiography, LVEF assessment, ICU utilization, and inpatient mortality were determined by calculating adjusted median odds ratio (MOR) using hierarchical logistic regression models. Temporal trends were assessed with Cochran-Armitage trend test. Results: Among 32,636 patients, we included 6234 (19.4 %) with cTn above ULN (age 68.7 ± 16.0 years, 56.5 % male, 51.5 % Caucasian), of whom 1365 (21.6 %) had ≥5-fold elevations. Across 55 sites, the median rate of invasive coronary angiography was 0.1 % with adjusted MOR 1.5(1.0,2.3), median LVEF assessment was 25.5 %, MOR 3.0(2.2,3.9), ICU utilization was 41.7 %, MOR 2.2(1.8,2.6), and mortality was 20.9 %, MOR 1.7(1.5,2.0). Over time, we noted a significant increase in invasive coronary angiography (p-trend = 0.001), and LVEF assessment (p-trend

People with kidney disease are disproportionately affected by atherosclerosis for unclear reasons. Soluble urokinase plasminogen activator receptor (suPAR) is an immune-derived mediator of kidney disease, levels of which are strongly associated with cardiovascular outcomes. We assessed suPAR’s pathogenic involvement in atherosclerosis using epidemiologic, genetic, and experimental approaches. We found serum suPAR levels to be predictive of coronary artery calcification and cardiovascular events in 5,406 participants without known coronary disease. In a genome-wide association meta-analysis including over 25,000 individuals, we identified a missense variant in the plasminogen activator, urokinase receptor (PLAUR) gene (rs4760), confirmed experimentally to lead to higher suPAR levels. Mendelian randomization analysis in the UK Biobank using rs4760 indicated a causal association between genetically predicted suPAR levels and atherosclerotic phenotypes. In an experimental model of atherosclerosis, proprotein convertase subtilisin/kexin–9 (Pcsk9) transfection in mice overexpressing suPAR (suPARTg) led to substantially increased atherosclerotic plaques with necrotic cores and macrophage infiltration compared with those in WT mice, despite similar cholesterol levels. Prior to induction of atherosclerosis, aortas of suPARTg mice excreted higher levels of CCL2 and had higher monocyte counts compared with WT aortas. Aortic and circulating suPARTg monocytes exhibited a proinflammatory profile and enhanced chemotaxis. These findings characterize suPAR as a pathogenic factor for atherosclerosis acting at least partially through modulation of monocyte function.

OBJECTIVES:. Older age is a key risk factor for adverse outcomes in critically ill patients with COVID-19. However, few studies have investigated whether preexisting comorbidities and acute physiologic ICU factors modify the association between age and death. DESIGN:. Multicenter cohort study. SETTING:. ICUs at 68 hospitals across the United States. PATIENTS:. A total of 5,037 critically ill adults with COVID-19 admitted to ICUs between March 1, 2020, and July 1, 2020. INTERVENTIONS:. None. MEASUREMENTS AND MAIN RESULTS:. The primary exposure was age, modeled as a continuous variable. The primary outcome was 28-day inhospital mortality. Multivariable logistic regression tested the association between age and death. Effect modification by the number of risk factors was assessed through a multiplicative interaction term in the logistic regression model. Among the 5,037 patients included (mean age, 60.9 yr [± 14.7], 3,179 [63.1%] male), 1,786 (35.4%) died within 28 days. Age had a nonlinear association with 28-day mortality (p for nonlinearity

Background Venous thromboembolism (VTE) contributes significantly to COVID‐19 morbidity and mortality. The urokinase receptor system is involved in the regulation of coagulation. Levels of soluble urokinase plasminogen activator receptor (suPAR) reflect hyperinflammation and are strongly predictive of outcomes in COVID‐19. Whether suPAR levels identify patients with COVID‐19 at risk for VTE is unclear. Methods and Results We leveraged a multinational observational study of patients hospitalized for COVID‐19 with suPAR and D‐dimer levels measured on admission. In 1960 patients (mean age, 58 years; 57% men; 20% Black race), we assessed the association between suPAR and incident VTE (defined as pulmonary embolism or deep vein thrombosis) using logistic regression and Fine‐Gray modeling, accounting for the competing risk of death. VTE occurred in 163 (8%) patients and was associated with higher suPAR and D‐dimer levels. There was a positive association between suPAR and D‐dimer (β=7.34; P=0.002). Adjusted for clinical covariables, including D‐dimer, the odds of VTE were 168% higher comparing the third with first suPAR tertiles (adjusted odds ratio, 2.68 [95% CI, 1.51–4.75]; P

Abstract Background While pre-existing cardiovascular disease (CVD) appears to be associated with poor outcomes in patients with Coronavirus Disease 2019 (COVID-19), data on patients with CVD and concomitant cancer is limited. The purpose of this study is to evaluate the effect of underlying CVD and CVD risk factors with cancer history on in-hospital mortality in those with COVID-19. Methods Data from symptomatic adults hospitalized with COVID-19 at 86 hospitals in the US enrolled in the American Heart Association’s COVID-19 CVD Registry was analyzed. The primary exposure was cancer history. The primary outcome was in-hospital death. Multivariable logistic regression models were adjusted for demographics, CVD risk factors, and CVD. Interaction between history of cancer with concomitant CVD and CVD risk factors were tested. Results Among 8222 patients, 892 (10.8%) had a history of cancer and 1501 (18.3%) died. Cancer history had significant interaction with CVD risk factors of age, body mass index (BMI), and smoking history, but not underlying CVD itself. History of cancer was significantly associated with increased in-hospital death (among average age and BMI patients, adjusted odds ratio [aOR] = 3.60, 95% confidence interval [CI]: 2.07–6.24; p

Abstract Cohort studies often provide a large array of data on study participants. The techniques of statistical learning can allow an efficient way to analyze large datasets in order to uncover previously unknown, clinically relevant predictors of morbidity or mortality. We applied a combination of elastic net penalized Cox regression and stability selection with the aim of identifying novel predictors of mortality in a cohort of prevalent hemodialysis patients. In our analysis we included 475 patients from the “rISk strAtification in end-stage Renal disease” (ISAR) study, who we split into derivation and confirmation cohorts. A wide array of examinations was available for study participants, resulting in over a hundred potential predictors. In the selection approach many of the well established predictors were retrieved in the derivation cohort. Additionally, the serum levels of IL-12p70 and AST were selected as mortality predictors and confirmed in the withheld subgroup. High IL-12p70 levels were specifically prognostic of infection-related mortality. In summary, we demonstrate an approach how statistical learning can be applied to a cohort study to derive novel hypotheses in a data-driven way. Our results suggest a novel role of IL-12p70 in infection-related mortality, while AST is a promising additional biomarker in patients undergoing hemodialysis.

Background Use of angiotensin‐converting enzyme inhibitors and angiotensin receptor blockers (ACEi/ARB) is thought to affect COVID‐19 through modulating levels of angiotensin‐converting enzyme 2, the cell entry receptor for SARS‐CoV2. We sought to assess the association between ACEi/ARB, biomarkers of inflammation, and outcomes in patients hospitalized for COVID‐19. Methods and Results We leveraged the ISIC (International Study of Inflammation in COVID‐19), identified patients admitted for symptomatic COVID‐19 between February 1, 2020 and June 1, 2021 for COVID‐19, and examined the association between in‐hospital ACEi/ARB use and all‐cause death, need for ventilation, and need for dialysis. We estimated the causal effect of ACEi/ARB on the composite outcomes using marginal structural models accounting for serial blood pressure and serum creatinine measures. Of 2044 patients in ISIC, 1686 patients met inclusion criteria, of whom 398 (23.6%) patients who were previously on ACEi/ARB received at least 1 dose during their hospitalization for COVID‐19. There were 215 deaths, 407 patients requiring mechanical ventilation, and 124 patients who required dialysis during their hospitalization. Prior ACEi/ARB use was associated with lower levels of soluble urokinase plasminogen activator receptor and C‐reactive protein. In multivariable analysis, in‐hospital ACEi/ARB use was associated with a lower risk of the composite outcome of in‐hospital death, mechanical ventilation, or dialysis (adjusted hazard ratio 0.49, 95% CI [0.36–0.65]). Conclusions In patients hospitalized for COVID‐19, ACEi/ARB use was associated with lower levels of inflammation and lower risk of in‐hospital outcomes. Clinical trials will define the role of ACEi/ARB in the treatment of COVID‐19. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT04818866.

OBJECTIVES:. Critically ill patients with coronavirus disease 2019 have variable mortality. Risk scores could improve care and be used for prognostic enrichment in trials. We aimed to compare machine learning algorithms and develop a simple tool for predicting 28-day mortality in ICU patients with coronavirus disease 2019. DESIGN:. This was an observational study of adult patients with coronavirus disease 2019. The primary outcome was 28-day inhospital mortality. Machine learning models and a simple tool were derived using variables from the first 48 hours of ICU admission and validated externally in independent sites and temporally with more recent admissions. Models were compared with a modified Sequential Organ Failure Assessment score, National Early Warning Score, and CURB-65 using the area under the receiver operating characteristic curve and calibration. SETTING:. Sixty-eight U.S. ICUs. PATIENTS:. Adults with coronavirus disease 2019 admitted to 68 ICUs in the United States between March 4, 2020, and June 29, 2020. INTERVENTIONS:. None. MEASUREMENTS AND MAIN RESULTS:. The study included 5,075 patients, 1,846 (36.4%) of whom died by day 28. eXtreme Gradient Boosting had the highest area under the receiver operating characteristic curve in external validation (0.81) and was well-calibrated, while k-nearest neighbors were the lowest performing machine learning algorithm (area under the receiver operating characteristic curve 0.69). Findings were similar with temporal validation. The simple tool, which was created using the most important features from the eXtreme Gradient Boosting model, had a significantly higher area under the receiver operating characteristic curve in external validation (0.78) than the Sequential Organ Failure Assessment score (0.69), National Early Warning Score (0.60), and CURB-65 (0.65; p < 0.05 for all comparisons). Age, number of ICU beds, creatinine, lactate, arterial pH, and Pao2/Fio2 ratio were the most important predictors in the eXtreme Gradient Boosting model. CONCLUSIONS:. eXtreme Gradient Boosting had the highest discrimination overall, and our simple tool had higher discrimination than a modified Sequential Organ Failure Assessment score, National Early Warning Score, and CURB-65 on external validation. These models could be used to improve triage decisions and clinical trial enrichment.

Summary: Many US states published crisis standards of care (CSC) guidelines for allocating scarce critical care resources during the COVID-19 pandemic. However, the performance of these guidelines in maximizing their population benefit has not been well tested. In 2,272 adults with COVID-19 requiring mechanical ventilation drawn from the Study of the Treatment and Outcomes in Critically Ill Patients with COVID-19 (STOP-COVID) multicenter cohort, we test the following three approaches to CSC algorithms: Sequential Organ Failure Assessment (SOFA) scores grouped into ranges, SOFA score ranges plus comorbidities, and a hypothetical approach using raw SOFA scores not grouped into ranges. We find that area under receiver operating characteristic (AUROC) curves for all three algorithms demonstrate only modest discrimination for 28-day mortality. Adding comorbidity scoring modestly improves algorithm performance over SOFA scores alone. The algorithm incorporating comorbidities has modestly worse predictive performance for Black compared to white patients. CSC algorithms should be empirically examined to refine approaches to the allocation of scarce resources during pandemics and to avoid potential exacerbation of racial inequities.

Background Limited information is available regarding in‐hospital cardiac arrest (IHCA) in patients with COVID‐19. Methods and Results We leveraged the American Heart Association COVID‐19 Cardiovascular Disease (AHA COVID‐19 CVD) Registry to conduct a cohort study of adults hospitalized for COVID‐19. IHCA was defined as those with documentation of cardiac arrest requiring medication or electrical shock for resuscitation. Mixed effects models with random intercepts were used to identify independent predictors of IHCA and mortality while accounting for clustering at the hospital level. The study cohort included 8518 patients (6080 not in the intensive care unit [ICU]) with mean age of 61.5 years (SD 17.5). IHCA occurred in 509 (5.9%) patients overall with 375 (73.7%) in the ICU and 134 (26.3%) patients not in the ICU. The majority of patients at the time of ICHA were not in a shockable rhythm (76.5%). Independent predictors of IHCA included older age, Hispanic ethnicity (odds ratio [OR], 1.9; CI, 1.4–2.4; P

Abstract Background Cardiotoxicity associated with anthracycline-based chemotherapies has limited their use in patients with preexisting cardiomyopathy or heart failure. Dexrazoxane protects against the cardiotoxic effects of anthracyclines, but in the USA and some European countries, its use had been restricted to adults with advanced breast cancer receiving a cumulative doxorubicin (an anthracycline) dose > 300 mg/m2. We evaluated the off-label use of dexrazoxane as a cardioprotectant in adult patients with preexisting cardiomyopathy, undergoing anthracycline chemotherapy. Methods Between July 2015 and June 2017, five consecutive patients, with preexisting, asymptomatic, systolic left ventricular (LV) dysfunction who required anthracycline-based chemotherapy, were concomitantly treated with off-label dexrazoxane, administered 30 min before each anthracycline dose, regardless of cancer type or stage. Demographic, cardiovascular, and cancer-related outcomes were compared to those of three consecutive patients with asymptomatic cardiomyopathy treated earlier at the same hospital without dexrazoxane. Results Mean age of the five dexrazoxane-treated patients and three patients treated without dexrazoxane was 70.6 and 72.6 years, respectively. All five dexrazoxane-treated patients successfully completed their planned chemotherapy (doxorubicin, 280 to 300 mg/m2). With dexrazoxane therapy, changes in LV systolic function were minimal with mean left ventricular ejection fraction (LVEF) decreasing from 39% at baseline to 34% after chemotherapy. None of the dexrazoxane-treated patients experienced symptomatic heart failure or elevated biomarkers (cardiac troponin I or brain natriuretic peptide). Of the three patients treated without dexrazoxane, two received doxorubicin (mean dose, 210 mg/m2), and one received daunorubicin (540 mg/m2). Anthracycline therapy resulted in a marked reduction in LVEF from 42.5% at baseline to 18%. All three developed symptomatic heart failure requiring hospitalization and intravenous diuretic therapy. Two of them died from cardiogenic shock and multi-organ failure. Conclusion The concomitant administration of dexrazoxane in patients with preexisting cardiomyopathy permitted successful delivery of anthracycline-based chemotherapy without cardiac decompensation. Larger prospective trials are warranted to examine the use of dexrazoxane as a cardioprotectant in patients with preexisting cardiomyopathy who require anthracyclines.

Background: South Asians are a high-risk ethnic group for cardiovascular disease despite having lower levels of conventional cardiovascular risk factors such as obesity and smoking. Ethnic differences in pulse wave reflections, arterial stiffness, and subclinical atherosclerosis as measured using augmentation index (AIX), pulse wave velocity (PWV), and carotid intima-media thickness (CIMT) may reflect some of this excess risk. Methods: We conducted a cross-sectional analysis of pooled data from three community-based sources in Atlanta, Georgia, USA. Data on 530 South Asians collected from local health fairs was compared with data on 507 White and 192 African Americans from the Emory Predictive Health Initiative and 351 White and 382 African Americans from the Morehouse and Emory Team up to Eliminate Health Disparities Study. Results: Linear regression models adjusted for age, sex, smoking, MAP, fasting glucose, TC, HDL-C, creatinine, and body mass index were used to assess the relationship between ethnicity and vascular function measures. In fully adjusted models, South Asians had higher heart rate corrected AIX as compared with Whites and African Americans (by 5.47%, p

IntroductionIdentifying patients at high risk of developing kidney disease could lead to early clinical interventions that prevent or slow disease progression. Soluble urokinase plasminogen activator receptor (suPAR) is an inflammatory biomarker thought to be involved in the pathogenesis and development of kidney disease. We aimed to determine whether elevated plasma suPAR measured at hospital admission is associated with incident kidney disease in patients presenting to the emergency department.Materials and MethodsThis was a retrospective registry-based cohort study performed at the Emergency Department of Copenhagen University Hospital Amager and Hvidovre, Hvidovre, Denmark. Patients were included in the study from November 2013 to March 2017 and followed until June 2017. Patients were excluded if they were diagnosed with kidney disease or died prior to index discharge. Plasma suPAR was measured at hospital admission, and the main outcome was time to incident kidney disease, defined by ICD-10 diagnosis codes for both chronic and acute kidney conditions. Association between suPAR and time to incident kidney disease was assessed by Cox proportional hazard regression analysis.ResultsIn total, 25,497 patients (median age 58.1 years; 52.5% female) were admitted to the emergency department and followed for development of kidney disease. In multivariable Cox regression analysis adjusting for age, sex, eGFR, CRP, cardiovascular disease, hypertension, and diabetes, each doubling in suPAR at hospital admission was associated with a hazard ratio of 1.57 (95% CI: 1.38–1.78, P < 0.001) for developing a chronic kidney condition and 2.51 (95% CI: 2.09–3.01, P < 0.001) for developing an acute kidney condition.DiscussionIn a large cohort of acutely hospitalized medical patients, elevated suPAR was independently associated with incident chronic and acute kidney conditions. This highlights the potential for using suPAR in risk classification models to identify high-risk patients who could benefit from early clinical interventions. The main limitation of this study is its reliance on accurate reporting of ICD-10 codes for kidney disease.

Background Women have higher circulating levels of soluble urokinase‐type plasminogen activator receptor (suPAR), and elevated suPAR is associated with cardiovascular risk. The independent association of sex with suPAR and the impact of sex on its association with cardiovascular risk are unknown. Methods and Results Plasma suPAR was measured using ELISA in 2 cohorts of 666 asymptomatic individuals (49 years, 65% women) and 4184 patients with coronary artery disease (63 years, 37% women). Independent association of sex with suPAR was studied using linear regression models adjusted for demographics, risk factors, and visceral adiposity in asymptomatic participants. Impact of sex on association of suPAR with all‐cause mortality was studied in patients with coronary artery disease using multivariable‐adjusted Cox models. Sex‐specific suPAR cutoffs for predicting all‐cause mortality were calculated. Asymptomatic women had 10% higher suPAR compared with men after adjusting for confounders, and visceral adiposity partly accounted for this association. Over a median follow‐up of 5.2 years, 795 deaths were recorded in patients with coronary artery disease. Log2‐transformed suPAR was independently associated with mortality (hazard ratio per 1‐SD 1.72, 95% CI 1.60–1.85) and an interaction with sex was noted (P=0.005). Association of suPAR with mortality was slightly weaker in women (hazard ratio 1.61, 95% CI 1.41–1.83) compared with men (hazard ratio 1.83, 95% CI 1.67–2.00). However, using sex‐specific suPAR cut‐offs (4392 pg/mL for women and 3187 pg/mL for men), a similar mortality incidence was observed for both sexes (38.5% and 35.5%, respectively, P=0.3). Conclusions Women have 10% higher plasma suPAR levels compared with men. Elevated sex‐specific plasma suPAR levels are equally predictive of risk of adverse events in both sexes.

Background: Global longitudinal strain (GLS) has incremental value in assessing left ventricular (LV) function in severe aortic stenosis and is related to clinical outcome after transcatheter aortic valve replacement (TAVR). We sought to identify relevant echocardiographic predictors of GLS improvement and myocardial function recovery after TAVR. Methods: We analyzed baseline and 12-month follow-up echocardiograms for LV strain analysis from 123 patients who underwent at Emory University Hospital with the Edwards SAPIEN valve between 7/2007 and 7/2013. Results: At baseline, 61 had reduced LV ejection fraction (LVEF) ≤50% (rEF), and 80 had preserved LVEF >50% (pEF). Higher baseline mean pressure gradient (MPG) and aortic peak velocity (AV Vmax) predicted myocardial function recovery defined as ≥20% improvement in global longitudinal strain (r = 0.29, p

Abstract Background Redox signaling, which can be assessed by circulating aminothiols, reflects oxidative stress (OS) status and has been linked to clinical cardiovascular disease and its risk factors. These, in turn, are related to executive function decline. OS may precede the pro-inflammatory state seen in vascular disease. The objective of this study is to investigate the association between aminothiol markers of OS and inflammation in cognitive decline, especially in the executive cognitive domain which is highly susceptible to cardiovascular risk factors and is an important predictor of cognitive disability. Methods The study design is that of a longitudinal cohort study within the setting of a large academic institution with participants being university employees (n = 511), mean age 49 years, 68% women, and 23% African-American. These participants were followed for four consecutive years with a yearly cognitive assessment conducted using computerized versions of 15 cognitive tests. Peripheral cystine, glutathione, their disulfide derivatives, and C-reactive protein (CRP) were measured. Results Lower levels of glutathione at baseline was associated with a decline in the executive domain over 4 years (covariate-adjusted relative risk (RR) for glutathione = 1.70 (95% CI = 1.02–2.85), p = 0.04). Furthermore, a longitudinal decline in glutathione level was associated with a faster decline in the executive domain (p = 0.03). None of the other OS markers or CRP were linked to cognitive decline over 4 years. Conclusion Increased OS reflected by decreased glutathione was associated with a decline in executive function in a healthy population. In contrast, inflammation was not linked to cognitive decline. OS may be an earlier biomarker that precedes the inflammatory phase of executive decline with aging.

Soluble urokinase-type plasminogen activator receptor (suPAR) strongly predicts outcomes and incident chronic kidney disease (CKD) in patients with cardiovascular disease (CVD). Whether the association between suPAR and CKD is a reflection of its overall association with chronic inflammation and poor CVD outcomes is unclear. We examined whether CVD biomarkers, including high-sensitivity C-reactive protein (hs-CRP), fibrin-degradation products (FDPs), heat-shock protein 70 (HSP-70), and high-sensitivity troponin I (hs-TnI) were associated with a decline in kidney function in the Emory Cardiovascular Biobank cohort, in which suPAR levels were shown to be predictive of both incident CKD and CVD outcomes. Methods: We measured suPAR, hs-CRP, HSP-70, FDP, and hs-TnI plasma levels in 3282 adults (mean age 63 years, 64% male, 75% estimated glomerular filtration rate [eGFR] >60 ml/min per 1.73 m2). Glomerular filtration rate was estimated using Chronic Kidney Disease–Epidemiology Collaboration (eGFR) at enrollment (n = 3282) and follow-up (n = 2672; median 3.5 years). Urine protein by dipstick at baseline was available for 1335 subjects. Results: There was a weak correlation among biomarkers (r range: 0.17−0.28). hs-CRP, FDPs, hs-TnI, and suPAR were independently associated with baseline eGFR and proteinuria. The median yearly decline in eGFR was −0.6 ml/min per 1.73 m2. hs-CRP (β: −0.04; P = 0.46), FDPs (β: −0.13; P = 0.08), HSP-70 (β: 0.05; P = 0.84), or hs-TnI (β: −0.01; P = 0.76) were associated with eGFR decline. suPAR remained predictive of eGFR decline even after adjusting for all biomarkers. Discussion: hs-CRP, FDP, HSP-70, and hs-TnI were not associated with eGFR decline. The specific association of suPAR with eGFR decline supported its involvement in pathways specific to the pathogenesis of kidney disease.

Background Educational attainment is an indicator of socioeconomic status and is inversely associated with coronary artery disease risk. Whether educational attainment level (EAL) among patients with coronary artery disease influences outcomes remains understudied. Methods and Results Patients undergoing cardiac catheterization had their highest EAL assessed using options of elementary/middle school, high school, college, or graduate education. Primary outcome was all‐cause mortality and secondary outcomes were a composite of cardiovascular death/non‐fatal myocardial infarction and non‐fatal myocardial infarction during follow‐up. Cox models adjusted for clinically relevant confounders were used to analyze the association of EAL with outcomes. Among 6318 patients (63.5 years, 63% men, 23% black) enrolled, 16%, 42%, 38%, and 4% had received graduate or higher, college, high school, and elementary/middle school education, respectively. During 4.2 median years of follow‐up, there were 1066 all‐cause deaths, 812 cardiovascular deaths/non‐fatal myocardial infarction, and 276 non‐fatal myocardial infarction. Compared with patients with graduate education, those in lower EAL categories (elementary/middle school, high school, or college education) had a higher risk of all‐cause mortality (hazard ratios 1.52 [95% CI 1.11–2.09]; 1.43 [95% CI 1.17–1.73]; and 95% CI 1.26 [1.03–1.53], respectively). Similar findings were observed for secondary outcomes. Conclusions Low educational attainment is an independent predictor of adverse outcomes in patients undergoing angiographic coronary artery disease evaluation. The utility of incorporating EAL into risk assessment algorithms and the causal link between low EAL and adverse outcomes in this high‐risk patient population need further investigation.

A recent publication by Mekonnen et al. demonstrated that among women with non-obstructive coronary artery disease, higher levels of circulating progenitor cells in the blood (CPC), were associated with impaired coronary flow reserve [1]. We performed a quality control assessment of the stability of circulating blood progenitor cells in blood samples stored at 4 °C, to determine the time period during which blood samples can be analyzed and yield consistent data for progenitor cell content. Healthy volunteers (n=6) were recruited and underwent phlebotomy, and blood was stored in EDTA tubes at 4 °C. Flow cytometry was performed to quantitate progenitor cell subsets at 0–4 h, 24 h, and 48 h post phlebotomy. All processed samples were fixed with 1% Paraformaldehyde and 1,000,000 total data events were collected. We found no significant differences in PC data for both CD34+ (P=0.68 for one-way ANOVA) and CD34+/CD133+ (P=0.74 for one-way ANOVA).

BackgroundType 2 diabetes mellitus is a major risk factor for cardiovascular disease; however, outcomes in individual patients vary. Soluble urokinase plasminogen activator receptor (suPAR) is a bone marrow–derived signaling molecule associated with adverse cardiovascular and renal outcomes in many populations. We characterized the determinants of suPAR in African Americans with type 2 diabetes mellitus and assessed whether levels were useful for predicting mortality beyond clinical characteristics, coronary artery calcium (CAC), and high‐sensitivity C‐reactive protein (hs‐CRP). Methods and ResultsWe measured plasma suPAR levels in 500 African Americans with type 2 diabetes mellitus enrolled in the African American‐Diabetes Heart Study. We used Kaplan‐Meier curves and Cox proportional hazards models adjusting for clinical characteristics, CAC, and hs‐CRP to examine the association between suPAR and all‐cause mortality. Last, we report the change in C‐statistics comparing the additive values of suPAR, hs‐CRP, and CAC to clinical models for prediction of mortality. The suPAR levels were independently associated with female sex, smoking, insulin use, decreased kidney function, albuminuria, and CAC. After a median 6.8‐year follow‐up, a total of 68 deaths (13.6%) were recorded. In a model incorporating suPAR, CAC, and hs‐CRP, only suPAR was significantly associated with mortality (hazard ratio 2.66, 95% confidence interval 1.63‐4.34). Addition of suPAR to a baseline clinical model significantly improved the C‐statistic for all‐cause death (Δ0.05, 95% confidence interval 0.01‐0.10), whereas addition of CAC or hs‐CRP did not. ConclusionsIn African Americans with type 2 diabetes mellitus, suPAR was strongly associated with mortality and improved risk discrimination metrics beyond traditional risk factors, CAC and hs‐CRP. Studies addressing the clinical usefulness of measuring suPAR concentrations are warranted.

BackgroundThe associations between high‐sensitivity troponin I (hsTnI) levels and coronary artery disease (CAD) severity and progression remain unclear. We investigated whether there is an association between hsTnI and angiographic severity and progression of CAD and whether the predictive value of hsTnI level for incident cardiovascular outcomes is independent of CAD severity. Methods and ResultsIn 3087 patients (aged 63±12 years, 64% men) undergoing cardiac catheterization without evidence of acute myocardial infarction, the severity of CAD was calculated by the number of major coronary arteries with ≥50% stenosis and the Gensini score. CAD progression was assessed in a subset of 717 patients who had undergone ≥2 coronary angiograms >3 months before enrollment. Patients were followed up for incident all‐cause mortality and incident cardiovascular events. Of the total population, 11% had normal angiograms, 23% had nonobstructive CAD, 20% had 1‐vessel CAD, 20% had 2‐vessel CAD, and 26% had 3‐vessel CAD. After adjusting for age, sex, race, body mass index, smoking, hypertension, diabetes mellitus history, and renal function, hsTnI levels were independently associated with the severity of CAD measured by the Gensini score (log 2 ß=0.31; 95% confidence interval, 0.18–0.44; P

BackgroundBeing unmarried is associated with decreased survival in the general population. Whether married, divorced, separated, widowed, or never‐married status affects outcomes in patients with cardiovascular disease has not been well characterized. Methods and ResultsA prospective cohort (inception period 2003–2015) of 6051 patients (mean age 63 years, 64% male, 23% black) undergoing cardiac catheterization for suspected or confirmed coronary artery disease was followed for a median of 3.7 years (interquartile range: 1.7–6.7 years). Marital status was stratified as married (n=4088) versus unmarried (n=1963), which included those who were never married (n=451), divorced or separated (n=842), or widowed (n=670). The relationship between marital status and primary outcome of cardiovascular death and myocardial infarction was examined using Cox regression models adjusted for clinical characteristics. There were 1085 (18%) deaths from all causes, 688 (11%) cardiovascular‐related deaths, and 272 (4.5%) incident myocardial infarction events. Compared with married participants, being unmarried was associated with higher risk of all‐cause mortality (hazard ratio [HR]: 1.24; 95% confidence interval [CI], 1.06–1.47), cardiovascular death (HR: 1.45; 95% CI, 1.18–1.78), and cardiovascular death or myocardial infarction (HR: 1.52; 95% CI, 1.27–1.83). Compared with married participants, the increase in cardiovascular death or myocardial infarction was similar for the participants who were divorced or separated (HR: 1.41; 95% CI, 1.10–1.81), widowed (HR: 1.71; 95% CI, 1.32–2.20), or never married (HR: 1.40; 95% CI, 0.97–2.03). The findings persisted after adjustment for medications and other socioeconomic factors. ConclusionsMarital status is independently associated with cardiovascular outcomes in patients with or at high risk of cardiovascular disease, with higher mortality in the unmarried population. The mechanisms responsible for this increased risk require further study.

BackgroundLower levels of circulating progenitor cells (PCs) reflect impaired endogenous regenerative capacity and are associated with aging, vascular disease, and poor outcomes. Whether biologic sex and sex hormones influence PC numbers remains a subject of controversy. We sought to determine sex differences in circulating PCs in both healthy persons and patients with coronary artery disease, and to determine their association with sex hormone levels. Methods and ResultsIn 642 participants (mean age 48 years, 69% women, 23% black) free from cardiovascular disease, we measured circulating PC counts as CD45med+ mononuclear cells coexpressing CD34 and its subsets expressing CD133, chemokine (C‐X‐C motif) receptor 4, and vascular endothelial growth factor receptor 2 epitopes using flow cytometry. Testosterone and estradiol levels were measured. After adjustment for age, cardiovascular risk factors, and body mass, CD34+ (β=−23%, P