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The impact of statins, angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers (ARBs) on coronavirus disease 2019 (COVID-19) severity and recovery is important given their high prevalence of use among individuals at risk for severe COVID-19. We studied the association between use of statin/angiotensin-converting enzyme inhibitors/ARB in the month before hospital admission, with risk of severe outcome, and with time to severe outcome or disease recovery, among patients hospitalized for COVID-19. We performed a retrospective single-center study of all patients hospitalized at University of California San Diego Health between February 10, 2020 and June 17, 2020 (n = 170 hospitalized for COVID-19, n = 5,281 COVID-negative controls). Logistic regression and competing risks analyses were used to investigate progression to severe disease (death or intensive care unit admission), and time to discharge without severe disease. Severe disease occurred in 53% of COVID-positive inpatients. Median time from hospitalization to severe disease was 2 days; median time to recovery was 7 days. Statin use prior to admission was associated with reduced risk of severe COVID-19 (adjusted OR 0.29, 95%CI 0.11 to 0.71, p < 0.01) and faster time to recovery among those without severe disease (adjusted HR for recovery 2.69, 95%CI 1.36 to 5.33, p < 0.01). The association between statin use and severe disease was smaller in the COVID-negative cohort (p for interaction = 0.07). There was potential evidence of faster time to recovery with ARB use (adjusted HR 1.92, 95%CI 0.81 to 4.56). In conclusion, statin use during the 30 days prior to admission for COVID-19 was associated with a lower risk of developing severe COVID-19, and a faster time to recovery among patients without severe disease.

Key Points Cardiac troponin level is prognostic for adverse cardiovascular outcomes in both sexes Increasingly sensitive assays for cardiac troponins will renew focus on sex-specific differences in troponin concentrations, and might increase the relevance of sex-specific cut-off points for diagnosis, prognosis, and risk prediction Healthy women have a higher natriuretic peptide level than healthy men, but the same cut-off points for diagnosis and prognosis of heart failure can generally be used in both sexes Soluble ST2 level is lower in healthy women than healthy men; however; a cut-off point of 35 ng/ml seems to be robust for prognosis in both sexes with heart failure Proneurotensin might improve prediction of incident cardiovascular disease, diabetes mellitus, and breast cancer in women, although further studies are needed to confirm these associations Measurement of biomarkers is a critical component of cardiovascular care, but sex-specific differences in these markers have not been fully integrated into clinical practice. In this Review, Daniels and Maisel assess the utility of sex-specific cut-off points when measuring cardiac troponins or natriuretic peptides in the diagnosis and prognosis of acute coronary syndrome and heart failure, respectively. They also discuss sex-specific differences in novel cardiovascular biomarkers, such as galectin-3, soluble ST2, and proneurotensin. Measurement of biomarkers is a critical component of cardiovascular care. Women and men differ in their cardiac physiology and manifestations of cardiovascular disease. Although most cardiovascular biomarkers are used by clinicians without taking sex into account, sex-specific differences in biomarkers clearly exist. Baseline concentrations of many biomarkers (including cardiac troponin, natriuretic peptides, galectin-3, and soluble ST2) differ in men versus women, but these sex-specific differences do not generally translate into a need for differential sex-based cut-off points. Furthermore, most biomarkers are similarly diagnostic and prognostic, regardless of sex. Two potential exceptions are cardiac troponins measured by high-sensitivity assay, and proneurotensin. Troponin levels are lower in women than in men and, with the use of high-sensitivity assays, sex-specific cut-off points might improve the diagnosis of myocardial infarction. Proneurotensin is a novel biomarker that was found to be predictive of incident cardiovascular disease in women, but not men, and was also predictive of incident breast cancer. If confirmed, proneurotensin might be a unique biomarker of disease risk in women. With any biomarker, an understanding of sex-specific differences might improve its use and might also lead to an enhanced understanding of the physiological differences between the hearts of men and women.

Statins have anti-inflammatory and immunomodulatory effects that may reduce the severity of coronavirus disease 2019 (COVID-19), in which organ dysfunction is mediated by severe inflammation. Large studies with diverse populations evaluating statin use and outcomes in COVID-19 are lacking. We used data from 10,541 patients hospitalized with COVID-19 through September 2020 at 104 US hospitals enrolled in the American Heart Association's COVID-19 Cardiovascular Disease (CVD) Registry to evaluate the associations between statin use and outcomes. Prior to admission, 42% of subjects (n = 4,449) used statins (7% on statins alone, 35% on statins plus anti-hypertensives). Death (or discharge to hospice) occurred in 2,212 subjects (21%). Outpatient use of statins, either alone or with anti-hypertensives, was associated with a reduced risk of death (adjusted odds ratio [aOR] 0.59, 95% CI 0.50-0.69), adjusting for demographic characteristics, insurance status, hospital site, and concurrent medications by logistic regression. In propensity-matched analyses, use of statins and/or anti-hypertensives was associated with a reduced risk of death among those with a history of CVD and/or hypertension (aOR 0.68, 95% CI 0.58-0.81). An observed 16% reduction in odds of death among those without CVD and/or hypertension was not statistically significant.

The clinical sequalae of SARS-CoV-2 infection are in part dependent upon age and pre-existing health conditions. Although the use of tobacco products decreases cardiorespiratory fitness while increasing susceptibility to microbial infections, limited information is available on how smoking affects COVID-19 severity. Therefore, we examined whether smokers hospitalized for COVID-19 are at a greater risk for developing severe complications than non-smokers. Data were from all hospitalized adults with SARS-CoV-2 infection from the American Heart Association’s Get-With-The-Guidelines COVID-19 Registry, from January 2020 to March 2021, which is a hospital-based voluntary national registry initiated in 2019 with 122 participating hospitals across the United States. Patients who reported smoking at the time of admission were classified as smokers. Severe outcome was defined as either death or the use of mechanical ventilation. Of the 31,545 patients in the cohort, 6,717 patients were 1:2 propensity matched (for age, sex, race, medical history, medications, and time-frame of hospital admission) and classified as current smokers or non-smokers according to admission data. In multivariable analyses, after adjusting for sociodemographic characteristics, medical history, medication use, and the time of hospital admission, patients self-identified as current smokers had higher adjusted odds of death (adjusted odds ratio [aOR], 1.41; 95% CI, 1.21–1.64), the use of mechanical ventilation (aOR 1.15; 95% CI 1.01–1.32), and increased risk of major adverse cardiovascular events (aOR, 1.27; 95% CI 1.05–1.52). Independent of sociodemographic characteristics and medical history, smoking was associated with a higher risk of severe COVID-19, including death.

Among patients with chronic heart failure (HF), it is known that soluble concentrations of the interleukin receptor family member ST2 (sST2) are prognostic for adverse outcome, including risk for progression of HF and death. Considerably less was known about the merits of serial testing of sST2 and whether such testing provides incremental information beyond single measurements; additionally, the influence of HF therapies on sST2 concentrations and whether sST2 values predicted benefit of therapy changes remained unclear. Recently, several studies indicate that serial testing for sST2 increases the prognostic information gained compared with a single measurement. When measured in patients with chronic HF, concentrations of sST2 appear to predict worsening left ventricular remodeling, and serial measurements of sST2 appear particularly useful for predicting HF events, such as worsening HF and risk for either hospitalization or death from HF. Values for sST2 are lower in those treated with several HF therapies; in turn, sST2 concentrations may predict benefit from specific HF therapy changes. Using an upper reference limit of 35 ng/ml, serial testing for sST2 in chronic HF thus appears useful. The promising role of sST2 for serial chronic HF therapy monitoring will be discussed.

Galectin-3 is a marker of myocardial fibrosis that has been implicated in the pathophysiologic pathway of fibrosis; its association with all-cause and cardiovascular disease (CVD) mortality in a community-based cohort free of baseline CVD has not been reported. Our aim was to determine the association between galectin-3 levels and all-cause and CVD mortality in community-dwelling older adults without known CVD. We measured plasma galectin-3 levels in 1,393 Rancho Bernardo Study participants without CVD with a mean age of 70 years. Participants were followed up for a mean of 11 years for coronary heart disease, CVD mortality, and all-cause mortality. During follow-up, 436 participants died (169 from CVD). In models adjusted for traditional CVD risk factors and renal function, galectin-3 was a significant predictor of CVD mortality (hazard ratio [HR] per SD log increase 1.30, 95% CI 1.10-1.53) and all-cause mortality (HR 1.12, 1.01-1.24), but not coronary heart disease (HR 1.09, 0.92-1.30). After further adjusting for N-terminal pro B-type natriuretic peptide, galectin-3 remained an independent predictor (HR 1.24, 1.05-1.47) of CVD mortality. Galectin-3 improved the c statistic (0.847-0.851, P = .003) for prediction of CVD death. Net reclassification improvement (>0) with the addition of galectin-3 was 35% (P < .0001); the integrated discrimination index was also significant (P = .03). Participants with both galectin-3 and N-terminal pro B-type natriuretic peptide above the median had increased risk of CVD death vs those with higher levels of only 1 of these markers (HR 1.74, 1.24-2.43). Higher levels of galectin-3 are independently associated with all-cause and CVD mortality among community-dwelling older adults with no known CVD at baseline.

To further explore the potential role of sST2 in the progression of cardiac disease, this section reviews both the associations with cross-sectional findings and longitudinal changes in cardiac structure and function measured by echocardiography and cardiac magnetic resonance imaging with sST2 levels in a variety of patient populations with or at-risk for cardiovascular disease. In a Pro-Brain Natriuretic Peptide Investigation of Dyspnea in the Emergency Department substudy in patients with acute dyspnea, sST2 levels were found associated with left ventricular ejection fraction (LVEF), and both estimated right ventricular (RV) systolic pressure and RV hypokinesis. In a large cohort of ambulatory patients referred for echocardiograms, sST2 was predominantly associated with RV and not LV structural findings. In contrast, in the Framingham Heart Study, a community cohort of >3,300 participants, sST2 was not associated with either echocardiographic finding, although in the Cardiovascular Health Study, sST2 appeared strongly associated with the presence of diastolic dysfunction. Little evidence exists on the relation of sST2 levels with longitudinal change in cardiac structure and function. A substudy of Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) evaluated the association among LV remodeling (defined as an increase in LV end-systolic and -diastolic volumes), sST2, and the benefit of eplerenone and found that sST2 levels were good surrogates of left ventricular remodeling. In the same line, the ProBNP Outpatient Tailored Chronic Heart Failure (PROTECT) study found that more time spent with an sST2 level less than the cutoff of 35 ng/L identified patients with a greater probability of a decrease in LV diastolic index over 1 year.

Coronary artery aneurysms that occur in 25% of untreated Kawasaki disease (KD) patients may remain clinically silent for decades and then thrombose resulting in myocardial infarction. Although KD is now the most common cause of acquired heart disease in children in Asia, the United States, and Western Europe, the incidence of KD in Egypt is unknown. We tested the hypothesis that young adults in Egypt presenting with acute myocardial ischemia may have coronary artery lesions because of KD in childhood. We reviewed a total of 580 angiograms of patients ≤40 years presenting with symptoms of myocardial ischemia. Coronary artery aneurysms were noted in 46 patients (7.9%), of whom 9 presented with myocardial infarction. The likelihood of antecedent KD as the cause of the aneurysms was classified as definite (n = 10), probable (n = 29), or equivocal (n = 7). Compared with the definite and probable groups, the equivocal group had more traditional cardiovascular risk factors, smaller sized aneurysms, and fewer coronary arteries affected. In conclusion, in a major metropolitan center in Egypt, 6.7% of adults aged ≤40 years who underwent angiography for evaluation of possible myocardial ischemia had lesions consistent with antecedent KD. Because of the unique therapeutic challenges associated with these lesions, adult cardiologists should be aware that coronary artery aneurysms in young adults may be because of missed KD in childhood.

N-terminal-pro–B-type natriuretic peptide (NT-proBNP) and cardiac troponin T (TnT) predict cardiovascular disease (CVD) risk in a variety of populations. Whether their predictive value varies by ethnicity is unknown. We sought to determine whether NT-proBNP and TnT improve prediction of incident coronary heart disease (CHD) and CVD, independent of CVD risk factors, in a multiethnic population; whether NT-proBNP improves prediction compared with the Framingham Risk Score or the Pooled Cohort Risk Equation; and whether a second NT-proBNP further improves prediction. Both NT-proBNP and TnT were measured in 5,592 MESA white, black, Hispanic, and Chinese participants (60% nonwhite; mean age 62.3 ± 10.3 years) in 2000 to 2002 and 2004 to 2005. We evaluated adjusted risk of incident CHD and CVD based on baseline and change in biomarker concentration. Participants were followed up through 2011 and incurred 370 CVD events (232 CHD). Concentrations of NT-proBNP and TnT varied by ethnicity. Both NT-proBNP and TnT were associated with an increased risk of events (adjusted hazard ratio [HR] for CHD [95% CI] for fifth quintile vs other 4 quintiles of NT-proBNP, 2.03 [1.50-2.76]; HR for CHD for detectable vs undetectable TnT, 3.95 [2.29-6.81]). N-terminal-pro–B-type natriuretic peptide improved risk prediction and classification compared with the Framingham Risk Score and the Pooled Cohort Risk Equation. Change in NT-proBNP was independently associated with events (HR for CHD per unit increase in ΔlogNT-proBNP, 1.95 [1.16-3.26]). None of the observed associations varied by ethnicity. Both NT-proBNP and TnT are predictors of incident CHD, independent of established risk factors and ethnicity, in a multiethnic population without known CVD. Change in NT-proBNP may add additional prognostic information.

Subsets of patients with a remote history of Kawasaki disease (KD) have coronary artery aneurysms with associated risks of late morbidity. In a pilot study, we previously showed that computed tomography (CT) coronary artery calcium (CAC) scoring detects late CAC in patients with aneurysms and a remote history of KD. We performed CT calcium volume scoring in 166 subjects (median age 19.5 years) with a remote history of KD (median interval from KD to CT 15.1 years). Coronary arteries were classified as normal (n = 100), transiently dilated (n = 23), persistently dilated (n = 10), remodeled aneurysm (n = 9), or aneurysm (n = 24) based on echocardiography. All subjects with coronary arteries classified as normal, persistently dilated, or remodeled aneurysm had zero CAC. Of the 24 subjects with coronary aneurysms, all but 5 had CAC (median volume 542 mm3; range 17 to 8,218 mm3). For subjects imaged ≥9 years after their acute KD (n = 144), the presence of CAC had a sensitivity of 95% and a specificity of 100% for detecting coronary artery abnormalities (defined as coronary artery aneurysm and/or stenosis). In conclusion, coronary calcification was not observed in subjects with a history of KD who had normal coronary arteries by echocardiography during the acute phase. Coronary calcification, which may be severe, occurs late in patients with coronary aneurysms. Therefore, CAC scanning may be a useful tool to screen patients with a remote history of KD or suspected KD and unknown coronary artery status.