Background Patients with pre-existing heart failure (HF) are likely at higher risk for adverse outcomes in coronavirus disease-2019 (COVID-19), but data on this population are sparse. Objectives This study described the clinical profile and associated outcomes among patients with HF hospitalized with COVID-19. Methods This study conducted a retrospective analysis of 6,439 patients admitted for COVID-19 at 1 of 5 Mount Sinai Health System hospitals in New York City between February 27 and June 26, 2020. Clinical characteristics and outcomes (length of stay, need for intensive care unit, mechanical ventilation, and in-hospital mortality) were captured from electronic health records. For patients identified as having a history of HF by International Classification of Diseases-9th and/or 10th Revisions codes, manual chart abstraction informed etiology, functional class, and left ventricular ejection fraction (LVEF). Results Mean age was 63.5 years, and 45% were women. Compared with patients without HF, those with previous HF experienced longer length of stay (8 days vs. 6 days; p < 0.001), increased risk of mechanical ventilation (22.8% vs. 11.9%; adjusted odds ratio: 3.64; 95% confidence interval: 2.56 to 5.16; p < 0.001), and mortality (40.0% vs. 24.9%; adjusted odds ratio: 1.88; 95% confidence interval: 1.27 to 2.78; p = 0.002). Outcomes among patients with HF were similar, regardless of LVEF or renin-angiotensin-aldosterone inhibitor use. Conclusions History of HF was associated with higher risk of mechanical ventilation and mortality among patients hospitalized for COVID-19, regardless of LVEF.

No abstract

Altogether, these data suggest that increased levels of miR-195 in failing myocardium regulate a novel pathway that involves direct SIRT3 suppression and enzymatic inhibition via increased acetylation of PDH and ATP synthase that are essential for cardiac energy metabolism.

Following the publication of our article, we became aware of a related publication by Reforgiato and coauthors that described increased de novo ceramide synthesis and inflammation adjacent to the necrotic core area in a mouse model of 30 minutes of ischemia and reperfusion injury (1). Similar to the findings of our study in a chronic model of ischemic cardiomyopathy 3 months following myocardial infarction and in a large cohort of patients with advanced heart failure, Reforgiato et al. found that ceramide accumulation was accompanied by increased levels of serine palmitoyltransferase (SPT), which could be inhibited by administration of myriocin, an inhibitor of SPT. Their study, which was performed in an animal model of acute ischemic injury, independently supports the findings of our systematic lipidomic study in patients with advanced heart failure before and after mechanical unloading and cardiomyopathy as well as Sptlc2-deletion mice. We believe the detailed lipidomic analysis in our study provides an important advance to the field. This analysis allowed the differentiation of various ceramide species, and we related specific ceramide chain lengths to the biologic phenotypes described. Further, we linked ceramide metabolism and de novo ceramide synthesis using various expression plasmids (sptlc1, -2 and -3) in cell culture experiments to changes in ceramide species accumulation and dysregulation of oxidative and glycolytic metabolism as typical for the failing myocardium. Thus, we linked the lipids to changes in their metabolic pathways. Together, these studies highlight a key role of de novo ceramide synthesis of distinct ceramide species and their accumulation following acute ischemic injury and in chronically failing myocardium.

Abnormal lipid metabolism may contribute to myocardial injury and remodeling. To determine whether accumulation of very long-chain ceramides occurs in human failing myocardium, we analyzed myocardial tissue and serum from patients with severe heart failure (HF) undergoing placement of left ventricular assist devices and controls. Lipidomic analysis revealed increased total and very long-chain ceramides in myocardium and serum of patients with advanced HF. After unloading, these changes showed partial reversibility. Following myocardial infarction (MI), serine palmitoyl transferase (SPT), the rate-limiting enzyme of the de novo pathway of ceramide synthesis, and ceramides were found increased. Blockade of SPT by the specific inhibitor myriocin reduced ceramide accumulation in ischemic cardiomyopathy and decreased C16, C24:1, and C24 ceramides. SPT inhibition also reduced ventricular remodeling, fibrosis, and macrophage content following MI. Further, genetic deletion of the SPTLC2 gene preserved cardiac function following MI. Finally, in vitro studies revealed that changes in ceramide synthesis are linked to hypoxia and inflammation. In conclusion, cardiac ceramides accumulate in the failing myocardium, and increased levels are detectable in circulation. Inhibition of de novo ceramide synthesis reduces cardiac remodeling. Thus, increased de novo ceramide synthesis contributes to progressive pathologic cardiac remodeling and dysfunction.