Myocyte Specific Upregulation of ACE2 in Cardiovascular Disease: Implications for SARS-CoV-2 mediated myocarditis

Nathan R Tucker; Mark Chaffin; Kenneth C Bedi; Irinna Papangeli; Amer-Denis Akkad; Alessandro Arduini; Sikander Hayat; Gökcen Eraslan; Christoph Muus; Roby Bhattacharyya; Christian M Stegmann; Kenneth B Margulies; Patrick T Ellinor

The predominant portal of entry for SARS-CoV-2 is via ACE2 expression in the upper respiratory epithelium and lungs, 3 yet ACE2 is also abundantly expressed in the intestine, kidney, heart and testes. The observation that twenty percent of hospitalized patients with COVID-19 in Wuhan, China had evidence cardiac injury resuggest a possible pathological role for myocardial ACE2 expression. 4 In a single-center report of 416 patients hospitalized with COVID-19, 19.7% had evidence of cardiac injury. Moreover, the presence of cardiac injury was associated with a 5fold increase in mechanical ventilation and a 51.2% mortality rate. In this context, the potential for a primary viral myocarditis with SARS-CoV-2 is gaining support. Prior findings of viral RNA from SARS-CoV-1, which also infects cells via ACE2, in 35% of autopsied hearts during an earlier SARS-CoV epidemic, lends credence to this possibility. 5 Involvement of ACE2 in COVID-19 pathogenesis has led to consideration of whether inhibitors of angiotensin converting enzyme (ACEi) and angiotensin receptor blockers (ARB) might modulate disease progression through increased expression of ACE2. 6 Indeed, trials proposing to test the impact of both initiation (NCT04312009) and withdrawal of these agents are being advanced during the current pandemic. This uncertainty has provoked public statements by three leading cardiovascular societies advising continuation of these agents in the absence of compelling new data. 7 To address these questions, we assessed ACE2 expression in normal and diseased human myocardial samples from the Penn Human Heart Tissue Biobank by bulk and single nucleus RNA-seq. Our group has previously utilized this approach to study the transcriptional diversity of the cell subtypes and associated gene programs in the normal human heart. 8 ACE2 expression was assessed in the left ventricles of 11 individuals with dilated cardiomyopathy (DCM), 15 individuals with hypertrophic cardiomyopathy (HCM), and 16 nonfailing controls defined as individuals without any overt indication of cardiac dysfunction. The baseline characteristics for the study population are provided in Supplementary Table 1. In an exploratory analysis, the effects of ACEi treatment on ACE2 expression were evaluated in the subset of patients with HCM, in which six individuals were receiving ACEi and eight that were not prescribed an ACEi.