Marked Up-Regulation of ACE2 in Hearts of Patients With Obstructive Hypertrophic Cardiomyopathy: Implications for SARS-CoV-2–Mediated COVID-19

Abstract

Objective: To explore the transcriptomic differences between patients with hypertrophic cardiomyopathy (HCM) and controls. Patients and Methods: RNA was extracted from cardiac tissue flash frozen at therapeutic surgical septal myectomy for 106 patients with HCM and 39 healthy donor hearts. Expression profiling of 37,846 genes was performed using the Illumina Human HT-12v3 Expression BeadChip. All patients with HCM were genotyped for pathogenic variants causing HCM. Technical validation was performed using quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot. This study was started on January 1, 1999, and final analysis was completed on April 20, 2020. Results: Overall, 22% of the transcriptome (8443 of 37,846 genes) was expressed differentially between HCM and control tissues. Analysis by genotype revealed that gene expression changes were similar among genotypic subgroups of HCM, with only 4% (1502 of 37,846) to 6% (2336 of 37,846) of the transcriptome exhibiting differential expression between genotypic subgroups. The qRT-PCR confirmed differential expression in 92% (11 of 12 genes) of tested transcripts. Notably, in the context of coronavirus disease 2019 (COVID-19), the transcript for angiotensin I converting enzyme 2 (ACE2), a negative regulator of the angiotensin system, was the single most up-regulated gene in HCM (fold-change, 3.53; q-value ¼1.30Â10 À23 ), which was confirmed by qRT-PCR in triplicate (fold change, 3.78; P¼5.22Â10 À4 ), and Western blot confirmed greater than 5-fold overexpression of ACE2 protein (fold change, 5.34; P¼1.66Â10 À6 ). Conclusion: More than 20% of the transcriptome is expressed differentially between HCM and control tissues. Importantly, ACE2 was the most up-regulated gene in HCM, indicating perhaps the heart's compensatory effort to mount an antihypertrophic, antifibrotic response. However, given that the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) uses ACE2 for viral entry,

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“…This possibility is supported by the heterogeneous expression of ACE2 in the human heart and may explain why pre-existing cardiovascular disease represents a strong risk factor for COVID-19 mortality. Consistent with this idea, ACE2 expression is increased in heart failure ( 30 , 40 ).…”

Heparin-binding protein levels correlate with aggravation and multiorgan damage in severe COVID-19

“…While false negative testing, as well as underlying chronic diseases exacerbated by the stress of infection, could be contributing factors, an inflammatory condition caused by SARS-CoV-2 may persist after viral RNA is no longer detectable. A secondary inflammatory storm may occur during this stage of infection, causing multi-organ failures [5,[8][9][10][11][12]. The aggravation of such inflammatory processes during otherwise a clinically stable state was also reported in 2002 during SARS as well as in some cases of severe community-acquired pneumonia [13][14][15].…”

Biophysics of human anatomy and physiology—a Special Issue in honor of Prof. Cristobal dos Remedios on the occasion of his 80th birthday

“…This position has allowed Cris, in a state of semi-retirement, to perform individual research projects supported by small grants 9 . Still heavily involved in collaborative research, Cris's most recent research effort concerned the analysis of cardiac tissue damage arising from COVID-19 infection (Bos et al 2020). Through telephone conversation, Cris explained that he had a hunch that related high levels of ACE2 expression on cardiac tissue to heart damage and thought that this may be an important factor in understanding the current systemic effects of the COVID-19 pandemic.…”