key: cord-0979429-xnw250i1
authors: Wang, Bingyan J.; Vadakke-Madathil, Sangeetha; Croft, Lori B.; Brody, Rachel I.; Chaudhry, Hina W.
title: HIF-1α Cardioprotection in COVID-19 Patients
date: 2022-01-24
journal: JACC Basic Transl Sci
DOI: 10.1016/j.jacbts.2021.12.001
sha: a7bdb4c6c2f7b0f3b6159b643b2c432a2e3ccb7d
doc_id: 979429
cord_uid: xnw250i1

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Myocardial injury with sustained cardiac involvement is noted in more than half (58%) of patients and can be detected months after SARS-CoV-2 infection. 1 

illness and frequently leads to both pulmonary and cardiovascular tissue hypoxia. 2 Hypoxia-inducible factor (HIF)-1a is a master transcriptional regulator of tissue hypoxia and has been reported to decrease the expression of angiotensin-converting enzyme 2 (ACE2), which may potentially attenuate SARS-CoV-2 cell entry and lessen the severity of COVID-19. Of note, decreased pathogenicity of SARS-CoV-2 has been reported at high-altitude regions, possibly secondary to reduced ACE2 in lungs of local inhabitants who are acclimatized to hypoxia. 3 In this study, we examined markers of tissue hypoxia in post-mortem samples of 8 patients (age range 39 to 76 years; median age 64 years) with known SARS-CoV-2 infection. The COVID-19 patients were divided into 2 groups based on left ventricular ejection fraction (LVEF). Patients with LVEF >50% were categorized as "normal LVEF" (range 58% to 63%), and patients with LVEF <45% as "low LVEF" (range 33% to 43%). Three non-COVID hearts from donors of noncardiac cause of death served as control hearts (age range 59 to 79 years, median age 60 years). HIF-1a expression, which was determined by immunohistochemistry, was significantly higher in the hearts of patients with normal LVEF in comparison to the low LVEF group, whereas scant HIF-1a þ cells were observed in non-COVID hearts ( Figure 1A) . HIF1a was immunolocalized to CD31 þ endothelial cells in both the low and normal LVEF groups. Notably, all HIF-1a þ cells in the heart were terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-negative ( Figure 1A ).

These findings suggest, but do not prove, that HIF-1a up-regulation confers cytoprotective responses in endothelial cells in the hearts of COVID-19 patients.

In normal LVEF patients, HIF-1a was predominantly expressed in nonmyocytes, with either nuclear or perinuclear localization ( Figure 1B ). By contrast, in low LVEF patients, HIF-1a accumulated in a speckled pattern in cardiomyocyte nuclei ( Figure 1B ). We then examined nuclear and sarcomeric ultrastructure by transmission electron microscopy. Similar to non-COVID control hearts, the nuclear envelope appeared thick and dense in the normal LVEF hearts ( Figure 1B) . In low LVEF hearts, the nuclear envelope was thinner, without disruption of the lamin membrane. Sarcomeric damage was noted in the low LVEF heart as evidenced by swollen Z lines, smeared I bands, contracted sarcomeres, and distorted myofibril arrangements, whereas sarcomere disarray was not apparent in the normal LVEF group or in the non-COVID control hearts. Fewer mitochondria were detected in the hearts of low and normal LVEF groups of COVID-19 as compared with the hearts of control subjects. The mitochondria were scattered among myofibrils, rather than regularly aligned rows, as noted in control hearts. Additionally, mitochondria in low LVEF hearts were smaller, with swollen cristae.

We also examined heart sections by coimmunostaining with nuclear envelope marker lamin B1 and HIF-1a. In non-COVID hearts, lamin B1 was continuously expressed in all cells ( Figure 1B) . In COVID-19 cardiomyocytes that lacked HIF-1a expression, lamin B1 expression was decreased in normal LVEF hearts, whereas it was undetectable in low LVEF hearts.

Nuclei of the HIF-1amyocytes appeared to be All studies and protocols were reviewed and exempted by the institutional review board at Mount Sinai Hospital to be "not human subjects." Dr Chaudhry is supported by Empire State Stem Cell Board IIRP grant, contract number C32608GG and NIH grant R01HL150345. Dr Chaudhry is the founder and equity holder of VentriNova, Inc. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Cardiac involvement in patients recovered from covid-2019 identified using magnetic resonance imaging

Hypoxia-an overlooked trigger for thrombosis in COVID-19 and other critically ill patients

Does the pathogenesis of SARS-CoV-2 virus decrease at high-altitude?

SARS-CoV-2 infection of human iPSC-derived cardiac cells reflects cytopathic features in hearts of patients with COVID-19

Differential sub-nuclear distribution of hypoxia-inducible factors (HIF)-1 and -2 alpha impacts on their stability and mobility

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