HIF1alpha Cardioprotection in COVID-19 Patients

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Abstract
Importance: SARS-CoV-2 infection directly causes severe acute respiratory illness, leading to systemic tissue hypoxia and ischemia including the heart. Myocardial cytopathy associated with hypoxic response has been largely overlooked in COVID-19 patients. Additionally, histology analysis and cardiac function of COVID-19 cases are often reported separately, rendering an incomplete understanding of COVID-19 cardiac symptoms. Objective: To examine the relationship between myocardial cellular responses to hypoxic stress versus cardiac functional alterations within the same COVID-19 patients. Design, Setting, and Participants: Cellular hypoxia Inducible Factor 1 alpha (HIF1α) expression was analyzed by immunohistochemistry using post-mortem COVID-19 heart and lung tissues with known cardiac echocardiography records from a total of 8 patients. Clinical echocardiography data were obtained from Mount Sinai Heart between March to December, 2020. All gender and age groups were considered as long as cardiac involvement meets the preserved (EF > 50%) or moderate to severe (EF < 45%) criteria with confirmed SARS-CoV-2 infection. Cell-type specific subcellular localization of HIF1α expression and nuclear stability was examined by immunohistochemistry and transmission electronic microscopy (TEM). Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) was used to quantify apoptosis. Main Outcomes and Measures: No planned outcomes of this study as this is a retrospective analysis based on post-mortem specimens exclusively. Results: Cardiac HIF1α expression was found to be significantly higher in patients with preserved EF levels than it was in the low EF group. In the preserved EF group, HIF1α is protective against apoptosis predominantly in endothelial cells and cardiac fibroblasts. In the low EF group, HIF1α protects cardiomyocyte nuclear integrity as evident by its nuclear accumulation with nuclear envelope preservation. Conclusions and Relevance: This study establishes a direct link of cardiac cellular responses to hypoxic stress with matching functional and histological data, serving as one of the first studies to bridge previous stand-alone clinical data and cellular data. The protective role of HIF1α in hearts may help predict cardiac involvement in not only COVID-19 patients, but also decipher the underlying mechanisms in other forms of viral cardiomyopathy. KEY POINTS: Question: Are hypoxic signaling pathways associated with cardiac functional alterations in COVID-19 patients? Findings: Cardiac HIF1α expression of COVID-19 patients with EF>50% or EF+ cells were found in patients with higher EF. HIF1α + endothelial cells are resistant to apoptosis, and HIF1α + cardiomyocytes are able to retain nuclear envelope under hypoxic stress. Meaning: HIF1α is cardioprotective in hearts of COVID-19 patients.

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