HIF1alpha Cardioprotection in COVID-19 Patients

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. 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<45% was analyzed and quantified. Increased cardiac HIF1α+ 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. ### Competing Interest Statement B.J.W, L.B.C, S.V.M, and R.I.B report no conflict of interest. H.W.C. is the founder and equity holder of VentriNova, Inc and listed inventor on multiple patents regarding cyclin A2-mediated cardiac repair and caudal-related homeobox 2 cells for cardiac repair. ### Funding Statement H.W.Chaudhry is supported by Empire State Stem Cell Board IIRP grant, contract number C32608GG, and NIH grant R01HL150345, NIH-NHLBI. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: All studies and protocols were reviewed and exempted by IRB at Mount Sinai Hospital to be not human subjects. All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes The data that support the findings of this study are available from the corresponding author upon reasonable request. All data generated or analyzed during this study are included in this published article (and its supplementary information files).