HIF1alpha Cardioprotection in COVID-19 Patients

  1. Bingyan J. Wang
  2. Sangeetha Vadakke-Madathil
  3. Lori B. Croft
  4. Rachel I. Brody
  5. Hina W. Chaudhry

Reviewed by

Read the full article See related articles

Listed in

Log in to save this article

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<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.

Article activity feed

  1. ScreenIT

    SciScore for 10.1101/2021.08.05.21258160: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    Ethicsnot detected.
    Sex as a biological variablenot detected.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.

    Table 2: Resources

    Antibodies
    SentencesResources
    Antibodies used in this study: HIF1α (Abcam ab51608, 1:200), MyBPC3 (ThermoFisher PA547925, 1:50),
    MyBPC3
    suggested: (Thermo Fisher Scientific Cat# PA5-47925, RRID:AB_2607814)
    Software and Algorithms
    SentencesResources
    Image brightness, contrast, and size were adjusted using Adobe Photoshop CS4 software.
    Adobe Photoshop
    suggested: (Adobe Photoshop, RRID:SCR_014199)
    Statistical Analysis: All data were quantified by ImageJ (analyze particle).
    ImageJ
    suggested: (ImageJ, RRID:SCR_003070)
    Statistical analysis was performed using GraphPad Prism 9.0 with unpaired t test, nonparametric, Kolmogorov-Smirnov. p value < 0.05 was considered statistically significant.
    GraphPad Prism
    suggested: (GraphPad Prism, RRID:SCR_002798)

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.

    Results from TrialIdentifier: No clinical trial numbers were referenced.

    Results from Barzooka: We found bar graphs of continuous data. We recommend replacing bar graphs with more informative graphics, as many different datasets can lead to the same bar graph. The actual data may suggest different conclusions from the summary statistics. For more information, please see Weissgerber et al (2015).

    Results from JetFighter: Please consider improving the rainbow (“jet”) colormap(s) used on page 24. At least one figure is not accessible to readers with colorblindness and/or is not true to the data, i.e. not perceptually uniform.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • No protocol registration statement was detected.

    Results from scite Reference Check: We found no unreliable references.

    About SciScore

    SciScore is an automated tool that is designed to assist expert reviewers by finding and presenting formulaic information scattered throughout a paper in a standard, easy to digest format. SciScore checks for the presence and correctness of RRIDs (research resource identifiers), and for rigor criteria such as sex and investigator blinding. For details on the theoretical underpinning of rigor criteria and the tools shown here, including references cited, please follow this link.

  2. Version published to 10.1101/2021.08.05.21258160v1 on medRxiv