SARS-CoV-2 Induces Cardiac Injury by Decreasing ACE2-Mediated Cardioprotection and Exacerbating AGE/RAGE-Mediated Mechanisms

There is an urgent and unmet clinical need to unveil the mechanisms of acute myocardial injury and chronic damage to the cardiovascular system in COVID-19 patients. Patients with pre-existing cardiovascular disease are highly susceptible to the more severe manifestations of COVID-19, with mortality rates 2-3-fold higher than the general population. In addition, there are growing evidences of direct severe cardiovascular consequences of COVID-19. Previous clinical data from patients with pneumonia, severe acute respiratory syndrome (SARS; SARS-CoV), and new emerging data suggest that COVID-19 increase the incidence of both acute and long-term risk of CV disease (CVD). Given the incidence of CVD in a rapidly aging population, it is of the utmost importance to assess the impact of COVID-19 on the heart. Of note, elevated cardiac enzymes and myocardial injury in patients infected with SARS-CoV-2 has also been reported in the pediatric population. A precision medicine approach conducted primarily on infected and/or recovered patients (adult and pediatric) will rapidly translate basic science into pre-clinical studies. This application, from the Department of Surgery, supported by the Office for Research and Irving Institute for Translational and Clinical research at Columbia University Irving Medical Center (CUIMC), is aimed to address the impact of SARS-CoV-2 virus on human surgically-retrieved CV tissues and primary-derived cells in pediatric and adult COVID-19 patients. IRBs and biobanking facilities are already in place. Mechanistically, we will test the hypothesis that SARS-CoV-2 induces cardiac injury by decreasing ACE2-mediated cardioprotection and exacerbating AGE/RAGE-mediated mechanisms. Two aims will be developed:

AIM 1: Does COVID-19 result in cardiac injury by decreasing ACE2-mediated cardioprotection and exacerbating AGE/RAGE-mediated mechanisms? Immunohistochemical assessment will be conducted on all collected human specimens using markers of extracellular matrix remodeling (pentachrome staining), glycation (AGEs), ROS, ACE2/RAGE signaling (ACE2 and RAGE), leukocyte infiltration, and cell death (DNA fragmentation). RT-PCR analysis will assess tissue expression of ACE2, RAGE and RAGE ligands HMGB1 and S100A12. Mechanistic interrogation will be conducted on patient-derived primary cells as per our prior publications to test whether CVD patients that survive COVID-19 demonstrate altered ACE2-mediated cardioprotection and response to ARBs/ACEis.

AIM 2: Can circulating markers related to RAGE signaling be used as biomarkers of CV injury in active or recovered COVID-19 patients? We will screen active/recovered COVID-19 patients undergoing cardiac surgery for markers of inflammation (IL2,7,10 and TNFa), cardiac injury (NT-proBNP and cardiac troponin, cTnI), and ACE2/RAGE (sRAGE, HMGB1, S100A12, AGEs, circulating ACE2, Ang[1-7]). We expect to find that ACE2/RAGE markers can be used in combination with inflammation and cardiac injury markers to identify patients with higher CV risk.