Immunologic basis of cardiac disease after severe COVID-19

ABSTRACT Coronavirus Disease 2019 (COVID-19) caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS- CoV-2) has become a widespread global pandemic. While the predominant clinical manifestation of severe COVID-19 is respiratory failure, other organ complications such as cardiac injury are common. Cardiac injury and cardiomyopathy are frequent cardiac manifestations during acute illness. Additionally, some survivors of COVID-19 are experiencing cardiopulmonary symptoms months after the acute illness, referred to as Post- Acute Sequelae of SARS-CoV-2 (PASC) or "Long COVID". Given the frequency of cardiovascular injury during COVID-19 and the persistence of symptoms for extended periods after the acute illness, there is an urgent need for studies of the late effects of SARS-CoV-2 on the cardiovascular system. We aim to investigate the central hypothesis that immune responses to severe COVID-19 cause acute inflammation and injury that result in clinically relevant myocardial fibrosis and dysfunction over the long-term. Since August 2020, we have been enrolling patients in a COVID-19 Immune Profiling (IP) Study, which includes a protocol to collect blood specimens from patients with COVID-19 at admission, during hospitalization, 1-3 months, and 3-12 months after recovery. We will co-enroll participants from this study and perform cardiac magnetic resonance imaging (CMR) and additional functional cardiopulmonary assessments at 3-12 months and 2-3 years after recovery. Our specific aims include, Aim 1) Identify innate immune profiles during severe COVID-19 that predict long- term cardiac damage. We will focus innate immunity measures in blood specimens collected at admission and early recovery, Aim 2) Establish whether adaptive immune responses contribute to cardiac injury after COVID- 19. We will quantify responses targeting SARS-CoV-2 as well as explore maladaptive responses targeting cardiac proteins. Analysis of blood specimens will be supplemented with exploratory studies of cardiac tissue, and Aim 3) Determine the long-term structural and functional cardiac abnormalities after severe COVID-19. This includes characterization of cardiac fibrosis and dysfunction, cardiopulmonary dysfunction, and clinical symptoms. Comparisons will be made with control participants who had influenza infection 1-2 years prior. Our proposal responds to urgent need for science characterizing long-term cardiac complications following COVID- 19. Our collaborative team has extensive experience spanning cardiology, infectious disease, immunology, and epidemiology, and will be led by a cardiologist with expertise in CMR and inflammatory cardiomyopathies, and an infectious diseases specialist with expertise in cardiovascular complications in the context of chronic viral infections. Successful completion of our work will help understand the long-term cardiovascular effects of severe COVID-19 illness. This knowledge could, in turn, help enhance health, lengthen life, and reduce illness and disability in COVID-19 survivors.