Cardiac Inflammatory and Microvascular Alterations Associated with Post-Acute Sequelae of SARS-CoV-2 Infection

Introduction: Many patients with post-acute sequelae of SARS-CoV-2 infection (PASC) or Long COVID have potential cardiac symptoms including chest pain, shortness of breath, and cardiac rhythm disturbances. These symptoms may be related to cardiac inflammatory and microvascular alterations and/or cardiac viral persistence. A more complete understanding of these cardiac pathologic changes is essential to decipher the mechanisms driving these symptoms.

Objective: This project will elucidate the cardiac inflammatory and microvascular alterations associated with Long COVID and determine the presence of cardiac viral persistence in these patients.

Methods: We will analyze heart tissue obtained at autopsy from patients in the post-acute phase following infection with SARS-CoV-2 who either have or do not have Long COVID. Decedents will be enrolled in the RECOVER Autopsy Cohort and/or have undergone autopsy at the local institution. Heart tissue will be analyzed by single-cell and single-nucleus RNA-seq (sc/nRNA-seq) with cell-cell interaction analysis to thoroughly analyze the cardiac inflammatory responses. The organization and activation state of the microvasculature will be determined and correlated with the inflammatory changes. The spatial distribution, relationship and activation state of distinct microvascular cells will be determined by performing cyclic immunofluorescent staining of tissue for markers of arterial endothelium, venous endothelium, pan-endothelium, lymphatic endothelium, pericytes, activated endothelium, and for markers of cytokine-mediated activation. The presence of SARS-CoV-2 will be assessed using ultrasensitive techniques. For genes identified by differential gene expression, corresponding proteins will be assessed by immunohistochemistry or immunofluorescence.

Results: Pending.

Conclusion/Discussion: Cardiac SARS-CoV-2 viral persistence occurs in a subset of patients with Long COVID. A more complete understanding of the cardiac inflammatory and microvascular alterations and their relationship to cardiac viral persistence in patients with Long COVID is essential to gain insights into the mechanisms of this disorder.

Key Topics:

• Advanced imaging analysis to define the long term impact of COVID on organ structure/function and characterize Long COVID phenotypes
• Assay and in vitro studies to gain mechanistic insights
• Biomarker, in-depth phenotyping assays and in vitro studies using tissue and other biospecimens
• Clinical assessment and pathogenesis of clinical manifestations
• Collaborative and systems biology approaches
• Linking autopsy findings with pathobiological mechanisms of Long COVID to guide targeted interventions
• Studies of vascular injury, thrombosis, and other potential mechanisms of Long COVID
• Therapeutic targets and drug development
• Viral persistence/reactivation