Project Summary/Abstract: Post-acute sequelae of SARS-CoV-2 (PASC) occurs up to 30% of COVID-19
infections and has emerged as a significant healthcare issue in the US. The mechanisms, optimal diagnostic
imaging tests, and therapies for persistent cardiac symptoms caused by PASC remain unknown. The CDC
describes PASC symptoms as difficult to explain and manage due to lack of knowledge and reliable test. This
study seeks to define the mechanism of persistent chest pain caused by PASC and establish an optimal cardiac
imaging test for guiding therapy. To minimize the influence of confounders, this project focuses on well-
characterized patients with persistent chest pain, which occurs in about 20% of PASC patients. Endothelial
inflammation and injury are important manifestations of acute COVID-19 infection, which may result in chronic
coronary microcirculatory dysfunction (CMD). Stress cardiovascular magnetic resonance (CMR) is the ideal
“one-stop-shop” imaging test for PASC patients with persistent chest pain, because it does not involve ionizing
radiation (i.e. safe for repetitive surveillance), is a proven modality for CMD, and uses standard clinical MRI
hardware and contrast agents; furthermore, it affords a comprehensive assessment of cardiovascular
abnormalities, including: obstructive coronary artery disease (coronary magnetic resonance angiography),
pulmonary hemodynamics (4D flow), myocardial inflammation (T2, T1), scar (late gadolinium enhancement),
diffuse fibrosis (extracellular volume fraction [ECV]), and contractile dysfunction (left ventricular ejection fraction
[LVEF], RVEF, strain). A comprehensive CMR is necessary to adjusts for potential confounders. Our central
hypothesis is that CMD is the mechanism for chest pain in a substantial proportion of symptomatic PASC
patients, despite having normal lung function and no history of heart disease prior to COVID infection. To test
our hypothesis, we will conduct a matched case-control study comparing MPRs between well-characterized
PASC patients with persistent chest pain, asymptomatic COVID-19 survivors matched for sex, age,
race/ethnicity, CAD risk factors, vaccine status, and severity of acute COVID illness, and matched healthy
controls. The objectives of this study are: (1) to determine whether CMR-derived MPR quantification is accurate
and precise; to determine whether MPR quantification and coronary MRA adds incremental value for diagnosing
CMD; (2) to determine whether MPRs are reduced in PASC patients with chest pain due to symptom status
and/or prior COVID infection; to determine whether MPRs predict chest pain better than other CMR indices,
clinical profiles, and blood biomarkers; (3) to determine whether temporal changes in MPRs differ between
treated and untreated PASC patients; whether temporal changes in MPRs correlate with temporal changes in
angina status. This proposal has high potential impact on PASC patients suffering from chest pain by identifying
and quantifying the mechanism of persistent chest pain, informing future development and applications of
mechanism-directed therapies for CMD, and ultimately improving cardiovascular health.
