Human Coronary Artery Plaque Transcriptomes and Cardiovascular Risk Assessment

Atherosclerotic coronary artery disease remains a leading cause of morbidity and mortality worldwide. While significant advancements have been made in understanding the pathogenesis of atherosclerosis through animal models and atherosclerotic plaques from non-coronary arterial beds, crucial knowledge gaps still exist

regarding human coronary atherosclerosis and the ability to predict plaque stability. Using a novel approach designed by our research team, this NIH R01 proposal aims to begin addressing these limitations by analyzing the transcriptome of human coronary atherosclerotic plaques (HCPs) from patients undergoing percutaneous

coronary interventions and investigating their role in predicting subsequent myocardial infarction and other major adverse cardiovascular events (MACE) following percutaneous coronary interventions (PCI). In Aim 1, we will determine differences in the composition, molecular functions, and biological processes of

HCP transcriptomes between plaques from patients with acute coronary syndromes (ACS) and stable coronary artery disease (CAD), as well as between men and women. This aim will involve sequencing the transcriptomes of HCPs obtained from 2,400 patients undergoing PCI across three centers with diverse racial

and ethnic backgrounds. Additionally, differences between ST-elevation myocardial infarction (STEMI) and non-ST-elevation myocardial infarction (NSTEMI) presentations will be explored. In Aim 2, we will evaluate the predictive value of HCP transcriptome data for future MACE. This aim involves a comprehensive follow-up of all subjects for 36 months post-PCI, during which MACE events, including

subsequent ACS, recurrent unplanned revascularization, and death, will be recorded. The transcriptomes of patients with and without MACE will be compared to identify transcriptome patterns with potential prognostic implications. Our exciting preliminary data from a pilot study involving 27 patients demonstrates the feasibility of obtaining

HCP transcriptomes. A solid infrastructure has been established, enabling subject recruitment, sample collection, and long-term follow-up for over 250 patients to date. The pilot study also highlights significant differences in gene expression, regulatory pathways, and cell populations between unstable plaques

associated with ACS and stable plaques in patients with stable angina. Importantly, our preliminary data also suggests there are significant differences in gene expression in coronary plaques in men compared to women and comparing those who had ACS following their index procedure compared to those who did not.

Successful completion of this study will contribute to a deeper understanding of human coronary atherosclerosis, elucidate critical biological differences between ACS and non-ACS plaques, and identify potential therapeutic targets. Furthermore, our findings may establish a first-of-its-kind tool for risk stratification

of MACE post-PCI, enhancing patient care and prognosis prediction.