Investigating Atherosclerosis and Chemotherapy-Induced Cardiomyopathy at the Single-Cell Resolution

Cardiovascular diseases (CVDs) and cancer are the leading causes of death worldwide. Central to many cardiovascular diseases, including myocardial infarction, angina, and stroke, is the process of atherosclerosis, or the hardening of blood vessels. Single-cell sequencing has been used to elucidate many areas of physiology and disease. To understand fundamentals of the cellular processes at play and to derive better treatment and prevention of CVDs, we first examined a publicly available human-derived single-cell dataset of coronary arteries. In doing so, we discovered processes involving smooth muscle cell differentiation (Chapter 2). We also uncovered technical gaps in current practices of single-cell analysis, which gave rise to the development of PlaqView (Chapter 3). PlaqView (www.plaqview.com) is a single-cell web portal aimed to curate, standardize, and provide access for reanalysis of cardiovascular single-cell datasets without the need for technical coding skills.
We further explore the role of cardiovascular diseases in the context of cancer (Chapter 4). For cancer patients, cardiovascular side-effects from chemotherapy are of special concern. To further our understanding of chemotherapy-induced cardiomyopathies, we designed, optimized, and performed single-nucleus multimodal sequencing on left-ventricular tissues from six human patients. Our results suggest that cardiomyopathy arising from chemotherapy side-effects is transcriptionally different from other forms of cardiomyopathy, despite the same standard of treatment currently used clinically. Furthermore, we discovered the specific expression of XIST in chemotherapy-induced cardiomyopathy and many potential off-target effects of standard heart-failure therapies. Our data, which will be publicly available through PlaqView, opens up many potential avenues of future study (Chapter 5).