Cardiac microvascular dysfunction Insights from COVID-19, myocardial infarction, and anthracycline-induced cardiotoxicity

Microvascular dysfunction is increasingly recognized as an important contributor to cardiovascular disease. Unlike obstructive epicardial coronary artery disease, abnormalities in the intramyocardial microvasculature are difficult to detect clinically, yet they can profoundly disturb tissue perfusion, vascular homeostasis, and cardiac remodelling. Structural and functional alterations of the microcirculation are therefore considered key drivers of disease progression across diverse pathological conditions.
This thesis investigates microvascular dysfunction in three distinct settings: viral infection in COVID-19 patients, ischemic injury in myocardial infraction (MI), and chemotherapy-induced cardiotoxicity. Using complementary approaches involving human tissue, in vitro cell models, and animal models, this work aimed to clarify the contribution of the cardiac microvasculature to disease progression and to identify mechanisms underlying endothelial dysfunction, vascular remodelling, and altered intercellular communication.
The findings demonstrate that microvascular dysfunction is a crucial and shared across these disease contexts. In COVID-19, cardiac microvascular injury was associated with increased NOX expression, atrial inflammation, and enhanced microvascular thrombogenicity. In MI, the intramyocardial microvasculature exhibited marked structural and molecular remodelling, including perivascular fibrosis, fibroblast activation, vascular phenotypic switching, and increased Follistatin-like 3 expression. These changes likely represent both a response to ischemic injury and repair and pre-existing microvascular pathology that may contribute to MI development and subsequent maladaptive remodelling. In chemotherapy-induced cardiotoxicity, oxidative stress, advanced glycation end product (AGE)–receptor for AGE (RAGE) signalling, and disturbed endothelial-fibroblast crosstalk impaired extracellular matrix homeostasis and promote persistent microvascular remodelling.
This thesis demonstrates that oxidative stress-driven endothelial dysfunction, inflammation, thrombogenicity, and fibrotic remodelling are interconnected mechanisms underlying cardiac microvascular pathology, and identifies the microvasculature as a potential therapeutic target.