Chronic Inflammation and Coronary Microvascular Dysfunction

Coronary microvascular dysfunction (CMD) represents a pivotal pathological hallmark across diverse cardiovascular pathologies, the progression of which is tightly coupled to systemic chronic inflammation. Clinically, CMD presents as ischemia with non-obstructive coronary arteries (INOCAs) and myocardial infarction with non-obstructive coronary arteries (MINOCAs), and contributes substantially to heart failure with preserved ejection fraction (HFpEF). Moving beyond conventional risk-factor stratification, this review dissects the mechanistic pathways through which individual comorbidities compromise coronary microcirculatory integrity. In hypertension, increased mechanical wall stress activates proinflammatory Nuclear factor κB (NF-κB)–mitogen-activated protein kinases (MAPK) signaling cascades. In contrast, in diabetes, chronic hyperglycemia drives microvascular injury through the reactive oxygen species (ROS)–advanced glycation end-products (AGEs) axis and Protein Kinase C (PKC)-dependent pathways. In obesity, adipokine dysregulation and gut-derived metabolites, notably trimethylamine N-oxide (TMAO), promote NLR family pyrin domain containing 3 (NLRP3) inflammasome activation, a central mechanism in obesity-related CMD. In the setting of heart failure (HF) and cardiomyopathies, damage-associated molecular pattern (DAMP)–Toll-like receptor (TLR) interactions and TGF-β/Smad signaling promote capillary rarefaction and interstitial fibrosis, thereby linking systemic inflammation to structural microvascular remodeling. Furthermore, both autoimmune-mediated endotheliitis and virus-induced cytokine surges reduce nitric oxide (NO) bioavailability and impair coronary flow reserve (CFR). Thus, by integrating emerging therapeutic strategies, including interleukin-1β (IL-1β) antagonists, SGLT2 inhibitors, and selected traditional medicines, we highlight approaches aimed at restoring microvascular homeostasis. Finally, we propose a personalized framework that leverages multi-omics profiling and artificial intelligence (AI) to modulate the inflammatory milieu, positioning inflammation-targeted interventions as a fundamental strategy for CMD prevention and management.