Vascular Dysfunction in Cardiac Cachexia: Molecular Mechanisms and Pharmacotherapies

Severe heart failure (HF) is accompanied by cardiac cachexia (CC), defined as significant weight loss, muscle atrophy, and metabolic abnormalities. Muscle wasting in patients with CC is closely associated with hormonal changes. Previous studies on the pathogenesis of CC have focused on the imbalance between catabolic and anabolic processes. Thus, this review focused on the role of endothelial dysfunction in CC. We summarized how inflammatory cytokines and neurohormonal factors cause vascular dysfunction, leading to reduced nutrient delivery and perfusion. Furthermore, we discuss both conventional and emerging therapeutic strategies that may ameliorate CC by targeting the vasculature. These include ghrelin, the vascular benefits of foundational HF drugs (angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor-neprilysin inhibitors (ARNIs), and beta-blockers), and the promise of novel agents, such as BTB and CNC homology 1 (BACH1) inhibitors and fibroblast growth factor 21 (FGF21) agonists. We also summarize the existing animal models of CC and discuss advanced imaging and omics technologies for future research. This review provides a novel perspective on CC pathogenesis and highlights promising avenues for therapeutic intervention.