Beyond the Failing Heart: Deciphering the Multisystem Biology ofHeart Failure Through Remodeling, Immunometabolism, Fibrosis,and Interorgan Crosstalk

Heart failure (HF) has traditionally been conceptualized as a primary hemodynamic pump failure characterized by reduced cardiac output and compensatory fluid retention. Modern translational science, however, reveals HF to be a systemic, multi-organ syndrome driven by interconnected maladaptive pathways. This comprehensive review and quantitative meta-analysis systematically decipher the multisystem biology of HF across four interconnected pillars: structural and subcellular myocardial remodeling, immunometabolic reprogramming, extracellular matrix (ECM) dynamics and fibrosis, and interorgan crosstalk (the cardiorenal, cardiohepatic, metabolic, and central nervous system axes).Through a systematic search of PubMed/MEDLINE, EMBASE, and Web of Science (2015–2026), we extracted quantitative metrics across 84 clinical cohorts and preclinical models (N = 42,680). Meta-analytic pooling demonstrates that microvascular endothelial inflammation and immunometabolic signaling (e.g., NLRP3 inflammasome activation, IL-1β/IL-6 signaling, and metabolic substrate switching from mitochondrial fatty acid oxidation to inefficient glycolysis) directly correlate with phenotypic progression in both HF with preserved ejection fraction (HFpEF) and HF with reduced ejection fraction (HFrEF). Furthermore, we quantify the impact of key systemic interventions—including SGLT2 inhibitors, GLP-1 receptor agonists, mineralocorticoid receptor antagonists, and targeted anti-inflammatory agents—on reversing adverse cardiac remodeling and dampening systemic interorgan decay.