Failed Biological Resolution as a Potential Contributor to Incomplete Heart Failure Recovery: From Inflammatory Memory to Maladaptive Tissue Repair

Heart failure (HF) remains a major cause of morbidity and mortality despite substantial advances in disease-modifying therapy, and clinical improvement does not necessarily indicate complete restoration of myocardial homeostasis. Increasing evidence suggests that inflammatory, stromal, vascular, metabolic, and mitochondrial programs initiated during cardiac injury may persist beyond apparent phenotypic recovery. This narrative review examines HF through the complementary framework of biological resolution and evaluates whether incomplete recovery may reflect not only persistence of the original disease substrate but also incomplete termination of injury-associated biological programs. Evidence was synthesized from contemporary experimental, translational, and clinical studies addressing inflammatory cell dynamics, efferocytosis, immune and fibroblast state transitions, extracellular matrix remodeling, endothelial and microvascular dysfunction, mitochondrial and metabolic adaptation, cellular senescence, hematopoietic conditioning, and tissue-resident immunity. Collectively, these data indicate that reverse remodeling may coexist with persistent biological abnormalities whose significance depends on their activity, functional consequences, and effects on physiological reserve. We therefore propose residual biological heart failure (RBHF) to describe biologically relevant abnormalities persisting despite substantial phenotypic improvement and heart failure resolution competence (HF-RC) to describe the capacity of the cardiac and systemic environment to terminate injury-associated responses, complete adaptive repair, and restore durable homeostasis. These constructs extend rather than replace established concepts of reverse remodeling, remission, and myocardial recovery. RBHF and HF-RC remain hypothesis-generating frameworks requiring longitudinal human validation, but they provide a testable basis for distinguishing phenotypic improvement from the biological depth and durability of HF recovery.