One Syndrome, Many Faces: A Unified Perspective on Heart Failure Phenotypes.

Heart failure (HF) remains a major clinical syndrome traditionally classified by left ventricular ejection fraction (EF) into three phenotypes: reduced (HFrEF), mildly reduced (HFmrEF), and preserved (HFpEF). Although EF-based phenotyping has served as a practical framework for diagnosis and treatment stratification, growing evidence challenges its pathophysiological specificity. Clinical trials often blur these categories by including patients with EF > 40% under the HFpEF umbrella, despite current guidelines reserving that range for HFmrEF. This inconsistency introduces ambiguity and undermines the concept of discrete disease entities. In this comprehensive review, we explore the hypothesis that HF is not a group of separate syndromes but rather a single entity manifesting along a spectrum determined by the balance between pathological insult and the patient's homeostatic adaptive capacity. Emerging data reveal that all HF phenotypes, regardless of EF, share common molecular, cellular, and systemic mechanisms, including neurohormonal activation, inflammation, mitochondrial dysfunction, fibrosis, and programmed cell death. We propose a paradigm shift: from viewing HF through the lens of EF stratification to a unified, mechanistically driven model that recognizes HF as a syndrome with variable manifestations. Reframing HF in this way could enhance diagnostic precision, therapeutic targeting, and research design.