Heart Failure with Reduced and Mildly Reduced Ejection Fraction: A Network Interpretive Framework of Mechanisms, Phenotypes, and Therapeutic Response

Heart failure (HF) classification is still primarily based on left ventricular ejection fraction, even though this parameter only partially reflects the biological mechanisms determining disease progression and therapeutic response. The aim of this review was to present a conceptual interpretive framework that analyzes the HFrEF (heart failure with reduced ejection fraction) and HFmrEF (heart failure with mildly reduced ejection fraction) phenotypes through the lens of the network organization of pathophysiological processes. This review integrates data on molecular and cellular mechanisms, clinical phenotypes, clinical trial results, and therapeutic recommendations. Particular attention was paid to the concepts of network coherence, pathway dominance, and the relationship between the disease’s biological architecture and treatment response. The proposed conceptual framework suggests that HFrEF is more often characterized by a relatively coherent pathophysiological architecture, in which neurohormonal activation, disturbances in calcium metabolism, mitochondrial dysfunction, and extracellular matrix remodeling constitute mutually reinforcing processes. HFmrEF, on the other hand, is presented as a heterogeneous category, encompassing patients with partial improvement of previous systolic dysfunction, patients progressing towards HFrEF, and HFpEF (heart failure with preserved ejection fraction)—like phenotypes associated with inflammation, endothelial dysfunction, microcirculatory disturbances, and metabolic dysregulation. In this approach, therapeutic response depends on whether the targeted pathway occupies a central position in the disease network. This review proposes a hypothesis-generating conceptual framework that complements, rather than replaces, the current ejection fraction-based classification of heart failure. Although the proposed framework requires prospective validation, it may facilitate a more mechanistic interpretation of HF phenotypes, support future biologically informed therapeutic strategies, and stimulate the design of mechanistically oriented clinical studies.