Histological changes of the diaphragm in heart failure: A scoping review of human and animal studies.

Diaphragmatic dysfunction, characterized by both impaired strength and endurance, is increasingly recognized as a key contributor to dyspnea and reduced exercise tolerance in heart failure (HF). While histological alterations in limb skeletal muscles have been well characterized, those in the diaphragm have not been systematically synthesized. This scoping review aimed to integrate findings from human and animal studies to characterize histological remodeling of the diaphragm following HF. A comprehensive search across five electronic databases followed by screening identified 20 eligible studies, including 2 in humans and 18 in animal models. The diaphragm exhibited several characteristic trends, including a fast-to-slow muscle type transition, muscle fiber atrophy predominantly affecting Type II fibers, increased capillarization, increased mitochondrial enzyme activity, reduced mitochondrial size, increased connective tissue (fibrosis), and increased apoptosis. Some of these alterations were similar to those observed in limb muscles; however, the fast-to-slow transition, increased capillarization, and increased mitochondrial enzyme activity contrasted with the typical slow-to-fast shift, capillary rarefaction, and reduced mitochondrial enzyme activity seen in limb muscles. Type II fiber-dominant atrophy and fibrosis likely underlie muscle weakness. Importantly, our findings suggest a mismatch between structural adaptations and functional outcomes. Specifically, while histological changes indicate a shift toward an endurance-oriented phenotype, HF is associated with reduced diaphragmatic endurance, suggesting that factors beyond structural remodeling contribute to reduced endurance. Our results provide insight into the mechanisms of diaphragmatic dysfunction in HF and highlight the diaphragm as a potential therapeutic target. Further accumulation of human data is needed to strengthen these findings.