Left Atrial Myopathy as a Phenotypic Axis in HFpEF: Implications for Pulmonary Hypertension, Exercise Intolerance, and Targeted Therapy

Heart failure with preserved ejection fraction (HFpEF) is a highly heterogeneous syndrome characterized by impaired ventricular relaxation, systemic inflammation, and multisystem cardiovascular dysfunction. Despite growing recognition of HFpEF as a major global health burden, effective targeted therapies remain limited due to an incomplete understanding of its phenotypic diversity. Increasing evidence suggests that left atrial (LA) myopathy represents a central mechanistic and phenotypic axis in HFpEF rather than merely a secondary consequence of elevated left ventricular filling pressures. LA myopathy encompasses structural remodeling, fibrosis, impaired compliance, and electrical dysfunction that collectively disrupt reservoir, conduit, and booster pump function. These abnormalities contribute to elevated filling pressures, pulmonary venous congestion, pulmonary vascular remodeling, and impaired exercise hemodynamics. Emerging data demonstrate strong associations between impaired LA strain, reduced compliance, pulmonary hypertension, atrial fibrillation, and adverse clinical outcomes in HFpEF. Importantly, LA dysfunction may identify a distinct HFpEF phenotype characterized by disproportionate pulmonary vascular disease and severe exercise intolerance. Advances in multimodality imaging, including speckle-tracking echocardiography and cardiac magnetic resonance imaging, have improved the ability to characterize atrial structure and function and may enable earlier recognition of atrial disease. Therapeutic strategies targeting neurohormonal activation, fibrosis, pulmonary vascular coupling, rhythm control, and interatrial pressure modulation are increasingly being explored as potential approaches to modify this phenotype. This narrative review examines the mechanistic basis of LA myopathy in HFpEF, its relationship with pulmonary hypertension and exercise intolerance, contemporary diagnostic approaches, prognostic significance, and emerging therapeutic implications. Reframing LA myopathy as a central phenotypic axis may facilitate phenotype-directed management and improve therapeutic precision in HFpEF.