Beyond Left Ventricular Ejection Fraction: Etiological Diagnosis as the Cornerstone of Precision Medicine in Heart Failure

Heart failure (HF) is not a single disease but a complex clinical syndrome representing the final common pathway of multiple cardiovascular disorders and remains one of the leading causes of morbidity, mortality and healthcare expenditure worldwide Although left ventricular ejection fraction (LVEF) remains fundamental for clinical classification and therapeutic decision-making, it provides only a limited representation of the biological heterogeneity underlying HF. Increasing evidence demonstrates that HF encompasses a heterogeneous spectrum of disorders characterized by distinct pathophysiological mechanisms, prognostic profiles and therapeutic responses. Consequently, identification of the underlying etiology has become a cornerstone of contemporary HF management. Recent advances in cardiovascular imaging, molecular biology and cardiovascular genetics have profoundly transformed the diagnostic approach to HF. Multimodality imaging – including echocardiography, cardiovascular magnetic resonance (CMR), cardiac computed tomography and nuclear imaging – allows accurate tissue characterization and facilitates recognition of infiltrative, inflammatory, ischemic and inherited cardiomyopathies . Likewise, the integration of circulating biomarkers, genetic testing and artificial intelligence has enabled increasingly refined phenotypic characterization beyond conventional LVEF-based classification. Etiological diagnosis directly influences therapeutic decision-making by identifying reversible causes of ventricular dysfunction, guiding disease-specific therapies, improving prognostic stratification and enabling family screening in inherited cardiomyopathies. Conditions such as transthyretin cardiac amyloidosis, inflammatory cardiomyopathies and genetically determined cardiomyopathies illustrate how early recognition may substantially modify clinical outcomes This review aims to highlight how the etiological diagnosis is reshaping contemporary HF management and the emerging role of multimodality imaging, cardiovascular genetics, biomarkers and artificial intelligence in the transition toward precision cardiovascular medicine.