Dilated cardiomyopathy (DCM) is characterized by progressive ventricular dilation and systolic dysfunction, yet the cellular damage that precedes intercellular fibrosis remains incompletely defined. Electron microscopy has long revealed autophagic vacuoles and myofilament lysis in cardiomyopathy, but their pathological significance has been debated for decades. Recent advances in ultrastructural analysis, including LC3 immunoelectron microscopy, have enabled more precise characterization of these changes and have renewed interest in the role of autophagy in cardiomyopathy. In this review, we integrate ultrastructural findings from a large cohort of patients with DCM with contemporary clinical imaging data to clarify the sequence of myocardial damage. Myofilament lysis consistently appears as the earliest structural abnormality, preceding intercellular fibrosis and ventricular remodeling. Autophagic vacuoles are frequently observed at sites of lysis, suggesting activation of a conserved cellular repair response rather than a mechanism of cell death. This interpretation is supported by external evidence, including LC3-based analyses demonstrating associations between autophagy and reverse remodeling, as well as experimental studies showing that sodium-glucose cotransporter 2 inhibitors enhance stress-adaptive pathways and mitochondrial energetics even in models with impaired mitophagy. By integrating electron microscopy with late gadolinium enhancement (LGE) on cardiac magnetic resonance imaging, we further demonstrate that autophagic activity provides prognostic information beyond conventional tissue characterization. In LGE-negative myocardium, the presence of autophagic vacuoles identifies a subgroup with a lower risk of heart-failure recurrence, whereas myofilament lysis alone shows limited prognostic value. These findings highlight the importance of distinguishing structural damage from cellular repair activity when evaluating cardiomyopathy. Collectively, the evidence supports a refined framework in which myofilament lysis precedes intercellular fibrosis, and autophagy represents an adaptive response that modulates clinical outcomes. Understanding these ultrastructural processes may inform future diagnostic strategies and therapeutic approaches for cardiomyopathy.
