Beyond morphology: A review of heterogeneous mechanisms and precision risk management in left ventricular non-compaction/left ventricular hypertrabeculation

Left ventricular non-compaction/left ventricular hypertrabeculation (LVNC/LVHT) has traditionally been regarded as a congenital cardiomyopathy caused by arrested myocardial compaction during embryogenesis. However, this classical concept is increasingly challenged by mounting clinical and basic evidence, in view of its marked heterogeneity in clinical presentation, imaging features, and genetic background. This review systematically synthesizes relevant research from recent years to propose that LVNC/LVHT is better understood not as a single discrete disease entity, but as a morphological endpoint resulting from diverse etiologies and mechanisms. This review critically appraises the phenotypic pitfalls of current imaging diagnostic criteria, highlighting the clinical dilemma of concurrent over-diagnosis and under-diagnosis that leads to inappropriate management. It then delineates two distinct pathogenic pathways: A developmental pathway associated with mutations in genes such as TAZ and MYH7 and dysregulation of signaling pathways including transforming growth factor-β and neuregulin 1–erythroblastic leukemia viral oncogene homolog; and an acquired/adaptive pathway linked to hemodynamic load-induced myocardial remodeling. Based on these insights, we propose an integrated classification framework subdividing LVNC/LVHT into development-driven, load-adaptive, and idiopathic benign trabeculation subtypes to resolve long-standing diagnostic confusion. We further introduce a multimodal risk stratification system incorporating cardiac structure and function, electrophysiology, genetics, circulating biomarkers, and systemic factors. This strategy aims to shift LVNC/LVHT management from a morphology-based, one-size-fits-all paradigm toward mechanism-guided, individualized precision care. Finally, we outline future directions, including validation of risk models, mechanistic studies, updated guidelines, and integration of artificial intelligence and multi-omics, to establish a novel precision diagnostic and therapeutic framework for LVNC/LVHT.