Left ventricular non-compaction cardiomyopathy (LVNC) is characterized by a thinned compact myocardium overlain by prominent trabeculations with deep recesses that communicate with the ventricular cavity. In normal development, the embryonic ventricle is “spongy”; trabeculation facilitates exchange before the coronary circulation forms, after which compaction transforms this scaffold into mature wall. This process depends on endocardial–myocardial signaling (Notch, neuregulin-1/ErbB, BMP10) and epicardial contribution. Genetic alterations or hemodynamic loads (e.g., pregnancy, elite athletes) can produce a non-compaction phenotype, which is sometimes transient.Objective: To integrate developmental biology and genetics to explain the LVNC phenotype, and translate this knowledge into practical clinical messages (diagnosis, risk stratification, family counseling, and therapies under investigation).Methods: Narrative review of the medical literature (2000–July 2024) searched in PubMed, Google Scholar, and CrossRef; we prioritized genetic studies, mechanistic models, and reviews/guidelines with clinical applicability.Results: Approximately 190 implicated genes have been identified (32 with strong evidence). Sarcomeric genes predominate, but transcriptional/epigenetic regulators, developmental signaling pathways such as Notch/BMP, mitochondrial genes, and cytoskeletal components are also involved. In pediatrics, the diagnostic yield of genetic testing approaches ~50% of cases, whereas in adults with isolated LVNC the yield is lower.Conclusions: LVNC is a heterogeneous phenotype with a complex genetic basis that engages multiple molecular pathways, including sarcomeric genes, epigenetic regulators, and signaling routes such as Notch/TGF-β and mitochondrial biogenesis. Diagnostic work-up should integrate genetic testing with clinical data and advanced imaging to distinguish physiological variants from pathological disease; guide cascade family screening (prioritizing carriers of pathogenic variants); and identify high-risk subgroups (e.g., arrhythmia-gene carriers) who may benefit from implantable defibrillators. Future work should harmonize genotype–phenotype criteria across diverse populations, develop pathway-directed therapies (Notch, TGF-β, mitochondrial dysfunction), and validate genomic biomarkers for risk stratification.
Tittonel et al. (Mon,) studied this question.