Key result
Genetics and CMR tissue characterization optimize sudden cardiac death risk stratification in NDLVC.
Why the study?
Patients with non-dilated left ventricular cardiomyopathy and nearly identical phenotypes face radically different outcomes, and disease heterogeneity complicates risk stratification and long-term surveillance. Furthermore, standardized guidelines tailored to gene-elusive phenotypes are lacking, making their long-term clinical outcomes challenging to predict.
This review synthesizes evidence on the prognostic divergence between genetic and gene-elusive non-dilated left ventricular cardiomyopathy, advocating for a multi-parametric, genotype-directed framework incorporating cardiac magnetic resonance and personalized risk scores to optimize sudden cardiac death prevention.
Non-dilated left ventricular cardiomyopathy (NDLVC) presents a unique clinical paradox: patients with nearly identical phenotypes can face radically different clinical outcomes. NDLVC has been recently recognized as a distinct dynamic phenotype within the spectrum of non-ischemic cardiomyopathies, linked by a high risk of life-threatening arrhythmias. Recent advances in genetics have overcome clinical phenotyping in prognostic accuracy. Specifically, gene-specific scores have been introduced to guide primary prevention ICD in high-risk gene carriers. On the other hand, while gene-elusive cases present a more favourable arrhythmic profile, their long-term clinical outcome is more challenging to predict. Despite advancements in therapeutic strategies, the heterogeneity of the disease represents an ongoing dilemma for risk stratification and long-term surveillance. This review offers a comprehensive analysis of NDLVC management in clinical practice, highlighting the profound prognostic divergence between genetic (both in actionable and VUS carriers) and gene-elusive cohorts. By synthesizing current evidence, we aim to clarify how genotype–phenotype correlations influence clinical outcomes and to provide a framework for more personalized approaches in the follow-up and treatment of these distinct patient populations. Furthermore, we address the current lack of standardized guidelines specifically tailored to gene-elusive phenotypes. In conclusion, NDLVC management requires a paradigm shift towards a multi-parametric, genotype-directed framework, where cardiac magnetic resonance tissue characterisation and personalized risk scores are essential to optimize sudden cardiac death prevention. Future research must leverage artificial intelligence and polygenic risk scores (PRSs) to integrate multi-parametric clinical-imaging data and refine risk stratification beyond traditional binary models. Concurrently, human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) will be pivotal as a translational platform to clarify VUS pathogenicity, unravel gene-specific arrhythmic mechanisms, and accelerate targeted therapeutic interventions.
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Castelli et al. (2026) conducted a review in Non-dilated left ventricular cardiomyopathy (NDLVC). Genetic status (actionable and VUS carriers) vs. Gene-elusive NDLVC was evaluated on Clinical outcomes and sudden cardiac death risk stratification. Genetic status and CMR tissue characterization drive a multi-parametric framework needed to optimize sudden cardiac death prevention in NDLVC compared to gene-elusive cohorts.
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