Molecular mechanisms and risk stratification of malignant ventricular arrhythmias in dilated cardiomyopathy: a comprehensive review

Background Sudden cardiac death (SCD) from malignant ventricular arrhythmias (VA) remains a major unresolved challenge in dilated cardiomyopathy (DCM). The traditional left ventricular ejection fraction (LVEF)-based strategy misses a substantial proportion of at-risk patients, yet no universally accepted alternative has been established. Objectives This review aims to synthesize current evidence on the molecular mechanisms of VA in DCM and to evaluate the utility of emerging multidimensional risk stratification tools—incorporating cardiac magnetic resonance (CMR), genetic testing, and clinical parameters—in refining SCD prediction and guiding implantable cardioverter-defibrillator (ICD) decisions. Methods We searched PubMed/MEDLINE, Embase, Web of Science, and the Cochrane Library from January 2000 to May 2026 using combinations of terms including “dilated cardiomyopathy,” “ventricular arrhythmia,” “sudden cardiac death,” “calcium handling,” “RyR2,” “SERCA2a,” “LMNA,” “FLNC,” “RBM20,” “cardiac magnetic resonance,” “late gadolinium enhancement,” and “risk stratification.” We focused on calcium handling remodeling, genotype-specific arrhythmic susceptibility, and myocardial fibrosis as the structural substrate for VA, and critically appraised the evidence for CMR-based quantification and genotype-guided risk assessment. Key findings Calcium dysregulation (RyR2-mediated sarcoplasmic reticulum Ca 2+ leak, SERCA2a dysfunction, and L-type calcium channel overactivation) is a core arrhythmic driver in DCM. Genotypes including LMNA, FLNC, RBM20, and desmosomal variants carry high VA risk independent of LVEF. Late gadolinium enhancement (LGE) on CMR—particularly ≥7.2% of left ventricular mass—substantially improves SCD prediction over LVEF alone. A stepwise CMR-based risk model and a bedside clinical prediction tool (incorporating age, LVEF, glucose, potassium, and eGFR) are now available for practical risk stratification. Conclusions A multidimensional approach integrating CMR quantification, genotype, and clinical parameters offers superior SCD risk stratification compared with LVEF alone. This framework can inform ICD decision-making and represents a practical path toward precision management of VA in DCM.