Long-term outcome and arrhythmic risk stratification in genotyped patients with left ventricular ring-like scar

Background The left ventricular ring-like (RL) scar detected by late gadolinium enhancement (LGE) cardiac magnetic resonance (CMR) represents a distinctive pattern of nonischemic myocardial fibrosis that has been associated with life-threatening ventricular arrhythmias. However, data guiding arrhythmic risk stratification and the role of genetic background in patients with this scar pattern remain limited. Purpose To evaluate long-term arrhythmic outcomes of genotyped patients with left ventricular RL scar, to determine the prognostic impact of genetic status and to identify independent clinical, electrocardiographic (ECG), and CMR predictors of major arrhythmic events (MAEs) in order to refine phenotypic characterization and improve risk stratification. Methods We conducted a multicenter, international, retrospective cohort study including adult patients with an RL scar (defined by subepicardial or midmyocardial LGE involving ≥3 contiguous segments within the same short-axis slice) identified by CMR who underwent comprehensive genetic testing. Consecutive patients were enrolled from 16 European tertiary referral centers. The primary endpoint was a composite of sustained ventricular tachycardia or ventricular fibrillation, appropriate implantable cardioverter-defibrillator therapy, or sudden arrhythmic cardiac death. Arrhythmic outcomes were evaluated according to clinical and instrumental variables and genotype status. Cox proportional hazards models were used to identify independent predictors of MAEs. Results The study included 523 patients. Pathogenic or likely pathogenic (P/LP) variants were identified in 298 patients (57%), including variants in high-risk cardiomyopathy genes in 222 (42%). During a median follow-up of 30 months (interquartile range 12-62 years), 96 patients (18.4%) experienced MAEs, corresponding to an incidence rate of 5.2 events per 100 patient-years. The incidence of MAEs did not differ between genotype-positive and genotype-negative patients, nor between carriers of P/LP variants in high-risk genes and genotype-negative patients (all p>0.05). At multivariable analysis, right axis deviation on surface ECG (hazard ratio [HR], 2.76), left ventricular ejection fraction <45% (HR, 1.81), right ventricular ejection fraction <40% (HR, 2.23), polymorphic premature ventricular complexes (HR, 1.88), and non-sustained ventricular tachycardia on ambulatory monitoring (HR, 1.72) were independently associated with MAEs. In contrast, genetic status was not independently associated with arrhythmic risk. Conclusions In the largest genotyped cohort of patients with an RL scar to date, this distinctive scar pattern was associated with a markedly elevated risk of MAEs, largely independent of genetic background. Easily obtainable ECG, imaging, and arrhythmic markers identify patients at particularly high risk and may improve risk stratification beyond genotype, with important implications for primary prevention strategies.Figure 1Figure 2