Refining risk stratification for ventricular arrhythmias in patients with desmoplakin cardiomyopathy

Background Patients with desmoplakin (DSP) cardiomyopathy are at elevated risk for life-threatening ventricular arrhythmias (VA) and sudden cardiac death (SCD), independent of traditional left ventricular ejection fraction (LVEF) cut-offs. The current risk stratification in DSP cardiomyopathy integrates clinical, imaging, and arrhythmic parameters to guide management for the primary prevention of SCD. The DSP risk score includes female sex, history of non-sustained ventricular tachycardia, natural logarithm of 24-hour premature ventricular complex burden, LVEF<50%, and presence of moderate to severe right ventricular (RV) systolic dysfunction. However, risk stratification for primary prevention implantable cardioverter defibrillator (ICD) is still insufficient. Purpose To identify novel predictors of ventricular arrhythmias in DSP mutation carriers and evaluate their incremental value beyond the DSP risk score. Methods We prospectively included consecutive patients with pathogenic or likely pathogenic DSP mutations from two referral centers. We assessed the outcome of life-threatening VA, defined as sustained ventricular tachycardia, SCD, aborted cardiac arrest, or appropriate ICD therapy including anti-tachycardia pacing or ICD shock. Low QRS voltage was defined as QRS amplitude < 5 mm in all limb leads or <10 mm in all precordial leads. Results We included 126 DSP genotype-positive patients (median age 44 years [interquartile range, IQR, 31-60], 54% women, 34% probands). During a median follow-up of 2.5 years (IQR 0.9-5.5), 21 (17%) patients experienced VA, corresponding to an annual incidence of 4.2% (95% confidence interval [CI] 2.76–6.50). Left ventricular mechanical dispersion (LVMD) assessed by myocardial strain (hazard ratio [HR] 1.4 per 10-ms increments, 95% CI 1.03-1.89, p=0.03), presence of low QRS voltage (HR 4.1, 95% CI 1.01-16.97, p=0.04) and maximal QRS duration (HR 2.1 per 10-ms increments, 95% CI 1.21-3.85, p=0.01) were independent predictors of VA. Receiver operating characteristic (ROC) curve analysis identified an optimal cut-off value of 55 ms for LVMD (sensitivity 84%, specificity 75%) and 105 ms for maximal QRS duration (sensitivity 82%, specificity 81%). Kaplan–Meier analysis showed a significantly higher event rate in patients with increased LVMD, prolonged QRS duration and low QRS voltage (Figure 1). The DSP risk score demonstrated good discrimination of patient risk for VA (C-statistic 0.75), while addition of the novel parameters significantly improved model performance (C-statistic 0.87, p=0.01) (Figure 2). Conclusion Left ventricular mechanical dispersion, low QRS voltage and maximal QRS duration are independent predictors of life-threatening VA in DSP cardiomyopathy. Incorporation of these parameters into the DSP risk score significantly improved arrhythmic risk discrimination, suggesting a possibility for a refined strategy to optimize primary prevention ICD decision-making.Fig 1.Kaplan–Meier survival analysisFig 2.