Mortality and risk factors for malignant ventricular arrhythmias in carriers of the phospholamban R14del mutation

Introduction: The phospholamban (PLN) R14del mutation causes dilated and/or arrhythmogenic cardiomyopathy and is associated with an increased risk of malignant ventricular arrhythmias (MVA) and end-stage heart failure. Objectives: To determine risk factors that predict MVA in carriers of PLN R14del and to assess their mortality risk. Methods and results: With non-invasive tools (ECG, echocardiography, Holter, exercise testing, and magnetic resonance imaging), we retrospectively evaluated clinical risk factors for MVA, defined as cardiopulmonary resuscitation (CPR), appropriate ICD treatment, and sudden cardiac death, in a multicenter cohort of 295 PLN R14del carriers. In a median follow-up period of 42 months (interquartile range: 6 to 111 months), 55 (19%) persons experienced a first episode of MVA: 8 persons received successful CPR, 38 received appropriate ICD treatment, and 9 persons died suddenly in the absence of heart failure. The youngest age at which an MVA was observed was 20 years (CPR). Independent risk factors for MVA were non-sustained or sustained ventricular tachycardia and left ventricular ejection fraction <45%, with hazard ratios of 2.4 (95% CI: 1.5–4.5) and 4.0 (95% CI: 1.8–9.1), respectively. In addition, we analyzed all-cause mortality (main outcome measure: standardized mortality ratio [SMR]). All-cause mortality of PLN R14del carriers was increased (SMR 1.7; 95% CI: 1.4–2.0) with significant excess mortality starting from the age of 25 years. Conclusions: Carriers of the PLN R14del mutation are at high risk for MVA and all-cause mortality. Implantation of an ICD could therefore be justified in PLN R14del carriers with a left ventricular ejection fraction <45%, even in the absence of ventricular arrhythmias. Excess mortality is observed starting from the age of 25 years. Cardiological screening of PLN R14del carriers is thus recommended to be initiated at the beginning of adulthood to prevent malignant outcomes.