Risk stratification in phospholamban p.(Arg14del) cardiomyopathy

In this thesis, the main focus was to improve risk stratification for major ventricular arrhythmia (VA) and heart failure in phospholamban (PLN) p.(Arg14del)-positive individuals, to guide selection for implantable cardioverter-defibrillator (ICD) implantation and future gene therapies.
Part I focused on sudden cardiac death (SCD) risk stratification. We showed that current strategies often overestimate ‘true’ SCD risk by relying on surrogate end points such as appropriate ICD therapy, which may lead to unnecessary ICD implantation and device-related complications. We therefore emphasize the importance of stricter end point definitions and dynamic risk prediction models that account for changes in risk over time.
Subsequent chapters focused on validating and improving the PLN p.(Arg14del) risk model for major VA. Longitudinal analyses demonstrated that the model maintained good performance up to three years of follow-up, supporting its use both at baseline and during follow-up. Comorbidities, lifestyle factors, cardiac magnetic resonance imaging with late gadolinium enhancement, extended rhythm monitoring, and polygenic risk scores did not substantially improve risk prediction beyond the existing model.
Part II laid the foundation for heart failure risk stratification and future gene therapy selection. Penalized regression analyses identified left ventricular ejection fraction, low-voltage ECG, and New York Heart Association functional class as the strongest predictors of heart failure outcomes. These predictors were incorporated into a dynamic risk model based on repeated electrocardiography and echocardiography measurements, enabling individualized risk estimation over time. This approach may support future patient selection for advanced therapies in PLN p.(Arg14del) cardiomyopathy and potentially other inherited heart diseases.