The impact of comorbidities and substance use on heart failure events and major ventricular arrhythmias in phospholamban p.(Arg14del) positive individuals

Abstract

Abstract Background Patients with the phospholamban (PLN) p.(Arg14del) variant can develop a severe cardiomyopathy, characterized by progressive heart failure (HF) and major ventricular arrhythmias (VA). However, there is a marked variability in disease expression among affected individuals. There is still a considerable gap of knowledge regarding the influence of comorbidities and substance use on disease progression. Purpose The aim of this study is to investigate whether specific comorbidities and substance use are associated with HF events or major VA events in PLN p.(Arg14del) positive individuals. Method Logistic regression analysis was conducted was conducted in a retrospective cohort of 880 PLN p.(Arg14del) positive individuals (N=847 without heart failure at baseline, N=810 without major arrhythmia at baseline and N=780 without both). Comorbidities and substance use at baseline were assessed in univariable and multivariable models with respect to HF events, major VA events, and a composite endpoint of these two referred to as ‘severe phenotype’. Heart failure was defined as heart failure hospitalization, left ventricle assist device implantation, heart transplantation or HF-related death. Major VA was defined as sustained VA, appropriate implantable cardioverter defibrillator intervention, or (aborted) sudden cardiac death. Results Of all tested comorbidities, only renal dysfunction defined as an eGFR (CKD-EPI) <60 ml/min per 1.73 m² was significantly and independently associated with all endpoints (p<0.001). In the substance use analysis, prior history of smoking was associated with heart failure and a severe phenotype (p<0.002 and p<0.021), however actively smoking was not associated with both endpoints. Conclusion Renal dysfunction and a history of smoking were the only factors identified to be associated with worse outcomes in PLN p.(Arg14del) positive individuals. Whether renal dysfunction signifies a risk factor or an early manifestation of disease has to be further elucidated.