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. 2025 Apr 22.
doi: 10.1002/ejhf.3672. Online ahead of print.

Age-related penetrance of phospholamban p.Arg14del cardiomyopathy

Tom E Verstraelen  1   2 , Freyja H M van Lint  3 , Remco de Brouwer  4 , Virginnio M Proost  1   2 , Esmee van Drie  3 , Laurens P Bosman  5 , Lotte Weverink  4 , Karim Taha  5 , Thais Bueren  1   2 , Aeilko H Zwinderman  6 , Cathelijne Dickhoff  7 , Toon Oomen  8 , Bas A Schoonderwoerd  9 , Tjeerd Germans  10 , Arjan C Houweling  11 , Juan R Gimeno-Blanes  12   13 , Folkert W Asselbergs  1   2 , Paul A van der Zwaag  14 , Anneline S J M Te Riele  5   13 , Rudolf A de Boer  4   13 , Maarten P van den Berg  4 , J Peter van Tintelen  3   13 , Arthur A M Wilde  1   2   13
Affiliations

Age-related penetrance of phospholamban p.Arg14del cardiomyopathy

Tom E Verstraelen et al. Eur J Heart Fail. .

Abstract

Aims: Previous studies have shown that carriers of the pathogenic p.Arg14del variant in phospholamban (PLN) have an increased risk of mortality, heart failure and malignant ventricular arrhythmias. However, there are sparse data on the penetrance of cardiac features in these mutation carriers, and the optimal starting age and intervals of clinical follow-up remain to be defined.

Methods and results: We collected clinical data from PLN p.(Arg14del) carriers. Cardiac penetrance was defined as the presence of a major event or risk factor. A major event consisted of malignant ventricular arrhythmias or symptomatic heart failure. Risk factors were low-voltage electrocardiogram, repolarization abnormalities, frequent premature complexes, left ventricular ejection fraction <45% or cardiac fibrosis on magnetic resonance imaging. Kaplan-Meier analysis with and without left truncation was used to assess penetrance. We identified 868 p.(Arg14del) carriers, with a median age of 43 (interquartile range [IQR] 29-55) years at first cardiac evaluation. Median follow-up was 5.3 (IQR 2.2-8.5) years and 207 (23.8%) carriers had a major event, at a mean age of 51 (± 15) years. Penetrance was age-related, with new cardiac phenotypes emerging from adolescence to senior age. At age 70, penetrance of a major event was 43% to 70%, penetrance of a risk factor was 84% to 100% depending on which Kaplan-Meier method was used.

Conclusion: Penetrance of a major cardiac event is high in PLN p.(Arg14del) carriers, with a penetrance up to 70% at age 70. Penetrance of a cardiac risk factor is nearly complete at older age. Furthermore, cardiac phenotypes can emerge from adolescence to senior age. Life-long cardiac follow-up is needed, starting from adolescence.

Keywords: Cardiomyopathy; Heart failure; Phospholamban.

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