Verstraelen Tom E, van Lint Freyja H M, de Brouwer Remco, Proost Virginnio M, van Drie Esmee, Bosman Laurens P, Weverink Lotte, Taha Karim, Bueren Thais, Zwinderman Aeilko H, Dickhoff Cathelijne, Oomen Toon, Schoonderwoerd Bas A, Germans Tjeerd, Houweling Arjan C, Gimeno-Blanes Juan R, Asselbergs Folkert W, van der Zwaag Paul A, Te Riele Anneline S J M, de Boer Rudolf A, van den Berg Maarten P, van Tintelen J Peter, Wilde Arthur A M
Department of Cardiology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.
Amsterdam Cardiovascular Sciences, Heart Failure and Arrhythmias, Amsterdam UMC, Amsterdam, The Netherlands.
Eur J Heart Fail. 2025 Apr 22. doi: 10.1002/ejhf.3672.
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.
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.
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.
既往研究表明，受磷蛋白（PLN）致病性p.Arg14del变异影响的携带者死亡、心力衰竭及恶性室性心律失常风险增加。然而，关于这些突变携带者心脏特征的外显率数据稀少，临床随访的最佳起始年龄和间隔仍有待确定。
我们收集了PLN p.(Arg14del)携带者的临床数据。心脏外显率定义为存在主要事件或危险因素。主要事件包括恶性室性心律失常或有症状的心力衰竭。危险因素为心电图低电压、复极异常、频发早搏、左心室射血分数<45%或磁共振成像显示的心脏纤维化。采用有或无左截断的Kaplan-Meier分析评估外显率。我们确定了868名p.(Arg14del)携带者，首次心脏评估时的中位年龄为43岁（四分位间距[IQR]29 - 55岁）。中位随访时间为5.3年（IQR 2.2 - 8.5年），207名（23.8%）携带者发生了主要事件，平均年龄为51岁（±15岁）。外显率与年龄相关，新的心脏表型从青春期到老年期均有出现。70岁时，主要事件的外显率为43%至70%，危险因素的外显率为84%至100%，具体取决于所使用的Kaplan-Meier方法。
PLN p.(Arg14del)携带者发生主要心脏事件的外显率较高，70岁时外显率高达70%。老年时心脏危险因素的外显率几乎为100%。此外，心脏表型可从青春期到老年期出现。需要从青春期开始进行终身心脏随访。
