152 Chapter 7 Clinical alterations in PLN-R14del patients The onset of PLN-R14del disease differs among patients and seems to be age-dependent. Typically, most patients begin experiencing symptoms at an average age ranging from 40 to 48 years.14–16 However, there is evidence of patients under 30 years old exhibiting ventricular tachycardia. Conversely, many PLN-R14del carriers remain asymptomatic17, highlighting the significant variability in disease penetrance associated with this mutation. In a Spanish family, a disease penetration of 75% was reported.5 Several factors may contribute to an individual’s disease onset and progression, including additional mutations, alterations in the PLN interactome18, external stressors like intense physical activity19–22, or combinations thereof. Interestingly, no association has been found between participation in high dynamic sports and malignant ventricular arrhythmias in PLN-R14del carriers.17 Therefore, further understanding of the interplay between genetic and environmental factors is crucial for both the diagnosis and management of this condition. To date, no studies have described an explanation for this disease penetrance variability. The clinical spectrum of the disease phenotype associated with PLN-R14del mutation varies from early stage ECG and ultrasound strain abnormalities to a moderate stage consisting of reduced left ventricular function, and ultimately progression into congestive biventricular failure, potentially accompanied by arrhythmias.23–28 At the structural level, the PLN-R14del mutation results in a biventricular phenotype, characterized by the presence of fibrosis, dilation of the heart, fibrofatty tissue replacement, and the formation of protein aggregates. These structural changes within the heart may provide the substrates necessary for the occurrence of ventricular arrhythmias.29 Notably, certain ECG abnormalities, such as low-voltage ECG with attenuated R amplitudes and inverted T-waves, are early indicators of the disease in individuals with the PLN-R14del mutation and can be attributed to the presence of cardiac fibrosis.30,31 Importantly, attenuated R amplitudes can serve as an early ECG marker, irrespective of any echocardiographic abnormalities, indicating a mutation-related remodeling process that precedes the onset of ventricular dysfunction.6 Since the discovery of PLN-R14del, several studies have investigated the underlying mechanisms of PLN-R14del cardiomyopathy. However, despite all efforts, PLN-R14del patients still wait desperately for customized therapy or even a curative treatment. In an attempt to understand the pathological characteristics of the disease, we performed a systematic search of studies providing the current knowledge on PLN-R14del cardiomyopathy, focusing on the structural and cellular characteristics of the disease (Table 1). The literature search was based on the following terminology in the title and/or abstract: ‘’PLN R14del’’; ‘’Phospholamban R14del’’; ‘’p.Arg14del’’; ‘’PLN Arg14del’’; ‘’Phospholamban Arg14del’’; ‘’R14del’’. The selected studies and data extraction were independently evaluated. The search found 82 studies, of which 81 fulfilled the selection criteria (Supplementary Table 1). Forty studies described the mutation effects in human patients, sixteen studies were performed in mice, seven in patient-
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