Myocardial fibrosis as an early feature in phospholamban p.Arg14del mutation carriers: phenotypic insights from cardiovascular magnetic resonance imaging

The pathogenic c.40-42delAGA (p.Arg14del) founder mutation in the phospholamban gene (PLN; locus 6q22.31; OMIM gene description number 172405) has been identified in 10-15% of patients diagnosed with dilated cardiomyopathy (DCM) and/or arrhythmogenic cardiomyopathy (ACM) in the Netherlands.1-3 It has also been found in several other European countries, Canada, and the USA. PLN is a transmembrane sarcoplasmic reticulum (SR) phosphoprotein that regulates SR Ca2b-ATPase (SERCA) activity and the p.Arg14del mutation has been shown to lead to calcium overload and consequent cardiomyocyte damage, and eventually to myocardial fibrosis.4,5 Indeed, examination of 20 whole heart specimens (autopsies and explants) of PLN p.Arg14del mutation carriers revealed extensive myocardial fibrosis in all cases.6,7 A striking clinical manifestation of PLN p.Arg14del mutation-related cardiomyopathy is the development of low-amplitude QRS complexes on the surface ECG,1,8 and it is likely that this is a reflection of underlying fibrosis, although this has not been proven. In addition, repolarization changes on the ECG, particularly of negative T-waves in the lateral leads, are an early manifestation in mutation carriers. Late gadolinium-enhanced (LGE) cardiovascular magnetic resonance (CMR) imaging has become the gold standard for non-invasive in vivo assessment of ventricular myocardial fibrosis; it allows the early identification and evaluation of both the extent and localization of myocardial fibrosis in different forms of cardiomyopathy.9-11 Importantly, LGE has consistently been shown to be a strong risk factor for sudden cardiac death (SCD) and overall mortality in a wide range of cardiomyopathies, e.g. DCM.12-16 In this study, we formulated three hypotheses based on the previous electrocardiographic and histopathological findings: (i) that LGE is present in a distinct subgroup of PLNp.Arg14del mutation carriers, (ii) that the ECG changes reflect fibrosis, and (iii) that, assuming that fibrosis is a substrate for ventricular arrhythmia (VA) in mutation carriers, the presence of LGE is associated with VA. We investigated CMR- and ECG parameters, and VA occurrence, in a large cohort of 150 mutation carriers to test these hypotheses. In particular, we analysed the extent and localization of CMR LGE together with ECG parameters to investigate whether the development of low-voltage QRS amplitude and/or repolarization changes are associated with left ventricular (LV) LGE. We also investigated whether these findings are associated with VA. Methods Source population Adult (>18 years old) PLN p.Arg14del mutation carriers who had undergone CMR imaging were selected from the PHORECAST registry (PHOspholamban RElated CArdiomyopathy STudy; http://www.phore cast.nl). Demographic and clinical parameters at the time of CMR were collected retrospectively in three Dutch hospitals (University Medical Center Groningen, Academic Medical Center Amsterdam, and Antonius Hospital Sneek). Our group included both index patients and their relatives referred to a cardiogenetics outpatient clinic for family cascade screening. Index patients in the cohort were not known to be related to each other.