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

Aims: The p.Arg14del founder mutation in the gene encoding phospholamban (PLN) is associated with an increased risk of malignant ventricular arrhythmia (VA) and heart failure. It has been shown to lead to calcium overload, cardiomyocyte damage, and eventually to myocardial fibrosis. This study sought to investigate ventricular function, the extent and localization of myocardial fibrosis and the associations with ECG features and VA in PLN p.Arg14del mutation carriers. Methods and results: Cardiovascular magnetic resonance (CMR) data of 150 mutation carriers were analysed retrospectively. Left ventricular (LV) and right ventricular (RV) volumes, mass, and ejection fraction were measured. The extent of late gadolinium enhancement (LGE) was expressed as a percentage of myocardial mass. All standard ECG parameters were measured. Occurrence of VA was analysed on ambulatory 24-h and/or exercise electrocardiography, if available. Mean age was 40 +/- 15 years, 42% males, and 7% were index patients while 93% were pre-symptomatic carriers identified after family cascade screening. Mean LV ejection fraction (LVEF) and RV ejection fraction were 58 +/- 9% and 55 +/- 9%, respectively. LV-LGE was present in 91% of mutation carriers with reduced LVEF (<45%) and in 30% of carriers with preserved LVEF. In carriers with positive LV-LGE, its median extent was 5.9% (interquartile range 3.2-12.7). LGE was mainly observed in the inferolateral wall. Carriers with inverted T-waves in the lateral ECG leads more often had LV-LGE (P < 0.01) than carriers without. Finally, the presence of LV-LGE, but not attenuated R-waves and inverted lateral T-waves, was independently associated with VA. Conclusion: LV myocardial fibrosis is present in many PLN p.Arg14del mutation carriers, and who still have a preserved LVEF. It is seen predominantly in the LV inferolateral wall and corresponds with electrocardiographic repolarization abnormalities. Although preliminary, myocardial fibrosis was found to be independently associated with VA. Our findings support the use of CMR with LGE early in the diagnostic work-up.