LAUSR

BACKGROUND Arrhythmogenic right ventricular cardiomyopathy type V (ARVC-5) is the most aggressive heterozygous form of ARVC. It is predominantly caused by a fully penetrant mutation (p.S358L) in the non-desmosomal gene TMEM43 - endemic to Newfoundland, Canada. To date, all familial cases reported worldwide share a common ancestral haplotype. It is unknown whether the p.S358L mutation by itself causes ARVC-5 or if the disease is influenced by genetic or environmental factors. OBJECTIVE To examine the phenotype, clinical course and the impact of exercise on patients with p.S358L ARVC-5 without the Newfoundland genetic background. METHODS We studied 62 affected individuals and 73 non-carriers from 3 TMEM43-p.S358L Spanish families. Impact of physical activity on phenotype was also evaluated. RESULTS Haplotype analysis revealed that the 3 Spanish families were unrelated to ARVC-5 patients with the Newfoundland genetic background. Two families shared 10 microsatellite markers in a 4.9 cM region surrounding TMEM43; the third family had a distinct haplotype. Affected individuals presented a 38.7% incidence of SCD, higher in males. LV involvement was common with 40% of mutation carriers showing LVEF<50%. Compared with non-carriers, R wave in V3 was lower (3.2±2.8 vs 7.5±3.6 mV; P<0.001) and QRS in right precordial leads wider (104.7±24.0 vs 88.2±7.7 ms;P=0.001). History of vigorous exercise showed a trend towards more ventricular arrhythmias only in women (P=0.053). CONCLUSIONS ARVC-5 is associated with high risk of SCD and characteristic clinical and ECG features irrespective of geographical origin and genetic background. Our data suggest that, as in desmosomal ARVC, vigorous physical activity could aggravate the phenotype of TMEM43 mutation carriers.