Clinical characteristics and determinants of the phenotype in TMEM43 arrhythmogenic right ventricular cardiomyopathy type 5

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 nondesmosomal 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 whether the disease is influenced by genetic or environmental factors.

Objective: The purpose of this study was 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 noncarriers from 3 TMEM43-p.S358L Spanish families. The impact of physical activity on the phenotype was also evaluated.

Results: Haplotype analysis revealed that the 3 Spanish families were unrelated to patients with ARVC-5 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. The affected individuals showed a 38.7% incidence of sudden cardiac death, which was higher in men. Left ventricular involvement was common, with 40% of mutation carriers showing a left ventricular ejection fraction of <50%. Compared with noncarriers, the R-wave voltage in lead V₃ was lower (3.2 ± 2.8 mV vs 7.5 ± 3.6 mV; P < .001) and QRS complex in right precordial leads wider (104.7 ± 24.0 ms vs 88.2 ± 7.7 ms; P = .001). A history of vigorous exercise showed a trend toward more ventricular arrhythmias only in women (P = .053).

Conclusion: ARVC-5 is associated with a high risk of sudden cardiac death and characteristic clinical and electrocardiographic 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.