Fernando Dominguez1, Esther Zorio2, Juan Jimenez-Jaimez3, Rafael Salguero-Bodes4, Robert Zwart5, Esther Gonzalez-Lopez1, Pilar Molina6, Francisco Bermúdez-Jiménez3, Juan F Delgado4, Aitana Braza-Boïls7, Belen Bornstein8, Jorge Toquero9, Javier Segovia1, J Peter Van Tintelen10, Enrique Lara-Pezzi11, Pablo Garcia-Pavia12. 1. Department of Cardiology, Hospital Universitario Puerta de Hierro, Madrid, Spain; CIBERCV, Madrid, Spain. 2. CIBERCV, Madrid, Spain; Department of Cardiology, Hospital Universitario La Fe, Valencia, Spain; CAFAMUSME Research group, IIS La Fe, Valencia, Spain. 3. Department of Cardiology, Hospital Universitario Virgen de las Nieves, Granada, Spain. 4. CIBERCV, Madrid, Spain; Department of Cardiology, Hospital Universitario 12 de Octubre, i+12, Facultad de Medicina UCM, Madrid, Spain. 5. Department of Genome Analysis, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands. 6. CAFAMUSME Research group, IIS La Fe, Valencia, Spain; Department of Pathology, Instituto de Medicina Legal y Ciencias Forenses and Histology Unit, Universitat de València, Valencia, Spain. 7. Department of Cardiology, Hospital Universitario La Fe, Valencia, Spain; CAFAMUSME Research group, IIS La Fe, Valencia, Spain. 8. Department of Biochemistry, Hospital Universitario Puerta de Hierro, Madrid, Spain. 9. Department of Cardiology, Hospital Universitario Puerta de Hierro, Madrid, Spain. 10. Department of Genetics, University Medical Centre Utrecht, University Utrecht, Utrecht, The Netherlands. 11. CIBERCV, Madrid, Spain; Myocardial Biology Programme, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain; National Heart and Lung Institute, Imperial College London, United Kingdom. Electronic address: elara@cnic.es. 12. Department of Cardiology, Hospital Universitario Puerta de Hierro, Madrid, Spain; CIBERCV, Madrid, Spain; Universidad Francisco de Vitoria (UFV), Pozuelo de Alarcón, Spain. Electronic address: pablogpavia@yahoo.es.
Abstract
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.
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.S358LARVC-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.
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