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CLINICAL RESEARCH: HYPERTROPHIC CARDIOMYOPATHY

Lifelong Left Ventricular Remodeling of Hypertrophic Cardiomyopathy Caused by a Founder Frameshift Deletion Mutation in the Cardiac Myosin-Binding Protein C Gene Among Japanese

Toru Kubo, MD^_*, Hiroaki Kitaoka, MD, PhD^_*, Makoto Okawa, MD^_*, Yoshihisa Matsumura, MD, PhD^_*, Nobuhiko Hitomi, MD^_*, Naohito Yamasaki, MD^_*, Takashi Furuno, MD^_*, Jun Takata, MD, PhD^_*, Masanori Nishinaga, MD, PhD^_*, Akinori Kimura, MD, PhD and Yoshinori L. Doi, MD, PhD, FACC^_*,_*

^_* Department of Medicine and Geriatrics, Kochi Medical School, Kochi, Japan
Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan

Manuscript received January 17, 2005; revised manuscript received April 25, 2005, accepted May 25, 2005.

^_* Reprint requests and correspondence: Dr. Yoshinori L. Doi, Department of Medicine and Geriatrics, Kochi Medical School, Oko-cho, Nankoku-shi, Kochi 783-8505, Japan (Email: ydoi{at}med.kochi-u.ac.jp).

OBJECTIVES: We studied the longitudinal evolution of hypertrophic cardiomyopathy (HCM) caused by a founder frameshift mutation in the cardiac myosin-binding protein C (MyBPC) gene.

BACKGROUND: Mutations in the MyBPC gene have been associated with delayed expression of HCM and a good prognosis. Few studies, however, demonstrated the phenotype-genotype correlations in the longitudinal study.

METHODS: We studied long-term evolution of clinical features of 15 unrelated families who were found to have an identical frameshift mutation in the MyBPC gene: a one-base deletion of a thymidine at nucleotide 11645 (V592fs/8).

RESULTS: Thirty-nine individuals in 15 families were genotype-positive. Thirty of the 39 individuals with the mutation were phenotype-positive. The disease penetrance was 100% in subjects 50 years and 65% in those <50 years. "End-stage" HCM (ejection fraction <50%) was observed in 7 (18%) of the 39 genotype-positive individuals (7 [23%] of the 30 phenotype-positive patients); 6 of them were 60 years or older. Seven patients were hospitalized for treatment of repeated congestive heart failure, and four patients died or had implantable cardioverter-defibrillator discharge (13%; incidence, 1.4%/year) during a mean follow-up period of 9.2 ± 5.5 years.

CONCLUSIONS: Elderly patients with a V592fs/8 mutation in the MyBPC gene may evolve into the "end-stage" HCM, characterized by left ventricular systolic dysfunction, cavity dilation, and irreversible heart failure. The clinical course in patients with this mutation is not benign in the long run, with progressive left ventricular remodeling with advancing age.

Abbreviations and Acronyms   AF = atrial fibrillation   ECG = electrocardiogram/electrocardiographic   EF = ejection fraction   HCM = hypertrophic cardiomyopathy   ICD = implantable cardioverter-defibrillator   LVEDD = left ventricular end-diastolic diameter   LVH = left ventricular hypertrophy   MLVWT = maximum left ventricular wall thickness   MyBPC = cardiac myosin-binding protein C