Development of left ventricular hypertrophy in adults with hypertrophic cardiomyopathy caused by cardiac myosin-binding protein C gene mutations

Objectives We sought to determine whether the development of left ventricul ar hypertrophy (LVH) can be demonstrated during adulthood in genetically af fected relatives with hypertrophic cardiomyopathy (HCM). Background Hypertrophic cardiomyopathy is a heterogeneous cardiac disease c aused by mutations in nine genes drat encode proteins of the sarcomere. Mut ations in cardiac myosin-binding protein C (MyBPC) gene have been associate d with age-related penetrance. Methods To further analyze dormancy of LVH in patients with HCM, we studied , using echocardiography and 12-lead electrocardiography, the phenotypic ex pression caused by MyBPC mutations in seven genotyped pedigrees. Results Of 119 family members studied, 61 were identified with a MyBPC muta tion, including 21 genetically affected relatives (34%) who did not express the HCM morphologic phenotype (by virtue of showing normal left ventricula r wall thickness). Of these 21 phenotype-negative individuals, 9 were child ren, presumably in the prehypertrophic phase, and 12 were adults. Of the 12 adults with normal wall thickness less than or equal to 12 mm (7 also with normal electrocardiograms), 5 subsequently underwent serial echocardiograp hy prospectively over four to six years. Of note, three of these five adult s showed development of LVH in mid-life, appearing for the first time at 33 , 34 and 42 years of age, respectively, not associated with outflow obstruc tion or significant symptoms. Conclusions In adults with HCM, disease-causing MyBPC mutations are not unc ommonly associated with absence of LVH on echocardiogram. Delayed remodelin g with the development of LVH appearing de novo in adulthood, demonstrated here for the first time in individual patients with prospectively obtained serial echocardiograms, substantiates the principle of age-related penetran ce for MyBPC mutations in HCM. These observations alter prevailing percepti ons regarding the HCM clinical spectrum and family screening strategies and further characterize the evolution of LVH in this disease. (J Am Coll Card iol 2001;38:315-21) (C) 2001 by the American College of Cardiology.