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CLINICAL STUDY: HYPERTROPHIC CARDIOMYOPATHY

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

Barry J. Maron, MD, FACC^*, Hideshi Niimura, MD, Susan A. Casey, RN, Marjorie K. Soper, MD, Gregory B. Wright, MD, FACC, J. G. Seidman, PhD and Christine E. Seidman, MD

^* Hypertrophic Cardiomyopathy Center, Minneapolis Heart Institute Foundation, Minneapolis, Minnesota, USA
First Department of Internal Medicine, Kagoshima University, Kagoshima, Japan
Children’s Heart Clinic, Minneapolis, Minnesota, USA
Howard Hughes Medical Institute and Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA

Manuscript received September 21, 2000; revised manuscript received March 19, 2001, accepted April 12, 2001.

Reprint requests and correspondence: Dr. Barry J. Maron, Hypertrophic Cardiomyopathy Center, Minneapolis Heart Institute Foundation, 920 East 28th Street, Suite 40, Minneapolis, Minnesota 55407
hcm.maron{at}mhif.org

OBJECTIVES

We sought to determine whether the development of left ventricular hypertrophy (LVH) can be demonstrated during adulthood in genetically affected relatives with hypertrophic cardiomyopathy (HCM).

BACKGROUND

Hypertrophic cardiomyopathy is a heterogeneous cardiac disease caused by mutations in nine genes that encode proteins of the sarcomere. Mutations in cardiac myosin-binding protein C (MyBPC) gene have been associated 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 expression caused by MyBPC mutations in seven genotyped pedigrees.

RESULTS

Of 119 family members studied, 61 were identified with a MyBPC mutation, including 21 genetically affected relatives (34%) who did not express the HCM morphologic phenotype (by virtue of showing normal left ventricular wall thickness). Of these 21 phenotype-negative individuals, 9 were children, presumably in the prehypertrophic phase, and 12 were adults. Of the 12 adults with normal wall thickness 12 mm (7 also with normal electrocardiograms), 5 subsequently underwent serial echocardiography prospectively over four to six years. Of note, three of these five adults 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 obstruction or significant symptoms.

CONCLUSIONS

In adults with HCM, disease-causing MyBPC mutations are not uncommonly associated with absence of LVH on echocardiogram. Delayed remodeling 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 penetrance for MyBPC mutations in HCM. These observations alter prevailing perceptions regarding the HCM clinical spectrum and family screening strategies and further characterize the evolution of LVH in this disease.

Abbreviations and Acronyms   DNA = deoxyribonucleic acid   ECG = electrocardiogram or electrocardiographic   HCM = hypertrophic cardiomyopathy   LV = left ventricle or left ventricular   LVH = left ventricular hypertrophy   MyBPC = myosin-binding protein C   SAM = systolic anterior motion

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