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CLINICAL RESEARCH: CARDIOMYOPATHY

Prevalence, Clinical Significance, and Genetic Basis of Hypertrophic Cardiomyopathy With Restrictive Phenotype

Toru Kubo, MD^_*,, Juan R. Gimeno, MD^_*, Ajay Bahl, MD^_*, Ulla Steffensen^_*, Morten Steffensen^_*, Eyman Osman, BSc^_*, Rajesh Thaman, MD^_*, Jens Mogensen, MD, PhD^_*,, Perry M. Elliott, MD, FACC^_*, Yoshinori Doi, MD, FACC and William J. McKenna, MD, FACC^_*,_*

^_* Department of Medicine, University College London, London, United Kingdom
Department of Medicine and Geriatrics, Kochi Medical School, Kochi, Japan
Department of Cardiology, Skejby University Hospital, Aarhus, Denmark. This study was supported by a grant from the British Heart Foundation

Manuscript received October 18, 2006; revised manuscript received February 1, 2007, accepted February 5, 2007.

^_* Reprint requests and correspondence: Dr. William J. McKenna, The Heart Hospital, University College London Hospitals Trust, 16-18 Westmoreland Street, London W1G 8PH, United Kingdom (Email: william.mckenna{at}uclh.nhs.uk).

Objectives: The purpose of this study was to determine the prevalence, clinical significance, and genetic basis of hypertrophic cardiomyopathy (HCM) with "restrictive phenotype" characterized by restrictive filling and minimal or no left ventricular hypertrophy.

Background: Hypertrophic cardiomyopathy is a heterogeneous myocardial disorder with a broad spectrum of clinical presentation and morphologic features. Recent reports indicated that some patients with restrictive cardiomyopathy, which is an uncommon condition defined by restrictive filling and reduced diastolic volumes with normal or near normal left ventricular wall thickness and contractile function, have features suggestive of HCM with mutations in cardiac troponin I, myocyte disarray at explant/autopsy, and relatives with HCM. Systematic evaluation of the restrictive phenotype in HCM patients has not been performed.

Methods: We evaluated 1,226 patients from 688 consecutive HCM families to identify individuals who fulfilled diagnostic criteria for "restrictive phenotype."

Results: Nineteen of 1,226 affected individuals (1.5%) from 16 families (2.3%) had the "restrictive phenotype." During follow up (53.7 ± 49.2 months), 17 patients (89%) experienced dyspnea (New York Heart Association functional class 2). The 5-year survival rate from all-cause mortality, cardiac transplantation, or implantable cardioverter-defibrillator discharge was 56.4%. Mutation analysis for 5 sarcomere genes was feasible in 15 of 16 probands. Mutations were found in 8: 4 in beta-myosin heavy chain, and 4 in cardiac troponin I.

Conclusions: The "restrictive phenotype" in isolation is an uncommon presentation of the clinical spectrum of HCM and is associated with severe limitation and poor prognosis. This phenotype may be associated with beta-myosin heavy chain and cardiac troponin I mutations.

Abbreviations and Acronyms   CI = confidence interval   E/A = peak E-wave/A-wave velocity ratio   FS = fractional shortening   HCM = hypertrophic cardiomyopathy   ICD = implantable cardioverter-defibrillator   LV = left ventricular   LVEDD = left ventricular end-diastolic diameter   LVESD = left ventricular end-systolic diameter   LVH = left ventricular hypertrophy   MLVWT = maximum left ventricular wall thickness   MYBPC3 = cardiac myosin-binding protein C gene   MYH7 = beta-myosin heavy chain gene   RCM = restrictive cardiomyopathy   R-E = Romhilt-Estes   TNNI3 = cardiac troponin I gene   TNNT2 = cardiac troponin T gene   TPM1 = alpha-tropomyosin gene

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