CLINICAL CARDIOLOGY CLINICIAN’S CORNER Hypertrophic Cardiomyopathy A Systematic Review Barry J. Maron, MD Context Throughout the past 40 years, a vast and sometimes contradictory litera- ture has accumulated regarding hypertrophic cardiomyopathy (HCM), a genetic car- YPERTROPHIC CARDIOMYOP- diac disease caused by a variety of mutations in genes encoding sarcomeric proteins athy (HCM) is a complex and and characterized by a broad and expanding clinical spectrum. relatively common genetic Objectives To clarify and summarize the relevant clinical issues and to profile rap- cardiac disease that has been idly evolving concepts regarding HCM. Hthe subject of intense scrutiny and in- Data Sources Systematic analysis of the relevant HCM literature, accessed through vestigation for more than 40 years.1-10 Hy- MEDLINE (1966-2000), bibliographies, and interactions with investigators. pertrophic cardiomyopathy is an impor- Study Selection and Data Extraction Diverse information was assimilated into tant cause of disability and death in a rigorous and objective contemporary description of HCM, affording greatest weight patients of all ages, although sudden and to prospective, controlled, and evidence-based studies. unexpected death in young people is per- Data Synthesis Hypertrophic cardiomyopathy is a relatively common genetic car- haps the most devastating component of diac disease (1:500 in the general population) that is heterogeneous with respect to disease- its natural history. Because of marked causing mutations, presentation, prognosis, and treatment strategies. Visibility at- heterogeneity in clinical expression, tached to HCM relates largely to its recognition as the most common cause of sudden natural history, and prognosis,11-20 HCM death in the young (including competitive athletes). Clinical diagnosis is by 2-dimen- often represents a dilemma to primary sional echocardiographic identification of otherwise unexplained left ventricular wall thick- care clinicians and cardiovascular spe- ening in the presence of a nondilated cavity. Overall, HCM confers an annual mortality rate of about 1% and in most patients is compatible with little or no disability and nor- cialists, even to those for whom this dis- mal life expectancy. Subsets with higher mortality or morbidity are linked to the com- ease is a focus of their investigative ca- plications of sudden death, progressive heart failure, and atrial fibrillation with embolic reers. Controversy abounds with regard stroke. Treatment strategies depend on appropriate patient selection, including drug treat- to diagnostic criteria, clinical course, and ment for exertional dyspnea (␤-blockers, verapamil, disopyramide) and the septal myotomy- management for which difficult ques- myectomy operation, which is the standard of care for severe refractory symptoms as- tions often arise, particularly among prac- sociated with marked outflow obstruction; alcohol septal ablation and pacing are alternatives titioners infrequently engaged in the to surgery for selected patients. High-risk patients may be treated effectively for sudden evaluation of HCM patients. Conse- death prevention with the implantable cardioverter-defibrillator. quently, it is timely to place in perspec- Conclusions Substantial understanding has evolved regarding the epidemiology and tive and clarify many of these relevant clinical course of HCM, as well as novel treatment strategies that may alter its natural clinical issues and profile the rapidly history. An appreciation that HCM, although an important cause of death and dis- evolving concepts regarding HCM. ability at all ages, does not invariably convey ominous prognosis and is compatible with normal longevity should dictate a large measure of reassurance for many patients. METHODS JAMA. 2002;287:1308-1320 www.jama.com A systematic search of the medical lit- erature involving 968 articles primar- tively small group of highly selected cen- sion, selective referral patterns, and di- ily related to English-language HCM ters in the United States, Canada, and Eu- verse mechanisms for morbidity and publications (1966-2000) from a var- rope. In addition, perceptions emanating mortality. Therefore, in HCM, the level ied and extensive number of authors from the author’s more than 25 years of of evidence governing management and centers was conducted through extensive experience with HCM inter- MEDLINE or bibliographies of pub- faced with the literature analysis. Many Author Affiliation: Minneapolis Heart Institute Foun- lished articles. These studies and oth- clinical HCM studies are observational dation, Minneapolis, Minn. Corresponding Author and Reprints: Barry J. ers before 1966 were analyzed to cre- and retrospective in design because of Maron, MD, Minneapolis Heart Institute Founda- ate a balanced appraisal of HCM. difficulty in organizing large prospec- tion, 920 E 28th St, Suite 60, Minneapolis, MN 55407 (e-mail: [email protected]). Published accounts of HCM have tive and randomized clinical trials for Clinical Cardiology Section Editor: Michael S. Lauer, come disproportionately from a rela- a disease with heterogeneous expres- MD, Contributing Editor. 1308 JAMA, March 13, 2002—Vol 287, No. 10 (Reprinted) ©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 HYPERTROPHIC CARDIOMYOPATHY decisions is derived primarily from non- contractile, structural, or regulatory activated protein kinase (PRKAG2) have randomized studies. I placed the great- functions).9,11-13,23-27 The physical simi- been reported to cause familial Wolff- est reliance on evidence-based investi- larity of these proteins makes it pos- Parkinson-White syndrome associated gational designs and large, statistically sible to regard the diverse HCM spec- with conduction abnormalities and powered and controlled studies, when trum as a single disease entity and LVH30,31 (because of glycogen accumu- available. primary sarcomere disorder. The mecha- lation in myocytes).31 This syndrome is nisms by which disease-causing muta- most appropriately regarded as a meta- RESULTS tions cause LV hypertrophy (LVH) and bolic storage disease distinct from HCM, Prevalence the HCM disease state are unresolved, which is caused by mutations in genes Epidemiological investigations with di- although several hypotheses have been encoding sarcomeric proteins. There- verse study designs have shown simi- suggested.28 fore, management and risk assessment lar estimates for prevalence of pheno- Three of the HCM-causing mutant of patients with Wolff-Parkinson- typically expressed HCM in the adult genes predominate, namely, ␤-myosin White syndrome and cardiac hypertro- general population at about 0.2% (1: heavy chain (the first identified), car- phy should not be predicated on data 500).20 Therefore, HCM is not rare and diac troponin T, and myosin-binding derived from patients with HCM. is the most common genetic cardiovas- protein C. The other genes each ac- Of potential importance for under- cular disease, with reports from many count for a minority of HCM cases, standing HCM pathophysiology are ge- countries. Nevertheless, a substantial namely, cardiac troponin I, regulatory netic animal models (ie, transgenic mice proportion of individuals harboring a and essential myosin light chains, titin, and rabbits)32-35 and spontaneously oc- mutant gene for HCM are probably un- ␣-tropomyosin, ␣-actin, and ␣-myosin curring animal diseases.36 In particu- detected clinically. Hypertrophic car- heavy chain. This diversity is com- lar, domestic cats with heart failure diomyopathy is, however, uncommon pounded by intragenic heterogeneity, commonly show a disease with clini- in routine cardiologic practice, affect- with more than 150 mutations identi- cal and morphologic features remark- ing no more than 1% of outpatients.21 fied, most of which are missense with a ably similar to HCM in humans.36 This limited exposure of clinicians to single amino acid residue substituted HCM understandably accounts for the with another.9,11-13,26,27 Molecular de- Diagnosis uncertainty that prevails regarding this fects responsible for HCM are usually Clinical diagnosis of HCM is estab- disease and its management. different in unrelated individuals, and lished most easily and reliably with 2-di- many other genes and mutations, each mensional echocardiography* by imag- Nomenclature accounting for a small proportion of fa- ing the hypertrophied but nondilated LV Since the first modern description in milial HCM, remain to be identified. chamber, in the absence of another car- 1958,1 HCM has been known by a con- Contemporary molecular genetic diac or systemic disease (eg, hyperten- fusing array of names, reflecting its clini- studies throughout the past decade have sion or aortic stenosis) capable of pro- cal heterogeneity and the skewed expe- provided important insights into the ducing the magnitude of hypertrophy rience of early investigators. Hypertrophic considerable clinical heterogeneity of evident (FIGURE 1and FIGURE 2A).19,22 cardiomyopathy22 is the preferred name HCM, including the preclinical diagno- Hypertrophic cardiomyopathy may be because it describes the overall disease sis of affected individuals without phe- initially suspected because of a heart spectrum without introducing mislead- notypic evidence of disease (ie, LVH murmur (occasionally during prepar- ing inferences that left ventricular (LV) by echocardiography or electrocar- ticipation sports examinations),43 posi- outflow tract obstruction