Vol. 49, No. 25, 2007 ISSN 0735-1097/07/$32.00 doi:10.1016/j.jacc.2007.04.016
Phenotypic Plasticity of Sarcomeric Protein Mutations*
Ali J. Marian, MD, FACC Houston, Texas
The practice of medicine today is founded primarily on thephenotypic characteristics of diseases. The recognition of common forms of cardiomyopathies as hypertrophic, dilated, restrictive, and arrhythmogenic right ventricular cardiomyopathies typiﬁes the phenotype-based approach to diseases. The approach clearly has had numerous positive impacts on the diagnosis, prognostication, prevention, and treatment of various diseases. The advent of the betablockers andinhibitors of the renin-angiotensin-aldosterone pathway in the treatment of systolic heart failure are testaments to the clinical utility of the phenotype-based approach. Despite the enormous impacts, however, the phenotype-based approach has considerable shortcomings. For example, the approach has failed to offer a cure for many diseases including systolic heart failure, in which pharmacologicinterventions reduce mortality by approximately 20% to 30% and prolong survival by a few months (1–3).
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Accordingly, the annual incidence of heart failure, the common “end” phenotype of many cardiovascular diseases, has increased to 550,000 cases (4). It affected approximately 5.2 million individuals in the U.S. alone and accounted for approximately 1,100,000 hospitalizations and57,000 deaths in 2004 (4). The inherent problem of the phenotype-based approach to the practice of medicine is that it does not provide sufﬁcient information on the cause and/or the pathogenesis of the disease. To cure a disease, it is necessary, at least in most cases, to understand the cause and the pathways involved in the pathogenesis of the phenotype. The dawning of modern molecular genetics hasraised the possibility of a switch from a phenotype-based to a
*Editorials published in the Journal of the American College of Cardiology reﬂect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. From the Center for Cardiovascular Genetic Research, The Brown Foundation Institute of Molecular Medicine, The University of TexasHealth Science Center, Houston, Texas. Supported by grants from the National Heart, Lung, and Blood Institute (R01-HL68884), Clinical Scientist Award in Translational Research from Burroughs Wellcome Fund, and The TexGen Fund from Greater Houston Community Foundation.
genotype-based approach to medicine. Elucidation of the molecular genetic basis of various cardiovascular diseases, although yetincomplete, has led to the categorization of the phenotypes according to their genetic etiology. For example, hypertrophic cardiomyopathy (HCM) is considered a disease of sarcomeric proteins, dilated cardiomyopathy (DCM) a disease of cytoskeletal proteins, and long QT syndrome a disease of ion channels. The clear advantages of the genotype-based as opposed to a phenotype-based approach are in earlydiagnosis of those at risk, before and independent of the clinical phenotype as well as in the accurate diagnosis of the true phenotype from phenocopy conditions. The clinical signiﬁcance of the ﬁrst advantage is evident by the possibility of interventions to prevent the evolving phenotype. The utility of an accurate diagnosis and distinction from a phenocopy state is well illustrated in certaincircumstances, such as Fabry disease, which could be clinically indistinguishable from HCM caused by mutations in sarcomeric proteins (5,6). Enzyme replacement therapy with alpha-galactosidase, the enzyme responsible for Fabry disease, has been shown to impart considerable clinical beneﬁt in management of patients with Fabry disease, while the conventional treatment offered for true HCM would...