JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY VOL. 64, NO. 3, 2014 ª 2014 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION ISSN 0735-1097/$36.00 PUBLISHED BY ELSEVIER INC. http://dx.doi.org/10.1016/j.jacc.2014.05.027 THE PRESENT AND FUTURE STATE-OF-THE-ART REVIEW The MOGE(S) Classification of Cardiomyopathy for Clinicians Eloisa Arbustini, MD,* Navneet Narula, MD,y Luigi Tavazzi, MD, PHD,z Alessandra Serio, MD, PHD,* Maurizia Grasso, BD, PHD,* Valentina Favalli, PHD,* Riccardo Bellazzi, ME, PHD,x Jamil A. Tajik, MD,k Robert O. Bonow, MD,{ Valentin Fuster, MD, PHD,# Jagat Narula, MD, PHD# ABSTRACT Most cardiomyopathies are familial diseases. Cascade family screening identifies asymptomatic patients and family members with early traits of disease. The inheritance is autosomal dominant in a majority of cases, and recessive, X-linked, or matrilinear in the remaining. For the last 50 years, cardiomyopathy classifications have been based on the morphofunctional phenotypes, allowing cardiologists to conveniently group them in broad descriptive categories. However, the phenotype may not always conform to the genetic characteristics, may not allow risk stratification, and may not provide pre-clinical diagnoses in the family members. Because genetic testing is now increasingly becoming a part of clinical work-up, and based on the genetic heterogeneity, numerous new names are being coined for the description of cardiomyopathies associated with mutations in different genes; a comprehensive nosology is needed that could inform the clinical phenotype and involvement of organs other than the heart, as well as the genotype and the mode of inheritance. The recently proposed MOGE(S) nosology system embodies all of these characteristics, and describes the morphofunctional phenotype (M), organ(s) involvement (O), genetic inheritance pattern (G), etiological annotation (E) including genetic defect or underlying disease/substrate, and the functional status (S) of the disease using both the American College of Cardiology/American Heart Association stage and New York Heart Association functional class. The proposed nomenclature is supported by a web-assisted application and assists in the description of cardiomyopathy in symptomatic or asymptomatic patients and family members in the context of genetic testing. It is expected that such a nomenclature would help group cardiomyopathies on their etiological basis, describe complex genetics, and create collaborative registries. (J Am Coll Cardiol 2014;64:304–18) © 2014 by the American College of Cardiology Foundation. ardiomyopathy is the heart muscle disease underscore the importance of providing cardiologists C sufficient to cause structural and functional with tools to better describe the patients and families myocardial abnormality in the absence of affected by a morphofunctional cardiomyopathic coronary artery disease, hypertension, valvular dis- phenotype. The American Heart Association (AHA) ease, and congenital heart disease. Based on the clin- classification grouped cardiomyopathies into genetic, ical and genetic evidence,mostcardiomyopathies mixed,andacquiredforms,andtheEuropeanSociety are inherited, and the recent classification systems of Cardiology classification proposed subgrouping of From the *Center for Inherited Cardiovascular Diseases, IRCCS Foundation Policlinico San Matteo, Pavia, Italy; yWeill Cornell Medical College, New York, New York; zGVM Care & Research, E.S. Health Science Foundation, Maria Cecilia Hospital, Cotignola, Italy; xUniversity of Pavia, Pavia, Italy; kSt. Luke’s Medical Center, Milwaukee, Wisconsin; {Northwestern University School of Medicine, Chicago, Illinois; and the #Icahn School of Medicine at Mount Sinai, New York, New York. This study was supported by Grants European Union INHERITANCE project n241924 and Italian Ministry of Health “Diagnosis and Treatment of Hypertrophic Cardiomyopathies” (nRF-PSM-2008-1145809) (to Dr. Arbustini), IRCCS Policlinico San Matteo, Pavia. Dr. Tavazzi has served as a member of the Speaker’s Bureau for Servier; has been a trial committee member for Servier, Cardiorentis, Boston Scientific, St. Jude Medical, CVIE Therapeutics, Vifor Pharma, and Medtronic. Dr. Narula has received research grants from GE Healthcare & Philips Healthcare. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. P. K. Shah, MD, served as the Guest Editor for this paper. Manuscript received April 30, 2014; revised manuscript received May 27, 2014, accepted May 28, 2014. JACC VOL. 64, NO. 3, 2014 Arbustini et al. 305 JULY 22, 2014:304– 18 MOGE(S) Classification of Cardiomyopathy each major type of cardiomyopathy into familial or arrhythmias. Numerous electrocardiographic ABBREVIATIONS genetic, and nonfamilial or nongenetic forms (1,2). markers have been shown to be associated AND ACRONYMS The American College of Cardiology (ACC)/AHA stag- with cardiomyopathy in a subset of the ACC = American College of ing of the heart failure (HF) included asymptomatic patients, including atrioventricular block Cardiology patients with a familial history of cardiomyopathy in (AVB), pre-excitation syndrome (Wolff-Par- AHA = American Heart the stage A or pre-HF (3). kinson-White syndrome [WPW]), repolariza- Association In the last 20 years, the systematic approach to tion abnormalities, or low QRS voltage. ARVC = arrhythmogenic right family screening has contributed to better assess- Echocardiography and cardiac magnetic reso- ventricular cardiomyopathy ment of familial cardiomyopathies. This method has nance imaging may reveal variable features AVB = atrioventricular block allowed the identification of family members who are within the similar phenotypes, including the DCM = dilated cardiomyopathy predisposed to disease development, based on the in- severity, distribution, and extent of myocar- EMF = endomyocardial fibrosis heritance of the cardiomyopathy-associated gene(s). dial hypertrophy, thickening of valves, non- HCM = hypertrophic The electrocardiographic and echocardiographic clues compaction, ventricular dilation, ventricular cardiomyopathy may show early (subclinical) cardiac involvement dysfunction, myocardial fibrosis, infiltrative LV = left ventricle – fi (4 10). On the other hand, the nongenetic cardiomy- or intramyocyte storage, or fatty in ltration of LVNC = left ventricular opathies may be described as associated with specific the myocardium (18,19).Althougheachsub- noncompaction etiologies, such as viral infections, autoimmune dis- type of cardiomyopathy is defined by its major RCM = restrictive eases, and endogenous or exogenous myocardial morphofunctional phenotype, a careful clin- cardiomyopathy toxicity. The contemporary diagnostic algorithms ical evaluation demonstrates high phenotype WPW = Wolff-Parkinson-White syndrome for work-up of cardiomyopathies are supported by variability. advanced imaging characterization, disease-specific Most cardiomyopathies demonstrate an auto- biomarkers, and genetic analyses (11). The number of somal dominant inheritance, but X-linked recessive, cardiomyopathies wherein the cause is identified (or autosomal recessive, or matrilineal inheritance may identifiable) is increasing, supported by the family occur in a minority of cases. Although elucidation screening and follow up for segregation studies of of family history and comprehensive assessment genotype with phenotype. of pedigree is the foremost necessity in family The morphofunctional phenotype-based classifi- studies (17,20,21),itmaynotbebyitselfsufficient cation of cardiomyopathies continues to offer cardi- to establish the diagnosis of familial cardiomyo- ologists the possibility of using a simple and clinically pathy. Cascade family screening and monitoring useful diagnostic language (Table 1). All treatment may be necessary to identify affected but asymp- protocols are currently based on the phenotype, as tomatic family members unaware of their disease, well as signs and symptoms. The phenotype-based or who display subclinical abnormalities by non- classification (hypertrophic cardiomyopathy [HCM], invasive imaging tests as early markers of the dilated cardiomyopathy [DCM], restrictive cardiomy- disease (16,17). opathy [RCM], arrhythmogenic right ventricular car- The knowledge of the genetic basis of all kinds diomyopathy [ARVC]/arrhythmogenic ventricular of cardiomyopathies has progressively increased cardiomyopathy, and left ventricular noncompaction (12–14,22). Linkage analyses (23), genome-wide asso- [LVNC]) describes the major forms of cardiomyopa- ciation studies (GWAS) (24,25), and whole-exome se- thy, but not their causes. However, cardiomyopathies quencing (WES) (26) have incrementally contributed are clinically heterogeneous diseases (12–17),and to the list of disease genes (Online Table 1), which within each subtype of cardiomyopathy there are now includes more than 100 genes. HCM is caused by differences in sex, age of onset, rate of progression, the mutations of genes that code for structural and risk of development of overt heart failure, and like- functional proteins of the sarcomere (15),whereas lihood of sudden death. In the DCM group, for DCM is caused by the mutation of genes related to example, there are patients with mildly enlarged structure and function of nuclear envelope, cyto- and mildly dysfunctional left ventricle (LV) that skeleton, sarcomere, and sarcoplasmic reticulum (27). develop life-threatening ventricular arrhythmias; ARVC is known as a collection of diseases of the yet, there may