The previously described classifications by the AHA and ESC have advanced the field substantially. The writing group of the AHA classification must be complemented for challenging an obsolete tradition and promulgating the importance of the genetic basis of cardiomyopathy. The ESC writing group, while recognizing the importance of the heritability of the cardiomyopathies, preferred to retain the practicality of their taxonomy for routine clinical use. Separately, both allow latitude for improvisation, and the WHF classification represents a stepwise union of the two characteristics of phenotype and genotype into a cogent classification system.8,9 The WHF writing group maintains that whereas a diagnosis based on phenotype is clinically useful, identification of genetic mutations provides comprehensive information about prognosis in cardiomyopathies. A substantially large number of disease genes have been either confirmed or suspected as candidate genes; genetic heterogeneity has been established, and the wider use of next-generation sequencing is likely to increase our understanding of the phenotypic expression of the disease process. The WHF classification is an attempt to combine the message of both preceding classifications and is based on the following principles:
Most cardiomyopathies are familial diseases. The epidemiology of cardiomyopathies is derived from studies executed in the pregenetic era and, as discussed earlier, in the AHA classification, the traditionally accepted prevalence of cardiomyopathy based on the diagnosis of overt phenotypes may be a gross underestimation of the actual prevalence of cardiomyopathic disorders. Familial cardiomyopathies are predominantly inherited as autosomal dominant traits and, less frequently, as autosomal recessive, X-linked recessive or dominant, and matrilineal disorders. Familial cardiomyopathy should be diagnosed when two or more family members are affected. The age dependence of the phenotype may require long-term follow-up for a comprehensive evaluation of the family. The diagnosis of familial cardiomyopathy is easily established in families where more members are contemporaneously affected. However, the diagnostic assumption of nonfamilial cardiomyopathy should rely either on the evidence of a nongenetic cause or should remain labeled as unknown wherein systematic screening is limited by family size, adoption, or deceased relatives. After comprehensive assessment of pedigree, cascade family screening is undertaken to allow for identification of all affected family members, including healthy carriers.
Familial cardiomyopathies have a genetic origin and display clinical and genetic heterogeneity. The list of candidate genes as the cause of cardiomyopathies is growing. Such genes are identified through linkage analyses, genome-wide association studies, and whole exome sequencing. With more than 100 genes identified, the list still remains incomplete, but the most common genes associated with the different types of cardiomyopathies have been recognized, and genetic testing is being translated into clinical reality.
Although all cardiomyopathic disorders are broadly classified as five major morphofunctional phenotypes, a careful clinical evaluation demonstrates high phenotypic variability.9 Various cardiomyopathy subsets show variations in gender predisposition, age of onset, rate of progression, complications, and risk of developing end-stage heart failure or life-threatening ventricular arrhythmias. For example, DCM patients with LMNA mutations may develop life-threatening ventricular arrhythmias even in the presence of only mild LV enlargement and dysfunction, whereas those with dystrophin mutations may carry only low arrhythmogenic risk even with extreme LV dilatation or dysfunction. Similarly, there are HCM patients with severe LV hypertrophy (> 30 mm) but low arrhythmogenic risk and those with mild or moderate hypertrophy but high arrhythmogenic risk. In addition, gene-specific traits and diagnostic markers (red flags) may be reproducibly associated with subgroups of cardiomyopathy patients; such red flags include atrioventricular block (AVB), pre-excitation syndrome (eg, Wolff-Parkinson-White [WPW] pattern or syndrome), repolarization abnormalities, or attenuated QRS voltage.9 Furthermore, noninvasive imaging may reveal variable severity, distribution, and extent of myocardial hypertrophy; valve pathology; LV noncompaction; varying extents of ventricular dilatation and dysfunction; and variations in extent and distribution of myocardial fibrosis, or intramyocytic storage, and fatty infiltration within the myocardium. An integrated multidisciplinary workup including ascertainment of inheritance pattern, determination of major clinical phenotype (eg, DCM or HCM), identification of cardiac markers (eg, AVB, short PR interval, WPW), characterization of extracardiac organ involvement (eg, ocular, muscle, skeletal, or neurologic traits), or measurement of biomarkers (eg, increased serum creatinine phosphokinase or lactic acidemia) provides a preliminary filter for selecting genes for testing. For instance, cardiolaminopathies are associated with AVB in up to 80% of cases; dystrophinopathies are inherited in male patients in the absence of male-to-male transmission of the disease and are associated with increased serum creatinine phosphokinase (80%); and myocardial storage diseases typically demonstrate concentric LV hypertrophy with short PR interval and/or WPW pattern or syndrome. The presence of clinical red flags in probands and/or relatives guides genetic testing and provides for a sustainable strategy for clinical translation. After the conclusion of methodical clinical workup, genetic testing is offered to patients and their families.
The genetic heterogeneity complicates the diagnostic workup of familial cardiomyopathies: several genes influencing the same or different pathway(s) may be associated with similar phenotypes, and identical gene mutations may result in altogether different phenotypes. For instance, the sarcomeric gene defects may be associated with HCM and DCM; desmosome genes, which are typically associated with the classical ARVC, may cause DCM; genes encoding intermediate filaments such as nuclear lamins may also be associated with ARVC; and nonsarcomeric genes are also known to be associated with HCM. An increasing number of cardiomyopathies are recognized to be associated with complex genetics. Studies interrogating panels of genes in single patients have demonstrated a higher than expected rate of patients who are carriers of more than one and up to several mutations in the same or in different genes, which might imply that the incomplete genetic penetrance or variable expressivity of gene mutations represents incomplete genotyping or that the presumptive disease-causing role has erroneously been assigned to a wrong gene and mutation. Although in vitro functional studies can contribute to elucidating the role of protein mutations in a given cardiomyopathy, the detection of mutations will continue to be faster than developing animal models or performing in vitro studies for confirmation of their functional roles. An approach to genetic testing could be clinically guided or more broad based (eg, large panels of disease-associated/candidate genes). It is becoming evident that interpreting the results, rather than performing the tests, is the greater challenge in the modern era of next-generation sequencing.
The knowledge of genetic background would allow an improved management strategy. The major clinical decisions (eg, implantable cardioverter-defibrillator implantation) are still based on mechanical (eg, LV ejection fraction in DCM) or morphologic (eg, maximal LV wall thickness in HCM) characteristics, regardless of the intrinsic disease risk related to the underlying genotype.14,15 However, such risk stratification based on anatomic and/or mechanical features has limitations. For example, patients with laminopathies may not always demonstrate substantial LV dysfunction and dilatation when their arrhythmogenic risk first manifests,15,16 and those with dystrophinopathies may be significantly less susceptible to the risk of malignant arrhythmias even when the left ventricle is dramatically enlarged and dysfunctional. Similarly, patients with troponinopathies may not manifest severe LV wall thickness, but may live with a high arrhythmogenic potential.16,17
Ever-increasing knowledge of genetic background may result in random nomenclature. Based on the underlying gene mutations,8 numerous new terms (eg, desmosomalopathies, cytoskeletalopathies, sarcomyopathies, channelopathies, cardiodystrophinopathies, cardiolaminopathies, zaspopathies, myotilinopathies, dystrophinopathies, αB-crystallinopathies, desminopathies, or caveolinopathies) are being proposed. These are likely to cloud the description of cardiomyopathy, and it has become important that a uniform nomenclature be developed.
The taxonomy should be a flexible, user-friendly system that can be used at the bedside. As was the case for the universal TNM staging for malignant tumors, an improved taxonomy for classification of cardiomyopathy should be comprehensive and user-friendly, allowing for easier communication among physicians and facilitating the development of multicenter/multinational registries to promote research in diagnosis and management of cardiomyopathies. We have received several suggestions from various investigators, and modifications have been proposed for ACM,18 endomyocardial fibrosis,19 and HCM.20
The cardiomyopathies in the WHF classification are described as disorders characterized by morphologically and functionally abnormal myocardium in the absence of any other disease that is sufficient, by itself, to cause the observed phenotype.8 In this classification, although the conventional phenotypic subtype of the cardiomyopathy continues to provide the basis for the classification, a genotype-based assessment dictates the diagnostic workup and treatment decisions in probands and relatives, as well as the follow-up plan. Once the genetic cause of the cardiomyopathy has been defined, the cascade family screening can help identify healthy mutation carriers who may eventually develop the phenotype over the ensuing years.12 Avoidance of competitive sport activity and tailored monitoring with early medical treatment may favorably influence the natural history of the disease and the development of the manifest phenotype, as well as the risk of life-threatening arrhythmias. Identification of genetic diseases may also help subjects and alert physicians to refrain from the use of injurious agents. For instance, agents triggering malignant hyperthermia (succinylcholine) or volatile anesthetics (halothane and isoflurane) are to be avoided in emerinopathies and laminopathies causing muscular dystrophy.21 Statins should be administered with caution in patients with genetic cardiomyopathies with possible involvement of the skeletal muscle, even when markers of myopathy are negative.22 Patients with disorders of the respiratory chain may need surgeries in the long term, but anesthetics may interfere with metabolism and may trigger unexpected complications.23 Patients with mitochondrial cardiomyopathy and epilepsy should not receive valproate because it could cause pseudoatrophy of the brain.24 Common indications for heart transplantation in patients with end-stage cardiomyopathy should take into account the specific diagnosis; conditions such as Danon disease or other comorbidities, such as mental retardation, are a matter of debate regarding indication for heart transplantation.25 Finally, genotype-based diagnoses can be pooled in large international databases for future clinical trials and validation of novel management strategies.
The most effective nosology system should encompass clinical presentation, organ involvement, genetic inheritance, and precise etiologic information. This could be optionally supplemented by the functional class/stage/status and should employ universally adopted terms. The WHF’s MOGE(S) classification system is the first attempt to integrate morphofunctional phenotype-based description, information on the involvement of extracardiac organs/tissues, clinical genetics in familial diseases (pattern of inheritance), and molecular genetics (disease gene and mutation). MOGE(S) can also describe “sporadic” nongenetic cardiomyopathies and specify their etiology if known. In the case of phenotypically sporadic cardiomyopathies, a genetic origin of the disease cannot be excluded unless a nongenetic cause is proven and clinical family screening has ruled out a familial disease. When not certain, each cardiomyopathy should be considered as a potentially genetic disease, allowing families to receive the same screening options offered to families with known familial cardiomyopathy.
MOGE(S) classification is inspired by the TNM staging system; it is a descriptive nosology algorithm that includes five essential descriptors of cardiomyopathies (Fig. 57–3), inherited and noninherited.8 These five attributes are morphofunctional phenotype (M), organ involvement (O), genetic or familial inheritance pattern (G), etiologic (E) description of genetic defect or nongenetic cause, and functional status (S), using the American College of Cardiology (ACC)/AHA stage (stage A-D) and New York Heart Association class (NYHA) (class I-IV). The “S” notation becomes especially useful when mutation carriers are healthy (phenotypically unaffected) or if they demonstrate preclinical imaging-verified early abnormalities suggestive of the cardiomyopathy.9 The use of MOGE(S) is supported by the app for Android downloadable from Google Play (Fig. 57–4) or by the user-friendly web app at http://moges.biomeris.com/moges.html (Fig. 57–5). The cardiac phenotype description precedes genetic information. The approach to the evaluation of cardiomyopathies should involve a comprehensive family history and identification of other accompanying disease characteristics (red flags) that may predict candidate gene involvement. Even if genetic information is not available, consideration of heritability allows conceptualizing of the disease as a familial process.
MOGE(S) classification of cardiomyopathies. MOGE(S) classification is inspired by the tumor-node-metastasis (TNM) staging system; it is a descriptive nosology algorithm that includes five descriptors of cardiomyopathies, inherited and noninherited. These five attributes are morphofunctional phenotype (M), organ involvement (O), genetic or familial inheritance pattern (G), etiologic (E) description of genetic defect or nongenetic cause, and the functional status (S) using the American College of Cardiology (ACC)/American Heart Association (AHA) stage (stage A-D) and New York Heart Association (NYHA) class (class I-IV). ARVC, arrhythmogenic right ventricular cardiomyopathy; LVNC, left ventricluar noncompaction. Reproduced with permission from Arbustini E, Narula N, Tavazzi L, et al. The MOGE(S) classification of cardiomyopathy for clinicians. J Am Coll Cardiol. 2014 Jul 22;64(3):304-301.9
MOGE(S) is supported by a web app (desktop version is available at http://moges.biomeris.com/moges.html; Android version is downloadable from Google Play). ACC, American College of Cardiology; AHA, American Heart Association; NYHA, New York Heart Association.
Drop-down menu for the easy adaptation of MOGE(S) classification (http://moges.biomeris.com/moges.html). This expanded view for the characterization of underlying genetic etiology highlights the pathologic mutations (red), variants of unknown significance (VUS; yellow), and single-nucleotide polymorphisms (SNP; green).
Morphofunctional Phenotype, or M
The morphofunctional presentation is described as a subscript to the notation M; for example, MD (DCM), MH (HCM), MA (ACM), MR (RCM), and MNC (LV noncompaction). ACM is categorized in three major subtypes, including classical right ventricular ACM (ARVC or RV-ACM), biventricular ACM (BV-ACM), and predominantly left ventricular ACM (LV-ACM). Unlike previous classifications, the mixed or overlapping phenotypes can be easily presented, such as HCM that evolves into dilated congestive phenotype (MH+D) or HCM presenting with predominant restrictive pattern (MH+R). Other combinations are possible, such as MD+NC, MA+NC, MH+NC, MH+R+D. The M notation can add key clinical red flags such as short PR interval (↓PR), WPW pattern or syndrome, and AVB (displayed as MH[↓PR], MH[WPW], and MD[AVB], respectively), or nonspecific or noncoded traits (such as hypertrabeculation when criteria for LV noncompaction are not fulfilled or any other trait specifically associated with the disease) can be added (Fig. 57–6). Most importantly, M allows the description of early phenotypes (ME), such as when the diagnostic criteria for the suspected clinical phenotype (such as DCM or HCM) are not fulfilled and imaging data indicate an increased LV diameter and a borderline LV function (ME[D]) or possible LV hypertrophy (ME[H]).26 Clinically healthy mutation carriers are described as M0[H] or M0[D] (0 is for zero). When the information about the cardiac phenotype is not available, such as with the deceased relatives, the description is MNA. Overall, the M notation is flexible and suitable for any clinical combination of disease phenotypes and clinical traits.
Morphologic descriptor and genotypic interaction. Three pedigrees with probands (arrows) demonstrating similar dilated cardiomyopathy (DCM) phenotypes (A-D) in the first two and restrictive cardiomyopathy (RCM; E-F) in the third patient. The identification of the causative genes and mutations underscores the importance of the genetic diagnosis on the management of the three families. The identification of a mutation in the Emerin (EMD) gene provides information about the genetic status of the offspring. The son of the proband is obligate negative because a male cannot transmit an X-linked defect to his son. However, the daughters of affected males in X-linked diseases are obligate carriers of the paternal mutations. The identification of a mutation in the lamin AC (LMNA) gene (middle panel) or desmin (DES) gene (right panel) provides evidence that offspring can inherit the mutation with 50% probability for each pregnancy. All patients had advanced atrioventricular block and increases in serum creatinine phosphokinase (sCPK) levels. Pedigree symbols are as follows: circles represent females, squares represent males, diagonal lines represent deceased, and solid-filled symbols denote the presence of the phenotype. ECG, electrocardiogram; EF, ejection fraction; HF, heart failure; HTx, heart transplantation; LVEDD, left ventricular end diastolic diameter; NYHA, New York Heart Association; PM, pace maker; SD, sudden death; TAPSE, tricuspid annular plane systolic excursion.
The notation O describes organ involvement in the subscript. The comprehensive presentation of the organs involved helps identify syndromes. Primary cardiomyopathy (as described in the AHA classification), that is, only cardiac involvement, is represented as OH. The involvement of other organs is added on the cardiac involvement, such as skeletal muscle involvement in dystrophin defect (OH+M); involvement of kidney, gastrointestinal system, skin/cutaneous, and eye in Anderson-Fabry disease (OH+K+G+C+E; Fig. 57–7); or involvement of auditory system, nervous system, liver, lungs, and mental retardation in mitochondrial DNA–related diseases (OH+A, OH+N, OH+L, OH+Lu, and OH+MR, respectively). The involvement of uncommon organs can be adopted on the basis of anatomic terms in the Systematized Nomenclature of Medicine topography (eg, thyroid [OH+T] and adrenal glands [OH+AD]). Healthy mutation carriers are described as (O0) because the heart is still clinically unaffected (M0). “O” is similarly represented in nongenetic disorders (eg, the liver involvement and hypereosinophilia [OH+L+↑Eo] in endomyocardial fibrosis).
The pedigree shows a typical family with the X-linked Anderson-Fabry disease (AFD), cardiac variant, caused by p.(Asn215Ser) in α-galactosidase. In the bottom half of the figure, the pathologic features of AFD in endomyocardial biopsy are shown. A. The hematoxylin and eosin stain shows a large number of vacuolated myocytes (glycosphingolipids are extracted in formalin-fixed, paraffin-embedded tissues). B. Immunogold electron microscopy view shows typical lamellar and dense osmiophilic bodies specifically immune-labeled by anti-GB3 antibodies. Pedigree symbols are as follows: circles represent females, squares represent males, diagonal lines represent deceased, and solid-filled symbols denote the presence of the phenotype.
Genetic Inheritance, or G
The notation G describes the genetic or familial inheritance as clinically identified from the family screening, with inheritance including autosomal dominant (GAD), autosomal recessive (GAR), X-linked (GXL), X-linked recessive (GXLR) or dominant (GXLD), and matrilineal (GM). A solitary involvement is described as sporadic (GS) cardiomyopathy after the family screening and review of medical records of deceased relatives of the proband. The patient with unknown (GU) or negative (GN) family history should also be described.
Underlying Etiology, or E
The fourth notation of MOGE(S), E, is represented in two steps. The first step is presented as a coupled subscript for the genetic (EG), or nongenetic nature (ENG) of the disease. For the genetic background (EG), if the genetic defect is identified and characterized, then the second step provides complete information on the gene mutation, such as in the case of HCM (EG-MYH7[p.Arg403Glu]), familial amyloidosis (EG-ATTR[p.Val122Ile]), or hemochromatosis (EG-HFE[p.Cys282Tyr Homozygous]). When the mutation is identified or when more than one mutation/genetic variant is identified, it is described by the standard colors used for characterizing pathologic mutations in human mutations databases. The color code describes possible and probable pathologic mutations in red; genetic variants of unknown significance in yellow; and single-nucleotide polymorphisms with possible functional significance in green (the apps conveniently guide filing this annotation; see Figs. 57–4 and 57–5). If the genetic characterization is not available, but the clinical and genetic family screening provides the necessary information, the (EG) notation is to be specified as obligate carrier (EG-OC), obligate noncarrier (EG-ONC), or the sporadic/de novo occurrence of mutation (EG-DN). These are important notations because they complement the data on inheritance in the G descriptor. A genetic test negative for the known family mutation is described as (EG-NEG); a negative genetic test is described as (EG-N). When the genetic test could not be done for any reason, the descriptor is (EG-0). Reporting on healthy family members who test negative for the culprit mutation(s) is essential for segregation study in the family. When all members of a single family are described, the MOGE(S) nomenclature system highlights mutations that do not fully segregate with the phenotype. The international nomenclature of genetic variants provides the principles for their description (http://varnomen.hgvs.org/). The in silico evaluation supports the interpretation of the significance of each variant (http://genetics.bwh.harvard.edu/pph2/, http://sift.jcvi.org/, http://evs.gs.washington.edu/EVS/, http://www.1000genomes.org/, http://www.umd.be/HSF/). The family studies provide the segregation data, and the pathologic or in vitro studies may contribute to document the abnormal expression of the mutated protein.
Similar to the genetic diseases (EG), the cause of the underlying disease in the nongenetic cardiomyopathies (ENG) is specified as below in two steps, with first notation being couplet. The first notation (ENG) is coupled as predominantly toxic/degenerative, inflammatory, infiltrative, or hypersensitivity disease or others, as presented in Fig. 57-3. The second step should detail the exact cause if known. Some specific examples are as below. A viral myocarditis caused by Coxsackie B3 virus, human cytomegalovirus, or Epstein-Barr virus using the taxonomy system as coded by the International Committee on Taxonomy of Viruses (http://www.ictvonline.org/index.asp) may be presented as ENG-M[HCMV], ENG-M[CB3], or ENG-M[EBV], respectively. Other types of myocarditides may include sarcoidosis (ENG-M[Sarcoid]) or giant cell myocarditis (ENG-M[Giant cell]). Other examples of nongenetic inflammatory variety include autoimmune etiology (ENG-AI[TYPE]), hypersensitivity (ENG-Hs[TYPE]), or eosinophilic disease as from a parasitic process (ENG-Eo[Type of Parasitic Disease]). Eosinophilic Loeffler endomyocarditis may be described, according to the cause, as either being idiopathic or part of a myeloproliferative disorder associated with the somatic chromosomal rearrangement of the PDGFRα or PDGFRβ genes that generate a fusion gene encoding constitutively active PDGFR tyrosine kinases. Nonheritable amyloidosis with kappa (ENG-A[K]), lambda (ENG-A[L]), or serum amyloid A protein (ENG-A[SAA]) characterization can be easily presented and distinguished from the genetic varieties (EG-A[TTR]). Similarly, the toxic cardiomyopathies, such as pheochromocytoma-related (ENG-T[Pheo]) or drug-induced (ENG-T[Chloroquine]) cardiomyopathy, are classifiable; when the former is in the context of a syndrome (eg, von Hippel-Lindau, multiple endocrine neoplasia type 2A/2B, or neurofibromatosis type 1), the name of the syndrome could be added (ENG-T[Pheo-VHL])).
The notation S describes the heart failure ACC/AHA stage A to D and NYHA functional class I to IV, combined such as SA-I or SC-III.27 Although there has been some resistance to the universal application of ACC/AHA and NYHA staging, we believe that this allows the most practical solution to the description of early cardiomyopathies and mutation-carrying healthy family members. The ACC/AHA guidelines include patients with a family history of cardiomyopathy in stage A heart failure, and there has never been a way to include them in a cardiomyopathy classification. Although criteria for early diagnosis of cardiomyopathy are not systematically documented, the increasing family screening and monitoring have revealed that cardiomyopathies such as laminopathies reveal a long preclinical or subclinical incubation before the onset of manifest clinical disease.
The MOGE(S) nosology combines morphofunctional trait and organ (system) involvement with familial inheritance pattern, while characterizing heritable and nonheritable mechanisms of disease. ACC/AHA staging with NYHA class description offers special value for the inclusion of genetically mutated but yet unaffected individuals in the classification. Just as was the case for the universal TNM staging for malignant tumors, it is expected that this description will be improved, revised, modified, and made more comprehensive and user-friendly in years to come. It will allow for a better understanding of the disease process and easier communication among providers and help develop multicenter and multinational registries to promote research in diagnosis and management of cardiomyopathies.
The Major Attributes of the World Heart Federation Classification
MOGE(S) is an example of a coding system that has a sound basis and retains the phenotypic classification of cardiomyopathies (as in the ESC classification) but also incorporates the innovative soul of the AHA classification. Furthermore, because of its flexibility, MOGE(S) can be conveniently modified, adapted, and implemented.
The MOGE(S) system of classification of cardiomyopathies not only allows the possibility of retaining a phenotype-based description, but also allows inclusion of information about extracardiac organ involvement, the heritability of the disease, and data on both genetic and nongenetic mechanisms. Addition of information pertaining to functional status and disease state also allows description of mutation carriers who are clinically healthy or show subclinical or early disease. One of the main barriers encountered today in drawing reliable epidemiologic and clinical information from large, international databases lies in the difference in adopted definitions of the same object in various settings.28 Descriptive definitions such as MOGE(S) might help to overcome such obstacles. If universally adopted, the cardiology community would have enough data to group cardiomyopathies based on their causes to herald an open era for the development of disease-specific drugs and clinical trials.