CHAPTER 57: CLASSIFICATION OF CARDIOMYOPATHIES

Clinical taxonomy aids understanding and facilitates appropriate categorization of diseases through the use of logical groups and hierarchies on the basis of predefined characteristics that are useful for the diagnosis and management of human ailments. The classification results in standardization of disease nomenclature. In the premolecular era, this process was predominantly driven by sorting clinical phenotypes (eg, heart failure, cardiomyopathies, arrhythmias) and pathology (eg, cancer). For clinically and etiologically complex diseases such as cardiomyopathies, the principles of classification have been historically based on morphofunctional phenotypes shared by similar disorders with potentially overlapping treatments. Traditionally, the cardiomyopathies have been considered idiopathic diseases. In the past two decades, clinical and molecular genetics and advanced imaging have helped elucidate the etiopathogenetic basis of cardiomyopathy, and it is more than likely that the term idiopathic will gradually become obsolete. Most cardiomyopathies have a genetic basis, and for many of those that are not heritable, the mechanisms are now known. More than 100 disease genes have now been confirmed as candidate genes, and the number is continually increasing. Advances in biotechnology have allowed for rapid identification of underlying causes.

Heart muscle disorders are relatively young diseases. In a famous editorial published in Heart in 1982, John F. Goodwin reviewed the 30-year history of cardiomyopathies,¹ starting from the early 1950, when Brigden published the St. Cyres lecture on “Uncommon Myocardial Diseases: The Non-coronary Cardiomyopathies.”² The evolution from description to definition and clustering of similar cardiomyopathies led to the first classification of cardiomyopathies in 1972, when Goodwin and Oakley defined cardiomyopathies as the heart muscle diseases of unknown cause and described them as dilated (DCM), hypertrophic (HCM), and restrictive (or obliterative) (RCM) cardiomyopathy types.³ In 1980, the World Health Organization (WHO) adopted the classification of cardiomyopathies as “heart muscle diseases of unknown cause” (Fig. 57–1) to distinguish cardiomyopathy from cardiac dysfunction as a result of known cardiovascular entities such as hypertension, ischemic heart disease, or valvular disease.⁴ In 1995, the WHO/International Society and Federation of Cardiology (ISFC) Task Force on the Definition and Classification of the Cardiomyopathies expanded the classification to include all diseases affecting heart muscle and to take into consideration etiology as well as the dominant pathophysiology.⁵ The WHO/ISFC task force added two more classes: arrhythmogenic cardiomyopathy (ACM; ie, arrhythmogenic right ventricular cardiomyopathy [ARVC]) and unclassified cardiomyopathy.⁵ In 1998, the ISFC evolved to become the World Heart Federation (WHF), and until recently, did not indulge in developing scientific statements, and the recommendations for both diagnosis and management of cardiomyopathies were not updated. The morphofunctional phenotype has continued to be the unique basis for classification of cardiomyopathy.

During this period, a substantial increase in the knowledge of the genetic etiology of cardiomyopathy led the American Heart Association (AHA) to propose revisions to the classification of cardiomyopathy. In a valiant departure from the original definition, Maron et al⁶ classified cardiomyopathy primarily on its genetic basis and secondarily on its phenotypic description. The European Society of Cardiology (ESC)⁷ retained the description in original morphofunctional categories, but added subclassification into familial and nonfamilial varieties. Both AHA and ESC classifications preferred to exclude specific heart muscle diseases from consideration as cardiomyopathic disorders. In 2013, the WHF established its commitment to developing scientific statements and proposed a novel methodology for the classification of cardiomyopathies.^8,9 This update combined the best of both the AHA and ESC classifications. The proposed nomenclature, inspired from the tumor-nodal (metastasis)-distant metastasis (TNM) staging of malignant tumors,¹⁰ was descriptive, flexibly modifiable, and expandable.

The International Classification of Diseases (ICD) of the WHO is the standard diagnostic tool for epidemiology, health management, and delivery of care. It is ubiquitous and easily able to monitor the incidence and prevalence of diseases and statistics related to morbidity and mortality. It underscores the importance of appropriate classification and reporting of diseases. It continues to classify cardiomyopathies based on the original WHO-ISFC recommendations.

In routine practice, physicians are expected to use ICD codes after completion of their diagnostic workup in patients with cardiomyopathy. Codes from the ICD-10 are available at the ICD website (http://www.icd10data.com/ICD10CM/Codes/I00-I99/I30-I52/I42-/).

The ICD code for cardiomyopathies is I42; cardiomyopathies complicating pregnancy and puerperium are excluded, as is ischemic cardiomyopathy. The I42 code recognizes DCM (or congestive cardiomyopathy) without specifications. The HCM codes distinguish obstructive and nonobstructive forms (I42.1 and I42.2). The endomyocardial disease code distinguishes endomyocardial fibrosis, a well-defined clinical and pathologic disease of the endocardium (I42.3); the code I42.3 also includes Loeffler endocarditis, which is now better classified as hypereosinophilic syndrome. Endocardial fibroelastosis is now recognized as a “reactive feature” associated with several different diseases, in particular, congenital heart diseases such as left ventricular (LV) hypoplastic heart syndrome, and is a common pathologic finding in overloaded hearts from any etiology. Restrictive cardiomyopathy also includes constrictive cardiomyopathy, which is an obsolete term no longer used in clinical practice. Other codes cover all unaccounted cardiomyopathies. Therefore, the statistics based on ICD codes are unlikely to be useful for any practical purposes. The WHO is working toward a revised classification system that is better aligned with current scientific knowledge and that is compatible with contemporary information systems and will submit the 11th revision of the ICD to the World Health Assembly in 2018.¹¹ The ICD system could become uniquely useful for the future global epidemiology of cardiomyopathies if the information is presented more systematically.

The Basis

The diverse cardiomyopathy classifications presented through the years have been designed either for clinicians or biomedical scientists, and have been based on etiology, anatomy, physiology, primary treatment, method of diagnosis (including histopathology), and patient symptoms. The AHA classification⁶ was developed in response to the following drawbacks of the traditional WHO-ISFC classification:

1. The traditional previously mentioned WHO-ISFC classification admixes morphologic with functional traits. The AHA authors pointed out that the clinical classification HCM-DCM-RCM was fraught with major limitations. The classification combines anatomic and functional traits, wherein the same disease could legitimately cross over to two or even three of the phenotypes. In HCM, the key descriptor is morphologic (ie, thickened LV walls are present, and diastolic dysfunction is common). Similarly, in DCM, the key descriptor is morphologic (ie, LV dilation). However, systolic dysfunction is an obligatory part of the definition of the disease and functionally more relevant than simple ventricular dilatation. On the other hand, the key property in RCM is mechanical (ie, diastolic dysfunction, generally with preserved systolic function). However, the disease has a precise morphologic phenotype characterized by dilated atria in the absence of LV hypertrophy or dilatation. Although in ARVC the original key descriptor was primarily right-sided morphologic involvement with a prominent arrhythmogenic profile, biventricular and predominantly left-sided variants are increasingly recognized. LV involvement complicates the clinical diagnosis, and it may be challenging to distinguish between ARVC with LV involvement from DCM with right ventricular involvement.

2. The overlapping phenotypes render traditional classification difficult. The HCM-DCM-RCM classification also failed to consider the heterogeneous clinical expression and natural history of these diseases. For example, HCM, infiltrative and storage cardiomyopathies are characterized by substantial LV hypertrophy with increased wall thickness in the absence of ventricular dilatation. These conditions are also frequently associated with restriction to diastolic filling, whereas purely restrictive forms of cardiomyopathy (without LV hypertrophy) are exceedingly rare. Investigation into the genetic basis of HCM and other cardiomyopathies has led to the identification of individuals with a disease-causing mutation who do not develop LV hypertrophy. Dilated forms of cardiomyopathy show a considerably increased cardiac mass with myocyte enlargement indicative of cardiac hypertrophy, although absolute LV wall thicknesses might remain normal. The end-stage phase of HCM could demonstrate hypertrophic, dilated, and restrictive components. Furthermore, some patients may evolve from one category to another as a consequence of remodeling during their natural clinical course. For example, HCM, amyloid, and other infiltrative myocardial diseases may progress from a nondilated (often hyperdynamic) state with ventricular stiffness to a dilated form with systolic dysfunction and heart failure. Finally, because quantitative assessments of ventricular size represent a continuum and patients can vary widely in the degree of chamber enlargement (and dimensional cutoff values are arbitrary), it is often difficult to discriminate dilated from nondilated forms of cardiomyopathy. This ambiguity may also apply to some rare, or newly identified, cardiac diseases in young patients for which little quantitative cardiac dimensional data are currently available.

3. Etiologically/genetically diverse cardiomyopathies present with similar phenotypes. Etiologic classification of cardiomyopathies also appears problematic, given that diseases with the same (or similar) phenotypes can harbor diverse etiologic mechanisms. For example, DCM may have genetic, infectious, autoimmune, and toxic causes (and in some cases still be designated as idiopathic); all may lead to the final common pathway of ventricular dilatation with systolic dysfunction. Alternatively, functional classifications with potential relevance to treatment considerations and theoretically most useful to clinicians are also flawed and of limited value because management strategies for these diseases constantly evolve.

The Definition

Within this broad definition, cardiomyopathies are usually associated with failure of myocardial performance, which may be mechanical (eg, diastolic or systolic dysfunction) or a primary electrical dysfunction that increases susceptibility to life-threatening arrhythmias. The ion channelopathies (long and short QT syndromes, Brugada syndrome, and catecholaminergic polymorphic ventricular tachycardia, among others) are primary electrical diseases without gross or histopathologic abnormalities in which the functional and structural myocardial abnormalities responsible for arrhythmogenesis are at the molecular level in the cardiomyocyte or sarcoplasmic membranes themselves. The basic pathologic abnormality in these diseases is not identifiable by either conventional noninvasive imaging or myocardial biopsy during life, or even by electron microscopic or autopsy examination of tissue. The ion channelopathies are included in this classification of cardiomyopathies based on the scientifically reasonable assertion that ion channel mutations are responsible for altering biophysical properties and protein structure of the cardiomyocyte, thereby creating structurally abnormal ion channel interfaces and architecture with electrical dysfunction, which are changes that could trigger primary life-threatening ventricular tachyarrhythmias.

The Classification

Cardiomyopathies were divided into two major groups based on predominant organ involvement. The primary cardiomyopathies were those solely or predominantly confined to heart muscle (Fig. 57–2A).⁶ The primary cardiomyopathies were further categorized into genetic, acquired, and mixed varieties and represented the novelty of the AHA classification. The secondary cardiomyopathies showed pathologic myocardial involvement as part of systemic (multiorgan) disorders. In prior classifications, the primary cardiomyopathies represented idiopathic processes. The systemic diseases associated with secondary forms of cardiomyopathies were previously referred to as specific cardiomyopathies⁴ or specific heart muscle diseases⁵ in prior classifications. Such vague nomenclature was abandoned in the AHA classification.

The Major Attributes of the American Heart Association Classification

The AHA classification introduced the concept of classification of primary cardiomyopathy based on genetic origin. A large body of evidence had become available in 2006 that supported the genetic basis of cardiomyopathies, and the writing group asserted that it was time that cardiomyopathies be appropriately termed on the basis of their cause (ie, genetic, acquired, or mixed). The phenotype hierarchically was subordinate to the genotype in the AHA classification, presaging the gigantic evolution of knowledge pertaining to the genetic etiology of cardiomyopathies and the need for integrating the diagnostic description with genotype first and phenotype subsequently. The AHA classification was a welcome change and was the result of expertise, knowledge, and deep research on the mechanism of disease. However, it has been somewhat difficult to translate the classification recommendation into clinical reality.

The Basis

The 2008 position paper of the ESC proposed the classification of cardiomyopathies that aimed at providing an algorithm for daily clinical practice.⁷ The following were key tenets of the proposal, specifically in response to the original WHO-ISFC classification and 2006 AHA classification:

1. Phenotypic characterization should precede genetic characterization. Although the ESC endorsed the necessity for identifying the causative genetic defect, as proposed by the AHA, the ESC scheme retained the morphofunctional phenotype as the basis of the classification and management of cardiomyopathy. Cardiomyopathy was grouped into morphofunctional phenotypes including DCM, HCM, RCM, ACM, and unclassified varieties. Each of these types was further divided into familial (genetic) and nonfamilial (nongenetic) forms. The insistence on the morphofunctional classification was based on the fact that the pathway from diagnosis to treatment in clinical practice rarely begins with the identification of the causative genetic mutation; instead, patients present with symptoms, clinical signs, or abnormal screening test results. Even if the genetic defect is identified in offspring or siblings, the clinically relevant disease necessitates demonstration of a morphologic phenotype.

2. The broad classification between primary and secondary cardiomyopathy should not be necessary. The original WHO-ISFC classification system had distinctly defined the cardiomyopathies as primary myocardial disorders (when the cause of the myocardial involvement was unknown) and secondary or specific-heart muscle diseases (when the etiology was known). However, in the AHA classification, the term primary cardiomyopathy was applied when the heart was the sole (or predominantly) involved organ, and the term secondary cardiomyopathy described heart muscle disease as an integral part of a systemic disorder.⁶ It was further contended that the application of the terms primary and secondary cardiomyopathy per the AHA recommendation would be difficult when primary cardiomyopathy was associated with major extracardiac manifestations, or secondary cardiomyopathy predominantly (or exclusively) involved the heart. Therefore, ESC panelists abandoned the distinction between primary and secondary cardiomyopathies.

3. Ion channelopathy should not be considered cardiomyopathy. Ion channelopathies, a genetic subtype included in the AHA classification of primary cardiomyopathy, was not accepted as a cardiomyopathy in the ESC classification because genes encoding for ion channels might not be associated with overt myocardial dysfunction.¹² The ESC expert panel contested that the genes encoding ion channels implicated in patients with DCM, conduction disorders, and arrhythmia did not yet provide sufficient evidence for the redesignation of channelopathy as cardiomyopathy.

4. The diagnosis of cardiomyopathy should be sought and not be considered a diagnosis of exclusion. Traditionally, the diagnosis of cardiomyopathy has been established after exclusion of other cardiovascular disorders. However, it is increasingly recognized that patients with cardiomyopathy have uncommon, but well-described myocardial trait(s). Therefore, ESC panelists recommended a diagnostic workup toward a positive, logical search of cardiomyopathy instead of one that was exclusion based. The aim has been to promote a greater appreciation of the broad spectrum of diseases that can result in cardiomyopathy and to abandon the differentiation between cardiomyopathies and specific heart muscle diseases (noncoronary, valvular, hypertensive, or congenital).

The Definition

The 2008 ESC classification defined cardiomyopathy as a myocardial disorder in which the heart muscle is structurally and functionally abnormal, which, in the absence of coronary artery, hypertensive, valvular, and congenital disease, is sufficient to cause the observed myocardial abnormality.

The Classification

In the 2008 ESC classification, cardiomyopathies are grouped into specific morphologic and functional phenotypes; each phenotype is then subclassified into familial and nonfamilial forms (Fig. 57–2B).⁷ In this context, familial refers to the occurrence, in more than one family member, of either the same disorder or a phenotype that is (or could be) caused by the same genetic mutation and not a result of acquired cardiac or systemic diseases in which the clinical phenotype is influenced by a genetic polymorphism. Most familial cardiomyopathies are monogenic disorders wherein the gene defect is sufficient by itself to cause the trait. A monogenic cardiomyopathy can be sporadic when the causative mutation is de novo (ie, has occurred in an individual for the first time within the family). In this classification system, patients with identified de novo mutations are assigned to the familial category because their disorder can be subsequently transmitted to their offspring. Nonfamilial cardiomyopathies are clinically defined by the presence of a cardiomyopathy in the index patient and the absence of disease in other family members (based on pedigree analysis and clinical evaluation). They are subdivided into idiopathic (no identifiable cause) and acquired cardiomyopathies in which ventricular dysfunction is a complication of the disorder rather than an intrinsic feature of the disease. In a departure from the 1995 WHO-ISFC classification, but similar to the AHA categorization, this taxonomy also excludes LV dysfunction secondary to coronary artery disease, hypertension, valve disease, and congenital heart disease, because the diagnosis and treatment of these disorders generally involve clinical management that may vary in some ways from management of cardiomyopathy. Different familial and nonfamilial genetic diseases may induce similar phenotype.

The Major Attributes of the European Society of Cardiology Classification

The ESC classification introduced the concept of “familial cardiomyopathies” and encouraged excavation for the genetic cause of the phenotype. Although it is implicit that a familial disease has a genetic origin, the definition of familial cardiomyopathy was directed at motivating physicians to elicit a detailed family history and execute thorough phenotyping assessment of probands and relatives to establish the diagnosis within the clinical encounter, independent of genetic testing that might not be universally available. In clinical practice, cardiologists still use the morphofunctional classification of cardiomyopathies (HCM, RCM, DCM, ARVC, and unclassified varieties) followed by further characterization into genetic or nongenetic subtypes. The subsequent documents of the ESC Working Group reinforced the recommendations for screening of relatives as the most powerful clinical tool for the recognition of familial cardiomyopathies¹³ and clinical monitoring of families in a phenotype-driven mindset to formulate a pretest hypothesis of specific gene defects.¹⁴

The Basis

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:

1. 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.

2. 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.

3. 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

4. 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.

5. 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 Definition

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 Classification

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.

Morphofunctional Phenotype, or M

The morphofunctional presentation is described as a subscript to the notation M; for example, M_D (DCM), M_H (HCM), M_A (ACM), M_R (RCM), and M_NC (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 (M_H+D) or HCM presenting with predominant restrictive pattern (M_H+R). Other combinations are possible, such as M_D+NC, M_A+NC, M_H+NC, M_H+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 M_H[↓PR], M_H[WPW], and M_D[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 (M_E), 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 (M_E[D]) or possible LV hypertrophy (M_E[H]).²⁶ Clinically healthy mutation carriers are described as M_0[H] or M_0[D] (0 is for zero). When the information about the cardiac phenotype is not available, such as with the deceased relatives, the description is M_NA. Overall, the M notation is flexible and suitable for any clinical combination of disease phenotypes and clinical traits.

Organ Involvement, or O

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 O_H. The involvement of other organs is added on the cardiac involvement, such as skeletal muscle involvement in dystrophin defect (O_H+M); involvement of kidney, gastrointestinal system, skin/cutaneous, and eye in Anderson-Fabry disease (O_H+K+G+C+E; Fig. 57–7); or involvement of auditory system, nervous system, liver, lungs, and mental retardation in mitochondrial DNA–related diseases (O_H+A, O_H+N, O_H+L, O_H+Lu, and O_H+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 [O_H+T] and adrenal glands [O_H+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 [O_H+L+↑Eo] in endomyocardial fibrosis).

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 (G_AD), autosomal recessive (G_AR), X-linked (G_XL), X-linked recessive (G_XLR) or dominant (G_XLD), and matrilineal (G_M). A solitary involvement is described as sporadic (G_S) cardiomyopathy after the family screening and review of medical records of deceased relatives of the proband. The patient with unknown (G_U) or negative (G_N) 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 (E_G), or nongenetic nature (E_NG) of the disease. For the genetic background (E_G), 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 (E_{G-MYH7[p.Arg403Glu]}), familial amyloidosis (E_{G-ATTR[p.Val122Ile]}), or hemochromatosis (E_{G-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 (E_G) notation is to be specified as obligate carrier (E_G-OC), obligate noncarrier (E_G-ONC), or the sporadic/de novo occurrence of mutation (E_G-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 (E_G-NEG); a negative genetic test is described as (E_G-N). When the genetic test could not be done for any reason, the descriptor is (E_G-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 (E_G), the cause of the underlying disease in the nongenetic cardiomyopathies (E_NG) is specified as below in two steps, with first notation being couplet. The first notation (E_NG) 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 E_NG-M[HCMV], E_NG-M[CB3], or E_NG-M[EBV], respectively. Other types of myocarditides may include sarcoidosis (E_{NG-M[Sarcoid]}) or giant cell myocarditis (E_{NG-M[Giant cell]}). Other examples of nongenetic inflammatory variety include autoimmune etiology (E_NG-AI[TYPE]), hypersensitivity (E_NG-Hs[TYPE]), or eosinophilic disease as from a parasitic process (E_{NG-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 (E_NG-A[K]), lambda (E_NG-A[L]), or serum amyloid A protein (E_NG-A[SAA]) characterization can be easily presented and distinguished from the genetic varieties (E_G-A[TTR]). Similarly, the toxic cardiomyopathies, such as pheochromocytoma-related (E_NG-T[Pheo]) or drug-induced (E_{NG-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 (E_{NG-T[Pheo-VHL])}).

Functional Status, or S

The notation S describes the heart failure ACC/AHA stage A to D and NYHA functional class I to IV, combined such as S_A-I or S_C-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.

Although the major emphasis was placed on cancer and diabetes²⁹ in the 2015 State of the Union Presidential Address, the concept of precision applies to the entire field of medicine. We are in progressive transition from pathology-based descriptive medicine to specific etiology–driven medicine. Precision medicine and personalized medicine are often used interchangeably, but they represent two sides of the same coin wherein the precision is directed at the specific diagnosis and the personalized management is directed at an individually tailored approach.³⁰ Precision cardiology aims at detecting the primary causes of heart diseases and developing targeted, personalized therapies.^31,32 The impact of such an approach is expected to be almost immediate for the diseases caused by a unique factor, noxa, or genetic defect. Cardiomyopathies are paradigmatic examples of feasible and sustainable precision diagnostic workup. Their genetic origin and convenient genetic testing offer an ideal platform for providing patients and families with clinical and etiologic diagnosis. In most cardiomyopathy families, the most common autosomal dominant transmission lends itself to a precise diagnosis and plays a major role in family health for preimplantation, prenatal, preclinical, and presymptomatic assessment. Personalized medical therapy guided by pharmacogenetics and inducible pluripotent stem cells are also becoming an attractive emerging application for the clinical practice.³³ Precision data would remain underused if they are not incorporated in classifications, nosology, and coding systems that can make meaningful contributions in novel etiology-based epidemiology of diseases.

We thank Dr. Gaetano Thiene, who contributed to the previous version of this chapter in the 13th edition.