Evolving Classification and Diagnostic Schemes in Childhood Cardiomyopathies

Since the original phenotypic classification of cardiomyopathies by the World Health Organization (WHO), as dilated (DCM), hypertrophic (HCM) and restrictive (RCM), a number of revised classification schemes have been proposed and published.1-7 In the 1980 WHO report cardiomyopathies were defined as heart muscle diseases of unknown cause, while heart muscle disease with a known cause (infective, metabolic/endocrine, storage or infiltrative diseases) were labeled as specific heart muscle disease.¹ Myocardial disorders due to coronary disease, valvular lesions and congenital heart disease were specifically excluded. In 1995 the WHO modified the definition of cardiomyopathies to “diseases of the myocardium associated with cardiac dysfunction,” and specific cardiomyopathies to include“heart muscle disease with an associated cardiac or systemic disorder.”² Examples of the latter category include ischemic, valvular, inflammatory and metabolic cardiomyopathy. Arrhythmogenic right ventricular cardiomyopathy (ARVC) was added as its own entity while “noncompacted myocardium” (LVNC) was grouped under the category of unclassified cardiomyopathies. Theine et al subsequently suggested adding channelopathies such as long or short QT syndromes, Brugada syndrome and catecholaminergic polymorphic ventricular tachycardia to the cardiomyopathy classification³ arguing that arrhythmias are a sign of cardiac dysfunction with abnormal myocytes, although hemodynamics are otherwise normal. Classification recommendations were updated in an American Heart Association (AHA) statement, American College of Cardiology (ACC) in 2006 and the European Society of Cardiology (ESC) in 2008, but terminology usage was not consistent between the statements.^5,6 A more integrated approach to describe cardiomyopathies termed the MOGE(S) classification was proposed by Arbustini et al in 2013.⁷ Five components of cardiomyopathic disorders are addressed: morphofunctional characteristic (M), organ involvement (O), genetic or familial inheritance pattern (G), and an explicit etiological annotation (E) with details of genetic defect or underlying disease/cause, information about the functional status (S) using the American College of Cardiology/ American Heart Association (ACC/AHA) (A to D) stage and New York Heart Association (NYHA) (I to IV) functional classes may be added at the discretion of the physician.⁷

When formulating the AHA scientific statement on Cardiomyopathy in Children: Classification and Diagnosis, Lipshultz and colleagues reviewed these and additional published classification systems to devise a practical system to classify the myriad causes of pediatric heart muscle disease.⁸ The basis of their classification system incorporates components of the MOGE(S)7 and ESC⁶ approaches using the morphofunctional phenotype as the pinnacle of the system as it forms the basis for diagnosis and management. The authors make the point that the phenotype must be present in an individual to be labeled with the disease, for example a child with a known pathogenic gene mutation for a cardiomyopathy, based on family screening, would not be considered to have the disease if the phenotype was not evident by standard imaging definitions.

The statement is divided into nine pragmatic sections, the first seven pertaining to incidence, classification scheme, diagnosis and testing and the classified cardiomyopathies followed by a brief summary and conclusions.

Section 1 reviews the incidence of primary pediatric cardiomyopathies and the rationale for the classification scheme the group developed, followed by the standard imaging modalities used for morphologic evaluation of pediatric cardiomyopathies.

Section 2 discusses the genetics of pediatric cardiomyopathies, genetic testing and its interpretation, application and limitations. Sarcomeric gene mutations are associated with HCM, DCM, RCM and LVNC, although other gene mutations are also reported. Genetic mutations associated with syndromes, neuromuscular, metabolic and mitochondrial disorders are also well described and should always be considered, especially in infants and young children. Table 2 in Section 4 lists multiple genes and their associated phenotypes, many of which may result in differing phenotypic manifestations. Members of the same family with the same mutation may develop different cardiomyopathy phenotypes or may not manifest disease, likely due to modifier genes, epigenetic and environmental factors as well as lifestyle. In some cases, multiple pathogenic variants may influence the morphofunctional phenotype. The author’s state that medical therapy and activity restrictions are not necessary in gene positive, phenotype negative individuals with the exception of those with ARVC due to desmosomal mutations as endurance and high intensity athletics are linked to disease progression.

Section 3 classifies the forms/etiologies of dilated cardiomyopathies including primary and secondary forms as well as metabolic and nutritional disorders. Structural heart disease including congenital heart disease is included. Congenital heart disease with myocardial dysfunction has been left out of many other classification systems. If dysfunction resolves with correction or adequate palliation of hemodynamic abnormalities it is reasonable to exclude these cases. In cases where dysfunction persists or progresses, end-stage heart failure can develop with a dilated phenotype, however determining the true frequency of DCM, particularly in single ventricle patients is difficult, given their abnormal ventricular morphology and flow patterns and concomitant problems such as progressive valvular insufficiency. In the absence of further congenital heart disease surgical options, medical therapies are similar to those for isolated DCM with end stage disease resulting in cardiac transplantation, if not otherwise contraindicated. Thus, inclusion of congenital heart disease in this section seems reasonable.

Section 4 includes primary and secondary forms of hypertrophic cardiomyopathy. While an ACC/AHA guideline recommends not including secondary forms of HCM as HCM, rather terming them syndromes with left ventricular hypertrophy,⁹ Lipshultz and colleagues recommend their inclusion based on the hypertrophic phenotype.(8) Since relatively more of the pediatric hypertrophic cardiomyopathy phenotypes are secondary to syndromes, metabolic and mitochondrial disorders compared to adults, and the pediatric literature refers to the cardiomyopathies in these diseases as HCM, their inclusion is justifiable.

Section 5 discusses RCM, encompassing diseases resulting in the most severe end of the spectrum of diastolic dysfunction due to abnormal compliance/relaxation of the myocardium without another predominant phenotype. Clinical presentations vary from asymptomatic to right and/or left heart failure, arrhythmias, conduction disturbances, thromboembolic complications and sudden death. Both primary and secondary forms are described. In addition, restrictive physiology may develop in those with the primary phenotype of DCM, HCM and LVNC.

Section 6 is devoted to LVNC. When originally defined in adult studies, the diagnosis of LVNC typically described isolated disease of the myocardium, excluding those with congenital heart disease, coronary anomalies, musculoskeletal anomalies and other systemic abnormalities.¹⁰ However, the adult literature now recognizes that LVNC does not always occur in isolation.These associations are clearly present in children with LVNC and are included in the current pediatric statement. In addition, LVNC can be isolated or occur with a mixed phenotype with DCM, HCM and RCM forms with survival driven by the associated non-LVNC phenotype.

Section 7 on cardiomyopathies associated with arrhythmia substrate has the potential to cause the most debate in regard to the channelopathies that cause arrhythmias, with otherwise absent hemodynamic dysfunction. This category also includes the cardiomyopathy formerly termed ARVC, with the preferred term now being arrhythmogenic cardiomyopathy (ACM/ARVC)¹¹, since it is now recognized that the disease can affect both ventricles and, less frequently, can be isolated to the left ventricle. ACM/ARVC is termed arrhythmogenic ventricular cardiomyopathy (AVC) in the current pediatric statement,⁸ The isolated left ventricular form may require further modifications to the currently used criteria for ARVC.¹²

In the summary the authors point out that their work is a statement rather than a guideline, due to the paucity of evidence and consensus in the classification and evaluation of pediatric cardiomyopathy. In the conclusion they highlight the need for a pediatric classification system, separate from the adult system. This comprehensive review is an excellent resource to help guide clinician’s when faced with these challenging patients.