**2. Classification of pediatric cardiomyopathies and their clinical characteristics**

The classification of cardiomyopathies in general still is a challenging and debated topic due to different approaches used by larger population-based studies and guidelines provided by different cardiologic societies [2]. In many cases, CMs were (and still are) classified mainly by the morphofunctional phenotype of the myocardium, although, more and more often, pathogenetic and genotypic criteria were included. The different classifications lead to inconsistencies in terminology between different published systems such as the AHA, ACC, or ESC guidelines, thus adding to the difficulty to finding common pathophysiological patterns and therapeutic approaches in different cardiomyopathy studies, even more so for the relatively rare pediatric CMs. One attempt to integrate the different disease characteristics in a single system is the MOGE(S) classification [5]. It includes the morphofunctional phenotype (M), organ involvement (O, e.g., isolated to the heart vs. systemic/multi-organ), genetic inheritance pattern (G), and etiological or explicit genetic defects (E). Optionally, the functional status (S) can be included. But, these characteristics still can be applied in different hierarchies. Thus, the widely used current ESC approach implies the morphofunctional phenotype as the highest category and the genetic and pathogenetic characteristics as subcategories, as the phenotype provides the basis for diagnosis and therapeutic management in the first place. Still, the pathogenetics are of great importance for genetic counseling of mutation-carrier families in order to provide long-term risk assessment and, if necessary, regular monitoring of (as yet) seemingly unaffected family members by a cardiologist. Hereinafter, the different CM types will be discussed with regard to their most prominent morphofunctional aspects and their general prevalence in children. An overview on pediatric CM types is given in **Figure 1**.

#### **2.1 Dilated cardiomyopathy**

Dilated cardiomyopathy (DCM) is by far the most common CM in adults as well as in children (50–70% of all pediatric CM cases), though the prognosis is generally much worse for the latter [6]. In a North American study, 46% of 1426 pediatric DCM patients underwent heart transplantation or died during a 5-year follow-up period [6]. The hallmarks of DCM are dilation of the left ventricle (LV) and systolic dysfunction in absence of a hemodynamic cause (e.g., coronary artery and aorta anomalies, sepsis and ischemia) [7]. In addition to LV dilation, other features such as reduced ventricular wall thickness, mass-to-volume ratio, and mitral regurgitation are

*Cardiomyopathies in Children: Genetics, Pathomechanisms and Therapeutic Strategies DOI: http://dx.doi.org/10.5772/intechopen.109896*

#### **Figure 1.**

*Overview on pediatric cardiomyopathy (CM) types. The thickness of the branches reflects the relative prevalence in children, except for the rare cardiomyopathies (restrictive, arrhythmogenic, non-compaction, and mixed-type CMs). Here, dual color reflects both primary and secondary etiologies; single-color primary etiology only for arrhythmogenic CM. HCM: Hypertrophic CM; DCM: Dilated CM; NMD: Neuromuscular disorders; GSD: Glycogen storage disorders; LSD: Lysosomal storage disorders; FAOD: Fatty acid oxidation disorders; SHD: Structural heart disease.*

observed in the patients. The dilation and decreased contractility can also affect the right ventricle, resulting, for example, in elevated pulmonary pressures and even in pulmonary and peripheral edemas. Again, the phenotype of DCM is highly diverse, ranging from asymptomatic to single or biventricular heart failure, failure to thrive, arrhythmias, and sudden cardiac death [7]. Manifold causes have been described for DCM and encompass primary (genetic and idiopathic) as well as secondary categories [5, 6]. Sometimes, structural heart diseases are associated with DCM, being the endstage condition of the former, often resulting in the diagnostic "hen and egg" challenge: is the DCM the consequence of the abnormal loading conditions, or are the latter a consequence of an abnormal myocardium? This can often be answered only by successful treatment of the hemodynamic dysfunction (and the subsequent recovery of the myocardium), which is not always possible. The same question applies to DCM associated with pulmonary conditions, which primarily affect the right ventricle.

Primary DCM is difficult to diagnose in absence of identified familial mutations, as all secondary causes have to be excluded first [5]. Thus, patients with de-novo mutations are diagnosed potentially later due to lack of family history. Most cases of idiopathic DCM are considered to have a genetic cause, and there is a growing number of idiopathic DCM cases being reclassified into familial DCM upon further investigation. The estimated occurrence of FDCM is about 30–50% of all DCM cases in children; the 5-year event-free survival rate is 50–60% [6]. The inheritance is autosomal dominant, and the affected genes encompass those encoding for cytoskeletal, sarcomeric, and Z-disk proteins [8]. In addition, DCM is common and a leading cause of mortality in children with neuromuscular disorders (NMDs) such as Duchenne muscular dystrophy, Barth syndrome, myofibrillar myopathies and so on, as well as Emery-Dreyfuss syndrome, caused by a mutation in *LMNA*, the gene encoding for lamin A/C [9, 10]. Primary mitochondrial disorders can also present with a DCM phenotype or develop it over time [11]. Altogether, this underlines the importance of extensive genetic testing of DCM as well as NMD patients.

The distinct feature of secondary DCM (as opposed to primary DCM) is that the underlying causes affect multiple organs and can sometimes be treated, although this is a very broad group of different disorders, accounting for 50–70% of pediatric DCM cases [6]. Also, the phenotype can be very diverse, as well as disease onset and progression. Thus, the common classification criteria here are the dilated morphology and systolic dysfunction in the first place. In case of DCM presentation in very young patients, secondary causes have to be considered in the first place, as primary DCM is expected to be more prevalent in adults. A common type of secondary DCM is the inflammatory DCM, which can be further classified into infectious and non-infectious (e.g., reactions to drugs or toxins, autoimmune diseases etc.) [6]. In children, noninfectious causes are generally rarer than the infectious, with viral myocarditis being the most common cause of inflammatory DCM in children. Especially in cases of viral myocarditis with subsequent DCM, the changes in the morphology of the heart are remarkable, usually starting without significant dilation during the early and acute phase of the infection and remodeling to a dilated phenotype over time. Attributing the myocarditis clearly to a virus can be challenging, though, so that as complete a history and examination as possible should be performed to rule out other causes such as toxin or drug exposure, cancer, metabolic disorders (e.g., thyroid hormone dysregulations, diabetes mellitus), and nutritional disorders/deficiencies [12, 13].

#### **2.2 Hypertrophic cardiomyopathy**

The hallmarks of hypertrophic cardiomyopathy (HCM) are a hypertrophied but not dilated ventricle without an underlying hemodynamic cause or physiological hypertrophy and relaxation abnormalities/diastolic dysfunction, whereas the systolic function is usually preserved or even enhanced. Thus, the main diagnostic criterion is the diastolic septal or LV wall thickness, which has to be adjusted for body size in children and is expressed as wall thickness z scores. The wall thickening often presents focally or regionally, so that not the whole ventricle is affected. Nevertheless, the pattern is very diverse, with global biventricular involvement in the most extreme cases. In addition, structural disturbances are common, and mixed phenotypes of HCM with non-compaction and restrictive CM have been described [14, 15]. Similar to other cardiomyopathies, HCM can further be subclassified into primary and secondary forms, with the former being caused by mainly sarcomeric mutations and the latter associated with a multitude of causes, for example, syndromic diseases like Noonan syndrome, lysosomal and glycogen storage diseases (e.g., Anderson-Fabry disease, Pompe and Danon disease), disorders of the fatty acid metabolism, mitochondrial diseases, and hyperinsulinism [2, 16–18]. The latter occurs only in newborn and results from an overproduction of insulin, due to primary causes like pancreatic hyperfunction or to secondary causes like maternal diabetes mellitus. Usually, in these cases, HCM resolves when the underlying hyperinsulinism is treated [2, 14, 19]. In total, HCM accounts for approximately 40% of all pediatric cardiomyopathies and is the second most common CM after DCM in children (**Figure 1**) [20]. The occurrence is ten times higher in children under 1 year of age than in those older than 1 year. In 75% of all HCM cases, idiopathic and genetic/familial HCM are the most common etiologies in children, though it is not clear how many of the idiopathic cases arise from underlying genetic causes that have not been identified yet [21, 22]. Survival in infants with HCM is overall poorer than in older patients, but the prognosis highly depends on etiology and age at diagnosis. For example, inborn errors of metabolism are associated with a very early diagnosis (mean age 6 months) and a 5-year survival

*Cardiomyopathies in Children: Genetics, Pathomechanisms and Therapeutic Strategies DOI: http://dx.doi.org/10.5772/intechopen.109896*

rate of only 42%, while for idiopathic non-infantile HCM (age at diagnosis older than 1 year), 94% of children survive 5 years [22]. Thus, early-onset HCM generally has a much worse prognosis, especially in infants with inborn metabolic errors and malformation syndromes, as well as for idiopathic HCM (5-year survival of 82% for earlyonset cases vs. 94% for non-infantile cases) [22].

#### **2.3 Restrictive cardiomyopathy**

Restrictive cardiomyopathy is in general a rare type of CM, characterized by enhanced ventricular stiffness, abnormal filling patterns, and enlarged atria but absent or very mild hypertrophy or dilation [23]. Thus, the systolic function is nearly normal, while the diastolic function is impaired. The primary diagnostic criterion is the abnormal myocardial stiffness, which is caused by dysfunctions within the myocytes or of the intracellular matrix such as fibrosis, and has to be distinguished from constrictive pericarditis, where the impaired filling results from an abnormal pericardium [24, 25]. As in other cardiomyopathies, the RCM phenotype can vary from asymptomatic to prominent heart failure, pulmonary hypertension, arrhythmias, and sudden death. Causes of RCM can be mutations in sarcomeric and nonsarcomeric genes (primary RCM), as well as infiltration (e.g., amyloidosis), storage disease (e.g., Anderson-Fabry disease), and autoimmune disorders [26]. An important cause of RCM particularly in tropical regions is endomyocardial fibrosis caused by parasitic infections [27]. In children, primary RCM accounts for less than 5% of all CM cases but has the worst outcome [4, 28, 29]. About 66% of the patients present with a pure RCM phenotype and have a 5-year mortality rate of approximately 20% and a 5 year transplantation rate of 58% [28]. In about 50% of children with RCM, pathogenic or likely pathogenic gene variants were found [8].

#### **2.4 Left ventricular non-compaction cardiomyopathy**

The most distinctive feature of LVNC is a prominent trabeculation of the left ventricle, as diagnosed by cardiac imaging, which can occur isolated and even without any functional disturbances as well as as part of congenital heart disease or together with skeletal muscle and other systemic abnormalities, for example, Barth syndrome [30]. In addition, it has been associated with atrial and ventricular arrhythmias, atrial fibrillation, and conduction defects. A popular hypothesis suggests that LVNC represents a failure of maturation of the myocardium during embryonic development, although there is also evidence of histological differences of LVNC and normal myocardium even in the embryonic state [31]. The fact that excessive trabeculation does not necessarily lead to functional disturbances also gives rise to controversial views on LVNC as unclassified CM or even just a morphological trait not per se associated with dysfunction [32]. LVNC can occur as mixed phenotype together with, for example, HCM, RCM, or DCM, the latter being the most frequent case in children. Similar to the clinical phenotype, the prognosis in patients with LVNC is highly variable, as the presence of other factors than hypertrabeculation appears to be a major factor [33]. Children with isolated LVNC have a 94% 5-year survival rate, while cases with mixed hypertrophic, restrictive, or dilated phenotypes and/or arrhythmias show significantly poorer outcomes [33]. Barth syndrome is a well-characterized inborn metabolic disease associated with LVNC and DCM. In the United Kingdom and France, about half of the infants diagnosed with Barth syndrome died or received a heart transplant

[34, 35]. Among the transplant-free survivors, cardiac function often stabilized or even recovered after 3 years of age [34, 35].

#### **2.5 Arrhythmogenic cardiomyopathy**

Arrhythmogenic cardiomyopathy (ACM) encompasses genetic diseases like AVC (arrhythmogenic ventricular CM), channelopathies, and non-genetic pacing-induced CMs. The clinical and pathological hallmarks of AVC are ventricular arrhythmias, palpitations, syncope in connection to physical exercise, cardiac arrest, impaired ventricular systolic function, and replacement of the myocardium by fibrous and/or fatty tissue. In some cases, patients may also present with ventricular tachycardia and/ or heart failure (HF). The formerly used term "arrhythmogenic right ventricular (RV) cardiomyopathy" was established because often the disease affects mainly the right ventricle. But, due to an increasing number of reports of biventricular or even isolated LV involvement, the more general term AVC is now recommended [36, 37]. AVC has an estimated incidence of 1:100 to 1:5000 in the general population and is an important cause of sudden cardiac death (SCD) in children and young adults (11% of all SCD cases and 22% of SCD cases in young athletes), male patients being more often and more severely affected than females [38]. The phenotype is highly diverse though, ranging from nearly normal hearts to severe biventricular dysfunction. The fibrofatty replacement of the muscle tissue is often considered to arise from ischaemic damage of the myocardium, often more prominent in the RV. In contrast, in the LV, often only an isolated fibrofatty scar is observed, leading to a higher risk of severe ventricular arrhythmias and SCD [39]. The diagnosis of AVC is based primarily on cMRI imaging- and/or biopsy-based evidence of fibrofatty replacement in the myocardium and electrocardiographic (ECG) abnormalities. As the disease mostly follows an autosomal-dominant inheritance pattern, family history assessment and genetic screening are also indicated. Common AVC mutations affect desmosomal proteins and proteins involved in cell-cell adhesion. Commercial screening panels are available but do not encompass all genes associated with AVC. For adults, the diagnostic criteria were described in the revised Task Force Criteria of the AHA, but they have only limited validity for pediatric patients, as children often may not exhibit all of the features (e.g., prominent fibrofatty replacement), despite being mutation carriers [40, 41]. Instead, in a larger study, a significantly increased occurrence of SCD and resuscitated SCD was found in pediatric patients compared to adults, while sustained tachycardia was observed significantly less often [42]. Furthermore, athletes were overrepresented among the pediatric patients compared to adults, suggesting an association between endurance exercise during adolescence and pediatric-onset AVC [42].

Channelopathies are inherited arrhythmic diseases typically without structural changes of the heart and myocardium, which is distinctive from, for example, desmosomal, sarcomeric, and cytoskeletal AVC [43]. Channelopathies arise from mutations in genes encoding cardiac ion channels and encompass long- and short-QT syndromes, catecholaminergic polymorphic ventricular tachycardia, Brugada syndrome, and Lenègre disease [43]. Typical phenotypic manifestations are syncopes, cardiac arrest during physical activity, arrhythmias, potentially leading to ventricular fibrillation and SCD. In children, Brugada syndrome has been linked to sudden infant death syndrome [44]. While the heart appears structurally normal, there are prominent changes in the electrocardiographic patterns, which are often characteristic of the specific type of channelopathy, such as prolonged QT intervals in LQTS. Pacinginduced cardiomyopathies arise from ventricular dysfunction caused by tachycardia,

*Cardiomyopathies in Children: Genetics, Pathomechanisms and Therapeutic Strategies DOI: http://dx.doi.org/10.5772/intechopen.109896*

arrhythmia, or frequent cardiac ectopy [45]. The phenotype often presents as heart failure symptoms in the presence of tachycardia and ventricular dysfunction or even cardiogenic shock in neonates and infants. Mostly though, the myocardium recovers at least partially after treatment of the underlying arrhythmia [46]. Pacing-induced cardiomyopathy can also occur in children with chronic RV pacing, for example, in cases with atrioventricular block, and develops over time after pacemaker implantation [47]. This type of CM is thought to arise from unwanted abnormal transmission of electric impulses to the LV and can recover after changing to a biventricular pacemaker.
