The North American Pediatric Cardiomyopathy Registry (PCMR) has provided epidemiologic and clinical descriptor data for all forms of primary pediatric cardiomyopathy over the past two decades (3). Beyond one year of life, DCM is the most common diagnosis leading to cardiac transplantation in both children and adult populations. DCM represents approximately half of diagnosed pediatric cardiomyopathy cases, with an estimated incidence rate of 0.57 cases/100,000 person years in the PCMR North American cohort. Boys were at a higher risk than girls, and African Americans showed a higher risk than whites. The PCMR data set found that DCM
in children is most commonly diagnosed during the first year of life (41% of all patients), reflecting the large influence of genetic disease burden in this age group. Despite frequently aggressive diagnostic efforts, the majority of 1462 pediatric patients with primary DCM diagnosed mostly in the 1990s were ultimately classified as having idiopathic disease. Six etiologic classifications were used in this data set, which included (a) idiopathic DCM (66%), (b) myocarditis (16%), (c) neuromuscular disorders (9%), (d) familial DCM (5%), (e) inborn errors of metabolism (4%), and (f) malformation syndromes (1%) (Table 73.1). With the advent of clinical genetic testing, most children can now be placed into specific diagnostic categories, but such specialized services may not be universally available (4). Single-gene defects of sarcomeric proteins such as myosin and troponin are most commonly described in HCM, where some defect can now be detected in about 60% of affected individuals (5). Mutations in sarcomeric proteins (actin, myosin, troponins) as well as force-transducing molecules (titin [TTN], dystrophin), nuclear proteins (lamin A/C [LMNA]), RNA-binding proteins, and multiple other structural and metabolic molecules have been found to be either directly causative or implicated in the pathogenesis of DCM. Genetic analysis is most likely to identify specific mutations in the setting of familial DCM, where about 35% of families are found to have defects in TTN, LMNA, β-myosin heavy chain (MYH7) or cardiac troponin T (TNNT2). As there may be diagnostic uncertainty, incomplete penetrance, and a variable time course of illness, it is an important standard of care to screen first-degree family members, which allows for an earlier diagnosis of co-affected yet asymptomatic family members, and leads to better survival (6).

DCM ultimately arises as a result of an intrinsic or extrinsic cardiomyocyte abnormality or cell injury. It is thought that postnatal cardiac myocytes do not regenerate, such that any insult that causes myocyte loss permanently decreases an individual’s complement of myocardial cells. As a result, any acute myocardial insult may place a person at risk for the development of cardiomyopathy later in life. Anthracycline cardiotoxicity can lead to the late development of DCM post-cancer treatment and is considered a classic example of this construct.

Decreased ventricular function and progressive left-ventricular (LV) dilatation are the phenotypic hallmarks of DCM. On serial echocardiograms, the LV size is monitored as the LV end-diastolic dimension, whereas contractility is monitored as the LV ejection fraction or as the LV shortening fraction. Some patients will show a gradual thinning of the LV walls, which is tracked as the left-ventricular posterior wall thickness (LVPWT). Importantly, children show age- and size-related variation and hence comparative findings must be normalized for age and body surface area (BSA). This is done by reporting Z-values, which represent an individual’s findings as the number of standard deviations away from normative mean values for age and size. Findings are considered abnormal for any Z-score that is greater than 2 (positive or negative). Of note, as this is normative data, roughly 2% of normal, unaffected, individuals may actually be considered to show abnormal findings using the Z = ±2 standard. Thus, it is always important to synthesize an entire data set with clinical data before classifying an individual based upon borderline echocardiographic results.

LV dysfunction is typically asymptomatic and subclinical in its early stages. Nevertheless, decreasing myocardial function and falling cardiac output (CO) initiate a variety of compensatory mechanisms targeted to maintain blood pressure and normal organ perfusion. The baroreceptor response is a primary mechanism, which combats a fall in CO. This results in catecholamine-mediated increases in heart rate, contractility, and systemic vascular resistance (SVR). Activation of the renin-angiotensin-aldosterone system augments preload by promoting fluid retention, and SVR is further increased via potent renin-induced peripheral vasoconstriction. These compensatory mechanisms are acutely adaptive and help maintain a stable physiology. However, over time and with progressive myocardial dysfunction, these normal physiologic responses become maladaptive and harmful to a failing heart. Increased SVR directly increases cardiac afterload and myocardial oxygen demand and decreases stroke volume. As heart failure progresses, increased intravascular volume raises filling pressures, which, in the extreme, can impede diastolic coronary perfusion and lead to systemic and pulmonary edema. These general mechanisms produce the clinical syndrome of congestive heart failure, where patients demonstrate a (a) subnormal CO, (b) volume overload, and (c) a high SVR state. One should
remember that a dilated heart is a less efficient pump that requires more energy to function, has more oxygen demand, and increased wall tension. Afterload is also affected by cardiac geometry, and increases with progressive cardiac dilatation. This is explained by the law of Laplace, which describes the wall tension of a sphere under pressure:

Tension = Pressure × Radius

A normal heart will hypertrophy when exposed to chronic volume load as a compensatory means to decrease the luminal radius, thereby lowering the wall stress and afterload. However, wall thinning is a pathophysiological hallmark of DCM, with many patients showing a progressively thinner LVPWT. Unfortunately, progressive LV dilation and wall thinning potentiate a worsening cycle of increasing afterload, worsening energy balance, and progressive heart failure.