Primary hypertrophic cardiomyopathy

The estimated prevalence of HCM among adults is reported to be 0.2% of the population [6]. Primary HCM (also known as sarcomeric HCM) is an autosomal dominant condition characterized by hypertrophy of the left ventricle, interventricular septum, and only occasionally right ventricular involvement [1,7]. The first gene for familial HCM was localized to chromosome 14q11.2‐q12 [8]. Over the past 30 years, more than 1000 distinct mutations have been identified in more than 20 genes [9–16]. Most mutations occur in genes encoding for sarcomeric or myofilament‐related proteins, including beta‐myosin heavy chain, cardiac myosin binding protein C, myosin essential light chains, myosin regulatory light chain2, cardiac troponin T, cardiac troponin I, alpha‐tropomyosin, z‐disk components, telethonin, muscle LIM protein, and actin. Sarcomere mutations are found in nearly 70% of adult and pediatric patients with a family history of HCM, as well as 30–40% of sporadic cases [17,18]. Mutations in myosin heavy chain and myosin binding protein C account for 80% of primary HCM. The identification of a pathogenic sarcomere gene mutation establishes a definitive diagnosis of HCM and the exact genetic etiology of disease. This information provides insight into the patient’s prognosis and guidance in the management of their family. However, because of the genetic and clinical heterogeneity seen in HCM, robust prediction of outcome based on the genotype has proven elusive. Nonetheless, adverse outcomes appear more prominent in HCM patients with sarcomere mutations than in patients without an identifiable mutation [19]. Alfares et al. reported on limited additional sensitivity in diagnostic rates (~32% of 2912 probands) based upon expanded genetic panels [20].

Secondary hypertrophic cardiomyopathy

Specific inborn errors of metabolism, neuromuscular disorders, and mitochondrial and syndromic diseases (i.e., Noonan, Costello, and LEOPARD syndromes) may manifest in HCM. These are called “secondary” HCMs [1,21]. In spite of the phenotypic similarities, secondary HCMs are widely different from primary HCM. Secondary HCMs usually present in infancy (up to 15% of infants with HCM) and have a poor outcome. Typically, patients with secondary HCM develop concentric HCM, often accompanied by involvement of the right ventricle [22,23]. Metabolic screening and, in certain cases, muscle biopsy will help delineate the etiology.

Metabolic diseases associated with secondary HCM include Fabry disease (glucocerebrosidase deficiency), Danon disease, and Pompe disease (acid‐maltase deficiency) [24–29].

Fabry disease is an X‐linked recessive disease that accounts for 4% of cases of unexplained LV hypertrophy in young men [25]. Symptoms usually start in the first decade of life, with acroparesthesiae, heat intolerance, and development of cutaneous angiokeratomas. From the second decade onwards patients develop proteinuria and neurologic manifestations, including vestibular and hearing disturbance and autonomic dysfunction. Cardiac involvement is present early in life but is usually not detected clinically until the third or fourth decade [24,25]. Early cardiomyopathy is characterized by concentric remodeling, progressing later to concentric biventricular hypertrophy, which causes diastolic dysfunction. Asymmetric septal hypertrophy and dynamic left ventricle outflow tract (LVOT) obstruction are rare (5–10% of cases), but do occur. The mitral and aortic valves are thickened and distorted, resulting in regurgitation. The diagnosis can readily be made by measuring serum levels of the enzyme alpha‐galactosidase A. This is of particular relevance because two recombinant enzyme preparations are approved for the treatment of Fabry disease.

Danon disease is an X‐linked deficiency of lysosome‐associated membrane protein type 2. It can present at variable ages as multisystemic disease with skeletal myopathy, mental retardation, and cardiomyopathy. Cardiac involvement is characterized by massive hypertrophy, ventricular pre‐excitation, and heart failure. Disease clinically confined to the heart is described in some cases with later onset [26].

Pompe disease (acid‐maltase deficiency) is an autosomal recessive disorder that may also result in HCM in infancy [27]. It is associated with severe skeletal muscle hypotonia, progressive weakness, hepatomegaly, and macroglossia. The electrocardiogram typically shows broad, high‐voltage QRS complexes and the concentric LV hypertrophy is typically severe.

Mitochondrial diseases may also result in HCM [29]. Friedreich ataxia, a progressive form of spinocerebellar degeneration due to lack of the mitochondrial protein frataxin, may also give rise to HCM, and all young adults with this condition should undergo routine screening. LV hypertrophy is typically concentric, and may be symmetric or asymmetric [30,31]. LV cavity dilation and systolic dysfunction occur in the third and fourth decade, leading to clinical deterioration [30].

Left ventricular noncompaction cardiomyopathy may result in an undulating phenotype, which may alternate between dilated and hypertrophic phenotypes [32]. Moreover, myocardial crypts represent a distinctive morphologic expression of HCM. The presence of myocardial crypts can resemble LV noncompaction [33].

Twenty percent of children with restrictive cardiomyopathy demonstrate an overlapping restrictive–hypertrophic phenotype which can lead to one or the other diagnosis. Furthermore, different family members with the same mutation can display different phenotypes consistent with one or the other type of cardiomyopathy [34].

Nonfamilial, nongenetic causes of LV hypertrophy that can mimic HCM include infants of mothers with diabetes, steroid‐induced LV hypertrophy, and obesity [1].

Anatomy

There is marked heterogeneity in the pattern and extent of LV hypertrophy from none to extreme. LV hypertrophy involves the basal and mid‐interventricular septum and is asymmetric with a septal‐to‐inferolateral wall thickness ratio of >1.3 in 60% of children and adolescents with primary HCM [2,3,35]. Up to 50% of infants with HCM demonstrate concentric LV hypertrophy [22,23]. Recently, spiral forms of HCM with variable extension of LV hypertrophy have been described [36]. Less common forms of HCM can be seen with LV hypertrophy limited to the mid or apical segments of the left ventricle. The LV cavity is typically small. This can occur with or without LVOT obstruction. The hypertrophy can develop early in life or in childhood or adolescence depending on the etiology. The mitral valve can be abnormal and thickened. The development of septal hypertrophy and anterior displacement of the mitral apparatus frequently leads to narrowing of the LVOT and the creation of a dynamic pressure gradient across the LVOT. Although this pressure gradient was initially attributed to a muscular sphincter action in the subaortic region, it is now considered to be related to further narrowing of an already small outflow tract by systolic anterior motion of the often elongated mitral valve leaflets against the hypertrophied septum [37,38].

M‐mode and 2D echocardiography

The primary step in the evaluation of a child with suspected HCM is to rule out underlying conditions that may masquerade as HCM. 2D echocardiography provides the primary screening tool to rule out the presence of HCM. HCM may manifest as asymmetric septal hypertrophy, concentric septal hypertrophy, posterior left ventricular (1–2%), mid‐ventricular (5%), or apical (2–3%) hypertrophy [35]. Most of these forms of LV hypertrophy may be associated with an obstruction to flow in the left ventricle and the development of a gradient (Figures 36.1 and 36.2). Obstructive HCM only occurs in 30% of patients at rest [52]. The presence, magnitude, and distribution of LV hypertrophy should be first determined using 2D imaging in the parasternal long‐axis, short‐axis, and apical four‐ and two‐chamber views as well as subcostal views (Figures 36.3 and 36.4, Videos 36.1–36.3). Accurate measurements of the interventricular septum and LV inferolateral wall thickness derived from 2D imaging should be taken at end‐diastole, indexed to body surface area, and z‐score measurements obtained [53]. A scoring system has been developed to quantify the extent of LV hypertrophy (Table 36.1). This often provides additional crucial data where there is an uneven distribution of septal hypertrophy [2].

The M‐mode can be used to detect systolic anterior motion of the mitral leaflets and mid‐systolic closure of the aortic valve (Figures 36.5 and 36.6). Neither of these findings are pathognomonic of HCM as they have also been described in other conditions (Table 36.2).

Assessment of diastolic function

Diastolic filling is impaired in HCM; this may result in breathlessness on exertion, elevated filling pressures, and left atrial enlargement [41,42]. Left atrial volume reflects chronic left atrial hemodynamic burden from LV diastolic dysfunction and mitral regurgitation and correlates well with the degree of myocardial fibrosis and degree of exercise intolerance in children with HCM [54]. The transmitral inflow pattern should be carefully assessed with spectral Doppler performed at the tips of the mitral leaflets from the apical four‐chamber view. The mitral E‐ and A‐wave pattern typically represents marked perturbations in diastolic relaxation with a reduced E‐wave velocity, increased A‐wave velocity (decreased E/A‐wave ratio), prolonged E‐wave deceleration time, and prolonged isovolumetric relaxation time (Figure 36.7) [55]. Conversely, in restrictive cardiomyopathy or when HCM patients develop a restrictive filling pattern, there is an increase in E‐wave velocity, decrease inA‐wave velocity (increased E/A‐wave ratio), and decreasedE‐wave deceleration time and isovolumetric relaxation time. In children a mid‐diastolic wave (L wave) can be seen, especially in the presence of bradycardia; this suggests increased left atrial pressure. Pseudo‐normalization may occur with intermediate degrees of diastolic dysfunction when the mitral E/A‐wave ratio is normal; however, the A‐wave reversal will be increased, lateral mitral tissue Doppler velocities will be diminished, and during the Valsalva maneuver there is a reduction of flow into the left heart, left atrial and diastolic ventricular pressures decrease, and there is an E‐wave velocity reduction and reversal of pseudo‐normal E/A‐wave pattern [56]. The use of the transmitral E/e´ lateral velocity ratio will be discussed later in this chapter. Pulmonary vein Doppler recordings demonstrate a progressive decrease in systolic flow and an increase in A‐wave reversal velocity and duration with increasing degrees of diastolic dysfunction (Figure 36.8).

In adult patients the LV filling pressure may be estimated comparing the time duration between the pulmonary venous A wave and the mitral A wave. Late diastolic left atrial contraction results in antegrade flow of blood through the mitral valve and retrograde flow into the pulmonary veins. In cases of elevated left heart filling pressures, the pulmonary venous A‐wave duration exceeds the mitral A‐wave duration [56]. In such cases this predicted a LV end‐diastolic pressure of >15 mmHg with 85% sensitivity and 79% specificity. This can be difficult to measure in children, however, because of increased heart rates and the small differences that may exist between these two measurements. A pediatric study demonstrated correlation between E/A‐wave ratio and LV filling pressures but poor correlation with tissue Doppler velocities [57].

Mitral valve function

In the presence of significant LVOT obstruction eddy currents are generated in the subaortic region. This hemodynamic abnormality results in anterior displacement of the mitral valve leaflets, known as systolic anterior motion (SAM) of the mitral valve [58]. The parasternal long‐axis view demonstrates SAM very well (Figure 36.9). SAM often results in noncoaptation of the mitral valve leaflets with a jet of mitral regurgitation directed posteriorly along the left atrial wall (Figures 36.10 and 36.11). Similar to the timing of LVOT obstruction, the mitral regurgitation is typically late in systole and may range from mild to severe (Videos 36.4–36.6) [59]. Given the high LV systolic pressures, the mitral regurgitant jet velocity may be in supraphysiologic ranges [38]. Severe mitral regurgitation may result in retrograde flow into the pulmonary veins, contributing to pulmonary venous and arterial hypertension.

Mitral regurgitation in patients with HCM can also be secondary to intrinsic mitral valve disease; this is present in roughly 40% of patients with HCM. The anterior leaflet is enlarged and redundant. The presence of a nonposteriorly directed jet in apical or parasternal long‐axis views suggests primary leaflet pathology independent of SAM [60]. The detection of intrinsic valve disease is particularly relevant in patients who are candidates for surgical myectomy, as the presence of intrinsic mitral valve disease is associated with persistence of mitral regurgitation if not addressed during surgery.

Left ventricular outflow tract Doppler

The degree of LVOT obstruction is often multifactorial and dynamic. The pattern of LVOT obstruction in HCM is typically in mid to late systole with no significant obstruction in early systole [39]. LV ejection typically diminishes during mid to late systole resulting in partial closure of the aortic valve, often with reopening with final ejection (Figure 36.6).

The presence of SAM usually indicates some form of LVOT obstruction, particularly when SAM persists for >40% of systole [39,52]. 2D imaging can also detect SAM in addition toM‐mode imaging.

The degree and location of LVOT obstruction is measured using color, pulsed‐wave, and continuous‐wave Doppler imaging typically from the apical five‐chamber view. Color Doppler imaging often demonstrates aliasing due to outflow tract gradients exceeding the Nyquist limit and provides a visual impression on where flow acceleration occurs (Figure 36.11). Pulsed‐wave Doppler traces are then obtained sequentially at the LV apex and mid LV cavity, as well as the proximal and distal LVOT (Figure 36.12). The peak velocity increases as the sample volume approaches the site of obstruction. This provides more accurate information on where the obstruction to flow begins. Pulsed‐wave Doppler is often inadequate to measure the true peak gradient because of aliasing. Continuous‐wave velocity is used to measure the true gradient (Figure 36.13) [38]. In those patients with SAM, the location of the obstruction is clear, and hence the direct use of continuous‐wave analysis is appropriate. In patients with a noncompliant left ventricle there may be evidence of pre‐systolic forward flow in the LVOT obstruction secondary to atrial contraction and the A wave being transmitted to the LVOT. This is akin to the appearance of antegrade diastolic flow in the pulmonary arteries in patients with restrictive right ventricle physiology. In addition, the degree of dynamic obstruction can be elucidated from the appearance of the Doppler envelope. A dagger shape to the spectral wave pattern indicates a dynamic form of obstruction [39].

Stay updated, free articles. Join our Telegram channel

Join