Hypertrophic Cardiomyopathy

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7 Hypertrophic Cardiomyopathy

Sean Jedrzkiewicz, Anna Woo

Background

• Hypertrophic cardiomyopathy (HCM) is defined as the presence of left ventricular hypertrophy occurring in the absence of a cardiac or systemic disorder (e.g., valvular aortic stenosis or systemic hypertension).1
• HCM is a genetic disease caused by a mutation of one of the cardiac sarcomeric proteins.
• This condition has an autosomal dominant pattern of inheritance.
• Initially regarded as a rare disorder, the prevalence of HCM in the general population is now estimated to be approximately 1 in 500.
• HCM is a heterogeneous disorder with a spectrum of clinical findings, ranging from completely asymptomatic individuals to severely affected patients.
• Clinical manifestations of HCM include dyspnea, chest pain, presyncope, and/or syncope.
• HCM may occasionally present as sudden cardiac death.
• The symptoms of HCM are largely attributable to diastolic filling abnormalities, dynamic left ventricular outflow tract (LVOT) obstruction, atrial or ventricular arrhythmias, and/or myocardial ischemia.
• Individuals with HCM are most commonly identified by echocardiography.
• Echocardiography is the modality of choice for the diagnosis, screening, and serial monitoring of patients with known or suspected HCM.

Overview of Echocardiographic Approach

• Echocardiography plays a vital role in the evaluation and management of patients with HCM (Box 7-1).
• Multiple echocardiographic techniques are used to assess patients with HCM:

• M-mode echocardiography
• Two-dimensional (2D) echocardiography
• Color Doppler imaging
• Pulsed and continuous wave Doppler
• Tissue Doppler imaging
• Strain imaging

Box 7-1 Summary of Role of Echocardiography in Evaluation of Patients with HCM

• Diagnosis

• Evaluation of probands
• Screening of family members

• Left ventricular hypertrophy

• Degree of hypertrophy
• Extent and pattern of hypertrophy

• LVOT obstruction
• Mitral regurgitation

• Presence of SAM
• Independent mitral valve disease

• Left ventricular diastolic function
• Left ventricular systolic function
• Left atrial size
• Selection of septal reduction therapy
• Intraprocedural monitoring during septal reduction therapy
• Prognostication

Step-by-Step Approach to the Evaluation of HCM

Step 1: Establish the Diagnosis of HCM

Key Points

• The traditional echocardiographic criteria for the diagnosis of HCM are the presence of the following1:

• Wall thickness ≥ 15 mm (any myocardial segment)
• Asymmetrical septal hypertrophy (defined as septal/posterior [inferior] wall thickness ratio > 1.3)
• In addition, the diagnosis of HCM requires the exclusion of cardiac or systemic conditions that could explain the degree of increased wall thickness detected (see Step 2 below).

Step 2: Exclude Other Causes of Increased Wall Thickness

• The presence of increased left ventricular wall thickness is not pathognomonic of HCM.2
• Left ventricular hypertrophy caused by a genetic defect of the cardiac sarcomeric proteins needs to be distinguished from other important causes (Box 7-2).

Box 7-2 Differential Diagnosis of HCM on Echocardiography

Other Causes of Left Ventricular Hypertrophy

• Athlete’s heart
• Systemic hypertension
• Aortic valve stenosis
• Fibrous subaortic stenosis
• Supravalvular stenosis

Disproportionate Ventricular Septal Hypertrophy

• Right ventricular hypertrophy
• D-transposition of the great arteries

Syndromic HCM

• Noonan’s syndrome
• LEOPARD syndrome
• Friedreich’s ataxia

Storage Diseases

• Fabry’s disease
• Glycogen storage disease (PRKAG2 cardiomyopathy, Danon’s disease, Pompe’s disease)
• Mucopolysaccharide storage disorders

Infiltrative Cardiomyopathy

• Amyloidosis
• Sarcoidosis

Key Points

• The main categories in the differential diagnosis of left ventricular increased wall thickness are the following:

• Nongenetic causes of left ventricular hypertrophy
• Disproportionate hypertrophy of ventricular septum
• Congenital syndromes associated with HCM
• Storage diseases/metabolic disorders
• Infiltrative cardiomyopathies

• Common causes of left ventricular hypertrophy are systemic hypertension and other conditions causing pressure-overload hypertrophy, such as valvular aortic stenosis, fibrous subaortic stenosis, and coarctation of the aorta.
• These non-monogenetic forms of left ventricular hypertrophy typically have a concentric (rather than asymmetrical) pattern of hypertrophy.
• However, they may be associated with a degree of focal septal hypertrophy (especially in the elderly) and/or the presence of systolic anterior motion (SAM) (see Step 4 below).
• Causes of disproportionate hypertrophy of the ventricular septum may occur with right ventricular hypertrophy and also with D-transposition of the great arteries.

Athlete’s Heart3

• Wall thickness may be ≥ 13 mm (up to 15 to 16 mm) in 2% of elite athletes, raising the possibility of underlying mild HCM.
• Differentiation between athlete’s heart and HCM may be difficult.

Key Points

• The diagnosis of HCM is favored over the diagnosis of athlete’s heart in the presence of the following:

• Family history of HCM
• Bizarre electrocardiographic patterns
• Asymmetrical (or other unusual) pattern of left ventricular hypertrophy
• Small left ventricular cavity size (<45 mm)
• Left atrial enlargement
• Abnormal left ventricular filling pattern

• Findings suggestive of athlete’s heart (rather than HCM) include the following:

• Left ventricular end-diastolic dimension >55 mm
• Regression of hypertrophy with deconditioning
• Maximum VO2 greater than 45 mL/kg/min (or > 110% predicted) on cardiopulmonary testing

Storage Diseases4

• The intramyocardial accumulation or infiltration of abnormal metabolic products in various storage diseases may mimic HCM on echocardiography (Figure 7-1).
• Fabry’s disease is an X-linked recessive disorder of glycosphingolipid metabolism due to a deficiency of the lysosomal enzyme α-galactosidase A.

• Patients with Fabry’s disease may have multisystem involvement, especially of the skin, kidneys, nervous system, and heart.
• A cardiac-specific variant of Fabry’s has been identified.
• Diagnosis of Fabry’s is made with the measurement of α-galactosidase levels.
• Genetic testing for the causative gene in Fabry’s, the α-galactosidase (GLA) gene, is also available.
• The detection of patients with Fabry’s disease is important since enzyme replacement therapy is available for the treatment of this condition.

• Mutations of genes regulating glycogen metabolism may also result in increased wall thickness on echocardiography.

• Mutations of the regulatory γ2 subunit of AMP-activated protein kinase (PRKAG2) gene cause a glycogen storage cardiomyopathy, which may be associated with ventricular preexcitation.
• Mutations of the lysosome-associated membrane protein 2 (LAMP2) gene (X-linked) cause Danon’s disease.
• Danon’s disease is a lysosomal glycogen storage disease characterized clinically by cardiomyopathy, electrophysiologic abnormalities, myopathy, and variable mental impairment.
• Mutations of the acid α-1,4-glucosidase gene cause Pompe’s disease, a glycogen storage disease.

image

Figure 7-1 Parasternal long-axis (A) and apical 4-chamber (C) views reveal impressive hypertrophy in an 18-year-old female patient. There is asymmetrical septal hypertrophy with extension to almost all left ventricular segments and right ventricular involvement. B, The wall segments measured the following: basal anteroseptum = 27 mm, mid-anteroseptum = 31 mm, basal anterior wall = 24 mm, and basal anterolateral wall = 21 mm. There was no SAM. C, Left ventricular cavity obliteration in systole with midventricular obstruction (D) noted at rest. The patient had an underlying diagnosis of glycogen storage disease type III.

Key Points

• The prevalence of Fabry’s disease has ranged from 3% in all male patients with left ventricular hypertrophy to as much as 6% in male patients with presumed late-onset HCM (defined as diagnosis at age ≥ 40 years).
• In a cohort of 24 patients with increased wall thickness and ventricular preexcitation, mutations of the PRKAG2 and LAMP2 genes were detected in 29% and 17% of patients, respectively.
• Clinical features distinguishing patients with LAMP2 mutations from patients with HCM caused by sarcomeric gene mutations included the following: male sex, early onset of disease (<17 years of age), ventricular preexcitation on electrocardiography, severe concentric hypertrophy, and elevation of two serum enzymes: creatine kinase (CK) and alanine aminotransferase (ALT).
• These storage diseases typically have a concentric pattern of left ventricular wall thickening.
• However, they occasionally manifest as disproportionate septal thickening and may have associated LVOT or intracavitary obstruction.

Infiltrative Cardiomyopathies

• Conditions such as cardiac amyloidosis or sarcoidosis are associated with increased wall thickness and may occasionally mimic HCM on echocardiography.
• In general, the infiltrative cardiomyopathies usually have the following distinguishing features compared with HCM:

• Electrocardiographic pattern of diffuse low voltages (in cardiac amyloidosis)
• A concentric pattern of increased wall thickness
• SAM or LVOT obstruction is typically absent
• Restrictive filling pattern

• See Chapter 3 on “Infiltrative/Restrictive Cardiomyopathies” for further details.

Septal Hypertrophy in the Elderly

• It may be difficult to distinguish between elderly patients with HCM and those with hypertensive heart disease.
• Elderly subjects may develop a sigmoid-shaped septum as an age-related phenomenon.
• Terms that have been used to describe this finding are “sigmoid septum,” “septal bulge,” and “discrete upper septal hypertrophy.”
• It is controversial whether this finding should be considered a subtype of HCM or whether it represents a benign anatomic variant.
• Findings on echocardiography that are more compatible with a septal bulge rather than HCM include the following:

• Focal hypertrophy limited to less than 3 cm of the length of the basal anterior septum
• Protrusion of the focal hypertrophy into the LVOT
• A normal left ventricular end-diastolic diameter
• Absence of other characteristic echocardiographic findings of HCM

Step 3: Assess Pattern and Severity of Left Ventricular Hypertrophy

• 2D echocardiography can accurately detect and characterize the degree and extent of hypertrophy in patients with HCM.

Key Points

• Asymmetrical septal hypertrophy (septal/posterior [inferior] wall thickness ratio > 1.3) is the classic echocardiographic pattern detected in patients with HCM.
• The predominant site of hypertrophy is the interventricular septum (usually the anterior portion of the septum), which occurs in greater than 90% of cases.

Anatomic Imaging

Acquisition

• Multiple transthoracic echocardiographic (TTE) views are necessary to assess the extent and severity of left ventricular hypertrophy (Figure 7-2).

• Parasternal long-axis view
• Parasternal short-axis views at three levels (base, midventricle, apex)
• Apical four-chamber view
• Apical long-axis view
• Measurements of cavity dimensions should be made in the parasternal long-axis view.5
• Measurements of the left ventricular wall segments (anteroseptal, inferoseptal, anterior, anterolateral, inferolateral, inferior) should be made in the parasternal short-axis views at the basal and midventricular levels.
• The apical septal, anterior, lateral, and inferior segments should be measured in the parasternal short-axis views at the apical level.
• Hypertrophied segments usually have either similar or slightly increased echogenicity in comparison with myocardial segments with normal wall thickness.
• In addition, diffuse bright echoes may be seen throughout the myocardium and may give a ground-glass appearance.
image

Figure 7-2 Optimal echocardiographic evaluation of the degree, extent, and distribution of hypertrophy in HCM requires imaging from multiple transthoracic windows. Parasternal long-axis (upper left panel), parasternal short-axis at the basal level (upper right panel), apical 4-chamber (lower left panel), and apical long-axis (lower right panel) views are shown in a patient with asymmetrical septal hypertrophy extending to the anterolateral wall, from base to apex.

Analysis

• Septal involvement may be limited to the basal level or the hypertrophy may extend to the left ventricular apex.

Key Points

• Two different septal morphologic subtypes have been described:

• “Reverse septal curvature”—the maximal thickness of the septum occurs at the midventricular level, predominant midseptal convexity toward the left ventricular cavity, with the cavity itself having an overall crescent shape (Figure 7-3A)
• “Basal septal morphologic subtype”—basal septal bulge, generally ovoid left ventricular cavity with the septum being concave toward the left ventricular cavity

• Young patients with HCM characteristically demonstrate the reverse septal curvature subtype, whereas older patients typically have the basal septal morphologic subtype.
• Patients with HCM and asymmetrical septal hypertrophy may have hypertrophy confined to the septum, or they commonly have hypertrophy of both the ventricular septum and the free wall (anterolateral wall segments).
• The distribution of hypertrophy can be in any pattern and can involve any myocardial segment (including the right ventricle).
• Other uncommon morphologic variants of HCM include asymmetrical apical HCM (predominant hypertrophy at the apical segments) and a concentric pattern of left ventricular hypertrophy.
• An ultrasound contrast agent should be administered when nonenhanced images are suboptimal for definitive diagnosis, such as in patients with suspected apical HCM.6
image

Figure 7-3 Spectrum and variation of HCM in two patients with this condition on 2D echocardiographic parasternal long-axis (top row), apical 4-chamber (middle row), and parasternal short-axis (bottom row) views. A, The patient had a typical pattern of asymmetrical septal hypertrophy (with maximal hypertrophy at the midventricular level). B, The patient had asymmetrical apical HCM.

Severity of Left Ventricular Hypertrophy

• Since there is considerable variability in the thickness of the different septal and posterior wall segments in patients with HCM, the conventional calculations of left ventricular mass are not applicable in these patients.5
• Therefore, a number of echocardiographic indices have been developed to measure the distribution, extent, and/or burden of left ventricular hypertrophy.7

• Wigle’s score: Incorporates the degree of septal thickness at the basal anteroseptum, the extent of septal involvement, and the presence or absence of anterolateral wall involvement (Table 7-1).
• Wall thickness (Spirito-Maron) index: Obtained by adding the maximal wall thickness (at either the basal or midventricular level) of four left ventricular regions (anterior septum, posterior septum, lateral wall, and posterior wall).
• Maximal left ventricular wall thickness: The most clinically relevant measurement is the determination of the maximal thickness of all the left ventricular myocardial segments. The presence of massive left ventricular hypertrophy, defined as a wall thickness of ≥ 30 mm, has considerable implications for patients’ management and prognosis (see “Key Measurements for Predicting Prognosis in Patients with HCM” below).1

TABLE 7-1 EXTENT OF HYPERTROPHY ACCORDING TO ECHOCARDIOGRAPHIC POINT SCORE

Extent of Hypertrophy Points
Septal thickness, mm (basal third of septum)  
15–19 1
20–24 2
25–29 3
>30 4
Extension to papillary muscles (basal two thirds of septum) 2
Extension to apex (total septal involvement) 2
Anterolateral wall extension 2
Maximum total 10

Other Morphologic Subtypes of HCM

Apical HCM

• This subtype of HCM was originally described in Japan in the 1970s (Figure 7-3B).
• The apical variant occurs in less than 10% of all patients with HCM.
• Prominent findings of patients with apical HCM include the presence of giant negative T waves (≥10 mm) in the precordial leads on electrocardiography and an “ace of spades” configuration to the left ventricle seen on imaging studies.
• Echocardiography can also identify potential complications of this condition, such as left atrial enlargement, impaired diastolic filling, apical infarction, or apical aneurysm formation.

HCM with Midventricular Obstruction

• The presence of midventricular obstruction is also an uncommon variant of HCM.
• Morphologic features of this condition include the following:

• “Hourglass”-shaped left ventricular cavity
• Midventricular obliteration in systole
• A distinct apical chamber
• Color turbulence at the midventricle
• Systolic pressure gradient at the midventricular level

Pitfalls

• Oblique cuts of the left ventricle can overestimate wall thickness and produce the appearance of asymmetrical septal hypertrophy.
• Apical or lateral wall hypertrophy can be poorly visualized due to foreshortening of the apex, poor transthoracic windows, and other technical limitations.
• Echocardiographic contrast agents can better define wall thickness, especially in patients with suspected apical HCM.

Step 4: Determine if There Is LVOT Obstruction

• LVOT obstruction is an important contributor to symptoms in patients with HCM.1
• Studies of cohorts of patients with HCM have shown that approximately 25% of patients have LVOT obstruction at rest.
• One recent study has suggested that 70% of patients with HCM have either resting or provocable LVOT obstruction.
• Early M-mode echocardiographic studies demonstrated the abnormalities in morphology of the LVOT and in the mitral apparatus that contribute to the development of dynamic LVOT obstruction.
• LVOT obstruction is due to SAM of the anterior mitral leaflet (Box 7-3).
• The mitral leaflets in patients with HCM may be elongated.
• These mitral leaflets coapt abnormally in the body of the leaflets, rather than at the tip.
• Rapid early left ventricular ejection out of the LVOT also contributes to the development of SAM and LVOT obstruction.
• Morphologic features of HCM that contribute to SAM and LVOT obstruction include narrowing of the LVOT by the following:

• Septal hypertrophy
• Anterior displacement of the mitral apparatus
• Anterior malposition of the papillary muscles

Box 7-3 Factors Contributing to Dynamic LVOT Obstruction

Narrowing of LVOT

• Septal hypertrophy
• Anterior displacement of mitral apparatus
• Anterior displacement of papillary muscles

Hydrodynamic Forces (Venturi and Drag Forces) Causing SAM

• Rapid early left ventricular ejection
• Elongated mitral leaflets

Key Points

• Although the nature of the hydrodynamic forces on the anterior mitral leaflet remains controversial, it is believed that the distal anterior mitral leaflet is subjected to Venturi and/or drag forces.2
• Therefore, SAM occurs and the tip of the anterior mitral leaflet typically develops a sharp anterior and superior angulation, leading to mitral leaflet–septal contact in early to midsystole (Figure 7-4).
• Simultaneous cardiac catheterization and M-mode echocardiographic studies have shown that mitral leaflet–septal contact occurs almost simultaneously with the onset of the LVOT pressure gradient.
• Furthermore, there is a linear relationship between the time of onset of SAM and the severity of LVOT obstruction.
• SAM of the anterior leaflet leads to an interleaflet gap, which results in a posteriorly directed jet of mitral regurgitation (see Step 5 below).
image

Figure 7-4 A–C, Schematic diagram of a transesophageal echocardiogram (TEE) in the frontal long-axis plane demonstrates the anterior and basal motion of the anterior mitral leaflet leading to leaflet-septal contact and failure of leaflet coaptation in midsystole. At the onset of systole (A), the coaptation point (arrow) is in the body of the mitral leaflets. During early systole (B) and midsystole (C), there is anterior and basal movement of the residual length of the anterior mitral leaflet (upper arrow) with septal contact and failure of leaflet coaptation (lower arrow). The interleaflet gap (lower arrow) results in a posteriorly directed jet of mitral regurgitation into the left atrial cavity (shaded area). D and E, Corresponding 2D TEE views with color flow imaging in a patient with obstructive HCM show septal hypertrophy, anterior motion of the anterior mitral leaflet, and color turbulence in the outflow tract with the posteriorly directed mitral regurgitation.

(A–C Reprinted with permission from Grigg LE, Wigle ED, Williams WG, et al. Transesophageal Doppler echocardiography is obstructive hypertrophic cardiomyopathy: clarification of pathophysiology and importance in intraoperative decision making. J Am Coll Cardiol. 1992;20:42-52.)

Step 4A: Assess for the Presence of LVOT Obstruction at Rest

Anatomic Imaging

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