**3. Genetic cardiomyopathies**

Echocardiography remains the cornerstone for the detection and longitudinal follow up of patients with genetic cardiomyopathy. Inherited cardiomyopathies may have autosomal dominant pattern of inheritance. As such, surveillance echocardiogram of asymptomatic family members may allow early detection and life saving therapeutic intervention.

#### **3.1. Hypertrophic Cardiomyopathy (HCM)**

#### *3.1.1. Introduction*

HCM is the most frequently encountered inherited cardiomyopathy. Echocardiography plays a central role in diagnosis of HCM and in elucidating the pathophysiology of this disorder.

#### *3.1.2. Features of HCM on standard echocardiogram:*

Key diagnostic features of HCM are apparent on standard echocardiogram and are described below.

#### **Distribution of left ventricular hypertrophy:**

Several morphologic variants are known. Asymmetrical septal hypertrophy is the most frequently encountered (Figure-4). Hypertrophy of more than one region of left ventricular wall and at times of right ventricular wall is also seen. In the apical variant of HCM, myocardial hypertrophy is confined to the apical region of the left ventricle. This type is more frequently encountered in non-Caucasians.

#### **Diagnostic criteria of Asymmetrical Septal Hypertrophy (ASH):**

Septal thickness of >15 mm and a septal to posterior free wall ratio (interventricular septum/ posterior wall ratio) >1.3 are established echocardiographic criteria for the diagnosis of ASH [12]. However asymmetric left ventricular hypertrophy by itself is not pathognomonic of HCM as it may be encountered in a variety of congenital or acquired conditions, including systemic hypertension, aortic stenosis and cardiac amyloidosis [14].

#### **Left ventricular function:**

Systolic function is usually normal or above normal. Despite preservation of global left ventricular function [15], significant impairment of longitudinal contractile function is present with attenuation of annular velocities, longitudinal strain and strain rate (see below) [16]. Progressive myocardial fibrosis in advanced disease state is associated with impairment of systolic function, segmental myocardial thinning and left ventricle cavity enlargement [17]. Given myocardial characteristics, impaired myocardial relaxation is frequently observed [18]. Echo methods of estimating left ventricular end-diastolic pressure (E/E' ratio) show hetero‐ geneity and lack specificity in HCM [19].

#### **Systolic Anterior Motion (SAM) of mitral valve:**

**•** Muscular dystrophies: Duchenne, Becker-type and myotonic dystrophy

Echocardiography remains the cornerstone for the detection and longitudinal follow up of patients with genetic cardiomyopathy. Inherited cardiomyopathies may have autosomal dominant pattern of inheritance. As such, surveillance echocardiogram of asymptomatic

HCM is the most frequently encountered inherited cardiomyopathy. Echocardiography plays a central role in diagnosis of HCM and in elucidating the pathophysiology of this disorder.

Key diagnostic features of HCM are apparent on standard echocardiogram and are described

Several morphologic variants are known. Asymmetrical septal hypertrophy is the most frequently encountered (Figure-4). Hypertrophy of more than one region of left ventricular wall and at times of right ventricular wall is also seen. In the apical variant of HCM, myocardial hypertrophy is confined to the apical region of the left ventricle. This type is more frequently

Septal thickness of >15 mm and a septal to posterior free wall ratio (interventricular septum/ posterior wall ratio) >1.3 are established echocardiographic criteria for the diagnosis of ASH [12]. However asymmetric left ventricular hypertrophy by itself is not pathognomonic of HCM as it may be encountered in a variety of congenital or acquired conditions, including systemic

Systolic function is usually normal or above normal. Despite preservation of global left ventricular function [15], significant impairment of longitudinal contractile function is present with attenuation of annular velocities, longitudinal strain and strain rate (see below) [16]. Progressive myocardial fibrosis in advanced disease state is associated with impairment of systolic function, segmental myocardial thinning and left ventricle cavity enlargement [17]. Given myocardial characteristics, impaired myocardial relaxation is frequently observed [18].

family members may allow early detection and life saving therapeutic intervention.

**3. Genetic cardiomyopathies**

**3.1. Hypertrophic Cardiomyopathy (HCM)**

*3.1.2. Features of HCM on standard echocardiogram:*

**Distribution of left ventricular hypertrophy:**

**Diagnostic criteria of Asymmetrical Septal Hypertrophy (ASH):**

hypertension, aortic stenosis and cardiac amyloidosis [14].

encountered in non-Caucasians.

**Left ventricular function:**

*3.1.1. Introduction*

8 Cardiomyopathies

below.

**•** Neuromuscular disorder: Friedreich's ataxia, Noonan's syndrome and lentiginosis

Systolic anterior motion of the anterior mitral leaflet with or without obstruction to flow across the left ventricular outflow tract is highly suggestive of HCM (Figure-4). This finding has a specificity of > 90% [20]. Of note, SAM may also be encountered in hypercontractile states, following mitral valve repair, with anomalous papillary muscle insertion, in patients with anteroapical infarction, in takotsubo cardiomyopathy who have hyperkinesia of basal left ventricularsegmentandinelderlywomenwithleftventricularhypertrophyandsigmoidshaped septum [21].

**Figure 4.** In panel A marked asymmetric septal hypertrophy (ASH) is noted (asterisk) in parasternal long axis display. Systolic anterior motion (SAM) of the mitral valve is seen in panel B (arrow). Turbulence of blood flow through the left ventricular outflow tract (LVOT) associated with posteriorly directed mitral regurgitation due to LVOT obstruction from SAM is present (panel C). Spectral Doppler through the LVOT confirms LVOT obstruction with a late peaking gra‐ dient of 60 mmHg (panel D). In this example Valsalva maneuver was used to confirm dynamic LVOT obstruction.

#### *3.1.3. Tissue doppler imaging and speckle strain*

Tissue Doppler and 2-D speckle techniques demonstrate impaired longitudinal velocity and strain even in non-hypertrophied myocardial segments. These indices of longitudinal fiber function are abnormal in inherited HCM even prior to grossly manifest left ventricular hypertrophy. The degree of functional impairment by these measures correlates with clinical outcome [22]. Furthermore, differentiation between pathologic and physiologic left ventricular hypertrophy is possible by documenting preserved longitudinal function in the latter which is impaired in HCM even when global left ventricular function is normal [23].

**3.3. Left ventricular non-compaction**

Left ventricular non-compaction (LVNC) is a distinct cardiomyopathy resulting from arrest of fetal development of the heart [28]. This leads to altered myocardial architecture that is seen as a two layered myocardium with a thin, compacted epicardial layer and a thick, noncompacted endocardial region (Figure-5). The non-compacted myocardial region is comprised of prominent trabeculations and deep intertrabecular recesses that directly communicate with the left ventricular cavity [29-30].The condition may present without any associated cardiac malformation and is then labeled isolated left ventricular non compaction (LVNC). Non compacted myocardium is also seen in conjunction with other cardiac abnormalities including cyanotic congenital heart disease, Ebstein's anomaly and other cardiomyopathies. Clinical presentation in LVNC is seen with congestive heart failure, ventricular arrhythmia and

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**Figure 5.** Marked trabeculation of LV myocardium is seen in the apical and inferolateral distribution (panel A) in this off axis projection of apical long axis of the heart. Ratio of non comapcted to compacted myocardium is consistent with the diagnosis of left ventricular non-compaction. Communication of deep intertrabecular recesses with LV cavity is noted on color Doppler (panel B) and following administration of echo contrast (panel C). Visual appearance of the

Trabeculation in the left ventricle wall is seen even in healthy volunteers. To separate benign left ventricular trabeculation from pathological LVNC following diagnostic criteria is pro‐

**•** Echocardiogram: ratio of non-compacted to compacted myocardium in end-systole of > 2:1

**•** Cardiac MRI: ratio of non-compacted to compacted myocardium in end-diastole of > 2.3:1

non compacted myocardium is also enhanced following echo contrast.

*3.3.2. Diagnostic criteria on cardiac imaging*

posed.

[31]

[32]

*3.3.1. Introduction*

systemic thromboembolism.

#### *3.1.4. Three dimensional echo*

A more accurate assessment of left ventricle mass and chamber volumes is made possible by 3DE. The clinical impact of this in routine clinical care is less apparent.

#### **3.2. Arrhythmogenic right ventricular cardiomyopathy/dysplasia**

#### *3.2.1. Introduction*

Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is a genetic cardiomy‐ opathywithautosomaldominantinheritance.However,phenotypeswithcutaneousmanifesta‐ tions have autosomal recessive inheritance. The disorder is pathologically characterized by fibrofatty infiltration of the right ventricle (RV) wall. In early stages, dysplasia is localized, affecting the RV inflow, RV outflow or RV apex. Progression to diffuse form is common. Clinical manifestation is with ventricular arrhythmias and RV systolic dysfunction [24-25].

#### *3.2.2. Echo diagnosis of ARVC/D*

Morphological and functional changes affecting the RV are divided into major and minor diagnostic criteria. In the proposed revision of ARVC/D task force document [26], right ventricle outflow tract (RVOT) long axis dimension of ≥ 32 mm (sensitivity/specificity: 75% and 95%, respectively), RVOT short axis dimension of ≥ 36 mm (sensitivity/specificity: 62% and 95%, respectively) and RV fractional area change of ≤33% (sensitivity/specificity: 55% and 95%, respectively) are considered as major criteria for the diagnosis of ARVC/D. Minor echo criteria are RVOT long axis dimension of ≥ 29 mm (sensitivity/specificity: 87% and 87%, respectively), RVOT short axis dimension of ≥ 32 mm (sensitivity/specificity: 80% and 80%, respectively) and RV fractional area change of ≤40% (sensitivity/specificity: 76% and 76%, respectively) [26]. Of interest, diastolic dimensions of the RV taken from the apical four-chamber view were least commonly enlarged [27]. Regional wall motion abnormali‐ ty of the apex and anterior wall is seen in approximately 70% of patients [27]. Other frequent morphologic abnormality include trabecular derangement, occurring in 54%, hyper-reflective moderator band in 34% and sacculations of RV free wall in 17% [27]. Given its predominant autosomal dominant inheritance screening of family members is recommended.

#### **3.3. Left ventricular non-compaction**

#### *3.3.1. Introduction*

*3.1.3. Tissue doppler imaging and speckle strain*

*3.1.4. Three dimensional echo*

*3.2.2. Echo diagnosis of ARVC/D*

*3.2.1. Introduction*

10 Cardiomyopathies

recommended.

Tissue Doppler and 2-D speckle techniques demonstrate impaired longitudinal velocity and strain even in non-hypertrophied myocardial segments. These indices of longitudinal fiber function are abnormal in inherited HCM even prior to grossly manifest left ventricular hypertrophy. The degree of functional impairment by these measures correlates with clinical outcome [22]. Furthermore, differentiation between pathologic and physiologic left ventricular hypertrophy is possible by documenting preserved longitudinal function in the latter which

A more accurate assessment of left ventricle mass and chamber volumes is made possible by

Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is a genetic cardiomy‐ opathywithautosomaldominantinheritance.However,phenotypeswithcutaneousmanifesta‐ tions have autosomal recessive inheritance. The disorder is pathologically characterized by fibrofatty infiltration of the right ventricle (RV) wall. In early stages, dysplasia is localized, affecting the RV inflow, RV outflow or RV apex. Progression to diffuse form is common. Clinical

Morphological and functional changes affecting the RV are divided into major and minor diagnostic criteria. In the proposed revision of ARVC/D task force document [26], right ventricle outflow tract (RVOT) long axis dimension of ≥ 32 mm (sensitivity/specificity: 75% and 95%, respectively), RVOT short axis dimension of ≥ 36 mm (sensitivity/specificity: 62% and 95%, respectively) and RV fractional area change of ≤33% (sensitivity/specificity: 55% and 95%, respectively) are considered as major criteria for the diagnosis of ARVC/D. Minor echo criteria are RVOT long axis dimension of ≥ 29 mm (sensitivity/specificity: 87% and 87%, respectively), RVOT short axis dimension of ≥ 32 mm (sensitivity/specificity: 80% and 80%, respectively) and RV fractional area change of ≤40% (sensitivity/specificity: 76% and 76%, respectively) [26]. Of interest, diastolic dimensions of the RV taken from the apical four-chamber view were least commonly enlarged [27]. Regional wall motion abnormali‐ ty of the apex and anterior wall is seen in approximately 70% of patients [27]. Other frequent morphologic abnormality include trabecular derangement, occurring in 54%, hyper-reflective moderator band in 34% and sacculations of RV free wall in 17% [27]. Given its predominant autosomal dominant inheritance screening of family members is

manifestation is with ventricular arrhythmias and RV systolic dysfunction [24-25].

is impaired in HCM even when global left ventricular function is normal [23].

3DE. The clinical impact of this in routine clinical care is less apparent.

**3.2. Arrhythmogenic right ventricular cardiomyopathy/dysplasia**

Left ventricular non-compaction (LVNC) is a distinct cardiomyopathy resulting from arrest of fetal development of the heart [28]. This leads to altered myocardial architecture that is seen as a two layered myocardium with a thin, compacted epicardial layer and a thick, noncompacted endocardial region (Figure-5). The non-compacted myocardial region is comprised of prominent trabeculations and deep intertrabecular recesses that directly communicate with the left ventricular cavity [29-30].The condition may present without any associated cardiac malformation and is then labeled isolated left ventricular non compaction (LVNC). Non compacted myocardium is also seen in conjunction with other cardiac abnormalities including cyanotic congenital heart disease, Ebstein's anomaly and other cardiomyopathies. Clinical presentation in LVNC is seen with congestive heart failure, ventricular arrhythmia and systemic thromboembolism.

**Figure 5.** Marked trabeculation of LV myocardium is seen in the apical and inferolateral distribution (panel A) in this off axis projection of apical long axis of the heart. Ratio of non comapcted to compacted myocardium is consistent with the diagnosis of left ventricular non-compaction. Communication of deep intertrabecular recesses with LV cavity is noted on color Doppler (panel B) and following administration of echo contrast (panel C). Visual appearance of the non compacted myocardium is also enhanced following echo contrast.

#### *3.3.2. Diagnostic criteria on cardiac imaging*

Trabeculation in the left ventricle wall is seen even in healthy volunteers. To separate benign left ventricular trabeculation from pathological LVNC following diagnostic criteria is pro‐ posed.


The most frequently involved segments are apical, followed by the inferior and lateral midsegments. Severity and distribution of non compacted segment is better appreciated with use of contrast echo.

important, as aortic stenosis may be overestimated on 2D echo (pseudo aortic stenosis) and underestimated by Doppler (low-gradient aortic stenosis) due to low flow state. Contractile

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**Secondary Mitral Regurgitation**: Altered mitral valve geometry from progressive LV cavity enlargement will lead to mitral regurgitation, which may be severe in advanced cases [37].

**Diastolic Dysfunction**: Presence of diastolic abnormality is established by Doppler interrog‐ ation of mitral inflow and mitral annular velocities. Severity of diastolic abnormality may be insightful and partly explanatory for the frequently observed discordance between degree of LV systolic dysfunction and severity of clinical symptoms. Patients with earlier stage of diastolic abnormality are less symptomatic when compared to those with more advanced diastolic dysfunction. Reduction in effective diastolic filling period is reflected by fusion of

**Figure 6.** Apical four chamber view shows a dilated LV cavity with a spherical appearance. RV cavity is normal in this example. Pulse-wave Doppler at mitral leaflet tip shows fusion of diastolic E and A waves. Latter is a reflection of re‐

**Right Ventricular (RV) Function**: RV enlargement to a similar degree as the LV is associated with poor outcome [39]. RV systolic function can be measured by fractional area change or by tricuspid annular plane systolic excursion (TAPSE) [40]. TAPSE < 14 mm is associated with

augmentation with dobutamine is helpful in clarification in such situations [64].

Presence of mitral regurgitation predicts poor outcome [38].

mitral diastolic E-wave and A-wave (Figure-6).

duced diastolic filling period.

Left ventricle contractile abnormality is present in patients with LVNC. The spectrum of myocardial function may range from normal to severe systolic dysfunction. Documentation of direct flow from ventricular cavity into inter-trabecular recesses either with color Doppler technique or following use of echo contrast is helpful in differentiating LVNC from other apical echocardiographic abnormalities such as apical hypertrophic cardiomyopathy and apical mural thrombus [31]. Information from 3DE is also helpful in identifying the extent of LVNC [33]. Screening of family members is advised.
