**3. Arrhythmogenic Right Ventricular Dysplasia/ Cardiomyopathy (ARVD/C)**

#### **3.1. Epidemiology**

*2.10.1. Medical therapy*

140 Cardiomyopathies

who are not responding to therapy [38].

defibrillator implantation (BiV ICD) [39].

*2.10.2. Device based therapy and the role of electrophysiology study*

Similar to other forms of cardiomyopathy, treatment with angiotensin converting enzyme inhibitors and angiotensin receptor blockers is important since they have anti-fibrotic prop‐ erties and have been shown to improve survival. β -blockers were also shown to improve survival in patients with heart failure. Since the initial cardiac lesions are due to granuloma formation which could progress with time to fibrosis, early recognition and initiation of corticosteroid treatment is important and could lead to improvement in LV function as well as achieve control of the arrhythmias [36]. In a Japanese retrospective study of 48 patients with cardiac sarcoidosis, only patients with pretreatment LVEF > 30% had improvement in their LV function with corticosteroid therapy, while those with pretreatment LVEF of < 30% showed little improvement [37]. The exact dose of corticosteroids and the duration of therapy are not well defined due to the absence of randomized controlled trials. In general, initial dose of 30 to 60 milligrams/day of prednisone is started for 8-12 weeks; with gradual taper to a daily dose of 5-10 mgs/day of prednisone over 6-12 months is recommended. Relapses could occur in up to 25% of patients [19, 38]. Use of Methotrexate, cyclosporine or hydroxychoroquine has been described and could be considered especially in patients with side effects to corticosteroids or

Patients presenting with heart block due to cardiac sarcoidosis could see improvement with corticosteroids therapy [36]. However, permanent pacemaker implantation is recommended even if there is a transient improvement in heart block with corticosteroids therapy [39]. Patients with depressed LVEF < 35%who do not improve with steroid therapy and patients who present with VT or survive cardiac arrest should undergo defibrillator (ICD) implantation [39]. Some experts advocate ICD implantation in patients with AVB due to cardiac sarcoidosis with extensive cardiac involvement on imaging studies even if the LVEF is still preserved [40]. The 2008 guidelines for device based therapy recommend consideration for defibrillator implantation to be based on LV function, presence of spontaneous or induced ventricular tachycardia, heart failure status and syncope. Patients with depressed LVEF < 35%, NYHA Class II-IV heart failure and wide QRS of > 120 milliseconds are candidates for biventricular

For patients with LVEF of 35-55%, programmed electrical stimulation (PES) could help in the risk stratification of these patients. In a study by Mehta et al, PES helped identify patients at risk of ventricular arrhythmias and only 1 of the 68 patients with negative PES died over 5 yrs [41]. In another series by Aizer et al, PES was predictive of arrhythmic events and ICD therapy; however 2 of the 20 patients with negative PES died or had spontaneous sustained VT during follow up [42]. Currently, PES is used for risk stratification, but the negative predictive value of programmed electrical stimulation needs further study and the clinician needs to utilize knowledge of the published literature as well as clinical judgment when considering ICD

therapy for primary prevention of SCD in sarcoidosis patients with LVEF of 35-55%.

There are no randomized trials for the prevention of sudden cardiac death in patients with cardiac sarcoidosis, and most of the efficacy is obtained from the experience of tertiary care Arrhythmogenic right ventricular Dysplasia/ Cardiomyopathy (ARVD/C) is an inherited myopathy characterized by fibrofatty infiltration of the right ventricular (RV) wall, with left ventricular involvement over time in some patients [47, 48]. Males are more commonly affected than females. The true prevalence of the disease is unknown, but familial involvement is seen in up to 50%, which means screening family members is essential. The overall incidence is thought to be 1:1000 to 1:5000, with certain regions in Greece and Italy having increased prevalence compared to the rest of the world [49].

#### **3.2. Environmental and genetic factors**

There is no clear environmental cause of ARVD/C, and the etiology is not fully understood. Family members of patients with ARVD/ C are affected in 30-50% of the time, and the disease has autosomal dominant inheritance with variable penetrance. Several genetic loci have been identified, and mostly are mutations in cardiac desmosomes. Desmosomes are membrane structures composed of plasma cell membrane proteins that are responsible for force trans‐ mission between the cells. Abnormal function of these structures leads to cell detachment, death and inflammatory reaction leading to fibrosis and fatty infiltration. The most common mutation involves the PKP2 gene, encoding the plakophilin 2. Other desomsomal mutations were identified in DSP gene, encoding desmoplakin, DSG2 gene, encoding desmgelin 2 and DSC2 gene, encoding desmocolin 2. Desmosomal mutations occur in 52% of North Americans with ARVD/C and are associated with ventricular tachycardia and younger age of presentation [50]. There is genetic variability that occurs in healthy subjects, and has been noted to be as high as 16%. However, certain mutations make the diagnosis of ARVD/C more likely, including radical mutations as well as certain missense mutations that are rare in Caucasians [51]. The autosomal recessive form is associated with woolly hair and palmoplantar keratosis, the so-called Naxos disease, since it was discovered in the Greek island of Naxos. This gene encodes plakoglobin and desmoplakin. This autosomal recessive form has been mapped to chromosome 17q21. In addition, the cardiac ryanodine receptor gene RyR2 may be involved in the disease and causes juvenile sudden death with minimal RV wall motion abnormalities [52]. Mutations in the transforming growth factor B3 (TGF-B3) were also found in a large family in ARVD/C [53].

to V4 in the presence of RBBB is considered minor criteria for diagnosis. QRS fragmentation, defined as deflections at the beginning of the QRS, on top of the R wave or at the nadir of the S wave, could be found in as many as 85% of patients with ARVD/C and it correlates with LV involvement [59]. Signal average electrocardiography is simple and non-invasive method that could be used for screening. Abnormalities on signal average ECG considered to be minor

Specific Forms of Cardiomyopathy: Genetics, Clinical Presentation and Treatment

http://dx.doi.org/10.5772/55628

143

Patients with ARVD/C can have ventricular tachycardia and frequent premature ventricular contractions (PVCs). Ventricular tachycardia in general has left bundle branch morphology and is caused by macro-reentry. There is evidence that adrenergic stimulation acts as a trigger for these arrhythmias [61]. Exercise testing can induce these arrhythmias in 50-60% of ARVD/ C patients. These arrhythmias could lead to syncope and SCD. In fact, ARVC/D accounts for 3 to 10% of death occurring in patients younger than 65 years [62] and is one of the causes of sudden cardiac death in athletes [63]. Patients with ARVD/D should not participate in

Ventricular tachycardia with left bundle branch (LBB) morphology and inferior axis is considered minor criteria, while VT with LBB morphology and superior axis is considered major criteria. Hoffmayer et al proposed criteria to differentiate idiopathic right ventricular outflow tract VT from ventricular tachycardia caused by ARVD/C. Since both conditions could present with ventricular tachycardia with left bundle branch morphology with inferior axis. In multivariate analysis, prolonged QRS duration in Lead I > 120 msec and transition in V5 or later predicted ARVD/C as the cause of VT [65]. Table 3 lists major and minor electrocardio‐

**Major Criteria Minor Criteria**

By 2D echo:

By MRI:

mL/m2 (female)

1) Regional RV akinesia or dyskinesia 2) and 1 of the following (end diastole): • PLAX RVOT ≥29 to <32 mm (corrected for body size [PLAX/BSA] ≥16 to <19 mm/m2) • PSAX RVOT ≥32 to <36 mm (corrected for body size [PSAX/BSA] ≥18 to <21 mm/m2) • fractional area change >33% to ≤40%

1) Regional RV akinesia or dyskinesia or dyssynchronous RV contraction 2) and 1 of the following:

• Ratio of RV end-diastolic volume to BSA ≥100 to <110 mL/m<sup>2</sup> (male) or ≥90 to <100

• RV ejection fraction >40% to ≤45%

criteria are listed in Table 3.

Global and/or regional dysfunction and structural alterations

moderate to high intensity exercise [64].

graphic and arrhythmia criteria for diagnosis of ARVD/C [56].

1) Regional RV akinesia, dyskinesia, or

2) and 1 of the following (end diastole): • PLAX RVOT ≥32 mm (corrected for body

• PSAX RVOT ≥36 mm (corrected for body

1) Regional RV akinesia or dyskinesia or dyssynchronous RV contraction 2) and 1 of the following:

• Ratio of RV end-diastolic volume to BSA ≥110 mL/m<sup>2</sup> (male) or ≥100 mL/m2 (female)

size [PLAX/BSA] ≥19 mm/m2)

size [PSAX/BSA] ≥21 mm/m2) • fractional area change ≤33%

• RV ejection fraction ≤40% By RV angiography:

By 2D echo:

aneurysm

By MRI:

#### **3.3. Pathology**

The hallmark of ARVD/C is fibrofatty infiltration of the RV wall. This occurs in the epicardial layers first and moves endocardially. The RV inflow, RV apex and RV outflow are typically affected, forming what is called the triangle of dysplasia. With time, the interventricular septum is affected too. LV involvement has been described and could be seen in up to 76% of patients [54]. It usually parallels right ventricular involvement and is associated with worse prognosis [55]. Table 3 shows the major and minor pathological criteria used by the Task Force for diagnosis [56]. Endomyocardial biopsy doesn't have high sensitivity, since it is usually performed in the interventricular septum rather than the RV free wall. However, endomyocardial biopsy might help exlude other disease that could mimic ARVD/C, especially sarcoidosis. [57]

#### **3.4. Clinical presentation**

The clinical course is variable and most patients present before age 40. Patients with ARVD/C can be asymptomatic for years. The most common clinical presentation is with palpitations (due to frequent ventricular ectopy and ventricular tachycardia), chest pain, syncope and sudden cardiac death. In fact sudden cardiac death could be the first manifestation of the disease [54]. With time patients might develop RV dilatation leading to symptoms and signs of right-sided heart failure including fatigue, abdominal fullness and lower extremity edema. LV involvement leads to systolic heart failure and is associated with worse prognosis [58].

#### **3.5. Electrocardiographic changes in ARVD/C**

Patients with ARVD usually have sinus rhythm. The Task force criteria specify some depola‐ rization abnormalities as major criteria for diagnosis, namely the presence of Epsilon wave (which could be seen in up to 30%, very specific but is not sensitive). If the ECG is highly amplified, Epsilon potentials could be detected in as many as 77% of patients with ARVD [59]. Repolarization abnormalities considered to be major criteria are inverted T waves in V1 to V3 or beyond in the absence of right bundle branch block (RBBB) [56, 60]. T wave inversion in V1 to V4 in the presence of RBBB is considered minor criteria for diagnosis. QRS fragmentation, defined as deflections at the beginning of the QRS, on top of the R wave or at the nadir of the S wave, could be found in as many as 85% of patients with ARVD/C and it correlates with LV involvement [59]. Signal average electrocardiography is simple and non-invasive method that could be used for screening. Abnormalities on signal average ECG considered to be minor criteria are listed in Table 3.

were identified in DSP gene, encoding desmoplakin, DSG2 gene, encoding desmgelin 2 and DSC2 gene, encoding desmocolin 2. Desmosomal mutations occur in 52% of North Americans with ARVD/C and are associated with ventricular tachycardia and younger age of presentation [50]. There is genetic variability that occurs in healthy subjects, and has been noted to be as high as 16%. However, certain mutations make the diagnosis of ARVD/C more likely, including radical mutations as well as certain missense mutations that are rare in Caucasians [51]. The autosomal recessive form is associated with woolly hair and palmoplantar keratosis, the so-called Naxos disease, since it was discovered in the Greek island of Naxos. This gene encodes plakoglobin and desmoplakin. This autosomal recessive form has been mapped to chromosome 17q21. In addition, the cardiac ryanodine receptor gene RyR2 may be involved in the disease and causes juvenile sudden death with minimal RV wall motion abnormalities [52]. Mutations in the transforming growth factor B3 (TGF-B3) were also found in a large family

The hallmark of ARVD/C is fibrofatty infiltration of the RV wall. This occurs in the epicardial layers first and moves endocardially. The RV inflow, RV apex and RV outflow are typically affected, forming what is called the triangle of dysplasia. With time, the interventricular septum is affected too. LV involvement has been described and could be seen in up to 76% of patients [54]. It usually parallels right ventricular involvement and is associated with worse prognosis [55]. Table 3 shows the major and minor pathological criteria used by the Task Force for diagnosis [56]. Endomyocardial biopsy doesn't have high sensitivity, since it is usually performed in the interventricular septum rather than the RV free wall. However, endomyocardial biopsy might help exlude other disease that could mimic ARVD/C,

The clinical course is variable and most patients present before age 40. Patients with ARVD/C can be asymptomatic for years. The most common clinical presentation is with palpitations (due to frequent ventricular ectopy and ventricular tachycardia), chest pain, syncope and sudden cardiac death. In fact sudden cardiac death could be the first manifestation of the disease [54]. With time patients might develop RV dilatation leading to symptoms and signs of right-sided heart failure including fatigue, abdominal fullness and lower extremity edema. LV involvement leads to systolic heart failure and is associated with worse prognosis [58].

Patients with ARVD usually have sinus rhythm. The Task force criteria specify some depola‐ rization abnormalities as major criteria for diagnosis, namely the presence of Epsilon wave (which could be seen in up to 30%, very specific but is not sensitive). If the ECG is highly amplified, Epsilon potentials could be detected in as many as 77% of patients with ARVD [59]. Repolarization abnormalities considered to be major criteria are inverted T waves in V1 to V3 or beyond in the absence of right bundle branch block (RBBB) [56, 60]. T wave inversion in V1

in ARVD/C [53].

142 Cardiomyopathies

**3.3. Pathology**

especially sarcoidosis. [57]

**3.4. Clinical presentation**

**3.5. Electrocardiographic changes in ARVD/C**

Patients with ARVD/C can have ventricular tachycardia and frequent premature ventricular contractions (PVCs). Ventricular tachycardia in general has left bundle branch morphology and is caused by macro-reentry. There is evidence that adrenergic stimulation acts as a trigger for these arrhythmias [61]. Exercise testing can induce these arrhythmias in 50-60% of ARVD/ C patients. These arrhythmias could lead to syncope and SCD. In fact, ARVC/D accounts for 3 to 10% of death occurring in patients younger than 65 years [62] and is one of the causes of sudden cardiac death in athletes [63]. Patients with ARVD/D should not participate in moderate to high intensity exercise [64].

Ventricular tachycardia with left bundle branch (LBB) morphology and inferior axis is considered minor criteria, while VT with LBB morphology and superior axis is considered major criteria. Hoffmayer et al proposed criteria to differentiate idiopathic right ventricular outflow tract VT from ventricular tachycardia caused by ARVD/C. Since both conditions could present with ventricular tachycardia with left bundle branch morphology with inferior axis. In multivariate analysis, prolonged QRS duration in Lead I > 120 msec and transition in V5 or later predicted ARVD/C as the cause of VT [65]. Table 3 lists major and minor electrocardio‐ graphic and arrhythmia criteria for diagnosis of ARVD/C [56].



**Major Criteria Minor Criteria**

PLAX indicates parasternal long-axis view; RVOT, RV outflow tract; BSA, body surface area; PSAX, parasternal short-axis

Right ventricular angiography could detect wall motion abnormalities, RV dilatation and even aneurysm formation in patients with ARVD/C. However, due to its invasive nature, difficulty in visually assessing RV wall motion abnormalities especially in the presence of premature

In patients with ARVD/C, the RV could be dilated with RV wall motion abnormalities and decreased RV function. Aneurysms could form in the RV free wall but also could be found in the inferior wall and apex. If adequate visualization of the walls is not possible because of poor windows, contrast injection could help overcome difficulties in delineating the RV wall. Right ventricular outflow (RVOT) enlargement is the most common abnormality found on TTE in patients with ARVD, and RVOT long axis dimension > 30 mm has the best sensitivity (89%) and specificity (86%) for diagnosing ARVD/C. Trabecular derangement, sacculations and hyper-reflective moderator band are less commonly found. Attention to regional RV wall motion abnormalities is important and could be seen in up to 80% of patients. Impaired RV function is seen in up to 67% of patients [66]. Occasionally, trans-esophageal echocardiography and intracardiac echocardiography could be used for diagnosis in patients with difficult images; however, they are more invasive. TTE is widely available, simple and non-invasive which makes it suitable as a primary diagnostic modality and should be performed in patients with PVCs and VT with left bundle branch block and inferior axis. Major and minor echocar‐

Cardiac sympathetic innervation is decreased in patients with ARVD/C, and radioisotopes with specific affinity to the ß receptors in the heart could help in early diagnosis. However, it has poor spatial resolution and the sensitivity and specificity of this modality is not well established [67]. Myocardial perfusion imaging could show decreased areas of radioisotope uptake in the RV, which could help in patients presenting with RVOT type VT. However, it is not widely used and doesn't have high sensitivity or specificity. Because of all this, radioiso‐ tope imaging is not considered as first line diagnostic imaging in patients with ARVD/C.

3) ARVC/D confirmed pathologically or by current Task Force Criteria in second-degree

http://dx.doi.org/10.5772/55628

145

relative

Specific Forms of Cardiomyopathy: Genetics, Clinical Presentation and Treatment

associated with ARVC/D in the patient under

evaluation

**Table 3.** Revised Task Force Criteria for the diagnosis of ARVD/C.

contractions makes it less attractive as a diagnostic modality.

diographic criteria for diagnosing ARVD/C are listed in Table 3 [56].

*3.6.1. Right ventricular contrast angiography*

view

**3.6. Imaging in ARVD/C**

*3.6.2. Echocardiography*

*3.6.3. Radioisotope imaging*


PLAX indicates parasternal long-axis view; RVOT, RV outflow tract; BSA, body surface area; PSAX, parasternal short-axis view

**Table 3.** Revised Task Force Criteria for the diagnosis of ARVD/C.

#### **3.6. Imaging in ARVD/C**

**Major Criteria Minor Criteria**

1) Residual myocytes 60% to 75% by morphometric analysis (or 50% to 65% if estimated), with fibrous replacement of the RV free wall myocardium in ≥1 sample, with or without fatty replacement of tissue on

1) Inverted T waves in leads V1 and V2 in individuals >14 years of age (in the absence of complete right bundle-branch block) or in

2) Inverted T waves in leads V1, V2, V3, and V4 in individuals >14 years of age in the presence of complete right bundle-branch

1) Late potentials by SAECG in ≥1 of 3 parameters in the absence of a QRS duration

4) Root-mean-square voltage of terminal 40

5) Terminal activation duration of QRS ≥55 ms measured from the nadir of the S wave to the end of the QRS, including R′, in V1, V2, or V3, in the absence of complete right bundle-

1) Nonsustained or sustained ventricular tachycardia of RV outflow configuration, left bundle-branch block morphology with inferior axis (positive QRS in leads II, III, and aVF and negative in lead aVL) or of unknown

2) >500 ventricular extrasystoles per 24 hours

1) History of ARVC/D in a first-degree relative in whom it is not possible or practical to determine whether the family member meets current Task Force criteria 2) Premature sudden death (<35 years of age) due to suspected ARVC/D in a first-

of ≥110 ms on the standard ECG 2) Filtered QRS duration (fQRS) ≥114 ms 3) Duration of terminal QRS <40 μV (lowamplitude signal duration) ≥38 ms

endomyocardial biopsy

V4, V5, or V6

block

ms ≤20 μV

branch block

axis

(Holter)

degree relative

Regional RV akinesia, dyskinesia, or

1) Inverted T waves in right precordial leads (V1, V2, and V3) or beyond in individuals >14 years of age (in the absence of complete right bundle-branch block QRS ≥120 ms)

1) Epsilon wave (reproducible low-amplitude signals between end of QRS complex to onset of the T wave) in the right precordial

1) Nonsustained or sustained ventricular tachycardia of left bundle-branch

morphology with superior axis (negative or indeterminate QRS in leads II, III, and aVF and

1) ARVC/D confirmed in a first-degree relative who meets current Task Force criteria 2) ARVC/D confirmed pathologically at autopsy or surgery in a first-degree relative 3) Identification of a pathogenic mutation† categorized as associated or probably

1) Residual myocytes <60% by morphometric analysis (or <50% if estimated), with fibrous replacement of the RV free wall myocardium in ≥1 sample, with or without fatty replacement of tissue on

endomyocardial biopsy

leads (V1 to V3)

positive in lead aVL)

aneurysm

Tissue

144 Cardiomyopathies

characterization of walls

Repolarization abnormalities

Depolarization/ conduction abnormalities

**Arrhythmias**

**Family history**

#### *3.6.1. Right ventricular contrast angiography*

Right ventricular angiography could detect wall motion abnormalities, RV dilatation and even aneurysm formation in patients with ARVD/C. However, due to its invasive nature, difficulty in visually assessing RV wall motion abnormalities especially in the presence of premature contractions makes it less attractive as a diagnostic modality.

#### *3.6.2. Echocardiography*

In patients with ARVD/C, the RV could be dilated with RV wall motion abnormalities and decreased RV function. Aneurysms could form in the RV free wall but also could be found in the inferior wall and apex. If adequate visualization of the walls is not possible because of poor windows, contrast injection could help overcome difficulties in delineating the RV wall. Right ventricular outflow (RVOT) enlargement is the most common abnormality found on TTE in patients with ARVD, and RVOT long axis dimension > 30 mm has the best sensitivity (89%) and specificity (86%) for diagnosing ARVD/C. Trabecular derangement, sacculations and hyper-reflective moderator band are less commonly found. Attention to regional RV wall motion abnormalities is important and could be seen in up to 80% of patients. Impaired RV function is seen in up to 67% of patients [66]. Occasionally, trans-esophageal echocardiography and intracardiac echocardiography could be used for diagnosis in patients with difficult images; however, they are more invasive. TTE is widely available, simple and non-invasive which makes it suitable as a primary diagnostic modality and should be performed in patients with PVCs and VT with left bundle branch block and inferior axis. Major and minor echocar‐ diographic criteria for diagnosing ARVD/C are listed in Table 3 [56].

#### *3.6.3. Radioisotope imaging*

Cardiac sympathetic innervation is decreased in patients with ARVD/C, and radioisotopes with specific affinity to the ß receptors in the heart could help in early diagnosis. However, it has poor spatial resolution and the sensitivity and specificity of this modality is not well established [67]. Myocardial perfusion imaging could show decreased areas of radioisotope uptake in the RV, which could help in patients presenting with RVOT type VT. However, it is not widely used and doesn't have high sensitivity or specificity. Because of all this, radioiso‐ tope imaging is not considered as first line diagnostic imaging in patients with ARVD/C.

#### *3.6.4. Magnetic resonance imaging*

Cardiac MRI has high resolution and helps in assessment of anatomy, function and hemody‐ namics of the right and left ventricle in patients with ARVD/C. Dilatation of the RVOT area, RV wall motion abnormalities, RV aneurysms, depress RV function and presence of fat infiltration of the RV wall all have been described in patients with ARVD/C [68-70]. However, MRI cannot be used in patients who have defibrillators and it depends on the experience of the center and reader [69]. Tagged MRI helps detect regional wall motion abnormalities in the RV and LV walls. Jain et al found that regional wall motion in the LV parallels the degree of RV function and is present in patients with grossly normal LV function [55]. LV abnormalities include intramyocardial fat as well as wall motion abnormalities, and could be seen in up to 27% of patients (Figure 1). Delayed enhancement MRI (DE MRI) has great sensitivity and could show increased signal in the RV (most commonly the basal sub-tricuspid region extending anteriorly to the RV outflow) in up to 67% of patients with ARVD/C. It is important to differentiate epicardial fat from fat infiltration of the RV wall. In patients with ARVD/C, areas of fat infiltration are most commonly dyskinetic. Relying on fat infiltration alone without wall motion or quantitative assessment of the RV and without adequate testing and attention to the task force criteria could lead to over diagnosis of ARVD/C [69]. Fat infiltration is very sensitive (84%) but has low specificity (79%) while regional RV wall motion abnormalities and RV enlargement are very specific but less sensitive [71]. Table 3 lists the major and minor MRI criteria used for diagnosing ARVD/C.

#### **3.7. Electrophysiology study and three dimensional electro-anatomical mapping**

Electrophysiologic testing with programmed electrical stimulation (PES) is used for risk stratification of sudden cardiac death in patients with ARVD/C but it has poor positive predictive value (35 to 49%) and limited negative predictive value (49 to 74%) in predict‐ ing arrhythmias and appropriate ICD shocks [72-74]. Electroanatomical mapping could help in detecting areas of scar in patients with ARVD/C. Corrado et al demonstrated that scar could accurately be localized in patients with ARVD/C and usually correlates with areas with wall motion abnormalities and fibrofatty infiltration at endomyocardial biopsy. Areas with low voltage of < 0.5 mV are considered scar areas, while healthy tissue usually has a voltage of > 1.5 mV [75]. Areas with voltage between 0.5 and 1.5 mV are considered transitional zone. It is important to insure appropriate contact using either fluoroscopy or intracardiac echocardiography and to obtain multiple points in the same area to confirm that it is a low voltage area. Furthermore, fractionated signals can be found in areas with low voltage and is evidence of slow conduction and could be part of the ventricular tachycardia circuit. Voltage mapping can help delineate the substrate for macro-reentrant VT in patients with ARVD [75]. Low voltage areas indicating scar are noted in the anterolateral RV free wall, apex, and inflow and outflow tracts of the RV and correlate with MRI findings [76]. Even in patients with ARVD and minimal scar, prolonged endocardial activation could be noted. In a study of 25 patients with left bundle branch VT, Tandri et al showed that patients with ARVD/C had prolonged endocardial activation > 65 msec while none of the patients with idiopathic RVOT VT had prolonged endocardial activa‐

tion [77]. Electroanatomical mapping is actually more sensitive than DE MRI in detecting areas with scar, (Figure 1). especially if the scar area is < 20% of the total RV area [78].

**Figure 1.** Representative cases of discordance between endocardial voltage mapping (EVM) and contrast-enhanced magnetic resonance (DE-MRI). **A**, Lateral view of the right ventricular (RV) EVM showing electroanatomical scar (EAS) in the RV inferobasal region and outflow tract. **B** and **C**, Basal short- and long-axis views of DE-MRI sequences showing no signs of delayed contrast enhancement (DE) in the RV free wall. Subepicardial DE is visible in the inferior and infer‐ oseptal regions of the left ventricle (LV; white arrows). **D**, Lateral view of EVM showing a large EAS affecting the infer‐ obasal, anterolateral, and, partly, RV outflow tract region. **E** and **F**, Basal short- and long-axis views of DE MRI showing neither RV nor LV DE. (From Martina Perazzolo Marra, MD, PhD et al "Imaging Study of Ventricular Scar in Arrhythmo‐ genic Right Ventricular Cardiomyopathy / Clinical Perspective : Comparison of 3D Standard Electroanatomical Voltage Mapping and Contrast-Enhanced Cardiac Magnetic Resonance" Circulation: Arrhythmia and Electrophysiology. 2012;

Specific Forms of Cardiomyopathy: Genetics, Clinical Presentation and Treatment

http://dx.doi.org/10.5772/55628

147

Diagnosis of ARVD/C is based on the Modified Task Force Criteria published in 2010 [56]. These criteria are specific and rely on the demonstration of structural, functional and electro‐ physiological changes to diagnose the disease. To diagnose ARVD/C, 2 major criteria, one major and two minor criteria or 4 minor criteria need to be fulfilled. The modified criteria are more sensitive in detecting the disease in first-degree relatives of affected members without compromising specificity and incorporate certain pathogenic mutations as major criteria for diagnosis. Furthermore, it offers more quantitative parameters in imaging studies for diagno‐

sis compared to the original 1994 criteria. Table 3 lists the modified criteria.

**3.8. Diagnosis of ARVD/C**

5: 91-100, With Permission)

**Figure 1.** Representative cases of discordance between endocardial voltage mapping (EVM) and contrast-enhanced magnetic resonance (DE-MRI). **A**, Lateral view of the right ventricular (RV) EVM showing electroanatomical scar (EAS) in the RV inferobasal region and outflow tract. **B** and **C**, Basal short- and long-axis views of DE-MRI sequences showing no signs of delayed contrast enhancement (DE) in the RV free wall. Subepicardial DE is visible in the inferior and infer‐ oseptal regions of the left ventricle (LV; white arrows). **D**, Lateral view of EVM showing a large EAS affecting the infer‐ obasal, anterolateral, and, partly, RV outflow tract region. **E** and **F**, Basal short- and long-axis views of DE MRI showing neither RV nor LV DE. (From Martina Perazzolo Marra, MD, PhD et al "Imaging Study of Ventricular Scar in Arrhythmo‐ genic Right Ventricular Cardiomyopathy / Clinical Perspective : Comparison of 3D Standard Electroanatomical Voltage Mapping and Contrast-Enhanced Cardiac Magnetic Resonance" Circulation: Arrhythmia and Electrophysiology. 2012; 5: 91-100, With Permission)

tion [77]. Electroanatomical mapping is actually more sensitive than DE MRI in detecting areas with scar, (Figure 1). especially if the scar area is < 20% of the total RV area [78].

#### **3.8. Diagnosis of ARVD/C**

*3.6.4. Magnetic resonance imaging*

146 Cardiomyopathies

criteria used for diagnosing ARVD/C.

Cardiac MRI has high resolution and helps in assessment of anatomy, function and hemody‐ namics of the right and left ventricle in patients with ARVD/C. Dilatation of the RVOT area, RV wall motion abnormalities, RV aneurysms, depress RV function and presence of fat infiltration of the RV wall all have been described in patients with ARVD/C [68-70]. However, MRI cannot be used in patients who have defibrillators and it depends on the experience of the center and reader [69]. Tagged MRI helps detect regional wall motion abnormalities in the RV and LV walls. Jain et al found that regional wall motion in the LV parallels the degree of RV function and is present in patients with grossly normal LV function [55]. LV abnormalities include intramyocardial fat as well as wall motion abnormalities, and could be seen in up to 27% of patients (Figure 1). Delayed enhancement MRI (DE MRI) has great sensitivity and could show increased signal in the RV (most commonly the basal sub-tricuspid region extending anteriorly to the RV outflow) in up to 67% of patients with ARVD/C. It is important to differentiate epicardial fat from fat infiltration of the RV wall. In patients with ARVD/C, areas of fat infiltration are most commonly dyskinetic. Relying on fat infiltration alone without wall motion or quantitative assessment of the RV and without adequate testing and attention to the task force criteria could lead to over diagnosis of ARVD/C [69]. Fat infiltration is very sensitive (84%) but has low specificity (79%) while regional RV wall motion abnormalities and RV enlargement are very specific but less sensitive [71]. Table 3 lists the major and minor MRI

**3.7. Electrophysiology study and three dimensional electro-anatomical mapping**

Electrophysiologic testing with programmed electrical stimulation (PES) is used for risk stratification of sudden cardiac death in patients with ARVD/C but it has poor positive predictive value (35 to 49%) and limited negative predictive value (49 to 74%) in predict‐ ing arrhythmias and appropriate ICD shocks [72-74]. Electroanatomical mapping could help in detecting areas of scar in patients with ARVD/C. Corrado et al demonstrated that scar could accurately be localized in patients with ARVD/C and usually correlates with areas with wall motion abnormalities and fibrofatty infiltration at endomyocardial biopsy. Areas with low voltage of < 0.5 mV are considered scar areas, while healthy tissue usually has a voltage of > 1.5 mV [75]. Areas with voltage between 0.5 and 1.5 mV are considered transitional zone. It is important to insure appropriate contact using either fluoroscopy or intracardiac echocardiography and to obtain multiple points in the same area to confirm that it is a low voltage area. Furthermore, fractionated signals can be found in areas with low voltage and is evidence of slow conduction and could be part of the ventricular tachycardia circuit. Voltage mapping can help delineate the substrate for macro-reentrant VT in patients with ARVD [75]. Low voltage areas indicating scar are noted in the anterolateral RV free wall, apex, and inflow and outflow tracts of the RV and correlate with MRI findings [76]. Even in patients with ARVD and minimal scar, prolonged endocardial activation could be noted. In a study of 25 patients with left bundle branch VT, Tandri et al showed that patients with ARVD/C had prolonged endocardial activation > 65 msec while none of the patients with idiopathic RVOT VT had prolonged endocardial activa‐

Diagnosis of ARVD/C is based on the Modified Task Force Criteria published in 2010 [56]. These criteria are specific and rely on the demonstration of structural, functional and electro‐ physiological changes to diagnose the disease. To diagnose ARVD/C, 2 major criteria, one major and two minor criteria or 4 minor criteria need to be fulfilled. The modified criteria are more sensitive in detecting the disease in first-degree relatives of affected members without compromising specificity and incorporate certain pathogenic mutations as major criteria for diagnosis. Furthermore, it offers more quantitative parameters in imaging studies for diagno‐ sis compared to the original 1994 criteria. Table 3 lists the modified criteria.

#### **3.9. Therapy**

Therapy of ARVD/C aims at suppressing ventricular arrhythmias, prevention of sudden cardiac death and treatment of right and/or left ventricular heart failure. Family members should be screened for the disease since most of the cases have autosomal dominant inheritance.

to identify the mutation involved and guide the screening of family members. Heart Trans‐

Specific Forms of Cardiomyopathy: Genetics, Clinical Presentation and Treatment

http://dx.doi.org/10.5772/55628

149

Noncompaction of the left ventricular myocardium is a rare disorder that occurs in isolation or with other congenital cardiac defects. It is caused by the arrest of compaction of the myocardial fibers, leading to prominent trabeculations giving the myocardium a spongy appearance. Patients can be asymptomatic and could present with syncope, chest pain, palpitations, shortness of breath and sudden cardiac death. Management of patients with isolated left ventricular non-compaction (ILVNC) involves treating heart failure, protection from sudden cardiac death, anticoagulation to prevent thromboembolic events, and screening

The true prevalence of isolated LV noncompaction is unknown, as most cases are referred to tertiary care centers. In clinical series, the prevalence ranges from 0.05 to 0.25%. The median age at diagnosis ranges from 90 days to 45 years and males are more commonly affected than

Noncompaction of the left ventricular myocardium is caused by the arrest of intrauterine compaction of the myocardial fibers, leading to prominent trabeculations giving the myocar‐ dium a spongy appearance [90]. It is often associated with other congenital cardiac anomalies, especially obstruction of the right or left ventricular outflow tracts. However, the deep intertrabecular recesses that persist in these cases are in communication with the ventricular cavity and the coronary circulation [87]. In contrast, the intertrabecular recesses in isolated LV noncompaction are in communication with the LV cavity only and not with the coronary circulation. Histologically, there is myocardial thickening as well as interstitial and subendo‐ cardial fibrosis [91]. Microcirculatory dysfunction is present in both compacted and noncom‐ pacted segments which might explain the subendocarial scar noted on biopsies as well as the

Familial involvement was high in initial reports describing isolated LV noncompaction [93] In later series involving adults, the familial recurrence ranged from 12 to 44%. Some mutations involving the G4.5 gene have X linked Inheritance [94, 95]. However, autosomal dominant

inheritance has also been reported with mutations in chromosome 11p15 [95, 96].

plantation is indicated in patients with advanced right and/or left sided heart failure.

**4. Isolated left ventricular non-compaction**

wall motion abnormalities noted in imaging [92].

**4.1. Introduction**

of family members.

**4.2. Epidemiology**

females [86-89].

**4.3. Pathology**

**4.4. Genetics**

Patients with ARVD/C should not participate in competitive sports and should avoid moderate to high intensity exercise. And since the occurrence of ventricular tachycardia is related to adrenergic stimulation, most of the patients with ARVD/C with sustained and NSVT are typically treated with β-blockers and given antiarrhythmic drugs. Sotalol was thought to suppress ventricular arrhythmias in patients with ARVD/C and is widely used in this population [79]. However, a recent publication from the North American ARVD/C registry showed that sotalol did not suppress ventricular arrhythmias or prevent ICD therapies while amiodarone had a better efficacy but only 10 patients received amiodar‐ one in this registry [80]. In patients with heart failure, β-blockers, angiotensin converting enzyme inhibitors and angiotensin receptor blockers are indicated. Catheter ablation for ventricular arrhythmias is used to treat sustained ventricular tachycardia that lead to syncope and ICD shocks in patients with ARVD/C. Both activation mapping as well as substrate mapping could be used to delineate the VT circuit [81]. The success rate of catheter ablation ranges from 32 to 88%, and most patients require two or three ablation proce‐ dures [82, 83]. For prevention of sudden cardiac death, implantable cardioverter defibrilla‐ tors (ICDs) are clearly indicated in patients with ARVD/C who survive cardiac arrest or have sustained VT. It is considered a class IIa indication in ARVD/C patients with one or more risk factors of sudden cardiac death (unexplained syncope, presence of nonsus‐ tained VT on ambulatory monitoring, extensive RV involvement, LV involvement and positive EPS study) [39]. However, there is no clear consensus on the risk factors for SCD in patients with ARVD/C, and the physician needs to utilize knowledge, experience and clinical judgment when considering ICD implantation for patients with this disease.

Since this is a young population, they are also likely to experience inappropriate shocks due to sinus tachycardia or other supraventricular arrhythmias especially atrial fibrillation. Inappropriate shocks occur frequently and could happen in 16 to 24% of patients [72-74]. Appropriate ICD shocks occur in 25 to 50% of patients with no prior VT or VF [74, 84]. Most therapies are clustered early, especially in the first 2 years [43]. Syncope, inducibility at EP study, left ventricular involvement, presence of non-sustained ventricular tachycardia or > 1000 PVCs at holter monitoring are important predictors of appropriate ICD therapy [73, 84]. Furthermore, due to the progressive nature of the disease, lead complications could occur late and lead repositioning or implantation of a new lead are not uncommon and could occur in 14% to 21% of patients [72, 73]. In general ICD therapy is life saving and is well tolerated and has become accepted standard of care in patients with ARVD/C who experience cardiac arrest, sustained VT, unexplained syncope or marked RV dilatation or LV involvement [39].

Prognosis is dependent on the rate of progression of the disease, presence of heart failure and the degree of LV involvement [85]. The diagnosis of ARVD/C should prompt genetic testing to identify the mutation involved and guide the screening of family members. Heart Trans‐ plantation is indicated in patients with advanced right and/or left sided heart failure.
