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

#### **4.1. Introduction**

**3.9. Therapy**

148 Cardiomyopathies

inheritance.

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

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 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 of family members.

#### **4.2. Epidemiology**

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 females [86-89].

#### **4.3. Pathology**

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 wall motion abnormalities noted in imaging [92].

#### **4.4. Genetics**

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].

Sarcomere protein gene defects are also found in patients with ILVNC. Mutations in cipher/ ZASP, a gene encoding for the Z-band, can cause dilated cardiomyopathy as well as ILVNC [97]. In a study of 63 unrelated patients with ILVNC, mutations in genes encoding sarcomere proteins were identified in 11 patients. These genes include β myosin heavy chain (MYH7), α-cardiac actin and cardiac troponin T. Similar sarcomere gene mutations, especially in MYH7 are also found in patients with hypertrophic and dilated cardiomyopathies [98]. These sarcomere mutations could account for up to 29% of mutations in ILVNC, but they do not predict clinical outcome [99].

**4.7. Imaging in isolated left ventricular non-compaction**

diagnoses in patients with difficult windows.

*4.7.2. Magnetic Resonance Imaging (MRI)*

Transthoracic echocardiography is the modality most commonly used to diagnose ILVNC [103]. The most common criteria used for diagnoses have been proposed by Jenni et al, with a ratio of noncompacted to compacted LV myocardium of 2 to 1 considered diagnostic [104]. This is typically measured at end systole in the parasternal short axis view. Deep intertrabec‐ ular recesses that are supplied from the LV cavity and absence of other congenital anomalies are part of Jenni's criteria. However, some experts suggest the ratio of noncompacted to compacted myocardium should be measured but in the parasternal short axis view at end diastole [103]. Chin et al proposed a measurement of compacted myocardium (C) to the total thickness of both compacted and noncompacted layers (C + NC) at end diastole, with the ratio of C/ (NC+C) of < 0.5 considered diagnostic. However, there is poor agreement between readers when it comes to the ratio of noncompated to compacted myocardium, with only 74% of agreement noted and there is poor agreement between these two criteria for diagnosis [105]. Jenni's criteria are more specific while Chin's criteria are more sensitive. In general the noncompacted segments most commonly involve the apex more than the base, and are seen mostly in the inferior wall and also in the lateral wall [104]. Multiple segments are usually involved (Figure 2). The right ventricle is involved in 40% of the cases [89, 105]. Wall motion abnormalities, impaired diastolic filling as measured from mitral inflow velocities are also seen. Depressed LV ejection fraction is noted in a lot of patients with LV noncompaction, and patients with severe LV dysfunction have a poor prognosis. It is important to differentiate ILVNC from hypertrophic cardiomyopathy (especially the apical variant), dilated cardiomy‐ opathy, arrhythmogenic right ventricular dysplasia and endocardial fibroelastosis. But in isolated LVNC, perfused recesses and hypokinetic segments are very specific, and the wall thickening noted is confined to certain walls of the LV. Visualization of the trabecular recesses could be enhanced using contrast. Transesophageal echocardiography could also be used in

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Magnetic resonance imaging (MRI) has been also used for diagnosis. Delayed gadolinium enhancement has been seen in both compacted and noncompacted myocardium. In compacted myocardium, delayed enhancement correlated well with fibrosis, while in the noncompacted segments, delayed enhancement correlated with fibrosis as well as mucoid degeneration of the endocardium [106]. MRI offers better spatial resolution and can help assess LV and RV functions, wall motion abnormalities, as well as the ratio of compacted and noncompacted segments, which has been shown to be an important predictor of major adverse cardiac events, including heart failure, ventricular arrhythmias and thromboembolism. A ratio of noncom‐ pacted to compacted myocardium of > 2.3 at end diastole had the best sensitivity (86%) and specificity (99%) in diagnosing ILVNC [107]. However, 140 patients (43%) of 323 patients in the MESA cohort had at least one area with trabeculated to compact ratio of > 2.3 and the authors advised caution in using these criteria alone for diagnosis of ILVNC [108]. The

*4.7.1. Echocardiography*

### **4.5. Clinical presentation**

Patients with isolated LV noncompaction can be asymptomatic for years and eventually could present with heart failure, arrhythmias, embolic events and sudden cardiac death. The clinical course is variable, with patients who are asymptomatic having a more stable clinical course, while patients presenting with heart failure having a progressive clinical course with heart failure and ventricular arrhythmias [100]. Most patients have some degree of LV dysfunction, which has been reported in up to 60% of patients in the four largest reports of LV noncom‐ paction [86, 87, 93, 101]. However, presentation as congestive heart failure with dyspnea on exertion has ranged from 30–68%. Patients could have systolic as well as diastolic dysfunction. Microcirculatory dysfunction could lead to ischemia and scar causing wall motion abnormal‐ ities and systolic heart failure. While impaired filling and abnormal relaxation from prominent trabeculations could lead to diastolic heart failure [92]. Several arrhythmias have been reported with ILVNC, including atrial fibrillation (5–29% in major reports), atrial tachycardia, prema‐ ture ventricular complexes and ventricular tachycardia (18–47% in major reports). Sudden cardiac death accounted for 50% of deaths in ILVNC. Presence of subendocardial scar can act as a substrate of reentry in these patients. Embolic complications in ILVNC could be due to thrombus formation in the recesses of the trabeculations, due to stagnant flow from severely depressed LV function or from atrial fibrillation. These emboli can go to the cerebrovascular circulation, peripheral circulation, or pulmonary circulation. The incidence of embolization has ranged from 21–38%. Anticoagulation to prevent thromboembolic complications is very important in ILVNC [91].

#### **4.6. Electrocardiogram**

Abnormalities noted in the electrocardiogram in patients with ILVNC include left bundle branch block, right bundle branch block, left ventricular hypertrophy with repolarization abnormalities, and AV block. Wolff-Parkinson-White syndrome has been described in children with ILVNC. Atrial fibrillation, frequent premature ventricular contractions with sustained and non-sustained ventricular tachycardia could be present and could be the first presentation of the disease. There is a high prevalence of early repolarization in patients with ILVNC, especially in those patients who present with malignant arrhythmias [86, 87, 102].

#### **4.7. Imaging in isolated left ventricular non-compaction**

#### *4.7.1. Echocardiography*

Sarcomere protein gene defects are also found in patients with ILVNC. Mutations in cipher/ ZASP, a gene encoding for the Z-band, can cause dilated cardiomyopathy as well as ILVNC [97]. In a study of 63 unrelated patients with ILVNC, mutations in genes encoding sarcomere proteins were identified in 11 patients. These genes include β myosin heavy chain (MYH7), α-cardiac actin and cardiac troponin T. Similar sarcomere gene mutations, especially in MYH7 are also found in patients with hypertrophic and dilated cardiomyopathies [98]. These sarcomere mutations could account for up to 29% of mutations in ILVNC, but they do not

Patients with isolated LV noncompaction can be asymptomatic for years and eventually could present with heart failure, arrhythmias, embolic events and sudden cardiac death. The clinical course is variable, with patients who are asymptomatic having a more stable clinical course, while patients presenting with heart failure having a progressive clinical course with heart failure and ventricular arrhythmias [100]. Most patients have some degree of LV dysfunction, which has been reported in up to 60% of patients in the four largest reports of LV noncom‐ paction [86, 87, 93, 101]. However, presentation as congestive heart failure with dyspnea on exertion has ranged from 30–68%. Patients could have systolic as well as diastolic dysfunction. Microcirculatory dysfunction could lead to ischemia and scar causing wall motion abnormal‐ ities and systolic heart failure. While impaired filling and abnormal relaxation from prominent trabeculations could lead to diastolic heart failure [92]. Several arrhythmias have been reported with ILVNC, including atrial fibrillation (5–29% in major reports), atrial tachycardia, prema‐ ture ventricular complexes and ventricular tachycardia (18–47% in major reports). Sudden cardiac death accounted for 50% of deaths in ILVNC. Presence of subendocardial scar can act as a substrate of reentry in these patients. Embolic complications in ILVNC could be due to thrombus formation in the recesses of the trabeculations, due to stagnant flow from severely depressed LV function or from atrial fibrillation. These emboli can go to the cerebrovascular circulation, peripheral circulation, or pulmonary circulation. The incidence of embolization has ranged from 21–38%. Anticoagulation to prevent thromboembolic complications is very

Abnormalities noted in the electrocardiogram in patients with ILVNC include left bundle branch block, right bundle branch block, left ventricular hypertrophy with repolarization abnormalities, and AV block. Wolff-Parkinson-White syndrome has been described in children with ILVNC. Atrial fibrillation, frequent premature ventricular contractions with sustained and non-sustained ventricular tachycardia could be present and could be the first presentation of the disease. There is a high prevalence of early repolarization in patients with ILVNC,

especially in those patients who present with malignant arrhythmias [86, 87, 102].

predict clinical outcome [99].

**4.5. Clinical presentation**

150 Cardiomyopathies

important in ILVNC [91].

**4.6. Electrocardiogram**

Transthoracic echocardiography is the modality most commonly used to diagnose ILVNC [103]. The most common criteria used for diagnoses have been proposed by Jenni et al, with a ratio of noncompacted to compacted LV myocardium of 2 to 1 considered diagnostic [104]. This is typically measured at end systole in the parasternal short axis view. Deep intertrabec‐ ular recesses that are supplied from the LV cavity and absence of other congenital anomalies are part of Jenni's criteria. However, some experts suggest the ratio of noncompacted to compacted myocardium should be measured but in the parasternal short axis view at end diastole [103]. Chin et al proposed a measurement of compacted myocardium (C) to the total thickness of both compacted and noncompacted layers (C + NC) at end diastole, with the ratio of C/ (NC+C) of < 0.5 considered diagnostic. However, there is poor agreement between readers when it comes to the ratio of noncompated to compacted myocardium, with only 74% of agreement noted and there is poor agreement between these two criteria for diagnosis [105]. Jenni's criteria are more specific while Chin's criteria are more sensitive. In general the noncompacted segments most commonly involve the apex more than the base, and are seen mostly in the inferior wall and also in the lateral wall [104]. Multiple segments are usually involved (Figure 2). The right ventricle is involved in 40% of the cases [89, 105]. Wall motion abnormalities, impaired diastolic filling as measured from mitral inflow velocities are also seen. Depressed LV ejection fraction is noted in a lot of patients with LV noncompaction, and patients with severe LV dysfunction have a poor prognosis. It is important to differentiate ILVNC from hypertrophic cardiomyopathy (especially the apical variant), dilated cardiomy‐ opathy, arrhythmogenic right ventricular dysplasia and endocardial fibroelastosis. But in isolated LVNC, perfused recesses and hypokinetic segments are very specific, and the wall thickening noted is confined to certain walls of the LV. Visualization of the trabecular recesses could be enhanced using contrast. Transesophageal echocardiography could also be used in diagnoses in patients with difficult windows.

#### *4.7.2. Magnetic Resonance Imaging (MRI)*

Magnetic resonance imaging (MRI) has been also used for diagnosis. Delayed gadolinium enhancement has been seen in both compacted and noncompacted myocardium. In compacted myocardium, delayed enhancement correlated well with fibrosis, while in the noncompacted segments, delayed enhancement correlated with fibrosis as well as mucoid degeneration of the endocardium [106]. MRI offers better spatial resolution and can help assess LV and RV functions, wall motion abnormalities, as well as the ratio of compacted and noncompacted segments, which has been shown to be an important predictor of major adverse cardiac events, including heart failure, ventricular arrhythmias and thromboembolism. A ratio of noncom‐ pacted to compacted myocardium of > 2.3 at end diastole had the best sensitivity (86%) and specificity (99%) in diagnosing ILVNC [107]. However, 140 patients (43%) of 323 patients in the MESA cohort had at least one area with trabeculated to compact ratio of > 2.3 and the authors advised caution in using these criteria alone for diagnosis of ILVNC [108]. The

yielded great results. Currently, the decision to implant a defibrillator (ICD) or biventricular defibrillator (BiV ICD) is clear in patients who have survived a cardiac arrest or in patients with LVEF <35% who qualify for an ICD or BIV ICD according to the current guidelines [39]. In a series of 30 patients with ILVNC who received ICDs or BiV ICDs according to the current guidelines, Kobza et al showed that appropriate ICD therapy (either shocks or antitachycardia pacing) occurred in 37% of cases with a mean follow up of 21 ± 16 months. Inappropriate shocks occurred in 13% of cases. In patients who received ICD therapy for primary prevention, 33% had appropriate ICD therapy with mean follow up of 27 ± 33 months. There were no predictors

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The prognosis of ILVNC varies. Initial reports were based on the experience in tertiary care centers led to the belief that the prognosis is poor, with progressive heart failure leading to death or transplantation in 47% of adults with ILVNC followed for 44 ± 39 months [91]. However, recent reports challenge this and asymptomatic patients in general have a good prognosis [113]. Certain clinical characteristics are more common in non-survivors compared to survivors, including higher LV end-diastolic diameter, New York Heart Association class III–IV heart failure, left bundle branch block, and persistent atrial fibrillation. Patients with such clinical characteristics need frequent follow up, with strong consideration for more aggressive treatment [86]. Family screening is important, with transthoracic echocardiography being the most common screening modality. Family members may have other forms of cardiomyopathy, like dilated or hypertrophic cardiomyopathy [113]. Recent advances in genetic testing will allow identification of the genetic mutation in the proband and help narrow

Cardiac Sarcoidosis, arrhythmogenic right ventricular dysplasia and isolated left ventricular noncompaction are rare forms of cardiomyopathy that affect young patients and put them at risk of sudden cardiac death. Early recognition and treatment is important. In the absence of clear guidelines to prevent sudden cardiac death in this young population, the clinician should use current knowledge, clinical judgment and expertise when treating these patients. Advan‐ ces in diagnostic imaging as well as genetic testing will help early diagnosis and identification

University of Colorado, Cheyenne Regional Medical Center, Cheyenne, Wyoming, USA

of appropriate ICD therapy [112].

the search for the genetic mutations.

**5. Conclusion**

of affected family members.

**Author details**

M. Obadah Al Chekakie

**Figure 2.** Apical 2 chamber view showing prominent trabeculations in the apex and inferior walls consistent with Iso‐ lated Left Ventricular Non-Compation.

calculation of trabeculated LV mass using MRI could help also in the diagnosis of ILVNC, with trabeculated LV mass of > 20% of the total LV mass having the highest sensitivity and specificity (93.7%) in diagnosing ILVNC [109].

#### *4.7.3. Other imaging modalities*

Computed tomography scan could be used to diagnose ILVNC and has high spatial resolution. Prominent trabeculations as well as deep intertrabecular recesses are typically seen [103]. Contrast ventriculography could also be used but is invasive. PET scan could show decreased myocardial flow reserve in noncompacted areas as well as microcirculatory dysfunction in both compacted and noncompacted myocardium but this has limited utility in establishing the diagnosis [92, 110]. To date, Echocardiography and MRI remain the most common modalities used for diagnosing ILVNC.

#### **4.8. Therapy**

Management of patients with ILVNC involves treating heart failure, protection from sudden cardiac death, anticoagulation to prevent thromboembolic events, and screening of family members. β-blockers, angiotensin converting enzyme inhibitors and angtiotensin receptor blockers are used and have been reported to improve symptoms and the LVEF [111]. Antico‐ agulation with coumadin is recommended in all patients, even if they don't have atrial fibrillation. Electrophysiology testing to predict the risk of sudden cardiac death has not yielded great results. Currently, the decision to implant a defibrillator (ICD) or biventricular defibrillator (BiV ICD) is clear in patients who have survived a cardiac arrest or in patients with LVEF <35% who qualify for an ICD or BIV ICD according to the current guidelines [39]. In a series of 30 patients with ILVNC who received ICDs or BiV ICDs according to the current guidelines, Kobza et al showed that appropriate ICD therapy (either shocks or antitachycardia pacing) occurred in 37% of cases with a mean follow up of 21 ± 16 months. Inappropriate shocks occurred in 13% of cases. In patients who received ICD therapy for primary prevention, 33% had appropriate ICD therapy with mean follow up of 27 ± 33 months. There were no predictors of appropriate ICD therapy [112].

The prognosis of ILVNC varies. Initial reports were based on the experience in tertiary care centers led to the belief that the prognosis is poor, with progressive heart failure leading to death or transplantation in 47% of adults with ILVNC followed for 44 ± 39 months [91]. However, recent reports challenge this and asymptomatic patients in general have a good prognosis [113]. Certain clinical characteristics are more common in non-survivors compared to survivors, including higher LV end-diastolic diameter, New York Heart Association class III–IV heart failure, left bundle branch block, and persistent atrial fibrillation. Patients with such clinical characteristics need frequent follow up, with strong consideration for more aggressive treatment [86]. Family screening is important, with transthoracic echocardiography being the most common screening modality. Family members may have other forms of cardiomyopathy, like dilated or hypertrophic cardiomyopathy [113]. Recent advances in genetic testing will allow identification of the genetic mutation in the proband and help narrow the search for the genetic mutations.
