Noncompaction cardiomyopathy

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Non-compaction cardiomyopathy (NCC), sometimes known as “spongiform cardiomyopathy” is a rare congenital cardiomyopathy that affects both children and adults. It refers to a type of cardiomyopathy where the myocardial development is hindered during the early stages of fetal development (the embryogenesis stage). ^{[1] [2]}. It results from the failure of myocardial development during embryogenesis.^[1][2] The phenotypic expression is variable. The can be symptoms of systolic dysfunction and heart failure, while in other patients there can be minimal symptoms and hypercontractility. The condition can occur as either an isolated disease or as part of constellation of other findings of congenital heart disease (frequently pulmonic stenosis, atrial septal defect, ventricular septal defect, or hypoplastic left ventricle. On echocardiography there is ventricular hypertrophy with deep recesses which tend to be located apically.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Non compaction cardiomyopathy was first identified as an isolated condition in 1984 by Engberding and Benber.^[1] They reported on a 33 year old female presenting with exertional dyspnea and palpitations. Investigations concluded persistence of myocardial sinusoids (now termed non compaction). Prior to this report, the condition was only reported in association with other cardiac anomalies, namely pulmonary or aortic atresia. Myocardial sinusoids is considered not an accurate term as endothelium lines the intertrabecular recesses.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Non-compaction cardiomyopathy can occur with or without associated congenital heart disease. When it occurs in the absence of congenital heart disease, it is called isolated non-compaction cardiomyopathy. If it occurs in the absence of congenital heart disease and only the left ventricle is involved, it is called isolated left ventricular non-compaction cardiomyopathy.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

This is a rare genetic disorder. It is hard to know the true prevalance of disease as the diagnosis may be missed on echocardiography, and studies of prevalance focus on patients referred to teriary referral centers with congestive heart failure. The prevalence may increase as imaging modalities improve. In the largest study to date, the prevalence was 0.014%^[1].

The incidence is estimated to be 0.12 cases per 100,000 children ^[2].

Others have estimated the rate to be as high as 0.81 per 100,000 infants per calender year.

There is an excess incidence of the disease in males (56% to 82%). This has been taken as evidence that in some cases there may be x-linked inheritance.

In the initial description of the disease, the median age at diagnosis was 7 with a range from 11 months to 22 years^[3]. Other studies have confirmed the presence of NCC in all age groups including the elderly.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Noncompaction cardiomyopathy is an inheritable disease, and if a family member is affected, consideration should be given to screening other family members. Symptoms may be quite variable in different family members. Recurrence occurs in about 40% of family members.

It is recommended that first degree relatives be screened by transthoracic echocardiography^[1].

Some highly specialized centers do offer genetic screening. Several potential genetic abnormalities have been identified:

• The gene that encodes for alpha-dystrobrevin^[2]. This is a dystrophin-associated protein which has been mapped to chromosome 18q12. The role of this protein is to preserve the structural integrity of the muscle membrane.
• An X-linked genetic defect which involves a mutation in the gene G4.5 (TAZ) of the Xq28 chromosome region (a gene which encodes for tafazzin), the same region of the chromosome involved in several myopathies with cardiac involvement are located. These include Barth syndrome^[3], Emery-Dreifuss muscular dystrophy, and myotubular myopathy. As a result, some patients with NCC may have features of Barth syndrome.
• Mutations of the ryanodine receptor 2 gene (RyR2) as has been seen in patients with arrhythmogenic right ventricular dysplasia.
• Deletions of the FKBP12 gene result in noncompaction in the mouse^[4].
• Knockout of the Peg1 gene has been associated with NCC in the mouse ^[5].
• LMNA mutations
• Abnormalities of transcription factors such as NKX2.5 and TBX5.
• Abnormalities of 11p15 as suggested in a GWAS analysis.
• 22q11 deletion
• Distal 5q deletion involving the CSX gene ^[6]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

The presence of NCC is associated with variable degrees of congestive heart failure and may or may not be associated with congenital heart disease or diseases in other organs ^[1][2][3].

• Abnormalities of the origin of the left coronary artery
• Pulmonary atresia
• Pulmonary stenosis
• Right or Left ventricle obstruction
• Hypoplastic left ventricle
• Mitral regurgitation

• Systolic dysfunction
• Diastolic dysfunction
• Restrictive filling patterns
• Subendocardial and microvascular ischemia

• Wolff-Parkinson-White syndrome
• Complete heart block
• Atrial fibrillation
• Tachyarrhythmias and sudden cardiac death

• Thrombus formation in the left ventricle

• Becker’s muscular dystrophy
• Mitochondrial myopathy
• Polyneuropathy and metabolic myopathy

• Emery-Dreifuss muscular dystrophy
• Myotubular cardiomyopathy
• Barth syndrome

In so far as noncompaction cardiomyopathy is a recently described entity, its association with long term clinical outcomes is not weel defined. In a study which documented the long term follow up of 34 patients who were symptomatic with NCC, 35% had died at the age of 42 +/- 40 months. 12% of the patients required cardiac transplantation due to heart failure^[4] . In another study, 60% of patients had either died or undergone cardiac transplantation within six years^[5]. In another study with 10 years of follow-up, 90% of patients had developed left ventricular dysfunction^[6].

The prognosis associated with NCC may be better than that reported in these series because only symptomatic patients were included in the aforementioned studies. Genetic testing reveals that there are patients with lesser degrees of symptoms, and the long-term prognosis in these patients has not been well defined.

Clinical features of patients who are at an increased risk of poor long-term mortality in whom consideration should be given to implantation of an automatic implantable cardiac defibrillator (AICD) and/or cardiac transplantation include:

• Higher left ventricular end diastolic diameter presentation
• New York heart Association class III or IV heart failure
• Permanent or persistent atrial fibrillation
• Presence of bundle branch block

If severe heart failure is present, pregnancy is not recommended^[7].

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

NCC is often missed or misdiagnosed. This can be attributed at least in part to the fact that non-compaction cardiomyopathy was only recently reported as an entity.

The normal heart can have prominent trabeculations, but these usually number less than 3.

In a recent study ^[1] of 53 patients with non-compaction cardiomyopathy, the first 42 were misdiagnosed with another form of heart disease. Improved awareness and improved imaging modalities allowed the correct diagnosis to be made in the last 11 cases. The most common misdiagnoses included:

• Dilated cardiomyopathy: 30 Cases
• Congenital heart disease: 6 Cases
• Ischemic heart disease: 2 Cases
• Disease of the heart valves: 2 Cases
• Dilated phase hypertensive cardiomyopathy: 1 Case
• Restrictive cardiomyopathy: 1 Case

Given the apical hypertrophy, the disease may also be mistaken for hypertrophic obstructive cardiomyopathy or apical hypertrophic cardiomyopathy. It can also be confused with arrhythmogenic right ventricular dysplasia, endocardial fibroelastosis, cardiac metastases, and left ventricular thrombus.

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