Elsevier

The Lancet

Volume 386, Issue 9995, 22–28 August 2015, Pages 813-825
The Lancet

Seminar
Left ventricular non-compaction cardiomyopathy

https://doi.org/10.1016/S0140-6736(14)61282-4Get rights and content

Summary

Left ventricular non-compaction, the most recently classified form of cardiomyopathy, is characterised by abnormal trabeculations in the left ventricle, most frequently at the apex. It can be associated with left ventricular dilation or hypertrophy, systolic or diastolic dysfunction, or both, or various forms of congenital heart disease. Affected individuals are at risk of left or right ventricular failure, or both. Heart failure symptoms can be induced by exercise or be persistent at rest, but many patients are asymptomatic. Patients on chronic treatment for compensated heart failure sometimes present acutely with decompensated heart failure. Other life-threatening risks of left ventricular non-compaction are ventricular arrhythmias or complete atrioventricular block, presenting clinically as syncope, and sudden death. Genetic inheritance arises in at least 30–50% of patients, and several genes that cause left ventricular non-compaction have been identified. These genes seem generally to encode sarcomeric (contractile apparatus) or cytoskeletal proteins, although, in the case of left ventricular non-compaction with congenital heart disease, disturbance of the NOTCH signalling pathway seems part of a final common pathway for this form of the disease. Disrupted mitochondrial function and metabolic abnormalities have a causal role too. Treatments focus on improvement of cardiac efficiency and reduction of mechanical stress in patients with systolic dysfunction. Further, treatment of arrhythmia and implantation of an automatic implantable cardioverter-defibrillator for prevention of sudden death are mainstays of therapy when deemed necessary and appropriate. Patients with left ventricular non-compaction and congenital heart disease often need surgical or catheter-based interventions. Despite progress in diagnosis and treatment in the past 10 years, understanding of the disorder and outcomes need to be improved.

Introduction

Left ventricular non-compaction cardiomyopathy (LVNC), which was first described by Grant1 in 1926, is a heterogeneous myocardial disorder characterised by prominent trabeculae, intratrabecular recesses, and a left ventricular myocardium with two distinct layers: compacted and non-compacted.2, 3, 4 Continuity exists between the left ventricular cavity and deep intra-trabecular recesses, both of which are filled with blood, and no evidence of communication with the epicardial coronary artery system is noted.5, 6 Although LVNC mainly affects the left ventricle, isolated right ventricular and biventricular non-compaction also occur.7, 8, 9 Imaging and assessment of pathological changes show that the disorder is characterised by a spongy left ventricular myocardium with abnormal trabeculations usually most evident in the left ventricular apex.3, 10 The American Heart Association formally classified LVNC as a distinct cardiomyopathy in 2006.11

LVNC has been known by several names, including spongy myocardium, fetal myocardium, non-compaction of the left ventricular myocardium, hypertrabeculation syndrome, and left ventricular non-compaction, among others.2, 3, 6, 10, 11, 12, 13, 14, 15, 16 The genesis of LVNC has been speculated to represent arrest of the final stage of myocardial morphogenesis (myocardial compaction).5, 6, 17, 18, 19, 20, 21, 22 However, this hypothesis does not explain why several types of LVNC occur, such as primary myocardial forms, a form associated with arrhythmias, and a form associated with congenital heart disease, including septal defects, right heart obstructive abnormalities (eg, pulmonic stenosis and Ebstein's anomaly), hypoplastic left heart syndrome, and others.10, 12, 23, 24, 25, 26, 27, 28, 29 In all types of LVNC, metabolic derangements can be noted, particularly in neonates and infants.10, 30, 31

Section snippets

Pathological changes

In the early embryo, the heart is a loose, interwoven mesh of muscle fibres.5, 6, 17, 19, 20, 21 The developing myocardium gradually condenses, and the large spaces within the trabecular meshwork disappear, resulting in condensing and compaction of the ventricular myocardium and solidification of the endocardial surfaces. Trabecular compaction is usually more complete in the left than in the right ventricular myocardium, and therefore right ventricular trabeculations are usually noted in the

Prevalence

Although LVNC has been deemed rare by some investigators, and its incidence and prevalence are uncertain, it seems to be the third most commonly diagnosed cardiomyopathy. Ritter and colleagues40 reported a prevalence of isolated LVNC of 0·05% among all adult echocardiographic examinations in a large institution. Aras and coworkers41 reported a prevalence of less than 0·14% in adults referred for echocardiograms. By contrast, Sandhu and colleagues42 recorded a 3·7% prevalence of definite or

Clinical features and diagnosis

Clinical presentation of LVNC is highly variable. It can occur at any age, range from asymptomatic to end-stage heart failure, or be associated with lethal arrhythmias, sudden cardiac death, or thromboembolic events (or combinations thereof).2, 3, 4, 7, 8, 9, 10, 12, 13, 14, 45, 46 Many patients are asymptomatic, and identified serendipitously by echocardiography after referral because of a murmur or for familial screening. Some patients with LVNC present with clinically significant arrhythmias

Benign LVNC

So-called benign LVNC is characterised by normal left ventricular size and wall thickness with preserved systolic and diastolic function. This subtype accounts for roughly 35% of patients and is a predictor of good outcomes in the absence of clinically significant arrhythmias.51 On the basis of this subtype, some adult cardiologists have stated that LVNC does not represent a cardiomyopathy and is a benign and normal variant.52 A possible explanation for this conclusion is that the severe forms

Imaging

Diagnosis of LVNC relies on non-invasive imaging studies—usually transthoracic echocardiography and cardiac MRI. However, the diagnostic criteria used for both these methods are highly controversial. Transthoracic echocardiography remains the most common diagnostic strategy, largely because of its widespread availability, ease of interpretability, and low cost. The most common diagnostic method is based on a ratio of the thickness of the non-compacted layer to that of the compacted layer, with

Arrhythmias

Supraventricular and ventricular arrhythmias, and bradyarrhythmias, many of which are life threatening, occur frequently in LVNC. The LVNC subtype associated with early-onset rhythm abnormalities generally has a substantial risk of sudden death. Implantable cardioverter defibrillators are highly effective for the prevention of sudden arrhythmic death in patients with LVNC, including those with severe left ventricular dysfunction, a previous history of sustained ventricular tachycardia or

Clinical genetics

Inheritance of LVNC is most often X-linked recessive or autosomal dominant, although autosomal recessive and mitochondrial (maternal) inheritance also occur.10, 14, 30, 79 X-linked LVNC, which is usually associated with the multisystem disorder Barth syndrome (caused by a mutation in the TAZ gene), affects men almost exclusively, although a woman with cardiomyopathy has been described.80 When LVNC is associated with congenital heart disease, the congenital cardiac defect might be heterogeneous;

Molecular genetics

The genetic causes of LVNC are heterogeneous, but share a final common pathway, similar to other forms of cardiomyopathy with heterogeneous causes. The specific final common pathway, however, depends on the clinical phenotype and resembles the genetic causes of the clinical subtype in cardiomyopathies devoid of LVNC. In LVNC, not only a final common pathway seems to be disturbed: in most cases, a primary pathway (such as the sarcomere) and a developmental pathway (such as the NOTCH pathway) are

Murine models

Several murine models are being used to discern the underlying mechanisms of LVNC. The most common conclusion reached so far is that hypertrabeculation results from altered regulation of cell proliferation, differentiation, and maturation during the formation of the ventricular wall, particularly if the NOTCH signalling pathway is affected, but other hypotheses have been shared.

FKBP1A is a member of the immunophilin protein family that interacts with several intracellular protein complexes,

Treatment and outcome

Treatment is predicated on making the correct phenotypic diagnosis because different phenotypes necessitate different surveillance and are associated with variable outcomes.51 Because LVNC is heritable, at-risk first-degree relatives are recommended to undergo screening, resulting in diagnosis of people who otherwise would have never undergone non-invasive imaging. Clinically available genetic testing has also affected management: panels that assess for known sarcomeric gene mutations

Search strategy and selection criteria

We searched PubMed, Medline, Current Contents, and OMIM with the search terms “left ventricular noncompaction”, “noncompaction cardiomyopathy”, “spongioform cardiomyopathy”, and “left ventricular hypertrabeculation” for articles in English published between Jan 1, 1950, and July 1, 2014. We identified trials in progress from ClinicalTrials.gov and clinicaltrialsregister.eu. We excluded outdated textbook chapters, but did use our own published and unpublished data.

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