Definition

Left ventricular hypertrabeculation or noncompaction (LVNC) is a myocardial disorder characterized by “spongy” myocardium with prominent trabeculae, separated by deep intertrabecular recesses; it typically affects the left ventricular apex and mid‐ventricle [1]. The intertrabecular recesses are lined with endothelium and communicate with the ventricular cavity, which distinguishes this feature from myocardial sinusoids. Although this anomaly typically affects the left ventricle (LV), involvement of the right ventricle (RV) has also been described [2,3]. LVNC can occur as an isolated anomaly or in association with other structural heart disease such as heterotaxy syndrome, ventricular septal defects, and left or right ventricular outflow obstructive lesions.

Epidemiology

Left ventricular noncompaction has been identified as the third most frequent cardiomyopathy in children, representing 5–9% of cardiomyopathies seen among various studies [2,4,5]. Investigators from the National Australian Childhood Cardiomyopathy Study (NACCS), the longest and most complete study of childhood cardiomyopathy, reported a mean annual incidence of newly diagnosed cases of 0.11 per 100,000 individuals at risk, with the highest incidence in the first year of life (0.83 per 100,000 at risk). There was a male preponderance (69%) due to a high proportion of subjects with Barth syndrome [6]. Studies in adult populations also suggest that LVNC is fairly rare, with a prevalence of 0.014% [7]; however, these data may be confounded by technical imaging limitations in adult studies. LVNC is more prevalent in black than white populations [8].

Etiology

Left ventricular noncompaction is a genetically heterogeneous myopathy, occurring both sporadically and in familial forms. LVNC has been associated with mutations in over 40 genes, many of which are involved in the pathogenesis of the muscular dystrophies and hereditary myopathies, and at least 14 chromosomal abnormalities [9]. Among a pediatric cohort of children with LVNC who underwent genetic testing, 13/75 (17%) of individuals had a positive cardiomyopathy genetic testing result, and 25/75 (33%) had a variant of uncertain significance. Likely pathogenic and pathogenic variants were found in the MYH7, MYBPC3, TPM1, and TNNT2 genes. The highest rate of genetic mutations was found among patients with LVNC and associated cardiovascular malformations (30%) followed by LVNC with associated cardiomyopathy (12%); none of the individuals with isolated LVNC had a pathogenic variant identified by genetic testing [10].

Developmental considerations

During normal cardiac development, the ventricular myocardium begins as a spongy meshwork of myocardial fibers with intertrabecular recesses that communicate with the ventricular cavity. Compaction of the myocardium then progresses from the epicardium towards the endocardium and from base to apex, with vascular recesses becoming capillaries that eventually connect with the epicardial coronary artery system [11]. Arrest in this normal embryologic process of myocardial compaction is thought to be responsible for the findings in LVNC. This assumption is supported by the similarity in the appearance of the left ventricular myocardium in LVNC with that of embryonic myocardium, and by reports of prenatal diagnosis [12,13] and also symptomatic cases described in patients from infancy through adulthood. Countering this pathogenetic assumption are several documented cases in which LVNC was diagnosed but where evidence of normal myocardial architecture had been demonstrated in previous echo studies [14,15]. It is possible, therefore, that the features of LVNC can be either a persistence of embryonic myocardial structure or a developmental pattern in a genetically impaired myocardium.

Clinical presentation

Left ventricular noncompaction has been seen with hypertrophic, hypokinetic, and restrictive phenotypes, raising the issue of whether these are separate diseases or a continuum. Although LVNC is usually asymptomatic, the classic description of the clinical course has included progressive heart failure, arrhythmia, and thromboembolism, with a poor long‐term prognosis. The segments of the LV with noncompacted myocardium may exhibit decreased systolic function as a result of hypoperfusion, ischemia, and fibrosis. These findings are confirmed by thallium imaging, positron emission tomography (PET) scanning, and myocardial biopsy [3,16]. Impaired diastolic filling with restrictive physiology is also associated with hypertrabeculated myocardium [2]. Patients may present with clinical symptoms of heart failure during fetal life, infancy, childhood, or adult years. Although there can be some improvement in function with aggressive medical management of heart failure, progression of the cardiomyopathic process often leads to cardiac transplantation or death from heart failure, arrhythmia, or stroke. In a series of adult LVNC patients, mortality was 47% over a 6‐year follow‐up period [17]. Based on a review of 155 cases of LVNC reported to the National Heart, Lung and Blood Institute Pediatric Cardiomyopathy Registry, there was a combined endpoint of death or transplant of 33% for the entire group, with a much lower rate among those patients without ventricular dysfunction. Notably, 12% of patients with LVNC and normal ventricular function progressed to a cardiomyopathy phenotype within 2 years [5]. Furthermore, patients with LVNC and dilated cardiomyopathy have been shown to carry a twofold higher risk of death or heart transplantation compared with matched subjects with dilated cardiomyopathy alone [6].

The natural history of LVNC is further elucidated by the detection of asymptomatic cases during family or population screening studies. These prospective investigations suggest that, at least in some patients, there may be a long preclinical phase with a much less dire natural history [3,18]. Electrocardiographic abnormalities are frequently observed in patients with LVNC, and may include left and right bundle branch block, ST‐ and T‐wave abnormalities, pathologic Q waves or poor R‐wave progression, biventricular hypertrophy, and Wolff–Parkinson–White syndrome. Arrhythmias are a common feature, with atrial fibrillation, supraventricular tachycardia, and ventricular tachycardia noted on baseline electrocardiogram (ECG) or Holter monitoring [2,17]. Sudden death from presumed ventricular arrhythmia is a recognized complication of LVNC, and aggressive management of ventricular arrhythmia with pharmacologic therapy or an implantable defibrillator is often warranted. Thrombus formation within the deep intertrabecular recesses and associated arrhythmia is a likely explanation for the frequent occurrence of thromboembolic events in these patients. Adult series have reported up to 24% of patients suffering from transient ischemic attack, stroke, or peripheral emboli [7]. Anticoagulation is recommended in patients with documented thromboembolic episodes or with thrombus visualized by echocardiography; antiplatelet agents are often recommended as a prophylactic measure at the time of initial diagnosis.

Morphology

The anatomic features of LVNC include multiple trabeculations affecting the apex and the inferior and lateral walls at the mid‐ventricle, with deep intertrabecular recesses that communicate with the cavity of the LV and are lined with endocardial endothelium (Figure 38.1). The epicardial layer of the myocardium is thin and compact. There are often histologic areas of ischemia within the noncompacted endocardial layer, and subendocardial fibrosis and endocardial fibroelastosis have been described in autopsied hearts [7,19]. Electron microscopy has been inconsistent in findings related to myofiber and mitochondrial morphology. Trabeculation also affects the RV in less than 50% of cases, but differentiation of pathologic from normal degrees of RV trabeculation may be difficult (Figure 38.2). Nonisolated LVNC occurs in association with ventricular septal defects (predominantly muscular), and with left or right ventricular outflow obstruction. Lesions affecting the left heart may include subaortic stenosis, valvar aortic stenosis, coarctation of the aorta, and hypoplastic left heart syndrome. Right heart obstruction may range from valvar pulmonary stenosis to pulmonary atresia and even tetralogy of Fallot [20]. LVNC has also been reported in association with heterotaxy syndrome, particularly in the setting of complete heart block. The association of LVNC with a wide variety of other congenital heart diseases raises the issue of whether there is a true association between LVNC and these other disorders, or whether the findings are coincidental.

Classification

Left ventricular noncompaction does not carry widespread recognition as a distinct form of cardiomyopathy. Whereas the American Heart Association defines it as a separate congenital cardiomyopathy, both the World Health Organization and the European Society of Cardiology consider it an unclassified cardiomyopathy [1,21,22]. This is based on multiple reasons, including heterogeneity in morphologic appearance, association with other forms of congenital heart disease, overlap with other forms of cardiomyopathy, range of clinical symptoms in patients with similar morphologic features, and genetic heterogeneity [23]. As more family and population screening studies have been reported, a larger number of asymptomatic individuals with LVNC have been identified [2].

Over the last 20 years, various authors have proposed imaging‐based diagnostic criteria for LVNC (Figure 38.3) [24–29]. Criteria have also been proposed for cardiac magnetic resonance (CMR) imaging [30]. However, validity and reproducibility of these criteria remain an ongoing concern. One study compared three proposed criteria against a cohort of patients with ventricular dysfunction (n = 199) and a prospective cohort of normal controls (n = 60). They found that 24% of patients fulfilled one or more diagnostic criteria for LVNC. In that subgroup of 69 patients, only 30% fulfilled all three diagnostic criteria. This suggests that the criteria are neither sensitive nor specific for the diagnosis of LVNC [8]. Pediatric studies have also failed to reach a consensus on which diagnostic criteria define LVNC. In one study of 104 patients with LVNC, agreement between two observers on the diagnosis of LVNC was 67%. Furthermore, the morphology of the myocardium changed over time and was not predictive of heart transplantation or death [31]. Another pediatric case–control study comparing three diagnostic criteria determined that an X/Y ratio <0.5 had the greatest inter‐rater reliability when measured in end‐diastole in the parasternal short‐axis view in the apical anterolateral segment [32].

Imaging

Echocardiography is the first‐line imaging modality used in the diagnosis and characterization of LVNC. The morphology of LVNC is readily seen by 2D and color flow mapping. The hallmark feature is prominent trabeculations, typically along the lateral and apical walls of the LV (Figure 38.4, Video 38.1). In LVNC, the noncompact, or trabeculated, inner layer is thicker than the compact layer. The trabeculations are more easily seen during diastole, whereas the two‐layer appearance of the myocardium is better seen in systole [26]. Both contrast echocardiography and CMR imaging can help define the continuity of the left ventricular cavity with the trabecular spaces, particularly when the quality of standard imaging is limited [30,33]. In addition to an evaluation of the morphologic features, a comprehensive assessment of ventricular size and systolic and diastolic function should be performed. The intertrabecular recesses should be examined for the presence of thrombus formation.

Speckle tracking is a novel marker that may help to distinguish LVNC from other forms of dilated cardiomyopathy. In a group of 10 patients with isolated LVNC, a solid body twist (or absent rotation) of the heart was found during systole, in contrast to an opposing twist direction from base to apex in those patients with normal hearts or in those with dilated cardiomyopathy [34]. However, speckle tracking has not gained widespread use because of limited reproducibility. Several imaging‐based risk factors for adverse clinical outcome in LVNC have been proposed, including: (i) ratio of noncompact to compact layers; (ii) number of affected segments; (iii) left ventricular end‐diastolic dimension; (iv) abnormal echocardiographic lateral mitral annular early diastolic tissue Doppler velocity (E <7.8 cm/s); and (v) ventricular dysfunction [7,31,35–39].

Prenatal assessment

Prenatal diagnosis of LVNC has been described [40]. Reported cases have involved ventricular dysfunction and right ventricular noncompaction [13]. A limitation of prenatal diagnosis is the difficulty in obtaining adequately high spatial resolution to detect trabeculations (Figure 38.5, Video 38.2). In the fetus with LVNC, there is a strong association with congenital heart disease, complete heart block, chromosomal/noncardiac abnormalities, and overall poor prognosis [40,41]. If ventricular function is poor, hydrops fetalis may develop. Color Doppler can be helpful to assess for flow within the trabecular recesses.