CHAPTER 60: LEFT VENTRICULAR NONCOMPACTION

Cardiac trabecular anatomy is characterized by extreme individual and population variability that corresponds to a sort of individual cardioprinting. In normal hearts, trabeculae undergo continuous and quantifiable geometric changes during the cardiac cycle; they actively provide mechanical leverage during early systolic ejection through contraction, and relaxation occurs during late diastole at larger ventricular volumes.¹ In the left ventricle, trabeculae can be minimally represented or may be so numerous and prominent that they confer a “spongy” appearance to the endocardial surface of the ventricles. The latter corresponds to the term left ventricular noncompaction (LVNC).

LVNC describes a ventricular wall anatomy characterized by the presence of disproportionate, prominent left ventricular (LV) trabeculae, a thin compacted layer, and deep intertrabecular recesses that are in continuity with the LV cavity and separated from the epicardial coronary arteries.² By definition, noncompaction pertains to the LV but may also involve the right ventricle, as either a biventricular³ or an isolated right ventricular variant.⁴ The American Heart Association (AHA) classification defines LVNC as a genetic/congenital cardiomyopathy,⁵ whereas the European Society of Cardiology (ESC) classification defines LVNC as a nonclassified entity.⁶ The recent MOGE(S) nosology (Morphofunctional phenotype, Organ(s) involvement, Genetic inheritance pattern, Etiologic annotation including genetic defect or underlying disease/substrate, and functional Status of the disease) proposes a simple description of the trait in individuals with either normal LV size and wall thickness and preserved systolic and diastolic function or in combination with hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), restrictive cardiomyopathy (RCM) or arrhythmogenic right ventricular cardiomyopathy (ARVC).⁷ This latter descriptive approach is the expression of the clinical uncertainties regarding the unique interpretation of LVNC as a cardiomyopathy.⁸

In the official guidelines of scientific societies, the requirements for the definition of a cardiomyopathy include “diseases of the myocardium associated with mechanical and/or electrical dysfunction” (AHA)⁵ and “myocardial diseases characterized by structurally and functionally abnormal heart muscle and absence of other diseases sufficient to cause the observed myocardial abnormality” (ESC).⁶ When isolated and benign, LVNC is not associated with mechanical and/or electrical dysfunction (AHA) and is characterized by some structural abnormality (trabeculation) with potentially normal function.⁸ By itself, the diagnosis of LVNC is based on one of the attributes that define cardiomyopathies, namely the abnormal LV morphology, but this does not obligatorily imply LV dysfunction. The increasing number of reports that describe LVNC in the normal population questions the definition of LVNC as cardiomyopathy. This chapter illustrates the current criteria for diagnosing LVNC, available data in normal populations, the association of LVNC with cardiomyopathies and disease genes, congenital heart diseases, rare syndromes affecting or not affecting cardiac function, acquired and possibly reversible LVNC, and diagnostic workup.

Diagnostic criteria have been established for echocardiography, cardiac magnetic resonance (CMR), and multidetector computed tomography (MDCT). The list of different criteria is by itself evidence that common, standardized, and uniform rules do not exist. This is likely because isolated LVNC represents a spectrum of LV trabecular morphology rather than an independent heart muscle disease. Table 60–1^{9,10,11,12,13,14,15,16,17,18,19,20,21,22} summarizes current diagnostic criteria that are based on ratios between thickness, mass, or volume or percentages of noncompacted (NC) and compacted LV. The number of NC segments provides information on the extent of LVNC. Alternative methods integrate the count or evaluation of the global trabeculation index. Figures 60–1 and 60–2 illustrate echocardiographic and CMR features of LVNC, respectively.

MDCT is useful when CMR is contraindicated or when echocardiography and CMR provide discordant data^22,23 and further adds the advantage of noninvasive investigation of the coronary tree. A computed tomography (CT) study that used the AHA 17-segment model and an end-diastolic NC-to-compacted (NC/C) ratio > 2.3 distinguished pathologic LVNC with 88% sensitivity and 97% specificity, with positive and negative predictive values of 78% and 99%, respectively.²³

The independent diagnostic contribution of the maximum thickness of the compacted layer is limited. In the context of using ratios or proportions, the same ratio can result from different absolute values of the two components. In most diagnostic indices, the ratios between compacted and noncompacted thickness, volume, or mass drive the diagnosis. However, reduced thickness of the compacted layer has been proposed as a novel echocardiographic criterion for noncompaction cardiomyopathy; a maximal systolic thickness < 8 mm of the compacted layer seems to be specific for LVNC and to differentiate LVNC from normal hearts as well as hearts with myocardial thickening caused by aortic valve stenosis. The addition of this criterion may eventually contribute preventing the overdiagnosis of LVNC.²⁴

Although the diagnostic gold standard is considered to be CMR, an ideal gold standard does not exist, and in fact, different CMR methods and software exist without concordance on diagnostic criteria.

LVNC diagnosed according to current criteria may occur in functionally normal hearts. In 2012, the publication of data in 1000 participants (551 women; age, 68.1 ± 8.9 years) of the Multi-Ethnic Study of Atherosclerosis (MESA) cohort suggested the need of re-evaluation of CMR criteria for LVNC. The thickness of trabeculated and compact myocardium was measured in eight LV regions on long-axis CMR steady-state free precession cine images. The study demonstrated (1) that 43% of subjects without cardiac disease or hypertension had an NC/C ratio > 2.3 in at least one myocardial segment; (2) NC/C ratio was not associated with age, sex, race/ethnicity, height, or weight; (3) the maximum thickness of trabeculation was positively associated with race/ethnicity (Chinese and black) and male sex; (4) there was a negative association of LV ejection fraction and a positive association of LV end-diastolic volume and LV end-systolic volume with the maximum NC/C ratio, versus a positive association of LV end-diastolic volume and LV end-systolic volume with maximum trabeculation thickness; and (5) there was a technique–related variability in measurement of thickness of trabeculation and compact myocardium as well as NC/C ratio. The study concluded that an NC/C ratio > 2.3 is common in a large population-based cohort.²⁵

In 2014, long-term follow-up data in 2742 participants in the MESA cohort (mean age, 68.7 years; 52.3% women; 56.4% with hypertension; 16.8% with diabetes) demonstrated that even in subjects with excessive trabeculation, there were no clinically relevant differences in LV volumes and systolic function changes among the quintiles of trabeculation extent. The authors found that 25% of participants exhibited at least one cardiac segment with NC/C ratio > 2.3 and that 8% of participants displayed two or more affected segments. Although LV volumes increased and LV ejection fraction decreased in the 9.5 years between the first and last examinations, there were no differences across the maximal NC/C ratio quintiles, and patients with greater trabeculation showed even smaller LV end-diastolic volume changes. There were no racial variations in the maximal NC/C ratio. Finally, adverse clinical events were scarce, despite the apparently high proportion of participants with a potential unmasked cardiomyopathy.²⁶

CMR studies in normal adult volunteers demonstrated the following sex- and age-related differences: (1) the compacted but not the trabeculated layer is thicker in men than in women; (2) the compacted layer thickens whereas the trabeculated layer thins with systole; (3) trabeculated LV segments show increased systolic thinning of trabeculated layers and greater thickening of the compact segments (P < .05) with age; (4) total wall thickening is neither sex nor age dependent; (5) there were no sex-specific differences in the trabeculated/compacted ratio at end systole or end diastole; and (6) in end systole, the trabeculated/compacted ratio was lower in older (50-79 years) compared to younger (20-49 years) subjects (P < .05).¹⁶ Overall, the application of current diagnostic criteria demonstrates that LVNC may occur in a relevant proportion of healthy individuals.

Epidemiology data reflect the context, methods, and clinical characteristics of the series in which LVNC has been observed. The precise proportion of LVNC remains elusive. Prevalence data demonstrate impressive discrepancies, with LVNC being paradoxically higher in imaging series obtained in normal individuals and in screening studies of volunteers^14,23,24 than in selected clinical series of children and adults.

Data on annual incidence of LVNC in children report values less than 0.1 per 100,000.²⁷ Isolated LVNC accounted for 9.2% of all cases in a population-based retrospective cohort study of primary cardiomyopathies in Australian children²⁸ (with LVNC identified as the third most frequent cardiomyopathy after DCM and HCM). This prevalence was close to that recorded in the Texas Children’s Hospital echocardiography database (9.5%).²⁹ In recent data from the Pediatric Cardiomyopathy Registry (1990-2008), 155 (4.8%) of 3219 children had LVNC. This was associated with DCM, HCM, RCM, or indeterminate cardiomyopathies in 120 children and isolated in 35 children. In the latter group, heart failure was not present in any individuals at time of diagnosis. The majority of children with isolated LVNC were referred for reasons such as heart murmurs, chest pain, or family history of cardiomyopathy. Few isolated patients with LVNC developed an associated cardiomyopathy phenotype during the 3.3-year follow-up.³⁰ In adult clinical series, the echocardiographic prevalence ranges from 0.014% to 0.26%.^{31,32,33,34,35}

As for sex, LVNC is reported to be more common in men (56%-82%) than women.^31,36,37,38 Ethnic or racial differences have been suggested in studies, with higher prevalence in blacks than whites.^25,39,40 In three groups of volunteers including patients diagnosed with LVNC according to criteria by Jenni et al,² healthy whites, and healthy blacks, the fractal dimension (FD) of the endocardial border was measured as a quantitative parameter distinguishing normal from abnormal trabecular patterns. Among healthy volunteers, blacks had a higher FD than whites in the apical third of the LV. Maximal apical FD was higher in individuals with LVNC compared to healthy volunteers.¹⁹ In 38 healthy elite male football (or soccer in the United States) players (mean age, 23.0; range, 19-34 years; European, n = 28; African, n = 10) who underwent CMR and electrocardiography (ECG), hypertrabeculation was assessed using the NC/C ratio on long-axis and short-axis segments; a greater degree of LV hypertrabeculation was seen in healthy African athletes, combined with biventricular ejection fraction reduction at rest.⁴⁰ Overall, ethnical differences should be taken into consideration when evaluating individuals of different races, including athletes.

The most cited pathogenetic hypothesis is embryogenic arrest of the normal process of trabecular maturation during early intrauterine life⁷ when the heart undergoes cardiac chamber maturation. Chamber maturation occurs through the formation of myocardial trabeculae, conduction system, and growth of compact myocardium. Cardiac trabeculation begins after the cardiac looping stage with the emergence of a network of myocardial cells covered by endothelial cells and projection in the left ventricular cavity. Projections propagate radially and vertically. The majority of myocytes are more differentiated in the luminal than mural side.⁴¹ Trabeculae then undergo compaction. The epicardial layers enter the myocardial wall and generate the coronary network, which is strictly accompanied by the formation of the compact layer.

Several molecular pathways are active in cardiac chamber maturation. These include the (1) Notch signaling pathway that is involved in the maturation of endocardium and cardiac chambers, with downregulation in the compacted myocardial layer⁴²; (2) bone morphogenic protein-10 signaling that modulates cardiomyocyte differentiation through activation of transcription factors⁴³; (3) fibroblast growth factor family and related receptors that contribute to the proliferation of the compact myocardium⁴⁴; (4) transmembrane paracrine ligand neuregulin, ERBB family receptors and ephrin signaling that regulate normal endothelial cell function and modulate directional migration of cardiomyocytes⁴⁵ (ephrin-B2 [EFNB2] and one of its receptors, EPHB4, are expressed in the endothelial cells lining trabeculae)⁴⁶; (5) semaphorin signaling pathway that modulates gene transcription and cardiac patterning⁴⁷; and (6) endothelin-1–endothelin-converting enzyme-1 and the G-protein–coupled endothelin receptor type A that modulate cardiomyocytes to differentiate into Purkinje cells.⁴⁸ Although all genes involved in pathways active in chamber maturation may potentially influence LV trabecular anatomy, none of the genes active in the above pathways to date has been identified as an LVNC-causing gene. The only exception is the MIB1 gene encoding an ubiquitin ligase that regulates endocytosis of Notch ligands. Endocytosis of Notch ligands in the signal-sending cells is needed for Notch activation.⁴⁹ To date, mutations in this gene have been reported in individuals with LVNC in two Spanish families.⁵⁰ Finally, extracellular matrix (ECM) interacts with cell compartments. ECM contains collagen, versican, and nephronectin^51,52; it separates endocardial, myocardial, and epicardial layers. ECM–cell interactions are mediated by integrins that modulate cell growth, migration, survival, and differentiation. During cardiac morphogenesis, matrix metalloproteases facilitate cell migration. ECM composition is regulated in part by the matrix metalloprotease ADAMTS1, which is necessary for trabeculation.⁵³

According to the embryogenetic hypothesis, the occurrence and extent of LVNC would be conditioned by the stage at which the arrest of the normal embryonic myocardial maturation takes place, considering that during the 5th and 8th week the myocardium becomes compacted from the basal segments to the apex and from epicardium to endocardium.⁵⁴ Causes of interruption of myocardial compaction are unknown.

Aside from the congenital embryonic hypothesis, serial echocardiographic evaluations demonstrate that there are forms of LVNC that are acquired and reversible²⁷ in training athletes,⁵⁵ pregnancy,⁵⁶ hematologic disorders,⁵⁷ myopathies,⁵⁸ chronic renal failure,⁵⁹ and bicuspid aortic valve.⁶⁰ In addition, patients with cardiomyopathies may develop LVNC during the course of the disease^61,62 (Fig. 60–3). Therefore, a unique pathogenetic hypothesis is unlikely to explain the possible acquired origin of the trait, the heterogeneity of disorders (cardiac and noncardiac) in which LVNC is observed, and its possible regression. At present, it appears prudent to describe the finding, whenever present, without assigning the definition of cardiomyopathy.⁸

LVNC can be regarded as an isolated entity or as one of the traits that may recur in other cardiac and noncardiac diseases. As a marker, it may suggest specific diagnoses (eg, tafazzinopathies [caused by mutations in the TAZ (Tafazzin, or G4.5) gene] in male infants with a dilated phenotype, or dystrobrevinopathy in adults).^63,64 As a structural trait with potential functional effects, it may cause or contribute to LV dysfunction in coexisting morphofunctional disorders such as cardiomyopathies or congenital heart diseases (CHDs). When the dysmorphology of the LV wall is prominent in the LV with an otherwise normal size and function, long-term follow-up may provide information regarding its potential role as either a predisposing factor or marker of risk for future progression through cardiomyopathy.

Barth syndrome is mentioned as a separate entity because it represents the paradigmatic example of LVNC cardiomyopathy. It should be suspected in all male infants with heart failure, DCM, and LVNC, especially when associated with other markers of disease. Barth syndrome is a rare X-linked recessive disorder characterized by cardiomyopathy, neutropenia, skeletal myopathy, prepubertal growth delay, and distinctive facial characteristics. The disease is caused by mutations in the G4.5 gene (TAZ).^64,65,66 The protein localizes to the mitochondrial membrane and plays a role in mitochondrial structure and function. LVNC and low mitochondrial membrane potential are reported as specific for Barth syndrome.⁶⁶ LVNC is commonly associated with LV dilation and dysfunction at onset.⁶⁴ Less commonly, Barth cardiomyopathy may present with a hypertrophic or hypertrophic-dilated phenotype. Heart involvement occurs in almost all children before the age of 5 years. Thereafter, the cardiomyopathy may demonstrate an intermittent course during which the heart can undergo remodeling. Improvement can be observed after infancy, with possible stabilization after the toddler years.⁶³ Heart failure is a major cause of morbidity and mortality. Overall, however, cardiac function varies and tends to decline over time. Arrhythmias, both supraventricular and ventricular, are more commonly reported in adolescents and young adults than in infants.^63,64

LVNC can occur in hearts fulfilling the diagnostic criteria for DCM, HCM, RCM, or ARVC. In these cases, cardiomyopathies and LVNC are both present. Family studies may contribute to unraveling whether the two traits (cardiomyopathy and LVNC) can exist as independent entities or are part of the same phenotype in all or some affected family members.

In the current Online Mendelian Inheritance in Man (OMIM) catalogue, 10 genes, one locus with unidentified gene, and one syndrome are formally associated with a Mendelian Inheritance in Man (MIM) phenotype number (Table 60–2). The candidacy of the DTNA gene for isolated LVNC is provisionally supported by absence of mutations in cardiomyopathies without LVNC. Alpha-dystrobrevinopathies are caused by mutations in DTNA, which is part of the cytoplasmic complex of the dystrophin-associated proteins.⁶⁷ Rare dilated and dysfunctional hearts and LVNC have been associated with mutations in MIB1 that encode Dapk-interacting protein 1 acting in the Notch pathway.⁵⁰ LVNC can be observed in cardiomyopathies with overlapping phenotypes, typically dilated HCM such as in mitochondrial DNA-related cardiomyopathies⁶⁸ (Table 60–3). The lists of cardiomyopathy genes associated with LVNC demonstrate wide heterogeneity (Tables 60–2 and 60–4) and remain incomplete (Fig. 60–4). All genes associated with LVNC also cause cardiomyopathies. They include genes encoding sarcomere proteins, nuclear envelope components, Z-band proteins, and ion channels.

Sarcomere Genes

Mutations in ACTC1 (cardiac actin alpha) were first reported in LVNC by Klaassen et al⁶⁹ in 2008, with identification of the p.(Glu101Lys) mutation described previously in apical HCM.⁷⁰ LVNC associated with mutations in ACTC1 gene is labeled in the OMIM catalogue as LVNC4. Mutations in the same gene also cause DCM, RCM, and HCM, as well as CHD.⁷¹ Several mutations in the MYH7 gene were reported in both children and adults with LVNC.^72,73,74 Nine diseases are allelic at the same locus (LVNC5, HCM, DCM, RCM, familial autosomal dominant Ebstein anomaly with LVNC, autosomal dominant and recessive myosin storage myopathy, Liang distal myopathy, and scapuloperoneal syndrome, myopathic type). Similar, but less complex, is the list of cardiomyopathies allelic at the MYBPC3 locus (HCM, DCM, and LVNC).^75,76 A relevant clinical observation is the potentially lethal phenotype of cardiomyopathy with LVNC in infants who carry compound heterozygous, double heterozygous, or homozygous truncating mutations.⁷⁷ Mutations in TPM1 (LVNC6)⁷⁸ and TNNT2 (LVNC9)⁷⁹ are less commonly associated with LVNC. The mechanisms by which mutations in sarcomere genes cause LVNC remain to be elucidated. Incomplete genotype is possible. Given the overlapping phenotypes associated with mutations of sarcomeric genes and the number of diseases allelic at the same loci, members of a family with the mutation may show different cardiac profiles, with or without the presence of LVNC (Fig. 60–5).

Mutations in Genes Encoding Nuclear Envelope Proteins

Mutations in genes encoding nuclear envelope proteins (ie, LMNA, which typically causes DCM and conduction disease) seem to be less common than those on sarcomere genes. To date, three LMNA mutations [p.(Arg644Cys), p.(Arg190W), and p.(Val455Glu)] have been described in patients with DCM and LVNC.^80,81,82 Given the high arrhythmogenic risk associated with LMNA mutations, these patients and families deserve the same monitoring and management strategies currently adopted for cardiolaminopathies without LVNC. Recent guidelines on the prevention of sudden death recommend that an implantable cardioverter-defibrillator (ICD) should be considered in patients with DCM, a confirmed disease-causing LMNA mutation, and clinical risk factors (Class IIa, Level B).⁸³ Risk factors include nonsustained ventricular tachycardia during ambulatory ECG monitoring, LV ejection fraction < 45% at first evaluation, male sex, and nonmissense mutations (insertion, deletion, truncation, or mutations affecting splicing). These factors correspond to those previously identified in a large European cohort of patients with dilated cardiolaminopathy.⁸⁴ LVNC can represent an early marker of cardiolaminopathy and may or may not segregate with DCM in the families (Fig. 60–6).

Genes Coding Z-Line Components

Genes coding Z-line components in both skeletal and cardiac muscle include the CYPHER-ZASP (LDB3) gene, which is a major candidate for LVNC.⁸⁵ In fact, carriers of mutations in LDB3 may demonstrate DCM or LVNC (MIM# LVNC4) and, less commonly, HCM and ARVC.^86,87 Mutations in the same gene also cause myofibrillar myopathy; experimental ablation of Cypher, the PDZ-LIM domain Z-line protein, causes a severe form of congenital myopathy and DCM with premature death.⁸⁸ The p.(Asp117Asn) variant in the LIM domain-binding protein 3–encoding Z-band alternatively spliced PDZ motif gene (ZASP) has been described in a patient with LVNC and conduction disturbances.⁸⁹ Patients with DCM and LVNC/hypertrabeculation carriers of p.(Asp117Asn) commonly carry a second mutation in a cardiomyopathy gene.

Cardiomyopathies Often Coexist With Muscle Dystrophies and Myopathies

Hypertrabeculation or noncompaction of the LV has been described in several neuromuscular disorders, including Duchenne muscular dystrophy (DMD) and mitochondrial myopathies.^12,62,63,68 In a large CMR study including 96 patients with DMD, 27 patients (28%) fulfilled criteria for the diagnosis of LVNC.⁶² LVNC was defined as a diastolic NC/C ratio > 2.3 and was measured according to the AHA 16-segment model. In patients with ejection fraction < 55%, the median NC/C ratio was 2.46 versus 3.69 for isolated LVNC patients and 1.54 for normal controls. The relevant contribution of this study goes beyond the prevalence of LVNC in DMD. Serial CMR in 78 boys with DMD demonstrated a mean rate of change in NC/C ratio per year of +0.36 that resulted from the progressive decrease of the compacted layer and relative increase of the NC layer.⁶² This information adds a “dynamic view” of NC anatomy in cardiomyopathies and potential prognostic information. LVNC was in fact associated with worsening LV systolic function. The progressive thinning of the compacted layer may result in a relative increased ratio of the two layers. This helps to explain the data reported by Kimura et al,⁹⁰ who found that LVNC is an independent negative prognostic factor in carriers of DMD defects.

Ion Channel Genes

Ion channel genes such as the sodium channel, type V, subunit alpha (SCN5A), genes encoding calcium-release channels such as the ryanodine receptor 2 (RYR2), and genes encoding calcium ion reservoir such as calsequestrin 2 (CASQ2, which is part of a protein complex that contains RYR2), typically cause diseases affecting the QT interval and catecholaminergic polymorphic ventricular tachycardia (CPVT; types 1 and 2). However, mutations in SCN5A have been reported in Japanese patients with LVNC.⁹¹ Mutations in RYR2 and CASQ2 cause LVNC.^92,93 More than 80% of carriers of exon 3 deletion in the RYR2 gene demonstrated LVNC and malignant arrhythmogenic phenotypes with syncope and CPVT.^92,93 A relevant contribution from RYR2-related LVNC is the demonstration that NC can develop during the evolution of the genetic disease. Specifically, a young patient with RYR2 deletion of exon 3 showed normal LV function and structure at the age of 14 years when he presented with two episodes of exertion syncope and demonstrated LVNC with normal function 2 years later when he presented with a third episode of syncope.⁹²

The nosology description of clinical, imaging, and genetic data does not meet LVNC-specific rules and criteria. Diagnoses such as “dilated LVNC” versus “DCM with LVNC” or “hypertrophic LVNC” versus “HCM with LVNC” are equally used to describe the phenotypes. When LV dilation and dysfunction are present, the diagnosis of LVNC cardiomyopathy is supported more by the DCM phenotype than by the trabecular morphology. When LVNC is observed in hearts with HCM, the diagnosis of LVNC cardiomyopathy is supported more by the HCM criteria than those of LVNC. Nonetheless, both descriptors (either leading or subordinating the LVNC to the cardiomyopathy diagnosis) give an immediate perception of the phenotype. In comparison, the diagnosis of “LVNC cardiomyopathy” may limit clinical information and, in parallel, automatically assigns a driving role to LVNC in the diagnosis.

LVNC can occur in hearts with CHD such as uni- or bicuspid aortic valves, aortic coarctation, diffuse aortic hypoplasia and subaortic stenosis, atrial/ventricular septal defects, Ebstein anomaly,^94,95,96 tetralogy of Fallot, double outlet right ventricle, and hypoplastic left heart syndrome.⁹⁷ These disorders can be sporadic or familial, with CHD recurring in more than one member of the family^94,95,96,97 (see Chap. 56).

Syndromes with LVNC (or syndromic LVNC) are either sporadic or familial. The NC morphology is one of the traits associated with both monogenic defects and chromosomal anomalies. Monogenic syndromes mostly include rare diseases. Some of them, such as Anderson-Fabry disease and Danon disease, are well known by cardiologists^98,99,100 because the HCM phenotype is often the first recognized manifestation. Other monogenic syndromes are less commonly observed in the cardiology setting (Table 60–5). Chromosomal anomalies are usually observed in complex syndromes that display several multiorgan defects. Chromosomal abnormalities include deletions, translocations, and trisomy or tetrasomy [1p36 deletion syndrome; interstitial 1q43-q43del; del(1)(q) syndrome; del5q35; 7p14.3p14.1 deletion; 8p23.1 del syndrome; 18p subtelomeric deletion; 22q11.2 deletion syndrome; 22q11.2 distal deletion syndrome; trisomy 13 and 18; tetrasomy 5q35.2–5q35; robertsonian translocation 13;14; mosaics such as 45,X/46XX and 45,X/46,X,i(Y)(p11)]. Most chromosomal abnormalities represent isolated cases.^94,95,96 Reasons for scientific and clinical interest include the possible identification of new disease or modifier genes when abnormal chromosomal regions involve novel candidate genes in patients with the typical syndrome and LVNC. Isolated LVNC has been reported in the Pierre-Robin sequence or syndrome (OMIM #261800), which is characterized by micrognathia, posterior displacement/retraction of the tongue (glossoptosis), upper airway obstruction, and congenital heart defects in 20% of cases.¹⁰¹

Right ventricular noncompaction (RVNC) can occur as an isolated entity,^4,102,103 in association with LVNC,⁵ with predominant right ventricular involvement,¹⁰⁴ or in patients with CHD.¹⁰⁵ In rare cases, it may cause right ventricular outflow tract obstruction as a result of hypertrophied spongy muscle at the infundibular region.¹⁰⁶ Given the complex trabecular anatomy of the right ventricle, the diagnosis is difficult but feasible with routine imaging tools and, when necessary, right ventriculography.¹⁰⁶ RVNC may be an occasional finding in family screening studies (Fig. 60–7).

The acquired and reversible forms of LVNC question the unique and a priori interpretation of the NC morphology as a genetic disease and cardiomyopathy.^{55,56,57,58,59,107,108} Acquired isolated LVNC has been reported in athletes^47,99,100 and pregnant women,⁵⁶ as well as in hematologic disorders,^57,109 chronic renal failure,⁵⁹ myopathies,⁵⁸ and bicuspid aortic valve.⁶⁰ These observations expand the spectrum of pathogenetic hypotheses from arrested embryogenesis maturation of LV trabeculae to acquired pathogenetic mechanisms, including hemodynamics, phenotype-driven trabecular gene expression, or epigenetic factors, as in CHD.¹¹⁰

Athletes

The identification of LVNC in preparticipation screening studies had demonstrated that intense physical training may induce increased trabeculation that may fulfill current diagnostic criteria for the diagnosis of LVNC. In a large series including more than 1000 asymptomatic athletes, 18% had increased LV trabeculation and 76 (8%) fulfilled echocardiographic criteria for LVNC.⁵⁵ The issue of athletes demonstrating LVNC is emerging from different sources^111,112 and in real life (Fig. 60–8). Distinguishing between pathologic LVNC and physiologic hypertrabeculation is a diagnostic challenge, and detection is becoming increasingly common with enhanced echocardiography and magnetic resonance imaging modalities.¹¹¹ The proportion of athletes who develop LVNC under intensive exercise is relevant (about 10%), but the proportion of those who do not develop LVNC under the same exercise levels is 90%. The impact of LVNC on otherwise normal hearts requires long-term follow-up studies to establish with certainty whether LVNC can be an early marker of myocardial disease or the phenotype of maladaptation of different individuals to strenuous physical effort. Therefore, “healthy” athletes diagnosed with LVNC should undergo deep phenotype examination, advanced imaging, and clinical monitoring as suggested by experts.¹⁰⁷

Pregnancy

A form of reversible LVNC has been described in pregnancy. In a prospective longitudinal echocardiographic study of 102 primigravida pregnant normotensive women (66 white women and 36 black women) without family history of cardiomyopathy or premature sudden cardiac death, 25% developed increased LV trabeculations during pregnancy. The finding was more common in black women than in white women. Furthermore, 10 women (9.8%) fulfilled the Jenni et al² criteria, 19 (18.6%) fulfilled the Chin et al⁹criteria, and 8 (7.8%) fulfilled both criteria for LVNC. There was no significant association between increased LV trabeculations and age, body mass index, systolic blood pressure, LV cavity dimension, stroke volume, or LV mass. Ethnicity was the only independent predictor for the presence of increased (three or more) trabeculations during pregnancy, with black women being almost three times more likely to develop increased LV trabeculations than white women during pregnancy after adjustment for the aforementioned factors. After delivery, 18 women (69.2%) showed complete resolution of LV trabeculations over a mean duration of 8.1 ± 4.2 months, whereas 7 women (27%) continued to display LV trabeculations, without predilection for ethnicity.⁵⁶ Further series are necessary to confirm this transient trabecular remodeling and the low risk.¹¹³ However, the study⁵⁶ adds evidence to the possibility that LVNC can not only be acquired, but also transient and, therefore, does not necessarily represent a primary myocardial disorder.¹¹⁴

Hematologic Diseases

LVNC has been described in patients affected by different hematologic disorders such as hereditary spherocytosis,¹¹⁵ essential thrombocytopenia,¹¹⁶ and β-thalassemia^57,117 with and without myocardial overload. In patients with β-thalassemia, isolated LVNC was identified in 13.3% of patients.⁵⁷ The mechanisms by which chronic anemia, hemolysis, or ineffective erythropoiesis may influence the remodeling of the trabecular compartments are not known. In patients with myocardial iron overload and siderosis, a preferential distribution of intramyocyte iron in the compacted or NC layers has not been observed.¹¹⁸ Myocardial T2*-weighted CMR values should be able to provide more information about intramyocyte iron storage. However, cardiac abnormalities could be triggered by toxic iron species such as non–transferrin-bound iron.¹¹⁸ Whether LVNC represents a physiologic adaptation to the chronic nonprimary cardiac disorders or a disease-related pathologic effect is not clear.¹⁰⁹

Chronic Renal Failure

LVNC has been reported in two patients with chronic renal failure. In both cases, echocardiography demonstrated a dilated LV with thickened walls and a thin, compacted myocardium on the epicardial side and a thicker noncompacted endocardial layer. Ratio between the noncompacted myocardium and the compaction myocardial layer fulfilled diagnostic criteria in both cases. Clinically relevant is the fact that oral anticoagulation therapy was initiated in both patients after the diagnosis of LVNC. Family screening with echocardiography in first-degree relatives of one of the patients did not show additional affected members. Regular echocardiographic monitoring of patients with chronic renal failure is suggested to diagnose cardiovascular diseases including this rare association.⁵⁹

Bicuspid Aortic Valve

A high prevalence of LVNC is reported in patients fulfilling the echocardiographic criteria for bicuspid aortic valve (BAV). Specifically, in one study, 12 (11.0%) of 109 patients with BAV fulfilled the criteria for LVNC, with nine of the 12 patients being men. Although the pathophysiologic basis of LVNC in patients with BAV is unclear, special attention should be given to the evaluation of LV trabecular anatomy.⁶⁰

Myopathies

LV hypertrabeculation may occur in patients affected by different neuromuscular diseases such as dystrophinopathies, metabolic myopathies, myotonic dystrophy, Leber hereditary optic neuropathy, and Barth syndrome. Several pathogenetic hypotheses have been advocated to explain the occurrence of LV hypertrabeculation, including “an inborn error to hypertrophy, which either starts during embryogenesis, early childhood, or in adulthood."¹² Alternative hypotheses include persisting sinusoids penetrating into the LV cavity or malfunctions of gap junctions.¹²

Considerations on Acquired Left Ventricular Noncompaction

All the above acquired conditions of LVNC demonstrate that a unique pathogenetic hypothesis of embryogenic defect is unlikely to explain acquired, late-onset, transient LVNC. Most studies on acquired LVNC are recent and constitute a stimulus to further explore this trait in cardiac and noncardiac diseases.

In patients with LVNC associated with cardiomyopathies, CHDs, or complex syndromes, clinical workup is guided by the primary disease rather than by the LVNC itself. Vice versa, in individuals demonstrating isolated LVNC with normal cardiac function and dimensions, the diagnostic workup should be tailored based on individual characteristics and findings emerging from cardiologic investigations, family history (and eventually screening), advanced imaging, and monitoring (Fig. 60–9). Over the past 20 years, LVNC has been repeatedly described as LVNC cardiomyopathy. Efforts by several groups of researchers to establish precise diagnostic criteria (Table 60–1) for diagnosing LVNC reflect the lack of gold standards for the diagnosis. The potentially dynamic evolution of LVNC, either progression or regression, and the possibility of controlling abnormal trabecular remodeling with current treatments are matters of investigation. A recent study reported LV mass reduction among patients with LVNC during β-blocker therapy.¹¹⁹

In patients with heart disease and LVNC, physical examination can contribute to the diagnosis. Extracardiac traits recurring in patients with LVNC (and vice versa) can eventually help to generate a diagnostic hypothesis, particularly in genetic cardiomyopathies, syndromes, and congenital heart defects.¹²⁰ Deep cardiomiopathy phenotyping can help to generate a clinical hypothesis, especially in patients with LVNC.¹²⁰

Genetic evaluation, both counseling and testing, is recommended for patients with cardiomyopathy and LVNC, patients diagnosed with one of the syndromes in which LVNC may recur, and individuals in whom LVNC is incidentally identified during medical screening.^121,122 A key question is whether the trait is familial or sporadic, and the answer may come from clinical family screening. In fact, isolated LVNC in individuals with normal LV size and function and nonthickened LV walls is asymptomatic and only detectable using imaging.

The medical genetic examination explores anthropometric profiles, facies, skin, eyes, hair, and skeletal and nervous systems.¹²⁰ Deep phenotyping may identify extracardiac traits that recur in syndromes with LVNC and that can be present in some family members. Data from probands and relatives contribute to generating family pedigrees, which give a “graphic” view of the mode of inheritance of the disease. In the post–genetic test phase, the pedigree shows the segregation of the mutation(s) with the phenotype, thus highlighting the correct interpretation of the genetic results.

Genetic testing should be performed in probands with LVNC and cardiomyopathy, in patients with familial CHD with LVNC, and in patients with syndromes including LVNC.¹²¹ The indication to perform genetic testing in individuals with normal LV function and an incidental diagnosis of LVNC is not regulated by guidelines. Genetic counseling and extensive clinical information are essential.^120,121 Probands should be aware that activation of genetic testing, in particular multigene panels, can demonstrate the presence of genetic variants of unknown significance whose role in the determination of the trait may remain uncertain, and therefore, results can be inconclusive. Athletes are especially exposed to the risk of labeling a potentially reversible trait with the diagnosis of a possible genetic disease, with obvious implications regarding suitability for sport activity and lifestyles.

In families with LVNC and cardiomyopathy, affected members may demonstrate different or combined cardiac phenotypes, with isolated LVNC in some relatives and cardiomyopathy with or without LVNC in others. Therefore, the segregation of LVNC may not coincide with the segregation of a coexisting cardiomyopathy. This explains why segregation studies are major contributors in unraveling the role of mutations, especially in families with complex genetics, when more than one pathologic mutation is identified.¹²³ Information gathered from large families can be usefully transferred to small families or single patients, especially when evaluating the role of debated genetic variants such as LDB3 p.(Asp117Asn), which was originally described as causing DCM and LVNC⁸⁵ and is now reported as a possible single nucleotide polymorphism.¹²⁴

ECG data do not provide LVNC-specific diagnostic information.¹²⁵ From available observations, it appears that although a normal ECG finding is rare in LVNC and observed in a minority of patients (from 6% to 13%), there are no changes specific to LVNC.^{125,126,127,128} However, certain ECG changes, such as negative T waves > 1 mm in depth in two or more leads (particularly V₄-V₆, II and aVF, or I and aVL), ST-segment depression ≥ 0.5 mm in depth in any lead, or pathologic Q waves (> 3 mm in depth or > 40 milliseconds in duration) in two or more leads (except III and aVR), are more compatible with a cardiomyopathy. A significant number of black athletes (almost 13%) show negative T waves in the anterior precordial leads that are not associated with structural disease.¹²⁹

Echocardiography

Echocardiography is the first-choice imaging tool for suspecting or diagnosing LVNC. It is noninvasive and easy to both perform and repeat. Serial echocardiographic investigations are sustainable and can be offered in both screening studies and the diagnostic setting. The different diagnostic criteria proposed to date are summarized in Table 60–1. The role of the thickness of the compacted myocardial layer in the diagnosis should be emphasized.²⁴

However, echocardiography has limitations. Visualization of the apex, which is commonly affected in LVNC, can be difficult. The profile of a dual-layered myocardium or trabeculations may not be sharp. Indistinct trabeculae may also result in diagnostic difficulty. Interpretation of echocardiographic findings may vary among experts. In a recent study, echocardiographic records from 100 patients with and without LV hypertrabeculation matched for age and systolic function were reviewed by experts according to the following predefined criteria: (1) greater than three prominent trabeculae at end diastole; (2) a noncompacted part of a two-layered myocardial structure formed by these trabeculations; (3) a ratio of > 2:1 of noncompacted to compacted layer at end systole; and (4) perfusion of the intertrabecular spaces from the ventricular cavity. The observers disagreed about presence or absence of LV hypertrabeculation in 35 cases, and even after mutual review, 11% cases remained questionable.¹³⁰ A possible limitation occurs when the short axis is not perpendicular to the LV long axis, which can give the morphologic appearance of prominent trabeculations mimicking LVNC.¹³ The above limitations are those currently listed in most review articles and scientific communications. However, modern echocardiographic instruments are providing high imaging quality. In addition, contrast-enhanced echocardiography can better profile endocardial borders and show trabeculations alternating with the intertrabecular recesses.¹³¹ Finally, three-dimensional echocardiography can further contribute to evaluate the extent of noncompacted myocardium. In 26 Olympic rowing athletes and 49 healthy volunteers, the trabeculated LV volume and its value normalized by LV end-diastolic volume were significantly higher in patients with LVNC as compared to controls and athletes. Given the high spatial resolution and accuracy in volumetric quantification, three-dimensional echocardiography can provide an accurate measurement of the extent of the noncompacted myocardium and identification of patients with LVNC.¹³²

Cardiac Magnetic Resonance

CMR is performed in patients with echocardiographic evidence or suspicion of LVNC. The use of balanced steady-state free precession (SSFP) cine imaging instead of simple gradient-echo imaging improves image quality and increases sensitivity for myocardial trabeculae, which are better seen at end diastole^{14,15,16,17,18,19,20} (Table 60–1). In clinical practice, an NC/C ratio > 2.3 is considered diagnostic for LVNC (Petersen criteria). Measures are taken in short axis at the midcavity and basal segments. A four-chamber view may be preferred in hearts with prominent apical LVNC. As a result of the complex right ventricular trabecular anatomy, right ventricular involvement in LVNC or isolated RVNC can be better evaluated with CMR than with echocardiography.^133,134,135 Criteria for the diagnosis of RVNC are not established. From observations in autopsy series, transmural thickness of the noncompacted right ventricle > 75% should correspond to a diagnosis of RVNC.¹³⁶ Dilatation of the right ventricle may be a supportive feature for the diagnosis.¹³⁷ The three-dimensional view shows the entire volume of the heart independently of the thoracic conformation of patients.¹³⁸ CMR further provides information on possible associated CHD, endocardial thrombi, or incidental extracardiac pathologies. In general, CMR performance is superior to echocardiography for characterization of the ventricular trabecular anatomy.¹⁷ Although myocardial fibrosis is not a criterion for the diagnosis of LVNC, late gadolinium enhancement is an adjunct value, useful in the general evaluation of the disease context in which LVNC is observed. CMR may have limitations in children because of lack of patient cooperation and small cardiac size.¹⁷ In any case, CMR is superior to two-dimensional echocardiography in assessing the extent of noncompaction and provides supplemental morphologic information beyond that obtained with conventional echocardiography.¹³⁹ However, CMR also has limitations. It is contraindicated in patients with old intracavitary device implantation and in those suffering claustrophobia. CMR is more expensive than echocardiography and may be more time consuming. In addition, serial CMR studies can be performed but at reasonably longer intervals than serial echocardiography.

Multidetector Computed Tomography

MDCT offers advantages to both patients and operators. Duration of the test is short, making it especially advantageous for those who suffer from claustrophobia. Newer scanners and dose modulation techniques have decreased the effective radiation exposure. In addition, CT can be used for patients with defibrillators or resynchronizing devices. A major advantage of MDCT is the information obtained regarding coronary arteries that excludes coronary artery disease as a cause of LVNC and detects coronary anomalies.^{23,140,141,142} With the increase in the number of thoracic and coronary MDCT angiographic studies, LVNC may be incidentally detected during examinations performed for other reasons. Major limitations include the administration of ionizing radiation and lower capability of characterizing myocardial tissue and identifying fibrosis compared with CMR. Cost-related limitations are similar to those of CMR, and serial studies are not routinely feasible.

There are no specific biomarkers for LVNC. Potentially useful markers are either those that provide information on myocardial injury or heart failure, namely troponins and natriuretic peptides. In genetic cardiomyopathies with LVNC, relevant biomarkers may be those that characterize the genetic disease and are equally increased in cardiomyopathy patients independent of LVNC (eg, in dystrophin cardiomyopathy).^62,90

Macroscopic pathology is highly informative. Both autopsy and hearts excised at transplantation may demonstrate typical features of LVNC.^8,136,143 However, microscopic features are nonspecific. Endomyocardial biopsy may show interstitial fibrosis, fibrous endocardial thickening, and nonspecific myocyte changes similar to those seen in cardiomyopathies. In rare cases of cardiac amyloidosis with imaging features of apical hypertrabeculations suggestive of LVNC, endomyocardial biopsy can play a diagnostic role for amyloid heart disease.¹⁴⁴

In general, the management of patients with LVNC consists of evidence-based treatments for systolic heart failure and arrhythmias as well as oral anticoagulation to prevent mural thrombosis. Indications for ICD placement are similar to those in other patients with DCM.¹⁴⁵

LVNC specific treatment does not exist. At present, the possible distinct clinical problem is the thrombogenic risk, which is present only in dysfunctional hearts. Therefore, decisions about anticoagulation can eventually be anticipated in patients with LV dilation and impaired systolic function.^146,147 Stroke and embolism are rare in patients with LV hypertrabeculation or LVNC, especially when rhythm and systolic function are normal. When present, atherosclerosis-related causes should be assessed.¹⁴⁶ The CHADS₂ (congestive heart failure, hypertension, age ≥ 75 years, diabetes mellitus, stroke) score may be useful for clinical decision making regarding oral anticoagulation for prevention of stroke and embolism in patients with increased LV trabeculations.¹⁴⁷

Patients diagnosed with Barth syndrome with heart failure should receive standard medications as per guidelines. Aspirin can eventually be added to decrease the risk of stroke in patients with severe LV dysfunction. The monitoring of arrhythmias and related prevention strategies should be maintained over the course of the patient’s life. Disease-specific treatments can include the administration of granulocyte colony-stimulating factor either routinely or in high-risk clinical situations (eg, infections, surgery) along with prophylactic antibiotics. Diets should include administration of uncooked cornstarch to prevent muscle protein loss overnight. Succinylcholine, a nondepolarizing neuromuscular blocker that could have a prolonged effect, should be avoided.⁶³ As a general rule, patients with Barth syndrome should be cared for by specialized pediatricians in the context of a multidisciplinary setting that guarantees continuity of care from the pediatric setting to adulthood.

In other conditions, such as HCM with LVNC or RCM with LVNC, anticoagulation treatment is driven more by complications of the native disease, such as left atrial dilation with and without arrhythmias.

Pregnant women can be incidentally diagnosed with LVNC or develop peripartum cardiomyopathy (PPCM; dilated, congestive phenotype) with features of LVNC.¹⁴⁸ The management of LVNC associated with PPCM and of LVNC in pregnant women with normal LV function and dimensions may differ. The former may require management of the PPCM with possible adjunct of anticoagulation (see Chap. 58), whereas the latter may potentially only require clinical monitoring.

The administration of medications such as β-blockers seems to decrease LV mass among patients with LVNC. It is not clear whether the effect is a result of the decrease of the trabeculae or the compacted LV myocardial mass or both. Effects of β-blocker treatment in LVNC require validation in prospective controlled studies.¹¹⁹

Prognosis in LVNC depends on the clinical presentation. Asymptomatic patients or individuals with LVNC and normal LV function have a good prognosis. This is demonstrated by the large group of asymptomatic (26%) first- and second-degree family members of patients with LVNC.¹⁴⁹ Alternatively, patients presenting with heart failure (New York Heart Association class III or IV), sustained ventricular arrhythmias, or left atrial dilation have an unfavorable prognosis.^149,150 Adverse outcomes of isolated LVNC occur in patients with advanced heart failure, dilated left heart with systolic dysfunction, reduced systolic blood pressure, pulmonary hypertension, and right bundle branch block.¹⁴⁹ Survival tracks closely with the presence of symptoms at presentation (69% when present v 100% when absent).¹³¹ In subgroups of patients (eg, DMD, Becker muscular dystrophy), the presence of LVNC is significantly associated with rapid deterioration in LV function and higher mortality.^62,90 Therefore, prognosis depends on the severity of the underlying cardiac disease rather than the trabecular anatomy of the LV.

LVNC is a morphology-based diagnosis that does not have, by itself, corresponding LV dysfunction. Based on current diagnostic criteria, LVNC can be identified in healthy individuals, or it can be acquired and reversible in pregnant women, athletes, and patients with hematologic disorders, myopathies, chronic renal failure, and bicuspid aortic valve. The observation of reversible LVNC in athletes suggests that it may represent a phenotypic variant of athlete’s heart.¹⁵¹

When associated with cardiomyopathies, CHDs, or syndromes, LVNC commonly has a genetic cause, which coincides with the cause of the underlying heart disease. The proportion of echocardiographic diagnoses is increasing, and this implies cascades of further clinical evaluation, including CMR, family studies, monitoring, and lifestyle modifications and/or restrictions.¹⁵²

Genetics often contribute to the overall interpretation of the finding of LVNC even in healthy individuals with normally functioning hearts. The specific role or impact of LVNC remains difficult to separate from that of the underlying heart disease. Although anticoagulation plans can be eventually anticipated in dilated and dysfunctional hearts, specific treatments do not exist. Therefore, isolated LVNC should require a precise definition (trabecular anatomy variant, adaptation, or heart muscle disease) and be a matter of consensus diagnostic criteria by scientific bodies.