**3. Aetiology and mechanisms**

There are several etiologic hypotheses for LVNC. It may occur as an isolated disease (isolated LVNC) or in association with genetic diseases and congenital defects, as observed more commonly in infancy. The condition may also be sporadic and acquired, in physiological or pathologic conditions, and may also be permanent or transient. Thus, LVNC can originate during embryonic development or be acquired later in life.

The theory that supports the embryogenic hypothesis has been based in observational foetal studies showing the coexistence of LVNC with heart block and congenital heart diseases and from experimental studies on LVNC [6]. In humans, the embryonic myocardium is composed of a loose meshwork of interwoven fibres separated by deep recesses, which communicate with the LV cavity, allowing an increase in the myocardial surface area and the exchange diffusion from the cavity. From the 5th*–*8th weeks of embryogenesis, LV trabecular compaction occurs simultaneously with the invasion of the myocardium by the coronary vasculature coming from the epicardium. The LV compaction progresses from the heart base to the apex and from the epicardium to the endocardium [1]. LVNC is thus thought to result from the arrest of trabecular compaction during this phase of embryogenesis. A second embryogenic hypothesis suggests that LVNC results from the inhibition of the regression of embryonic structures that would maintain the looseness of cells or of cell bundles [7].

On the other hand, evidence supports the hypothesis that the pathogenetic mechanisms leading to noncompaction may occur in adult life, ending in acquired forms of LVNC and supporting a non‐embryogenic theory. This is the case of young athletes, pregnant women, patients with sickle cell disease, and renal failure, which may present the phenotype of LVNC. In athletes, the phenotype seems to relate to intensive training, but in a small proportion of 0.9% has been found to develop ultimately LV dysfunction suggestive of a LVNC cardiomyopathy [8]. In pregnancy, an important proportion of women, described as up to 25% were found to develop LVNC phenotype de novo, which was reversible. This pattern was not shown to be associated with deleterious clinical events and has been proposed to result from a response to increased loading conditions [9]. Also, in sickle cell disease, this pattern has been found and hypothesised to result from chronic anaemia and increased preload, resulting in a stimulus for hypertrabeculation [10].

### **4. Genetics**

identified, and the condition is now included among the cardiomyopathies, but currently there is an intense debate whether LVNC is a distinct entity or a trait common to several car-

Left ventricular noncompaction (LVNC) is defined by essential markers: an inner noncompacted layer with prominent left ventricular (LV) trabeculae and deep intertrabecular recesses, and a thin compacted layer. There is a spectrum of morphologic variability, ranging from hearts with different degrees of noncompaction extension and amount, and right ventricular

From hearts obtained from autopsies or transplantation, LVNC diagnosis is based on the presence of a two‐layered ventricular wall, comprising a thinner compact epicardial layer and an inner noncompacted layer, with prominent trabeculations associated with deep, intertrabecular recesses that communicate with the ventricular cavity but not with the coronary

Noncompacted areas are commonly located at the LV apex and mid‐apical wall segments, but typically spares the interventricular septum. When associated with hypertrophic cardiomyopathy phenotype (HCM), the hypertrophied septum coexists with the LVNC phenotype. Other described associations include dilated cardiomyopathy (DCM) and, more rarely, restrictive cardiomyopathy (RCM) or arrhythmogenic right ventricular cardiomyopathy (ARVC). Besides the relationship of LVNC with other cardiomyopathies, which may share the same genetic basis, there has been considerable controversy regarding the differentiation from normal LV trabeculation, which seems to occur in some normal asymptomatic individu-

Histopathology has shown continuity between the endothelium of inter‐trabecular recesses and that of the endocardium, distinguishing LVNC from persistent sinusoids. Other findings have included loosely organised myocytes and endocardial and subendocardial replacement fibrosis suggestive of ischaemic necrosis, which has been demonstrated by imaging tech-

LV dilatation and ischemia are frequently present, and thrombus formation in the recesses

There are several etiologic hypotheses for LVNC. It may occur as an isolated disease (isolated LVNC) or in association with genetic diseases and congenital defects, as observed more commonly in infancy. The condition may also be sporadic and acquired, in physiological or pathologic conditions, and may also be permanent or transient. Thus, LVNC can originate

may occur, which may be associated with possible thromboembolic events.

during embryonic development or be acquired later in life.

diac conditions [3].

involvement.

circulation [2, 3].

niques *in vivo* [5].

**2. Anatomy and pathology**

60 Cardiomyopathies - Types and Treatments

als as found in analysis from the MESA study [4].

**3. Aetiology and mechanisms**

The LVNC trait may be familial, inherited, or non‐familial, sporadic. Non‐familial forms are diagnosed when LVNC is proven absent in relatives. As presented above, sporadic LVNC can be acquired and may be transient, as in highly trained athletes, sickle cell anaemia patients, and pregnancy. Many familial cases identified to date are associated with mutations in the same genes that cause other types of cardiomyopathies but may also occur isolated.

In fact, several studies suggest that noncompaction of the LV myocardium is a genetically heterogeneous disorder [11], with a familial and a sporadic form. Studies of the familial form have shown that LVNC may be transmitted as an autosomal dominant inheritance with incomplete penetrance, as an autosomal recessive, and as X‐linked traits. Sporadic cases of LVNC and *de novo* mutations have also been recognised. To date, several disease *loci* have been identified.

The Barth syndrome was the first recognised genetic LVNC, characterised by dilated cardiomyopathy associated with LVNC. It is an X‐linked disease with mutations in the G4.5 gene, located at Xq28, which encodes the tafazzins (a family of proteins) with acetyltransferase functions in the mitochondria. This mutation was also identified in an X‐linked severe neonatal LVNC, allelic with the Barth syndrome.

Another mutation, located in the α‐dystrobrevin gene, was identified subsequently in patients with LVNC and associated with congenital heart diseases. [12]; α‐dystrobrevin is a cytoskeletal protein component of the dystrophin associated glycoprotein complex, which links the extracellular matrix to the dystrophin cytoskeleton of the muscle fibre. This mutation was associated with a significant phenotypic variability with variable severity.

Mutations in the Z‐line protein Cypher/ZASP have been identified in association with LVNC and dilated cardiomyopathy. This protein appears to play an important role in the maintenance of the normal myocyte architecture of cardiac and skeletal muscle.

Another LVNC phenotype has been reported in association with a mutation in the Lamin A/C protein, which has been linked to dilated cardiomyopathy, conduction system diseases, and muscular dystrophy.

Recently, LVNC has been linked to sarcomere gene mutations, causing hypertrophic cardiomyopathy. In a study of 247 families with cardiomyopathy, a mutation in the α‐cardiac actin gene, essential for cell maintenance, was associated with LVNC, apical hypertrophic cardiomyopathy, and septal defects. Moreover, in a large study of patients with phenotype of LVNC, nine heterozygous mutations were identified in a proportion of the probands in genes encoding α‐myosin heavy chain (MYH7), β‐cardiac actin (ACTC), and cardiac troponin T (TNNT2), with 100% penetrance in the family members [13]. Another study identified a mutation in the sarcomeric TPM1 gene, at 15q22.1, in a family with LVNC and a history of sudden death.

Some studies have suggested that the phenotype for isolated LVNC may appear during adult life in patients with muscular dystrophy and with myocarditis. Nevertheless, these cases were not followed serially clinically and with an imaging modality, and the significance of the LV hypertrabeculation described is still unclear.

Although, many genes associated with LVNC are associated with additional phenotypes, like hypertrophic or dilated cardiomyopathies or congenital heart defects, several mutations were described in association with isolated LVNC. For instance, mutations in gene MIB1 were identified in two families with LVNC and autosomal dominant inheritance [14]. Recently, an important role in trabeculation for endocardial expression of a Notch ligand, Fkbp1a, was reported, [15] which was confirmed in a mouse model, suggesting its direct involvement in the LVNC phenotype.

A large number of genes have been identified in relation with the LVNC phenotype in association with other cardiomyopathies, congenital and acquired heart diseases, as well as part of syndromes; specific genetic mutations have been related with the LVNC phenotype, and there is a need for large databases and systematic follow‐up with clinical and imaging to obtain definite conclusions on the clinical and prognostic significance of LVNC phenotype in relation with the genotype.

The role of modifying genes or epigenetics and load changes may influence the relationship of genotype‐phenotype and contribute to explain the phenotype variability.
