**2. Embryonic development of compacted myocardium**

The underlying mechanisms for LVNC remain largely unknown, but many studies associate it with the failure of compaction of trabecular myocardium during embryogenesis [16]. The development of the functionally competent, compacted, and multilayered myocardial wall is a two-part process consisting of trabeculation followed by a compaction process set at the midgestational period of cardiogenesis [17]. When the myocardial spiral system enfolds, myocyte recruitment and proliferation lead to myocardial maturation with the development of protrusions into the lumen. Endocardial cells invaginate, and cardiomyocytes in specific regions along the inner wall of the heart form sheet-like protrusions into the lumen to give rise to the trabecular myocardium [16]. The intertrabecular recesses communicate with the blood-filled cavity of the heart tube to increase the surface area for gas exchange and blood. This mechanism favors the concomitant increase in myocardial mass despite the absence of a distinct epicardial coronary circulation [18].

The trabecular myocardium starts undergoing compaction between weeks 5 and 8 of human embryonic development and coincides with the invasion of the developing coronary vasculature from the epicardium. Compaction is gradual, from the epicardial to the endocardial surface and from the basal segments of the ventricle moving toward the apex [19]. Vascular endothelial growth factor (VEGF) and angiopoietin-1 may be involved with triggering compaction [2]. As a result of the compaction process, the intertrabecular recesses disappear almost entirely leaving a smooth endocardial ventricular surface. Compaction is more pronounced in the LV than in the right ventricle (RV), therefore the RV endomyocardial surface is more heavily trabeculated (**Figure 2**) [19]. On the other hand, noncompaction indicates failure of compact myocardium formation, leaving spongy myocardium and deep intertrabecular recesses [20].

#### **2.1 Etiopathophysiology of LVNC and genotype: phenotype correlation**

While the etiology of LVNC is not clearly understood, it is largely considered that hypertrabeculation or noncompaction in LVNC has a genetic origin with typically autosomal dominant inheritance if the implicated genes encode components of the sarcomere, Z-disc, or cytoskeleton [21]. Autosomal recessive, X-linked, and mitochondrial inheritance patterns have also been found [3, 22]. One large retrospective multicenter study showed that nearly one-third of the LVNC patients had genetic variants in at least one cardiomyopathy-causative gene [14]. LVNC

#### **Figure 2.**

*Gross morphopathologic appearance of LVNC. a. Heart from a individual with left ventricular noncompaction. Note the spongy appearance of the ventricular wall, caused by 'holes' in the myocardium, which represent deep trabeculations. The heart is thick and has a dilated chamber (that is, hypertrophic and dilated). In life this ventricle functioned poorly. LV, left ventricle; LVNC, trabeculations of left ventricular noncompaction. b. Numerous excessive prominent trabeculations and deep intertrabecular recesses is noted by arrows. The trabecular zone (noncompacted layer, X) in the LV is at least twice thick as the compact layer (Y) of the ventricular wall. (Adopted from Towbin and Bowles, Nature 415, 227–233. 2002).*

has also been reported in many complex syndromes [23, 24] and neuromuscular disorders [25–27]. LVNC can also be considered congenital or acquired, and several hypotheses have been proposed for the development of LVNC [28]. The primary hypothesis for congenital LVNC is the embryonic hypothesis, which attributes the hypertrabeculation of LVNC to the arrest in normal ventricular compaction during myocardial embryogenesis [29]. The etiology of LVNC can be described as having two components, congenital and modifier factors**.**

Genetically, LVNC is heterogeneous and has been associated with chromosomal defects and genetic mutations in myosin heavy chain 7 (*MYH7*) [21, 30], LIM domain-binding protein 3 (*ZASP*), α-dystrobrevin (*DTNA*), tafazzin (*TAZ/G4.5*), ion channels, and proteins found in the sarcomere, cytoskeleton, and mitochondria. Alterations in the NOTCH signaling pathway, associated with morphological development, and WNT pathway signaling, embryonically involved in body axis patterning and cell polarity, are also linked to LVNC [20, 31]. In some categories of LVNC, the genotype–phenotype correlation is identifiable. Tafazzin mutations, one of the first mutations linked to LVNC, are characteristic of Barth syndrome, an X-linked genetic disorder that commonly presents with LVNC. Tafazzin, an inner mitochondrial membrane protein, catalyzes phospholipid cardiolipin synthesis, which is essential for mitochondrial integrity and energy production in cardiomyocytes [29, 32]. Family studies have identified mutations in hyperpolarization-activated cyclic nucleotidegated channel 4 (*HCN4*), sodium voltage-gated channel alpha subunit 5 (*SCN5A*), and ankyrin 2 (*ANK2*) as genetic abnormalities underlying sinus bradycardia-associated LVNC [33]. Lamin A/C (*LMNA*) mutations, which are also found in dilated cardiomyopathies, are associated with the early onset of advanced atrioventricular block [34]. A 6.8-megabase locus on chromosome 11p15, containing muscle LIM protein (*MLP/ CSRP3*) and SOX6, was implicated in an autosomal dominant pedigree of LVNC [35]. The V470I variant in bone morphogenetic protein 10 (*BMP10*) and W143X variant in neuregulin (*NRG1*) were identified in two unrelated LVNC probands and their affected family members [36]. Impaired BMP receptor binding ability, perturbed proliferation and differentiation processes, and intolerance to stretch in mutant cardiomyoblasts may underlie myocardial noncompaction in these families.

#### *Left Ventricular Noncompaction Cardiomyopathy: From Clinical Features to Animal Modeling DOI: http://dx.doi.org/10.5772/intechopen.101085*

The causal nature of genetic defects is further complicated by the overlap of genetic mutations in distinct cardiomyopathies. LVNC can be categorized based on its association with dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM), and other forms of heart muscle disease. Using next-generation sequencing, several groups revealed a wide range of pathogenic variants in LVNC patients and an association between pathogenic variants and poor prognoses, especially in those patients harboring multiple pathogenic variants [10, 11, 37, 38]. Variants in *MYH7* were associated with HCM, DCM, and restrictive cardiomyopathy (RCM). Patients with sarcomeric genes variants had more frequent findings of trabeculations and likelihood fibrosis in the interventricular septum of the myocardium [11]. Variants in mindbomb homolog 1 (*MIB1*), *LMNA,* and *MLP* were linked to LVNC associated with DCM. Myosin-binding protein C (*MYBPC3*) mutations are associated with LVNC-hypertrophic cardiomyopathy, while *SCN5A* and *DSP* variants are reported causative for arrhythmogenic cardiomyopathy (ACM), DCM, and cardiac conduction system dysfunction disorders including Brugada syndrome and long QT syndrome. Interestingly, truncating variants in the *LAMP2* gene that is causative for Danon disease were identified in LVNC patients by Li et.al [37]. In addition, mitochondrial genome mutations [39], chromosomal abnormalities such as 1p36 deletion, 7p14·3p14·1 deletion, 18p subtelomeric deletion, 22q11·2 deletion, distal 22q11·2, 8p23·1 deletion trisomies 18 and 13, and tetrasomy 5q35·2–5q35 have been associated with syndromic LVNC [40–44]. Patients with Coffin–Lowry syndrome (*RPS6KA3* mutation), Sotos syndrome (*NSD1* mutation), and Charcot–Marie–Tooth disease type 1A (*PMP22* duplication) have also been reported to manifest clinical signs of LVNC [23, 45–47]. Titin encoded by the *TTN* gene with 364 exons is the largest protein, expressed in striated muscles [48]. A missense variant *TTN* A178D identified by high throughput next-generation whole-genome sequencing techniques that have been implicated in clinical genetics practice over the last decade has recently been associated with autosomal dominant LVNC and DCM [49]. Nonetheless, a genotype–phenotype correlation may not be identifiable for all mutations and variants. Genetic defects may have incomplete penetrance and variable expressivity or have no causal relationship between genotype and phenotype [2].

The embryonic hypothesis does not explain acquired LVNC that presents after birth, some forms of which are potentially reversible. Acquired LVNC, has been identified in athletes, pregnant women, and patients with sickle cell anemia, myopathies, and chronic renal failure [50]. The etiology of acquired LVNC is merely speculative. One such hypothesis argues that mild LVNC can remain undetected until transient LV dilation allows LVNC to become visible under precise and accurate imaging [51]. It is also speculated that acquired LVNC may be due to cardiac remodeling from increased preload and altered hemodynamics [29]. Ventricular trabeculation in athletes, particularly in the LV apex, allows for increased compliance which reduces wall stress and strain [52]. Given the high risk of possible cardiac embolic events from thrombus formation in the intertrabecular recesses, clinical trials for thromboembolic events in isolated LVNC have been suggested [53–55].

#### **2.2 Diagnosis and therapeutic strategy**

The clinical manifestations of LVNC vary widely, including no symptoms, thromboembolic events (ventricular or systemic arterial), LV dilation, impaired contractility with heart failure leading to pulmonary edema, arrhythmia including ventricular tachycardia and atrial fibrillation, and sudden cardiac death. Patients with neuromuscular disorder and LVNC may present with elevation in muscle form of creatine kinase, CK-MM (creatine kinase, muscle isoform) consistent with skeletal myopathy [7].

Echocardiography is the first-line diagnostic routine and an accessible technique to detect abnormal trabeculations or a "spongy" appearance of the myocardium. Several diagnostic criteria have been developed to define LVNC through echocardiographic analysis. A ratio of >2:1 in thickness of noncompacted to compacted layers during diastole is deemed diagnostic for LVNC [56, 57]. Compared with echocardiography, cardiac magnetic resonance (CMR) imaging offers more indepth anatomic and functional features of the noncompacted myocardium. Late gadolinium enhancement specifically provides detection of cardiac fibrosis. CMR criteria developed by Petersen et al*.* to accurately diagnose pathologic noncompaction is based on a noncompaction to compaction ratio at end-diastole of >2.3 [58]. Quantitative CMR criteria by Jacquier *et al*. define LV noncompacted mass > 20% of the total mass for accurate LVNC diagnosis [59], while Grothoff et al. propose LV mass > 25% of the total mass as well as a noncompacted mass > 15 g/m2 [60]. Despite all these proposed criteria, there are wide inconsistencies and poor specificity, and it remains difficult to accurately differentiate normal variants in trabeculations from pathological LVNC [61]. Therefore, data matrices 0f echocardiography and CMR imaging measurements, electrocardiogram features, and clinical genetics of the patient and relatives are helpful for confirming the clinical diagnosis [7].

Genetic testing in patients with LVNC and family members has been important in identifying genetic causes of cardiac dysfunction. Testing can be done on genes known to be associated with LVNC and other forms of cardiomyopathy as well as genes involved in syndromic diseases such as metabolic abnormalities, mitochondrial dysfunction, Barth syndrome, and storage diseases. Identification of pathogenic variants in probands and family members can be followed by segregation studies in the family [15].

Treatment strategy in LVNC depends on clinical presentations and complications, and clinical needs are managed according to corresponding guidelines [62]. The key targets of clinical management are the treatment of heart failure (including beta-blockers, angiotensin-converting enzyme inhibitors, angiotensin-II receptor blockers, aldosterone antagonists, diuretics, and heart transplantation), arrhythmias (including ablation and implantation of an implantable cardioverter-defibrillator in patients with life-threatening events), and oral anticoagulation. In patients with congenital heart disease and LVNC, surgery for the congenital abnormalities takes precedence when feasible. In many cases, palliative surgery ultimately fails because of the myocardial abnormality, and cardiac transplantation is required [63].
