**1. Introduction**

Cardiac development consists of four stages including embryonic cardiac chamber maturation [Carnegie stage (CS) 11 in humans and embryonic day (E) 8.5 in mice], trabeculation (at CS 12 in humans and E9.5 in mice), compaction (CS 22 in humans and E14.5 in mice) and cardiomyocyte proliferation (E11-E17.5 in mice). Originating from

embryonic mesodermal germ layer cells that differentiate into mesothelium, endothelium, and myocardium followed by gastrulation, the exterior lining of the heart is made up of mesothelial pericardium. Whereas the interior lining of the heart, lymphatic, and blood vessels, arise from endothelium. During cardiac development, the atrial septation (primary atrial septum formation) begins at E10.5 to E13.5 in mice, which is comparable to Carnegie stages (CS 14 to 18) in humans or estimated gestational age (EGA) of 6 6/7–8 weeks. The ventricular septation proceeds from E11.5 to E13.5 in mice and EGA 8–9 1/7 weeks (CS 18–22) in human fetuses. Outflow septation, the transformation of a right ventricle (RV) single outflow tract into pulmonary and aortic arteries originating from the right and left ventricles, starts at E11.5–E13.5 in the mouse and EGA 7 3/7–8 weeks (CS 16–18) in humans [1]. While the separation of atrioventricular (AV) valves from endocardial cushions at the center of cardiac loop occurs at 9 1/7 weeks (CS 22). By the end of 9 1/7 weeks (CS22), all of the major structures of the heart are formed, with the average spanning period of EGA 6 4/7–9 3/7 weeks [2–4].

During cardiac development, trabeculation followed by a compaction step (CS 12 to CS 22), is vital in the developmental stages of humans (**Figure 1**). Emerging from the developing ventricular wall and stretching into the ventricular lumen, trabeculae projections consist of cardiomyocytes lined by an endothelial layer of the endocardium and are an important element of ordered ventricular formation. Any defects during trabeculation, compaction of remodeling junctions, or cardiac chamber maturation, could lead to the inhibition of well compacted myocardium with persisting trabeculations resulting in the condition left ventricular noncompaction (LVNC).

The trabeculation process is further defined by three sequential steps resulting in fusion with myocardium layer that is compacted and progression into a mature thickened ventricular wall. Initially, the trabecular ridges start to emerge while the myocardial projections progress into the lumen. This is followed by the expansion of trabeculae projections, creating a trabeculae network. In the final remodeling step of trabeculae formation, trabeculae growth ceases and they compact together contributing to ventricular radial thickening [6, 7]. Importantly, the LV of a healthy heart has three distinct trabeculation types (hypertrophic, fibrotic or both) [8] and is less trabeculated than RV [9]. Upon stimulation of ventricular trabeculations during the compaction phase of embryonic development, the growth of trabecula ceases and the ends of the trabecula thicken, with the spaces in between the trabecular buds developing into capillaries [10, 11]. The persistence of a trabecular mesh caused by myocardial noncompaction can occur due to irregularities arising in the maturation process of the cardiac chamber. However, the step of remodeling ventricular trabeculae for compaction is believed to be correlated with congenital or acquired mutations of genes associated with cardiomyocytes and the powerhouse of the cell, mitochondria. Unfortunately, complications arising from disruption in the compaction process, referred to as noncompaction, can result in heart failure and neonatal death [12].

In normal human embryo development, the compaction of myocardium begins after the 5th week of embryonic life. To form a well-developed compacted epicardial and a well-compacted endocardial layer, vascular endothelial growth factor (VEGF) and angiopoietin [13] triggers these loosely interwoven muscle fibers of the myocardium to condense, thus removing the large flattened trabeculae spongy mesh from early embryonic development prior to resolving the intertrabecular recesses into capillaries. This gradual progression of trabeculae compaction occurs faster in the LV than in the RV. However, the etiology of LVNC is poorly understood and occurs as a spectrum of pathological conditions, ranging from asymptomatic to the risk of RV failure and fetal heart failure [14]. Due to its relatively low prevalence in combination

#### **Figure 1.**

*Progression of left ventricular trabeculation to compaction: Trabeculation and compaction of endocardial cells (yellow), cardiomyocytes (orange in left image, red in right image), cardiac jelly (purple), epicardial cells (blue) of a LV followed by the maturation step in mouse and human are shown (figure adapted and modified from Zhang et al. [5]).*

with less sensitive detection techniques for noncompaction, less is known regarding its etiology and therapy compared to other cardiomyopathies. While the occurrence of LVNC is independent of sex or age, the prevalence varies among different ethnic groups: with a greater occurrence within black populations. Lastly, the pathophysiological impact of LV noncompaction is poorly understood, though it is expected to a have an association with altered ventricular systolic and diastolic function [15, 16].
