Left Ventricular Noncompaction Develops Even in Late Fetal Life　― The Need for Fetus-Specific Diagnostic Criteria ―

Left ventricular noncompaction (LVNC) is either a feature of a distinct cardiomyopathy or represents morphological characteristics shared by different diseases or conditions. LVNC is diagnosed based on the ventricular wall morphology and is characterized by prominent LV trabeculations, deep intertrabecular recesses, and a thin, compacted layer.¹ The spectrum of clinical features of LVNC is diverse, and cases of LVNC have been reported in all age groups, from fetuses to adults.^2–4

Article p ????

Adult cases of sporadic LVNC may be identified in highly trained athletes, patients with sickle cell anemia, and pregnant women. This evidence suggests that increased trabeculation may occur in response to an increased mechanical load or physiological adaptation mechanisms. It is unclear whether genetic abnormalities underlie LVNC in these adult cases. In contrast, pediatric cases of familial or nonfamilial LVNC may be identified in isolation or in association with other cardiac diseases, such as congenital heart disease, arrhythmias,⁵ and cardiomyopathies (hypertrophic, restrictive, dilated, and arrhythmogenic), or complex syndromes affecting multiple organs, including mitochondrial diseases caused by mutations in both nuclear and mitochondrial genes. This evidence suggests that LVNC in pediatric cases may occur during heart development and fetal life.

The clinical diagnosis of LVNC is based on the prominent appearance of LV trabeculae and the ratio between compacted and noncompacted LV wall (N/C ratio). In clinical practice, 2D grayscale echocardiography is the first diagnostic tool used for LVNC in all age groups, and cardiac magnetic resonance (CMR) imaging is also used. Several diagnostic criteria for LVNC with echocardiography or CMR have been proposed,⁶ but there is no current gold standard for LVNC diagnosis in all age groups, especially in fetuses. Fetal echocardiographic studies may contribute to establishing diagnostic criteria for fetal LVNC and elucidating the pathogenic mechanisms of LVNC and its association with other cardiac diseases. Arunamata et al⁷ studied the echocardiography-based diagnosis and prognosis of fetal LVNC, finding that 22 of 24 fetuses with LVNC had congenital heart disease and 15 had complete heart block. Sun et al⁸ demonstrated the genetic and clinical features of fetal LVNC in a single center in China. Of 37 fetuses, 26 (70%) were male, and 19 (51%) had congenital heart disease, with right-sided lesions being the most common, followed by ventricular septal defects; 16 fetuses had biventricular noncompaction, and 14 had confined LV noncompaction. Of 20 fetuses undergoing copy number variation sequencing and whole-exome sequencing, 9 (47%) had positive genetic results: non-sarcomere gene mutations in 7, sarcomere gene (TPM1) mutations in 1, and pathogenic copy number variant in 1. In contrast, Hirono et al² recently analyzed the genetic background of 33 fetuses with LVNC in a Japanese population using next-generation sequencing, including 81 genes associated with cardiomyopathy, and found that variants of sarcomere genes (MYH7, TPM1, etc.) accounted for 75%. They also reported a higher N/C ratio in the LV posterior wall as an independent risk factor for death in patients with fetal-onset LVNC.

In this issue of the Journal, Ozawa et al⁹ investigate the clinical characteristics of fetal cardiomyopathy based on Japanese nationwide retrospective surveys (Figure 1). This is the first longitudinal study of the clinical and echocardiographic features in patients with fetal-onset cardiomyopathy during the fetal and perinatal periods. One of the most interesting findings of their study was the time-dependent changes in the N/C ratio of the LV wall in patients with LVNC. The N/C ratio in patients with LVNC is significantly higher than that in patients with dilated cardiomyopathy (DCM) or hypertrophic cardiomyopathy (HCM) before and after birth. In addition, the N/C ratio in patients with LVNC increases in a time-dependent manner from the 2nd and 3rd trimesters of pregnancy to the postnatal period, whereas this change is not observed in patients with fetal-onset DCM and HCM (Figure 2).

Figure 1.

Phenotypes and clinical characteristics of fetal-onset cardiomyopathy in Japan.⁹ Incidence of (A) mitral regurgitation, (B) congenital heart disease, (C) family history of cardiomyopathy, (D) death or heart transplantation, in each cardiomyopathy. DCM, dilated cardiomyopathy; HCM, hypertrophic cardiomyopathy; LVNC, left ventricular noncompaction cardiomyopathy.

Figure 2.

Developmental process of ventricular trabeculation/compaction and the possible pathogenesis of left ventricular noncompaction (LVNC). DCM, dilated cardiomyopathy; HCM, hypertrophic cardiomyopathy; N/C, ratio of noncompacted to compacted layer.

Previous experimental studies have shown that the process of cardiac trabeculation begins with early ventricular myocardial development.¹⁰ After the cardiac looping stage, trabeculae formation initiates with endocardial cell invagination and the emergence of myocytes through delamination (migration) from specific regions along the inner compacted myocardium. The outer compacted layers of myocytes proliferate, and the epicardium enters the myocardial wall and forms the coronary vasculature. As development proceeds, the trabecular myocardium collapses toward the myocardial wall, which contributes to the formation of a thicker and more compacted ventricular wall. Finally, the compacted ventricular wall forms a mature and multilayered spiral myocardium during late fetal life. Several molecular mechanisms have been demonstrated to contribute to ventricular development and trabeculation. Neuregulin 1 signaling through ErbB4/ErbB2 leading to FAK phosphorylation appears to be integral to cardiac trabecular formation. Notch signaling in the endocardium is also critical for cardiac trabecular formation. Mouse models, together with human TAZ and Barth syndrome data, provide additional evidence that genetic pathways may directly lead to hypertrabeculation and noncompaction.

A series of genetically engineered mouse models showing a ventricular noncompaction phenotype have suggested the possible pathogenesis of LVNC. One potential hypothesis is that abnormal myocardial morphogenesis occurs during early heart development, when the increased number and thickness of trabeculae, so-called hypertrabeculation, develops, and myocyte organization fails to evolve from the embryonic spongiform condition to the compacted, mature state. Another potential hypothesis is that LVNC occurs as a result of the lack of trabecular remodeling toward the compact wall during and after trabeculation. These hypotheses are associated with ventricular myocardial development at an early gestational age. Ozawa et al⁹ present an additional possible hypothesis for the pathogenesis of LVNC based on their longitudinal observations using fetal echocardiography; that is, environmental factors such as an increased mechanical load or stress on the intrinsically impaired myocardial wall may induce increased trabeculation and noncompaction during the middle and late gestational ages (Figure 1). This insight is important for understanding and managing fetal-onset LVNC.

Ozawa et al estimate that the incidence of LVNC is 1.49 per 100,000 babies.⁹ These data are compatible with data from a previous report¹¹ that showed that LVNC occurred in 0.81 per 100,000 infants/year. As reported, the prognosis in infants with LVNC is poor because of heart failure and/or concomitant congenital heart disease. Therefore, we must establish fetus-specific diagnostic criteria for LVNC. Ozawa et al propose that an N/C ratio ≥1.6 at the LV apex on fetal echocardiography is a possible predictor of LVNC after birth.⁹ However, their study was retrospective, and the number of patients with LVNC was limited. Therefore, further large-scale cohort studies using high-resolution imaging modalities and consistent measurement protocols are required to establish fetus-specific diagnostic criteria for LVNC.

Disclosure

The author declares no conflicts of interest.

IRB Information

None.

References

• 1.   Ichida F. Left ventricular noncompaction. Circ J 2009; 73: 19–26.
• 2.   Hirono K, Hata Y, Ozawa SW, Toda T, Momoi N, Fukuda Y, et al. A burden of sarcomere gene variants in fetal-onset patients with left ventricular noncompaction. Int J Cardiol 2021; 328: 122–129.
• 3.   Saito K, Ibuki K, Yoshimura N, Hirono K, Watanabe S, Watanabe K, et al. Successful cardiac resynchronization therapy in a 3-year-old girl with isolated left ventricular non-compaction and narrow QRS complex: A case report. Circ J 2009; 73: 2173–2177.
• 4.   Sakuma M, Hayashi T, Kamishirado H, Akiya K, Takayanagi K, Morooka S. Isolated noncompaction of the left ventricular myocardium in an elderly patient. Circ J 2004; 68: 964–967.
• 5.   Nozaki Y, Kato Y, Uike K, Yamamura K, Kikuchi M, Yasuda M, et al. Co-phenotype of left ventricular non-compaction cardiomyopathy and atypical catecholaminergic polymorphic ventricular tachycardia in association with R169Q, a ryanodine receptor type 2 missense mutation. Circ J 2020; 84: 226–234.
• 6.   Zuccarino F, Vollmer I, Sanchez G, Navallas M, Pugliese F, Gayete A. Left ventricular noncompaction: Imaging findings and diagnostic criteria. AJR Am J Roentgenol 2015; 204: W519–W530.
• 7.   Arunamata A, Punn R, Cuneo B, Bharati S, Silverman NH. Echocardiographic diagnosis and prognosis of fetal left ventricular noncompaction. J Am Soc Echocardiogr 2012; 25: 112–120.
• 8.   Sun H, Hao X, Wang X, Zhou X, Zhang Y, Liu X, et al. Genetics and clinical features of noncompaction cardiomyopathy in the fetal population. Front Cardiovasc Med 2021; 7: 617561.
• 9.   Ozawa SW, Takarada S, Okabe M, Miyao N, Nakaoka H, Ibuki K, et al. Clinical characteristics and prognosis of fetal left ventricular noncompaction in Japan. Circ J, doi:10.1253/circj.CJ-20-1148.
• 10.   Zhang W, Chen H, Qu X, Chang CP, Shou W. Molecular mechanism of ventricular trabeculation/compaction and the pathogenesis of the left ventricular noncompaction cardiomyopathy (LVNC). Am J Med Genet C Semin Med Genet 2013; 163: 144–156.
• 11.   Arbustini E, Weidemann F, Hall JL. Left ventricular noncompaction: A distinct cardiomyopathy or a trait shared by different cardiac diseases? J Am Coll Cardiol 2014; 64: 1840–1850.