*3.4. Characteristics of Patients with Adverse Events*

Adverse events were observed in 4 patients, and 4 patients died (Table 4 and Figure 1). Although cardiac death, LV assist device implantation, HT, and ICD shock were classified as MACEs in this study, none of the patients underwent HT or LV assist device implantation or experienced ICD shock. Aside from 1 patient, 3 died at early infancy and never underwent surgery.

The condition of 8 patients worsened postoperatively (Table 5 and Figure 1), all patients had VSDs, 3 had variants in *MYH7*, 6 underwent BVR, and long-term medical therapy were required in all patients for myocardial dysfunction after their latest surgeries.

The analysis of the multivariable proportional hazards model revealed that CHF during follow-up, LVEF of < 24%, LVDD z-score of > 8.56, and N/C ratio of the LV apex of > 8.33 at the last visit were risk factors for survival without MACE occurrence (Table 6). Patients with LVNC and CHD had a worse prognosis than those with VSDs (Figure 3).

**Figure 3.** Event-free survival to the endpoint of major adverse cardiac events in LVNC with CHD and VSD groups. LVNC; left ventricular noncompaction, VSD; ventricular septal defect.


**Table 4.** Summary of death cases.

septal disease, TVD; tricuspid valve dysplasia. BVR; biventricular repair, CHF; congestive heart failure.



CHD; congenital heart disease, FH; family history, CM; cardiomyopathy, DORV; double outlet of right ventricle, VSD; ventricular septal defect, IAA; interruption of aortic arch, Ebstein; Ebstein's anomaly, CoA; coarctation of aorta, TGA; transposition of the great arteries, ASD; atrial septal disease, PDA; patent ductus arteiosus, BVR; biventricular repair, PAB; pulmonary arterybanding,bilPAB;bilateralpulmonaryarterybanding.


**Table 6.** Univariate analysis of risk factors for death in the patients with LVNC.

CI, confidence interval, UCG; cardiac ultrasound, LVEF; left ventricular ejection fraction, LVDD; left ventricular diastolic dimension, N/C; ratio of noncompacted/compacted layer.

#### **4. Discussion**

LVNC is associated with CHD, ranging from PDA or atrial septal defects/VSDs to more severe diseases such as Ebstein's anomaly [4]. Our study demonstrated three features: (1) pathogenic variants were identified in more than half of the patients; (2) patients with LVNC had lower EFs than those with VSDs throughout the study period; and (3) postoperative deterioration was observed in several patients.

A variety of genetic disorders are associated with LVNC, including Z-disk and sarcomere gene variants, mitochondrial disorders, and ion channel gene variants [18–22]. Thus, structural congenital malformations and impaired LV myocardial differentiation may be caused by genetic abnormalities. Additionally, for the development of LVNC in a patient with genetic variants, remarkable change of hemodynamic circulation in the fetus may be a cofactor [23]. In our results, variants in *MYH7* were most commonly identified and the variants significantly increase the risk of LVNC by rare variant collapsing analysis. The mechanisms by which variants in the *MYH7* gene induce LVNC remain unclear. Analyzing the positions of these variants against their amino acid location showed several hotspots wherein variants are more popular, which seemed to tend to be in key functional locations. We observed that all variants in *MYH7* associated with LVNC were found in the segment 1 domain. Moreover, enrichment of pathogenic variants was observed in the crucial functional domains of the ATP-binding domain [24–26]. It suggested that the majority of the identified variants affect the force output by affecting either regulation of the ATPase cycle, movement of the lever, or interaction between myosin and actin. Remarkably, the location of variants in *MYH7* in LVNC was different from that in hypertrophic cardiomyopathy (HCM) patients. Hotspots of HCM were mostly located in the surface spanning the converter domain and the myosin mesa; the flat surface of the myosin catalytic domain [27]. It is important to distinguish variant types and assess them in light of well-known disease mechanisms. Therefore, to understand the pathophysiology and development of LVNC, it is critically notable for the patients with LVNC and CHD to characterize genetic variants and phenotypic abnormalities.

Children with LVNC and CHD have a higher incidence of CHF than patients with VSDs. Additionally, our results showed that the condition of 8 of the 30 patients (26.7%) worsened postoperatively, whether palliative or radical. The underlying pathophysiologic mechanisms of CHF remain unclarified. Systolic dysfunction in LVNC is believed to be due to subendocardial hypoperfusion [1,28]. It is also believed that diastolic dysfunction occurs by a restrictive filling pattern and abnormal relaxation because of the presence of LV hypertrabeculation [29]. These speculations are based on the evidence that the noncompact layer has typically low perfusion, which has been

demonstrated on multiple modalities [30]. Functionally, LV torsion is more common in patients with LVNC [31]. LV twist is generated by the movement of two orthogonally oriented muscular bands of a helical myocardial structure concomitant with a clockwise rotation of the base and counterclockwise rotation of the apex in LV [32]. Van Dalen et al. used two-dimensional speckle tracking echocardiography and demonstrated that LV basal and apical rotation are in the same direction, resulting in a lack of LV twist in patients with LVNC [33]. Bellavia et al. reported that in adults, the value of LV rotation/torsion excessively decreased in patients with LVNC, whereas normal EF were retained when compared with those in controls [31]. Nawaytow et al. reported that almost half of the children with LVNC exhibit reverse apical rotation, resulting in decreased LV torsion and untwist rate, which are associated with the degree of LVNC [34]. These previous studies might support that the deterioration of LV function occurs during the perioperative period, although LV systolic function was preserved preoperatively because of its unique structure.

In our study, 13 patients were diagnosed with LVNC postoperatively. The existence of additional triggers such as dynamic hemodynamic changes during the perioperative period were suggested. Indeed, the etiology of LVNC remains unknown. One possibility is that primary abnormality in early myocardial morphogenesis may cause LVNC. Another possibility is that prenatal or postnatal additional triggers such as pressure overload on the LV may cause LVNC. LVNC in the setting of CHD may be one of the models where both hemodynamic and genetic factors interact with each other, resulting in abnormal LV differentiation Thus, additional stress to the myocardium may trigger the worsening of systolic function in patients with LVNC and CHD because LVNC is more frequently associated with systolic dysfunction than that of CHD without LVNC.

There were no predictors of postoperative CHF in this study. Preoperative preserved systolic function did not predict the outcome of patients with LVNC and CHD. In fact, not all patients with LVNC had systolic dysfunction during the preoperative evaluation. Most patients with LVNC and CHD had mildly depressed systolic function preoperatively. These facts may complicate the establishment of medical treatment during the operative period and optimal timing of surgery.

In our study, patients with LVNC and CHD were observed to have a higher frequency of arrhythmias (24.5%). Recently, it was demonstrated in pediatric patients that LVNC with associated CHD confers additional risk [35]. Although there were no data relationships between mortality and the prevalence of arrhythmias in patients with LVNC and CHD, our data suggest that more attention should be paid to the occurrence of arrhythmia and CHF because of the higher prevalence of these symptoms.
