*Article* **Left Ventricular Noncompaction and Congenital Heart Disease Increases the Risk of Congestive Heart Failure**

**Keiichi Hirono 1,\*, Yukiko Hata 2, Nariaki Miyao 1, Mako Okabe 1, Shinya Takarada 1, Hideyuki Nakaoka 1, Keijiro Ibuki 1, Sayaka Ozawa 1, Naoki Yoshimura 3, Naoki Nishida 2, Fukiko Ichida <sup>4</sup> and LVNC study collaborators**


Received: 12 February 2020; Accepted: 9 March 2020; Published: 13 March 2020

**Abstract:** Background: Left ventricular noncompaction (LVNC) is a hereditary cardiomyopathy that is associated with high morbidity and mortality rates. Recently, LVNC was classified into several phenotypes including congenital heart disease (CHD). However, although LVNC and CHD are frequently observed, the role and clinical significance of genetics in these cardiomyopathies has not been fully evaluated. Therefore, we aimed to evaluate the impact on the perioperative outcomes of children with concomitant LVNC and CHD using next-generation sequencing (NGS). Methods: From May 2000 to August 2018, 53 Japanese probands with LVNC (25 males and 28 females) were enrolled and we screened 182 cardiomyopathy-associated genes in these patients using NGS. Results: The age at diagnosis of the enrolled patients ranged from 0 to 14 years (median: 0.3 months). A total of 23 patients (43.4%) were diagnosed with heart failure, 14 with heart murmur (26.4%), and 6 with cyanosis (11.3%). During the observation period, 31 patients (58.5%) experienced heart failure and 13 (24.5%) developed arrhythmias such as ventricular tachycardia, supraventricular tachycardia, and atrioventricular block. Moreover, 29 patients (54.7%) had ventricular septal defects (VSDs), 17 (32.1%) had atrial septal defects, 10 had patent ductus arteriosus (PDA), and 7 (13.2%) had Ebstein's anomaly and double outlet right ventricle. Among the included patients, 30 underwent surgery, 19 underwent biventricular repair, and 2 underwent pulmonary artery banding, bilateral pulmonary artery banding, and PDA ligation. Overall, 30 genetic variants were identified in 28 patients with LVNC and CHD. Eight variants were detected in *MYH7* and two in *TPM1.* Echocardiography showed lower ejection fractions and more thickened trabeculations in the left ventricle in patients with LVNC and CHD than in age-matched patients with VSDs. During follow-up, 4 patients died and the condition of 8 worsened postoperatively. The multivariable proportional hazards model showed that heart failure, LV ejection fraction of < 24%, LV end-diastolic diameter z-score of > 8.56, and noncompacted-to-compacted ratio of the left ventricular apex of > 8.33 at the last visit were risk factors for survival. Conclusions: LVNC and CHD are frequently associated with genetic abnormalities. Knowledge of the association between CHD and LVNC is important for the awareness of clinical implications during the preoperative and postoperative periods to identify the populations who are at an increased risk of additional morbidity.

**Keywords:** left ventricular noncompaction; congenital heart disease; congestive heart failure; non-ischemic cardiomyopathy; genetics

#### **1. Introduction**

Left ventricular noncompaction (LVNC) is the most recently classified cardiomyopathy. First described in 1990, it is characterized by a pattern of thickened trabeculations and deep intertrabecular fossa communicating with the left ventricular (LV) cavity [1]. LVNC has a wide spectrum, ranging from asymptomatic to severe congestive heart failure (CHF) with concomitant risks of arrhythmia, systemic thromboembolization, and sudden cardiac death. Although its diagnosis has primarily focused on the identification of trabeculation, other features are important to classify the specific subtypes of LVNC [2]. The specific phenotype of LVNC has the risk of adverse clinical outcomes in children and may occasionally be seen in association with congenital heart disease (CHD) [3].

The etiology of LVNC in patients with CHD has been unknown [4]. Previously, LVNC occurs most frequently in patients with Ebstein's anomaly, following with septal defects, LV outflow tract obstructive lesions, hypoplastic left heart syndrome, and other right heart lesions [3–5]. However, the natural history of patients with LVNC and CHD has not been fully elucidated. In addition, it is considered difficult to estimate prognosis and to identify the surgical indications in children with LVNC because they have highly variable clinical presentations. Therefore, the aim of our study was to evaluate the impact on the perioperative outcomes of patients with concomitant LVNC and CHD.

#### **2. Methods**

#### *2.1. Subjects*

From May 2000 to August 2018, 53 Japanese probands with LVNC and CHD were referred to our institution for genetic testing from several institutions in Japan. Patients aged < 18 years diagnosed as LVNC at the participating institutions were eligible for this study. Patients with secondary etiologies of cardiomyopathy (e.g., endocrine, rheumatic, pulmonary, and immunologic diseases; systemic hypertension; and cardiotoxic exposures), those with a pacemaker because of rhythm disturbance, and those with non-follow-up records were excluded. Clinical data were retrospectively retrieved from the patients' medical records according to the following time course: initial visit, preoperation, postoperation, and last visit. Cardiac death, LV assist device implantation, heart transplant (HT), and implantable cardioverter-defibrillator (ICD) shock were classified as major adverse cardiac events (MACEs).

Age matched patients with ventricular septal defects (VSDs) were selected from the Toyama University Hospital Database for comparison. All these patients underwent a surgery during the same period to endorse similarity of medical management.

Informed consent was gained from all patients or their guardians according to the institutional guidelines. The study protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki as reflected in the *a priori* approval of the Research Ethics Committee of the University of Toyama, Japan.

#### *2.2. Endpoint Assessment*

Primary outcome was the time to the combined endpoint of MACEs, whereas secondary outcomes were arrhythmia, thromboembolic events, echocardiographic parameters, and genetic status.

#### *2.3. Electrocardiogram Collection*

All electrocardiograms were assessed independently by two well-trained investigators (K.H. and N.M.) who were blinded to the clinical data. The two investigators judged more than 95% consistency. The final judgment was made by a third experienced investigator (electrophysiologist) in

cases of disagreement. The criteria for J wave and fragmented QRS were based on the description by Antzelevitch, Yan, and Das [6,7].
