Prevalence and cardiovascular outcomes of left ventricular hypertrabeculation in children

Left ventricular (LV) hypertrabeculation, previously defined as LV noncompaction, is a myocardial disease characterized by the presence of an extensive trabeculated myocardium separated into two distinct compacted and noncompacted layers.1,2 The aetiology of LV hypertrabeculation is heterogeneous, and pathogenic variants in genes encoding sarcomeric, cytoskeletal, and mitochondrial proteins have been identified in affected patients. In childhood,3 LV hypertrabeculation can occur as an isolated finding or in association with hypertrophic, dilated, or overlapping phenotypes. While isolated LV hypertrabeculation is considered a benign condition, patients with a dilated phenotype exhibit worse outcomes.4 However, due to the lack of specific diagnostic criteria, limited awareness among clinicians, and its rarity, several knowledge gaps exist regarding LV hypertrabeculation in children. Among other aspects, limited data are available on the prevalence and outcomes of children with LV hypertrabeculation. The study aimed to evaluate the prevalence, clinical characteristics, and outcomes of children with LV hypertrabeculation. Between December 2001 and September 2022, consecutive paediatric patients (<18 years old) diagnosed with LV hypertrabeculation in a third-level referral centre for paediatric and adult cardiomyopathies and congenital heart diseases in the South of Italy (Monaldi Hospital, University of Campania ‘Luigi Vanvitelli’, Campania Region, Naples, Italy) were included into this observational cohort study. Experienced paediatric cardiologists conducted the primary evaluation of patients admitted to our outpatient clinic. Patients underwent a basal cardiovascular evaluation, including family history, physical examination, standard 12-lead electrocardiogram, and transthoracic echocardiography. In the presence of an echocardiographic examination suspicious for LV hypertrabeculation [i.e. presence of pronounced trabeculation or visual impression of a noncompacted to compacted ratio (NC/C) > 1], patients underwent a second echocardiographic investigation by an expert in adult and paediatric cardiomyopathies to evaluate the presence of diagnostic criteria for LV hypertrabeculation. The diagnosis of LV hypertrabeculation was defined according to previous published criteria (proposed by Jenni et al.5), consisting of the presence of multiple echocardiographic trabeculations, multiple deep intertrabecular recesses communicating with the ventricular cavity, and a two-layered structure of the endocardium with a NC/C ≥ 2, measured in systole and short-axis view. Dilated cardiomyopathy (DCM) was defined with a dilated LV and reduced systolic function (i.e. LV end-diastolic diameter z-score >2 and LV ejection fraction <45%),4 while hypertrophic cardiomyopathy (HCM) was defined by otherwise unexplained hypertrophy (i.e. diastolic LV maximal wall thickness z-score >2, in the absence of overload conditions). Patients with LV hypertrabeculation and an overlapping cardiomyopathy phenotype (DCM or HCM) underwent molecular genetic testing using next-generation sequencing panel containing 202 genes associated with cardiomyopathies. Major cardiovascular events (MACEs) were a composite of heart failure (HF)-related death or hospitalization. In total, 30 303 children underwent a basal cardiovascular evaluation, with 180 individuals having an echocardiographic examination suspicious for LV hypertrabeculation and requiring a second echocardiographic evaluation (Figure 1). Among these, 140 (0.46%) individuals (mean age 11.0 ± 5.3 years, 64% males, 13% infants) had mild LV trabeculation (NC/C between 1.0 and 1.9). These patients were followed up for a median of 46 [interquartile range (IQR) 24–60] months, and no MACEs were reported. Summary of the study results. (A) illustrates the prevalence of mild left ventricular trabeculation and left ventricular hypertrabeculation in the overall cohort. Specifically, among 30 303 children who underwent a basal cardiovascular evaluation, 180 individuals underwent a second echocardiographic assessment due to the suspicion of left ventricular hypertrabeculation. Among these, 140 (0.46%) individuals exhibited mild left ventricular trabeculation, and 40 (0.13%) patients were diagnosed with left ventricular hypertrabeculation. (B) shows the aetiology of patients with left ventricular hypertrabeculation and provides a description of the clinical and genetic characteristic of individuals with an overlapping dilated cardiomyopathy and hypertrophic cardiomyopathy phenotype. CHDs, congenital heart diseases; DCM, dilated cardiomyopathy; HCM, hypertrophic cardiomyopathy; LV, left ventricular; MACE, major adverse cardiovascular event; NC/C, noncompacted to compacted ratio. In contrast, 40 patients [median age 5.5 (IQR 1.0–11.0) years, 54% males, 27% infants) met the diagnostic criteria for LV hypertrabeculation, resulting in a prevalence of 0.13% (95% confidence interval 0.09–0.18%). These patients were significantly younger than those with mild LV trabeculation (P < 0.001). Moreover, 23 patients (57%) exhibited isolated LV hypertrabeculation, 9 (23%) had concomitant congenital heart defects, and 8 had an overlapping cardiomyopathy phenotype: 6 (15%) DCM and 2 (5%) HCM. The two patients with HCM carried a pathogenic/likely pathogenic (P/LP) variant in a sarcomeric gene, while among the six patients with DCM, three patients had a P/LP variant in TAZ and were diagnosed with Barth syndrome, two had a pathogenic variant in TTN, and one had no P/LP variants found. During a median follow-up of 41 (IQR 22–90) months, 4 patients experienced a MACE. Two patients with DCM had a HF-related death, and two patients had hospitalizations for acute HF. No MACEs occurred among patients with isolated LV hypertrabeculation or those with HCM. This study describes the prevalence of LV hypertrabeculation and mild LV trabeculations in a large cohort of consecutive paediatric patients. The findings indicate that in otherwise healthy children, the presence of excessive trabeculations, whether in the form of mild LV trabeculation or isolated LV hypertrabeculation, does not appear to have independent prognostic significance. In contrast, the very rare patients presenting with a DCM phenotype experience a poor prognosis. The recent European Society of Cardiology guidelines on the management of cardiomyopathies consider LV hypertrabeculation as a phenotypic trait rather than a specific cardiomyopathy.2 This study supports the message that, in paediatric patients, the presence of a LV hypertrabeculation, in the absence of additional morphological, functional, or electrical features, should be considered a benign condition that does not require strict periodic follow-up. This study has several limitations. First, it is subject to limitations associated with retrospective analyses, such as missing data and survival bias. Second, patients were diagnosed with LV hypertrabeculation using echocardiographic criteria, and confirmation through cardiac magnetic resonance was not performed. Third, the quality of echocardiographic images has improved over time, potentially impacting the estimation of disease prevalence. Last, the short follow-up duration is inadequate for providing recommendations regarding the follow-up timing of these patients. Tailored studies with extended follow-up periods are required to validate these findings. E.M. and G.L. contributed to the conception or design of the work. E.M., M.C., A.M., N.G., A.C., G.D., F.V., A.F., and C.C. contributed to the acquisition, analysis, or interpretation of data for the work. E.M. drafted the manuscript. C.P., G.P., E.B., M.G.R., and G.L. critically revised the manuscript. All gave final approval and agreed to be accountable for all aspects of work ensuring integrity and accuracy. None declared. Data supporting the findings of this study are available from the corresponding author on request.