Left ventricular hypertrabeculation/non-compaction (LVHT/LVNC) is a genetic cardiomyopathy characterized by an abnormal myocardial wall structure, prominent trabeculations, and deep intertrabecular recesses. The myocardium typically exhibits a two-layered configuration, consisting of a non-compacted inner layer and a thin compacted outer layer. LVHT/LVNC demonstrates considerable phenotypic variability, with the non-compacted regions most frequently involving the apex, posterior, and lateral walls of the left ventricle, and, in some cases, extending to the right ventricle. LVHT/LVNC can manifest as hypertrophic, dilated, or restrictive cardiomyopathy subtypes, further underscoring its heterogeneity [1]. Traditionally, the development of LVHT/LVNC has been attributed to disrupted cardiac morphogenesis during the mid-to-late stages of embryogenesis. Under normal conditions, trabecular myocardium progressively compacts toward the ventricular wall, forming a dense and functional myocardial layer. Most trabeculae are ultimately incorporated into the compact myocardium during this process [2]. In contrast, LVHT/LVNC is often associated with dysregulated activation of key developmental signaling pathways, such as Notch and Wnt pathway, which impair cardiomyocyte proliferation, polarity, and sarcomere assembly, ultimately leading to myocardial non-compaction [3]. Accordingly, classical LVHT/LVNC has been regarded as a congenital cardiomyopathy resulting from arrested myocardial compaction during development.

However, the 2023 European Society of Cardiology (ESC) Guidelines for the management of cardiomyopathies have revised this view [4], stating that LVNC should no longer be considered a distinct cardiomyopathy. Particularly in adult-onset cases, it is now regarded as a morphological trait that may coexist with other cardiac abnormalities. The term “hypertrabeculation” has been recommended as a more accurate descriptor of this phenotype in such contexts. LVHT is frequently associated with additional structural or functional abnormalities, reflecting its clinical and genetic heterogeneity. Isolated LVHT tends to have a favorable prognosis and is often asymptomatic, whereas cases associated with ventricular hypertrophy or dilation are typically marked by accelerated clinical progression. Indeed, the risk of progression in patients with dilated LVHT is comparable to that observed in dilated cardiomyopathy (DCM) [5]. These observations suggest that LVHT may not independently determine risk of progression to heart transplantation.

Furthermore, due to the possibility that many adult LVHT patients have experienced a prolonged subclinical phase before diagnosis [6], predicting long-term outcomes remains challenging. Nevertheless, LVHT is characterized by distinctive pathological and anatomical features. For instance, increased myocardial fibrosis is more common in LVHT than in other cardiomyopathies [7], and significant thinning of the compacted myocardial layer has been linked to worse clinical outcomes [8]. Improvement in the LVHT phenotype has been shown to enhance left ventricular systolic function [9], supporting the notion that the disease’s unique etiology and morphology may confer specific prognostic implications. Given these considerations, we hypothesized that LVHT patients with heart failure may harbor unique risk factors for progression to transplantation that are not solely explained by conventional clinical indicators. In this study, we sought to define the genetic, transcriptional, and pathological features of LVHT in the context of heart failure, and to identify novel determinants of disease progression toward heart transplantation.