SnRNA-Seq in LVHT Patients from Heart Transplantation

Background: Left ventricular hypertrabeculation/non-compaction (LVHT/LVNC) is characterized by a thinned myocardial wall, prominent trabeculations, and deep intertrabecular recesses. It presents with unique cardiac morphology and hemodynamic features, yet displays considerable clinical heterogeneity and unclear transplant risk. To date, no studies have explored the relationship between LVHT transcriptomic or pathological features and the risk of heart transplantation.Methods: We included 74 patients diagnosed with LVHT, of whom 63 underwent WES to assess genetic variants. Explanted heart tissue was obtained from 24 patients who received heart transplantation, and snRNA-seq was performed on the compacted and non-compacted layers of the left ventricle in 3 LVHT patients, compared with 3 normal controls. Additionally, myocardial composition, fibrosis, fat content, and the extent of non-compaction were evaluated histopathologically.Results: Genetic variants were identified in 46% of patients but were not associated with increased risk of transplantation (P = 0.76). The compacted and non-compacted layers of LVHT hearts exhibited highly similar transcriptional profiles. Notch signaling was enriched in LVHT-related cardiomyocyte clusters. MAML3, a Notch coactivator, was significantly upregulated in LVHT compared to both DCM and normal myocardium, and was associated with faster progression to transplantation (P = 0.046). Histopathological analysis further revealed that both myocardial fibrosis (P = 0.02) and the anatomical distribution of non-compaction (P < 0.01) were linked to cardiac function and transplant outcomes.Conclusion: LVHT is associated with distinct transcriptional and pathological features that influence transplant risk. MAML3, a Notch pathway related molecule, may serve as a potential marker of disease progression in LVHT.