Cardiovascular pathology : the official journal of the Society for Cardiovascular Pathology · 2025
Genetic mutations, pathology, and single-nucleus transcriptomic landscape in LVHT patients reveal differential progression to heart transplantation.
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Wang Yifan, Wang Weiteng, Mo Han, Hua Xiumeng, Cui Hao, Chen Xiao, Zhang Yue, Liu Shun, Zhao Yiqi, Song Jiangping
Аннотация
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 but displays considerable clinical heterogeneity. The factors influencing disease progression to heart transplantation remain unclear. No studies have investigated the relationship between transcriptomic or pathological features of LVHT and progression to transplantation.
METHODS: We enrolled 74 patients diagnosed with LVHT, among whom 63 underwent whole-exome sequencing to assess genetic variants. Explanted heart tissue was obtained from 24 patients who received heart transplantation, and single-nucleus RNA sequencing was performed on the compacted and non-compacted layers of the left ventricle in 3 LVHT patients, compared with 3 normal controls. In addition, myocardial composition, fibrosis, fat content, and the extent of non-compaction were evaluated histopathologically.
RESULTS: Genetic variants were detected in 46 % of patients but were not associated with progression to heart transplantation. 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 with other cardiomyopathies and normal myocardium, and was associated with faster progression to transplantation. Histopathological analysis further demonstrated that both myocardial fibrosis and the anatomical distribution of non-compaction were linked to cardiac function and transplant outcomes.
CONCLUSION: LVHT is associated with distinct transcriptomic and pathological features that influence the rate of progression to heart transplantation. The Notch pathway-related molecule MAML3 may serve as a potential marker of disease progression in LVHT.
METHODS: We enrolled 74 patients diagnosed with LVHT, among whom 63 underwent whole-exome sequencing to assess genetic variants. Explanted heart tissue was obtained from 24 patients who received heart transplantation, and single-nucleus RNA sequencing was performed on the compacted and non-compacted layers of the left ventricle in 3 LVHT patients, compared with 3 normal controls. In addition, myocardial composition, fibrosis, fat content, and the extent of non-compaction were evaluated histopathologically.
RESULTS: Genetic variants were detected in 46 % of patients but were not associated with progression to heart transplantation. 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 with other cardiomyopathies and normal myocardium, and was associated with faster progression to transplantation. Histopathological analysis further demonstrated that both myocardial fibrosis and the anatomical distribution of non-compaction were linked to cardiac function and transplant outcomes.
CONCLUSION: LVHT is associated with distinct transcriptomic and pathological features that influence the rate of progression to heart transplantation. The Notch pathway-related molecule MAML3 may serve as a potential marker of disease progression in LVHT.