Abstract Body: Background:
Hypoplastic left heart syndrome (HLHS) is a severe congenital heart disease (CHD) characterized by an underdeveloped left ventricle. Survival depends on staged palliative surgeries that reconfigure circulation, forcing the single right ventricle (RV) to support systemic circulation. However, the RV experiences excessive volume overload, pressure overload and hypoxia, leading to progressive heart failure. The molecular mechanisms underlying HLHS-associated heart failure remain unclear.
Hypothesis:
We hypothesize that cardiac cells undergo senescence. Multiple types of senescent cells orchestrate a tissue microenvironment that contributes to heart failure.
Methods:
We analyzed RV tissue from 21 pediatric HLHS patients across heart failure stages using single-nucleus RNA sequencing and spatial transcriptomics. Longitudinal samples from the same patient were compared before and after ventricular assist device (VAD) placement to assess the effects of mechanical unloading. Additionally, we used patient-derived induced pluripotent stem cells (iPSCs) to investigate the transmissibility of senescence from HLHS cardiomyocytes to healthy donor cardiomyocytes.
Results:
HLHS hearts exhibited widespread CM senescence at birth, preceding heart failure. Spatial transcriptomics identified a unique senescent microvascular niche comprising hypoxic endothelial cells and pericytes, mechanically stressed senescent fibroblasts, and macrophages with impaired efferocytosis. This microenvironment was specific to HLHS and absent in pediatric failing hearts with dilated or hypertrophic cardiomyopathy. VAD placement alleviated CM senescence and largely reversed the senescent niche. iPSC-derived cardiomyocyte experiments further demonstrated that senescence is transmissible from HLHS cardiomyocytes to healthy donor cells, suggesting a mechanism for disease propagation.
Conclusions:
Cardiomyocyte senescence and a senescent microvascular niche are key features of HLHS-associated heart failure. The reversal of senescence following mechanical unloading highlights senolytic therapies as a potential treatment strategy.