Ventricular Assist Device Unloading Reverses Microvascular Senescence in Single Ventricle Disease
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Ventricular Assist Device Unloading Reverses Microvascular Senescence in Single Ventricle Disease Author list: Xiao Li1,2#, Diwakar Turaga3,4#, Yi Zhao1, Chang-Ru Tsai5, Richard Gang Li1, Yuka Morikawa1, Hanna J Tadros3,6, Md Abdul Hassan Samee5, Iki Adachi7,8, and James F. Martin1,5* Affiliations: 1The Texas Heart Institute at Baylor College of Medicine, Houston, TX 77030, USA. 2Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA. 3Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA. 4Division of Critical Care Medicine, Texas Children's Hospital, Houston, TX 77030, USA. 5Department of Integrative Physiology, Baylor College of Medicine, Houston, TX 77030, USA. 6Division of Cardiology, Texas Children’s Hospital, Houston, TX 77030, USA. 7Department of Surgery, Baylor College of Medicine, Houston, TX 77030, USA. 8Division of Congenital Heart Surgery, Texas Children's Hospital, Houston, TX 77030, USA. # These authors contributed equally *Corresponding author. Email: jfmartin@bcm.edu Abstract: Patients with hypoplastic left heart syndrome (HLHS) have an underdeveloped left ventricle and require multiple surgeries to reconfigure cardiac blood flow for survival. We studied myocardial microenvironment cell states using single nuclear RNA-sequencing and spatial transcriptomics on HLHS right ventricles at birth before heart failure develops; in post-surgical patients in heart failure; and in patients treated for heart failure by ventricular assist device (VAD), which unloads the heart and relieves hypoxia and volume overload. HLHS cardiomyocytes within the heart, as well as cardiomyocytes derived from induced pluripotent stem cells are senescent, indicating cardiomyocyte intrinsic senescence. Spatial transcriptomics revealed a microvasculature niche within capillary beds that contained hypoxic endothelial cells and pericytes and senescent cardiac fibroblasts with increased YAP activity, indicating a mechanically stressed and hypoxic microenvironment. This niche is similar to adult myocardial infarction but not pediatric dilated cardiomyopathy with heart failure pointing to a prominent role of hypoxia in senescence. The microvascular senescent niche was improved by VAD providing insight into the potential to reverse cardiac cell states that lead to heart failure.
