Smith Michael A, Guardado Eleana S, Boehme Jason, Datar Sanjeev A, Maltepe Emin, Swami Naveen, Raff Gary W, Bodansky Aaron, Chelladurai Prakash, Moreno Joseph, Prince Annelise Renee, Powers Nevan, Huang Guo N, de Jesus Perez Vinicio, Fineman Jeffrey R
Division of Pediatric Critical Care, Department of Pediatrics, University of California, San Francisco, California, United States.
Division of Pulmonary, Allergy, and Critical Care Medicine, Wall Center for Cardiopulmonary Research, Stanford University, Stanford, California, United States.
Am J Physiol Heart Circ Physiol. 2025 Oct 1;329(4):H907-H919. doi: 10.1152/ajpheart.00181.2025. Epub 2025 Sep 9.
Right ventricular (RV) failure is the primary cause of death among patients with pulmonary arterial hypertension (PAH). Patients with congenital heart disease-associated PAH (CHD-PAH) demonstrate improved outcomes compared with patients with other forms of PAH, which is related to the maintenance of an adaptively hypertrophied RV. In an ovine model of CHD-PAH, we aimed to elucidate the cellular, microvascular, and transcriptional adaptations to congenital pressure overload that support RV function. Fetal surgery was performed on late gestation lambs to insert an aortopulmonary graft, leading to a persistent congenital left-right shunt and RV pressure load. At 3 days and 4-6 wk of life, shunt RV myocardial structure, growth mechanisms, and transcriptomes were compared with age-matched control and unoperated fetal RV. At 4-6 wk of age, shunt lambs demonstrate significant RV enlargement (shunt 37.1 ± 7.6 g vs. control 15.9 ± 1.9 g, < 0.001) but maintain stable microvascular density (fetal 3.0 ± 1.2 vs. shunt 2.9 ± 0.5 vs. control 3.1 ± 1.2 capillaries per 1,000 µm, > 0.05). Shunt RV cardiomyocytes are significantly more numerous and smaller by cross-sectional area than age-matched controls (shunt 73.3 ± 11.0 µm vs. control 99.2 ± 9.8 µm, = 0.013). At 3 days, shunt RV cardiomyocytes show evidence of increased proliferative capacity and ongoing hyperplasia compared with controls. RNA sequencing analyses reveal a distinct transcriptomic profile in shunt RV consistent with a delay in terminal differentiation and metabolic adaptations to support adaptive function. This study provides novel insights into the roles of microvascular preservation and cardiomyocyte hyperplasia in the development of adaptive RV hypertrophy in CHD-PAH. In this study, we utilize an ovine model of congenital heart disease-associated pulmonary arterial hypertension (CHD-PAH) to unveil the structural and transcriptional changes that underlie the maintenance of an adaptively hypertrophied right ventricle (RV). In CHD-PAH, the RV hypertrophies while maintaining microvascular density and expanding its cardiomyocyte population, structural and cellular adaptations that are critical to supporting RV function. These findings provide novel insight into myocardial growth mechanisms that are triggered by congenital pressure overload.
右心室（RV）衰竭是肺动脉高压（PAH）患者的主要死因。与其他形式的PAH患者相比，先天性心脏病相关性PAH（CHD-PAH）患者的预后有所改善，这与适应性肥厚的右心室的维持有关。在CHD-PAH的绵羊模型中，我们旨在阐明支持右心室功能的对先天性压力过载的细胞、微血管和转录适应性。对妊娠晚期羔羊进行胎儿手术，植入主动脉肺动脉分流管，导致持续性先天性左右分流和右心室压力负荷。在出生后3天和4-6周，将分流右心室的心肌结构、生长机制和转录组与年龄匹配的对照和未手术的胎儿右心室进行比较。在4-6周龄时，分流羔羊表现出明显的右心室增大（分流组37.1±7.6 g vs.对照组15.9±1.9 g，P<0.001），但微血管密度保持稳定（胎儿组每1000 µm有3.0±1.2条毛细血管，分流组为2.9±0.5条，对照组为3.1±1.2条，P>0.05）。分流右心室心肌细胞的数量明显多于年龄匹配的对照组，且横截面积更小（分流组73.3±11.0 µm vs.对照组99.2±9.8 µm，P = 0.013）。在出生后3天，与对照组相比，分流右心室心肌细胞显示出增殖能力增加和持续增生的证据。RNA测序分析揭示了分流右心室中独特的转录组谱，这与终末分化延迟和代谢适应性以支持适应性功能一致。本研究为微血管保留和心肌细胞增生在CHD-PAH适应性右心室肥厚发展中的作用提供了新的见解。在本研究中，我们利用先天性心脏病相关性肺动脉高压（CHD-PAH）的绵羊模型来揭示维持适应性肥厚右心室（RV）的结构和转录变化。在CHD-PAH中，右心室肥大，同时保持微血管密度并扩大其心肌细胞群体，这些结构和细胞适应性对于支持右心室功能至关重要。这些发现为先天性压力过载引发的心肌生长机制提供了新的见解。
