Right ventricular (RV) failure remains the strongest determinant of survival in pulmonary hypertension (PH). We aimed to identify relevant mechanisms, beyond pressure overload, associated with maladaptive RV hypertrophy in PH. To separate the effect of pressure overload from other potential mechanisms, we developed in pigs two experimental models of PH (M1, by pulmonary vein banding and M2, by aorto-pulmonary shunting) and compared them with a model of pure pressure overload (M3, pulmonary artery banding) and a sham-operated group. Animals were assessed at 1 and 8 months by right heart catheterization, cardiac magnetic resonance and blood sampling, and myocardial tissue was analyzed. Plasma unbiased proteomic and metabolomic data were compared among groups and integrated by an interaction network analysis. A total of 33 pigs completed follow-up (M1, n = 8; M2, n = 6; M3, n = 10; and M0, n = 9). M1 and M2 animals developed PH and reduced RV systolic function, whereas animals in M3 showed increased RV systolic pressure but maintained normal function. Significant plasma arginine and histidine deficiency and complement system activation were observed in both PH models (M1&M2), with additional alterations to taurine and purine pathways in M2. Changes in lipid metabolism were very remarkable, particularly the elevation of free fatty acids in M2. In the integrative analysis, arginine–histidine–purines deficiency, complement activation, and fatty acid accumulation were significantly associated with maladaptive RV hypertrophy. Our study integrating imaging and omics in large-animal experimental models demonstrates that, beyond pressure overload, metabolic alterations play a relevant role in RV dysfunction in PH.

右心室 （RV） 衰竭仍然是肺动脉高压 （PH） 生存的最强决定因素。我们旨在确定与 PH 中适应不良的 RV 肥大相关的相关机制，而不仅仅是压力超负荷。为了将压力超负荷的影响与其他潜在机制区分开来，我们在猪中开发了两种 PH 实验模型 （M1，通过肺静脉束带和 M2，通过主动脉-肺分流），并将它们与纯压力超负荷模型 （M3，肺动脉束带） 和一个假手术组进行比较。在 1 个月和 8 个月时通过右心导管插入术、心脏磁共振和血液采样对动物进行评估，并分析心肌组织。在各组之间比较血浆无偏倚的蛋白质组学和代谢组学数据，并通过交互网络分析进行整合。共有 33 头猪完成了随访 （M1， n = 8;M2，n = 6;M3，n = 10;和 M0， n = 9）。M1 和 M2 动物发生 PH 并降低 RV 收缩功能，而 M3 中的动物表现出 RV 收缩压增加但维持正常功能。在两种 PH 模型 （M1&M2） 中均观察到显著的血浆精氨酸和组氨酸缺乏以及补体系统激活，M2 中牛磺酸和嘌呤途径的额外改变。脂质代谢的变化非常显著，尤其是 M2 中游离脂肪酸的升高。在综合分析中，精氨酸-组氨酸-嘌呤缺乏、补体激活和脂肪酸积累与适应不良的 RV 肥大显著相关。我们在大型动物实验模型中整合成像和组学的研究表明，除了压力超负荷之外，代谢改变在 PH 的 RV 功能障碍中起着相关作用。