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）患者生存的最强决定因素。我们的目的是确定除了压力超负荷之外与PH 中适应不良的右心室肥大相关的相关机制。为了将压力超负荷的影响与其他潜在机制分开，我们在猪身上开发了两种 PH 实验模型（M1，通过肺静脉束带，M2，通过主动脉肺分流），并将它们与纯压力超负荷模型（M3，肺动脉结扎组）和假手术组。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，并对心肌组织进行分析。对各组之间血浆无偏蛋白质组和代谢组数据进行比较，并通过相互作用网络分析进行整合。共有 33 头猪完成了随访（M1，n  = 8；M2，n  = 6；M3，n  = 10；M0，n  = 9）。 M1 和 M2 动物出现 PH 并降低 RV 收缩功能，而 M3 动物表现出 RV 收缩压升高但保持正常功能。在两种 PH 模型（M1 和 M2）中均观察到显着的血浆精氨酸和组氨酸缺乏以及补体系统激活，并且 M2 中的牛磺酸和嘌呤途径发生了额外的改变。脂质代谢的变化非常显着，特别是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右心室肥大显着相关。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 功能障碍中也发挥着相关作用。