Lo Muzio Francesco Paolo, Caputo Alessia, Statello Rosario, Hu Mirko, Maestri Roberta, Pelà Giovanna, Cabassi Aderville, Burattini Margherita, Rozzi Giacomo, Berrettoni Silvia, Montanini Barbara, Rossi Stefano, Fassina Lorenzo, Luciani Giovanni Battista, Condorelli Gianluigi, Miragoli Michele
Department of Medicine and Surgery, University of Parma, Via Gramsci 14, 43124, Parma, Italy.
Department of Cardiology, Angiology and Intensive Care Medicine, Deutsches Herzzentrum Der Charité, Campus Virchow-Klinikum, Berlin, Germany.
J Transl Med. 2025 Jul 12;23(1):787. doi: 10.1186/s12967-025-06792-w.
Pulmonary arterial hypertension (PAH) is a severe condition characterized by elevated pulmonary arterial pressure, leading to significant morbidity and mortality. Despite ongoing research, its pathophysiology remains incompletely understood. Traditionally, PAH has been regarded as predominantly affecting the right ventricle (RV), often overlooking its potential impact on the left ventricle (LV), particularly in patients with preserved LV ejection fraction (EF).
In this study, we investigate the late-stage effects of PAH on both electrical and mechanical functions, as well as their coupling, in each ventricle using the monocrotaline-treated rat model. Specifically, an integrative approach combining in-vivo epicardial potential mapping, in-situ video kinematic evaluation, and transcriptomic analysis was performed on rats injected with monocrotaline (MCT, n = 22) or saline solution (Physio, n = 16).
Our findings reveal that PAH induces global increases in refractoriness from 88.8 ± 1.9 ms to 152.7 ± 3.9 ms and reductions in conduction velocity in the RV from 0.59 ± 0.01 m/s to 0.55 ± 0.01 m/s and from 0.28 ± 0.01 m/s to 0.25 ± 0.01 m/s along and across the fiber orientation, respectively. Notably, a significant increase in electromechanical delay from 24.9 ± 1.2 ms to 35.8 ± 5.2 ms was also observed in the RV. In the LV, PAH also results in increased refractoriness from 95.4 ± 3.0 ms to 140.0 ± 11.5 ms and reduced transverse conduction velocity by 14%, despite preserved EF. Transcriptomic analysis indicates that while both ventricles exhibit upregulation of extracellular matrix remodeling-related genes, the RV primarily shows downregulation of electromechanical-related genes. On the contrary, an upregulation of the inflammatory pathways was detected mainly in the LV, alongside a downregulation of mitochondrial metabolism-related genes.
Our findings revealed that both ventricles showed structural remodeling but only the RV underwent electromechanical alteration, while the LV displayed metabolic and inflammatory alteration. This was further validated by the preserved EF in the advanced stage of PAH. Our work highlights that a more comprehensive understanding of PAH pathophysiology can lead to targeted therapeutic strategies, challenging the conventional RV-centric perspective.
肺动脉高压（PAH）是一种严重疾病，其特征为肺动脉压力升高，会导致显著的发病率和死亡率。尽管研究不断，但对其病理生理学仍未完全理解。传统上，PAH一直被认为主要影响右心室（RV），常常忽视其对左心室（LV）的潜在影响，尤其是在左心室射血分数（EF）保留的患者中。
在本研究中，我们使用野百合碱处理的大鼠模型，研究PAH对每个心室的电功能和机械功能及其耦合的晚期影响。具体而言，对注射野百合碱（MCT，n = 22）或生理盐水（Physio，n = 16）的大鼠进行了结合体内心外膜电位标测、原位视频运动学评估和转录组分析的综合方法。
我们的研究结果显示，PAH使右心室的整体不应期从88.8±1.9毫秒增加到152.7±3.9毫秒，沿纤维方向和跨纤维方向的传导速度分别从0.59±0.01米/秒降低到0.55±0.01米/秒以及从0.28±0.01米/秒降低到0.25±0.01米/秒。值得注意的是，右心室的机电延迟也从24.9±1.2毫秒显著增加到35.8±5.2毫秒。在左心室，尽管EF保留，但PAH也导致不应期从95.4±3.0毫秒增加到140.0±11.5毫秒，横向传导速度降低14%。转录组分析表明，虽然两个心室都表现出细胞外基质重塑相关基因的上调，但右心室主要表现为机电相关基因的下调。相反，炎症途径的上调主要在左心室中检测到，同时线粒体代谢相关基因下调。
我们的研究结果表明，两个心室均出现结构重塑，但只有右心室发生机电改变，而左心室表现出代谢和炎症改变。这在PAH晚期EF保留的情况下得到了进一步验证。我们的工作强调，对PAH病理生理学更全面的理解可以带来有针对性的治疗策略，挑战了传统的以右心室为中心的观点。
