Untangling the mechanisms of pulmonary arterial hypertension-induced right ventricular stiffening in a large animal model
Untangling the mechanisms of pulmonary arterial hypertension-induced right ventricular stiffening in a large animal model
复制标题
阐明大型动物模型中肺动脉高压引起的右心室僵硬的机制
DOI：
10.1016/j.actbio.2023.09.043
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发表时间：
2023
影响因子：
9.7
通讯作者：
Timek, Tomasz A.
中科院分区：
文献类型：
--
作者：
Kakaletsis, Sotirios;Malinowski, Marcin;Snider, J. Caleb;Mathur, Mrudang;Sugerman, Gabriella P.;Luci, Jeffrey J.;Kostelnik, Colton J.;Jazwiec, Tomasz;Bersi, Matthew R.;Timek, Tomasz A.
肺动脉高压（PHT）是一种生存率低的毁灭性疾病。在PHT中，慢性压力超负荷导致右心室（RV）硬化;因此，阻碍舒张期充盈。多种机制可能导致RV硬化，包括室壁增厚、微结构紊乱和心肌硬化。每种机制的相对重要性尚不清楚。我们的目标是使用一个大型动物模型来解开这些机制。因此，我们通过肺动脉结扎法诱导绵羊肺动脉高压（PAH）。八周后，心脏进行解剖和扩散张量MRI，以表征壁增厚和微结构紊乱。此外，对心肌样本进行组织学和基因表达分析以量化成分变化，并进行机械测试以量化心肌硬化。最后，我们使用有限元建模来理清每个硬化机制的相对重要性。我们发现PAH动物的RV在基底和游离壁增厚，PAH诱导过度胶原合成，增加心肌细胞横截面积，并导致微结构紊乱，与纤维化基因表达增加一致。我们还发现心肌本身明显硬化。重要的是，心肌硬化与胶原合成显著相关。最后，我们的计算模型预测，心肌硬度有助于右心室硬化显着超过其他机制。因此，心肌硬化可能是PAH进展的最重要预测因素。鉴于心肌硬度和胶原合成之间的相关性，胶原敏感的成像方式可能有助于估计心肌硬度和预测PAH outcomes.Statement of significance心室硬化是肺动脉高压诱导的右心衰竭的重要因素。然而，导致心室硬化的机制尚未完全了解。我们工作的新颖性在于通过使用大型动物模型结合空间和方向敏感的实验技术来回答这个问题。我们发现，心肌僵硬是导致心室僵硬的主要机制。临床上，这些知识可用于改善肺动脉高压患者的诊断、预后和治疗策略。
Pulmonary hypertension (PHT) is a devastating disease with low survival rates. In PHT, chronic pressure overload leads to right ventricle (RV) stiffening; thus, impeding diastolic filling. Multiple mechanisms may contribute to RV stiffening, including wall thickening, microstructural disorganization, and myocardial stiffening. The relative importance of each mechanism is unclear. Our objective is to use a large animal model to untangle these mechanisms. Thus, we induced pulmonary arterial hypertension (PAH) in sheep via pulmonary artery banding. After eight weeks, the hearts underwent anatomic and diffusion tensor MRI to characterize wall thickening and microstructural disorganization. Additionally, myocardial samples underwent histological and gene expression analyses to quantify compositional changes and mechanical testing to quantify myocardial stiffening. Finally, we used finite element modeling to disentangle the relative importance of each stiffening mechanism. We found that the RVs of PAH animals thickened most at the base and the free wall and that PAH induced excessive collagen synthesis, increased cardiomyocyte cross-sectional area, and led to microstructural disorganization, consistent with increased expression of fibrotic genes. We also found that the myocardium itself stiffened significantly. Importantly, myocardial stiffening correlated significantly with collagen synthesis. Finally, our computational models predicted that myocardial stiffness contributes to RV stiffening significantly more than other mechanisms. Thus, myocardial stiffening may be the most important predictor for PAH progression. Given the correlation between myocardial stiffness and collagen synthesis, collagen-sensitive imaging modalities may be useful for estimating myocardial stiffness and predicting PAH outcomes.Statement of significanceVentricular stiffening is a significant contributor to pulmonary hypertension-induced right heart failure. However, the mechanisms that lead to ventricular stiffening are not fully understood. The novelty of our work lies in answering this question through the use of a large animal model in combination with spatially- and directionally sensitive experimental techniques. We find that myocardial stiffness is the primary mechanism that leads to ventricular stiffening. Clinically, this knowledge may be used to improve diagnostic, prognostic, and therapeutic strategies for patients with pulmonary hypertension.