State Key Laboratory of Respiratory Diseases, National Center for Respiratory Medicine, Guangdong Key Laboratory of Vascular Diseases, National Clinical Research Center for Respiratory Diseases, Guangzhou Institute of Respiratory Health, GMU-GIBH Joint School of Life Sciences, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, 510120, Guangdong, China.
The Jackson Laboratory, Bar Harbor, Maine, 04609, USA.
Respir Res. 2023 Aug 17;24(1):202. doi: 10.1186/s12931-023-02501-7.
Right heart failure is the leading cause of death in pulmonary hypertension (PH), and echocardiography is a commonly used tool for evaluating the risk hierarchy of PH. However, few studies have explored the dynamic changes in the structural and functional changes of the right heart during the process of PH. Previous studies have found that pulmonary circulation coupling right ventricular adaptation depends on the degree of pressure overload and other factors. In this study, we performed a time-dependent evaluation of right heart functional changes using transthoracic echocardiography in a SU5416 plus hypoxia (SuHx)-induced PH rat model. Rats were examined in 1-, 2-, 4-, and 6-week using right-heart catheterization, cardiac echocardiography, and harvested heart tissue. Our study found that echocardiographic measures of the right ventricle (RV) gradually worsened with the increase of right ventricular systolic pressure, and right heart hypofunction occurred at an earlier stage than pulmonary artery thickening during the development of PH. Furthermore, sarco-endoplasmic reticulum calcium ATPase 2 (SERCA2), a marker of myocardial damage, was highly expressed in week 2 of SuHx-induced PH and had higher levels of expression of γ-H2AX at all timepoints, as well as higher levels of DDR-related proteins p-ATM and p53/p-p53 and p21 in week 4 and week 6. Our study demonstrates that the structure and function of the RV begin to deteriorate with DNA damage and cellular senescence during the early stages of PH development.
右心衰竭是肺动脉高压（PH）患者死亡的主要原因，超声心动图是评估 PH 风险分层的常用工具。然而，很少有研究探讨 PH 过程中右心结构和功能变化的动态变化。既往研究发现，肺循环耦联右心室适应性取决于压力过载程度等因素。本研究采用 SU5416 加缺氧（SuHx）诱导的 PH 大鼠模型，通过经胸超声心动图对右心功能变化进行时相关评估。通过右心导管、心脏超声和心脏组织采集，在 1、2、4 和 6 周时对大鼠进行检测。我们的研究发现，随着右心室收缩压的升高，右心室超声心动图指标逐渐恶化，在 PH 发展过程中，右心功能障碍发生的时间早于肺动脉壁增厚。此外，肌浆内质网钙 ATP 酶 2（SERCA2）是心肌损伤的标志物，在 SuHx 诱导的 PH 的第 2 周高度表达，在所有时间点 γ-H2AX 的表达水平更高，第 4 周和第 6 周 DDR 相关蛋白 p-ATM 和 p53/p-p53 和 p21 的表达水平也更高。本研究表明，在 PH 早期发展过程中，右心室的结构和功能开始随着 DNA 损伤和细胞衰老而恶化。
