Serial and regional assessment of the right ventricular molecular and functional response to pressure-loading

Background: Right ventricular(RV) function determines outcomes in RV pressure-loading. A better understanding of the time-course and regional distribution of RV remodeling may help optimize targets and timing for therapeutic intervention. We sought to characterize RV remodeling between zero and 6-weeks after initiation of RV pressure-loading. Methods and results: Thirty-six rats were randomized to either sham surgery or to pulmonary artery banding(PAB). After echocardiography and conductance catheter studies, groups of rats were euthanized at 1-week, 3-weeks, and 6-weeks after sham surgery, or induction of RV pressure-loading, for RV histological, RNA and molecular analysis. A vigorous inflammatory response characterized by increased RV inflammatory cytokines, chemokines and macrophage markers was observed at 1-week following PAB. Metabolic changes, TGF-β1 canonical signaling, collagenous fibrosis deposition and apoptosis were already significantly increased by 1-week after PAB. Genes marking fibroblast activation were upregulated at 1-week but not 6-week post-PAB surgery. Mitochondrial dysfunction as evidenced by increased PDK activity and decreased PDH phosphorylation significantly at 6-week post PAB. These processes preceded the development of overt myocardial hypertrophy and impaired echo parameters of systolic and diastolic function which occurred significantly from 3-weeks after PAB. Conclusion: RV myocardial inflammation, metabolic shift, metabolic gene transcription and pro-fibrotic signaling occur early after initiation of pressure-loading when RV pressures are only moderately elevated, before the development of overt myocardial hypertrophy and dysfunction, suggesting that adaptive hypertrophy and maladaptive remodeling occur simultaneously. These results suggest that therapeutic intervention to reduce adverse RV remodeling may be needed earlier and at lower thresholds than currently employed背景：右心室（Right ventricular, RV）功能是右心室压力负荷状态下预后的决定性因素。对右心室重构的时间进程与区域分布的深入认知，有助于优化治疗干预的靶点与时机。本研究旨在明确右心室压力负荷诱导后0至6周内的右心室重构特征。 方法与结果：将36只大鼠随机分为假手术组与肺动脉环扎术（Pulmonary Artery Banding, PAB）组。在完成超声心动图与电导导管检测后，分别于假手术或右心室压力负荷造模后的第1、3、6周处死各组大鼠，用于右心室组织学、RNA及分子生物学分析。PAB造模后第1周即可观察到以右心室炎症因子、趋化因子及巨噬细胞标志物水平升高为特征的剧烈炎症反应；造模后第1周，代谢重塑、转化生长因子β1（Transforming Growth Factor-β1, TGF-β1）经典信号通路、胶原纤维化沉积及细胞凋亡水平即已显著升高。标记成纤维细胞活化的基因在PAB术后第1周出现上调，但术后第6周无此变化；PAB术后第6周，以丙酮酸脱氢酶激酶（Pyruvate Dehydrogenase Kinase, PDK）活性升高、丙酮酸脱氢酶（Pyruvate Dehydrogenase, PDH）磷酸化水平降低为特征的线粒体功能障碍显著出现。上述病理过程均早于显性心肌肥厚及超声心动图显示的收缩、舒张功能损伤的发生——后者于PAB术后第3周起显著出现。 结论：右心室心肌炎症、代谢重塑、代谢基因转录及促纤维化信号通路在压力负荷诱导早期即已出现，此时右心室压力仅为中度升高，且早于显性心肌肥厚与功能障碍的发生，提示适应性肥厚与不良重构可同时发生。本研究结果提示，针对右心室不良重构的治疗干预，可能需要比当前临床所采用的更早开展、且采用更低的干预阈值。