Okumura Kenichi, Kato Hideyuki, Honjo Osami, Breitling Siegfried, Kuebler Wolfgang M, Sun Mei, Friedberg Mark K
The Labatt Family Heart Center, Division of Cardiology and Cardiovascular Surgery, Hospital for Sick Children and University of Toronto, Toronto, ON, Canada.
J Mol Med (Berl). 2015 Jun;93(6):663-74. doi: 10.1007/s00109-015-1251-9. Epub 2015 Jan 18.
Left ventricular (LV) function influences outcomes in right ventricular (RV) failure. Carvedilol reduces mortality in LV failure and improves RV function in experimental pulmonary arterial hypertension (PAH). However, its impact on ventricular-ventricular interactions and LV function in RV afterload is unknown. We investigated effects of carvedilol on biventricular fibrosis and function in a rat model of persistent PAH. Rats were randomized into three groups: Sham controls, PAH, and PAH + carvedilol. Severe PAH was induced by 60 mg/kg subcutaneous monocrotaline. In the treatment group, oral carvedilol (15 mg/kg/day) was started 2 weeks after monocrotaline injection and continued for 3 weeks until the terminal experiment. Echocardiography and exercise performance were performed at baseline and repeated at the terminal experiment with hemodynamic measurements. LV and RV myocardium were analyzed for hypertrophy, fibrosis, and molecular signaling by protein and mRNA analysis. PAH and PAH + carvedilol rats experienced severely elevated pulmonary arterial pressures and RV hypertrophy. Despite similar RV systolic pressures, carvedilol reduced biventricular collagen content (RV fibrosis area; 13.4 ± 6.5 vs. 5.5 ± 2.7 %, p < 0.001) and expression of transforming growth factor-β1 (TGFβ1) (RV TGFβ1/glyceraldehyde 3-phosphate dehydrogenase (GAPDH) ratio; 1.16 ± 0.39 vs. 0.57 ± 0.22, p < 0.01) and connective tissue growth factor (CTGF) (RV CTGF/GAPDH ratio; 0.49 ± 0.06 vs. 0.35 ± 0.17, p < 0.05). RV pro-apoptotic caspase-8 was increased in PAH compared to controls and was significantly reduced in both ventricles compared to PAH animals by carvedilol. Tissue effects were accompanied by improved biventricular systolic and diastolic performance and exercise treadmill distance (36 ± 30 vs. 80 ± 33 m, p < 0.05). In RV pressure-load, carvedilol improves biventricular fibrosis and function through abrogation of TGFβ1-CTGF signaling.
• RV afterload caused biventricular injury and dysfunction through TGFβ1-CTGF signaling. • Carvedilol reduced biventricular TGFβ1-CTGF signaling, fibrosis, and apoptosis. • Carvedilol improved cardiac output and biventricular function. • Improved fibrosis and hemodynamics occurred despite persistent RV afterload.
左心室（LV）功能影响右心室（RV）衰竭的预后。卡维地洛可降低左心室衰竭的死亡率，并改善实验性肺动脉高压（PAH）中的右心室功能。然而，其对心室-心室相互作用以及右心室后负荷下左心室功能的影响尚不清楚。我们在持续性PAH大鼠模型中研究了卡维地洛对双心室纤维化和功能的影响。大鼠被随机分为三组：假手术对照组、PAH组和PAH + 卡维地洛组。通过皮下注射60 mg/kg的野百合碱诱导严重PAH。在治疗组中，卡维地洛口服（15 mg/kg/天）在野百合碱注射后2周开始，并持续3周直至终末实验。在基线时进行超声心动图和运动能力测试，并在终末实验时重复进行，同时进行血流动力学测量。通过蛋白质和mRNA分析对左心室和右心室心肌进行肥大、纤维化和分子信号分析。PAH组和PAH + 卡维地洛组大鼠的肺动脉压力严重升高且右心室肥大。尽管右心室收缩压相似，但卡维地洛降低了双心室胶原含量（右心室纤维化面积；13.4±6.5%对5.5±2.7%，p<0.001）以及转化生长因子-β1（TGFβ1）的表达（右心室TGFβ1/甘油醛-3-磷酸脱氢酶（GAPDH）比值；1.16±0.39对0.57±0.22，p<0.01）和结缔组织生长因子（CTGF）（右心室CTGF/GAPDH比值；0.49±0.06对0.35±0.17，p<0.05）。与对照组相比，PAH组右心室促凋亡半胱天冬酶-8增加，而与PAH动物相比，卡维地洛使双心室中的该酶显著降低。组织效应伴随着双心室收缩和舒张功能的改善以及运动平板距离的增加（36±30米对80±33米，p<0.（此处原文似乎有误，推测应为p<0.05））。在右心室压力负荷下，卡维地洛通过消除TGFβ1-CTGF信号改善双心室纤维化和功能。
• 右心室后负荷通过TGFβ1-CTGF信号导致双心室损伤和功能障碍。
• 卡维地洛降低双心室TGFβ1-CTGF信号、纤维化和凋亡。
• 卡维地洛改善心输出量和双心室功能。
• 尽管右心室后负荷持续存在，但纤维化和血流动力学仍得到改善。
