Growth hormone-releasing hormone agonists reduce myocardial infarct scar in swine with subacute ischemic cardiomyopathy.
Growth hormone-releasing hormone agonists reduce myocardial infarct scar in swine with subacute ischemic cardiomyopathy.
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DOI：
10.1161/jaha.114.001464
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发表时间：
2015-03-31
影响因子：
5.4
通讯作者：
Hare JM
中科院分区：
文献类型：
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作者：
Bagno LL;Kanashiro-Takeuchi RM;Suncion VY;Golpanian S;Karantalis V;Wolf A;Wang B;Premer C;Balkan W;Rodriguez J;Valdes D;Rosado M;Block NL;Goldstein P;Morales A;Cai RZ;Sha W;Schally AV;Hare JM
生长激素释放激素激动剂（GHRH-As）通过激活心脏内的GHRH信号通路刺激大鼠心肌梗死（MI）后的心脏修复。我们在猪亚急性心肌梗死模型中检验了GHRH-As给药预防心室重构的假设。12只雌性约克郡猪（25 - 30 kg）接受了冠状动脉左前降支（MI）的短暂闭塞。MI后两周，将猪随机接受30 μg/kg GHRH-A（MR-409）（GHRH-A组; n=6）或溶媒（安慰剂组; n=6）注射。在多个时间点获得心脏磁共振成像和压力-容积环。通过免疫组织化学方法对脑梗死区、边缘区和远端（非梗死区）的GHRH受体进行评估。四周的GHRH-A治疗导致疤痕质量减少（GHRH-A：−21.9±6.42%; P=0.02;安慰剂：10.9±5.88%; P=0.25;双因素方差分析; P=0.003）和瘢痕大小（左心室质量百分比）（GHRH-A：−38.38±4.63; P=0.0002;安慰剂：−14.56±6.92; P=0.16;双因素方差分析; P=0.02）。这伴随着舒张期应变的改善。与大鼠不同，通过连续血流动力学压力-容积分析测量，猪的梗死面积减少并不伴随心脏功能改善。心脏组织中GHRH受体丰富，与安慰剂组相比，GHRH-A组的边缘区密度更大。在亚急性缺血性心肌病的大型动物模型中，每日皮下注射GHRH-A是可行且安全的。此外，GHRH-A治疗显著减少了梗死面积并改善了舒张期应变，表明GHRH通路的局部激活导致了修复过程。
Growth hormone–releasing hormone agonists (GHRH‐As) stimulate cardiac repair following myocardial infarction (MI) in rats through the activation of the GHRH signaling pathway within the heart. We tested the hypothesis that the administration of GHRH‐As prevents ventricular remodeling in a swine subacute MI model. Twelve female Yorkshire swine (25 to 30 kg) underwent transient occlusion of the left anterior descending coronary artery (MI). Two weeks post MI, swine were randomized to receive injections of either 30 μg/kg GHRH‐A (MR‐409) (GHRH‐A group; n=6) or vehicle (placebo group; n=6). Cardiac magnetic resonance imaging and pressure–volume loops were obtained at multiple time points. Infarct, border, and remote (noninfarcted) zones were assessed for GHRH receptor by immunohistochemistry. Four weeks of GHRH‐A treatment resulted in reduced scar mass (GHRH‐A: −21.9±6.42%; P=0.02; placebo: 10.9±5.88%; P=0.25; 2‐way ANOVA; P=0.003), and scar size (percentage of left ventricular mass) (GHRH‐A: −38.38±4.63; P=0.0002; placebo: −14.56±6.92; P=0.16; 2‐way ANOVA; P=0.02). This was accompanied by improved diastolic strain. Unlike in rats, this reduced infarct size in swine was not accompanied by improved cardiac function as measured by serial hemodynamic pressure–volume analysis. GHRH receptors were abundant in cardiac tissue, with a greater density in the border zone of the GHRH‐A group compared with the placebo group. Daily subcutaneous administration of GHRH‐A is feasible and safe in a large animal model of subacute ischemic cardiomyopathy. Furthermore, GHRH‐A therapy significantly reduced infarct size and improved diastolic strain, suggesting a local activation of the GHRH pathway leading to the reparative process.