Horrigan M C, Malycky J L, Ellis S G, Topol E J, Nicolini F A
Joseph J. Jacobs Center for Thrombosis and Vascular Biology, Department of Cardiology, The Cleveland Clinic Foundation, Ohio, USA.
Int J Cardiol. 1999 Apr 10;68 Suppl 1:S85-91. doi: 10.1016/s0167-5273(98)00296-4.
In a canine model of permanent coronary occlusion it has been shown that basic fibroblast growth factor (bFGF) reduced infarct size and this was associated with an increase in myocardial capillary density a week after infarction. In a preliminary work from our own laboratory using a model of occlusion followed by prolonged reperfusion we observed a similar reduction in infarct size without evidence of myocardial neovascularization. The aim of the present investigation was to evaluate the effects of bFGF on infarct size and blood flow to the infarct zone in an acute experiment in which myocardial neovascularization would be excluded as a mechanism by the short duration of the study. Seventeen mongrel dogs were anesthetized and the heart was exposed through a left thoracotomy. The left anterior descending (LAD) coronary artery was isolated and occluded for 3 h. Fifteen min after LAD occlusion dogs received bFGF 20 microg of bFGF (n=6) or placebo (n=11) by intracoronary injection infused over 5 min. We measured heart rate, aortic pressure, regional coronary blood flow (CBF), regional shortening fraction (SF) at 1, 30 and 180 min of occlusion, then the LAD was reperfused for 5 min then the dogs were euthanized and infarct size was measured. Regional CBF was similar between the two groups of dogs throughout all the study. The SF was similar between the two groups prior the onset of ischemia and at the beginning of the ischemic period. After 180 min of ischemia SF was 2.7+/-4.1% for bFGF and -3.1+/-4.7 for placebo (P=0.049), and during reperfusion SF was 3.4+/-4.6% for bFGF and 0.4+/-1.0% for placebo treated dogs (P=0.023). The infarct size, normalized for the area at risk was 14.2+/-5.2% in bFGF group vs 25.8+/-8.2% in placebo group (P=0.015). In summary we have demonstrated that bFGF significantly limits myocardial necrosis after acute coronary occlusion, and that this occurred without an increase in regional myocardial perfusion and within a period of time too brief for angiogenesis to have occurred. By exclusion, it appears that the salutary effect of bFGF is likely to be mediated by a cellular mechanism. The mechanism or mechanisms responsible for myocardial salvage by bFGF may have significant potential to be exploited in the clinical arena as the basis for therapies to protect the acutely ischemic myocardium.
在永久性冠状动脉闭塞的犬模型中，已表明碱性成纤维细胞生长因子（bFGF）可减小梗死面积，且这与梗死后一周心肌毛细血管密度增加有关。在我们自己实验室的一项初步研究中，使用闭塞后长时间再灌注的模型，我们观察到梗死面积有类似减小，但没有心肌新生血管形成的证据。本研究的目的是在一项急性实验中评估bFGF对梗死面积和梗死区域血流的影响，在该实验中，由于研究持续时间短，心肌新生血管形成机制将被排除。17只杂种犬麻醉后，通过左胸切开术暴露心脏。分离左前降支（LAD）冠状动脉并闭塞3小时。LAD闭塞15分钟后，犬通过冠状动脉内注射在5分钟内输注20微克bFGF（n = 6）或安慰剂（n = 11）。我们在闭塞1、30和180分钟时测量心率、主动脉压、局部冠状动脉血流（CBF）、局部缩短分数（SF），然后LAD再灌注5分钟，然后对犬实施安乐死并测量梗死面积。在整个研究过程中，两组犬的局部CBF相似。在缺血发作前和缺血期开始时，两组的SF相似。缺血180分钟后，bFGF组的SF为2.7±4.1%，安慰剂组为-3.1±4.7%（P = 0.049），再灌注期间，bFGF治疗的犬SF为3.4±4.6%，安慰剂治疗的犬为0.4±1.0%（P = 0.023）。以危险区域面积标准化后的梗死面积，bFGF组为14.2±5.2%，安慰剂组为25.8±8.2%（P = 0.015）。总之，我们已证明bFGF可显著限制急性冠状动脉闭塞后的心肌坏死，且这发生在局部心肌灌注未增加且血管生成发生时间过短的时间段内。通过排除法可知，bFGF的有益作用可能是由细胞机制介导的。bFGF挽救心肌的一种或多种机制在临床领域作为保护急性缺血心肌的治疗基础可能具有巨大的开发潜力。
