Centre for Heart Research, Westmead Institute for Medical Research, The University of Sydney, Westmead, NSW 2145, Australia.
Department of Cardiology, Westmead Hospital, Westmead, NSW 2145, Australia.
Sci Transl Med. 2020 Jan 1;12(524). doi: 10.1126/scitranslmed.aay2140.
Therapies that target scar formation after myocardial infarction (MI) could prevent ensuing heart failure or death from ventricular arrhythmias. We have previously shown that recombinant human platelet-derived growth factor-AB (rhPDGF-AB) improves cardiac function in a rodent model of MI. To progress clinical translation, we evaluated rhPDGF-AB treatment in a clinically relevant porcine model of myocardial ischemia-reperfusion. Thirty-six pigs were randomized to sham procedure or balloon occlusion of the proximal left anterior descending coronary artery with 7-day intravenous infusion of rhPDGF-AB or vehicle. One month after MI, rhPDGF-AB improved survival by 40% compared with vehicle, and cardiac magnetic resonance imaging showed left ventricular (LV) ejection fraction improved by 11.5%, driven by reduced LV end-systolic volumes. Pressure volume loop analyses revealed improved myocardial contractility and energetics after rhPDGF-AB treatment with minimal effect on ventricular compliance. rhPDGF-AB enhanced angiogenesis and increased scar anisotropy (high fiber alignment) without affecting overall scar size or stiffness. rhPDGF-AB reduced inducible ventricular tachycardia by decreasing heterogeneity of the ventricular scar that provides a substrate for reentrant circuits. In summary, we demonstrated that rhPDGF-AB promotes post-MI cardiac wound repair by altering the mechanics of the infarct scar, resulting in robust cardiac functional improvement, decreased ventricular arrhythmias, and improved survival. Our findings suggest a strong translational potential for rhPDGF-AB as an adjunct to current MI treatment and possibly to modulate scar in other organs.
针对心肌梗死后瘢痕形成的治疗方法可以预防心力衰竭或室性心律失常导致的死亡。我们之前已经证明，重组人血小板衍生生长因子 AB（rhPDGF-AB）可改善心肌梗死后啮齿动物模型的心脏功能。为了推进临床转化，我们在具有临床相关性的猪心肌缺血再灌注模型中评估了 rhPDGF-AB 治疗。36 头猪随机分为假手术组或球囊阻塞左前降支近端，同时接受 7 天静脉内输注 rhPDGF-AB 或载体。心肌梗死后 1 个月，rhPDGF-AB 治疗组的存活率比载体组提高了 40%，心脏磁共振成像显示左心室射血分数提高了 11.5%，这是由左心室收缩末期容积减少驱动的。压力-容积环分析显示，rhPDGF-AB 治疗后心肌收缩力和能量学得到改善，而对心室顺应性的影响最小。rhPDGF-AB 增强了血管生成，并增加了瘢痕各向异性（高纤维排列），而不影响整体瘢痕大小或硬度。rhPDGF-AB 通过减少提供折返电路基质的心室瘢痕的异质性，减少了可诱导性室性心动过速。总之，我们证明 rhPDGF-AB 通过改变梗死瘢痕的力学特性来促进心肌梗死后的心脏伤口修复，从而实现强大的心脏功能改善、减少室性心律失常和提高存活率。我们的发现表明，rhPDGF-AB 作为当前心肌梗死治疗的辅助手段具有很强的转化潜力，并且可能调节其他器官的瘢痕。
