Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.
Am J Cardiovasc Drugs. 2011 Oct 1;11(5):295-302. doi: 10.2165/11592760-000000000-00000.
Ischemic heart disease is the leading cause of death and a major cause of hospital admissions, with the number of affected patients increasing worldwide. The current management of ischemic heart disease has three major therapeutic options: medication, percutaneous coronary intervention (PCI), and coronary artery bypass grafting (CABG). However, the prognosis for patients with severe ischemic heart disease without indications for PCI or CABG still remains poor due to the lack of effective treatments. It is therefore crucial to develop alternative therapeutic strategies for severe ischemic heart disease. Extracorporeal shock wave (SW) therapy was introduced clinically more than 20 years ago to fragment kidney stones, which has markedly improved the treatment of urolithiasis. We found that a low-energy SW (about 10% of the energy density used for urolithiasis) effectively increases the expression of vascular endothelial growth factor (VEGF) in cultured endothelial cells. Based on this in vitro study, we initiated in vivo studies and have demonstrated that extracorporeal cardiac SW therapy with a low-energy SW up-regulates the expression of VEGF, induces neovascularization, and improves myocardial ischemia in a porcine model of chronic myocardial ischemia, without any adverse effects in vivo. On the basis of promising results in animal studies, we performed a series of clinical studies in patients with severe coronary artery disease without indication for PCI or CABG, including, firstly, an open trial followed by a placebo-controlled, double-blind study. In both studies, our extracorporeal cardiac SW therapy improved symptoms, exercise capacity, and myocardial perfusion in patients with severe coronary artery disease. Importantly, no procedural complications or adverse effects were noted. The SW therapy was also effective in ameliorating left ventricular remodeling after acute myocardial infarction (MI) in pigs and in enhancing angiogenesis in hind-limb ischemia in rabbits. Based on these animal studies, we are also conducting clinical studies in patients with acute MI and in those with peripheral artery disease. Thus, our extracorporeal cardiac SW therapy appears to be an effective, safe, and non-invasive angiogenic approach in cardiovascular medicine and its indication could be extended to a variety of ischemic diseases in the near future. In this article, we briefly summarize our work in animals and humans, and discuss the advantages and perspectives of our extracorporeal SW therapy.
缺血性心脏病是全球范围内导致死亡的主要原因之一，也是住院治疗的主要原因之一，其患病人数不断增加。目前，缺血性心脏病的治疗方法主要有三种：药物治疗、经皮冠状动脉介入治疗（PCI）和冠状动脉旁路移植术（CABG）。然而，对于没有 PCI 或 CABG 适应证的严重缺血性心脏病患者，由于缺乏有效的治疗方法，其预后仍然较差。因此，开发治疗严重缺血性心脏病的替代治疗策略至关重要。体外冲击波（SW）治疗在 20 多年前被引入临床，用于击碎肾结石，这显著改善了尿石症的治疗效果。我们发现，低能量 SW（约为肾结石治疗能量密度的 10%）可有效增加培养内皮细胞中血管内皮生长因子（VEGF）的表达。基于这项体外研究，我们启动了体内研究，并证明了体外心脏 SW 治疗使用低能量 SW 可上调 VEGF 的表达，诱导新生血管形成，并改善慢性心肌缺血猪模型中的心肌缺血，而在体内没有任何不良反应。在动物研究取得有希望的结果的基础上，我们对严重冠状动脉疾病且没有 PCI 或 CABG 适应证的患者进行了一系列临床研究，首先是一项开放试验，然后是一项安慰剂对照、双盲研究。在这两项研究中，我们的体外心脏 SW 治疗均改善了严重冠状动脉疾病患者的症状、运动能力和心肌灌注。重要的是，没有观察到程序并发症或不良反应。SW 治疗还可改善猪急性心肌梗死后的左心室重构，并增强兔后肢缺血模型中的血管生成。基于这些动物研究，我们还在急性心肌梗死和外周动脉疾病患者中开展了临床试验。因此，我们的体外心脏 SW 治疗似乎是一种有效的、安全的、非侵入性的血管生成方法，在心血管医学及其适应证中可以扩展到不久的将来各种缺血性疾病。在本文中，我们简要总结了我们在动物和人类中的工作，并讨论了我们的体外 SW 治疗的优势和前景。
