Low-Energy Shockwave Treatment Distal To Peripheral Vascular Disease

描述(申请人提供)：外周血管疾病(PVD)在西方世界老龄化的人口中变得越来越常见。与大血管PVD相关的肾血管性高血压(RVH)会导致下游微血管(MV)重构和丢失，而血管再通后往往是不可逆的。遗憾的是，恢复微循环和改善RVH和PVD预后的适当策略尚未确定，仍然迫切需要。无创低能量体外冲击波治疗(SWT)是一种新的实验策略，它产生的机械力对细胞膜施加局部应力，并在心血管和肌肉骨骼系统引发生物反应，包括抑制炎症和刺激新的MV形成。值得注意的是，这种新方法在保护慢性RVH微循环和提高MV存活率方面的潜力尚未被探索。我们开发了新的猪RVH模型，并对其进行了表征，这种模型非常接近人类的病理生理学。此外，我们开发和改进了独特的成像技术，非常适合于探测PVD的MV适应性过程，以及它们对MV损伤和生存的潜在贡献。这些工具现在提供了一个独特的机会来评估低能量体外SWT对RVH的病理生理学和预后的影响，以及用新的干预措施修改它们的可行性。支持这一建议的工作假设是，SWT治疗RVH-PVD是安全的，可以减少MV损伤，改善功能和氧合，从而在恢复上游血管通畅时改善恢复。为了验证这一假设，我们将利用先进的多探测器CT(MDCT)、磁共振成像(MRI)和使用创新工具的微型CT来研究SWT的效果。此外，SWT改善肾脏恢复前景的能力将在接受血管重建和支架植入的PVD猪身上进行测试。将追求两个具体目标：具体目标1将检验SWT是安全的假设，并在4周后改善血管阻塞远端的功能和结构。具体目标2将验证SWT将恢复肾恢复潜力的假说，以回应PVD的血运重建。这些研究将促进我们对PVD远端MV损伤发病机制的认识，并可能建立一种新的、临床可行的治疗策略。MV网络的改进在心血管医学领域是一项很有前途的技术，但这一前沿技术尚未应用于RVH-PVD。因此，这些研究可能会对PVD的管理做出重大贡献。

DESCRIPTION (provided by applicant): Peripheral vascular disease (PVD) is becoming increasingly common in the aging population of the Western world. Renovascular hypertension (RVH) associated with large vessel PVD induces remodeling and loss of downstream microvessels (MV), which are often irreversible after restoration of vascular patency. Alas, adequate strategies to restore the microcirculation and improve outcomes in RVH and PVD are yet to be identified and remain in dire need. Non-invasive low-energy extracorporeal shock wave treatment (SWT) is a novel experimental strategy, which generates mechanical forces that exert localized stress on cell membranes and elicit biological responses in the cardiovascular and musculoskeletal systems, including suppression of inflammation and stimulation of new MV formation. Remarkably, the potential of this novel approach to protect the microcirculation in chronic RVH and increase MV viability has not been explored. We have developed and characterized novel swine models of RVH that closely mimic human pathophysiology. Furthermore, we have developed and refined unique imaging techniques ideally suited for probing MV adaptive processes in PVD, as well as their potential contribution to MV injury and viability. These tools now provide a unique opportunity to assess the effects of low-energy extracorporeal SWT on pathophysiology and outcomes in RVH, and the feasibility of modifying them with novel interventions. The working hypothesis underlying this proposal is that SWT in RVH-PVD is safe, and would decrease MV injury, improve function and oxygenation, and thereby improve recovery upon restoration of upstream vascular patency. To test this hypothesis, we will study the effects of SWT utilizing a combination of cutting- edge multi-detector CT (MDCT), magnetic resonance imaging (MRI), and micro-CT using innovative tools. Furthermore, the ability of SWT to improve renal recovery prospects will be tested in PVD pigs undergoing revascularization and stenting. Two specific aims will be pursued: Specific Aim 1 will test the hypothesis that SWT is safe, and would improve function and structure distal to vascular obstruction 4 weeks later. Specific Aim 2 will test the hypothesis that SWT would restore the recovery potential of the kidney in response to revascularization of PVD. The proposed studies will advance our understanding of the pathogenesis of MV injury distal to PVD, and may establish a novel, clinically feasible therapeutic strategy. Improvement of the MV network is a promising technique in cardiovascular medicine, but this cutting edge approach is yet to be applied in RVH-PVD. Thus, these studies will likely contribute significantly towards management of PVD.