Treating Primary aldosteronism-induced hypertension via microwave thermal therapy

项目摘要 在这个美国-爱尔兰三方研发伙伴关系计划R 01研究计划中，我们提出开发， 优化和评估微创微波热治疗（MWT）系统， 原发性醛固酮增多症的确定性治疗。原发性醛固酮增多症（PA）占所有患者的5 - 12%。 高血压，并赋予更高的风险，心血管和脑血管并发症相比， 年龄和血压（BP）匹配的原发性高血压。然而，PA仍然诊断不足， 治疗不足，主要原因是大多数受影响者缺乏明确的管理选择 个体目前单侧PA的确定方法是手术切除肾上腺，而双侧PA则是手术切除肾上腺。 疾病通过药物管理;由于脱靶抗雄激素，药物治疗通常耐受性差 方面的影响.在所有确诊为PA的患者中，只有约30%接受了手术， 正常的皮质限制了单侧疾病的手术选择， 肾上腺皮质功能不全伴双侧肾上腺切除术因此，这一总体目标 一项提案是图像引导方法的开发、优化和实验评估 用于APA的亚消融MWT和肾上腺功能的治疗后评估。一是 采用一系列体外研究来确定用于渲染的最佳热剂量范围 功能亢进的肾上腺细胞在亚消融热剂量下死亡。然后我们将验证 在体内小鼠肿瘤模型中，在这些热剂量下破坏肾上腺细胞功能， 通过核磁共振温度成像追踪。接下来，我们将开发一个系统， 通过精确的微波辐射时空控制将MWT输送到功能亢进的肾上腺 细胞我们将开发实时技术，从实时成像中识别目标组织， 通过术前PET/CT成像定位功能亢进的肾上腺细胞， 引导施用器放置和能量输送。最后，我们将开发一种非碘化造影剂 适合于在MWT后立即验证肾上腺细胞功能，从而提供了一种方法， 评估治疗结果。将在大型动物模型中评价整个系统。如果 成功，并在未来的研究中转化为人类，这种方法将首次扩展到 对单侧和双侧APA患者进行明确的PA管理。 !

PROJECT SUMMARY In this tripartite US-Ireland R&D partnership program R01 research plan, we propose the development, optimization, and evaluation of a minimally-invasive microwave thermal therapy (MWT) system for definitive treatment of primary aldosteronism. Primary aldosteronism (PA) accounts for 5 - 12% of all hypertension and confers a higher risk for cardiovascular and cerebrovascular complications compared to age and blood pressure (BP) matched essential hypertension. Yet PA remains under-diagnosed and under-treated, largely due to the lack of definitive management options for the majority of affected individuals. The current definitive approach to unilateral PA is surgical adrenalectomy, while bilateral disease is managed medically; medical therapy is often poorly tolerated due to off target anti-androgen effects. Only ~30% of all individuals diagnosed with PA undergo surgery, and collateral resection of normal cortex limits the option of surgery to unilateral disease, given the inevitable risk for adrenocortical insufficiency with bilateral adrenalectomy. Therefore, the overall objective of this proposal is the development, optimization, and experimental evaluation of an image-guided approach for sub-ablative MWT of APAs, and for post-treatment assessment of adrenal function. First, we will employ a series of in vitro studies to determine the optimal range of thermal doses for rendering hyperfunctioning adrenal cells defunct, at sub-ablative thermal doses. We will then verify the ability to disrupt adrenal cell function at these thermal doses in an in vivo mouse tumor model, with thermal dose tracked via MRI temperature imaging. Next, we will develop a system employing microwave applicators with precise spatio-temporal control of microwave radiation to deliver MWT to hyperfunctioning adrenal cells. We will develop real-time techniques for identifying the targeted tissue from real-time imaging, informed by pre-procedural PET/CT imaging localizing the hyperfunctioning adrenal cells, in order to guide applicator placement and energy delivery. Finally, we will develop a non-iodinated contrast agent suitable for verifying adrenal cell function, immediately post MWT, thereby providing a means for assessing treatment outcome. The overall system will be evaluated in a large animal model. If successful, and translated to humans in future studies, this approach will, for the first time, extend definitive management of PA to individuals with unilateral and bilateral APAs. !