Evaluating the Mechanisms of Afferent Renal Nerve Ablation as a Treatment for Hypertension

评估传入肾神经消融治疗高血压的机制

• 批准号: 10604700
• 负责人: Arthur Trenton de la Cruz-Lynch
• 金额: $ 3.99万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10604700
• 关键词: Ablation; Acetates; Address; Aftercare; Anatomy; Antihypertensive Agents; Applications Grants; Biological Markers; Blood Pressure; Blood Volume; Brain; CXCL10 gene; CXCR3 gene; Capsaicin; Cardiac Output; Cardiovascular Diseases; Catheters; Cells; Chronic; Clinical; Clinical Trials; Deoxycorticosterone; Disease; Doctor of Philosophy; Drug resistance; Echocardiography; Efferent Neurons; Ensure; Enzyme-Linked Immunosorbent Assay; Ethanol; Foundations; Functional disorder; Future; Goals; Harvest; Hemorrhagic Shock; Human; Hypertension; IL17 gene; Immune; Immunohistochemistry; Implant; Inflammation; Inflammatory; Interleukin-1 alpha; Intervention; Kidney; Laboratories; Life Style Modification; Liver; Measurement; Measures; Methods; Modeling; Monitor; Nerve; Nervous System; Operative Surgical Procedures; Organ; Output; Patients; Peripheral; Pharmaceutical Preparations; Physicians; Physiological; Plasma; Play; Pre-Clinical Model; Property; Rattus; Reporting; Research; Resistance; Resistant Hypertension; Rodent; Rodent Model; Role; Saline; Sampling; Scientist; Sensory; Septic Shock; Sheep; Spleen; TNF gene; Technology; Testing; Therapeutic; Translating; Translational Research; Treatment Efficacy; Tunica Adventitia; Urine; afferent nerve; blood pressure reduction; blood pressure regulation; cardiovascular risk factor; chemokine; clinically relevant; clinically significant; comparative efficacy; cytokine; experimental study; heart function; hemodynamics; high salt diet; hypertension treatment; insight; minimally invasive; neuroregulation; neurotransmission; novel; novel therapeutics; preservation; pressure; renal artery; response; sheep model; skills; success; telemetering; transmission process; urinary

PROJECT SUMMARY/ABSTRACT Hypertension (HTN) is one of the most important risk factors for cardiovascular disease. Nearly half of HTN patients are resistant or nonadherent to lifestyle modification and drug-based therapy, so novel therapies are desperately needed. While HTN is associated with increased global sympathetic nerve activity, renal efferent nerves have traditionally been the focus of research since they transmit sympathetic nerve impulses from the brain to regulate blood pressure. However, the kidneys are also innervated by renal afferent (sensory) nerves, which project to circuits in the brain that modulate sympathetic nerve output and cause HTN. Clinical trials using catheter-based total (efferent and afferent) renal nerve ablation (TRDN) have been shown to effectively lower arterial pressure in treatment-resistant HTN patients. Despite this intervention’s efficacy, it is unknown if ablation of the efferent or afferent renal nerves is more important in lowering arterial pressure. To elucidate the role that afferent renal nerves play in HTN, our laboratory developed a novel method of afferent renal nerve ablation (ARDN) and found that ARDN was as effective as TRDN in decreasing arterial pressure in the deoxycorticosterone acetate and high salt diet (DOCA-salt) induced HTN rodent model. Clinically, if ARDN can lower arterial pressure to the same degree as TRDN, efferent renal nerves could be preserved to maintain blood pressure and volume in response to hemorrhagic or septic shock. Furthermore, TRDN has shown variable efficacy in certain patients, and the lack of biomarkers to predict the arterial pressure response to TRDN is a major gap in the field. Recent studies from our lab suggest that the presence of specific inflammatory cytokines in the urine can identify renal inflammation. These cytokines can overstimulate afferent renal nerves and cause increased global sympathetic nerve output and HTN. I plan on translating our findings from DOCA-salt HTN rodents to the DOCA-salt HTN sheep model. The anatomic, physiologic, and hemodynamic properties of HTN sheep more closely resemble human pathophysiology and allows for the use of human TRDN catheters. Therefore, the overall goal of this proposal is to develop and validate a catheter-based ARDN method using the HTN sheep model to address current gaps in the field and move closer to a clinical therapeutic for hypertension. Our central hypothesis is that catheter-based ARDN will decrease arterial pressure to the same degree as TRDN, and the arterial pressure response to TRDN can be predicted by specific urinary markers of renal inflammation. I will test this hypothesis with the following aims: (1) Compare the efficacy of catheter-based ARDN versus TRDN in an established model of HTN in sheep. (2) Validate the utility of urinary biomarkers to measure renal inflammation associated with HTN to predict the anti-HTN efficacy of TRDN. If successful, the results of the proposed studies will provide a translational platform to subsequently move into clinical trials of catheter-based ARDN in humans. Furthermore, this catheter-based neuromodulation approach can also be applied to other organs (liver, spleen) in which chronic inflammation drives other neurogenically based diseases.

项目摘要/摘要 高血压（HTN）是心血管疾病最重要的危险因素之一。近一半的HTN 患者对生活方式改良和基于药物的治疗具有抗性或不牢固性，因此新型疗法是 迫切需要。 HTN与全球交感神经活动增加有关，肾脏有效 传统上，神经是研究的重点，因为它们从 大脑调节血压。但是，孩子们也受到肾脏传入（感觉）神经的支配， 哪个项目向大脑中的圆圈调节，以调节交感神经输出并引起HTN。使用临床试验 基于导管的总（传出和传入）肾神经消融（TRDN）已有效降低 耐治疗的HTN患者中的动脉压。尽管这种干预的效率，但尚不清楚是否消融 在降低动脉压的有效或传入的肾神经中更重要。阐明角色 传入的肾神经在HTN中发挥作用，我们的实验室开发了一种新颖的传入肾神经消融方法 （ARDN），发现ARDN与TRDN一样有效，可在降低动脉压中 乙酸脱氧核心酮和高盐饮食（DOCA盐）诱导的HTN啮齿动物模型。临床上，如果Ardn可以 与TRDN相同程度的下动脉压，可以保留有效的肾神经以保持血液 响应出血或败血性休克的压力和体积。此外，TRDN显示了变量 某些患者的功效以及缺乏预测动脉压反应TRDN的功效是 该领域的主要差距。我们实验室的最新研究表明，特定炎症细胞因子的存在 在尿液中可以识别肾脏注射。这些细胞因子会过分刺激传入的肾神经，并导致 增加了全球交感神经的神经输出和HTN。我计划从Doca-Salt HTN翻译我们的发现 Doca-Salt HTN绵羊模型的啮齿动物。 HTN的解剖学，生理和血液动力学特性 绵羊更像人类的病理生理学，并允许使用人类TRDN导管。 因此，该提案的总体目标是使用该方法开发和验证基于导管的ARDN方法 HTN绵羊模型解决了该领域的当前差距，并靠近临床治疗以进行高血压。 我们的中心假设是，基于成型的ARDN将使动脉压降低到与TRDN相同的程度， 并且可以通过肾脏注射的特定尿标志物来预测对TRDN的动脉压反应。 我将以以下目的检验该假设：（1）比较基于导管的ARDN与TRDN的效率 在既有的HTN绵羊中的既定模型中。 （2）验证尿生物标志物测量肾脏的效用 与HTN相关的炎症，以预测TRDN的抗HTN效率。如果成功， 拟议的研究将提供一个翻译的平台，以随后进入基于导管的临床试验 人类中的ardn。此外，这种基于导管的神经调节方法也可以应用于其他 器官（肝脏，脾脏），其中慢性炎症驱动其他基于神经源的疾病。