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.

项目总结/摘要 高血压是心血管疾病的重要危险因素之一。近一半的HTN 患者对生活方式改变和基于药物的治疗有抵抗力或不依从，因此， 迫切需要的。虽然HTN与交感神经活动增加有关，但肾传出神经活动增加。 神经传统上一直是研究的焦点，因为它们将交感神经冲动从 大脑调节血压。然而，肾脏也受肾传入（感觉）神经支配， 它投射到大脑中调节交感神经输出并导致HTN的回路。临床试验使用 基于导管的全（传出和传入）肾神经消融（TRDN）已被证明有效降低 难治性HTN患者的动脉压。尽管这种干预的有效性，它是未知的，如果消融 传出或传入肾神经在降低动脉压方面更为重要。为了阐明 肾传入神经在HTN中的作用，我们实验室开发了一种新的肾传入神经消融方法 （ARDN），并发现ARDN在降低动脉压方面与TRDN一样有效。 醋酸脱氧皮质酮和高盐饮食（DOCA-盐）诱导的HTN啮齿动物模型。临床上，如果ARDN能够 降低动脉压至与TRDN相同的程度，可保留传出肾神经以维持血液 压力和容量对出血性或感染性休克的反应。此外，TRDN显示了变量 在某些患者中的疗效，以及缺乏生物标志物来预测动脉压对TRDN的反应， 外地的大缺口。我们实验室最近的研究表明，特定炎症细胞因子的存在 可以鉴别肾脏炎症。这些细胞因子可过度刺激传入肾神经， 增加了交感神经输出和HTN。我打算把DOCA盐HTN的发现 将啮齿类动物与DOCA-盐HTN绵羊模型进行比较。HTN的解剖、生理和血液动力学特性 绵羊的病理生理学更接近人类，并且允许使用人类TRDN导管。 因此，本提案的总体目标是开发和验证基于导管的ARDN方法， HTN绵羊模型，以解决该领域目前的差距，并更接近高血压的临床治疗。 我们的中心假设是，基于导管的ARDN将降低动脉压的程度与TRDN相同， 通过特异性的肾脏炎症标志物可以预测动脉压对TRDN的反应。 我将通过以下目的来检验这一假设：（1）比较基于导管的ARDN与TRDN的疗效 在羊的HTN模型中。(2)尿生物标志物在肾功能测定中的应用 与HTN相关的炎症来预测TRDN的抗HTN功效。如果成功， 拟议的研究将提供一个转化平台，随后进入基于导管的临床试验， 人类的ARDN。此外，这种基于导管的神经调节方法也可以应用于其他神经调节。 慢性炎症驱动其他神经源性疾病的器官（肝、脾）。