Planning Grant for Reduction of Uric Acid to Prevent Hypertension (RAPHY) Trial

降低尿酸预防高血压 (RAPHY) 试验规划拨款

• 批准号: 7641968
• 负责人: DANIEL I FEIG
• 金额: $ 17.48万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-15 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7641968
• 关键词: Adolescent; Adult; Advisory Committees; Affect; Aftercare; Age; Alcohol consumption; Allopurinol; American; Angiotensin Receptor; Angiotensins; Animal Model; Animals; Attenuated; Blood Pressure; Body Weight decreased; Cardiovascular Diseases; Cessation of life; Chronic; Clinical; Clinical Trials; Clinical trial protocol document; DASH diet; Data; Development; Diabetes Mellitus; Diastolic blood pressure; Disease; Dose; Double-Blind Method; End stage renal failure; Epidemic; Essential Hypertension; Functional disorder; Funding; Goals; Grant; Heart failure; Homeostasis; Human; Hypertension; Incidence; Inflammation; Insulin Resistance; Intake; Kidney; Mediating; Metabolic; Metabolic syndrome; Multi-Institutional Clinical Trial; National Heart, Lung, and Blood Institute; Nitric Oxide; Obesity; Oxidative Stress; Pamphlets; Pathogenesis; Patients; Physical activity; Placebos; Population; Preparation; Prevalence; Preventive; Public Health; Recommendation; Renin; Renin-Angiotensin System; Research Design; Research Ethics Committees; Research Personnel; Role; Serum; Site; Sodium; Stroke; System; Testing; Uric Acid; Vascular Diseases; Woman; abstracting; arteriole; blood pressure regulation; cardiovascular risk factor; control trial; follow-up; grasp; high risk; hypertension control; hypertension prevention; improved; men; novel; prevent; public health relevance; research study; vasoconstriction; young adult

DESCRIPTION (provided by applicant): Reduction of Uric Acid to Prevent Hypertension (RAPHY Trial) (Abstract) Hypertension affects one-third of the US population and is the major cause of cardiovascular disease. An elevated uric acid consistently predicts the development of hypertension and is commonly present in new onset hypertension. We found that nearly 90% of new onset hypertension in adolescents is associated with a high uric acid. In a recent double blind study we found that BP became normal in 86% of such adolescents when serum uric acid was lowered to < 5 mg/dl (vs 3% of placebo-treated subjects). Raising uric acid in animals also causes hypertension which is mediated by activation of the renin-angiotensin system, inhibition of endothelial function (lowering nitric oxide), and the development of vascular disease in the kidneys. Furthermore, both clinical and experimental studies also suggest lowering uric acid may have other benefits, including improvement in endothelial function and a reduction in the development of metabolic syndrome and diabetes. Our preliminary data suggest that uric acid mediated hypertension develops in a two step fashion, first by reversible vasoconstriction mediated by the renin-angiotensin system and reduction of endothelial NO, the second by irreversible alteration of renal afferent arterioles leading to a permanent sodium dependent hypertension. These data suggest that there may be a window of opportunity for the prevention of hypertension in the young. Consequently, we propose a 15-center clinical trial to test the hypotheses that lowering uric acid will reduce the progressive rise in blood pressure and decrease the incidence of insulin resistance. Power analysis indicates that we will need 400 prehypertensive (by JNC7 criteria for adults and 4th Task Force criteria for adolescents) subjects age 12-50 with elevated uric acid levels (>6.0 mg/dl) to detect a 5 mmHg difference in systolic or diastolic BP between treated and control subjects after 1 year of treatment and after 2 years of post treatment follow up. The primary endpoints will be change in systolic and diastolic blood pressure and prevalence of insulin resistance at 12 and 36 months. The combined adolescent and young adult trial will determine the utility of hypouricemic therapy and the age range during which the therapy is effective. If the hypothesis is correct, this study will provide a novel and effective way to reduce the epidemic of hypertension, obesity and cardiovascular disease that current grips the world's population. PUBLIC HEALTH RELEVANCE: Planning Grant: Project Narrative Our preliminary studies in both animal models and human clinical trials suggest that elevated serum uric acid may be causally involved in the development of essential hypertension in adolescents. We propose a multi-center clinical trial to determine if reduction of serum uric acid will prevent the progressive rise in blood pressure in those at highest risk for development of hypertension, patients with pre-hypertension. This trial may provide a new paradigm for preventive therapy of hypertension, a disease that effecting more than 30% of Americans and causes nearly 1 million deaths a year in the USA.

描述（由申请人提供）：减少尿酸以防止高血压（Raphy试验）（摘要）高血压会影响美国人群的三分之一，并且是心血管疾病的主要原因。升高的尿酸一致地预测了高血压的发展，并且通常存在于新发作高血压中。我们发现，青少年中近90％的新发作高血压与高尿酸有关。在最近的一项双盲研究中，我们发现，当血清尿酸降低至<5 mg/dL时，在86％的此类青少年中，BP变得正常（占安慰剂治疗受试者的3％）。促进动物中的尿酸还会引起高血压，这是通过激活肾素 - 血管紧张素系统的激活，抑制内皮功能（降低一氧化氮）以及肾脏中血管疾病的发展而介导的。此外，临床和实验研究都表明，降低尿酸可能具有其他益处，包括内皮功能的改善以及代谢综合征和糖尿病的发展减少。我们的初步数据表明，尿酸介导的高血压以两步的方式发展，首先是由肾素 - 血管紧张素系统介导的可逆血管收缩和减少内皮NO的介导的，第二个是由于肾脏传入小动脉的不可逆转改变导致永久性钠依赖性钠依赖性高血压。这些数据表明，可能会有预防年轻人预防高血压的机会之窗。因此，我们提出了一项15个中心的临床试验，以测试降低尿酸将减少血压逐渐升高并降低胰岛素抵抗发生率的假设。功率分析表明，我们将需要400个型预性（根据成人的JNC7标准和青少年的第4个工作队标准）年龄在12-50岁之间，尿酸水平升高（> 6.0 mg/dl）才能在治疗和治疗后接受治疗和治疗后接受治疗和对照2年后，在治疗和对照组中的尿酸差异为5 mmHg差异。主要终点是在12和36个月时胰岛素抵抗的收缩压和舒张压的发生变化。青少年和年轻的成人试验合并将确定降低疗法的效用以及治疗有效的年龄范围。如果假设正确，这项研究将提供一种新颖而有效的方法来减少当前控制世界人群的高血压，肥胖和心血管疾病的流行。 公共卫生相关性：计划赠款：我们在动物模型和人类临床试验中的初步研究的项目叙述表明，升高的血清尿酸可能与青少年基本高血压的发展有关。我们提出了一项多中心临床试验，以确定血清尿酸的减少是否会防止高血压患者患有高血压患者的最高风险患者的血压逐渐升高。该试验可能为预防性治疗高血压提供了新的范式，该疾病在美国每年导致30％以上的美国人，并在美国造成近100万人死亡。