Clinical benefits and mechanism of action of angiotensin-II receptor blocker on Cardiovascular remodeling in patients with repaired coarctation of aorta

血管紧张素II受体阻滞剂对主动脉缩窄修复患者心血管重塑的临床疗效及作用机制

• 批准号: 10734120
• 负责人: Alexander Egbe
• 金额: $ 69.53万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-25 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10734120
• 关键词: Adult; Adverse event; Aerobic; Age; Angiotensin II Receptor; Antihypertensive Agents; Aorta; Aortic coarctation; Atherosclerosis; Blood Pressure; Blood Vessels; Borderline Hypertension; Cardiac; Cardiac Output; Cardiovascular system; Cessation of life; Chronic; Clinical; Coronary; Coronary Arteriosclerosis; Data; Development; Echocardiography; Exercise; Exhibits; Fibrosis; Functional disorder; Future; Goals; Guidelines; Health Care Costs; Heart failure; High Prevalence; Hypertension; Imaging Techniques; Impairment; Knowledge; Left; Left Ventricular Dysfunction; Left Ventricular Remodeling; Life; Longevity; Losartan; Magnetic Resonance Imaging; Medical; Mission; Morbidity - disease rate; Multi-Institutional Clinical Trial; Myocardial Ischemia; Operative Surgical Procedures; Outcome; Oxygen Consumption; Patients; Pharmaceutical Preparations; Physiologic intraventricular pressure; Placebos; Population; Prevention; Public Health; Randomized; Recommendation; Relaxation; Research; Severities; Structure; Testing; Time; Translating; United States National Institutes of Health; Ventricular; Ventricular Dysfunction; burden of illness; cardiac magnetic resonance imaging; cardiovascular disorder risk; cohort; congenital heart disorder; disability; extracellular; hemodynamics; hypertension control; hypertension treatment; hypertensive; improved; indexing; innovation; novel; novel therapeutics; premature; pressure; prevent; repaired; response; sudden cardiac death; tau Proteins

PROJECT SUMMARY/ABSTRACT The median survival in adults with repaired coarctation of aorta (COA) is ~55 years, and more that 50% of deaths are due to end-stage heart failure and sudden cardiac death from left ventricular (LV) systolic/diastolic dysfunction. LV dysfunction results from chronic pressure overload from hypertension, which in turn leads to LV remodeling (increased fibrosis and stiffness, and impaired relaxation). LV dysfunction has been observed in COA patients with borderline hypertension or stage 1 hypertension (B/S1) (blood pressure 120-139/80-89 mmHg), even though the severity of hypertension in these patients is considered significant enough to warrant antihypertensive therapy based on the current guidelines. Additionally, COA patients with B/S1 hypertension have impaired aerobic capacity and exhibit hypertensive response to exercise, both of which are associated with cardiovascular adverse events The pathophysiologic mechanisms responsible for LV remodeling and abnormal hemodynamic response to exercise in this subset of COA patients are not well understood but are postulated to be due to increased aortic stiffness. We recently demonstrated that a 2-week course of angiotensin-II receptor blocker (ARB) improved aortic stiffness, coronary flow reserve (CFR), cardiac output reserve and vasodilatory reserve (VDR) during exercise. However, it is unknown whether these hemodynamic changes will lead to LV reserve remodeling (decreased fibrosis and stiffness, and improved relaxation) and improved aerobic capacity during long-term therapy. Our long-term goal is to prevent early cardiovascular death in COA patients, by identifying and modifying the pathophysiologic mechanisms leading to LV dysfunction and vascular complications in this population. Our overall objective for this application is to determine whether ARB might promote LV reserve remodeling and improve aerobic capacity, and to delineate the mechanisms of response to ARB. Our central hypothesis is that ARB will promote LV reserve remodeling and improve aerobic capacity by improving CFR and VDR. This hypothesis will be tested by pursuing two specific aims: (1) Determine whether ARB promotes LV reverse remodeling in patients with repaired COA and B/S1 hypertension and delineate the mechanisms of response to ARB; (2) Determine whether ARB improves aerobic capacity and delineate the mechanisms of response to ARB. We will randomize 80 subjects 1:1 to ARB (losartan 50 mg) or placebo for 52 weeks. These subjects will undergo multi-domain assessment of cardiovascular structure and function at baseline and after 52 weeks of therapy. This proposal is innovative because it will novel magnetic resonance imaging techniques to assess cardiovascular response to ARB in patients with repaired COA. The results will be significant because it will enable the development of novel management paradigms for prevention of LV dysfunction and cardiovascular death in this population.

项目总结/摘要 主动脉缩窄（COA）修复成人的中位生存期约为55年， 死亡是由于终末期心力衰竭和左心室（LV）收缩/舒张期心脏性猝死 功能障碍LV功能障碍由高血压引起的慢性压力超负荷引起，这反过来又导致 LV重塑（纤维化和僵硬增加，舒张功能受损）。在以下患者中观察到LV功能障碍： 临界高血压或1期高血压（B/S1）COA患者（血压120-139/80-89 mmHg），即使这些患者的高血压严重程度被认为足以保证 根据现行指南进行降压治疗。此外，患有B/S1高血压的COA患者 有氧能力受损，并表现出对运动的高血压反应，这两者都与 与心血管不良事件相关的LV重塑和心室重构的病理生理机制 在COA患者的这一亚组中，对运动的异常血流动力学反应尚不清楚， 推测是由于主动脉僵硬度增加所致。我们最近证明， 血管紧张素II受体阻滞剂（ARB）可改善主动脉僵硬度、冠状动脉血流储备（CFR）、心输出量 血管舒张储备（VDR）。然而，目前尚不清楚这些血流动力学 变化将导致LV储备重构（纤维化和僵硬减少，松弛改善）， 在长期治疗期间改善有氧能力。我们的长期目标是预防早期心血管疾病 COA患者死亡，通过识别和改变导致LV的病理生理机制 功能障碍和血管并发症。我们对这个应用程序的总体目标是 确定ARB是否可以促进LV储备重塑和改善有氧能力，并描述 对ARB的反应机制。我们的中心假设是，ARB将促进LV储备重构 通过提高CFR和VDR来提高有氧能力。 这一假设将通过追求两个具体目标进行检验：（1）确定ARB是否促进LV逆转 修复COA和B/S1高血压患者的重构，并描述对 ARB;（2）确定ARB是否可以提高有氧能力并描述其反应机制 仲裁号我们将80例受试者以1：1的比例随机分配至ARB（氯沙坦50 mg）或安慰剂组，持续52周。这些受试者将 在基线时和治疗52周后接受心血管结构和功能的多领域评估 疗法这项建议是创新的，因为它将新颖的磁共振成像技术，以评估 修复COA患者对ARB的心血管反应。结果将是显著的，因为它将 能够开发新的管理模式，以预防LV功能障碍和心血管疾病 死亡在这个人口。