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.

项目摘要/摘要 主动脉（COA）修复的成年人的中位存活率约为55年，而更多的50％ 死亡是由于末期心力衰竭和左心室（LV）收缩/舒张期突然心脏死亡造成的 功能障碍。 LV功能障碍是由高血压导致的慢性压力超负荷引起的，这又导致 LV重塑（纤维化和刚度增加，放松受损）。 LV功能障碍已在 COA临界高血压或1期高血压（B/S1）（血压120-139/80-89）患者 MMHG），即使这些患者的高血压严重程度被认为足够重要 基于当前指南的降压治疗。此外，患有B/S1高血压的COA患者 有氧运动能力受损并表现出对运动的高血压反应，这两种都与 随着心血管不良事件的病理生理机制，负责LV重塑和 在这一部分COA患者中，对运动的异常血液动力学反应尚不清楚，但是 假定是由于主动脉僵硬增加。我们最近证明了为期2周的课程 血管紧张素-II受体阻滞剂（ARB）改善主动脉刚度，冠状动脉流量（CFR），心输出量 锻炼过程中的储备和血管舒张储备（VDR）。但是，尚不清楚这些血流动力学是否 变化将导致LV储备重塑（纤维化和刚度降低，放松的改善）和 长期治疗期间有氧能力提高。我们的长期目标是防止早期心血管 COA患者死亡，通过识别和修改导致LV的病理生理机制 该人群的功能障碍和血管并发症。我们对此应用的总体目标是 确定ARB是否可以促进LV储备重塑并提高有氧运动能力，并描述 对ARB的反应机制。我们的中心假设是ARB将促进LV储备重塑 并通过改善CFR和VDR来提高有氧能力。 该假设将通过追求两个具体目的来检验：（1）确定ARB是否促进LV反面 修复的COA和B/S1高血压患者的重塑，并描述了对 arb; （2）确定ARB是否提高了有氧能力并描述了对 arb。我们将将80受试者1：1随机为ARB（Losartan 50 mg）或安慰剂52周。这些主题会 在基线和52周后，对心血管结构和功能进行多域评估 治疗。该建议具有创新性，因为它将新颖的磁共振成像技术评估 维修COA患者对ARB的心血管反应。结果将是重要的，因为它将 启用用于预防LV功能障碍和心血管的新型管理范式的发展 该人群的死亡。