Pathophysiologic Mechanism for Arrhythmias and Impaired Aerobic Capacity in Tetralogy of Fallot

法洛四联症心律失常和有氧能力受损的病理生理机制

• 批准号: 10458752
• 负责人: Alexander Egbe
• 金额: $ 57.29万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10458752
• 关键词: Adult; Aerobic; Age; American; Arrhythmia; Blood Tests; Cardiovascular system; Cessation of life; Chronic; Clinical; Clinical Trials; Complication; Data; Deterioration; Development; Diagnostic; Disease; Early treatment; Enrollment; Event; Exercise Test; Future; Goals; Health Care Costs; Heart; Heart Atrium; Hypertension; Image; Impairment; Inferior vena cava structure; Knowledge; Laboratories; Life; Life Expectancy; Link; Mission; Morbidity - disease rate; Operative Surgical Procedures; Outcome; Oxygen Consumption; Pathogenesis; Patients; Persons; Population; Postoperative Period; Prevention; Prevention therapy; Process; Public Health; Pulmonary Valve Insufficiency; Recurrence; Reporting; Research; Risk; Risk Factors; Symptoms; Techniques; Testing; Tetralogy of Fallot; Therapeutic Intervention; Time; Troponin; Uncertainty; United States National Institutes of Health; Ventricular Arrhythmia; arm; burden of illness; cardiac magnetic resonance imaging; cohort; disability; effective therapy; evidence base; extracellular; follow-up; hemodynamics; imaging biomarker; improved; improved outcome; indexing; innovation; mortality; novel therapeutics; premature; pressure; prevent; pro-brain natriuretic peptide (1-76); pulmonary valve replacement; repaired; right ventricular failure; symptomatic improvement; treatment strategy

PROJECT SUMMARY/ABSTRACT Right heart failure (RHF) is the leading cause of mortality in people with repaired tetralogy of Fallot (TOF), and the sequence of events leading to this suboptimal outcome begins with pulmonary regurgitation (PR) and right heart (RH) remodeling. Arrhythmias and impaired aerobic capacity are the most common presentations prior to the onset of RHF, but performing pulmonary valve replacement (PVR) after the onset of these symptoms is not associated with improved outcomes. Recent data show that elevated right atrial pressure (RA hypertension), as estimated by echocardiographic assessment of inferior vena cava (IVC) size and collapsibility (IVC hemo- dynamics), precedes the onset of arrhythmias and impaired aerobic capacity in TOF patients, and it is associ- ated with accelerated RH remodeling, symptomatic deterioration and mortality in this population. However, the mechanism linking RA hypertension, RH remodeling and symptomatic deterioration, and the extent to which performing PVR prior to the onset of RA hypertension improves clinical outcomes are unknown. The long-term goal is to prevent premature cardiovascular deaths in TOF patients by modifying the risk factors for mortality. The overall objective is to delineate the pathophysiologic mechanism linking RA hypertension, RH remodeling and onset of symptoms such as arrhythmias and impaired aerobic capacity, since symptomatic status is a risk factor for mortality in the TOF population. Our central hypothesis is that RA hypertension leads to accelerated RH remodeling and onset of symptoms (arrhythmias and impaired aerobic capacity), and that performing PVR prior to onset of RA hypertension is associated with RH reverse remodeling and improvement of symptoms. This hypothesis will be tested by pursuing two specific aims: (1) Determine the mechanism linking RA hyper- tension (assessed by IVC hemodynamics), RH remodeling and onset of symptoms (arrhythmias and impaired aerobic capacity) in TOF patients with moderate-severe PR; (2) Determine the extent to which performing PVR prior to the onset of RA hypertension is associated with RH reverse remodeling (improvement of imaging and biomarker indices of RH remodeling) and improvement of symptoms (less arrhythmias and improved aerobic capacity). Under the first aim, 150 asymptomatic subjects (75 in each arm) will undergo imaging, laboratory blood tests, exercise test, and patient reported quality of assessment at baseline, 12 months and 24 months. Under the second aim, 120 subjects (60 in each arm) undergoing PVR for clinical indications will be enrolled to undergo multi-domain assessments at baseline (prior to PVR), 12 months and 24 months similar to the first aim. This proposal is innovative because it will delineate the mechanisms responsible for symptomatic deterio- ration, and the impact of PVR on these mechanisms. The results will be significant because it will set the stage for future clinical trials to test the survival benefits of PVR performed at different stages of disease pathogene- sis, and development of novel therapies for the prevention and early treatment of RHF.

项目摘要/摘要 右心衰竭（RHF）是法尔洛特修复四部曲（TOF）的人死亡的主要原因， 导致这种次优结果的事件序列始于肺反流（PR）和右 心脏（RH）重塑。心律不齐和有氧运动受损是最常见的表现 RHF的发作，但在这些症状发作后进行肺动脉瓣置换（PVR）不是 与改善的结果有关。最近的数据表明，右心理压力升高（RA高血压）， 通过超声心动图评估下腔静脉（IVC）的大小和可折叠性的评估（IVC血液 - 动力学），在心律不齐和TOF患者的有氧运动能力受损之前，这是相关的 该人群中加速的RH重塑，症状恶化和死亡率。但是， 连接RA高血压，RH重塑和有症状恶化的机制以及多大程度 在RA高血压发作之前进行PVR可以改善临床结果。长期 目的是通过改变死亡率的危险因素来防止TOF患者的心血管过早死亡。 总体目的是描述连接RA高血压的病理生理机制，RH重塑 以及诸如心律不齐和有氧运动障碍之类的症状发作，因为症状状态是一种风险 TOF人群死亡率的因素。我们的中心假设是RA高血压导致加速 RH症状的重塑和发作（心律不齐和有氧能力受损），并且执行PVR RA高血压发作之前，与RH反向重塑和症状改善有关。 该假设将通过追求两个具体目的来检验：（1）确定与RA超级联系的机制 张力（通过IVC血液动力学评估），RH重塑和症状发作（心律不齐和受损 中度重度PR的TOF患者的有氧能力）； （2）确定执行PVR的程度 在RA高血压发作之前，与RH反向重塑有关（改进成像和 RH重塑的生物标志物指数）和症状的改善（心律不齐和有氧运动改善 容量）。在第一个目标下，150名无症状受试者（每只手臂中有75名）将进行成像，实验室 血液测试，运动测试和患者报告了基线，12个月零24个月的评估质量。 在第二个目标下，将招募120名接受PVR的受试者（每只手臂60名受试者） 在基线（PVR之前）进行多域评估，12个月零24个月类似于第一个 目的。该提案具有创新性 评估以及PVR对这些机制的影响。结果将很重要，因为它将设定舞台 对于将来的临床试验，以测试在疾病病原体不同阶段进行的PVR的生存益处 SIS，以及用于预防和早期治疗RHF的新型疗法的发展。