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.

项目总结/摘要 右心衰竭（RHF）是法洛四联症（TOF）修复患者死亡的主要原因， 导致这种次优结果的事件顺序始于肺动脉返流（PR）和右心室返流（右心室返流）。 心脏（RH）重塑。心律失常和有氧能力受损是最常见的表现之前， RHF的发作，但在这些症状发作后进行肺动脉瓣置换术（PVR）， 与改善的结果相关。最近的数据显示，右心房压力升高（RA高血压）， 通过超声心动图评估下腔静脉（IVC）的大小和可扩张性（IVC血流量）， 动力学），在TOF患者心律失常和有氧能力受损的发作之前，它与 加速RH重塑，症状恶化和死亡率。但 RA高血压、RH重塑和症状恶化之间的联系机制，以及 在RA高血压发作前进行PVR是否能改善临床结局尚不清楚。长期 目的是通过改变死亡的危险因素来预防TOF患者的心血管性过早死亡。 总体目标是阐明RA高血压、RH重塑 和症状的发作，如心律失常和有氧能力受损，因为症状状态是一个风险， TOF人群的死亡率因素。我们的中心假设是RA高血压导致加速的 RH重塑和症状发作（心律失常和有氧能力受损），以及进行PVR 在RA发作前，高血压与RH逆转重塑和症状改善相关。 这一假设将通过追求两个具体目标进行检验：（1）确定RA高表达与高表达之间的联系机制， 张力（通过IVC血流动力学评估）、RH重塑和症状发作（心律失常和受损 有氧能力）;（2）确定进行PVR的程度， 在RA发作之前，高血压与RH逆向重塑相关（影像学和 RH重塑的生物标志物指数）和症状改善（心律失常减少和有氧运动改善 能力）。在第一个目标下，150名无症状受试者（每组75名）将接受影像学、实验室检查、 基线、12个月和24个月时的血液检查、运动试验和患者报告的评估质量。 根据第二个目标，将入组120例（每组60例）接受PVR治疗临床适应症的受试者， 在基线（PVR前）、12个月和24个月时接受多领域评估，与第一次评估相似 瞄准这项建议是创新的，因为它将描述负责症状性疾病的机制， 定量，以及PVR对这些机制的影响。结果将是重要的，因为它将为 用于未来的临床试验，以测试在疾病致病基因的不同阶段进行PVR的生存益处- sis，并开发新的治疗方法，用于预防和早期治疗RHF。