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.

项目概要/摘要 右心衰竭 (RHF) 是法洛四联症修复术后 (TOF) 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瓣反流 (PR) 和右侧 心脏（RH）重塑。心律失常和有氧能力受损是最常见的症状 RHF 的发作，但在这些症状出现后进行肺动脉瓣置换术 (PVR) 并不适用 与改善结果相关。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) 大小和塌陷度（IVC 血液- 动力学），先于 TOF 患者出现心律失常和有氧能力受损，并且它与 与该人群中 RH 重塑加速、症状恶化和死亡率有关。然而， RA 高血压、RH 重塑和症状恶化之间的联系机制，以及程度 在 RA 高血压发作之前进行 PVR 能否改善临床结果尚不清楚。长期来看 目标是通过改变死亡危险因素来预防 TOF 患者过早心血管死亡。 总体目标是描绘 RA 高血压、RH 重塑之间的病理生理机制 以及出现心律失常和有氧能力受损等症状，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 高血压会导致加速 RH 重塑和症状出现（心律失常和有氧能力受损），以及进行 PVR RA 发病前高血压与 RH 逆转重塑和症状改善相关。 该假设将通过追求两个具体目标来检验：（1）确定 RA 超-相关机制 张力（通过 IVC 血流动力学评估）、RH 重塑和症状出现（心律失常和受损） 有氧能力）中度至重度 PR 的 TOF 患者； (2) 确定执行 PVR 的程度 RA 高血压发病前与 RH 逆转重塑（影像学改善和 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） 容量）。第一个目标是，150 名无症状受试者（每组 75 名）将接受影像学、实验室检查 血液测试、运动测试以及患者报告的基线、12 个月和 24 个月的评估质量。 根据第二个目标，将招募 120 名接受临床适应症 PVR 的受试者（每组 60 名） 在基线（PVR 之前）、12 个月和 24 个月时进行与第一次类似的多领域评估 目的。该提案具有创新性，因为它将描述负责症状恶化的机制。 配比，以及 PVR 对这些机制的影响。结果将非常重要，因为它将奠定基础 用于未来的临床试验，以测试在疾病发病的不同阶段进行 PVR 的生存益处 sis，以及开发预防和早期治疗 RHF 的新疗法。