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: 10661539
• 负责人: Alexander Egbe
• 金额: $ 56.86万
• 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/10661539
• 关键词: Acceleration; Adult; Aerobic; Age; American; Arrhythmia; Biological Markers; Blood Tests; Cardiovascular system; Cessation of life; Chronic; Clinical; Clinical Trials; Complication; Data; Deterioration; Development; Diagnostic; Disease; Early treatment; Echocardiography; 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; 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)是法洛四联症修复术(TOF)患者死亡的主要原因， 导致这一次优结局的事件序列始于肺返流(PR)和右 心脏(RH)重构。心律失常和有氧能力受损是最常见的表现 RHF的发病，但在这些症状出现后进行肺动脉瓣置换术(PVR)并不是 与改善结果相关。最近的数据显示，右房压力升高(RA高血压)， 通过超声心动图评估下腔静脉(IVC)的大小和塌陷性(IVC血- 动力学)，在TOF患者发生心律失常和有氧能力受损之前，它是相关联的 伴随着加速的RH重塑，症状恶化和死亡率。然而， RA高血压、RH重塑和症状恶化之间的联系机制及其程度 在RA高血压发作之前进行PVR对临床结果的改善尚不清楚。长期的 目标是通过改变死亡率的危险因素来预防TOF患者的心血管过早死亡。 总体目标是阐明RA高血压、RH重塑的病理生理机制。 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人群中死亡的因素。我们的中心假设是RA高血压导致加速 RH重构和症状的出现(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有关。 这一假说将通过追求两个具体目标来检验：(1)确定RA过度兴奋的机制。 张力(通过下腔静脉血流动力学评估)、RH重构和症状的出现(心律失常和受损 中重度PR患者的有氧能力)；(2)确定实施PVR的程度 在RA发病之前，高血压与RH反向重构有关(成像和 RH重塑的生物标志物指标)和症状的改善(心律失常减少和有氧能力改善 容量)。在第一个目标下，150名无症状受试者(每只手臂75名)将接受成像，实验室 在基线、12个月和24个月时，血液测试、运动测试和患者报告的质量评估。 在第二个目标下，120名因临床适应症而接受PVR的受试者(每组60人)将被登记为 在基线(在PVR之前)、12个月和24个月进行多领域评估，与第一次类似 瞄准。这项建议是创新的，因为它将勾勒出负责对症状进行威慑的机制。 定量，以及PVR对这些机制的影响。结果将是意义重大的，因为它将为 对于未来的临床试验，以测试在疾病病原体的不同阶段进行PVR的生存益处- SIS，以及开发预防和早期治疗风湿性心衰的新疗法。

项目成果

Prevalence and risk of progressive aortic aneurysm and dissection in adults with conotruncal anomalies.

患有圆锥干异常的成人进行性主动脉瘤和夹层的患病率和风险。

• DOI: 10.1093/ehjci/jeab273
• 发表时间: 2022
• 期刊: European heart journal. Cardiovascular Imaging
• 作者: Egbe,AlexanderC;Miranda,WilliamR;Bonnichsen,CrystalR;Jain,CCharles;Crestanello,JuanA;Francois,Christopher;Katta,RenukaR;Iftikhar,Momina;Goda,AhmedY;Andi,Kartik;Gandhi,Sangeetha;Connolly,HeidiM
• 通讯作者: Connolly,HeidiM