PITCH HF Right Ventricular Pulmonary Vascular Reserve Ancillary Study

PITCH HF 右心室肺血管储备辅助研究

• 批准号: 8607730
• 负责人: Gregory Dyer Lewis
• 金额: $ 30.42万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-18 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8607730
• 关键词: Address; Ancillary Study; Arginine; Biochemical; Biological Markers; Blood; Blood Vessels; Cardiac Output; Cardiopulmonary; Chronic; Clinical; Data; Decision Making; Development; Devices; Diagnosis; Early Diagnosis; Echocardiography; Environmental air flow; Exercise; Exercise stress test; Functional disorder; Goals; Heart; Heart failure; Hepatic; Individual; K-Series Research Career Programs; Kidney; Kinetics; Laboratories; Left; Left ventricular structure; Lung; Measurement; Measures; Mediating; Metabolic; Metabolic Marker; Modality; Multicenter Trials; Nitric Oxide Pathway; Outcome; Oxygen; Parents; Pathway interactions; Patients; Performance; Pharmacotherapy; Physiological; Placebos; Prognostic Marker; Protocols documentation; Pulmonary Hypertension; Reaction Time; Relative (related person); Research; Rest; Right ventricular structure; Signal Transduction; Site; Staging; Structure; Survival Rate; Testing; Tryptophan; Tryptophan 2,3 Dioxygenase; United States National Institutes of Health; Vasodilation; Vasodilator Agents; Ventricular; Work; adverse outcome; base; candidate marker; experience; hemodynamics; improved; indexing; innovation; mortality; novel; novel marker; phosphoric diester hydrolase; pressure; prognostic; public health relevance; response; small molecule; tadalafil; therapeutic target; uptake

Project Summary: Heart failure due to left ventricular systolic dysfunction (LVSD) is commonly associated with the development of pulmonary hypertension (LVSD-PH). However, the response of the right ventricle (RV) to increased pulmonary arterial pressure (PAP) at rest and during exercise is highly variable in LVSD-PH and remains poorly understood. When overt RV dysfunction at rest occurs it is associated with reduced exercise capacity, renal and hepatic dysfunction, and increased mortality. Patients with LVSD-PH will be studied in PITCH, the parent trial for this ancillary study. PITCH will test the hypothesis that compared to placebo, the pulmonary vasodilator tadalafil will improve outcomes in patients with LVSD-PH. This trial represents an ideal setting in which to determine how the RV responds to elevated PAP in LVSD-PH. We will employ a longitudinal, serial measurement study (at baseline and 3 months) using a multi-modality physiologic testing protocol consisting of cardiopulmonary exercise testing (CPET) and simultaneous echocardiography and blood draws at rest and during exercise. The underlying premise of this ancillary study is that abnormal pulmonary vasodilatory capacity, as reflected by steep PAP increment relative to cardiac output (i.e. ¿PAP/¿CO or RV-PV reserve) with exercise, is a major determinant of RV dysfunction and adverse outcomes in HF, and therefore should be a therapeutic target. The goal of this research is to identify easily measured cardiopulmonary exercise testing (CPET) indices that reflect abnormal ¿PAP/¿CO as well as vasoactive metabolites that mark abnormal ¿PAP/¿CO. This proposal addresses an unmet clinical need for improved physiologic and circulating biomarkers to characterize RV-PV reserve in HF. Markers of RV- PV reserve may aid in earlier detection of RV dysfunction in HF and identify patients most likely to benefit from RV-afterload reducing therapies that have recently shown promise. Our experience in leading CPET and Echo core laboratories for multicenter trials will greatly facilitate completion of this multi-center ancillary study in 154 subjects at 15 sites. Our preliminary data demonstrate that CPET measurements during submaximal exercise closely reflect ¿PAP/¿CO and may provide additive functional and prognostic significance to resting measurements. We have also identified candidate metabolic signatures of RV-PV reserve with a focus on metabolites from pathways involved in vasodilation. In Aim 1 we will define CPET parameters that reflect abnormal ¿PAP/¿CO and assess their ability to predict 6 and 18 month AHEFT Clinical Composite Scores (HFCC score). Based on novel preliminary findings, in Aim 2 we will investigate the utility of vasoactive small molecules, including arginine metabolites and indoleamine 2,3- dioxygenase-dependent tryptophan metabolites, as biomarkers of RV-PV reserve and assess their prognostic significance in predicting long term HFCC scores. In Aim 3 we will determine whether 0-3 mo changes in echo, CPET, and metabolite markers of RV-PV reserve in the two treatment groups predict long term HFCC scores.

项目摘要：左心室收缩功能障碍 (LVSD) 引起的心力衰竭通常与 随着肺动脉高压（LVSD-PH）的发展。然而，右心室（RV）的反应 静息时和运动时肺动脉压 (PAP) 升高在 LVSD-PH 和 仍然知之甚少。当静息时出现明显的右心室功能障碍时，这与运动量减少有关 能力、肾和肝功能障碍以及死亡率增加。 LVSD-PH 患者将在 PITCH（这项辅助研究的母体试验）中进行研究。 PITCH 将进行测试 与安慰剂相比，肺血管扩张剂他达拉非将改善患者预后的假设 与 LVSD-PH。该试验代表了一个理想的环境，可以确定 RV 如何响应升高的 LVSD-PH 中的 PAP。我们将采用纵向、系列测量研究（基线和 3 个月），使用 多模态生理测试方案，包括心肺运动测试 (CPET) 和 在休息和运动时同时进行超声心动图检查和抽血。这样做的基本前提是 辅助研究表明肺血管舒张能力异常，如 PAP 相对增量陡峭所反映 运动时心输出量（即 PAP/CO 或 RV-PV 储备）的变化，是 RV 功能障碍的主要决定因素 和心力衰竭的不良后果，因此应该成为治疗目标。这项研究的目标是 识别容易测量的心肺运动测试 (CPET) 指数，这些指数反映了异常的 ¿PAP/¿CO 以及标记异常 ¿PAP/¿CO 的血管活性代谢物。该提案解决了未满足的临床问题 需要改进的生理和循环生物标志物来表征心力衰竭中的 RV-PV 储备。 RV 标记- PV 储备可能有助于及早发现 HF 中的 RV 功能障碍，并确定最有可能受益的患者 最近显示出希望的 RV 后负荷减轻疗法。 我们在领先的 CPET 和 Echo 核心实验室进行多中心试验方面的经验将极大地促进 完成了这项多中心辅助研究，涉及 15 个地点的 154 名受试者。我们的初步数据表明 次最大运动期间的 CPET 测量密切反映“PAP/”CO，并可提供附加信息 静息测量的功能和预后意义。我们还确定了候选代谢 RV-PV 储备的特征，重点关注参与血管舒张途径的代谢物。在目标 1 中，我们 将定义反映异常 ¿PAP/¿CO 的 CPET 参数并评估其预测 6 和 18 的能力 月 AHEFT 临床综合评分（HFCC 评分）。基于新颖的初步发现，在目标 2 中，我们将 研究血管活性小分子的效用，包括精氨酸代谢物和吲哚胺 2,3- 双加氧酶依赖性色氨酸代谢物，作为 RV-PV 储备的生物标志物并评估其预后 预测长期 HFCC 分数的重要性。在目标 3 中，我们将确定回声是否在 0-3 个月内发生变化， 两个治疗组中的 CPET 和 RV-PV 储备代谢标志物可预测长期 HFCC 评分。