PITCH HF Right Ventricular Pulmonary Vascular Reserve Ancillary Study

项目摘要：左心室收缩功能不全(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 对静息和运动时肺动脉压(PAP)升高的影响在LVSD-PH和 人们对此仍然知之甚少。当静息状态下出现明显的RV功能障碍时，与运动减少有关 能力，肾和肝功能障碍，以及死亡率增加。 LVSD-PH患者将在Pitch中进行研究，这是这项辅助研究的父母试验。音调将会测试 假设与安慰剂相比，肺血管扩张剂他达拉非将改善患者的预后 使用LVSD-PH。这项试验代表了确定房车如何响应提升的理想设置 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 由心肺运动试验(CPET)和 在休息和运动时同时进行超声心动图和抽血。这背后的前提是 辅助性研究是肺血管扩张能力异常，表现为PAP陡增相对 心输出量(即PAP/CO或RV-PV储备)运动是RV功能障碍的主要决定因素 以及HF的不良后果，因此应该成为治疗的靶点。这项研究的目标是 确定容易测量的反映PAP/CO异常的心肺运动试验(CPET)指数 以及标志着PAP/CO异常的血管活性代谢物。这项建议解决了一项未得到满足的临床 需要改进的生理学和循环生物标志物来表征心衰患者的RV-PV储备。房车的标志物- PV储备可能有助于更早地发现心力衰竭患者的右室功能障碍，并确定最有可能受益的患者 RV-减少后负荷治疗，最近显示出希望。 我们在领导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 在15个地点的154名受试者中完成这项多中心辅助研究。我们的初步数据表明 次极量运动期间的CPET测量与PAP/CO密切相关，并可能提供附加指标 静息测量的功能和预后意义。我们还确定了候选新陈代谢 RV-PV储备的信号，重点是参与血管扩张的途径的代谢物。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)。根据新的初步发现，在目标2中，我们将 研究血管活性小分子的作用，包括精氨酸代谢物和吲哚乙胺2，3- 依赖双加氧酶的色氨酸代谢物作为RV-PV储备的生物标志物及其预后评估 对预测长期HFCC评分的意义。在目标3中，我们将确定0-3个月的回声是否发生变化， CPET和RV-PV储备代谢物标记物预测两个治疗组的长期HFCC评分。

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.