PITCH HF Right Ventricular Pulmonary Vascular Reserve Ancillary Study

项目总结：左心室收缩功能障碍（LVSD）导致的心力衰竭通常与 随着肺动脉高压（LVSD-PH）的发展。然而，右心室（RV）的反应 静息和运动时肺动脉压（PAP）升高在LVSD-PH中高度可变， 仍然知之甚少。当静息时发生明显的RV功能障碍时，与运动减少有关 容量、肾和肝功能不全以及死亡率增加。 LVSD-PH患者将在PITCH（本辅助研究的母试验）中进行研究。PITCH将测试 假设与安慰剂相比，肺血管扩张剂他达拉非将改善患者的结局 该试验代表了一种理想的设置，在其中确定RV如何响应于LVSD-PH升高。 在LVSD-PH中的PAP。我们将采用纵向、连续测量研究（基线和3个月）， 多模态生理测试方案，包括心肺运动测试（CPET）和 同时在休息和运动时进行超声心动图和抽血。这背后的前提是 辅助研究是异常肺血管舒张能力，如由相对于肺动脉压的急剧增加所反映的， 心输出量（即<$PAP/<$CO或RV-PV储备）与运动的关系是RV功能障碍的主要决定因素 以及HF的不良结局，因此应该成为治疗靶点。这项研究的目的是 识别容易测量的反映异常<$PAP/<$CO的心肺运动试验（CPET）指标， 以及标志着异常PAP/CO的血管活性代谢物。该提案解决了未满足的临床 需要改进生理和循环生物标志物来表征HF中的RV-PV储备。RV标志物- 肺静脉储备可能有助于早期检测HF患者的RV功能障碍，并确定最有可能受益于 RV后负荷减少疗法最近显示出希望。 我们在领先的CPET和Echo核心实验室进行多中心试验的经验将极大地促进 在15个研究中心的154名受试者中完成了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测量密切反映了<$PAP/<$CO， 对静息测量的功能和预后意义。我们还确定了候选代谢物 RV-PV储备的特征，重点是来自涉及血管舒张的途径的代谢物。在目标1中， 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）。基于新的初步发现，在目标2中，我们将 研究血管活性小分子，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产物，作为RV-PV储备的生物标志物，并评估其预后 预测长期HFCC评分的意义。在目标3中，我们将确定0-3个月的超声心动图是否发生变化， 两个治疗组中的CPET和RV-PV储备的代谢物标志物可预测长期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.