Farha Samar, Saygin Didem, Park Margaret M, Cheong Hoi I, Asosingh Kewal, Comhair Suzy Aa, Stephens Olivia R, Roach Emir C, Sharp Jacqueline, Highland Kristin B, DiFilippo Frank P, Neumann Donald R, Tang W H Wilson, Erzurum Serpil C
Lerner Research Institute.
Heart and Vascular Institute.
JCI Insight. 2017 Aug 17;2(16). doi: 10.1172/jci.insight.95240.
Right-sided heart failure is the leading cause of death in pulmonary arterial hypertension (PAH). Similar to left heart failure, sympathetic overactivation and β-adrenoreceptor (βAR) abnormalities are found in PAH. Based on successful therapy of left heart failure with β-blockade, the safety and benefits of the nonselective β-blocker/vasodilator carvedilol were evaluated in PAH.
PAH Treatment with Carvedilol for Heart Failure (PAHTCH) is a single-center, double-blind, randomized, controlled trial. Following 1-week run-in, 30 participants were randomized to 1 of 3 arms for 24 weeks: placebo, low-fixed-dose, or dose-escalating carvedilol. Outcomes included clinical measures and mechanistic biomarkers.
Decreases in heart rate and blood pressure with carvedilol were well tolerated; heart rate correlated with carvedilol dose. Carvedilol-treated groups had no decrease in exercise capacity measured by 6-minute walk, but had lower heart rates at peak and after exercise, and faster heart rate recovery. Dose-escalating carvedilol was associated with reduction in right ventricular (RV) glycolytic rate and increase in βAR levels. There was no evidence of RV functional deterioration; rather, cardiac output was maintained.
Carvedilol is likely safe in PAH over 6 months of therapy and has clinical and mechanistic benefits associated with improved outcomes. The data provide support for longer and larger studies to establish guidelines for use of β-blockers in PAH.
ClinicalTrials.gov NCT01586156FUNDING. This project was supported by NIH R01HL115008 and R01HL60917 and in part by the National Center for Advancing Translational Sciences, UL1TR000439.
右心衰竭是肺动脉高压（PAH）的主要死因。与左心衰竭相似，PAH患者存在交感神经过度激活和β-肾上腺素能受体（βAR）异常。基于β受体阻滞剂成功治疗左心衰竭，本研究评估了非选择性β受体阻滞剂/血管扩张剂卡维地洛在PAH中的安全性和益处。
卡维地洛治疗PAH心力衰竭（PAHTCH）研究是一项单中心、双盲、随机对照试验。经过1周的导入期后，30名参与者被随机分为3组，每组接受24周的治疗：安慰剂组、低固定剂量组或剂量递增卡维地洛组。观察指标包括临床指标和机制性生物标志物。
卡维地洛降低心率和血压的效果耐受性良好；心率与卡维地洛剂量相关。卡维地洛治疗组通过6分钟步行试验测得的运动能力没有下降，但运动峰值时和运动后的心率较低，且心率恢复更快。剂量递增的卡维地洛与右心室（RV）糖酵解速率降低和βAR水平升高有关。没有证据表明RV功能恶化；相反，心输出量得以维持。
卡维地洛在PAH患者中进行6个月以上的治疗可能是安全的，并且具有与改善预后相关的临床和机制性益处。这些数据为开展更大规模、更长时间的研究以建立PAH中使用β受体阻滞剂的指南提供了支持。
ClinicalTrials.gov NCT01586156资助。本项目由美国国立卫生研究院R01HL115008和R01HL60917资助，并部分由推进转化科学国家中心UL1TR000439资助。
