Abstract
Background: The therapeutic benefits of β-blockers are well established in left heart failure. The Pulmonary Arterial Hypertension Treatment with Carvedilol for Heart Failure [PAHTCH] study showed safety and possible benefit of carvedilol in pulmonary arterial hypertension (PAH) associated right heart failure over 6 months. This study aims at evaluating the short-term cardiovascular effects and early mechanistic biomarkers of carvedilol therapy.Methods: Thirty patients with pulmonary hypertension (PH) received low dose carvedilol (3.125 mg twice daily) for 1 week prior to randomization to placebo, low-dose, or dose-escalating carvedilol therapy. Echocardiography was performed at baseline and 1 week. Exercise capacity was assessed by 6 min walk distance (6MWD). The L-arginine/nitric oxide pathway and other biological markers of endothelial function were measured.Results: All participants tolerated 1 week of carvedilol without adverse effects. After 1 week of carvedilol, 6MWD and heart rate at peak exercise did not vary (both p > 0.1). Heart rate at rest and 1 min post walk dropped significantly (both p < 0.05) with a trend for increase in heart rate recovery (p = 0.08). Right ventricular systolic pressure (RVSP) decreased by an average of 13 mmHg (p = 0.002). Patients who had a decrease in RVSP of more than 10 mm Hg were defined as responders (n = 17), and those with a lesser drop as non-responders (n = 13). Responders had a significant drop in pulmonary vascular resistance (PVR) after 1 week of carvedilol (p = 0.004). In addition, responders had a greater decrease in heart rate at rest and 1 min post walk compared to non-responders (both p < 0.05). Responders had higher plasma arginine and global bioavailability of arginine at baseline compared to non-responders (p = 0.03 and p = 0.05, respectively). After 1 week of carvedilol, responders had greater increase in urinary nitrate (p = 0.04). Responders treated with carvedilol had a sustained drop in RVSP and PVR after 6 months of carvedilol with no change in cardiac output.Conclusions: Low-dose carvedilol for 1 week can potentially identify a PH responder phenotype that may benefit from β-blockers that is associated with less endothelial dysfunction.Clinical Trial Registration: http://www.clinicaltrials.gov. identifier: NCT01586156.
Highlights
Pulmonary arterial hypertension (PAH) is a progressive pulmonary vascular disease defined by elevated pulmonary arterial pressure leading to right-sided heart failure
A double-blind, randomized, controlled trial of Pulmonary Arterial Hypertension Treatment with Carvedilol for Heart Failure (PAHTCH) showed that carvedilol is safe over 6 months of therapy and has clinical and mechanistic benefits associated with improved outcomes [11]
The Pulmonary Arterial Hypertension Treatment with Carvedilol for Heart Failure (PAHTCH) clinical trial was approved by the Institutional Review Board at the Cleveland Clinic
Summary
Pulmonary arterial hypertension (PAH) is a progressive pulmonary vascular disease defined by elevated pulmonary arterial pressure leading to right-sided heart failure. In a prospective non-randomized cohort study of 94 patients, β-blockers were reported to be safe in PAH, as defined by pulmonary hemodynamic, functional, or cardiac outcomes over 2 months [8]. In another small pilot study, carvedilol was found to be safe in patients with stable PAH and right ventricular (RV) dysfunction and was associated with an improvement in RV ejection fraction [9]. A double-blind, randomized, controlled trial of Pulmonary Arterial Hypertension Treatment with Carvedilol for Heart Failure (PAHTCH) showed that carvedilol is safe over 6 months of therapy and has clinical and mechanistic benefits associated with improved outcomes [11]. This study aims at evaluating the short-term cardiovascular effects and early mechanistic biomarkers of carvedilol therapy
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