Endothelial Phenotype Evoked by Low Dose Carvedilol in Pulmonary Hypertension

Hoi I. Cheong, Samar Farha*, Margaret M. Park, James D. Thomas, Didem Saygin, Suzy A.A. Comhair, Jacqueline Sharp, Kristin B. Highland, W. H.Wilson Tang, Serpil C. Erzurum

*Corresponding author for this work

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Article number180
JournalFrontiers in Cardiovascular Medicine
Volume5
DOIs
StatePublished - Dec 12 2018

Keywords

  • carvedilol
  • nitric oxide
  • pulmonary hypertension
  • right ventricle
  • β-blockers

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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    Cheong, H. I., Farha, S., Park, M. M., Thomas, J. D., Saygin, D., Comhair, S. A. A., Sharp, J., Highland, K. B., Tang, W. H. W., & Erzurum, S. C. (2018). Endothelial Phenotype Evoked by Low Dose Carvedilol in Pulmonary Hypertension. Frontiers in Cardiovascular Medicine, 5, [180]. https://doi.org/10.3389/fcvm.2018.00180