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

TITLE=Endothelial Phenotype Evoked by Low Dose Carvedilol in Pulmonary Hypertension

JOURNAL=Frontiers in Cardiovascular Medicine

VOLUME=5

YEAR=2018

URL=https://www.frontiersin.org/journals/cardiovascular-medicine/articles/10.3389/fcvm.2018.00180

DOI=10.3389/fcvm.2018.00180

ISSN=2297-055X

ABSTRACT=<p><bold>Background:</bold> 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.</p><p><bold>Methods:</bold> 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.</p><p><bold>Results:</bold> 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 <italic>p</italic> &gt; 0.1). Heart rate at rest and 1 min post walk dropped significantly (both <italic>p</italic> &lt; 0.05) with a trend for increase in heart rate recovery (<italic>p</italic> = 0.08). Right ventricular systolic pressure (RVSP) decreased by an average of 13 mmHg (<italic>p</italic> = 0.002). Patients who had a decrease in RVSP of more than 10 mm Hg were defined as responders (<italic>n</italic> = 17), and those with a lesser drop as non-responders (<italic>n</italic> = 13). Responders had a significant drop in pulmonary vascular resistance (PVR) after 1 week of carvedilol (<italic>p</italic> = 0.004). In addition, responders had a greater decrease in heart rate at rest and 1 min post walk compared to non-responders (both <italic>p</italic> &lt; 0.05). Responders had higher plasma arginine and global bioavailability of arginine at baseline compared to non-responders (<italic>p</italic> = 0.03 and <italic>p</italic> = 0.05, respectively). After 1 week of carvedilol, responders had greater increase in urinary nitrate (<italic>p</italic> = 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.</p><p><bold>Conclusions:</bold> 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.</p><p><bold>Clinical Trial Registration:</bold><ext-link ext-link-type="uri" xlink:href="http://www.clinicaltrials.gov" xmlns:xlink="http://www.w3.org/1999/xlink">http://www.clinicaltrials.gov</ext-link>. identifier: NCT01586156.</p>