title: Carvedilol improves biventricular fibrosis and function in experimental pulmonary hypertension.
abstract: Left ventricular (LV) function influences outcomes in right ventricular (RV) failure. Carvedilol reduces mortality in LV failure and improves RV function in experimental pulmonary arterial hypertension (PAH). However, its impact on ventricular-ventricular interactions and LV function in RV afterload is unknown. We investigated effects of carvedilol on biventricular fibrosis and function in a rat model of persistent PAH. Rats were randomized into three groups: Sham controls, PAH, and PAH + carvedilol. Severe PAH was induced by 60 mg/kg subcutaneous monocrotaline. In the treatment group, oral carvedilol (15 mg/kg/day) was started 2 weeks after monocrotaline injection and continued for 3 weeks until the terminal experiment. Echocardiography and exercise performance were performed at baseline and repeated at the terminal experiment with hemodynamic measurements. LV and RV myocardium were analyzed for hypertrophy, fibrosis, and molecular signaling by protein and mRNA analysis. PAH and PAH + carvedilol rats experienced severely elevated pulmonary arterial pressures and RV hypertrophy. Despite similar RV systolic pressures, carvedilol reduced biventricular collagen content (RV fibrosis area; 13.4 ± 6.5 vs. 5.5 ± 2.7 %, p < 0.001) and expression of transforming growth factor-β1 (TGFβ1) (RV TGFβ1/glyceraldehyde 3-phosphate dehydrogenase (GAPDH) ratio; 1.16 ± 0.39 vs. 0.57 ± 0.22, p < 0.01) and connective tissue growth factor (CTGF) (RV CTGF/GAPDH ratio; 0.49 ± 0.06 vs. 0.35 ± 0.17, p < 0.05). RV pro-apoptotic caspase-8 was increased in PAH compared to controls and was significantly reduced in both ventricles compared to PAH animals by carvedilol. Tissue effects were accompanied by improved biventricular systolic and diastolic performance and exercise treadmill distance (36 ± 30 vs. 80 ± 33 m, p < 0.05). In RV pressure-load, carvedilol improves biventricular fibrosis and function through abrogation of TGFβ1-CTGF signaling.
  
  
  CONCLUSIONS
  • RV afterload caused biventricular injury and dysfunction through TGFβ1-CTGF signaling. • Carvedilol reduced biventricular TGFβ1-CTGF signaling, fibrosis, and apoptosis. • Carvedilol improved cardiac output and biventricular function. • Improved fibrosis and hemodynamics occurred despite persistent RV afterload.
authors.affiliation: The Labatt Family Heart Center, Division of Cardiology and Cardiovascular Surgery, Hospital for Sick Children and University of Toronto, Toronto, ON, Canada.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Okumura
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Kato
authors.forename: Osami
authors.initials: O
authors.lastname: Honjo
authors.forename: Siegfried
authors.initials: S
authors.lastname: Breitling
authors.forename: Wolfgang M
authors.initials: WM
authors.lastname: Kuebler
authors.forename: Mei
authors.initials: M
authors.lastname: Sun
authors.forename: Mark K
authors.initials: MK
authors.lastname: Friedberg
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000627:therapeutic use*; D002227:Carbazoles / Q000627:therapeutic use*; D000077261:Carvedilol; D055513:Connective Tissue Growth Factor / Q000378:metabolism; D005355:Fibrosis; D006352:Heart Ventricles / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D006439:Hemodynamics / Q000187:drug effects; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008297:Male; D011412:Propanolamines / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D018497:Ventricular Dysfunction, Right / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology
chemical_list: D000959:Antihypertensive Agents; D002227:Carbazoles; D011412:Propanolamines; D053773:Transforming Growth Factor beta1; D000077261:Carvedilol; D055513:Connective Tissue Growth Factor