title: Chronic treatment with carvedilol improves ventricular function and reduces myocyte apoptosis in an animal model of heart failure.
abstract: BACKGROUND
  Beta blocker treatment has emerged as an effective treatment modality for heart failure. Interestingly, beta-blockers can activate both pro-apoptotic and anti-apoptotic pathways. Nevertheless, the mechanism for improved cardiac function seen with beta-blocker treatment remains largely unknown. Carvedilol is a non-selective beta-blocker with alpha-receptor blockade and antioxidant properties. We therefore studied the impact of the effects of carvedilol in an animal model of end-stage heart failure.
  
  
  RESULTS
  To test whether chronic treatment with beta-blockade decreases apoptosis, we treated myopathic turkeys with two dosages of carvedilol, 1 mg/kg (DCM1) and 20 mg/kg (DCM20), for four weeks and compared them to non-treated DCM animals (DCM0) and to control turkeys (CON). Echocardiographic measurements showed that non-treated DCM animals had a significantly lower fractional shortening (FS) when compared to CON (68.73 +/- 1.37 vs. 18.76 +/- 0.59%, p < 0.001). Both doses of carvedilol significantly improved FS (33.83 +/- 10.11 and 27.73 +/- 6.18% vs. 18.76 +/- 0.59% for untreated DCM, p < 0.001). DCM left ventricles were characterized by a higher percentage of apoptotic nuclei when compared to CON (5.64 +/- 0.49 vs. 1.72 +/- 0.12%, respectively p < 0.001). Both doses of carvedilol significantly reduced the number of apoptotic nuclei (2.32 +/- 0.23% and 2.36 +/-6% 1 mg and 20 mg/kg respectively).
  
  
  CONCLUSIONS
  Carvedilol improves ventricular function. Furthermore, treatment with carvedilol decreased the incidence of apoptosis in cardiac myocytes from failing hearts at both doses. These data suggest that the inhibition of apoptosis with carvedilol may lead to improvement in ventricular function and may underlie a beneficial effect of beta-blockade independent of heart rate lowering effects.
authors.affiliation: Boston University Medical Center, Boston, USA. okaforc1@mail.nih.gov
authors.forename: Chukwuka C
authors.initials: CC
authors.lastname: Okafor
authors.forename: Cynthia
authors.initials: C
authors.lastname: Perreault-Micale
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Hajjar
authors.forename: Djamel
authors.initials: D
authors.lastname: Lebeche
authors.forename: Klara
authors.initials: K
authors.lastname: Skiroman
authors.forename: George
authors.initials: G
authors.lastname: Jabbour
authors.forename: Angelia A
authors.initials: AA
authors.lastname: Doye
authors.forename: Michael X
authors.initials: MX
authors.lastname: Lee
authors.forename: Nancy
authors.initials: N
authors.lastname: Laste
authors.forename: Judith K
authors.initials: JK
authors.lastname: Gwathmey
mesh_terms: D000317:Adrenergic alpha-Antagonists / Q000627:therapeutic use; D000319:Adrenergic beta-Antagonists / Q000627:therapeutic use; D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D002227:Carbazoles / Q000627:therapeutic use*; D009202:Cardiomyopathies / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology; D000077261:Carvedilol; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D004353:Drug Evaluation, Preclinical; D005664:Furazolidone / Q000009:adverse effects; D006333:Heart Failure / Q000139:chemically induced / Q000473:pathology* / Q000517:prevention & control*; D032342:Muscle Cells / Q000166:cytology* / Q000187:drug effects*; D011412:Propanolamines / Q000627:therapeutic use*; D014422:Turkeys; D018754:Ventricular Dysfunction / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology; D016276:Ventricular Function / Q000187:drug effects* / Q000502:physiology
chemical_list: D000317:Adrenergic alpha-Antagonists; D000319:Adrenergic beta-Antagonists; D000975:Antioxidants; D002227:Carbazoles; D011412:Propanolamines; D000077261:Carvedilol; D005664:Furazolidone