title: Glucagon-like peptide-1 and the exenatide analogue AC3174 improve cardiac function, cardiac remodeling, and survival in rats with chronic heart failure.
abstract: BACKGROUND
  Accumulating evidence suggests glucagon-like peptide-1 (GLP-1) exerts cardioprotective effects in animal models of myocardial infarction (MI). We hypothesized that chronic treatment with GLP-1 or the exenatide analog AC3174 would improve cardiac function, cardiac remodeling, insulin sensitivity, and exercise capacity (EC) in rats with MI-induced chronic heart failure (CHF) caused by coronary artery ligation.
  
  
  METHODS
  Two weeks post-MI, male Sprague-Dawley rats were treated with GLP-1 (2.5 or 25 pmol/kg/min), AC3174 (1.7 or 5 pmol/kg/min) or vehicle via subcutaneous infusion for 11 weeks. Cardiac function and morphology were assessed by echocardiography during treatment. Metabolic, hemodynamic, exercise-capacity, and body composition measurements were made at study end.
  
  
  RESULTS
  Compared with vehicle-treated rats with CHF, GLP-1 or AC3174 significantly improved cardiac function, including left ventricular (LV) ejection fraction, and end diastolic pressure. Cardiac dimensions also improved as evidenced by reduced LV end diastolic and systolic volumes and reduced left atrial volume. Vehicle-treated CHF rats exhibited fasting hyperglycemia and hyperinsulinemia. In contrast, GLP-1 or AC3174 normalized fasting plasma insulin and glucose levels. GLP-1 or AC3174 also significantly reduced body fat and fluid mass and improved exercise capacity and respiratory efficiency. Four of 16 vehicle control CHF rats died during the study compared with 1 of 44 rats treated with GLP-1 or AC3174. The cellular mechanism by which GLP-1 or AC3174 exert cardioprotective effects appears unrelated to changes in GLUT1 or GLUT4 translocation or expression.
  
  
  CONCLUSIONS
  Chronic treatment with either GLP-1 or AC3174 showed promising cardioprotective effects in a rat model of CHF. Hence, GLP-1 receptor agonists may represent a novel approach for the treatment of patients with CHF or cardiovascular disease associated with type 2 diabetes.
authors.affiliation: Amylin Pharmaceuticals Inc, San Diego, CA 92121, USA.
authors.forename: Que
authors.initials: Q
authors.lastname: Liu
authors.forename: Christen
authors.initials: C
authors.lastname: Anderson
authors.forename: Anatoly
authors.initials: A
authors.lastname: Broyde
authors.forename: Clara
authors.initials: C
authors.lastname: Polizzi
authors.forename: Rayne
authors.initials: R
authors.lastname: Fernandez
authors.forename: Alain
authors.initials: A
authors.lastname: Baron
authors.forename: David G
authors.initials: DG
authors.lastname: Parkes
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D002316:Cardiotonic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D002908:Chronic Disease; D004195:Disease Models, Animal; D018619:Echocardiography, Doppler, Pulsed; D017079:Exercise Tolerance / Q000187:drug effects; D052216:Glucagon-Like Peptide 1 / Q000008:administration & dosage / Q000494:pharmacology*; D051272:Glucose Transporter Type 1 / Q000378:metabolism; D051275:Glucose Transporter Type 4 / Q000378:metabolism; D006333:Heart Failure / Q000097:blood / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D006439:Hemodynamics / Q000187:drug effects; D055104:Infusions, Subcutaneous; D007328:Insulin / Q000097:blood; D008297:Male; D009203:Myocardial Infarction / Q000097:blood / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism; D010455:Peptides / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013318:Stroke Volume / Q000187:drug effects; D013997:Time Factors; D016277:Ventricular Function, Left / Q000187:drug effects*; D017725:Ventricular Pressure / Q000187:drug effects; D020257:Ventricular Remodeling / Q000187:drug effects*
chemical_list: C553564:AC3174; D001786:Blood Glucose; D002316:Cardiotonic Agents; D051272:Glucose Transporter Type 1; D051275:Glucose Transporter Type 4; D007328:Insulin; D010455:Peptides; C495679:Slc2a1 protein, rat; C495694:Slc2a4 protein, rat; D052216:Glucagon-Like Peptide 1