title: Blockade of A2B adenosine receptor reduces left ventricular dysfunction and ventricular arrhythmias 1 week after myocardial infarction in the rat model.
abstract: BACKGROUND
  Remodeling occurs after myocardial infarction (MI), leading to fibrosis, dysfunction, and ventricular tachycardias (VTs). Adenosine via the A2B adenosine receptor (A2BAdoR) has been implicated in promoting fibrosis.
  
  
  OBJECTIVE
  To determine the effects of GS-6201, a potent antagonist of the A2BAdoR, on arrhythmogenic and functional cardiac remodeling after MI.
  
  
  METHODS
  Rats underwent ischemia-reperfusion MI and were randomized into 4 groups: control (treated with vehicle), angiotensin-converting enzyme inhibitor (treated with enalapril 1 day after MI), GS-6201-1d (treated with GS-6201 1 day after MI), GS-6201-1w (treated with GS-6201 administered 1 week after MI) . Echocardiography was performed at baseline and 1 and 5 weeks after MI. Optical mapping, VT inducibility, and histologic analysis were conducted at follow-up.
  
  
  RESULTS
  Treatment with the angiotensin-converting enzyme inhibitor improved ejection fraction (57.8% ± 2.5% vs 43.3% ± 1.7% in control; P < .01), but had no effect on VT inducibility. Treatment with GS-6201 improved ejection fraction (55.6% ± 2.6% vs 43.3% ± 1.7% in control; P < .01) and decreased VT inducibility (9.1% vs 68.4% in control; P < .05). Conduction velocities were significantly higher at border and infarct zones in hearts of rats treated with GS-6201 than in those of other groups. The conduction heterogeneity index was also significantly lower in hearts of rats treated with GS-6201. Histologic analysis showed that while both GS-6201 and enalapril decreased fibrosis in the noninfarct zone, only GS-6201 reduced the heterogeneity of fibrosis at the border, which is consistent with its effect on VT reduction.
  
  
  CONCLUSIONS
  Treatment with an A2BAdoR antagonist at 1 week results in the improvement in cardiac function and decreased substrate for VT. The inhibition of fibrogenesis by A2BAdoR antagonists may be a new target for the prevention of adverse remodeling after MI.
authors.affiliation: Cardiac Electrophysiology and Cardiovascular Research Institute, University of California, San Francisco, California.
authors.forename: Hao
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Gilead Sciences, Inc, Foster City, California.
authors.forename: Hongyan
authors.initials: H
authors.lastname: Zhong
authors.affiliation: Cardiac Electrophysiology and Cardiovascular Research Institute, University of California, San Francisco, California.
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Everett
authors.affiliation: Cardiac Electrophysiology and Cardiovascular Research Institute, University of California, San Francisco, California.
authors.forename: Emily
authors.initials: E
authors.lastname: Wilson
authors.affiliation: Cardiac Electrophysiology and Cardiovascular Research Institute, University of California, San Francisco, California.
authors.forename: Roger
authors.initials: R
authors.lastname: Chang
authors.affiliation: Gilead Sciences, Inc, Foster City, California.
authors.forename: Dewan
authors.initials: D
authors.lastname: Zeng
authors.affiliation: Gilead Sciences, Inc, Foster City, California.
authors.forename: Luiz
authors.initials: L
authors.lastname: Belardinelli
authors.affiliation: Cardiac Electrophysiology and Cardiovascular Research Institute, University of California, San Francisco, California. Electronic address: olgin@medicine.ucsf.edu.
authors.forename: Jeffrey E
authors.initials: JE
authors.lastname: Olgin
mesh_terms: D058917:Adenosine A2 Receptor Antagonists / Q000627:therapeutic use*; D000818:Animals; D004195:Disease Models, Animal; D004562:Electrocardiography; D005500:Follow-Up Studies; D006329:Heart Conduction System / Q000187:drug effects / Q000503:physiopathology; D008297:Male; D009203:Myocardial Infarction / Q000150:complications* / Q000188:drug therapy / Q000503:physiopathology; D011687:Purines / Q000627:therapeutic use*; D011720:Pyrazoles / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013318:Stroke Volume / Q000187:drug effects; D017180:Tachycardia, Ventricular / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D013997:Time Factors; D016896:Treatment Outcome; D018487:Ventricular Dysfunction, Left / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D020257:Ventricular Remodeling / Q000187:drug effects*
chemical_list: D058917:Adenosine A2 Receptor Antagonists; D011687:Purines; D011720:Pyrazoles; C518643:3-ethyl-1-propyl-8-(1-(3-trifluoromethylbenzyl)-1H-pyrazol-4-yl)-3,7-dihydropurine-2,6-dione
keywords: 5′-N-ethylcarboxamidoadenosine; A(2B) adenosine receptor; A(2B)AdoR; ACEI; APD(80); CV; EF; Fibrosis; LV; MI; Myocardial infarction; NECA; Optical mapping; PCL; Remodeling; VT; Ventricular tachycardia; action potential duration at 80% repolarization; angiotensin-converting enzyme inhibitor; conduction velocity; ejection fraction; left ventricular; myocardial infarction; pacing cycle length; ventricular tachycardia