title: Effects of omapatrilat on cardiac nerve sprouting and structural remodeling in experimental congestive heart failure.
abstract: BACKGROUND
  Congestive heart failure (CHF) results in decreased cardiac sympathetic innervation.
  
  
  OBJECTIVE
  The purpose of this study was to test the hypothesis that therapy with the vasopeptidase inhibitor omapatrilat (OMA) attenuates cardiac neuronal remodeling in CHF.
  
  
  METHODS
  We induced CHF in dogs with rapid ventricular pacing for 5 weeks with (CHF+OMA group, n = 8) or without (CHF group, n = 10) concomitant OMA treatment (10 mg/kg twice daily). Cardiac catheterization and echocardiography were performed to determine cardiac structure and hemodynamic parameters. Myocardial nerve density was determined by immunocytochemical staining with anti-growth associated protein 43 (GAP43) and anti-tyrosine hydroxylase (TH) antibodies. Seven normal dogs were used as histologic controls.
  
  
  RESULTS
  In the CHF group, ascites developed in 3 dogs and 4 dogs died, compared with no ascites or death in the CHF+OMA group (P = .07). In the 6 CHF dogs that survived, all had atrial fibrosis, severely depressed left ventricular systolic function, and increased atrial and ventricular chamber size. OMA treatment decreased the atrial and ventricular chamber sizes and the degree of atrial fibrosis. Most CHF dogs showed severe myocardial denervation, although some showed normal or abnormally high nerve counts. OMA treatment prevented heterogeneous reduction of nerve density. The left ventricular TH-positive nerve densities were 128 +/- 170 microm(2)/mm(2), 261 +/- 185 microm(2)/mm(2), and 503 +/- 328 microm(2)/mm(2) (P < .05), and the atrial GAP43-positive nerve densities were 1,683 +/- 1,365 microm(2)/mm(2), 305 +/- 368 microm(2)/mm(2), and 1,278 +/- 1,479 microm(2)/mm(2) (P < .05) for the control, CHF, and CHF+OMA groups, respectively.
  
  
  CONCLUSIONS
  CHF results in heterogeneous cardiac denervation. Long-term OMA treatment prevented the reduction of nerve density and promoted beneficial cardiac structural remodeling.
authors.affiliation: Division of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota 55905, USA. cha.yongmei@mayo.edu
authors.forename: Yong-Mei
authors.initials: YM
authors.lastname: Cha
authors.forename: Margaret M
authors.initials: MM
authors.lastname: Redfield
authors.forename: Sonia
authors.initials: S
authors.lastname: Shah
authors.forename: Win-Kuang
authors.initials: WK
authors.lastname: Shen
authors.forename: Michael C
authors.initials: MC
authors.lastname: Fishbein
authors.forename: Peng-Sheng
authors.initials: PS
authors.lastname: Chen
mesh_terms: D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000097:blood / Q000187:drug effects; D002317:Cardiovascular Agents / Q000494:pharmacology*; D004195:Disease Models, Animal; D004285:Dogs; D006325:Heart Atria / Q000294:innervation / Q000378:metabolism / Q000503:physiopathology; D006333:Heart Failure / Q000188:drug therapy* / Q000503:physiopathology*; D006352:Heart Ventricles / Q000294:innervation / Q000378:metabolism / Q000503:physiopathology; D017379:Hypertrophy, Left Ventricular / Q000188:drug therapy / Q000503:physiopathology; D008297:Male; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D020097:Natriuretic Peptide, Brain / Q000097:blood / Q000187:drug effects; D009417:Nerve Tissue / Q000187:drug effects*; D011725:Pyridines / Q000494:pharmacology*; D012083:Renin / Q000097:blood / Q000187:drug effects; D013318:Stroke Volume / Q000187:drug effects; D013841:Thiazepines / Q000494:pharmacology*; D018487:Ventricular Dysfunction, Left / Q000188:drug therapy / Q000503:physiopathology; D017725:Ventricular Pressure / Q000187:drug effects; D020257:Ventricular Remodeling / Q000187:drug effects*
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D002317:Cardiovascular Agents; D011725:Pyridines; D013841:Thiazepines; D020097:Natriuretic Peptide, Brain; C106266:omapatrilat; D009320:Atrial Natriuretic Factor; D012083:Renin