Effects of omapatrilat on cardiac nerve sprouting and structural remodeling in experimental congestive heart failure

Yong Mei Cha, Margaret M. Redfield, Sonia Shah, Win Kuang Shen, Michael C. Fishbein, Peng Sheng Chen

Research output: Contribution to journalArticle

22 Scopus citations

Abstract

Background: Congestive heart failure (CHF) results in decreased cardiac sympathetic innervation. Objectives: 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 μm2/mm2, 261 ± 185 μm2/mm2, and 503 ± 328 μm2/mm2 (P < .05), and the atrial GAP43-positive nerve densities were 1,683 ± 1,365 μm2/mm2, 305 ± 368 μm2/ mm2, and 1,278 ± 1,479 μm2/mm2 (P < .05) for the control, CHF, and CHF + OMA groups, respectively. Conclusion: CHF results in heterogeneous cardiac denervation. Long-term OMA treatment prevented the reduction of nerve density and promoted beneficial cardiac structural remodeling.

Original languageEnglish (US)
Pages (from-to)984-990
Number of pages7
JournalHeart rhythm
Volume2
Issue number9
DOIs
StatePublished - Sep 1 2005

Keywords

  • Heart failure
  • Innervation
  • Remodeling

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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