Dysautonomia due to reduced cholinergic neurotransmission causes cardiac remodeling and heart failure.

Published

Journal Article

Overwhelming evidence supports the importance of the sympathetic nervous system in heart failure. In contrast, much less is known about the role of failing cholinergic neurotransmission in cardiac disease. By using a unique genetically modified mouse line with reduced expression of the vesicular acetylcholine transporter (VAChT) and consequently decreased release of acetylcholine, we investigated the consequences of altered cholinergic tone for cardiac function. M-mode echocardiography, hemodynamic experiments, analysis of isolated perfused hearts, and measurements of cardiomyocyte contraction indicated that VAChT mutant mice have decreased left ventricle function associated with altered calcium handling. Gene expression was analyzed by quantitative reverse transcriptase PCR and Western blotting, and the results indicated that VAChT mutant mice have profound cardiac remodeling and reactivation of the fetal gene program. This phenotype was attributable to reduced cholinergic tone, since administration of the cholinesterase inhibitor pyridostigmine for 2 weeks reversed the cardiac phenotype in mutant mice. Our findings provide direct evidence that decreased cholinergic neurotransmission and underlying autonomic imbalance cause plastic alterations that contribute to heart dysfunction.

Full Text

Duke Authors

Cited Authors

  • Lara, A; Damasceno, DD; Pires, R; Gros, R; Gomes, ER; Gavioli, M; Lima, RF; Guimarães, D; Lima, P; Bueno, CR; Vasconcelos, A; Roman-Campos, D; Menezes, CAS; Sirvente, RA; Salemi, VM; Mady, C; Caron, MG; Ferreira, AJ; Brum, PC; Resende, RR; Cruz, JS; Gomez, MV; Prado, VF; de Almeida, AP; Prado, MAM; Guatimosim, S

Published Date

  • April 2010

Published In

Volume / Issue

  • 30 / 7

Start / End Page

  • 1746 - 1756

PubMed ID

  • 20123977

Pubmed Central ID

  • 20123977

Electronic International Standard Serial Number (EISSN)

  • 1098-5549

Digital Object Identifier (DOI)

  • 10.1128/MCB.00996-09

Language

  • eng

Conference Location

  • United States