title: Dysautonomia due to reduced cholinergic neurotransmission causes cardiac remodeling and heart failure.
abstract: 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.
authors.affiliation: Department of Physiology, Institute of Biological Sciences, Federal University of Minas Gerais, Av. Antônio Carlos 6627, Belo Horizonte, MG CEP 31270-901, Brazil.
authors.forename: Aline
authors.initials: A
authors.lastname: Lara
authors.forename: Denis D
authors.initials: DD
authors.lastname: Damasceno
authors.forename: Rita
authors.initials: R
authors.lastname: Pires
authors.forename: Robert
authors.initials: R
authors.lastname: Gros
authors.forename: Enéas R
authors.initials: ER
authors.lastname: Gomes
authors.forename: Mariana
authors.initials: M
authors.lastname: Gavioli
authors.forename: Ricardo F
authors.initials: RF
authors.lastname: Lima
authors.forename: Diogo
authors.initials: D
authors.lastname: Guimarães
authors.forename: Patricia
authors.initials: P
authors.lastname: Lima
authors.forename: Carlos Roberto
authors.initials: CR
authors.lastname: Bueno
authors.forename: Anilton
authors.initials: A
authors.lastname: Vasconcelos
authors.forename: Danilo
authors.initials: D
authors.lastname: Roman-Campos
authors.forename: Cristiane A S
authors.initials: CA
authors.lastname: Menezes
authors.forename: Raquel A
authors.initials: RA
authors.lastname: Sirvente
authors.forename: Vera M
authors.initials: VM
authors.lastname: Salemi
authors.forename: Charles
authors.initials: C
authors.lastname: Mady
authors.forename: Marc G
authors.initials: MG
authors.lastname: Caron
authors.forename: Anderson J
authors.initials: AJ
authors.lastname: Ferreira
authors.forename: Patricia C
authors.initials: PC
authors.lastname: Brum
authors.forename: Rodrigo R
authors.initials: RR
authors.lastname: Resende
authors.forename: Jader S
authors.initials: JS
authors.lastname: Cruz
authors.forename: Marcus Vinicius
authors.initials: MV
authors.lastname: Gomez
authors.forename: Vania F
authors.initials: VF
authors.lastname: Prado
authors.forename: Alvair P
authors.initials: AP
authors.lastname: de Almeida
authors.forename: Marco A M
authors.initials: MA
authors.lastname: Prado
authors.forename: Silvia
authors.initials: S
authors.lastname: Guatimosim
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D018678:Cholinergic Agents / Q000378:metabolism*; D004452:Echocardiography; D006333:Heart Failure / Q000378:metabolism* / Q000503:physiopathology; D006339:Heart Rate / Q000502:physiology; D006439:Hemodynamics; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism; D018408:Patch-Clamp Techniques; D010641:Phenotype; D054969:Primary Dysautonomias / Q000503:physiopathology*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000235:genetics / Q000378:metabolism; D013564:Sympathetic Nervous System / Q000378:metabolism; D009435:Synaptic Transmission / Q000502:physiology*; D020257:Ventricular Remodeling / Q000502:physiology*; D050494:Vesicular Acetylcholine Transport Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D018678:Cholinergic Agents; D043562:Receptors, G-Protein-Coupled; D050494:Vesicular Acetylcholine Transport Proteins; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D002118:Calcium