Document Detail


Diminished cardiac fibrosis in heart failure is associated with altered ventricular arrhythmia phenotype.
MedLine Citation:
PMID:  20233273     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
OBJECTIVES: We sought to define the role of interstitial fibrosis in the proarrhythmic phenotype of failing ventricular myocardium.
BACKGROUND: Multiple cellular events that occur during pathological remodeling of the failing ventricle are implicated in the genesis of ventricular tachycardia (VT), including interstitial fibrosis. Recent studies suggest that ventricular fibrosis is reversible, and current anti-remodeling therapies attenuate ventricular fibrosis. However, the role of interstitial fibrosis in the proarrhythmic phenotype of failing ventricular myocardium is currently not well defined.
METHODS: Class II histone deacetylases (HDACs) have been implicated in promoting collagen biosynthesis. As these enzymes are inhibited by protein kinase D1 (PKD1), we studied mice with cardiomyocyte-specific transgenic over-expression of a constitutively active mutant of PKD1 (caPKD). caPKD mice were compared with animals in which cardiomyopathy was induced by severe thoracic aortic banding (sTAB). Hearts were analyzed by echocardiographic and electrocardiographic means. Interstitial fibrosis was assessed by histology and quantified biochemically. Ventricular arrhythmias were induced by closed-chest, intracardiac pacing.
RESULTS: Similar degrees of hypertrophic growth, systolic dysfunction and mortality were observed in the two models. In sTAB mice, robust ventricular fibrosis was readily detected, but myocardial collagen content was significantly reduced in caPKD mice. As expected, VT was readily inducible by programmed stimulation in sTAB mice and VT was less inducible in caPKD mice. Surprisingly, episodes of VT manifested longer cycle lengths and longer duration in caPKD mice.
CONCLUSION: Attenuated ventricular fibrosis is associated with reduced VT inducibility, increased VT duration, and significantly longer arrhythmia cycle length.
Authors:
Jorge Massare; Jeff M Berry; Xiang Luo; Farhana Rob; Janet L Johnstone; John M Shelton; Rhonda Bassel-Duby; Joseph A Hill; R Haris Naseem
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Journal of cardiovascular electrophysiology     Volume:  21     ISSN:  1540-8167     ISO Abbreviation:  J. Cardiovasc. Electrophysiol.     Publication Date:  2010 Sep 
Date Detail:
Created Date:  2010-11-05     Completed Date:  2011-02-18     Revised Date:  2013-07-25    
Medline Journal Info:
Nlm Unique ID:  9010756     Medline TA:  J Cardiovasc Electrophysiol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1031-7     Citation Subset:  IM    
Copyright Information:
© 2010 Wiley Periodicals, Inc.
Affiliation:
Department of Internal Medicine (Cardiology), University of Texas Southwestern Medical Center, Dallas, Texas 75390-8573, USA.
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MeSH Terms
Descriptor/Qualifier:
Action Potentials
Animals
Cardiomyopathy, Dilated / complications*,  enzymology,  pathology,  physiopathology
Disease Models, Animal
Electrophysiologic Techniques, Cardiac
Fibrosis
Genotype
Heart Failure / enzymology,  etiology*,  pathology,  physiopathology
Male
Mice
Mice, Inbred C57BL
Mice, Transgenic
Mutation
Myocardium / enzymology,  pathology*
Phenotype
Protein Kinase C / genetics,  metabolism
Tachycardia, Ventricular / enzymology,  etiology*,  genetics,  pathology,  physiopathology,  prevention & control
Up-Regulation
Ventricular Remodeling*
Grant Support
ID/Acronym/Agency:
HL-006296/HL/NHLBI NIH HHS; HL-075173/HL/NHLBI NIH HHS; HL-080144/HL/NHLBI NIH HHS; R01 HL075173/HL/NHLBI NIH HHS; R01 HL080144/HL/NHLBI NIH HHS; R01 HL090842/HL/NHLBI NIH HHS; T32 HL007360/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
EC 2.7.10.-/protein kinase D; EC 2.7.11.13/Protein Kinase C
Comments/Corrections

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