Dataset Information

Diminished cardiac fibrosis in heart failure is associated with altered ventricular arrhythmia phenotype.

ABSTRACT: We sought to define the role of interstitial fibrosis in the proarrhythmic phenotype of failing ventricular myocardium.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.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.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.Attenuated ventricular fibrosis is associated with reduced VT inducibility, increased VT duration, and significantly longer arrhythmia cycle length.

SUBMITTER: Massare J

PROVIDER: S-EPMC3703442 | biostudies-literature | 2010 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Diminished cardiac fibrosis in heart failure is associated with altered ventricular arrhythmia phenotype.

Massare Jorge J Berry Jeff M JM Luo Xiang X Rob Farhana F Johnstone Janet L JL Shelton John M JM Bassel-Duby Rhonda R Hill Joseph A JA Naseem R Haris RH

Journal of cardiovascular electrophysiology 20100901 9

<h4>Objectives</h4>We sought to define the role of interstitial fibrosis in the proarrhythmic phenotype of failing ventricular myocardium.<h4>Background</h4>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 ...[more]

PMID: 20233273

Similar Datasets

Project description:Background:Left ventricular assist devices (LVADs) have revolutionized and improved the care of the sickest heart failure (HF) patients, and it is imperative that they receive appropriate ventricular unloading. Assessing this critical parameter with current methodologies (labs, imaging) is usually suboptimal in this patient population. Hence it is imperative to elucidate the molecular underpinnings involved in ventricular unloading. We have previously identified the cytoskeletal protein ?II spectrin as an essential nodal protein involved in post-translational targeting and ?II spectrin protein levels are significantly altered in multiple forms of human and animal HF. We therefore hypothesized that the ?II spectrin pathway would play a critical role in LVAD remodeling. Methods:Human heart failure samples were obtained from patients undergoing heart transplantation. Wild type (WT) mice and our previously validated ?II spectrin conditional knock out (?II cKO) mice were used for animal experiments. Transaortic constriction (TAC) was performed on WT mice. Protein expression was assessed via immunoblots, and protein interactions were assessed with co-immunoprecipitation. Transcriptome analysis was performed using isolated whole hearts from control adult WT mice (n = 3) compared to ?II cKO spectrin mice (n = 3). Results:We report that hearts from mice selectively lacking ?II spectrin expression in cardiomyocytes displayed altered transcriptional regulation of cardiac ankyrin repeat protein (CARP). Notably, CARP protein expression is increased after TAC. Additionally, our findings illustrate that prior to LVAD support, CARP levels are elevated in HF patients compared to normal healthy controls. Further, for the first time in a LVAD population, we show that elevated CARP levels in HF patients return to normal following LVAD support. Conclusion:Our findings illustrate that CARP is a dynamic molecule that responds to reduced afterload and stress, and has the potential to serve as a prognostic biomarker to assess for an adequate response to LVAD therapy.

Dataset Information

Diminished cardiac fibrosis in heart failure is associated with altered ventricular arrhythmia phenotype.

Publications

Diminished cardiac fibrosis in heart failure is associated with altered ventricular arrhythmia phenotype.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets