Altered expression of a limited number of genes contributes to cardiac decompensation during chronic ventricular tachypacing in dogs

Abstract

Ojaimi C, Qanud K, Hintze TH, Recchia FA. Altered expression of a limited number of genes contributes to cardiac decompensation during chronic ventricular tachypacing in dogs. Physiol Genomics 29: 76 -83, 2007. First published December 12, 2006; doi:10.1152/physiolgenomics.00159.2006.-Our aim was to determine the changes in the gene expression profile occurring during the transition from compensated dysfunction (CD) to decompensated heart failure (HF) in pacing-induced dilated cardiomyopathy. Twelve chronically instrumented dogs underwent left ventricular pacing at 210 beats/min for 3 wk and at 240 beats thereafter, and four normal dogs were used as control. The transition from CD to HF occurred between the 3rd and 4th wk of pacing, with end-stage HF at 28 Ϯ 1 days. RNA was extracted from left ventricular tissue at control and 3 and 4 wk of pacing (n ϭ 4) and tested with the Affymetrix Canine Array. We found 509 genes differentially expressed in CD vs. control (P Յ 0.05, fold change ՆϮ2), with 362 increasing and 147 decreasing; 526 genes were differentially expressed in HF vs. control (P Յ 0.05; fold change ՆϮ2), with 439 increasing and 87 decreasing. To better understand the transition, we compared gene alterations at 3 vs. 4 wk pacing and found that only 30 genes differed (P Յ 0.05; fold change of Ϯ2). We conclude that a number of processes including normalization of gene regulation during decompensation, appearance of new upregulated genes and maintenance of gene expression all contribute to the transition to overt heart failure with an unexpectedly small number of genes differentially regulated. heart failure; pacing dog; microarray OVER THE PAST YEARS OTHER authors and we have used chronically instrumented dogs with high-frequency cardiac pacing to study pathophysiological and molecular mechanisms related to the development of dilated cardiomyopathy. This model of congestive heart failure is characterized by a very predictable evolution and reproduces many key features of the human disease, including progressive ventricular chambers dilation and wall thinning, decreased contractility, neurohormonal activation, beta adrenergic desensitization, and altered metabolism (19). In particular, we could determine functional and metabolic changes occurring only between the 3rd and 4th wk of pacing, i.e., during the transition from compensated to decompensated failure (25). The marked cardiac functional impairment and systemic deterioration observed during this relatively short phase of transition suggests the occurrence of profound molecular alterations. Their identification would provide notable insights in the pathophysiology and clinical management of heart failure. Unfortunately, given the complexity of the heart failure syndrome, such molecular changes are likely very numerous and interrelated, while most studies have been focused on single or selected groups of molecules, due to the limitations of the classical methods of analysis.More recently, global gene transcript profiling has emerged as a powerful tool f...

Key pathways associated with heart failure development revealed by gene networks correlated with cardiac remodeling

“…1). Thus, the genomic alterations are consistent with our previous findings (15) as well as other independent studies (17,23).…”

“…The development of clinically overt HF was associated with only limited further changes in the myocardial transcriptome. Considering the profound phenotypic alterations of the failing heart, this finding seems surprising, however, it is in agreement with studies showing that the transition from compensated to decompensated HF during chronic ventricular tachypacing in dogs is associated with only few transcriptional changes (6,23). Our study extends this observation, demonstrating that ventricular tachypacing-associated transcriptional changes occur very early after initiation of pacing, setting the stage for maladaptive remodeling processes and the subsequent development of HF.…”

“…To identify a robust gene expression profile of canine tachypacing-induced HF, we compared our results to a recent study by Ojaimi et al (23), which focused on stage-specific gene expression patterns during the transition from compensated to decompensated HF using the same HF model. We performed a functional classification of their publicly available microarray data (GSE5247) and found a high concordance of gene expression patterns between both studies, suggesting a common and robust disease-specific genomic fingerprint (Fig.…”

“…The transcriptomic profiles of rapid ventricular pacing-induced HF of the current study were compared with a recent microarray study examining the myocardial gene expression during the transition from compensated to decompensated heart failure in canines (23). This study was downloaded from Gene Expression Omnibus (GEO accession number GSE5247) and analyzed similarly to the current study (GSE9794).…”

Reactive Oxygen Species (ROS) Signaling in Cardiac Remodeling and Failure

“…Furthermore, chronic MAO-A inhibition has been found to protect against the development of pressure-overload-induced LV contractile dysfunction and dilatation, while acute ischemia-reperfusion injury was reduced in MAO-A-deficient mice (Pchejetski et al 2007;Kaludercic et al 2010). Although the majority of studies to date have focused on the MAO-A isoform, myocardial expression of MAO-B is also reported to be increased in dogs with chronic rapid ventricular pacing-induced CHF (Ojaimi et al 2007), suggesting that ROS produced by this isoform may also play an important role in cardiac remodeling.…”