Cardiac Resynchronization Therapy Corrects Dyssynchrony-induced Regional Gene Expression Changes on a Genomic Level
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ABSTRACT:
ORGANISM(S): Canis lupus familiaris
PROVIDER: GSE14661 | GEO | 2010/01/05
SECONDARY ACCESSION(S): PRJNA112351
REPOSITORIES: GEO
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Project description:Cardiac electromechanical dyssynchrony causes regional disparities in workload, oxygen consumption, and myocardial perfusion within the left ventricle. We hypothesized that such dyssynchrony also induces region-specific alterations in the myocardial transcriptome that are corrected by cardiac resynchronization therapy (CRT).Adult dogs underwent left bundle branch ablation and right atrial pacing at 200 bpm for either 6 weeks (dyssynchronous heart failure, n=12) or 3 weeks, followed by 3 weeks of resynchronization by biventricular pacing at the same pacing rate (CRT, n=10). Control animals without left bundle branch block were not paced (n=13). At 6 weeks, RNA was isolated from the anterior and lateral left ventricular (LV) walls and hybridized onto canine-specific 44K microarrays. Echocardiographically, CRT led to a significant decrease in the dyssynchrony index, while dyssynchronous heart failure and CRT animals had a comparable degree of LV dysfunction. In dyssynchronous heart failure, changes in gene expression were primarily observed in the anterior LV, resulting in increased regional heterogeneity of gene expression within the LV. Dyssynchrony-induced expression changes in 1050 transcripts were reversed by CRT to levels of nonpaced hearts (false discovery rate <5%). CRT remodeled transcripts with metabolic and cell signaling function and greatly reduced regional heterogeneity of gene expression as compared with dyssynchronous heart failure.Our results demonstrate a profound effect of electromechanical dyssynchrony on the regional cardiac transcriptome, causing gene expression changes primarily in the anterior LV wall. CRT corrected the alterations in gene expression in the anterior wall, supporting a global effect of biventricular pacing on the ventricular transcriptome that extends beyond the pacing site in the lateral wall.
| S-EPMC2801868 | biostudies-literature
Project description:This SuperSeries is composed of the following subset Series: GSE14327: Cardiac Resynchronization Therapy (1-color design) GSE14338: Cardiac Resynchronization Therapy (2-color design) Refer to individual Series
2010-05-16 | E-GEOD-14661 | biostudies-arrayexpress
Project description:Cardiac Resynchronization Therapy Corrects Dyssynchrony-induced Regional Gene Expression Changes on a Genomic Level
| PRJNA112351 | ENA
Project description:Right ventricular free wall (RVFW) pacing results in left ventricular dyssynchrony with early septal shortening followed by late lateral contraction that reciprocally stretches the septum. Dyssynchrony is disadvantageous to cardiac mechano-energetics, yet little is known about its molecular consequences. We tested the hypothesis that dyssynchrony selectively alters regional gene expression in mice, employing a novel miniature implantable cardiac pacemaker. Mice were subjected to 1-week overdrive RVFW pacing (720 min-1, baseline HR 520-620 min-1) to induce dyssynchrony (pacemaker: 3V lithium battery, rate programmable, 0.8 grams, bipolar lead). Electrical capture was confirmed by pulsed-wave Doppler at implantation and terminal study, and dyssynchrony by echocardiography. Gene expression from left ventricular septal and lateral-wall myocardium were assessed by microarray (dual-dye method, Agilent) using oligonucleotide probes and dye swap. Identical analysis was applied to 4 synchronously contracting controls. Of 22,000 genes surveyed, only 18 genes displayed significant (p<0.01) differential expression between septal/lateral walls exceeding 1.5-fold relative to any disparities in synchronous controls. These changes were confirmed by qPCR with excellent correlations. Most (16) of the genes showed greater septal expression. Of particular interest were 7 genes coding proteins involved with stretch responses, matrix remodeling, stem cell differentiation to myocyte lineage, and Purkinje fiber differentiation. One-week cardiac dyssynchrony triggers regional differential expression differences in relatively few select genes. Such analysis using a murine implantable pacemaker should facilitate molecular studies of cardiac dyssynchrony and help elucidate novel mechanisms by which stress/stretch stimuli due to dyssynchrony impact the normal and failing heart. Keywords: Murine cardiac dyssynchrony and differential gene expression, Agilent, microarray, pacing
2005-11-03 | GSE3535 | GEO
Project description:Small animal models of afterload stress have contributed much to our present understanding of the progression from hypertension to heart failure. High-sensitivity methods for phenotyping cardiac function in vivo, particular in the setting of compensated cardiac hypertrophy, may add new information regarding alterations in cardiac performance that can occur even during the earliest stages of exposure to pressure overload. We have developed an echocardiographic analytical method, based on speckle-tracking-based strain analyses, and used this tool to rapidly phenotype cardiac changes resulting from afterload stress in a small animal model. Adult mice were subjected to ascending aortic constriction, with and without subsequent reversal of the pressure gradient. In this model of compensated hypertrophic cardiac remodeling, conventional echocardiographic measurements did not detect changes in left ventricular (LV) function at the early time points examined. Strain analyses, however, revealed a decrement in basal longitudinal myofiber shortening that was induced by aortic constriction and improved following relief of the pressure gradient. Furthermore, we observed that pressure overload resulted in LV segmental dyssynchrony that was attenuated with return of the afterload to baseline levels. Herein, we describe the use of echocardiographic strain analyses for cardiac phenotyping in a mouse model of pressure overload. This method provides evidence of dyssynchrony and regional myocardial dysfunction that occurs early with compensatory hypertrophy, and improves following relief of aortic constriction. Importantly, these findings illustrate the utility of a rapid, non-invasive method for characterizing early cardiac dysfunction, not detectable by conventional echocardiography, following afterload stress.
| S-EPMC3613376 | biostudies-literature
Project description:Cardiac dyssynchrony arises from conduction abnormalities during heart failure and worsens morbidity and mortality. Cardiac resynchronization therapy (CRT) re-coordinates contraction using bi-ventricular pacing, but the cellular and molecular mechanisms involved remain largely unknown. The aim is to determine how dyssynchronous heart failure (HFdys ) alters the phospho-proteome and how CRT interacts with this unique phospho-proteome by analyzing Ser/Thr and Tyr phosphorylation. Phospho-enriched myocardium from dog models of Control, HFdys , and CRT is analyzed via MS. There were 209 regulated phospho-sites among 1761 identified sites. Compared to Con and CRT, HFdys is hyper-phosphorylated and tyrosine phosphorylation is more likely to be involved in signaling that increased with HFdys and was exacerbated by CRT. For each regulated site, the most-likely targeting-kinase is predicted, and CK2 is highly specific for sites that are "fixed" by CRT, suggesting activation of CK2 signaling occurs in HFdys that is reversed by CRT, which is supported by western blot analysis. These data elucidate signaling networks and kinases that may be involved and deserve further study. Importantly, a possible role for CK2 modulation in CRT has been identified. This may be harnessed in the future therapeutically to compliment CRT, improving its clinical effects.
| S-EPMC6417799 | biostudies-literature
Project description:AimsTo evaluate the effects of cardiac resynchronization therapy (CRT) on long-term survival of patients without baseline left ventricular (LV) mechanical dyssynchrony.Methods and resultsA total of 290 heart failure patients (age 67 ± 10 years, 77% males) without significant baseline LV dyssynchrony (<60 ms as assessed with tissue Doppler imaging) were treated with CRT. Patients were divided according to the median LV dyssynchrony measured after 48 h of CRT into two groups. All-cause mortality was compared between the subgroups. In addition, the all-cause mortality rates of these subgroups were compared with the all-cause mortality of 290 heart failure patients treated with CRT who showed significant LV dyssynchrony (≥60 ms) at baseline. In the group of patients without significant LV dyssynchrony, median LV dyssynchrony increased from 22 ms (inter-quartile range 16-34 ms) at baseline to 40 ms (24-56 ms) 48 h after CRT. The cumulative mortality rates at 1-, 2-, and 3-year follow-up of patients with LV dyssynchrony ≥40 ms 48 h after CRT implantation were significantly higher when compared with patients with LV dyssynchrony <40 ms (10, 17, and 23 vs. 3, 8, and 10%, respectively; log-rank P< 0.001). Finally, the cumulative mortality rates at 1-, 2-, and 3-year follow-up of patients with baseline LV dyssynchrony were 3, 8, and 11%, respectively (log-rank P= 0.375 vs. patients with LV dyssynchrony <40 ms). Induction of LV dyssynchrony after CRT was an independent predictor of mortality (hazard ratio: 1.247; P= 0.009).ConclusionIn patients without significant LV dyssynchrony, the induction of LV dyssynchrony after CRT may be related to a less favourable long-term outcome.
| S-EPMC3345550 | biostudies-literature
Project description:Right ventricular free wall (RVFW) pacing results in left ventricular dyssynchrony with early septal shortening followed by late lateral contraction that reciprocally stretches the septum. Dyssynchrony is disadvantageous to cardiac mechano-energetics, yet little is known about its molecular consequences. We tested the hypothesis that dyssynchrony selectively alters regional gene expression in mice, employing a novel miniature implantable cardiac pacemaker. Mice were subjected to 1-week overdrive RVFW pacing (720 min-1, baseline HR 520-620 min-1) to induce dyssynchrony (pacemaker: 3V lithium battery, rate programmable, 0.8 grams, bipolar lead). Electrical capture was confirmed by pulsed-wave Doppler at implantation and terminal study, and dyssynchrony by echocardiography. Gene expression from left ventricular septal and lateral-wall myocardium were assessed by microarray (dual-dye method, Agilent) using oligonucleotide probes and dye swap. Identical analysis was applied to 4 synchronously contracting controls. Of 22,000 genes surveyed, only 18 genes displayed significant (p<0.01) differential expression between septal/lateral walls exceeding 1.5-fold relative to any disparities in synchronous controls. These changes were confirmed by qPCR with excellent correlations. Most (16) of the genes showed greater septal expression. Of particular interest were 7 genes coding proteins involved with stretch responses, matrix remodeling, stem cell differentiation to myocyte lineage, and Purkinje fiber differentiation. One-week cardiac dyssynchrony triggers regional differential expression differences in relatively few select genes. Such analysis using a murine implantable pacemaker should facilitate molecular studies of cardiac dyssynchrony and help elucidate novel mechanisms by which stress/stretch stimuli due to dyssynchrony impact the normal and failing heart. Experiment Overall Design: Left ventricle segments from the mouse heart - septal and lateral, were isolated from 4 dyssynchronous mice that were kept separate. RNA from the synchronous mice were pooled into a control septal and lateral sample. Functional genomic analysis was conducted on these 10 RNA samples with fluorophore reversal, such that each sample was assayed on two different microarrays. Corresponding septal and lateral samples from the same heart were paired on the same microarray to measure the relative differences in gene expression between the different regions of the heart then differences were compared across multiple mice to find overlapping genes that were affected by the pacememaker implantation.
2008-06-12 | E-GEOD-3535 | biostudies-arrayexpress
Project description:We tested a circumferential mechanical dyssynchrony index (circumferential uniformity ratio estimate [CURE]; 0 to 1, 1 = synchrony) derived from magnetic resonance-myocardial tagging (MR-MT) for predicting clinical function class improvement following cardiac resynchronization therapy (CRT).There remains a significant nonresponse rate to CRT. MR-MT provides high quality mechanical activation data throughout the heart, and delayed enhancement cardiac magnetic resonance (DE-CMR) offers precise characterization of myocardial scar.MR-MT was performed in 2 cohorts of heart failure patients with: 1) a CRT heart failure cohort (n = 20; left ventricular ejection fraction of 0.23 +/- 0.057) to evaluate the role of MR-MT and DE-CMR prior to CRT; and 2) a multimodality cohort (n = 27; ejection fraction of 0.20 +/- 0.066) to compare MR-MT and tissue Doppler imaging septal-lateral delay for assessment of mechanical dyssynchrony. MR-MT was also performed in 9 healthy control subjects.MR-MT showed that control subjects had highly synchronous contraction (CURE 0.96 +/- 0.01), but tissue Doppler imaging indicated dyssynchrony in 44%. Using a cutoff of <0.75 for CURE based on receiver-operator characteristic analysis (area under the curve: 0.889), 56% of patients tested positive for mechanical dyssynchrony, and the MR-MT CURE predicted improved function class with 90% accuracy (positive and predictive values: 87%, 100%); adding DE-CMR (% total scar <15%) data improved accuracy further to 95% (positive and negative predictive values: 93%, 100%). The correlation between CURE and QRS duration was modest in all cardiomyopathy subjects (r = 0.58, p < 0.001). The multimodality cohort showed a 30% discordance rate between CURE and tissue Doppler imaging septal-lateral delay.The MR-MT assessment of circumferential mechanical dyssynchrony predicts improvement in function class after CRT. The addition of scar imaging by DE-CMR further improves this predictive value.
| S-EPMC2678755 | biostudies-literature
Project description:Cardiac resynchronisation therapy (CRT) is an accepted treatment for heart failure patients with depressed left ventricular (LV) function and dyssynchrony. However, despite better clinical outcome and improved cardiac function after CRT in the majority of eligible heart failure patients, a large proportion of implanted patients do not seem to benefit clinically from this therapy. In this review we consider whether genetic factors may play a role in modulating response to CRT and summarise the few genetic studies that have investigated the role of genetic variation in candidate genes.
| S-EPMC4692826 | biostudies-literature