Bilchick Kenneth C, Saha Sudip K, Mikolajczyk Ed, Cope Leslie, Ferguson Will J, Yu Wayne, Girouard Steven, Kass David A
Division of Cardiology, Department of Medicine, School of Medicine, Baltimore, Maryland, USA.
Physiol Genomics. 2006 Jul 12;26(2):109-15. doi: 10.1152/physiolgenomics.00281.2005. Epub 2006 May 2.
Routine clinical right ventricular pacing generates left ventricular dyssynchrony manifested by early septal shortening followed by late lateral contraction, which, in turn, reciprocally stretches the septum. Dyssynchrony is disadvantageous to cardiac mechanoenergetics and worsens clinical prognosis, yet little is known about its molecular consequences. Here, we report the influence of cardiac dyssynchrony on regional cardiac gene expression in mice. Mice were implanted with a custom-designed miniature cardiac pacemaker and subjected to 1-wk overdrive right ventricular free wall pacing (720 beats/min, baseline heart rate 520-620 beats/min) to generate dyssynchrony (pacemaker: 3-V lithium battery, rate programmable, 1.5 g, bipolar lead). Electrical capture was confirmed by pulsed-wave Doppler and dyssynchrony by echocardiography. Gene expression from the left ventricular septal and lateral wall myocardium was assessed by microarray (dual-dye method, Agilent) using oligonucleotide probes and dye swap. Identical analysis was applied to four synchronously contracting controls. Of the 22,000 genes surveyed, only 18 genes displayed significant (P < 0.01) differential expression between septal/lateral walls >1.5 times that in synchronous controls. Gene changes were confirmed by quantitative PCR with excellent correlations. Most of the genes (n = 16) showed greater septal expression. Of particular interest were seven genes coding proteins involved with stretch responses, matrix remodeling, stem cell differentiation to myocyte lineage, and Purkinje fiber differentiation. One week of iatrogenic cardiac dyssynchrony triggered regional differential expression 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.
常规临床右心室起搏会导致左心室不同步，表现为早期室间隔缩短，随后是晚期侧壁收缩，进而反向拉伸室间隔。不同步对心脏机械能量学不利，并会恶化临床预后，但对其分子后果知之甚少。在此，我们报告了心脏不同步对小鼠局部心脏基因表达的影响。给小鼠植入定制设计的微型心脏起搏器，并进行1周的右心室游离壁超速起搏（720次/分钟，基础心率520 - 620次/分钟）以产生不同步（起搏器：3伏锂电池，速率可编程，1.5克，双极导联）。通过脉冲波多普勒确认电捕获，通过超声心动图确认不同步。使用寡核苷酸探针和染料交换，通过微阵列（双染料法，安捷伦）评估左心室室间隔和侧壁心肌的基因表达。对四个同步收缩的对照进行相同分析。在所检测的22000个基因中，只有18个基因在室间隔/侧壁之间显示出显著（P < 0.01）差异表达，是同步对照中差异表达的1.5倍以上。通过定量PCR证实了基因变化，相关性良好。大多数基因（n = 16）在室间隔中的表达更高。特别令人感兴趣的是七个编码与拉伸反应、基质重塑、干细胞向心肌细胞谱系分化以及浦肯野纤维分化相关蛋白质的基因。一周的医源性心脏不同步在相对较少的特定基因中引发了局部差异表达。使用小鼠可植入起搏器进行此类分析应有助于心脏不同步的分子研究，并有助于阐明不同步引起的应激/拉伸刺激影响正常心脏和衰竭心脏的新机制。
