Spragg David D, Leclercq Christophe, Loghmani Morteza, Faris Owen P, Tunin Richard S, DiSilvestre Deborah, McVeigh Elliot R, Tomaselli Gordon F, Kass David A
Division of Cardiology, Department of Medicine, Johns Hopkins University, Baltimore, MD, USA.
Circulation. 2003 Aug 26;108(8):929-32. doi: 10.1161/01.CIR.0000088782.99568.CA. Epub 2003 Aug 18.
Left ventricular (LV) mechanical dyssynchrony induces regional heterogeneity of mechanical load and is an independent predictor of mortality and sudden death in heart failure (HF) patients. We tested whether dyssynchrony also induces localized disparities in the expression of proteins involved with mechanical stress, function, and arrhythmia susceptibility.
Eleven dogs underwent tachycardia-induced HF pacing, either from the right atrium or high right ventricular free wall. Whereas global LV dysfunction was similar between groups, LV contractile coordination assessed by tagged MRI was markedly dyssynchronous with right ventricular pacing but synchronous with right atrial pacing. In dyssynchronous failing hearts, the lateral LV endocardium displayed a 2-fold increase in phosphorylated erk mitogen-activated protein kinase expression (with no change in phospho-p38 or phospho-jnk), a 30% decline in sarcoplasmic reticulum Ca2+-ATPase, an 80% reduction in phospholamban, and a 60% reduction in the gap junction protein connexin43, relative to neighboring myocardial segments. In contrast, hearts from both right atrial-paced HF dogs and an additional 4 noninstrumented control animals showed minimal regional variability in protein expression.
LV dyssynchrony in failing hearts generates myocardial protein dysregulation concentrated in the late-activated, high-stress lateral endocardium. Such molecular polarization within the LV creates transmural and transchamber expression gradients of calcium handling and gap junction proteins that may worsen chamber function and arrhythmia susceptibility.
左心室（LV）机械不同步会导致机械负荷的区域异质性，并且是心力衰竭（HF）患者死亡率和猝死的独立预测因素。我们测试了不同步是否也会导致参与机械应力、功能和心律失常易感性的蛋白质表达出现局部差异。
11只犬接受了心动过速诱导的HF起搏，起搏部位为右心房或右心室游离壁高位。尽管两组之间的整体左心室功能障碍相似，但通过标记MRI评估的左心室收缩协调性在右心室起搏时明显不同步，而在右心房起搏时则是同步的。在不同步的衰竭心脏中，相对于相邻心肌节段，左心室外侧心内膜磷酸化的erk丝裂原活化蛋白激酶表达增加了2倍（磷酸化p38或磷酸化jnk无变化），肌浆网Ca2 + -ATP酶下降了30%，受磷蛋白减少了80%，间隙连接蛋白连接蛋白43减少了60%。相比之下，右心房起搏的HF犬和另外4只未植入仪器的对照动物的心脏在蛋白质表达上显示出最小的区域变异性。
衰竭心脏中的左心室不同步会导致心肌蛋白调节异常，集中在晚期激活、高应力的外侧心内膜。左心室内的这种分子极化产生了钙处理和间隙连接蛋白的跨壁和跨腔表达梯度，这可能会使心室功能和心律失常易感性恶化。
