Tomek Jakub, Rodriguez Blanca, Bub Gil, Heijman Jordi
Life Sciences Interface Doctoral Training Centre, University of Oxford, Oxford, United Kingdom;
Department of Physiology, Anatomy and Genetics, British Heart Foundation Centre of Research Excellence, University of Oxford, Oxford, United Kingdom.
Am J Physiol Heart Circ Physiol. 2017 Aug 1;313(2):H338-H353. doi: 10.1152/ajpheart.00094.2017. Epub 2017 May 26.
The border zone (BZ) of the viable myocardium adjacent to an infarct undergoes extensive autonomic and electrical remodeling and is prone to repolarization alternans-induced cardiac arrhythmias. BZ remodeling processes may promote or inhibit Ca and/or repolarization alternans and may differentially affect ventricular arrhythmogenesis. Here, we used a detailed computational model of the canine ventricular cardiomyocyte to study the determinants of alternans in the BZ and their regulation by β-adrenergic receptor (β-AR) stimulation. The BZ model developed Ca transient alternans at slower pacing cycle lengths than the control model, suggesting that the BZ may promote spatially heterogeneous alternans formation in an infarcted heart. β-AR stimulation abolished alternans. By evaluating all combinations of downstream β-AR stimulation targets, we identified both direct (via ryanodine receptor channels) and indirect [via sarcoplasmic reticulum (SR) Ca load] modulation of SR Ca release as critical determinants of Ca transient alternans. These findings were confirmed in a human ventricular cardiomyocyte model. Cell-to-cell coupling indirectly modulated the likelihood of alternans by affecting the action potential upstroke, reducing the trigger for SR Ca release in one-dimensional strand simulations. However, β-AR stimulation inhibited alternans in both single and multicellular simulations. Taken together, these data highlight a potential antiarrhythmic role of sympathetic hyperinnervation in the BZ by reducing the likelihood of alternans and provide new insights into the underlying mechanisms controlling Ca transient and repolarization alternans. We integrated, for the first time, postmyocardial infarction electrical and autonomic remodeling in a detailed, validated computer model of β-adrenergic stimulation in ventricular cardiomyocytes. Here, we show that β-adrenergic stimulation inhibits alternans and provide novel insights into underlying mechanisms, adding to a recent controversy about pro-/antiarrhythmic effects of postmyocardial infarction hyperinnervation.Listen to this article's corresponding podcast at http://ajpheart.podbean.com/e/%CE%B2-ar-stimulation-and-alternans-in-border-zone-cardiomyocytes/.
梗死灶周边存活心肌的边界区（BZ）会经历广泛的自主神经和电重构，且易发生复极交替引发的心律失常。BZ重构过程可能促进或抑制钙及/或复极交替，并且可能对室性心律失常的发生有不同影响。在此，我们使用犬心室心肌细胞的详细计算模型来研究BZ中交替现象的决定因素及其受β-肾上腺素能受体（β-AR）刺激的调控。与对照模型相比，BZ模型在较慢的起搏周期长度下出现钙瞬变交替，这表明BZ可能促进梗死心脏中空间异质性交替现象的形成。β-AR刺激消除了交替现象。通过评估下游β-AR刺激靶点的所有组合，我们确定了肌浆网（SR）钙释放的直接（通过兰尼碱受体通道）和间接[通过肌浆网（SR）钙负荷]调节是钙瞬变交替的关键决定因素。这些发现已在人心室心肌细胞模型中得到证实。在一维链模拟中，细胞间耦联通过影响动作电位的上升支间接调节交替现象的可能性，减少了SR钙释放的触发因素。然而，β-AR刺激在单细胞和多细胞模拟中均抑制了交替现象。综上所述，这些数据突出了交感神经超支配在BZ中通过降低交替现象的可能性而具有的潜在抗心律失常作用，并为控制钙瞬变和复极交替的潜在机制提供了新的见解。我们首次在经过验证的心室心肌细胞β-肾上腺素能刺激详细计算机模型中整合了心肌梗死后的电和自主神经重构。在此，我们表明β-肾上腺素能刺激抑制交替现象，并对潜在机制提供了新的见解，这增加了最近关于心肌梗死后超支配的促心律失常/抗心律失常作用的争议。收听本文对应的播客：http://ajpheart.podbean.com/e/%CE%B2-ar-stimulation-and-alternans-in-border-zone-cardiomyocytes/ 。
