Electrotonic Myofibroblast-to-Myocyte Coupling Increases Propensity to Reentrant Arrhythmias in Two-Dimensional Cardiac Monolayers
Electrotonic Myofibroblast-to-Myocyte Coupling Increases Propensity to Reentrant Arrhythmias in Two-Dimensional Cardiac Monolayers
复制标题
DOI：
10.1529/biophysj.108.136473
复制
发表时间：
2008-11-01
影响因子：
3.4
通讯作者：
Jalife, Jose
中科院分区：
文献类型：
--
作者：
Zlochiver, Sharon;Munoz, Viviana;Jalife, Jose
在缺血性心肌病和心力衰竭等病理条件下，成纤维细胞分化为肌成纤维细胞可能导致肌细胞-成纤维细胞通过间隙连接电偶联。我们假设肌成纤维细胞增殖和异质细胞偶联增加显著改变二维心波传播和再入动力学。在起搏和持续再入期间，使用电压敏感染料对新生大鼠心室的肌细胞和肌成纤维细胞的共培养进行光学定位。通过沉默RNAi或腺病毒过表达Cx43，系统地改变了肌成纤维细胞/肌细胞的比例，分别减少或增加了肌成纤维细胞的连接偶联。通过二维模型的数值模拟，量化了异细胞耦合对传导速度（CV）和再入动力学的影响。在模拟和实验中，再入频率和CV随着肌成纤维细胞/肌细胞面积比的增大而减小；传播复杂性增加，导致波分形和再入倍增。CV与偶联之间的关系是双相的：随着异细胞偶联的增加，CV开始下降，随后增加。低杂胞耦合导致波前破碎和波浪形；在高耦合时，波前变得更平滑。异细胞耦合改变传导速度、再入稳定性和波传播的复杂性。该结果为肌细胞-肌成纤维细胞电相互作用改变波传播和再入性心律失常倾向的机制提供了新的见解。
In pathological conditions such as ischemic cardiomyopathy and heart failure, differentiation of fibroblasts into myofibroblasts may result in myocyte-fibroblast electrical coupling via gap junctions. We hypothesized that myofibroblast proliferation and increased heterocellular coupling significantly alter two-dimensional cardiac wave propagation and reentry dynamics. Co-cultures of myocytes and myofibroblasts from neonatal rat ventricles were optically mapped using a voltage-sensitive dye during pacing and sustained reentry. The myofibroblast/myocyte ratio was changed systematically, and junctional coupling of the myofibroblasts was reduced or increased using silencing RNAi or adenoviral overexpression of Cx43, respectively. Numerical simulations in two-dimensional models were used to quantify the effects of heterocellular coupling on conduction velocity ( CV) and reentry dynamics. In both simulations and experiments, reentry frequency and CV diminished with larger myofibroblast/myocyte area ratios; complexity of propagation increased, resulting in wave fractionation and reentry multiplication. The relationship between CV and coupling was biphasic: an initial decrease in CV was followed by an increase as heterocellular coupling increased. Low heterocellular coupling resulted in fragmented and wavy wavefronts; at high coupling wavefronts became smoother. Heterocellular coupling alters conduction velocity, reentry stability, and complexity of wave propagation. The results provide novel insight into the mechanisms whereby electrical myocyte-myofibroblast interactions modify wave propagation and the propensity to reentrant arrhythmias.