Spach M S, Heidlage J F, Dolber P C, Barr R C
Department of Pediatrics, Duke University Medical Center, Durham, NC 27710, USA.
Circ Res. 2000 Feb 18;86(3):302-11. doi: 10.1161/01.res.86.3.302.
The increased incidence of arrhythmias in structural heart disease is accompanied by remodeling of the cellular distribution of gap junctions to a diffuse pattern like that of neonatal cardiomyocytes. Accordingly, it has become important to know how remodeling of gap junctions due to normal growth hypertrophy alters anisotropic propagation at a cellular level (V(max)) in relation to conduction velocities measured at a macroscopic level. To this end, morphological studies of gap junctions (connexin43) and in vitro electrical measurements were performed in neonatal and adult canine ventricular muscle. When cells enlarged, gap junctions shifted from the sides to the ends of ventricular myocytes. Electrically, normal growth produced different patterns of change at a macroscopic and microscopic level. Although the longitudinal and transverse conduction velocities were greater in adult than neonatal muscle, the anisotropic velocity ratios were the same. In the neonate, mean V(max) was not different during longitudinal (LP) and transverse (TP) propagation. However, growth hypertrophy produced a selective increase in mean TP V(max) (P<0.001), with no significant change in mean LP V(max). Two-dimensional neonatal and adult cellular computational models show that the observed increases in cell size and changes in the distribution of gap junctions are sufficient to account for the experimental results. Unexpectedly, the results show that cellular scaling (cell size) is as important (or more so) as changes in gap junction distribution in determining TP properties. As the cells enlarged, both mean TP V(max) and lateral cell-to-cell delay increased. V(max) increased because increases in cell-to-cell delay reduced the electric current flowing downstream up to the time of V(max), thus enhancing V(max). The results suggest that in pathological substrates that are arrhythmogenic, maintaining cell size during remodeling of gap junctions is important in sustaining a maximum rate of depolarization.
结构性心脏病中心律失常发生率的增加伴随着缝隙连接细胞分布的重塑，形成类似于新生儿心肌细胞的弥散模式。因此，了解正常生长性肥大导致的缝隙连接重塑如何在细胞水平上改变各向异性传播速度（V(max)）与宏观水平测量的传导速度之间的关系变得至关重要。为此，对新生和成年犬心室肌进行了缝隙连接（连接蛋白43）的形态学研究和体外电测量。当细胞增大时，缝隙连接从心室肌细胞的侧面转移到末端。在电学上，正常生长在宏观和微观水平上产生了不同的变化模式。尽管成年肌肉的纵向和横向传导速度比新生肌肉更快，但各向异性速度比相同。在新生儿中，纵向（LP）和横向（TP）传播期间的平均V(max)没有差异。然而，生长性肥大导致平均TP V(max)选择性增加（P<0.001），而平均LP V(max)没有显著变化。二维新生和成年细胞计算模型表明，观察到的细胞大小增加和缝隙连接分布变化足以解释实验结果。出乎意料的是，结果表明细胞缩放（细胞大小）在决定TP特性方面与缝隙连接分布变化同样重要（或更重要）。随着细胞增大，平均TP V(max)和横向细胞间延迟均增加。V(max)增加是因为细胞间延迟的增加减少了直到V(max)时向下游流动的电流，从而提高了V(max)。结果表明，在致心律失常的病理底物中，缝隙连接重塑过程中维持细胞大小对于维持最大去极化速率很重要。
