Functional anatomy of the murine sinus node: high-resolution optical mapping of ankyrin-B heterozygous mice
Functional anatomy of the murine sinus node: high-resolution optical mapping of ankyrin-B heterozygous mice
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DOI：
10.1152/ajpheart.00756.2009
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发表时间：
2010-08-01
影响因子：
4.8
通讯作者：
Efimov, Igor R.
中科院分区：
文献类型：
--
作者：
Glukhov, Alexey V.;Fedorov, Vadim V.;Efimov, Igor R.
Glukhov AV，Fedorov VV，安德森ME，Mohler PJ，Efimov IR。小鼠窦房结的功能解剖：ankrex-B杂合子小鼠的高分辨率光学映射。Am J Physiol Heart Circ Physiol 299：H482-H491，2010.首次发表于2010年6月4日; doi：10.1152/ajpheart.00756.2009。小鼠被广泛用作研究窦房结（SAN）起搏分子机制的遗传平台。最近，研究表明，从锚蛋白-B（AnkB）缺陷小鼠分离的SAN细胞显示出严重的起搏功能障碍，类似于携带锚蛋白2等位基因变体的个体。然而，这些结果仅限于孤立的SAN细胞，因此没有评估广泛分布的心房起搏复合体的功能解剖学（例如：例如，在一个实施例中，主起搏器和辅助起搏器的动态相互作用）。我们在一个完整的小鼠心房准备，其中包括SAN，房室交界处（AVJ），和两个心房，不包括大部分的隔膜起搏器功能进行了研究。使用电压敏感染料和CMOS相机ULTIMA-L的光学标测来标测野生型（WT）小鼠（n = 7）和人类SAN疾病的AnkB杂合（AnkB（+/-）; n = 9）小鼠模型中有或没有自主调节的自发起搏器活动。在野生型小鼠中，异丙肾上腺素加速了SAN速率（10 μ M：从325 +/-19到510 +/-33次/分，P <0.01），并使SAN内的主要起搏点位置向上移动了0.77 +/-0.11 mm。ACh使SAN频率降低（从333 +/-26次/分降至96 +/-22次/分，P <0.01），并使起搏点在SAN内向左移位或突然移向AVJ。异丙肾上腺素后，AnkB（+/-）小鼠表现出更大的心跳间变异性（周期长度的SD：13.4 +/-3.6 vs. 2.5 +/-0.8 ms，P <0.01 vs. WT小鼠），主要起搏器的无序移位（2.04 +/-0.37 mm，P <0.05 vs. WT小鼠），并竞争多个起搏器，导致SAN和AVJ区域之间的主要起搏器位置的逐搏变化。值得注意的是，AnkB（+/-）小鼠也显示出对ACh的敏感性降低（速率分别减慢32 +/-12% vs. 67 +/-4%，P <0.05，AnkB（+/-）vs. WT小鼠）。总之，AnkB功能障碍导致SAN异常在一个孤立的小鼠心房制备。虽然AnkB功能障碍显著改变单个SAN细胞功能，但心脏自律性的机制显然是复杂的，并且表型可以通过起搏器复合物内细胞的动态相互作用而部分补偿。这些新发现强调了整个心房分布式起搏器复合体（包括SAN和AVJ）功能解剖的重要性，并清楚地表明了AnkB在心脏自律性中的作用。
Glukhov AV, Fedorov VV, Anderson ME, Mohler PJ, Efimov IR. Functional anatomy of the murine sinus node: high-resolution optical mapping of ankyrin-B heterozygous mice. Am J Physiol Heart Circ Physiol 299: H482-H491, 2010. First published June 4, 2010; doi:10.1152/ajpheart.00756.2009.-The mouse is widely used as a genetic platform to investigate the molecular mechanisms of sinoatrial node (SAN) pacemaking. Recently, it has been shown that isolated SAN cells from the ankyrin-B (AnkB)-deficient mice display severe pacemaking dysfunction similar to individuals harboring ankyrin 2 allele variants. However, these results have been limited to isolated SAN cells only and thus did not evaluate the functional anatomy of the widely distributed atrial pacemaker complex (e. g., the dynamic interaction of primary and subsidiary pacemakers). We studied pacemaker function in an intact mouse atrial preparation, which included the SAN, atrioventricular junction (AVJ), and both atria, excluding most of the septum. Optical mapping with a voltage-sensitive dye and CMOS camera ULTIMA-L was used to map spontaneous pacemaker activity with or without autonomic modulation in wild-type (WT) mice (n = 7) and in the AnkB heterozygous (AnkB(+/-); n = 9) mouse model of human SAN disease. In WT mice, isoproterenol accelerated the SAN rate (for 10 mu M: from 325 +/- 19 to 510 +/- 33 beat/min, P < 0.01) and shifted the leading pacemaker site superiorly by 0.77 +/- 0.11 mm within the SAN. ACh decreased the SAN rate (from 333 +/- 26 to 96 +/- 22 beats/min, P < 0.01) and shifted the leading pacemaker either inferiorly within the SAN or abruptly toward the AVJ. After isoproterenol, AnkB(+/-) mice exhibited a larger beat-to-beat variability (SD of a cycle length: 13.4 +/- 3.6 vs. 2.5 +/- 0.8 ms, P < 0.01 vs. WT mice), disorganized shift of the leading pacemaker (2.04 +/- 0.37 mm, P < 0.05 vs. WT mice), and competing multiple pacemakers, resulting in beat-to-beat changes of the leading pacemaker location site between the SAN and AVJ regions. Notably, AnkB(+/-) mice also displayed a reduced sensitivity to ACh (rate slowing by 32 +/- 12% vs. 67 +/- 4%, P < 0.05, AnkB(+/-) vs. WT mice, respectively). In conclusion, AnkB dysfunction results in SAN abnormalities in an isolated mouse atria preparation. While AnkB dysfunction dramatically alters single SAN cell function, the mechanisms underlying cardiac automaticity are clearly complex, and phenotypes may be partially compensated by the dynamic interaction of cells within the pacemaker complex. These new findings highlight the importance of the functional anatomy of the entire atrial distributed pacemaker complex, including the SAN and AVJ, and clearly demonstrate the role of AnkB in cardiac automaticity.