Functional anatomy of the murine sinus node: High-resolution optical mapping of ankyrin-B heterozygous mice

Alexey V. Glukhov, Vadim V. Fedorov, Mark Anderson, Peter J. Mohler, Igor R. Efimov

Research output: Contribution to journalArticle

Abstract

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 μM: 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.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume299
Issue number2
DOIs
StatePublished - Aug 2010
Externally publishedYes

Fingerprint

Ankyrins
Sinoatrial Node
Anatomy
Isoproterenol
Cell Communication

Keywords

  • Action potential
  • Autonomic control
  • Pacemaker
  • Sinoatrial node

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)
  • Cardiology and Cardiovascular Medicine

Cite this

Functional anatomy of the murine sinus node : High-resolution optical mapping of ankyrin-B heterozygous mice. / Glukhov, Alexey V.; Fedorov, Vadim V.; Anderson, Mark; Mohler, Peter J.; Efimov, Igor R.

In: American Journal of Physiology - Heart and Circulatory Physiology, Vol. 299, No. 2, 08.2010.

Research output: Contribution to journalArticle

@article{cab3573ebef94869a49753a9fa6ad779,
title = "Functional anatomy of the murine sinus node: High-resolution optical mapping of ankyrin-B heterozygous mice",
abstract = "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 μM: 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.",
keywords = "Action potential, Autonomic control, Pacemaker, Sinoatrial node",
author = "Glukhov, {Alexey V.} and Fedorov, {Vadim V.} and Mark Anderson and Mohler, {Peter J.} and Efimov, {Igor R.}",
year = "2010",
month = "8",
doi = "10.1152/ajpheart.00756.2009",
language = "English (US)",
volume = "299",
journal = "American Journal of Physiology",
issn = "0363-6135",
publisher = "American Physiological Society",
number = "2",

}

TY - JOUR

T1 - Functional anatomy of the murine sinus node

T2 - High-resolution optical mapping of ankyrin-B heterozygous mice

AU - Glukhov, Alexey V.

AU - Fedorov, Vadim V.

AU - Anderson, Mark

AU - Mohler, Peter J.

AU - Efimov, Igor R.

PY - 2010/8

Y1 - 2010/8

N2 - 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 μM: 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.

AB - 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 μM: 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.

KW - Action potential

KW - Autonomic control

KW - Pacemaker

KW - Sinoatrial node

UR - http://www.scopus.com/inward/record.url?scp=77955457622&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77955457622&partnerID=8YFLogxK

U2 - 10.1152/ajpheart.00756.2009

DO - 10.1152/ajpheart.00756.2009

M3 - Article

C2 - 20525877

AN - SCOPUS:77955457622

VL - 299

JO - American Journal of Physiology

JF - American Journal of Physiology

SN - 0363-6135

IS - 2

ER -