| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH |
|
|
|
|||||||
|
|||||||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1 Department of Bioengineering, University of California San Diego, San Diego, California, United States
2 Bioengineering and Medicine, University of California San Diego, La Jolla, California, United States
3 Department of Bioengineering, University of California-San Diego, La Jolla, California, United States
* To whom correspondence should be addressed. E-mail: amcculloch{at}ucsd.edu.
The role of sustained components of INa and IKv43 in shaping the action potentials of myocytes isolated from the canine left ventricle is unknown. Here we investigate the hypothesis that these two currents may contribute substantially to heterogeneity of early repolarization and arrhythmic risk. Quantitative data from voltage clamp and expression profiling experiments were used to complete meaningful modifications to an existing "local control" model of canine midmyocardial myocyte excitation-contraction coupling for epicardial and endocardial myocytes. We include 1) heterogeneous IKv43 , IKs , and ISERCA density; 2) modulation of IKv43 by KChIP2 channel subunits; 3) a possible Ca2+-dependent open state inactivation of IKv43; 4) a sustained component of the inward Na+ current, INaL. The resulting simulations illustrate ways in which KChIP2- and Ca2+-dependent control of IKv43 can result in a sustained outward current which can neutralize INaL in a rate- and subtype-dependent manner. Both these currents appear to play significant roles in modulating AP duration and rate-dependence in midmyocardial myocytes. Furthermore, an increased ratio of IKv43 to INaL is capable of protecting epicardial myocytes from the early after-depolarizations resulting from the SCN5A-I1768V mutation-induced increase in INaL. Experimentally observed transmural differences in Ca2+ handling, including greater SR Ca2+ content and faster Ca2+ transient decay rates on the epicardium, were recapitulated in our simulations. By design, these models allow upward integration into organ models, or may be used as a basis for further investigations into cellular heterogeneities.
This article has been cited by other articles:
|
|
 |
|
  S. G. Campbell, E. Howard, J. Aguado-Sierra, B. A. Coppola, J. H. Omens, L. J. Mulligan, A. D. McCulloch, and R. C. P. Kerckhoffs Effect of transmurally heterogeneous myocyte excitation-contraction coupling on canine left ventricular electromechanics Exp Physiol, May 1, 2009; 94(5): 541 - 552. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. G Campbell, S. N Flaim, C. H Leem, and A. D McCulloch Mechanisms of transmurally varying myocyte electromechanics in an integrated computational model Phil Trans R Soc A, September 28, 2008; 366(1879): 3361 - 3380. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Michailova, W. Lorentz, and A. McCulloch Modeling transmural heterogeneity of KATP current in rabbit ventricular myocytes Am J Physiol Cell Physiol, August 1, 2007; 293(2): C542 - C557. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y.-J. Qu, V. E. Bondarenko, C. Xie, S. Wang, M. S. Awayda, H. C. Strauss, and M. J. Morales W-7 modulates Kv4.3: pore block and Ca2+-calmodulin inhibition Am J Physiol Heart Circ Physiol, May 1, 2007; 292(5): H2364 - H2377. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH |
| Visit Other APS Journals Online |
