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Circulation Research. 2006;98:1237-1239
doi: 10.1161/01.RES.0000225859.82676.ba
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(Circulation Research. 2006;98:1237.)
© 2006 American Heart Association, Inc.

Editorials

Transmural Gradients of Repolarization and Excitation–Contraction Coupling in Mouse Ventricle

Céline Fiset, Wayne R. Giles

From the Research Center (C.F.), Montreal Heart Institute, Quebec, Canada; and the Departments of Bioengineering and Medicine (W.R.G.), University of California San Diego, La Jolla, Calif.

Correspondence to Wayne R. Giles, PhD, Professor, Departments of Bioengineering and Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0412. E-mail wgiles{at}bioeng.ucsd.edu



See related article, pages 1306–1313


Key Words: transmural repolarization • Kv4.2/4.3K channel beta subunits

The effects of changes in action potential waveform on excitation–contraction coupling in mammalian ventricle were first identified almost 40 years ago.1 Many important details concerning the relationship between action potential duration and tension development have been elucidated.2 Recent work has demonstrated significant effects on the intracellular Ca transient and excitation–contraction coupling of early repolarization of the action potential, which is strongly regulated by a Ca2+-independent transient outward K+ current denoted Ito.3–6 The molecular physiology and some aspects of the pharmacology of this current are now quite well understood, based, in part, on a series of comprehensive articles from the Nerbonne et al,7,8 Strauss and Campbell,9 and others.6 Interestingly, a somewhat similar transient outward K+ current is expressed in neurons10 and in selected regions near the intraventricular septum of mammalian hearts.11–13

One of the most striking features of the transient outward K+ current in mammalian ventricle is the difference in its transmural expression, with significantly higher expression levels in epi- than in endocardium14 (see also references 8, 9, 11). The basis for this transmural heterogeneity, and also for the higher levels of expression in the right ventricle compared with the left, continues to be a topic of intense investigation. Significant new information and plausible working hypotheses for the way in which this heterogeneity can regulate excitation–contraction coupling are a focus of work from the laboratory of Santana et al.15 Their most recent article is published in this issue of Circulation Research.16 This article provides new evidence for the ways in which the calcineurin/NFATc3 signalling complex can contribute to the transmural gradient of Ito in the left ventricle of the adult mouse heart.

The magnitude of Ito, Kv4.2, and Kv4.3 have been reported to be reduced by both acute and long-term activation of various receptor-mediated pathways in response to neurohormonal factors. Moreover, gene transfer technology has provided new insights concerning the role of Ito, Kv4.2, and Kv4.3 in the hypertrophic response.6,17,18 A number of lines of evidence suggest that the reduction of Ito (and of Kv4.2 and Kv4.3) can prolong APD, increase Ca2+ entry via ICaL, and activate calcineurin phosphatase activity. Calcineurin in turn dephosphorylates NFAT which is in the cytosol. Once dephosphorylated, NFAT can translocate into the nucleus and (with several other factors) can activate transcription and protein synthesis.6,16,17 Accordingly, these studies have suggested that prolongation of APD can result in protein synthesis and contribute to a hypertrophic response or other forms of adaptation. In contrast, the present article by Rossow et al16 concludes that the activation of the calcineurin pathway occurs before changes in Kv4.2/Ito in mouse ventricle and that this is a significant causative factor in the transmural heterogeneity of APD.

Alternate biochemical pathways which contribute to this heterogeneity have been identified previously. These include contributions from a homeodomain transcription factor Irx5,19 the KChIPs beta subunit for Kv4.2, 4.3,8,9,20–22 and association with the CD26-related dipeptidyl aminopeptidase-like protein, DPPX.23–25

Attempts to place the elegant work by the Santana laboratory16 into the context of the pathophysiological mechanisms for excitation-contraction coupling in the left ventricle will require some additional work and integration of a number of important considerations. These include:

  1. Action potential duration in general and the part of the waveform most strongly regulated by Ito are dependent on transient or maintained heart rate or stimulus frequency. The experiments in Rossow et al16 have been done at 1 Hz which is far below normal mouse heart rates. Thus, ECG parameters,26,27 action potential waveforms,27,28 and relative sizes of underlying repolarizing currents29 are difficult to relate to findings from the hearts of larger mammals. Furthermore, repolarization of the action potential of mouse ventricle is strongly modulated by Kv1.5,8,29,30 and this transcript is not expressed in the ventricles of other mammals.
  2. The present work needs to be put into the context of both short and long-term hormonal regulation of Ito. Specifically, previous work demonstrating an important role of the renin–angiotensin system in regulating Ito31,32 needs to be considered as do the findings which demonstrate that thyroid hormone can alter transmural heterogeneity.33,34
  3. It is reasonable to expect that in the setting of a variety of short- or long-term pathophysiological insults the tissue redox status will be altered. This specifically free radical generation is known to modulate the size and kinetics of Ito, which may account for some of the changes in this current in the setting of Diabetes34,35 or a variety of other situations where mitogen activation of intracellular cell signaling is important.36
  4. Factors other than the way in which Ito regulates the action potential waveform in the mouse heart or early repolarization in mammalian ventricle should be borne in mind. For example, it is known that Ito can modulate intercellular coupling and result in discontinuous conduction in rabbit ventricle,37 and somewhat similar alterations in electrotonic load can result in altered Ito amplitude.38
  5. The calcineurin/NFAT pathway for regulation of Ito has been invoked in pacing-induced cardiac remodeling40 as well as after myocardial infarction.42 However, significant reprogramming of ion channel genes occurs after these and other challenges.41 The adult myocardium can approximate the electrophysiological phenotype found in early development.43 The K+ channel alpha subunit, Kv1.4, can thus contribute significant repolarizing current under these circumstances but has not been shown to be altered by the biochemical pathways which have been the focus of the work of Santana et al,16 interesting and important mechanistic questions remain.

These comments reflect the reality that repolarization and specifically the all-or-none repolarization which underlies APD heterogeneity and dispersion is extremely complex. The Santana et al article is based on comprehensive and elegant multidisciplinary work. It provides significant new information concerning one component of this complex multifactorial process: excitation–contraction coupling. Ongoing experimental work will benefit from the parallel development of mathematical models for the action potential44–46 of the species and myocytes of interest. The ability to integrate multidisciplinary findings using Systems Biology will be valuable. Mathematical models provide a means for incorporating and evaluating essential biophysical phenomena. These include: the partial reactivation of Ito during mid and final repolarization9 and the dynamic regulation of the Na+/Ca2+ exchanger by altered Na+ or Ca2+, and by transmembrane voltage47 (see also reference 3). These nonlinear processes must be accounted for and related to the other essential steps in ventricular Ca2+ homeostasis which contribute to excitation–contraction coupling under physiological conditions, eg, sympathetic neurotransmission,48,49 and in the setting of ventricular challenge or compromise.


*    Acknowledgments
 
Funding is gratefully acknowledged from the Canadian Institutes of Health Research and the National Institutes of Health.


*    Footnotes
 
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.


*    References
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