doi: 10.1161/01.RES.0000159184.81111.2b
© 2005 American Heart Association, Inc.
Editorials |
An Intimate Relationship
Ca2+ and Cardiac Ion Channels
From the Department of Pharmacology, Center for Molecular Therapeutics (P.A.B., H.E.D.J.t.K.), Columbia University, New York, NY; and the Department of Medicine, Physiology, and Biophysics (H.E.D.J.t.K.), University of Calgary, Alberta, Canada.
Correspondence to Dr Penelope A. Boyden, Dept of Pharmacology, Columbia College of Physicians and Surgeons, 630 West 168th St., New York, NY 10032. E-mail pab4{at}columbia.edu
Key Words: action potentials • Cai transients • APD restitution
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Introduction |
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We last offered our ideas on the role of reverse EC coupling in the initiation of arrhythmias in 2001.1 At that time we emphasized that spurious Ca2+ release or oscillations in Ca2+ levels could serve as possible triggers for arrhythmias. Since then much has been done to confirm this role for intracellular Ca2+.
At that time we did not discuss the role of Ca2+ cycling in the maintenance or conversion of stable tachycardias to VF. However, in consideration of the new data on the role of APD restitution in the initiation of VF (increase in wavebreaks; eg, see Garfinkel et al2), we turn our attention now to the role Ca2+ cycling in the myocyte and its impact on APD restitution relations in the isolated rabbit ventricular cell.3 Goldhaber et al consider the role of Ca2+ using different types of APD restitution protocols to emphasize the dynamic nature of intracellular Ca2+ changes and its subsequent impact on the myocyte APD.
In their study APD alternans is coupled to Ca2+ cycling, which in itself is not new since others have observed that APD alternans demonstrates a hystersis and is inhibited with BAPTA-AM buffering.4 Some have suggested that repolarization alternans is more closely associated with Ca2+ than APD restitution.5–7 In fact there has been a large body of work implying that APD alternans and Ca2+ cycling are intimately linked (eg, see8,9). However caution must be raised because Chudin et al10 have reported that the dynamics of Cai are altered even when an AP clamp waveform is used. Although the Chudin data may have little relation to the AP dynamics and Ca2+ cycling of normal ventricular myocytes (such as those used in the study of Goldhaber), they may well contribute to our understanding of the dynamics of Cai cycling in the highly remodeled myocyte where little or no frequency-dependent APD shortening exists due to remodeled potassium channels (eg, epicardial border zone cells).
An important conclusion of Goldhaber and his colleagues is that it is the accumulation of myocyte Ca2+ (measured here as a FURA2 ratio) that contributes to the appearance of APD alternans (see Figures 1B and 3B3). Although not measured in these experiments, others have aligned these Ca2+ changes with intracellular Na+ accumulation.11 A recent model that takes into account the spatially (subcellular) localized nature of Ca2+ release events shows a steep relation between SR release, diastolic calcium, and Ca2+-dependent inactivation of ICaL.12 The time course of decay of the experimentally observed Ca2+ transient in some ways can predict the Ca2+ accumulation seen during rapid pacing. In fact, choice of dye to measure such changes may affect this outcome. Recently two photon studies have shown clearly that Ca2+ transients in Rhod2-loaded cells decay faster than those in FURA2-loaded cells13 suggesting that Ca2+ alternans would be seen in FURA2-loaded cells well before Rhod2 cells. Finally, onset of Ca2+ alternans is related to the underlying nature of the Ca2+ release processes. In the normal guinea pig heart, spatial heterogeneity of intrinsic cell function exists with LV basal area cells showing longer and smaller Ca2+ transients than those of the apex.14 Interestingly, this is the same area that is prone to Ca2+ alternans but not where APD restitution is the steepest.5
In Goldhaber et al,3 treatment of cells with ryanodine/thapsigargin eliminated alternans and affected the APD restitution curves appropriately (flattened them). Although not necessarily a cause and an effect, it shows proof of the principle in that blocking Ca2+ release and uptake has an effect on APD alternans/restitution. Was there less Ca2+ accumulation with drug during such protocols? This is difficult to state because studies such as those depicted in Figure 3B3 were not reported for drug protocols.
On the other hand, treatment of single cells with BAPTA-AM (or putting BAPTA salt in the cAMP containing pipette solution) also abolished APD alternans but failed to flatten APD restitution curves. Again there is a disconnect between APD restitution parameters and alternans consistent with the studies of Pruvot et al.5 As discussed by the authors, their data suggest that just by buffering diastolic Ca2+ changes one may not achieve the required antifibrillatory effectiveness (if the flattening of the APD restitution curve is a goal of therapy). However, it is not clear what effect of BAPTA had on Ca2+ cycling in these experiments. Did it eliminate Cai accumulation during the protocols? In particular did it buffer Ca2+ in the microdomain between sarcolemmal channels and the SR?
It is highly likely that the Ca2+ cycling effects resulting from the BAPTA maneuvers were not similar to those of the ryanodine/thapsigargin experiments. BAPTA by virtue of its buffering power would likely reduce the effectiveness of Ca2+ released by the SR as well as modulate activity of numerous Ca2+ dependent kinases (eg, Ca2+ dependent CaM KII).
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Can We or Should We Divorce This Intimate Relationship Between Ca2+ and Cardiac Ion Channels? |
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If there is such an important relationship between Ca2+ cycling and the occurrence of APD alternans, then should we begin to consider focusing on this point as antiarrhythmic (antifibrillatory) therapy? Most certainly. However, currently approved antiarrhythmics already include drugs that affect Ca2+ cycling, and they don’t seem to be useful (eg, the pore channel blocker verapamil). Perhaps we need drugs that are more selective in their perturbation of the Ca2+ cycling system; drugs that normalize Ca2+ turnover, ones that normalize Ca2+ dependent protein actions, others that normalize channel changes brought about by Ca2+ ion, and finally ones that normalize cardiac mechanics if nonuniform tissues are involved (which of course is not the case in Goldhaber et al where normal single cells are used). Examples here might include drugs that affect CaMKII function (see Anderson15), agents that are highly specific for critical Ca2+ dependent ion channels (such as apamin sensitive SK2 channels recently functionally and molecularly described in mouse and human atria16).
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Acknowledgments |
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Supported by grants HL-58860 from the National Heart, Lung, and Blood Institute, Bethesda, MD, and Canadian Institutes of Health Research and Alberta Heritage Foundation for Medical Research.
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Footnotes |
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See related article, pages 459–466
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
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References |
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1. Boyden PA, Ter Keurs HEDJ. reverse excitation-contraction coupling: Ca2+ ions as initiators of arrhythmias. J Cardiovasc Electr. 2001; 12: 382–385.[CrossRef]
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3. Goldhaber JI, Xie L-H, Duong T, Motter C, Khuu K, Weiss JN. Action potential duration restitution and alternans in rabbit ventricular myocytes: the key role of intracellular calcium cycling. Circ Res. 2005; 96: 459–466.
4. Walker ML, Wan X, Kirsch GE, Rosenbaum DS. Hysteresis effect implicates calcium cycling as a mechanism of repolarization alternans. Circulation. 2003; 108: 2704–2709.
5. Pruvot E, Katra RP, Rosenbaum DS, Laurita KR. Role of calcium cycling versus restitution in the mechanism of repolarization alternans. Circ Res. 2004; 94: 1083–1090.
6. Banville I, Chattipakorn N, Gray RA. Restitution dynamics during pacing and arrhythmias in isolated pig hearts. J Cardiovasc Electr. 2004; 15: 455–463.[CrossRef]
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11. Harrison SM, Boyett MR. The role of NaCa exchanger in the rate dependent increase in contraction in guinea pig ventricular myocytes. J Physiol. 2005; 482: 555–566.
12. Shiferaw Y, Watanabe MA, Garfinkel A, Weiss JN, Karma A. Model of intracellular calcium cycling in ventricular myocytes. Biophys J. 2003; 85: 3666–3686.[Medline] [Order article via Infotrieve]
13. Rubart M, Wang E, Dunn KW, Field LJ. Two photon molecular excitation imaging of Ca2+ transients in Langedorff-perfused mouse hearts. Am J Physiol. 2003; 284: C1654–C1668.
14. Katra RP, Pruvot E, Laurita KR. Intracellular calcium handling heterogeneities in intact guinea pig. Am J Physiol. 2004; 286: H648–H656.
15. Anderson ME. Calmodulin kinase signaling in heart: an intriguing candidate target for therapy of myocardial dysfunction and arrhythmias. Pharmacol Ther. In press.
16. Xu Y, Tuteja D, Zhang Z, Xu D, Zhang Y, Rodriguez J, Nie L, Tuxson HR, Young JN, Glatter KA, Vazquez AE, Yamoah EN, Chiamvimonvat N. Molecular Identification and functional roles of a Ca2+ activated K channel in human and mouse hearts. J Biol Chem. 2003; 278: 49085–49094.
Related Article:
Circ. Res. 2005 96: 459-466.
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