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(Circulation Research. 2006;99:223.)
© 2006 American Heart Association, Inc.

Editorials

Life, Sudden Death, and Intracellular Calcium

D.A. Eisner, L.A. Venetucci, A.W. Trafford

From the Unit of Cardiac Physiology, University of Manchester, United Kingdom.

Correspondence to D.A. Eisner, Unit of Cardiac Physiology, University of Manchester, Core Technology Facility, 46 Grafton St, Manchester M13 9NT, U.K. E-mail eisner{at}man.ac.uk

See related articles, pages 283–291 and 292–298

Key Words: RyR • SR • calcium

Since the original studies of Ringer,¹ calcium (Ca²⁺) has become almost synonymous with contraction in the heart. Two papers in the current issue of Circulation Research focus on other roles of this cation.¹ Wu and Bers² show that Ca²⁺ in the nuclear envelope is in a store that is functionally interconnected with the sarcoplasmic reticulum (SR), a result that may have implications for the role of calcium in controlling gene transcription.² The other area and the main focus of this editorial is the role of Ca²⁺ ions in arrhythmogenesis. Liu et al³ present important data concerning the occurrence of arrhythmias in a mouse expressing a mutant SR Ca²⁺ release channel (ryanodine receptor [RyR]). To discuss this result, we will first briefly summarize current concepts in the area.

It is now known that most of the calcium that activates contraction comes from an intracellular store (the SR) and is released through the RyR. Release occurs through the process of calcium-induced calcium release. This depends on the fact that the probability of the RyR being open is increased by an increase of cytoplasmic Ca²⁺ concentration ([Ca²⁺]_i). The entry of a small amount of Ca²⁺ into the cell through the L-type Ca²⁺ current thereby triggers much more release from the SR. It has been appreciated for a long time that such a Ca²⁺-induced Ca²⁺ release mechanism is inherently prone to positive feedback as the Ca²⁺ released will tend to further activate the RyR. Both theoretical⁴ and experimental⁵ studies have shown that this positive feedback is avoided by the fact that a single L-type channel and associated RyRs act as a functional unit that under normal conditions does not influence other units. Under these conditions if Ca²⁺ is released in one region of the cell there is no tendency for the release to spread to other regions. The release of Ca²⁺ from a single unit is measured as a "Ca²⁺ spark."⁵ However, if the cell is overloaded with Ca²⁺ then release in one part of the cell propagates throughout the cell⁶ as a wave, a result shown to be caused by Ca²⁺ sparks initiating waves.⁷ It has long been known that cellular Ca²⁺ overload produces Ca²⁺ waves that activate Ca²⁺ extrusion on the electrogenic Na-Ca²⁺ exchange⁸ and this leads to delayed afterdepolarizations (DADs).^9,10

Ca²⁺ waves seem to occur when the Ca²⁺ content of the SR exceeds a certain threshold.¹¹ In many studies (including those reviewed above) it is the SR Ca²⁺ content that is increased to above normal levels to generate waves (Figure B.). However, waves can also be produced by maneuvers that increase the open probability of the RyR and thereby decrease the threshold concentration (Figure C). An experimental example of this is the application of low concentrations of caffeine.^12,13 In addition, it has also been suggested that in heart failure phosphorylation of the RyR can lead to its dissociation from the accessory protein FKBP12.6, and mice with reduced FKBP12.6 show increased incidence of arrhythmias.¹⁴ Panel C, which is taken from experimental data in which RyR opening is potentiated with caffeine,¹² shows a decrease of SR content. This occurs because the greater Ca²⁺ release from the SR results in more efflux from the cell. If a similar decrease of SR Ca²⁺ content occurs with the mutant RyR mouse, then there will be implications for cardiac contractility. In addition, it is important to know what happens to the open probability of the RyR when it is activated by higher cytoplasmic Ca²⁺ as occurs in systole.

View larger version (10K): [in this window] [in a new window]   Diagram showing the effects of various maneuvers on SR content and spontaneous Ca2+ release. In all panels the solid line shows SR Ca2+ content and the dashed line the threshold SR Ca2+ content at which Ca2+ release occurs. Conditions show (left to right): control, here the SR Ca2+ content is less than the threshold and there is no spontaneous Ca2+ release; Ca2+ overload, the SR Ca2+ content has been increased to above the threshold and spontaneous Ca2+ release is seen; Sensitized RyR, the threshold is now decreased. The traces for Ca2+ overload and sensitized RyR are taken from Reference 12

Recent genetic studies have shown that some familial cases of catecholaminergic polymorphic ventricular tachycardia are related to mutations in the RyR.^15,16 When such RyRs are expressed in heterologous systems, then the mutations show increased spontaneous Ca²⁺ release caused by a sensitization to intra-SR Ca²⁺.¹⁷ The important advance produced by Liu et al is that they have studied this mutation by expressing it in mouse hearts. One important result is that the transgenic mice show DADs even under control conditions, following a train of stimuli, whereas the normal mice do not. However, no extra systoles are seen even in the transgenic animals. This is presumably because the DADs occur after too long a delay to be seen before the next stimulated beat and are therefore only seen at the end of a train of stimulation. The cellular model therefore mimics the intact human in showing that RyR mutation only produces arrhythmias in the presence of catecholamines. An unanswered question concerns why catecholamines are required to produce extra systoles. In particular, does this result from phosphorylation of the RyR or, alternatively, from an effect on phospholamban to increase SR Ca²⁺ ATPase activity and, thence, SR content or on the L-type Ca²⁺ current to increase cell and therefore SR loading with Ca²⁺? It would be particularly interesting to know whether other maneuvers that increase cellular Ca²⁺ loading also potentiate the arrhythmogenic effects of this mutation.

As well as the particular mutation studied in the present work, there are many other mutations of the RyR that have been associated with cardiac arrhythmias and a variety of different arrhythmias.¹⁸ It will be interesting to discover what features determine the type of arrhythmia that is produced.

Other studies have suggested that dissociation of FKBP12.6 from the RyR can be implicated in arrhythmogenic activity. This dissociation can be prevented by the compound K201 (also known as JTV 519), and this compound has been reported to be antiarrhythmic.¹⁹ However, Liu et al find that this compound has no effect on the cellular arrhythmic effects of the RyR mutation and, furthermore, that FKBP12.6 binding to the RyR is unaffected by the mutation. The overall picture is perhaps that anything that increases Ca²⁺ efflux through the RyR may be arrhythmogenic, and it does not matter whether FKBP12.6 is involved.

Finally, perhaps as a consequence of both its size and its intracellular location, the RyR has come belatedly to the transgenic table. We confidently expect rapid advances in the next few years.

	Acknowledgments

 
Source of Funding

Funding was provided by the British Heart Foundation.

Disclosures

None.

	Footnotes

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

	References

Top References

 

1. Ringer S. A further contribution regarding the influence of the different constituents of the blood on the contraction of the heart. J Physiol (Lond). 1883; 4: 29–42.[Free Full Text]
2. Wu X, Bers DM. Sarcoplasmic reticulum and nuclear envelope are one highly interconnected Ca²⁺ store throughout cardiac myocyte. Circ Res. 2006; 99: 283–291.[Abstract/Free Full Text]
3. Liu N, Colombi B, Memmi M, Zissimopoulos S, Rizzi N, Negri S, Imbriani M, Napolitano C, Lai FA, Priori SG. Arrhythmogenesis in catecholaminergic polymorphic ventricular tachycardia: insights from a RyR2 R4496C knock-in mouse model. Circ Res. 2006; 99: 292–298.[Abstract/Free Full Text]
4. Stern MD. Theory of excitation-contraction coupling in cardiac muscle. Biophys J. 1992; 63: 497–517.[Abstract/Free Full Text]
5. Cheng H, Lederer WJ, Cannell MB. Calcium sparks: elementary events underlying excitation-contraction coupling in heart muscle. Science. 1993; 262: 740–744.[Abstract/Free Full Text]
6. Trafford AW, O’Neill SC, Eisner DA. Factors affecting the propagation of locally activated systolic Ca²⁺ transients in rat ventricular myocytes. Pflügers Archiv. 1993; 425: 181–183.[CrossRef][Medline] [Order article via Infotrieve]
7. Cheng H, Lederer MR, Lederer WJ, Cannell MB. Calcium sparks and [Ca²⁺]_i waves in cardiac myocytes. Am J Physiol. 1996; 270: C148–C159.[Medline] [Order article via Infotrieve]
8. Mechmann S, Pott L. Identification of Na-Ca²⁺ exchange current in single cardiac myocytes. Nature. 1986; 319: 597–599.[CrossRef][Medline] [Order article via Infotrieve]
9. Ferrier GR, Saunders JH, Mendez C. A cellular mechanism for the generation of ventricular arrhythmias by acetylstrophanthidin. Circ Res. 1973; 32: 600–609.[Abstract/Free Full Text]
10. Rosen MR, Gelband H, Hoffman BF. Correlation between effects of ouabain on the canine electrocardiogram and transmembrane potentials of isolated Purkinje fibers. Circulation. 1973; 47: 65–72.[Abstract/Free Full Text]
11. Díaz ME, Trafford AW, O’Neill SC, Eisner DA. Measurement of sarcoplasmic reticulum Ca²⁺ content and sarcolemmal Ca²⁺ fluxes in isolated rat ventricular myocytes during spontaneous Ca²⁺ release. J Physiol (Lond). 1997; 501: 3–16.[CrossRef][Medline] [Order article via Infotrieve]
12. Trafford AW, Sibbring GC, Díaz ME, Eisner DA. The effects of low concentrations of caffeine on spontaneous Ca²⁺ release in isolated rat ventricular myocytes. Cell Calcium. 2000; 28: 269–276.[CrossRef][Medline] [Order article via Infotrieve]
13. Nam GB, Burashnikov A, Antzelevitch C. Cellular Mechanisms underlying the development of catecholaminergic ventricular tachycardia. Circulation. 2005; 111: 2727–2733.[Abstract/Free Full Text]
14. Wehrens XH, Lehnart SE, Huang F, Vest JA, Reiken SR, Mohler PJ, Sun J, Guatimosim S, Song LS, Rosemblit N, D’Armiento JM, Napolitano C, Memmi M, Priori SG, Lederer WJ, Marks AR. FKBP12.6 deficiency and defective calcium release channel (ryanodine receptor) function linked to exercise-induced sudden cardiac death. Cell. 2003; 113: 829–840.[CrossRef][Medline] [Order article via Infotrieve]
15. Priori SG, Napolitano C, Tiso N, Memmi M, Vignati G, Bloise R, Sorrentino V, Danieli GA. Mutations in the cardiac ryanodine receptor gene (hRyR2) underlie catecholaminergic polymorphic ventricular tachycardia. Circulation. 2001; 103: 196–200.[Abstract/Free Full Text]
16. Laitinen PJ, Brown KM, Piippo K, Swan H, Devaney JM, Brahmbhatt B, Donarum EA, Marino M, Tiso N, Viitasalo M, Toivonen L, Stephan DA, Kontula K. Mutations of the cardiac ryanodine receptor (RyR2) gene in familial polymorphic ventricular tachycardia. Circulation. 2001; 103: 485–490.[Abstract/Free Full Text]
17. Jiang D, Wang R, Xiao B, Kong H, Hunt DJ, Choi P, Zhang L, Chen SRW. Enhanced store overload-induced Ca²⁺ release and channel sensitivity to luminal Ca²⁺ activation are common defects of RyR2 mutations linked to ventricular tachycardia and sudden death. Circ Res. 2005; 97: 1173–1181.[Abstract/Free Full Text]
18. Priori SG, Napolitano C, Memmi M, Colombi B, Drago F, Gasparini M, DeSimone L, Coltorti F, Bloise R, Keegan R, Cruz Fiho FES, Vignati G, Benatar A, DeLogu A. Clinical and molecular characterization of patients with catecholaminergic polymorphic ventricular tachycardia. Circulation. 2002; 106: 69–74.[Abstract/Free Full Text]
19. Wehrens XH, Lehnart SE, Reiken SR, Deng SX, Vest JA, Cervantes D, Coromilas J, Landry DW, Marks AR. Protection from cardiac arrhythmia through ryanodine receptor-stabilizing protein calstabin2. Science. 2004; 304: 292–296.[Abstract/Free Full Text]

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