This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Houser, S. R. Search for Related Content PubMed PubMed Citation Articles by Houser, S. R. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Medline Plus Health Information Arrhythmia Hazardous Substances DB CALCIUM COMPOUNDS CALCIUM, ELEMENTAL Related Collections Arrythmias-basic studies Calcium cycling/excitation-contraction coupling Heart failure - basic studies Ion channels/membrane transport

(Circulation Research. 2000;87:725.)
© 2000 American Heart Association, Inc.

Editorial

When Does Spontaneous Sarcoplasmic Reticulum CA²⁺ Release Cause a Triggered Arrythmia? Cellular Versus Tissue Requirements

Steven R. Houser

From the Cardiovascular Research Group, Temple University, School of Medicine, Philadelphia, Pa.

Correspondence to Steven R. Houser, PhD, Cardiovascular Research Group, Temple University, School of Medicine, 3400 N Broad St, Philadelphia, PA 19034. E-mail srhouser{at}unix.temple.edu

Key Words: triggered arrhythmias • nonreentrant arrhythmias • Ca²⁺ overload • Ca²⁺-activated currents • Na⁺-Ca²⁺ exchange

	Introduction

Top Introduction Triggered Activity in Single... Triggered Activity in the... References

 
Ventricular arrhythmias are a major cause of sudden premature death in patients with ischemic heart disease, hypertrophy, and congestive heart failure. The processes that initiate these arrhythmias include reentry, abnormal automaticity, and triggered activity.^{1 2} In the past three decades, there has been substantial investigation into each of these processes.^{3 4} This discussion will focus on triggered activity caused by delayed afterdepolarizations (DADs).

Triggered activity has been widely studied for more than 20 years in whole hearts, isolated myocytes, and muscle and in Purkinje fiber preparations.^{5 6} Two general types of triggered afterdepolarizations have been observed and characterized. Early afterdepolarizations occur during the plateau phase of long-duration action potentials (APs). These secondary depolarizations involve either reactivation of the L-type Ca²⁺ channel or Na⁺ channel.^{6 7} DADs occur after repolarization of the AP to the resting potential and are caused by spontaneous release of Ca²⁺ from the sarcoplasmic reticulum (SR).^{6 8 9 10 11 12} The resulting elevation of cytosolic free Ca²⁺ activates inward current(s) that causes diastolic depolarization. When DADs are of a sufficient magnitude, an AP is induced. In the intact heart, these APs can propagate throughout the myocardium to cause extra heartbeats. In addition, if they find the ventricle in a partially refractory state or with conduction abnormalities, these APs can lead to tachyarrhythmias and fibrillation.

It is well established that DADs result from spontaneous Ca²⁺ release from a Ca²⁺-overloaded SR.^{9 10 11} Many early studies of DADs used cardiac glycosides to increase cellular and SR Ca²⁺ and induce Ca²⁺ overload. It is now clear that many other factors including hypoxia, ischemia, increased sympathetic nerve activity, sympathomimetic drugs, hypertrophy, and heart failure can produce Ca²⁺ overload and DADs.¹⁰ In whole hearts, each of these conditions is associated with an increased propensity for cardiac arrhythmias.^{2 9}

The Ca²⁺-activated membrane current(s) that links spontaneous SR Ca²⁺ release to membrane depolarization has also been well studied^{12 13} and is the topic of an article¹⁴ in this issue of Circulation Research. Three unique currents have been shown to cause DADs. A Ca²⁺-activated nonselective transient inward current (I_ti) was identified in many early studies.^{5 6} Ca²⁺-activated Cl^– conductance¹⁵ and electrogenic forward-mode Na⁺-Ca²⁺ exchange (NCX) current^{16 17} have also been shown to be responsible for DADs in certain cell types. Schlotthauer and Bers¹⁴ used caffeine-induced SR Ca²⁺ release (cDADs) to study the membrane basis of DADs in rabbit ventricular myocytes and to define a quantitative relationship between the magnitude of SR Ca²⁺ release (and the resulting change in free cytosolic Ca²⁺) and the size of DADs. They provide strong evidence to support the hypothesis that NCX current primarily induces cDADs in rabbit ventricular myocytes. It is not clear why myocytes from different species or from different portions of the heart (Purkinje fiber versus atrial or ventricular myocytes) rely on different Ca²⁺-activated currents to produce DADs. However, this is not a critical unresolved issue. The factors that determine whether a DAD will result in a propagating AP (a triggered beat) are the relevant unresolved pieces of the puzzle. Given that studies of DAD mechanisms in intact myocardium are technically demanding, most investigations have been performed in single cardiac myocytes in which myocyte membrane potentials, ionic currents, and cytosolic free [Ca²⁺] are more easily measured.

	Triggered Activity in Single Myocytes

Top Introduction Triggered Activity in Single... Triggered Activity in the... References

 
The factors that determine whether a DAD will be of sufficient magnitude to induce an AP in an isolated myocyte seem to be well established. The study by Schlotthauer and Bers¹⁴ is the first to quantify the relationship between the amount of SR Ca²⁺ release and DAD amplitude. These investigators clearly show that a large amount of Ca²⁺ must be released from the SR to produce a DAD of sufficient size to cause an AP. This prerequisite will be met in both isolated myocytes and myocytes in the intact heart, because Ca²⁺ overload of the SR is required to induce DADs.

The spontaneous SR Ca²⁺ release that causes DADs in single myocytes often begins in a small region of the cell. The locally elevated Ca²⁺ diffuses to adjacent junctional SR to activate Ca²⁺ release channels and induce Ca²⁺ release that can then propagate throughout the cell. This propagated SR Ca²⁺ release has been termed "Ca²⁺ waves." Focal SR Ca²⁺ release that induces Ca²⁺ waves causes small, long-duration DADs that usually do not induce an AP because the local membrane currents in regions of the cell with high Ca²⁺ are insufficient to depolarize the cell to threshold. Therefore, if spontaneous SR Ca²⁺ release in an isolated myocyte is to cause an AP, the release must be more synchronous than during a Ca²⁺ wave.^{18 19} This can occur when spontaneous release occurs in different regions of the same cell at about the same time. Schlotthauer and Bers¹⁴ applied depolarizing current at different rates and amplitudes to single cells to mimic different levels of asynchrony, and their results support these hypotheses.

The magnitude and synchrony of spontaneous SR Ca²⁺ release are not the only important features that will determine whether a DAD will cause an AP in an isolated myocyte. Two other important factors will be the density and properties of the Ca²⁺-activated currents and the density and properties of the inward rectifying K⁺ channels (I_K1) that produce the outward current that counteract Ca²⁺-activated inward current. An example of how alterations of these factors could precipitate arrhythmias is the failing ventricular myocyte in which the density of the sarcolemmal NCX is thought to be increased.²⁰ In these myocytes, the inward NCX current for any given level of free cytosolic Ca²⁺ should be increased. The resulting DADs should be larger than normal and more likely to produce an AP. Along these same lines, some studies have shown that I_K1 density is smaller than normal in failing ventricular myocytes.²¹ This change would cause any Ca²⁺-activated inward currents induced at the resting potential to produce a greater depolarization in a failing than a normal ventricular myocyte.

The consensus from studies performed in single isolated myocytes during the past two decades is that spontaneous Ca²⁺ release from a Ca²⁺-overloaded SR is essential for the initiation of DADs. Whether a DAD induces an AP in an isolated myocyte depends on the synchrony of spontaneous release within the cell, the abundance and properties of the Ca²⁺-activated inward current source, and the properties of the outward currents that counterbalance this inward current. The study by Schlotthauer and Bers¹⁴ rigorously quantifies the relationship between some of these processes.

	Triggered Activity in the Intact Heart

Top Introduction Triggered Activity in Single... Triggered Activity in the... References

 
The factors that determine whether a DAD will be of sufficient magnitude to induce an AP in the intact heart are much more complex than in an isolated myocyte and are not as well established. First, it is unlikely that spontaneous Ca²⁺ release in a single myocyte of the intact heart would ever be able to induce an AP, even if the Ca²⁺ release within that cell was well synchronized. This difference between the electrical consequences of synchronized spontaneous SR Ca²⁺ release in an isolated myocyte (an AP) versus in the same cell in the cardiac syncytium (a small localized depolarization) results from the fact that in the intact heart, neighboring cells would act as a current sink that would prevent sufficient depolarization to reach threshold. Therefore, a requirement for AP initiation from a DAD in the intact heart (the source of the nonreentrant arrhythmia) would appear to be that a cluster of cells would have to be involved and that the Ca²⁺ release within each of the cells and among these cells would have to be well synchronized. Other factors that would need to be considered include the electrical coupling between myocytes within the DAD cluster and the coupling between this cell cluster and their neighbors into which the AP would propagate.

The factors that determine whether a DAD will occur in a cluster of myocytes and whether it will induce a propagating AP are difficult to study in the intact heart. However, the use of recently developed imaging²² and mapping techniques²³ in animal and tissue models with stable and/or inducible nonreentrant arrhythmias should help us to break significant ground. In particular, the local factors that set the stage for the development of DAD-related nonreentrant arrhythmias need to be better clarified. These factors could include local alterations in adrenergic activation, blood supply, myocyte signaling, and the interstitial and/or myocyte remodeling that modifies the electrical coupling of a region of myocardium to its surround.

In conclusion, the study by Schlotthauer and Bers¹⁴ appears to be a critical analytical description of our understanding of how DADs can induce an AP in a single isolated myocyte. However, we need to remember that the DAD-induced initiation of an AP in the intact heart is much more complicated and may involve essential features that are not present in studies performed in single cells.

	Acknowledgments

 

This work was supported by grants from the National Institutes of Health, National Heart, Lung, and Blood Institute (HL-33921 and HL-61495). The author thanks Valentino Piacentino III for commenting on this editorial.

	Footnotes

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

	References

Top Introduction Triggered Activity in Single... Triggered Activity in the... References

 

1. Binah O, Rosen MR. Mechanisms of ventricular arrhythmias. Circulation. 1992;85(suppl):I-25–I-31.
2. Hoffman BF, Rosen MR. Cellular mechanisms for cardiac arrhythmias. Circ Res. 1981;49:1–15.[Free Full Text]
3. Wit AL, Rosen MR, Hoffman BF. Electrophysiology and pharmacology of cardiac arrhythmias, II: relationship of normal and abnormal electrical activity of cardiac fibers to the genesis of arrhythmias. Am Heart J. 1974;88:515–524.[Medline] [Order article via Infotrieve]
4. Nuss HB, Kaab S, Kass DA, Tomaselli GF, Marbán E. Cellular basis of ventricular arrhythmias and abnormal automaticity in heart failure. Am J Physiol. 1999;277:H80–H91.[Abstract/Free Full Text]
5. Kass RS, Lederer WJ, Tsien RW, Weingart R. Role of calcium ions in transient inward currents and aftercontractions induced by strophanthidin in cardiac Purkinje fibres. J Physiol (Lond). 1978;281:187–208.[Abstract/Free Full Text]
6. Marban E, Robinson SW, Weir WG. Mechanisms of arrhythmogenic delayed and early afterdepolarizations in ferret ventricular muscle. J Clin Invest. 1986;78:1185–1192.
7. January CT, Riddle JM. Early afterdepolarizations: mechanism of induction and block. A role for L-type Ca²⁺ current. Circ Res. 1989;64:977–990.[Abstract/Free Full Text]
8. Antzelevitch C, Sicouri S. Clinical relevance of cardiac arrhythmias generated by afterdepolarizations: role of M cells in the generation of U waves, triggered activity and torsade de pointes. J Am Coll Cardiol. 1994;23:259–277.[Abstract]
9. Fozzard HA. Afterdepolarizations and triggered activity. Basic Res Cardiol. 1992;87:105–113.
10. Kass RS, Lederer WJ, Tsien RW, Weingart R. Role of calcium ions in transient inward currents and aftercontractions induced by strophanthidin in cardiac Purkinje fibers. J Physiol (Lond). 1978;281:187–208.
11. Fedida D, Noble D, Rankin AC, Spindler AJ. The arrhythmogenic transient inward current I_ti and related contractions in isolated guinea-pig myocytes. J Physiol (Lond). 1987;392:523–542.[Abstract/Free Full Text]
12. Kass RS, Tsien RW, Weingart R. Ionic basis of transient inward current induced by strophanthidin in cardiac Purkinje fibers. J Physiol (Lond). 1978;281:209–226.[Abstract/Free Full Text]
13. Zygmunt A, Goodrow RJ, Weigel CM. I_Na/Ca and I_Cl(Ca) contribute to isoproterenol-induced delayed afterdepolarizations in midmyocardial cells. Am J Physiol. 1998;44:H1979–H1992.
14. Schlotthauer K, Bers DM. Sarcoplasmic reticulum Ca²⁺ release causes myocyte depolarization: underlying mechanism and threshold for triggered action potentials. Circ Res. 2000;87:774–780.[Abstract/Free Full Text]
15. Szigeti G, Rusznak Z, Kovacs L, Papp Z. Calcium-activated transient membrane currents are carried mainly by chloride ions in isolated atrial, ventricular and Purkinje cells of rabbit hearts. Exp Physiol. 1998;83:137–153.[Abstract]
16. Egdell RM, MacLeod KT. Ca extrusion during aftercontractions in cardiac myocytes: the role of the sodium-calcium exchanger in the generation of the transient inward current. J Mol Cell Cardiol. 2000;32:85–93.[Medline] [Order article via Infotrieve]
17. Hilgemann DW, Collins A, Matsuoka S. Steady state and dynamic properties of cardiac sodium-calcium exchange: secondary modulation by cytoplasmic calcium and ATP. J Gen Physiol. 1992;100:933–961.[Abstract/Free Full Text]
18. Lakatta EG. Functional implications of spontaneous sarcoplasmic reticulum Ca²⁺ release in the heart. Cardiol Res. 1992;26:193–214.
19. Capogrossi MC, Houser SR, Bahinski A, Lakatta EG. Synchronous occurrence of spontaneous localized calcium release from the sarcoplasmic reticulum generates action potentials in rat cardiac ventricular myocytes at normal resting membrane potential. Circ Res. 1987;61:498–503.[Abstract/Free Full Text]
20. Pogwizd SM, Qi M, Samerel AM, Bers DM. Upregulation of Na⁺-Ca²⁺ exchanger expression and function in an arrhythmogenic rabbit model of heart failure. Circ Res. 1999;85:1009–1019.[Abstract/Free Full Text]
21. Beukelmann DJ, Nabauer M, Erdmann E. Alterations of K⁺ currents in isolated human ventricular myocytes from patients with terminal heart failure. Circ Res. 1993;73:379–385.[Abstract/Free Full Text]
22. Salama G, Kanai AJ, Huang D, Efimov IR, Girouard SD, Rosenbaum DS. Hypoxia and hypothermia enhance spatial heterogeneities of repolarization in guinea pig hearts: analysis of spatial autocorrelation of optically recorded action potential durations. J Cardiovasc Electrophysiol. 1999;2:164–183.
23. Morley GE, Vaidya D, Samie FH, Lo C, Delmar M, Jalife J. Characterization of conduction in the ventricles of normal and heterozygous Cx43 knockout mice using optical mapping. J Cardiovasc Electrophysiol. 1999;10:1361–1375.[Medline] [Order article via Infotrieve]

This article has been cited by other articles:

				A. Orlandi, F. Pagani, D. Avitabile, G. Bonanno, G. Scambia, E. Vigna, F. Grassi, F. Eusebi, S. Fucile, M. Pesce, et al. Functional properties of cells obtained from human cord blood CD34+ stem cells and mouse cardiac myocytes in coculture Am J Physiol Heart Circ Physiol, April 1, 2008; 294(4): H1541 - H1549. [Abstract] [Full Text] [PDF]

				X. H.T. Wehrens Leaky ryanodine receptors cause delayed afterdepolarizations and ventricular arrhythmias Eur. Heart J., May 1, 2007; 28(9): 1054 - 1056. [Full Text] [PDF]

				N. Ono, H. Hayashi, A. Kawase, S.-F. Lin, H. Li, J. N. Weiss, P.-S. Chen, and H. S. Karagueuzian Spontaneous atrial fibrillation initiated by triggered activity near the pulmonary veins in aged rats subjected to glycolytic inhibition Am J Physiol Heart Circ Physiol, January 1, 2007; 292(1): H639 - H648. [Abstract] [Full Text] [PDF]

				L.-S. Song, E. A. Sobie, S. McCulle, W. J. Lederer, C. W. Balke, and H. Cheng Orphaned ryanodine receptors in the failing heart. PNAS, March 14, 2006; 103(11): 4305 - 4310. [Abstract] [Full Text] [PDF]

				R. P. Katra and K. R. Laurita Cellular Mechanism of Calcium-Mediated Triggered Activity in the Heart Circ. Res., March 18, 2005; 96(5): 535 - 542. [Abstract] [Full Text] [PDF]

This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Houser, S. R. Search for Related Content PubMed PubMed Citation Articles by Houser, S. R. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Medline Plus Health Information Arrhythmia Hazardous Substances DB CALCIUM COMPOUNDS CALCIUM, ELEMENTAL Related Collections Arrythmias-basic studies Calcium cycling/excitation-contraction coupling Heart failure - basic studies Ion channels/membrane transport