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(Circulation Research. 2006;98:1232.)
© 2006 American Heart Association, Inc.

Editorials

Is the Ryanodine Receptor a Target for Antiarrhythmic Therapy?

Christian Pott, Joshua I. Goldhaber

From the Departments of Physiology and Medicine and the Cardiovascular Research Laboratories, David Geffen School of Medicine at UCLA, Los Angeles, Calif.

Correspondence to Joshua I. Goldhaber, MD, David Geffen School of Medicine at UCLA, Cardiology, BH-407 CHS, 10833 LeConte Ave, Los Angeles, CA 90095. E-mail jgoldhaber{at}mednet.ucla.edu

See related article, pages 1299–1305

Key Words: arrhythmias • calcium • sarcoplasmic reticulum • sodium-calcium exchange • tetracaine

In cardiac myocytes, Ca²⁺ influx and efflux must be in balance to ensure cellular viability, normal contractile function, and a stable heart rhythm. Therefore Ca²⁺ fluxes between the major cellular compartments and the extracellular space have to adapt to a wide range of changing conditions. Failure to do so can result in Ca²⁺ overload of the sarcoplasmic reticulum (SR), leading to arrhythmogenic spontaneous release of SR Ca²⁺ by ryanodine receptors (RyRs). Recently, it was shown that suppressing RyR open probability (P_o) was protective in a mouse model of a congenital arrhythmia caused by increased Ca²⁺ leak from RyRs. It was suggested that such a strategy could be applied more widely to treat patients with common ventricular arrhythmias.¹ Is it possible to suppress SR Ca²⁺ release without jeopardizing contractile function and aggravating Ca²⁺ overload?

In this issue of Circulation Research, Venetucci et al² answer this question by using the analytic techniques they have used so successfully in the past to examine Ca²⁺ fluxes and autoregulation in normal cells.³ Their surprising finding is that reducing RyR Po in Ca²⁺-overloaded myocytes not only suppresses arrhythmogenic spontaneous Ca²⁺ release, but also increases the amplitude of the Ca²⁺ transient while maintaining Ca²⁺ homeostasis. To fully appreciate this finding, it is essential to review the profile of Ca²⁺ fluxes under both physiological conditions and during arrhythmogenic events.

Under normal conditions, Ca²⁺ enters the cardiomyocyte at the beginning of each contractile cycle through L-type Ca²⁺ channels (LCCs) and minimally raises the cytoplasmic Ca²⁺ concentration. This "trigger calcium" binds to RyRs and induces an even greater release of stored Ca²⁺ from the SR into the cytoplasm, which causes myofilament contraction. Survival of the cell, as well as relaxation, both depend on the reuptake of 75% of the cytoplasmic Ca²⁺ by SERCA into the SR.⁴ Most of the remaining Ca²⁺ is extruded by the sodium-calcium exchanger (NCX), with minimal amounts of removal by the sarcolemmal Ca²⁺ pump. The removal of Ca²⁺ by NCX leaves the cell containing the exact same amount of Ca²⁺ it started out with.⁵

Yet the high gain positive feedback system of Ca²⁺-induced Ca²⁺ release in heart muscle poses a challenge for the maintenance of Ca²⁺ homeostasis. Calcium released from the SR by RyRs could conceivably spread to and activate all of the other RyRs in the cell, resulting in an asynchronous and slow release of SR Ca²⁺ (eg, a Ca²⁺ wave) with each action potential. Stern et al⁶ predicted that synchronous contraction, graded release, and stability required "local control," using physical separation of individual Ca²⁺ release units, or couplons.⁷ The "local-control" theory predicts that an increase in Ca²⁺ current will recruit more release units and thereby increase global SR Ca²⁺ release to provide an inotropic response. This theory has been supported by the identification of individual Ca²⁺ release sites known as Ca²⁺ sparks.⁸

Physiologic beta adrenergic stimulation, for example during exercise, increases Ca²⁺ influx via LCCs and increases SR Ca²⁺ uptake by SERCA, mainly as a result of G protein–mediated phosphorylation of LCCs and phospholamban.⁴ NCX activity also increases because of increased binding of Ca²⁺ to the NCX catalytic site,⁹ but SERCA still out-competes NCX for Ca²⁺ and therefore SR Ca²⁺ content increases. As we discuss below, the increase in SR Ca²⁺ load may increase the risk of spontaneous Ca²⁺ release and triggered arrhythmias.

Cellular Ca²⁺ overload is also a hallmark of ATP depletion during myocardial ischemia. Surprisingly, energy deprivation does not decrease SR Ca²⁺ content.¹⁰ How can this be? During the metabolic stress of ischemia, the free energy available for SERCA function eventually declines. These same changes in free energy lead to reduced Ca²⁺ influx through LCCs,¹⁰ reduced RyR Ca²⁺ sensitivity, and P_o and consequently reduced Ca²⁺ release from the SR.¹¹ If the RyR P_o remains reduced while SERCA activity is maintained, Ca²⁺ overload of the SR may eventually occur. Na⁺ gain may further reduce Ca²⁺ removal by NCX, leaving more Ca²⁺ to be taken up by SERCA into the SR. As luminal SR Ca²⁺ content increases, RyR P_o will increase,¹² a process reinforced by the rise in cytoplasmic Ca²⁺. Both of these effects eventually override the inhibitory effects of metabolic stress on the RyR, resulting in spontaneous release of Ca²⁺ and generation of Ca²⁺ waves.

Ca²⁺ released into the cytoplasm during a Ca²⁺ wave is handled by the myocyte in two ways: (1) re-uptake by the SR (assuming SERCA activity remains), and (2) removal from the cell by NCX. Efflux of Ca²⁺ by NCX generates a transient inward current (I_TI), which is capable of bringing Na⁺ channels to threshold and producing delayed after-depolarizations or DADs.¹³ Pogwizd et al¹⁴ demonstrated that most ventricular arrhythmias in non-ischemic cardiomyopathy are initiated by non-reentrant mechanisms, exemplified by DADs. And up to 50% of ventricular arrhythmias in ischemic cardiomyopathy may be initiated by after-depolarizations, though the proportions remain controversial.¹⁵ Amazingly, despite reductions in SERCA expression and increases in NCX expression, increased catecholamine levels in heart failure lead to SR Ca²⁺ overload and DADs.¹⁶ The use of beta agonists in the treatment of systolic failure further increases SR Ca²⁺ load and risk of DADs, likely explaining the arrhythmogenicity of these drugs and the poor outcomes associated with their clinical use.¹⁷ It has also been suggested that increased leak of Ca²⁺ from the SR during diastole in the setting of heart failure¹⁸ can trigger Ca²⁺ waves and therefore DADs. Finally, several well-defined genetic mutations of the RyR and its associated proteins lead to increased RyR P_o and therefore DADs. In particular, dissociation of the accessory protein calstabin2 has been shown to occur in patients with catecholaminergic polymorphic ventricular tachycardia (CPVT), and these patients are predisposed to triggered arrhythmias.^1,19

Can homeostasis be achieved in the setting of Ca²⁺"overload" and activation of an arrhythmogenic current? Venetucci et al² address this question by quantifying Ca²⁺ fluxes during application of isoproterenol to isolated rat ventricular myocytes. They demonstrate that the spontaneous diastolic release of Ca²⁺ under these conditions maintains cellular Ca²⁺ balance by matching the increased Ca²⁺ influx caused by beta stimulation with a burst of additional Ca²⁺ efflux. In other words, the exact amount of Ca²⁺ necessary to restore Ca²⁺ balance is released spontaneously into the cytoplasm during diastole and is removed from the cell by NCX.

Although spontaneous SR Ca²⁺ release balances cellular Ca²⁺, subsequent stimulated Ca²⁺ transients are reduced in amplitude compared with transients not preceded by a Ca²⁺ wave. There are three potential causes for this: (1) Ca²⁺-dependent inhibition of I_Ca, (2) Ca²⁺-dependent adaptation or inactivation of LCCs and RyRs, and (3) depletion of SR Ca²⁺ content. Thus, Venetucci et al² show that spontaneous Ca²⁺ release is not only arrhythmogenic, but also detrimental to systolic force generation.

In a mouse model of CPVT, arrhythmia frequency can be reduced by using an experimental compound, JTV519, to enhance the binding of calstabin2 to RyR2 and thus reduce RyR P_o.¹ Venetucci et al use the drug tetracaine to apply a similar strategy to reduce spontaneous Ca²⁺ release in cells overloaded with Ca²⁺ (and thus prone to increased RyR P_o) during exposure to isoproterenol.

Tetracaine is a local anesthetic with Na⁺ channel blocking properties. However, unlike related local anesthetics such as lidocaine, tetracaine has the additional effect of reducing RyR P_o.²⁰ Venetucci et al² find that reducing RyR P_o with tetracaine not only eliminates spontaneous Ca²⁺ release, but also relieves the inhibition of systolic Ca²⁺ transients (though the increase in the systolic Ca²⁺ transient only occurs if Ca²⁺ overload and spontaneous Ca²⁺ release is present before application of tetracaine). Reducing arrhythmogenic spontaneous Ca²⁺ releases while increasing the systolic Ca²⁺ transient would appear to be an ideal strategy to both strengthen contraction and reduce arrhythmias in patients with heart failure.

A note of caution must be sounded, however. Although after-depolarizations likely trigger the majority of lethal ventricular arrhythmias in heart failure, and perhaps in ischemia as well, pharmacological suppression of arrhythmia triggers (eg, PVCs) has not been a successful strategy in clinical trials,²¹ presumably because of unintended changes in the electrophysiological milieu of the myocardium. Thus, suppressing arrhythmia triggers may not be a sufficient antiarrhythmic strategy. It is more likely that modulating parameters that are known to maintain reentrant arrhythmias, such as restitution slope,²² is also an essential component of arrhythmia suppression.

	Acknowledgments

 
This work was supported by Koln Fortune and the German Research Foundation (DFG PO 1004/[1]-1) (C.P.), National Institutes of Health grant no. HL70828, and the Laubisch Foundation for Cardiovascular Research (J.I.G.).

	Footnotes

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

	References

Top References

 

1. 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]
2. Venetucci LA, Trafford AW, Diaz ME, O’Neill SC, Eisner DA. Reducing ryanodine receptor open probability as a means to abolish spontaneous Ca²⁺ release and increase Ca²⁺ transient amplitude in adult ventricular myocytes. Circ Res. 2006; 98: 1299–1305.[Abstract/Free Full Text]
3. Diaz ME, Graham HK, O’Neill SC, Trafford AW, Eisner DA. The control of sarcoplasmic reticulum Ca²⁺ content in cardiac muscle. Cell Calcium. 2005; 38: 391–396.[CrossRef][Medline] [Order article via Infotrieve]
4. Bers DM. Excitation-contraction Coupling and Cardiac Contractile Force, 2nd ed. Dordrecht, The Netherlands: Kluwer; 2001.
5. Bridge JHB, Smolley JR, Spitzer KW. The relationship between charge movements associated with I_Ca and I_Na-Ca in cardiac myocytes. Science. 1990; 248: 376–378.[Abstract/Free Full Text]
6. Stern MD. Theory of excitation-contraction coupling in cardiac muscle. Biophys J. 1992; 63: 497–517.[Abstract/Free Full Text]
7. Stern MD, Pizarro G, Rios E. Local control model of excitation-contraction coupling in skeletal muscle. J Gen Physiol. 1997; 110: 415–440.[Abstract/Free Full Text]
8. 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]
9. Philipson KD, Nicoll DA, Ottolia M, Quednau BD, Reuter H, John S, Qiu Z. The Na⁺/Ca²⁺ exchange molecule: an overview. Ann N Y Acad Sci. 2002; 976: 1–10.[Abstract/Free Full Text]
10. Goldhaber JI, Parker JM, Weiss JN. Mechanisms of excitation-contraction coupling failure during metabolic inhibition in guinea-pig ventricular myocytes. J Physiol. 1991; 443: 371–386.[Abstract/Free Full Text]
11. Overend CL, Eisner DA, O’Neill SC. Altered cardiac sarcoplasmic reticulum function of intact myocytes of rat ventricle during metabolic inhibition. Circ Res. 2001; 88: 181–187.[Abstract/Free Full Text]
12. Györke I, Györke S. Regulation of the cardiac ryanodine receptor channel by luminal Ca²⁺ involves luminal Ca²⁺ sensing sites. Biophys J. 1998; 75: 2801–2810.[Abstract/Free Full Text]
13. Goldhaber JI. Sodium-calcium exchange: the phantom menace. Circ Res. 1999; 85: 982–984.[Free Full Text]
14. Pogwizd SM, McKenzie JP, Cain ME. Mechanisms underlying spontaneous and induced ventricular arrhythmias in patients with idiopathic dilated cardiomyopathy. Circulation. 1998; 98: 2404–2414.[Abstract/Free Full Text]
15. Rubart M, Zipes DP. Mechanisms of sudden cardiac death. J Clin Invest. 2005; 115: 2305–2315.[CrossRef][Medline] [Order article via Infotrieve]
16. Pogwizd SM, Schlotthauer K, Li L, Yuan W, Bers DM. Arrhythmogenesis and contractile dysfunction in heart failure: Roles of sodium-calcium exchange, inward rectifier potassium current, and residual beta-adrenergic responsiveness. Circ Res. 2001; 88: 1159–1167.[Abstract/Free Full Text]
17. Cuffe MS, Califf RM, Adams KF Jr, Benza R, Bourge R, Colucci WS, Massie BM, O’Connor CM, Pina I, Quigg R, Silver MA, Gheorghiade M. Short-term intravenous milrinone for acute exacerbation of chronic heart failure: a randomized controlled trial. J Am Med Assoc. 2002; 287: 1541–1547.[Abstract/Free Full Text]
18. Marks AR. Cardiac intracellular calcium release channels: role in heart failure. Circ Res. 2000; 87: 8–11.[Free Full Text]
19. Scoote M, Williams AJ. The cardiac ryanodine receptor (calcium release channel): emerging role in heart failure and arrhythmia pathogenesis. Cardiovasc Res. 2002; 56: 359–372.[Abstract/Free Full Text]
20. Xu L, Jones R, Meissner G. Effects of local anesthetics on single channel behavior of skeletal muscle calcium release channel. J Gen Physiol. 1993; 101: 207–233.[Abstract/Free Full Text]
21. Echt DS, Liebson PR, Mitchell LB, Peters RW, Obias-Manno D, Barker AH, Arensberg D, Baker A, Friedman L, Greene HL, et al. Mortality and morbidity in patients receiving encainide, flecainide, or placebo: the cardiac arrhythmia suppression trial. N Engl J Med. 1991; 324: 781–788.[Abstract]
22. Goldhaber JI, Xie LH, 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.[Abstract/Free Full Text]

Related Article:

Reducing Ryanodine Receptor Open Probability as a Means to Abolish Spontaneous Ca²⁺ Release and Increase Ca²⁺ Transient Amplitude in Adult Ventricular Myocytes

L.A. Venetucci, A.W. Trafford, M.E. Díaz, S.C. O’Neill, and D.A. Eisner
Circ. Res. 2006 98: 1299-1305. [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 Google Scholar Google Scholar Articles by Pott, C. Articles by Goldhaber, J. I. Search for Related Content PubMed PubMed Citation Articles by Pott, C. Articles by Goldhaber, J. I. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Medline Plus Health Information Arrhythmia Hazardous Substances DB CALCIUM COMPOUNDS CALCIUM, ELEMENTAL Related Collections Related Article