doi: 10.1161/01.RES.0000225872.03255.b6
© 2006 American Heart Association, Inc.
Editorials |
Is the Ryanodine Receptor a Target for Antiarrhythmic Therapy?
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 (Po) 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 Po and consequently reduced Ca2+ release from the SR.11 If the RyR Po 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 Po 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 (ITI), 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 Po 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 ICa, (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 Po.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 Po) 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 Po.20 Venetucci et al2 find that reducing RyR Po 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.
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Acknowledgments |
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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.).
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Footnotes |
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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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 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.
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.
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 ICa and INa-Ca in cardiac myocytes. Science. 1990; 248: 376–378.
6. Stern MD. Theory of excitation-contraction coupling in cardiac muscle. Biophys J. 1992; 63: 497–517.[Medline] [Order article via Infotrieve]
7. Stern MD, Pizarro G, Rios E. Local control model of excitation-contraction coupling in skeletal muscle. J Gen Physiol. 1997; 110: 415–440.
8. Cheng H, Lederer WJ, Cannell MB. Calcium sparks: elementary events underlying excitation-contraction coupling in heart muscle. Science. 1993; 262: 740–744.
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.[CrossRef][Medline] [Order article via Infotrieve]
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.
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.
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.[Medline] [Order article via Infotrieve]
13. Goldhaber JI. Sodium-calcium exchange: the phantom menace. Circ Res. 1999; 85: 982–984.
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.
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.
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.
18. Marks AR. Cardiac intracellular calcium release channels: role in heart failure. Circ Res. 2000; 87: 8–11.
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.
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.
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.
Related Article:
Circ. Res. 2006 98: 1299-1305.
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