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(Circulation Research. 2003;93:487.)
© 2003 American Heart Association, Inc.

Editorial

Sarcoplasmic Reticulum Ca²⁺ and Heart Failure

Roles of Diastolic Leak and Ca²⁺ Transport

Donald M. Bers, David A. Eisner, Héctor H. Valdivia

From the Department of Physiology (D.M.B.), Loyola University Chicago, Maywood Ill; Department of Medicine (D.A.E.), University of Manchester, Manchester, UK; and Department of Physiology (H.H.V.), University of Wisconsin, Madison Wis.

Correspondence to Donald M. Bers, Department of Physiology, Loyola University Chicago, 2160 S First Ave, Maywood, IL 60153. E-mail dbers{at}lumc.edu; and Héctor H. Valdivia, Department of Physiology, University of Wisconsin Medical School, 1300 University Ave, Madison, WI 53706. E-mail valdivia@physiology.wisc.edu

Key Words: heart failure • ryanodine receptors • calcium sparks

Heart failure (HF) is a leading cause of death and enormous effort has focused at understanding the molecular and cellular mechanisms of the decreased cardiac contractility. While changes of other components contribute, it is generally agreed that much of the contractile deficit is due to reduced myocyte Ca²⁺ transients.^1,2 Alterations in Ca²⁺ current (I_Ca) and action potential characteristics are also seen in HF, but a central factor limiting Ca²⁺ transient amplitude is a decrease of sarcoplasmic reticulum (SR) Ca²⁺ content.^3–6 HF is extremely complex, but it is easy to appreciate how reduced SR Ca²⁺ content would reduce SR Ca²⁺ release, myofilament activation, and contractility. Despite agreement that SR Ca²⁺ content is reduced in HF, controversy exists about why SR content is low.

How Is SR Ca²⁺ Content Decreased in Heart Failure?

SR Ca²⁺ content reflects the balance between Ca²⁺ uptake (via SERCA) and Ca²⁺ efflux via ryanodine receptor (RyR). Thus, reduced SR content in HF must be due to reduced Ca²⁺ pumping by SERCA or increased SR Ca²⁺ leak via RyRs. Both are supported by experimental data (below). Transsarcolemmal Ca²⁺ fluxes also affect SR Ca²⁺ load. That is, reduced Ca²⁺ influx (eg, via I_Ca) or enhanced Ca²⁺ extrusion via Na⁺-Ca²⁺ exchange (NCX) can unload the SR. Results are not unanimous, but most groups find little alteration in peak I_Ca density in HF, while many find evidence of enhanced NCX expression and function.^1,2 Increased NCX function can compete with SERCA during [Ca²⁺]_i decline, extruding more Ca²⁺ from the cell and depleting the SR. In the new steady state, a larger fraction of activating Ca²⁺ also enters the cell at each beat in HF (eg, smaller Ca²⁺ release causes less I_Ca inactivation). Indeed, acute NCX overexpression can decrease SR Ca²⁺ content.⁷ While NCX alterations can reduce SR Ca²⁺ load in HF, we focus here on SERCA and RyR function.

SR Ca²⁺ release occurs during both systolic SR Ca²⁺ release triggered by I_Ca and diastolic SR Ca²⁺ leak due to the finite stochastic RyR open probability (P_o), manifest mainly as Ca²⁺ sparks.¹ Recent publications have raised controversy as to the importance of increased SR Ca²⁺ leak in HF.^8–13 While reduced SERCA function, enhanced diastolic SR Ca²⁺ leak, and increased NCX function may all contribute to SR Ca²⁺ unloading in HF (and are not mutually exclusive), recent studies focused on SERCA¹⁰ or diastolic leak¹² as crucial. Here, we comment on key arguments and summarize the issue as we see it.

Evidence for Decreased SERCA Pumping

While there is not complete agreement, most laboratories find evidence for depressed SERCA expression and/or function in HF (including human).^1,2,4–6,10 The level of phospholamban (PLB) phosphorylation may also be decreased (depressing SERCA function further).¹ There are still questions about how functional downregulation of SERCA comes about during HF and its absolute extent. However, some degree of SERCA dysfunction is generally accepted to contribute to both systolic and diastolic dysfunction in HF.

Evidence for Increased RyR Leak

Marks’ group spearheaded the hypothesis of enhanced diastolic SR Ca²⁺ leak in HF.^8,12,13 Their biochemical and single-channel RyR bilayer recording placed this hypothesis in a compelling molecular mechanism. They showed that an RyR macromolecular complex includes cAMP-dependent protein kinase (PKA), phosphatases (PP1 and PP2a), and FKBP12.6. They found that the RyR was "hyperphosphorylated" by PKA in HF and attributed this to hyperadrenergic state and loss of RyR-associated phosphatases (despite increased global myocyte phosphatases). This RyR phosphorylation caused FKBP12.6 dissociation from the RyR and altered RyR gating, analogous to when FKBP12.6 is displaced from RyRs by FK-506 or rapamycin.^14,15 Single-channel RyR recordings showed increased overall P_o in HF, with some openings at lower conductance levels, resulting in a net increase in ion flux. In cellular terms, this would translate into increased diastolic SR Ca²⁺ leak and reduced SR Ca²⁺ content. This diastolic leak hypothesis has many attractions and support from another laboratory.^16,17

Limitations of the RyR Hyperphosphorylation Hypothesis

This is an important hypothesis but requires further testing. Some published data are inconsistent with critical aspects of the theory and its universality in HF. One limitation is a lack of supporting data in intact myocytes. For example, more frequent Ca²⁺ sparks might be expected in HF myocytes, but to our knowledge this has not been reported. This contrasts with strong cellular data concerning altered SERCA and/or NCX function in HF myocytes.

PKA-dependent RyR effects have mainly been studied in lipid bilayers, where RyRs are divorced from their natural environment. Even in this simplified system, results are divergent.^8,18 One study¹⁸ showed that PKA increased initial RyR P_o in response to a jump in [Ca²⁺] (simulating a cellular I_Ca trigger), but then P_o relaxed rapidly to a lower steady-state level, such that PKA slightly reduced steady-state P_o. In contrast, another study⁸ (steady-state effects only) found that PKA increased overall P_o and caused subconductance states. This difference is unresolved.

It is difficult to study RyR properties in intact cells, because PKA increases both I_Ca and SR Ca²⁺-ATPase activity, which independently alter SR Ca²⁺ release. Nevertheless, cellular data are essential and were provided by Li et al.⁹ They used mice lacking phosphorylatable PLB (to avoid altered SR Ca²⁺-ATPase) and avoided PKA effects on I_Ca by studying SR Ca²⁺ release in both permeabilized and intact quiescent myocytes. PKA-dependent RyR phosphorylation (measured) did not significantly activate diastolic SR Ca²⁺ leak (assessed by Ca²⁺ spark frequency, Figure 1B). Nor did PKA alter Ca²⁺ spark amplitude, duration, or spatial spread. In control myocytes (with PLB present), PKA dramatically increased Ca²⁺ spark frequency, an effect attributed to the measured increases in SR Ca²⁺ content.⁹ This was not a study of HF, but it was concluded that if diastolic SR Ca²⁺ leak is increased in HF, additional factors to RyR phosphorylation may be involved.

View larger version (31K): [in this window] [in a new window]   Figure 1. A, RyR Po versus [Ca2+], with data points27 and proposed shifts.9 Phosphorylation (PO4) and hyperphosphorylation (hyper-PO4) curves are shifted by 0.5- and 1-log unit. B, Ca2+ spark frequency (±PKA activation) in mouse ventricular myocytes that lack phospholamban (PLB-KO) or express nonphosphorylatable PLB (PLB-DM).9

The altered RyR phosphorylation hypothesis⁸ (Figure 1A) is that RyR activation shifts to lower [Ca²⁺]_i with physiological sympathetic activation, enhancing SR Ca²⁺ release during excitation-contraction coupling (without causing diastolic leak). In HF, RyR hyperphosphorylation causes additional shift, resulting in diastolic SR Ca²⁺ leak and SR Ca²⁺ depletion. Note that even control phosphorylation should increase diastolic Ca²⁺ leak (unless leak is irrelevant to load) and would not be selective for hyperphosphorylation. Contrary to concerns,¹² the cellular PKA studies of Li et al⁹ were done precisely where any increase in Ca²⁺ spark frequency (or P_o) should be most readily apparent (several fold increases would be expected, Figure 1). Certainly other factors dramatically alter Ca²⁺ spark frequency in intact cardiac myocytes (eg, [Ca²⁺]_i, [Ca²⁺]_SR, and CaMKII).^9,19 We believe that appropriate data in intact cells (and animals) are the overriding context within which data from isolated systems (eg, bilayers) must be placed in interpreting physiological importance.

The effect of PKA-dependent RyR phosphorylation during excitation-contraction coupling is also controversial, with both increases and decreases reported.^20,21 In summary, how PKA modulates RyR in intact cells is not resolved.

Universality of RyR Hyperphosphorylation in HF?

Another issue is the universality of RyR dysfunction (hyperphosphorylation^8,12) in HF. Jiang et al¹⁰ found in HF unaltered RyR density (measured by [³H]ryanodine binding and immunoblotting) and RyR activity at a wide range of [Ca²⁺] (measured with [³H]ryanodine binding and single channel experiments) or RyR phosphorylation (assessed by back-phosphorylation and phospho-specific antibody²²). It was suggested¹² that Jiang et al¹⁰ did not measure (1) RyR number in samples subjected to back-phosphorylation or (2) RyR activity at diastolic [Ca²⁺]. However, Figure 4 of Jiang et al¹⁰ did show unaltered RyR density in control versus HF in those samples. They also showed that at 100 nmol/L Ca²⁺, both RyR activity and [³H]ryanodine binding (indicative of RyR P_o) were equivalent in control and HF RyRs (Figures 4C and 5A through 5C in Reference 10). Single-channel recordings showed neither altered RyR P_o nor the subconductance states typical of FKBP12.6 dissociation.¹⁵ However, traces at 100 nmol/L [Ca²⁺] were short, and pooled statistics were not reported. Figure 2B here shows these data, and that RyR P_o was not increased in HF. These criticisms thus seem unfounded.

View larger version (31K): [in this window] [in a new window]   Figure 2. RyR density and gating in control and HF. A, [3H]Ryanodine binding Bmax to SR-enriched microsomes (left) and Western blots (right). B, Single-channel RyR2 gating at 100 nmol/L Ca2+ (top) and aggregate histograms (n=6, bottom). Inset, RyR Po at 100 nmol/L Ca2+ (n values on bars). Methods as described in Reference 10.

A central tenet of the RyR-PKA/diastolic Ca²⁺ leak hypothesis is that RyR phosphorylation causes FKBP12.6 dissociation from the RyR. It was suggested¹² that Jiang et al¹⁰ could not assess FKBP12.6 dissociation because their microsomes contained cytosolic FKBP12. While immunoprecipitated RyRs may provide clearer results, these microsomes should not contain appreciable cytosolic protein. Also, both FKBP12 and FKBP12.6 can associate with cardiac RyRs (although FKBP12 competes poorly in dog).²³ Thus, microsomal FKBP12 may still be RyR bound,¹⁰ especially in humans. Since RyR phosphorylation by PKA did not change microsomal FKBP12.6 or FKBP12 levels, phosphorylation did not dissociate either FKBP from RyR. This issue remains controversial.

Impact of Increased SR Ca²⁺ Leak Versus SERCA and NCX Changes

Most Ca²⁺ released via Ca²⁺ sparks returns to the SR due to stronger Ca²⁺ transport by the SR Ca²⁺-ATPase versus NCX. However, the SR unloading effect of enhanced leak would be synergistic with the typical SERCA and NCX changes seen in HF. Local diastolic Ca²⁺ sparks could also leave RyRs refractory, exacerbating the load-dependent reduction of fractional SR Ca²⁺ release.

If RyR hyperphosphorylation shifts RyR Ca²⁺ sensitivity (Figure 1A) during both diastole and systole, then the SR load-lowering effect of diastolic leak would be partly offset by enhanced fractional SR Ca²⁺ release during systole. This is what RyR sensitization by moderate caffeine concentration does.²⁴ That is, SR Ca²⁺ load went down due to leak (and enhanced extrusion), but steady-state Ca²⁺ transients were unaltered. So, the hypothesized SR Ca²⁺ leak could contribute to SR Ca²⁺ unloading but might not alter systolic function.

Finally, HF is heterogeneous and complex. Relative contributions of SERCA, NCX, and SR Ca²⁺ leak probably vary in different origins and stages of HF. While we should seek to understand if there are technical reasons for different results,^8,10 we should also embrace the difference for the potential clues it may hold for further understanding fundamental mechanisms. Hasenfuss et al²⁵ segregated HF patients based on diastolic dysfunction. Forty-four percent of patients with best-preserved diastolic function had large increases in NCX expression but only modest SERCA downregulation, whereas 34% (with more diastolic dysfunction) had more profound SERCA downregulation but modest NCX upregulation. In detailed Ca²⁺ transients analyses, Piacentino et al⁶ found human HF data most like the latter group, Pogwizd et al⁵ found results more like the former group in nonischemic rabbit HF, and O’Rourke et al²⁶ found in-between behavior in a rapid-pacing-induced dog HF.

In summary, three mechanisms may contribute to reduced SR Ca²⁺ load in HF (reduced SERCA function, enhanced NCX function, and enhanced SR Ca²⁺ leak). However, relative contributions may vary among models and disease stages. More quantitative cellular data regarding SR Ca²⁺ leak are required to better understand how this pathway might compare to SERCA and NCX alterations in being causative of, and a therapeutic target in, HF.

Footnotes

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

Hector H. Valdivia is a consultant for Procter & Gamble Pharmaceuticals.

References

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				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]

				S. E. Litwin "Ryanogate": Who Leaked the Calcium? Circ. Res., February 3, 2006; 98(2): 165 - 168. [Full Text] [PDF]

				Y. Ji, W. Zhao, B. Li, J. Desantiago, E. Picht, M. A. Kaetzel, J. E. J. Schultz, E. G. Kranias, D. M. Bers, and J. R. Dedman Targeted inhibition of sarcoplasmic reticulum CaMKII activity results in alterations of Ca2+ homeostasis and cardiac contractility Am J Physiol Heart Circ Physiol, February 1, 2006; 290(2): H599 - H606. [Abstract] [Full Text] [PDF]

				M. R. Sharma, L. H. Jeyakumar, S. Fleischer, and T. Wagenknecht Three-Dimensional Visualization of FKBP12.6 Binding to an Open Conformation of Cardiac Ryanodine Receptor Biophys. J., January 1, 2006; 90(1): 164 - 172. [Abstract] [Full Text] [PDF]

				M. E. Anderson The Fire From Within: The Biggest Ca2+ Channel Erupts and Dribbles Circ. Res., December 9, 2005; 97(12): 1213 - 1215. [Full Text] [PDF]

				T. R. Shannon, F. Wang, and D. M. Bers Regulation of Cardiac Sarcoplasmic Reticulum Ca Release by Luminal [Ca] and Altered Gating Assessed with a Mathematical Model Biophys. J., December 1, 2005; 89(6): 4096 - 4110. [Abstract] [Full Text] [PDF]

				K. Wang, Y. Tu, W.-J. Rappel, and H. Levine Excitation-Contraction Coupling Gain and Cooperativity of the Cardiac Ryanodine Receptor: A Modeling Approach Biophys. J., November 1, 2005; 89(5): 3017 - 3025. [Abstract] [Full Text] [PDF]

				K. R. Sipido and D. Eisner Something old, something new: Changing views on the cellular mechanisms of heart failure Cardiovasc Res, November 1, 2005; 68(2): 167 - 174. [Full Text] [PDF]

				J. Fauconnier, A. Lacampagne, J.-M. Rauzier, G. Vassort, and S. Richard Ca2+-dependent reduction of IK1 in rat ventricular cells: A novel paradigm for arrhythmia in heart failure? Cardiovasc Res, November 1, 2005; 68(2): 204 - 212. [Abstract] [Full Text] [PDF]

				Z. Kubalova, D. Terentyev, S. Viatchenko-Karpinski, Y. Nishijima, I. Gyorke, R. Terentyeva, D. N. Q. da Cunha, A. Sridhar, D. S. Feldman, R. L. Hamlin, et al. Abnormal intrastore calcium signaling in chronic heart failure PNAS, September 27, 2005; 102(39): 14104 - 14109. [Abstract] [Full Text] [PDF]

				L.-S. Song, Y. Pi, S.-J. Kim, A. Yatani, S. Guatimosim, R. K. Kudej, Q. Zhang, H. Cheng, L. Hittinger, B. Ghaleh, et al. Paradoxical Cellular Ca2+ Signaling in Severe but Compensated Canine Left Ventricular Hypertrophy Circ. Res., September 2, 2005; 97(5): 457 - 464. [Abstract] [Full Text] [PDF]

				S. Viatchenko-Karpinski, D. Terentyev, L. A. Jenkins, L. O. Lutherer, and S. Gyorke Synergistic interactions between Ca2+ entries through L-type Ca2+ channels and Na+-Ca2+ exchanger in normal and failing rat heart J. Physiol., September 1, 2005; 567(2): 493 - 504. [Abstract] [Full Text] [PDF]

X. H. T. Wehrens, S. E. Lehnart, S. Reiken, R. van der Nagel, R. Morales, J. Sun, Z. Cheng, S.-X. Deng, L. J. de Windt, D. W. Landry, et al. Enhancing calstabin binding to ryanodine receptors improves cardiac and skeletal muscle function in heart failure PNAS, July 5, 2005; 102(27): 9607 - 9612. [Abstract] [Full Text] [PDF]