doi: 10.1161/01.CIR.0000070984.65122.9C
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(Circulation. 2003;107:2395.)
© 2003 American Heart Association, Inc.
Editorial |
How Do ß-Blockers Improve Ventricular Function in Patients With Congestive Heart Failure?
From the Cardiology Division, University of Utah Health Sciences Center, Salt Lake City.
Correspondence to William H. Barry, MD, Division of Cardiology, University of Utah Health Sciences Center, 50 North Medical Dr, Salt Lake City, UT 84132. E-mail whbarry{at}med.utah.edu
Key Words: Editorials • heart failure • ventricles • receptors, adrenergic, beta
The binding of ß-adrenergic agonists such as norepinephrine and isoproterenol to the ß-1 adrenergic receptor (AR) in the sarcolemma of the ventricular myocyte increases intracellular levels of cAMP via Gs protein-induced stimulation of adenyl cyclase. cAMP activates protein kinase A (PKA), which causes phosphorylation of proteins involved in Ca2+ homeostasis, such as phospholamban and the L-type Ca2+ channel, increasing the intracellular calcium ion concentration ([Ca2+]i) transient, and thus causing a positive inotropic effect. It is now very well established that patients with congestive heart failure due to ischemic or idiopathic dilated cardiomyopathy are in a hyperadrenergic state.1 Treatment of these patients with ß-adrenergic receptor-blocking drugs reduces morbidity and mortality,2 improves ventricular function, and reverses pathological remodeling.3 Clinical and experimental animal studies have suggested a number of mechanisms by which chronic exposure to this class of drugs, which have a negative inotropic effect in normal myocardium, could have an apparently paradoxical beneficial effect in failing myocardium.
See p 2459
Seminal work by Bristow and associates4 showed that ß-1 AR density is reduced in the failing myocardium, and receptor density is increased by treatment with some ß-AR blockers.5 An increase in ß-receptor density may restore toward normal an available positive inotropic reserve in patients with heart failure. In isolated myocytes, a cytotoxic effect of prolonged adrenergic stimulation can be demonstrated,6 suggesting that ß-blockade may reduce a deleterious effect of the chronic hyperadrenergic state on myocyte survival. Treatment with ß-blockers also slows the heart rate. Because failing myocardium displays a decrease in contractility with increasing rate of stimulation,7 this may improve ventricular function. At slow rates of stimulation, the myocyte action potential is prolonged, allowing for more Ca2+ influx via Na/Ca exchange, and permitting more complete relaxation and reloading of the sarcoplasmic reticulum (SR) with Ca2+, despite a reduced expression of SR Ca2+ ATPase SERCA2a, which is present in the myocardium of many patients with heart failure.8 Finally, the reduced expression of SERCA2a and 
-myosin heavy chains9 may be restored toward normal by changes in gene expression induced by ß-blocking drugs.10 This could improve systolic and diastolic function.
In this issue of Circulation, Reiken et al11 describe another possible mechanism by which ß-blockers may improve SR function and thus calcium homeostasis and contractility in failing myocardium: A reduction in PKA-mediated hyperphosphorylation of the SR calcium release channel. The cardiac calcium release channel, or ryanodine receptor 2 (RyR2), is a macromolecular complex comprised of homotetramers, with each of the 4 subunits containing a PKA phosphorylation site and capable of binding 1 molecule of FK506-binding protein (FKBP12.6). The channel complex, which is opened by exposure to Ca2+ entering the myocyte via the L-type Ca2+ channel during excitation-contraction coupling, also includes phosphatases, which can induce dephosphorylation. As Reiken et al11 discuss, work from their group has shown that FKBP12.6 is dissociated from RyR2 by exposure to FK506, or by hyperphosphorylation, and this causes the RyR2 calcium release channel to display an increased sensitivity to Ca2+, a greater open probability resulting in a "leaky" channel that could cause SR Ca2+ depletion, and impaired cooperativity between RyR subunits. Reiken et al11 studied myocardium obtained from hearts of 9 patients with heart failure not treated with ß-blockers, from 10 patients with heart failure treated with ß-blockers, and from 5 normal patients. In patients with heart failure, there was a reduced binding of FKBP12.6 to RyR2 associated with hyperphosphorylation of RyR2 detected by a back phosphorylation technique and abnormal RyR2 channel function in planar lipid bilayers characterized by an increased opening probability and greater prevalence of subconductance states. All these abnormalities were reversed toward normal in myocardium from patients with heart failure who had been treated with ß-blockers. Reiken et al11 suggest that RyR2 hyperphosphorylation due to increased activation of PKA (and reduced phosphatase activity) results in dissociation of FKBP12.6 from RyR2, thus inducing a SR Ca2+ leak with SR Ca2+ depletion and hence a negative inotropic effect. Treatment with ß-blockers is proposed to improved myocardial function by decreasing the degree of phosphorylation of RyR2, thus decreasing the degree of dissociation of FKBP12.6 and enhancing SR function.
It is somewhat surprising that hyperphosphorylation of RyR2 is present in heart failure, in which there is downregulation of ß-ARs. Indeed, some studies have shown that phosphorylation of phospholamban, another substrate for PKA-mediated phosphorylation, is actually reduced in myocardium from patients with heart failure.12 However, recent work13 has demonstrated that there are discrete microdomains within cardiac myocytes in which effects of PKA may be regulated by the binding of the enzyme to its anchoring proteins and by co-localization of phosphodiesterases and phosphatases that can regulate regional concentrations of cAMP and of phosphorylated substrates, respectively. Variable alterations in these factors may explain why one target of PKA might be hyperphosphorylated whereas another might be hypophosphorylated in the failing myocyte. There are data from several experimental studies in animal models that are consistent with the hypothesis that hyperphosphorylation of RyR2 does occur with heart failure.11 That this causes dissociation of FKBP12.6 from RyR2 and results in SR Ca2+ depletion is supported by work of Yano et al.14 These investigators found that defective interaction of FKBP12.6 with RyR2 in a canine model of pacing-induced heart failure is associated with an abnormal SR Ca2+ leak, which they suggest may contribute to impaired function of the myocardium. In addition, we recently reported that dissociation of FKBP12.6 from RyR2 by exposure of rabbit ventricular myocytes to FK506 causes depletion of SR Ca2+ stores and a resulting decrease in the myocyte [Ca2+]i transient.15
Despite these supportive findings, there are some results that seem to challenge the concept that hyperphosphorylation-induced dissociation of FKBP12.6 is an important factor in abnormal Ca2+ homeostasis in heart failure. Jiang et al16 have reported that RyR2 isolated from failing human myocardium displayed no differences in vitro in open probability or the incidence of subconductance states as compared with controls. In addition, they detected no difference in the degree of RyR2 phosphorylation. Preliminary work by Terentyev et al17 has shown that in permeabilized myocytes from rats with heart failure induced by chronic isoproterenol administration, exposure to phosphatases PP1 and PP2a induced activation of Ca sparks and depletion of Ca2+ stores. They suggest that their results are inconsistent with the idea that heart failure is associated with hyperphosphorylation of RyR, rendering the Ca2+ release channel leaky to Ca2+. To some extent, these discrepancies may result from the fact that different experimental techniques have been used in different animal models of heart failure, and that different species were used. For example, dissociation of FKBP12.6 from RyR2 by exposure to FK506 is associated with an increase in the [Ca2+]i transient in rat18 and mouse15 myocytes, but causes a decrease in the [Ca2+]i transient in rabbit myocytes.15 Nevertheless, the importance of hyperphosphorylation of RyR2 in influencing myocyte contractility in heart failure needs and is certain to receive further investigation.
Finally, we should consider whether phosphorylation-induced dissociation the FKBP12.6 from RyR2 is important in normal physiology and whether alteration of the FKBP12.6–RyR2 interaction may be significant in other clinical situations. Reiken et al11 suggest that the acute increase in RyR2 phosphorylation induced by PKA may be a component of the "fight or flight" response by increasing RyR2 sensitivity to Ca2+ and thus enhancing SR Ca2+ release and the [Ca2+]i transient. This would cause an acute increase in contractility, along with PKA-induced increases in the SR Ca2+ uptake induced by phospholamban phosphorylation, and the increase in the L-type Ca2+ current induced by phosphorylation of the Ca2+ channel. This is plausible, but one might question why a positive inotropic effect, rather than a negative inotropic effect resulting from depletion of SR Ca2+ due to Ca2+ release channel leakiness, would predominate in the presence of hyperphosphorylation-induced dissociation of FKBP12.6 from RyR2. The reason may relate to the degree to which SR Ca2+ stores can be maintained in the face of an increased SR Ca2+ leak. For example, FK506 induces depletion of SR Ca2+ in rabbit myocytes and decreases the [Ca2+]i transient, whereas in mouse SR Ca2+ stores are not depleted and FK506 increases the transient.15 Thus, in normal myocardium, during sympathetic stimulation with activation of ß-adrenergic receptors, stimulation of SR Ca2+ uptake by phosphorylation of phospholamban might be sufficient to maintain SR Ca2+ stores despite a SR Ca2+ release channel leak with a resulting positive inotropic effect due to increased sensitivity of RyR2 to Ca2+. In failing myocardium, because of downregulation of SERCA2a and possibly reduced phosphorylation of phospholamban,12 this compensatory increase in SR Ca2+ uptake might be inadequate to maintain SR Ca2+ stores.
The immunosuppressive actions of FK506 (tacrolimus) are well known and result from the ability of a complex of FK506 and FKBP to bind to calcineurin and inhibit its phosphatase activity, resulting in the inhibition of T-lymphocyte activation.19 Use of FK506 in pediatric transplant recipients has been reported to be associated with the development of hypertrophic cardiomyopathy.20 Long-term exposure to ryanodine, which impairs SR Ca2+ release channel function, has been reported to induce hypertrophy in rats.21 Therefore, FK506 could possibly induce hypertrophy in young patients because of its ability to cause dissociation of FKBP12.6 from RyR2, thus inducing SR dysfunction. No significant myocardial effects of the use of tacrolimus in adult patients have been recognized, but could theoretically occur. Further study of the clinical significance of modulation of RyR2 function by drugs, intracellular signaling pathways, and other RyR2-associated proteins such as sorcin22 in heart failure and other conditions is clearly warranted.
Footnotes
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
References
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