Published online before print February 23, 2009, doi: 10.1161/CIRCULATIONAHA.108.774752
(Circulation. 2009;119:1231-1240.)
© 2009 American Heart Association, Inc.
Heart Failure |
Mechanisms of Enhanced β-Adrenergic Reserve From Cardiac Resynchronization Therapy
From the Division of Cardiology, Department of Medicine, Johns Hopkins Medical Institutions, Baltimore (K.C., S.K.D., T.A., R.S.T., V.L.D., T.P.A., K.J., G.F.T., D.A.K.); Reproductive Biology and Medicine Branch, Section on Medical Neuroendocrinology, National Institute of Child Health and Human Development, Bethesda (E.W.L., K.P.); and Laboratory of Cardiovascular Science, Gerontology Research Center, National Institute on Aging, National Institutes of Health, Baltimore (W.-Z.Z., R.-p.X.), Md.
Correspondence to David A. Kass, MD, 720 Rutland Ave, Ross Bldg 835, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205. E-mail dkass{at}jhmi.edu
Received February 21, 2008; accepted November 24, 2008.
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Abstract |
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Background— Cardiac resynchronization therapy (CRT) is the first clinical heart failure treatment that improves chamber systolic function in both the short-term and long-term yet also reduces mortality. The mechanical impact of CRT is immediate and well documented, yet its long-term influences on myocyte function and adrenergic modulation that may contribute to its sustained benefits are largely unknown.
Methods and Results— We used a canine model of dyssynchronous heart failure (DHF; left bundle ablation, atrial tachypacing for 6 weeks) and CRT (DHF for 3 weeks, biventricular tachypacing for subsequent 3 weeks), contrasting both to nonfailing controls. CRT restored contractile synchrony and improved systolic function compared with DHF. Myocyte sarcomere shortening and calcium transients were markedly depressed at rest and after isoproterenol stimulation in DHF (both anterior and lateral walls), and CRT substantially improved both. In addition, β1 and β2 stimulation was enhanced, coupled to increased β1 receptor abundance but no change in binding affinity. CRT also augmented adenylate cyclase activity over DHF. Inhibitory G-protein (G
i) suppression of β-adrenergic stimulation was greater in DHF and reversed by CRT. Gi expression itself was unaltered; however, expression of negative regulators of Gi signaling (particularly RGS3) rose uniquely with CRT over DHF and controls. CRT blunted elevated myocardial catecholamines in DHF, restoring levels toward control.
Conclusions— CRT improves rest and β-adrenergic–stimulated myocyte function and calcium handling, upregulating β1 receptors and adenylate cyclase activity and suppressing Gi-coupled signaling associated with novel RGS upregulation. The result is greater rest and sympathetic reserve despite reduced myocardial neurostimulation as components underlying its net benefit.
Key Words: adenylate cyclase • heart failure • myocytes • pacing • receptors, adrenergic, beta • RGS proteins
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Introduction |
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Congestive heart failure is a leading cause of morbidity and mortality worldwide, commanding more than $30 billion in healthcare spending annually in the United States alone.1 Over the past decade, arguably the most significant advance in congestive heart failure treatment has been biventricular pacing (cardiac resynchronization therapy [CRT]), which improves cardiac function, symptoms, and prognosis in a subgroup of congestive heart failure patients with discoordinate contraction resulting from conduction delay.2–5 CRT abruptly improves systolic chamber function and energetic efficiency by reducing wasted reciprocal stretch of 1 wall by an otherwise out-of-phase contraction of the opposing region.3,6,7 CRT chronically suppresses progressive cardiac dilation,8 enhances myocardial gene expression of calcium handling proteins,9,10 and blunts fetal gene expression (eg, brain natriuretic peptide).11 CRT is the only heart failure treatment to date that can increase systolic function both in the short-term and long-term but also prolong survival, something not yet achieved by drug therapy.
Editorial p 1192
Clinical Perspective p 1240
To date, the mechanisms for CRT benefits have been studied principally at the chamber level and largely in human subjects at rest. Its impact on myocyte rest and reserve function has been little studied, although recent investigations have revealed that CRT improves cardiac reserve, coupled to increasing heart rate.12–14 Contractile reserve also is importantly modulated by β-adrenergic signaling, something that is often downregulated in failing hearts.15,16 CRT rapidly blunts efferent sympathetic stimulation reflected by peripheral muscle sympathetic nerve activity,17 and such changes have been chronically linked to clinical efficacy.18 However, whether and how CRT alters β-adrenergic signaling at the cellular level is unknown.
Accordingly, the present study tested whether CRT can ameliorate cardiac myocyte β-adrenergic reserve abnormalities and identified signaling mechanisms for such effects. To achieve this, we used a recently described canine model of dyssynchronous heart failure (DHF) with or without CRT treatment.19 Here, we reveal that CRT substantially improves both rest and β-adrenergic receptor (β-AR)–stimulated myocyte contraction and calcium cycling throughout the ventricle, restoring a more normal balance of reduced myocardial adrenergic stimulation with enhanced cellular responsiveness. Enhanced β-AR signaling is linked to a selective rise in β1 receptors and adenylate cyclase activity and upregulation of regulators of G-protein signaling that accompany suppression of inhibitory G-protein modulation.
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Methods |
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Canine Model of DHF and CRT
Details of the canine model were recently reported.19 Briefly, dogs (n=32) were subjected to left bundle radiofrequency ablation followed by 6 weeks of atrial tachypacing (
200 bpm; DHF) or 3 weeks of atrial pacing (dyssynchrony) and then 3 weeks of biventricular pacing (left ventricular lateral and right ventricular anteroapical epicardium) at the same rapid rate (CRT). Sham DHF dogs (n=3) with both surgical ventricular leads placed but not used were also studied. Noninstrumented dogs (n=13) served as controls. Echocardiography and tissue Doppler studies were performed at 3 and 6 weeks in conscious animals to assess left ventricular dyssynchrony,19 chamber dimensions, and ejection fraction. At the end of the study, dogs were anesthetized with pentobarbital, pacing was suspended, and a micromanometer (Millar Instruments Inc, Houston, Tex) was advanced to record left ventricular pressures. The chest was opened; hearts were rapidly harvested under cold cardioplegia; and myocardium was frozen for tissue analysis (endocardial and mid/epicardial segments from septum and left ventricular lateral) or for myocyte isolation from anteroseptal and lateral walls. Details of these procedures have been reported20,21 and are provided in the online-only Data Supplement.
Eight additional animals were chronically instrumented with sonomicrometers to derive left ventricular volume (Sonometrics, Washington, DC) and micromanometers (Konigsberg Instruments Inc, Pasadena, Calif) to measure left ventricular pressure and assigned to CRT or DHF groups. Left ventricular function was assessed in the conscious state at both 3 and 6 weeks to obtain paired invasive hemodynamic data.
Myocyte Function Studies
Myocyte sarcomere shortening and whole-cell calcium transients were assessed with an inverted microscope (Ellipse TE2001, Nikon, Tokyo, Japan) equipped with an image/fluorescence system (MyoCam, IonOptix, Milton, Mass). Details are provided in the online-only Data Supplement.
Protein and Gene Expression
Myocardium was homogenized in lysis buffer (Cell Signaling Technology, Danvers, Mass), and 50 to 100 µg was loaded for gel electrophoresis using standard methods.20 Gi-1/2/3, Gs, RGS2, RGS3, RGS4, GRK2 (Santa Cruz Biotechnology, Santa Cruz, Calif; each at 1:400), and GAPDH (IMGENEX, San Diego, Calif; 1:10000) were probed. Membrane fractions were obtained and probed for some assays, and gene expression was assessed by real-time polymerase chain reaction with the SYBR Green polymerase chain reaction master mix (Applied Biosystems, Foster City, Calif) and ABI PRISM7900 (online-only Data Supplement).
β-AR and Adenylyl Cyclase Activity
Adenylyl cyclase activity was determined by timed cAMP synthesis in 30 to 50 µg/100 µL membrane preparation aliquots with a commercial assay (Amersham, Uppsala, Sweden) to measure cAMP22 (online-only Data Supplement). All samples were assayed in duplicate.
Radioligand Binding Assay
β-AR radioligand binding studies were performed in myocardial membrane fractions with the nonselective β-AR antagonist [125I]-cyanopindolol as described23 (for details, see the online-only Data Supplement).
Myocardial Catecholamines
Myocardial catecholamines were measured in left ventricular myocardium, with samples weighed and homogenized in 4x volume of 0.4 mol/L perchloric acid containing 0.5 mmol/L EDTA and centrifuged at 5000 rpm at 4°C. Catecholamines were extracted from the supernatant with an alumina extraction procedure and quantified by liquid chromatography with electrochemical detection as described.24 Concentration was normalized to tissue weight.
Statistical Analysis
Comparisons of results from the 3 different experimental groups (no repeated measures) were performed by 1-way ANOVA with a Tukey multiple-comparison test. Cells derived from different regions in the same heart were treated as independent groups because heart identification per se was not significant in any analysis. Molecular/biochemical analyses contrasting region and group effects were assessed by 2-way ANOVA. Echocardiography data obtained in the same heart at 3 and 6 weeks were analyzed by repeated-measures ANOVA. Data are presented as mean±SEM.
The authors had full access to and take full responsibility for the integrity of the data. All authors have read and agree to the manuscript as written.
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Results |
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Chamber and Regional Mechanics in DHF Versus CRT Hearts
Example myocardial strain-time waveforms and pressure-strain loops from anteroseptal and lateral regions are shown in Figure 1A and 1B for control, DHF, and CRT hearts. In DHF, early septal shortening was accompanied by lateral stretch (vice versa in late systole), and pressure-strain loops showed marked heterogeneity of regional work (loop area). Synchrony was restored in CRT hearts (summary data in Figure 1C). Group results for echocardiography-derived ejection fraction and stroke volume are displayed in Figure 1D. Both groups were dyssynchronous at 3 weeks; thus, the decline in both variables was similar at that time (compared with 66% and 35-mL control values, respectively). At 6 weeks, however, CRT improved function, whereas function worsened in DHF (P<0.05 by unpaired t test; P<0.01 by 2-way repeated-measures ANOVA, paired changes). Invasive end-diastolic and end-systolic pressures were similarly altered at the end of the study, although contractile function assessed by dP/dtmax normalized to instantaneous developed pressure was improved by CRT (Figure 1E). CRT hearts also generated nearly twice the mean ventricular power compared with DHF (285 versus 146 W; P<0.03). Contractile improvement by CRT also was shown by paired analysis in chronically instrumented conscious dogs (Table I of the online-only Data Supplement).
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P<0.01 vs NL, P<0.05 vs DHF.
CRT Improves Basal and β-Adrenergic–Stimulated Myocyte Function
Figure 2A shows example myocyte sarcomere shortening and calcium transient tracings at rest and after isoproterenol stimulation. In DHF cells, rest and isoproterenol-stimulated shortening was markedly depressed compared with controls and associated with slow systolic and relengthening rates. This was mirrored by depressed peak Ca2+ transients and delayed upstroke and decay kinetics under both conditions. CRT myocytes had modestly improved rest function but a markedly improved response to isoproterenol. Summary data are provided in Figure 2B, with results from endocardium and epicardium combined because they were similar. Intriguingly, improved function and adrenergic reserve were observed in myocytes from both early activated anteroseptal and late-activated lateral walls, indicating a global effect from CRT. These data were further confirmed in studies performed at 27°C (0.5 Hz) (Figure I of the online-only Data Supplement). DHF-CRT disparities were not due to the surgical preparation because sham-DHF data were identical to those from the primary DHF group (ie, without surgically placed leads; online-only Data Supplement Figure II). Finally, we examined β-adrenergic responsiveness in the intact heart. Starting from similar baselines, dobutamine (10 µg · kg–1 · min–1) enhanced maximal and minimal dP/dt more in CRT than in DHF hearts (36.4±8.6% versus 10.0±5.6% and 26.1±2.3% versus 5.6±5.0%, respectively; both P<0.04).
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0.05 vs control and CRT;
CRT Enhances β-AR Number, Not Binding Affinity
Figure 2C displays radiolabeled β-AR binding assay data. Concentration-binding curves and corresponding Scatchard plots (top) revealed that maximal binding (receptor density, Bmax) was significantly depressed in DHF hearts but increased toward normal in CRT. No differences were found in binding affinity between groups (Kd; Figure 2C, bottom right).
CRT Improves β1 and β2-AR Responsiveness
Both β1 regulation and β2-AR regulation were depressed in DHF hearts and improved by CRT (Figure 3A). Reduced responsiveness in DHF was related partly to depression of gene expression for both receptor subtypes; however, β1 but not β2-AR expression rose with CRT, increasing the β1/β2 ratio (Figure 3B). This relative rise in β1 was confirmed by competitive binding assays (Figure 3C). Receptor subtype binding affinity was also examined; again, no differences were found between controls and either HF group (online-only Data Supplement Figure III). β-AR signaling (notably β1) can decline as a result of phosphorylation by G-receptor kinase 2 (GRK-2), and GRK-2 levels often rise in experimental and human cardiac failure.25 GRK-2 protein expression rose in DHF but remained elevated with CRT (Figure 3D); thus, it was unlikely to explain the differential β-AR responses.
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CRT Enhances Adenylate Cyclase Activity and Myocyte Response to Forskolin
We next tested whether dysregulation of adenylate cyclase may have contributed to the DHF phenotype and its improvement by CRT. Example myocyte shortening and Ca2+ transients are displayed in Figure 4A and summarized in Figure 4B. In DHF, sarcomere shortening stimulated by forskolin was greatly depressed in both regions. However, peak Ca2+ transients were essentially normalized in the anteroseptal wall despite reduced shortening, whereas in the lateral wall, they remained somewhat depressed. This suggests dysregulation at the myofilament level in DHF, particularly in the anterolateral wall. CRT improved forskolin-shortening responses in both regions, although they remained below controls, yet restored peak Ca2+ transients to control levels.
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P<0.001 vs control; 
P<0.02 vs DHF).These results indicated that CRT enhanced adenylate cyclase reserve activation. We further tested this finding in vitro by measuring cAMP generation resulting from isoproterenol or forskolin stimulation (Figure 4C). Adenylate cyclase activity was depressed in both regions in DHF hearts and significantly improved with CRT.
CRT Suppresses GI Signaling Enhanced in DHF
Another important mechanism for downregulated β-AR stimulation is inhibition by Gi stimulation, which can increase in human and experimental heart failure.26–28 To test for this, myocytes were pretreated with pertussis toxin (PTX) to suppress Gi, followed by isoproterenol stimulation. PTX had no impact on basal contraction in DHF or CRT myocytes (Figure 5A) but markedly enhanced the isoproterenol response in DHF cells, effectively restoring contraction to levels observed in CRT cells without PTX pretreatment. In contrast, PTX negligibly affected the isoproterenol response in CRT cells, suggesting that CRT itself had resulted in functional Gi inactivation.
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Gi protein expression (membrane fraction) was increased in DHF hearts but was, if anything, even slightly greater in CRT hearts (Figure 6A). Stimulatory G protein (Gs) was unchanged from control in both groups (data not shown). An alternative mechanism to suppress Gi signaling is enhancing negative regulators of G-protein signaling (RGS) proteins, GTPases, which restore the trimeric G-protein complex to suppress receptor-coupled activation. RGS2, RGS3, and RGS4 suppress Gi in the heart,29 and both RGS2 and RGS3 protein expression rose selectively in CRT but not DHF myocardium, the latter being similar to control (Figure 6B). These changes were observed in both regions and myocardial layers (Figure 6C). Increased RGS3 expression in CRT hearts was confirmed at the mRNA level (Figure 6D), and selective increases in RGS4 mRNA were observed. Thus, CRT specifically enhanced RGS proteins that can inhibit Gi signaling.
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CRT Reduces Myocardial Catecholamines
Improved rest and β-AR–stimulated function was accompanied by a concomitant withdrawal of myocardial catecholamine stimulation. In DHF hearts, myocardial catecholamine levels rose in both anteroseptal and lateral walls (somewhat more in the lateral walls; Figure 7), yet they declined toward control values with CRT. Thus, CRT restored adrenergic responsiveness while simultaneously reducing the cardiac catecholamine stimulation, analogous to the normal balance.
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Discussion |
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The direct effect of CRT as mediated by biventricular stimulation is to offset conduction delay so that both regions of the heart are stimulated and contract more synchronously. This immediately improves function because the heart no longer transfers blood from 1 side to the other but rather ejects it into the periphery.6 Here, we reveal that over time CRT potently benefits underlying myocyte function and calcium transients and prominently enhances their β-adrenergic responsiveness. In part, the latter is related to upregulation of β1-AR abundance, enhanced adenylate cyclase activation, and suppression of inhibitory G-protein activity likely linked to upregulation of RGS proteins such as RGS3. Such RGS changes have not been previously reported in heart failure therapy and may reflect a unique feature of CRT.
DHF myocytes displayed depressed rest function and peak and activation/decay kinetics in the Ca2+ transient, and CRT enhanced both. The detailed mechanisms of these resting changes were not explored in the present study; they are the focus of a companion investigation from our group.30 In the other study, we report marked depression of the Ca2+ current-voltage dependence in the lateral wall and reduced whole-cell Ca2+ transients in both regions (as shown here), both being ameliorated by CRT. DHF hearts also have reduced Cavβ2 gene expression (component of ICa) and SERCA2 gene and protein expression that are not observed in CRT, whereas expression of ryanodine receptor and phospholamban is lower and Na+-Ca2+ exchanger is higher in both models. These changes were not regional. Other factors for altered rest function and calcium handling may be the capacity of CRT to reduce cytokine (tumor necrosis factor-), p38 mitogen-activated protein kinase, and calcium-calmodulin kinase expression/activity, as we previously reported in this model.19 Deficits in both rest and isoproterenol (or forskolin) -stimulated cell shortening and Ca2+ were similar in both early- and late-activated regions in DHF, and both improved with CRT. This finding is intriguing because it highlights a global rather than purely regional impact of dyssynchrony and its amelioration by resynchronization. Such global changes are concordant with prior observations on cell survival signaling in the DHF and CRT models,19 although other modifications such as those in gap junction and stress kinases proteins have appeared more regional.19,20 DHF behavior could reflect an overall failure state made worse by abnormal regional loading. CRT modestly improved global function but largely resolved loading disparities. Because early- and late-contracting regions adversely load each other, this could affect signaling more generally throughout the heart. CRT also improves chamber efficiency,7 which in turn could alter neurostimulation, myocyte function, and reserve more globally.
The major focus of the present study was on β-AR responsiveness because depression of this signaling is a common feature of cardiac failure. In addition to the impact of impaired calcium homeostasis, impaired β-adrenergic responsiveness arises from multiple abnormalities, including reduced receptor abundance (expression, internalization, and/or degradation), receptor desensitization, increased Gi signaling, and reduced adenylate cyclase activity.15,16,31 Therapies such as angiotensin-converting enzyme inhibition32 and β-blockade33 and ventricular assist devices34 enhance β-AR signaling via several of these mechanisms. Although CRT did not target a specific neurohormone nor profoundly unload the left ventricle while restoring cardiac output (as occurs with assist devices), it markedly improved β-AR reserve. Some mechanisms associated with CRT such as the rise in β1 expression and improved adenylate cyclase activity share similarities to earlier therapies. However, others are novel such as reduced Gi signaling associated not with lowered expression per se but rather with increased levels of inhibitory RGS proteins.
Gi-coupled signaling can play several roles. One is depressing adrenergic stimulation,27,35 which is particularly true for the β2-AR,36 although Gi crosstalk between receptor subtypes has shown that it can blunt β1 stimulation of L-type Ca2+ currents.37 In this regard, DHF hearts displayed evidence of enhanced functional Gi coupling, whereas this was effectively removed by CRT, despite ameliorated but still persisting heart failure. Enhanced Gi stimulation can also be a cardioprotective effect against apoptosis.27,38,39 Yet long-term suppression of Gi by CRT does not appear to enhance cell death but does just the opposite, as previously shown in the current model19 and suggested in a human study.40 One key difference is likely the concomitant decline in catecholamine stimulation by CRT, reducing adrenergic-mediated toxicity. CRT acutely lowers sympathetic nerve stimulation17,18 in humans attributed to its increase in stroke volume, whereas long-term suppression is observed in CRT responders.18 Here, we show this downregulation at the myocardial level, restoring a more normal balance between catecholamine stimulation and myocyte adrenergic responsiveness.
CRT upregulated both RGS2 and RGS3 expression, which is intriguing given their role in blunting adrenergic responses by enhancing β2-AR–Gi modulation.31,41 To the best of our knowledge, this is the first example of RGS upregulation by a heart failure therapy and is further reflected by suppressed Gi-coupled signaling. Neither RGS species was enhanced in DHF hearts, similar to human heart failure data,42 whereas RGS4 protein increased in both, consistent with findings in human congestive heart failure.43 RGS3 and RGS4 regulate both Gi and Gq signaling,44,45 whereas RGS2 more specifically targets Gq,29,46 and its upregulation with CRT may blunt this signaling (eg, angiotensin, endothelin). RGS3 upregulation may have additional effects such as redirecting the activation of Rho GTPases via Gi-coupled receptors to switch from Rac1 to RhoA activation.47
Our study has some limitations. First, the model shortens the time course of CRT usually studied in humans, much as tachypacing itself abbreviates the time course of heart failure. However, as previously reported19 and examined here more fully, the DHF model mimics many pathophysiological features of the dyssynchronous failure, and improvements with CRT similarly share many characteristics seen in humans. Second, animals were not cotreated with angiotensin-converting enzyme inhibitors or adrenergic blockers (eg, carvedilol). Although such therapies can themselves enhance adrenergic reserve, the fact that CRT improves heart function and exercise capacity in patients already on such treatments and assists in the use of β-blockers in previously intolerant patients48 supports independent mechanisms. Our goal here was to identify changes related to CRT itself.
When CRT was first introduced, broad skepticism existed that such an intervention would prove beneficial given the complexity of underlying abnormal signaling in heart failure. Subsequent trials that revealed its utility raised suspicions that more may be transpiring beneath the surface. The present findings come nearly 7 years after CRT was first approved for human use in the United States and show that such suspicions were warranted. Enhancement of β-AR responsiveness and reduced cardiac catecholamine stimulation are likely important mechanisms whereby CRT improves systolic function and reserve and reduces long-term mortality.
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Acknowledgments |
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Sources of Funding
This work was supported by National Heart, Lung, and Blood Institute grants PO1-HL077180 (Drs Kass and Tomaselli) and RO1:HL-089297, the Peter Belfer Laboratory and Abraham and Virginia Weiss Professorship (Dr Kass), and the Intramural Research Program of the National Institutes of Health, National Institute on Aging (Dr Xiao).
Disclosures
Dr Kass has served as a consultant to or on the advisory board of Boston Scientific Consulting. The other authors report no conflicts.
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The online-only Data Supplement is available with this article at http://circ.ahajournals.org/cgi/content/full/CIRCULATIONAHA.108.774752/DC1.
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