doi: 10.1161/01.RES.0000102042.83024.CA
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© 2003 American Heart Association, Inc.
Reviews |
What Is the Role of ß-Adrenergic Signaling in Heart Failure?
From the Institute of Pharmacology (M.J.L., S.E.), Wuerzburg, Germany; Institute of Experimental and Clinical Pharmacology (T.E.), Universitaetsklinikum Hamburg-Eppendorf, Germany.
Correspondence to Martin Lohse, Institute of Pharmacology, Versbacher Straße 9, 97078 Wuerzburg, Germany. E-mail lohse{at}toxi.uni-wuerzburg.de
Steven Houser Guest Editor
This Review is part of a thematic series on Unanswered Questions in Heart Failure, which includes the following articles:
Is Depressed Myocyte Contractility Centrally Involved in Heart Failure?
What Is the Role of ß-Adrenergic Signaling in Heart Failure?
What Causes Sudden Death in Heart Failure?
Is Abnormal Cell Growth and Hypertrophy the Cause of Heart Failure?
Does Energy Starvation Cause Heart Failure?
What Mechanisms Underlie Diastolic Dysfunction in Heart Failure?
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Abstract |
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Top
Abstract
IntroductionThis review addresses open questions about the role of ß-adrenergic receptors in cardiac function and failure. Cardiomyocytes express all three ß-adrenergic receptor subtypes—ß1, ß2, and, at least in some species, ß3. The ß1 subtype is the most prominent one and is mainly responsible for positive chronotropic and inotropic effects of catecholamines. The ß2 subtype also increases cardiac function, but its ability to activate nonclassical signaling pathways suggests a function distinct from the ß1 subtype. In heart failure, the sympathetic system is activated, cardiac ß-receptor number and function are decreased, and downstream mechanisms are altered. However, in spite of a wealth of data, we still do not know whether and to what extent these alterations are adaptive/protective or detrimental, or both. Clinically, ß-adrenergic antagonists represent the most important advance in heart failure therapy, but it is still debated whether they act by blocking or by resensitizing the ß-adrenergic receptor system. Newer experimental therapeutic strategies aim at the receptor desensitization machinery and at downstream signaling steps.
Key Words: ß-adrenergic receptors • G proteins • transgenic mice • cardiac hypertrophy • apoptosis
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Introduction |
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The human heart expresses ß1- and ß2-adrenergic receptors at a ratio of about 70:30; both subtypes increase cardiac frequency and contractility.1,2 In addition, ß3-receptors have been described to mediate negative inotropic effects,3 but their role remains uncertain.4 All three subtypes appear to occur in cardiomyocytes, but they seem to possess distinct intracellular signaling and functional properties.5,6
Two well-established lines of evidence suggest that the ß-adrenergic receptor system plays a major role in heart failure. First, there is a pronounced activation of the sympathetic system in patients with heart failure that is inversely correlated with survival.7 Second, cardiac ß-receptors, in particular the ß1 subtype, are downregulated in heart failure,1,8 and the remaining receptors are uncoupled from Gs, presumably via increased activity of the receptor kinases GRK2 and/or GRK5.9–11 Furthermore, an increase in G
i subunits antagonizes ß-adrenergic signaling.12–14 Clinically, the use of ß-receptor antagonists in heart failure, pioneered in the 1970s,15 is now standard treatment.16–19
In spite of these major advances, many fundamental questions have remained unanswered. Why does the heart express three different ß-receptors and what are the differences between the subtypes? Are the alterations of the ß-receptors in heart failure detrimental or beneficial? Does the ß-receptor system contribute to the pathogenesis of heart failure? And why are ß-blockers effective in the treatment of heart failure? This review will attempt to elucidate open questions in understanding myocardial ß-adrenergic signaling with respect to its role in cardiac hypertrophy and failure.
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ß-Adrenergic Receptor Subtypes and Their Signaling |
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ß-Adrenergic Receptors in the Heart
The classical subdivision of ß-receptors defines the ß1 subtype as the one that stimulates cardiac muscle, and the ß2 subtype that relaxes smooth muscle.20 Both receptors couple to Gs and thereby elevate cAMP, but distinct downstream signaling decreases contractility in smooth muscle cells and increases it in cardiomyocytes. However, the ß1-receptor contributes to relaxation of blood vessels21 and the ß2-receptor to cardiac contractility.2 Even though the predominant cardiac ß1 subtype (
70% to 80% depending on species) is the strongest stimulus for cardiac function, the expression levels are quite small: no more than 50 to 70 fmol/mg membrane protein in most species. Therefore, there is little receptor reserve. Expression of the ß3 subtype is essentially limited to adipose tissue,22 but several groups have reported ß3-receptor effects and mRNA in human, guinea pig, and canine heart and cardiomyocytes.3,23,24 However, in contrast to its Gs-mediated signaling in adipose tissue, these reports suggest coupling to a nonclassical Gi/nitric oxide pathway mediating negative inotropic effects. In mice, cardiac-specific overexpression of ß3-receptors enhanced cardiac contractility,25 and experiments with ß1/ß2 knockout mice provided no or very modest ß3-receptor effects.4,26,27 Thus, the importance of this subtype remains to be defined.
A fourth receptor subtype, ß4, had been postulated to mediate cardiostimulatory effects of the antagonist CGP12177. However, studies with ß1- and ß2-receptor knockout mice have led to the conclusion that the ß4 effects are mediated by the ß1-receptor.28,29
ß-Receptors occur also on nonmyocyte cells in the heart, and these cells can—eg, by paracrine effects—affect cardiomyocyte function and fate. The communication between these cells will constitute a major research topic.
ß-Adrenergic Receptor Signaling
Why should the heart express several different subtypes of ß-adrenergic receptors? Evidence has been accumulating that subtype differences are important for cardiac function and failure.
First, the three receptor subtypes have different affinities for their ligands (Figure 1). Second, there is increasing evidence for specific subcellular localizations and distinct signaling pathways. The basic hypothesis is that spatial segregation of receptors allows their association with other—equally segregated—proteins to form "signalosomes" that mediate subtype-specific responses.
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Signaling by cardiac ß-receptors has been studied in great detail (Figures 1 and 2
). The classical common pathway is activation of adenylyl cyclases via Gs, resulting in increased cAMP levels. The primary target for cAMP is protein kinase A (PKA). PKA phosphorylates several proteins that are essential for cardiac function: L-type calcium channels,30,31 phospholamban,32 troponin I,33 ryanodine receptors,34 myosin binding protein-C (MyBP-C),35 and protein phosphatase inhibitor-1.36 This affects cardiomyocyte contractile behavior by increasing Ca2+ influx (L-type channel), increasing Ca2+ reuptake into the sarcoplasmic reticulum (phospholamban/SERCA), and modulating myofilament Ca2+ sensitivity (troponin I, MyBP-C). Another target of cAMP are cAMP-gated HCN pacemaker channels.37
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Most studies agree that in cardiomyocytes the cAMP pathway is stimulated through ß1- as well as ß2-receptors. However, even though the ß2 subtype causes greater adenylyl cyclase stimulation than the ß1 subtype in transfected cells38,39 and in cardiomyocytes,40,41 the ß1 subtype confers greater functional effects in cardiomyocytes.2 One explanation for this difference is that cAMP generated by ß2-receptor stimulation is not equivalent to cAMP-generated via ß1-receptors. Another explanation is the existence of additional signaling pathways that modify the Gs/adenylyl cyclase/PKA pathway.
Such additional nonclassical signaling is particularly important for the ß2 (and perhaps the ß3) subtype, but less for the ß1-receptor. Many coupling proteins have been identified for the three ß-receptor subtypes,42 but only a few of them have been demonstrated in the heart (Figure 1). Nonclassical signaling for the ß1-adrenergic receptor—studied less—may include a calcium signal not inhibitable by inactive cAMP analogues.43 It will be a major task to elucidate the physiological role(s) of these nonclassical signaling pathways.
Compartmentation of ß-Adrenergic Signaling
Receptor-generated signals are usually measured as global changes in second messenger concentrations, which are implicitly assumed to change in a uniform manner. This simplistic view would mean that intracellular signaling uses neither spatial nor temporal information. However, evidence is accumulating that this is not the case, and that compartmentation of intracellular signaling may be more than an excuse for results that are difficult to interpret.
Studies on intact hearts and isolated cardiomyocytes helped to establish this concept.44,45 Work in the 1970s suggested that PKA activation by prostaglandin E and isoprenaline exerted differential effects on glycogen phosphorylase phosphorylation in rat heart.46 Similarly, cAMP accumulation via the glucagon-like peptide receptor was recently found to be completely uncoupled from inotropic effects in cardiomyocytes.47 Different "efficacies" of cAMP generated via ß-receptor activation or via direct adenylyl cyclase stimulation with forskolin further suggested spatial compartmentation of cAMP in cardiomyocytes.48 Recent electrophysiological studies showed that localized stimulation of ß-receptors on frog cardiomyocytes activated L-type Ca2+ channels in the vicinity of the receptors, whereas forskolin activated also distant Ca2+ channels.49 Inhibition of isoprenaline effects by acetylcholine50 and NO were also locally restricted.51 Imaging of cAMP in neonatal cardiomyocytes showed that the noradrenaline-induced cAMP signal diffused only 1 µm, but phosphodiesterase inhibition led to generalized cAMP elevation.52 Thus, cAMP degradation by phosphodiesterases may spatially limit cAMP signals.
Several pieces of evidence point toward differences in compartmentation between ß1- and ß2-receptors.5,6 First, ß2-receptors can couple, in addition to Gs, also to Gi, whereas ß1-receptors couple only to Gs.53 Gi coupling is enhanced by PKA-mediated ß2-receptor phosphorylation. Second, the PKA phosphorylation pattern induced by ß1- and ß2-receptor stimulation seems different, at least in some species. Two groups found only ß1-induced troponin I phosphorylation in rats,54,55 whereas others described phosphorylation via both subtypes in human heart.56 Phospholamban phosphorylation has been reported after ß1- but not ß2-receptor activation in canine and human cardiomyocytes,54,57 while in other studies, particularly in human heart, both subtypes caused phosphorylation.55,56 ß1-Receptor stimulation increased PKA activity in the particulate fraction of cardiomyocytes, whereas after ß2-receptor stimulation this increase was limited to the soluble fraction.55 In adult rat cardiomyocytes, the complete absence of a cAMP signal after ß2-receptor stimulation has been reported.58
Which mechanisms permit spatial compartmentation of cardiomyocyte ß-adrenergic signaling? First, receptors might have different cell surface localizations. In one study, the ß2 subtype was copurified with cardiomyocyte caveolae, while the ß1 subtype was more evenly distributed.59 In another study, the ß1 subtype was preferentially localized in caveolae on rat neonatal cardiomyocytes, and this was taken as a reason for efficient adenylyl cyclase coupling.40 Second, the receptors are probably embedded into large signalosomes, which might differ between the ß1 and the ß2 subtype. ß2-Receptor signalosomes containing an entire signaling chain have recently been demonstrated in neurons.60 And third, postreceptor signaling may also be spatially organized.61 cAMP signals might be spatially regulated via their site of generation (receptor localization) and via localized destruction (phosphodiesterases). Several experiments show loss of spatial localization after phosphodiesterase inhibition.48,52,62 ß2 Receptors can actively recruit phosphodiesterase 4 to the plasma membrane.63 Downstream signaling proteins also have specific localizations. In particular, PKA is spatially localized via binding to A-kinase anchoring proteins64 and the same applies for protein phosphatases65 and possibly their inhibitors.
In addition to spatial compartmentation, ß-receptor coupling is also temporally regulated. First, ß-receptors desensitize. This is most prominent for the ß2 subtype and small for the ß3 subtype.66,67 Desensitization occurs via receptor phosphorylation either by PKA or by G protein–coupled receptor kinases, GRKs,68,69 plus ß-arrestins.70 Both mechanisms uncouple receptors from G proteins.71 In addition, the receptor/ß-arrestin complex recruits several proteins that initiate nonclassical signaling pathways. Since the GRK/ß-arrestin mechanism is most prominent for the ß2 subtype, this explains why nonclassical signaling pathways are most prominent for this subtype. Furthermore, PKA-induced phosphorylation of ß2-receptors promotes switching from Gs to Gi.27,72 And finally, prolonged stimulation results in receptor downregulation, ie, a reduction in receptor number.73 In summary, ß-receptor signaling is a multifaceted process, and our current understanding seems still incomplete.
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Alterations of the ß-Adrenergic System in Heart Failure |
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Numerous studies show alterations of the cardiac ß-receptor system in failing hearts.1,2,74–76 They include a reduction of the ß1 subtype and its mRNA by up to
50%, correlated to disease severity,75,76 while the ß2-receptor levels remained unchanged in most studies. It is still not clear why downregulation in heart failure is specific for the ß1 subtype. The remaining ß-receptors are desensitized, presumably mostly via GRKs (see below). In addition, up to 2-fold increases of Gi—particularly Gi2—and its mRNA occur early in heart failure12–14,77 and may cause reduced responsiveness of many Gs-coupled receptor systems.78–81 In addition, canine heart failure models show downregulation of Gs82 and of adenylyl cyclases V and VI,83 which are rate-limiting in the ß-receptor system.84 Heart failure–induced elevated catecholamine levels most likely cause all these alterations that functionally limit the contractile reserve. Even though these changes have been confirmed repeatedly, their interpretation is uncertain. They can be interpreted either as a beneficial mechanism that protects the heart from the detrimental effects of chronic ß-receptor stimulation, including arrhythmias, energy dysbalance, hypertrophy, and apoptosis—even though they deprive the heart from the benefits of short-term ß-adrenergic responsiveness. Alternatively, they may lead to further deterioration of heart failure, since they disable the heart to meet its demands. Depending on these interpretations, therapeutic strategies might attempt either to inhibit the ß-receptor system even further or to restore its sensitivity. Both apparently contrasting strategies are currently being pursued.
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Role of GRKs in Heart Failure |
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Increased GRK activity appears to be a major factor contributing to ß-receptor desensitization in failing hearts.85,86 Numerous studies have demonstrated upregulation of GRK activity and GRK2 mRNA in patients and animal models of heart failure and hypertrophy.11,87,88 This has led to the hypothesis that cardiac function might be restored by inhibiting GRKs.86 No GRK inhibitors have so far been described that would allow a testing of this hypothesis, but several studies with the C-terminus of GRK2 ("ßARKct") appear to support it. This 184 amino acid C-terminus inhibits GRK-mediated receptor phosphorylation,89 and its overexpression has led to reduction of heart failure in several heart failure models.86,90,91
However, again the alternative hypothesis is that increased GRK activity is part of a protective adaptation. This hypothesis would be compatible with the long-term damage caused by chronic stimulation or transgenic ß1-receptor overexpression,92,93 and with the beneficial effects of ß-blockers in heart failure patients.16 In this case, the beneficial effects of ßARKct might be mediated by mechanisms distinct from GRK2 inhibition.
In fact, ßARKct impairs many Gß
pathways, and several lines of evidence suggest that Gß inhibition ("scavenging") is important for its effects. First, the detrimental ß-receptor–mediated effects appear to be due more to the cAMP than to nonclassical signaling since (1) transgenic overexpression of the ß1 subtype is more detrimental than that of the ß2 subtype93,94 even though the ß1 subtype activates essentially only the cAMP pathway and does not internalize well,6,95 and (2) the detrimental effects of ß1-receptor overexpression are very similar to those of overexpression of Gs or PKA.96–98 Second, GRK2 transgenic mice show no overt cardiac pathology,99 arguing against a detrimental role of GRK activity per se. Third, in a transgenic mouse model of heart failure, ß-blockers conferred a benefit in addition to ßARKct, suggesting an unrelated mechanism of action for the two principles.91 And fourth, the protective effects of ßARKct on heart failure progression have been reproduced with N-terminally truncated phosducin,100 a supposedly "pure" Gß-binding protein101 that did not restore the cAMP signal.
Thus, ß-receptor blockade and ßARKct might be regarded as independent and complementary therapeutic principles in heart failure. The usefulness and the mechanisms of ßARKct and of "pure" GRK inhibitors will be questions for future investigations.
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Cardiac ß-Adrenergic Receptor Transgenic Mice |
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Transgenic cardiac overexpression of ß2-receptors in mice at 20 to 30 pmol/mg protein led to marked enhancement of basal contractility94 but caused no overt cardiac pathology.102 Adenovirus-mediated ß2-receptor overexpression enhanced myocardial contractility in a rabbit heart failure model.103 However, later studies showed that 50-fold overexpression of ß2-receptors was well tolerated, whereas 350-fold overexpression induced cardiac pathology.104 High-density ß2-receptor overexpression rescued left ventricular contractility after myocardial infarction105 but worsened cardiac function after aortic banding106 and negatively affected several genetic heart failure models,86 including G
q overexpression.107 Lower levels (30-fold overexpression) had beneficial effects in the same model,107 suggesting an expression optimum for enhancing cardiac function via ß2-receptors.
Cardiac overexpression of ß1-receptors in transgenic mice caused cardiomyocyte hypertrophy, followed by fibrosis and heart failure.93,108 Calcium transients were prolonged, and expression of the sarcoplasmic reticulum (SR) protein junction was reduced.109 Interestingly, ß1-receptor transgenic mice develop marked cardiomyocyte hypertrophy without a major increase in heart weight,93 indicating a dramatic loss of ventricular cardiomyocytes, perhaps via apoptosis.108 ß1 as well as 1 agonists have long been known to cause hypertrophy.110 These data indicate that the ß1-receptor system is ideally suited for short-term increases in cardiac function but causes marked damage after prolonged activation.
The differences reported between ß1-versus ß2-receptor overexpression are remarkable. Since both subtypes activate cAMP signaling, they must be due to nonclassical, receptor-specific pathways such as ß2-receptor coupling to Gi and mitogen-activated protein (MAP) kinases.72,111,112 In addition, compartmentation of cAMP signals might cause differences between ß1 and ß2-receptor–generated cAMP.98 The potential clinical implications of these differences are obvious. For example, ß1-selective antagonists might be superior to nonselective blockers in heart failure, because they would leave the ß2-receptor operational. And increasing ß2-receptors to an optimum level might also be beneficial.103
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Which Mechanisms Mediate Detrimental ß1-Receptor Effects? |
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Candidate Downstream Targets
The potentially ß1-selective damage must be mediated via ß1-initiated signals. Since the major ß1 signal in cardiomyocytes is the cAMP/PKA pathway, the prime suspects are the targets of PKA-mediated phosphorylation. Identifying the relevant targets is difficult since our knowledge is mostly derived from acute ß-receptor stimulation, while in heart failure ß-adrenergic activation lasts for years. Adaptive changes and transcriptional/translational alterations may dominate long-term responses. A striking example of opposite effects of short-versus long-term ß-adrenergic stimulation is the sodium proton exchanger NHE1.
Phospholamban
The most prominent cardiac target of PKA is phospholamban (PLB), a 52 amino acid phosphoprotein that controls SR Ca2+ uptake by inhibiting SERCA.32 PKA-mediated phosphorylation of PLB relieves this inhibition. Experiments with PLB knockout mice indicate that PLB mediates the positive lusitropic and part of the positive inotropic ß-receptor effects.113,114 Even though phospholamban is a major PKA target in cardiomyocytes, it is probably not responsible for the detrimental ß1-receptor effects. First, PLB knockout rescued several (but not all115,116) heart failure models including ß1-receptor transgenic mice,117 suggesting that phospholamban inhibition by PKA is not detrimental. Second, gene therapy approaches inhibiting phospholamban118,119 or augmenting SERCA120,121 ameliorated several heart failure models. However, there may be important differences between mice and humans, since two inactivating mutations of phospholamban have recently been reported to cause heart failure in patients.122,123 At present, it is unclear how these findings can be integrated.
Other Calcium Regulatory Proteins
Ryanodine receptor (RyR) hyperphosphorylation by PKA leading to increased open probability has been implicated in the pathogenesis of heart failure.34 Others have disputed this observation124 or attributed the PKA-induced increase in SR Ca2+ release to an indirect mechanism involving phospholamban.125 Thus, the role of RyR phosphorylation in heart failure awaits clarification.126
PKA-mediated phosphorylation opens L-type Ca2+ channels triggering SR Ca2+ release through the RyR.114 Basal L-type currents are maintained127 in heart failure, but single-channel recordings show an increased open probability.128 Further PKA targets are MyBP-C and troponin I, which may disinhibit myosin actin interaction35 and reduce Ca2+ sensitivity of myofilaments,129 respectively. It is not clear whether these effects contribute to heart failure.
A functional imbalance between pathways in or decreasing diastolic Ca2+ might lead to elevated cytosolic Ca2+ levels as a common final pathway in failing cardiomyocytes.130 The downstream mechanisms exerting possible detrimental Ca2+ effects and the roles of Ca2+-dependent proteins such as calcineurin and CaM kinase remain to be elucidated.131
Protein Phosphatases and Protein Phosphatase Inhibitor-1
Recent evidence indicates a regulatory role for phosphatases in cardiomyocytes.132 Phosphatase 2A occurs in ß2-receptor signalosomes in neurons60 and colocalizes with the RyR.34 Heart failure is accompanied by increased global protein phosphatase (PP) activity.132 The protein phosphatase inhibitor-1, PPI-1, inhibits PP1 only in its PKA-phosphorylated form and seems to amplify ß-adrenergic signaling in cardiomyocytes.133,134 PPI-1 mRNA, protein, and phosphorylation are reduced by 2- to 5-fold in failing human hearts,134,135 leading to reduced PP1 inhibition.132 Expression of constitutively active PPI-1 rescued the function of failing cardiomyocytes.133 In order to delineate a role of PPI-1 in heart failure, the proteins regulated by PPI-1–sensitive dephosphorylation need to be identified.
Sodium Proton Exchanger NHE1
A remarkable example of how fundamentally short- and long-term effects can differ is the involvement of the cardiac sodium proton exchanger NHE1 in the detrimental effects of chronic ß-receptor stimulation. Acute ß-receptor stimulation may inhibit NHE1.136 However, in ß1-receptor transgenic mice NHE1 is upregulated, and pharmacological NHE1 inhibition prevented the development of hypertrophy, fibrosis, and heart failure.137 The mechanisms of the protective effects of NHE1 inhibition, the roles of intracellular sodium and calcium, and NHE1 regulation remain to be investigated.137,138
Apoptosis
ß-Receptor stimulation causes apoptosis of isolated rat cardiomyocytes. Different approaches demonstrate proapoptotic effects of ß1 and antiapoptotic effects of ß2-receptors.139–141 These in vitro studies are paralleled by findings in transgenic mice where ß1-receptor and Gs overexpression markedly increased cardiomyocyte apoptosis.108,142 However, the studies differ as to the responsible intracellular signaling pathways. ß2-Receptor–mediated stimulation of p38 MAP kinase111 and activation of Akt kinase via Gi141 have been proposed as antiapoptotic mediators. The proapoptotic effect of ß1-receptors has been found to be dependent on reactive oxygen species,143 while others imply PKA-independent activation of CaMK.43 Thus, the mechanistic links for the opposing effects of ß1-versus ß2-receptor stimulation on cardiomyocyte apoptosis remain uncertain. Nor is it clear how much ß1-receptor–mediated apoptosis contributes to heart failure.144
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Impact on Clinical Medicine |
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ß-Adrenergic Receptor Polymorphisms
Genes for all three ß-receptor subtypes contain single nucleotide polymorphisms. Eighteen ß1-receptor variants145 and 13 ß2-receptor variants have been described,146 but only two ß1 and three ß2 variant genes are common and have been extensively studied with respect to cardiovascular function (Table). Two attractive hypotheses arise from these studies.
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First, the ß1-receptor Gly389 variant (allele frequency 25% in whites, 42% in blacks) shows reduced cAMP signals147 and may represent an impaired variant of the potentially harmful ß1-receptor. Clinical studies have given mixed results (Table), suggesting that the more active Arg389 variant may be detrimental in some contexts. For example, the risk for heart failure in blacks was increased for the Arg389 variant only when combined with the 2C-receptor deletion polymorphism (allele frequency 4% in whites, 38% in blacks),148 which is a risk factor by itself.149 Large cohort studies investigating more complete sets of such polymorphisms including complete haplotypes will be needed for an answer.
Second, the ß2-receptor Ile164 variant is a rare variant of the potentially protective ß2-receptor displaying reduced agonist-binding and activity when expressed in fibroblasts38 or transgenic mice.150 Healthy volunteers or patients heterozygous for the Ile164 variant exhibited lower chronotropic and inotropic response to the ß2 agonist terbutaline, reduced exercise capacity, and decreased survival in heart failure (Table). These findings support the hypothesis that an impaired ß2-receptor represents a risk factor for cardiovascular disease and particularly heart failure.
The Gly16 and the Gln27 variants of the ß2-receptor may exhibit altered agonist-induced downregulation and have been associated with decreased exercise capacity. These data are inconsistent and have been discussed elsewhere.151
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ß-Blockade in Heart Failure |
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Since the pioneering work in the 1970s,152 it took two decades until ß-blockers turned from contraindication to standard treatment in heart failure.16 Blocking ß-receptors when cardiac function depends on sympathoadrenergic drive long appeared counterintuitive. Today, three large studies with bisoprolol, metoprolol, and carvedilol show a similar reduction in the risk of death by a third or more, a benefit greater than of any other drug used in heart failure.16
Why Do ß-Blockers Work in Heart Failure?
How can long-term application of negative inotropic compounds increase cardiac index, exercise capacity, and survival? Two basic mechanisms might explain this paradox: a block of the detrimental consequences of sustained ß1-receptor stimulation or resensitization of the cardiac ß-receptor system. We are not aware of studies that would permit a definitive decision, but several arguments support the role of blocking detrimental ß1 effects.
First, ß-blockers showed benefits in all patient subgroups, including those with high and low heart rate, blood pressure, and ejection fraction.18 Thus, the benefit is not restricted to patients with high heart rate. Second, ß-blockers exert antiarrhythmic effects, which may explain why they caused larger reductions in sudden deaths than in total mortality. Antiarrhythmic effects are particularly important since altered calcium handling makes failing hearts very susceptible to arrhythmias. Third, ß-blockers might prevent the hypertrophic, proapoptotic, and pronecrotic effects of cardiomyocyte ß1-receptor stimulation. Fourth, ß-blockers might improve the energy balance in failing hearts, which show energy starvation153 and high-energy phosphate depletion,154 since they reduce heart rate and improve diastolic filling and blood flow. ß-Blockers apparently induce a partial switch from fatty acid to glucose metabolism by inhibiting carnitine palmitoyl transferase.7 And finally, ß-blockers reverse failure-specific alterations in cardiac gene expression, which may be involved in progression of the disease.155–158
The resensitization hypothesis is supported by the fact ß-blockers upregulate ß-receptor levels and normalize elevated GRK and Gi levels.155–159 While these receptors are partially available even in the continued presence of ß-blockers,160 it is doubtful whether their increase is functionally relevant.161,162 However, resensitization of downstream elements does result in enhanced responses to phosphodiesterase inhibitors.161
Differences Between ß-Blockers
Bisoprolol, carvedilol, and metoprolol have been shown to be beneficial in heart failure, and others may follow. Metoprolol and bisoprolol are ß1-selective and have modest inverse activity (ie, they decrease the spontaneous activity of the receptor in the absence of agonist),163 whereas carvedilol is nonselective, shows no inverse activity,163 dissociates slowly from the receptor,164 and is a radical scavenger and 1-receptor antagonist. All three compounds led to similar clinical results, but carvedilol was superior to metoprolol in the recent COMET trial.165 Methodological criticism aside, this trial does not answer the questions of possibly protective ß2-receptors and whether the additional properties of carvedilol are important. A role for intrinsic activity is supported by the observations that the strong partial agonist xamoterol163 was detrimental in heart failure,19 and the weak partial agonist bucindolol166 was ineffective in the BEST trial.167 The beneficial ß-blockers are neutral (carvedilol) or inverse agonistic (bisoprolol, metoprolol).163 However, because of the low constitutive activity of the ß1-receptor, it is uncertain how important inverse agonism is. Taken together, the question is still open which pharmacological properties of ß-blockers make them effective in heart failure.
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Conclusions |
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Overwhelming evidence supports a major role for the ß-adrenergic system in heart failure. While this system is ideally suited for short-term increases in cardiac performance, its long-term activation is apparently detrimental. These damaging effects appear to be mainly due to stimulation of the ß1 subtype, but the responsible signaling pathways need to be identified. Relevant beneficial effects of the ß2 subtype remain to be confirmed, again together with the elucidation of the responsible—presumably nonclassical—signaling pathways. And the role of the ß3-receptor in the heart is still unclear.
The many changes in the ß-adrenergic system in heart failure are most likely a protective adaptation. ß-Blockers presumably act by (further) inhibiting the detrimental effects of ß1-receptor stimulation, but perhaps also by resensitizing downstream signaling elements. Future questions include the role of resensitization, the essential properties of clinically effective ß-blockers, and the importance of the many downstream signaling steps in finding new strategies for the treatment of heart failure.
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Footnotes |
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Original received May 21, 2003; revision received October 3, 2003; accepted October 8, 2003.
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D. Rottlaender, J. Matthes, S. F. Vatner, R. Seifert, and S. Herzig Functional Adenylyl Cyclase Inhibition in Murine Cardiomyocytes by 2'(3')-O-(N-Methylanthraniloyl)-Guanosine 5'-[{gamma}-Thio]triphosphate J. Pharmacol. Exp. Ther., May 1, 2007; 321(2): 608 - 615. [Abstract] [Full Text] [PDF]
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H.-J. Hippe, M. Luedde, S. Lutz, H. Koehler, T. Eschenhagen, N. Frey, H. A. Katus, T. Wieland, and F. Niroomand Regulation of Cardiac cAMP Synthesis and Contractility by Nucleoside Diphosphate Kinase B/G Protein {beta}{gamma} Dimer Complexes Circ. Res., April 27, 2007; 100(8): 1191 - 1199. [Abstract] [Full Text] [PDF]
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C. Yan, C. L. Miller, and J.-i. Abe Regulation of Phosphodiesterase 3 and Inducible cAMP Early Repressor in the Heart Circ. Res., March 2, 2007; 100(4): 489 - 501. [Abstract] [Full Text] [PDF]
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C. Yan, B. Ding, T. Shishido, C.-H. Woo, S. Itoh, K.-I. Jeon, W. Liu, H. Xu, C. McClain, C. A. Molina, et al. Activation of Extracellular Signal-Regulated Kinase 5 Reduces Cardiac Apoptosis and Dysfunction via Inhibition of a Phosphodiesterase 3A/Inducible cAMP Early Repressor Feedback Loop Circ. Res., March 2, 2007; 100(4): 510 - 519. [Abstract] [Full Text] [PDF]
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L. A. Gardner, A. P. Naren, and S. W. Bahouth Assembly of an SAP97-AKAP79-cAMP-dependent Protein Kinase Scaffold at the Type 1 PSD-95/DLG/ZO1 Motif of the Human beta1-Adrenergic Receptor Generates a Receptosome Involved in Receptor Recycling and Networking J. Biol. Chem., February 16, 2007; 282(7): 5085 - 5099. [Abstract] [Full Text] [PDF]
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L. M. DiPilato and J. Zhang FRETting Mice Shed Light on Cardiac Adrenergic Signaling Circ. Res., November 10, 2006; 99(10): 1021 - 1023. [Full Text] [PDF]
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L. A. Gardner, S. J. Tavalin, A. S. Goehring, J. D. Scott, and S. W. Bahouth AKAP79-mediated Targeting of the Cyclic AMP-dependent Protein Kinase to the beta1-Adrenergic Receptor Promotes Recycling and Functional Resensitization of the Receptor J. Biol. Chem., November 3, 2006; 281(44): 33537 - 33553. [Abstract] [Full Text] [PDF]
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R. Fischmeister, L. R.V. Castro, A. Abi-Gerges, F. Rochais, J. Jurevicius, J. Leroy, and G. Vandecasteele Compartmentation of Cyclic Nucleotide Signaling in the Heart: The Role of Cyclic Nucleotide Phosphodiesterases Circ. Res., October 13, 2006; 99(8): 816 - 828. [Abstract] [Full Text] [PDF]
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J. Kim, A. Ogai, S. Nakatani, K. Hashimura, H. Kanzaki, K. Komamura, M. Asakura, H. Asanuma, S. Kitamura, H. Tomoike, et al. Impact of Blockade of Histamine H2 Receptors on Chronic Heart Failure Revealed by Retrospective and Prospective Randomized Studies J. Am. Coll. Cardiol., October 3, 2006; 48(7): 1378 - 1384. [Abstract] [Full Text] [PDF]
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G. H. Hankes, J. L. Ardell, J. Tallaj, C.-C. Wei, I. Aban, M. Holland, P. Rynders, R. Dillon, R. Cardinal, D. B. Hoover, et al. beta1-Adrenoceptor blockade mitigates excessive norepinephrine release into cardiac interstitium in mitral regurgitation in dog Am J Physiol Heart Circ Physiol, July 1, 2006; 291(1): H147 - H151. [Abstract] [Full Text] [PDF]
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B. Boivin, C. Lavoie, G. Vaniotis, A. Baragli, L.-R. Villeneuve, N. Ethier, P. Trieu, B. G. Allen, and T. E. Hebert Functional {beta}-adrenergic receptor signalling on nuclear membranes in adult rat and mouse ventricular cardiomyocytes Cardiovasc Res, July 1, 2006; 71(1): 69 - 78. [Abstract] [Full Text] [PDF]
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F. Rochais, A. Abi-Gerges, K. Horner, F. Lefebvre, D. M.F. Cooper, M. Conti, R. Fischmeister, and G. Vandecasteele A Specific Pattern of Phosphodiesterases Controls the cAMP Signals Generated by Different Gs-Coupled Receptors in Adult Rat Ventricular Myocytes Circ. Res., April 28, 2006; 98(8): 1081 - 1088. [Abstract] [Full Text] [PDF]
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Z.-S. Zhang, H.-J. Cheng, K. Onishi, N. Ohte, T. Wannenburg, and C.-P. Cheng Enhanced Inhibition of L-type Ca2+ Current by {beta}3-Adrenergic Stimulation in Failing Rat Heart J. Pharmacol. Exp. Ther., December 1, 2005; 315(3): 1203 - 1211. [Abstract] [Full Text] [PDF]
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B. Ding, J.-i. Abe, H. Wei, H. Xu, W. Che, T. Aizawa, W. Liu, C. A. Molina, J. Sadoshima, B. C. Blaxall, et al. A positive feedback loop of phosphodiesterase 3 (PDE3) and inducible cAMP early repressor (ICER) leads to cardiomyocyte apoptosis PNAS, October 11, 2005; 102(41): 14771 - 14776. [Abstract] [Full Text] [PDF]
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J.-F. Wang, A. Meissner, S. Malek, Y. Chen, Q. Ke, J. Zhang, V. Chu, T. G. Hampton, C. S. Crumpacker, W. H. Abelmann, et al. Propranolol ameliorates and epinephrine exacerbates progression of acute and chronic viral myocarditis Am J Physiol Heart Circ Physiol, October 1, 2005; 289(4): H1577 - H1583. [Abstract] [Full Text] [PDF]
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J.-Q. He, R. C. Balijepalli, R. A. Haworth, and T. J. Kamp Crosstalk of {beta}-Adrenergic Receptor Subtypes Through Gi Blunts {beta}-Adrenergic Stimulation of L-Type Ca2+ Channels in Canine Heart Failure Circ. Res., September 16, 2005; 97(6): 566 - 573. [Abstract] [Full Text] [PDF]
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C. Perrino, S. V. Naga Prasad, M. Patel, M. J. Wolf, and H. A. Rockman Targeted Inhibition of {beta}-Adrenergic Receptor Kinase-1-Associated Phosphoinositide-3 Kinase Activity Preserves {beta}-Adrenergic Receptor Signaling and Prolongs Survival in Heart Failure Induced by Calsequestrin Overexpression J. Am. Coll. Cardiol., June 7, 2005; 45(11): 1862 - 1870. [Abstract] [Full Text] [PDF]
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E. I. Dedkov, L. P. Christensen, R. M. Weiss, and R. J. Tomanek Reduction of heart rate by chronic {beta}1-adrenoceptor blockade promotes growth of arterioles and preserves coronary perfusion reserve in postinfarcted heart Am J Physiol Heart Circ Physiol, June 1, 2005; 288(6): H2684 - H2693. [Abstract] [Full Text] [PDF]
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C. Perrino, S. V. Naga Prasad, J. N. Schroder, J. A. Hata, C. Milano, and H. A. Rockman Restoration of {beta}-Adrenergic Receptor Signaling and Contractile Function in Heart Failure by Disruption of the {beta}ARK1/Phosphoinositide 3-Kinase Complex Circulation, May 24, 2005; 111(20): 2579 - 2587. [Abstract] [Full Text] [PDF]
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H. Tachibana, H.-J. Cheng, T. Ukai, A. Igawa, Z.-S. Zhang, W. C. Little, and C.-P. Cheng Levosimendan improves LV systolic and diastolic performance at rest and during exercise after heart failure Am J Physiol Heart Circ Physiol, February 1, 2005; 288(2): H914 - H922. [Abstract] [Full Text] [PDF]
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Y. Xiang, F. Naro, M. Zoudilova, S.-L. C. Jin, M. Conti, and B. Kobilka Phosphodiesterase 4D is required for {beta}2 adrenoceptor subtype-specific signaling in cardiac myocytes PNAS, January 18, 2005; 102(3): 909 - 914. [Abstract] [Full Text] [PDF]
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G.-X. Zhang, S. Kimura, A. Nishiyama, T. Shokoji, M. Rahman, L. Yao, Y. Nagai, Y. Fujisawa, A. Miyatake, and Y. Abe Cardiac oxidative stress in acute and chronic isoproterenol-infused rats Cardiovasc Res, January 1, 2005; 65(1): 230 - 238. [Abstract] [Full Text] [PDF]
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D. S. O'Leary, J. A. Sala-Mercado, R. A. Augustyniak, R. L. Hammond, N. F. Rossi, and E. J. Ansorge Impaired muscle metaboreflex-induced increases in ventricular function in heart failure Am J Physiol Heart Circ Physiol, December 1, 2004; 287(6): H2612 - H2618. [Abstract] [Full Text] [PDF]
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J. He, M. Bellini, J. Xu, A. M. Castleberry, and R. A. Hall Interaction with Cystic Fibrosis Transmembrane Conductance Regulator-associated Ligand (CAL) Inhibits {beta}1-Adrenergic Receptor Surface Expression J. Biol. Chem., November 26, 2004; 279(48): 50190 - 50196. [Abstract] [Full Text] [PDF]
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N. W. Siecke and P. A. Insel Clarifying the effects of adrenergic receptor polymorphisms by measuring synaptic parameters J. Am. Coll. Cardiol., November 16, 2004; 44(10): 2016 - 2018. [Full Text] [PDF]
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T. Tang, M. H. Gao, D. M. Roth, T. Guo, and H. K. Hammond Adenylyl cyclase type VI corrects cardiac sarcoplasmic reticulum calcium uptake defects in cardiomyopathy Am J Physiol Heart Circ Physiol, November 1, 2004; 287(5): H1906 - H1912. [Abstract] [Full Text] [PDF]
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L. Barki-Harrington, C. Perrino, and H. A Rockman Network integration of the adrenergic system in cardiac hypertrophy Cardiovasc Res, August 15, 2004; 63(3): 391 - 402. [Abstract] [Full Text] [PDF]
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C. Sesti and R. A. Kloner Gene Therapy in Congestive Heart Failure Circulation, July 20, 2004; 110(3): 242 - 243. [Full Text] [PDF]
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M. Mongillo, T. McSorley, S. Evellin, A. Sood, V. Lissandron, A. Terrin, E. Huston, A. Hannawacker, M. J. Lohse, T. Pozzan, et al. Fluorescence Resonance Energy Transfer-Based Analysis of cAMP Dynamics in Live Neonatal Rat Cardiac Myocytes Reveals Distinct Functions of Compartmentalized Phosphodiesterases Circ. Res., July 9, 2004; 95(1): 67 - 75. [Abstract] [Full Text] [PDF]
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A. Morimoto, H. Hasegawa, H.-J. Cheng, W. C. Little, and C.-P. Cheng Endogenous {beta}3-adrenoreceptor activation contributes to left ventricular and cardiomyocyte dysfunction in heart failure Am J Physiol Heart Circ Physiol, June 1, 2004; 286(6): H2425 - H2433. [Abstract] [Full Text] [PDF]
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S. Engelhardt, L. Hein, V. Dyachenkow, E. G. Kranias, G. Isenberg, and M. J. Lohse Altered Calcium Handling Is Critically Involved in the Cardiotoxic Effects of Chronic {beta}-Adrenergic Stimulation Circulation, March 9, 2004; 109(9): 1154 - 1160. [Abstract] [Full Text] [PDF]
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