the role of adrenergic receptor polymorphisms in heart failure · adrenergic receptor polymorphisms...

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Braz J Med Biol Res 39(10) 2006

Adrenergic receptor polymorphisms in heart failure

The role of adrenergic receptorpolymorphisms in heart failure

1Grupo de Insuficiência Cardíaca e Transplante, Serviço de Cardiologia,Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brasil2Laboratório de Fisiologia Cardiovascular, Departamento de Fisiologia,Instituto de Biociências, Universidade Federal do Rio Grande do Sul,Porto Alegre, RS, Brasil

A. Biolo1, A.S. Rosa1,N.G. Mazzotti1, S. Martins1,A. Belló-Klein2, L.E. Rohde1

and N. Clausell1

Abstract

The main function of the cardiac adrenergic system is to regulatecardiac work both in physiologic and pathologic states. A betterunderstanding of this system has permitted the elucidation of its rolein the development and progression of heart failure. Regardless of theinitial insult, depressed cardiac output results in sympathetic activa-tion. Adrenergic receptors provide a limiting step to this activationand their sustained recruitment in chronic heart failure has proven tobe deleterious to the failing heart. This concept has been confirmed byexamining the effect of ß-blockers on the progression of heart failure.Studies of adrenergic receptor polymorphisms have recently focusedon their impact on the adrenergic system regarding its adaptivemechanisms, susceptibilities and pharmacological responses. In thisarticle, we review the function of the adrenergic system and itsmaladaptive responses in heart failure. Next, we discuss major adre-nergic receptor polymorphisms and their consequences for heartfailure risk, progression and prognosis. Finally, we discuss possibletherapeutic implications resulting from the understanding of polymor-phisms and the identification of individual genetic characteristics.

CorrespondenceN. Clausell

Divisão de Cardiologia

Hospital de Clínicas de Porto Alegre

Rua Ramiro Barcelos, 2350, Sala 2060

90035-003 Porto Alegre, RS

Brasil

Fax: +55-51-2101-8344

Received October 27, 2005

Accepted July 11, 2006

Key words• Heart failure• Adrenergic receptor• Polymorphisms

Brazilian Journal of Medical and Biological Research (2006) 39: 1281-1290ISSN 0100-879X Review

Introduction

Heart failure (HF) is a significant healthproblem worldwide and despite many recentadvances in treatment, HF-related morbidityand mortality remain elevated (1). Regard-less of the initial insult, depressed cardiacoutput results in sympathetic activation. Sev-eral experimental and clinical studies havedemonstrated that this sustained adrenergicdrive can be deleterious to the failing heart,contributing to HF progression, perpetua-tion and presentation (2). This concept has

been confirmed by the benefits of ß-blockersin patients with heart failure (3-5). Advancesin the knowledge of specific molecular char-acteristics and adaptations of the adrenergicsystem have permitted a better understand-ing of its role in the development and pro-gression of heart failure (6).

The adrenergic system in the healthyheart

The adrenergic system, or sympatheticautonomous nervous system, is responsible

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for a variety of adaptive events that occur inresponse to increases in oxygen and nutrientdemands. The system consists of nervousstructures, neurotransmitters, vasoactive sub-stances, hormones, and specific receptors(adrenergic receptors, AR). The heart andperipheral circulation undergo short-termmodifications to regulate cardiac output, ar-terial pressure and blood flow distribution asa result of the interaction between the centralnervous center and peripheral effector struc-tures. When acutely activated, the sympa-thetic nervous system stimulates the release ofneurotransmitters and vasoactive substances,

regulating cardiac output and promoting bloodflow redistribution and arterial pressure modi-fications, respectively (7). AR are key signal-ing elements regulating the intensity of adre-nergic activation (Figure 1) (8).

AR are transmembrane proteins of myo-cardial cells that act by coupling to a G-protein, which in turn can be excitatory (Gs)or inhibitory (Gi). They represent the limit-ing stage of the cardiac response to an adre-nergic stimulus. When norepinephrine bindsto the AR, a cascade of events is immedi-ately triggered to obtain an intracellular re-sponse. A kinase-dependent pathway regu-

Figure 1. Representation of asynaptic gap with the maincomponents of the cardiac adre-nergic signaling. Release of nor-epinephrine is regulated bypresynaptic α2c-adrenergic re-ceptor (AR). After being re-leased, norepinephrine binds toß-AR, that are G-protein-coupledtransmembrane receptors. Onbinding to ligands, the stimula-tory G-protein (Gs) activatesadenylate cyclase and the inhib-itory G-protein (Gi) reduces itsactivity. Both ß1- and ß2-AR arenormally coupled to Gs protein,but ß2-AR may also couple toGi. The stimulation and functionof these receptors modulate ef-fector molecules responsible forregulating cardiomyocyte con-traction and hypertrophy (8).

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lates the inotropic and chronotropic cardiacresponse.

There are two principals AR: α and ß (6,9).The α-AR are subdivided into two classes.The post-synaptic α1-AR plays a role in hy-pertrophy and myocardial remodeling whereasthe α2-AR is pre-synaptic in the heart and itsmain function is to inhibit norepinephrine re-lease in the synaptic gap (10).

The ß-AR are classically divided into 3subtypes (ß1, ß2, and ß3), having a fourthsubtype that has not been well characterized.The ß1-AR is the dominant subtype in thenon-failing heart, representing 70-80% of ß-ARs (11,12). ß1 and ß2 receptors are pharma-cologically distinguished by differences in af-finities for both receptor agonists and selectiveantagonists. Although both receptors are stim-ulated by isoproterenol, a nonselective fullagonist, the binding affinity for epinephrine ishigher (10- to 30-fold) for the ß1-AR subtype(13). Knowledge of ß3-AR is poor; it probablyacts by regulating metabolic functions andcontributing to negative inotropism and myo-cardial relaxation. It also seems to regulatenitric oxide production (14).

ß-AR signaling and differences betweenß-AR subtypes are also important for theunderstanding of adrenergic system func-tion. Both ß1 and ß2 subtypes are coupled toGs protein, which stimulates adenylyl cycla-ses, resulting in the conversion of ATP tocAMP, which in turn binds to regulator sub-units of protein kinase-A (PKA) and phos-phorylation of a number of target intracellu-lar proteins. However, unlike ß1-ARs, ß2-ARs couple to a number of signaling path-ways in addition to the Gs-dependent path-way. The ß2-AR can bind to Gi, with nega-tive inotropic effects, preferentially doing sowhen in the phosphorylated form. Further-more, the ß2-AR appears to modulate sev-eral types of G-protein-independent signal-ing, and recently the association of ß2-ARwith an anti-apoptotic role has been described(see below). These differences in post-re-ceptor coupling have physiological conse-

quences in the pathophysiology of heart fail-ure (15).

There are also differences between ß1-and ß2-ARs regarding their ability to pro-mote apoptosis, a process implicated in myo-cardial remodeling and HF. While activa-tion of ß1-ARs results in an increased rate ofcardiomyocyte apoptosis, ß2-AR couplingto Gi seems to be cardioprotective. This anti-apoptotic effect is probably linked to cou-pling to the phosphatidylinositol 3 kinasepathway (16,17).

The adrenergic system in the failingheart

Conditions involving contractile cardiacdysfunction result in hemodynamic over-load, which activates several adaptivemechanisms. Thus, in HF in the presence ofsystolic dysfunction, adrenergic activationis an important response to support cardiacwork at minimal effective levels. Levels ofcirculating norepinephrine are increased inpatients with HF, reflecting adrenergic sys-tem activation. This results from increasedrelease, as well as reduced uptake of norepi-nephrine. Nevertheless, in chronic situations,an initially adaptive response of the adrener-gic system becomes inadequate or even harm-ful. In fact, increased plasma norepineph-rine levels are associated with severity and aworse prognosis in HF (18-20). To avoidperpetuation of this situation, regulatorymechanisms have been developed aiming toattenuate adrenergic responses.

AR are the key for adrenergic systemregulation and in pathologic situations theirfunction and distribution are dramaticallyaltered (7,9,21). Desensitization and down-regulation of AR are the principal mechan-isms observed in HF.

Desensitization is the mechanism bywhich cells decrease effector responses, de-spite the presence of ligands, usually a de-fect in G-protein coupling. Multiple regula-tory adjustments produce desensitization of

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downstream effector responses in the failingheart, resulting in a marked attenuation ofthe response to catecholamines. In heart fail-ure, both ß1- and ß2-ARs are significantlydesensitized due to uncoupling of the recep-tor from its respective signaling pathways(6,22). Two molecular processes are in-volved: increased ß-AR phosphorylation andup-regulation of the Gi protein. Phosphory-lation is primarily mediated by increasedabundance and activity of G-protein-coupledreceptor kinases, and is directly dependenton agonist occupancy. Thus, phosphoryla-tion is stimulated by sympathetic overactiv-ity as seen in HF. These desensitization pro-cesses lead to reduction in the amount ofcAMP being generated for a given adrener-gic stimulation (23). Thus, cardiomyocytessuffer the consequences of functioning athigher levels of adrenergic activation tomaintain the cardiac work. Potentially dam-aging cAMP-independent pathways maybecome more activated and other cAMP-dependent pathways can be activated be-sides that responsible for controlling cardiaccontractility, which may make adrenergicactivation even more myopathic.

Down-regulation is the reduction in acti-vated receptor expression on the cell mem-brane. Receptors are continuously translo-cating from the membrane into endosomesat a slow rate but this rate is dramaticallyincreased in the presence of an agonist. Fromthe endosomes, receptors can be either re-cycled back to the plasma membrane orrouted to lysosomes for degradation (22,24).In HF patients, selective ß1-AR down-regu-lation occurs as the proportion of ß1:ß2-ARsapproximates 50:50, shifting from the physi-ologic ratio of 76:24 (12). This decrease inreceptor numbers is in part a product ofelevated lysosomal degradation of preexist-ing receptors as well as decreased mRNAand protein synthesis (22,25). Also, over-stimulation leads to PKA- and PKC-medi-ated phosphorylation of ß-receptors, whichin turn will transform the receptors into bet-

ter targets for internalization. In addition,phosphorylation by ß-AR kinase also medi-ates receptor down-regulation as phospho-rylated ß-receptors bind to ß-arrestin, whichinterferes with receptor coupling with Gs

proteins and enhances internalization anddegradation of the receptors (22). It has beensuggested that the selective ß1-AR down-regulation in HF is related in part to a reduc-tion in ß1-AR synthesis, as indicated by itsreduced mRNA levels, which are more evi-dent for ß1-AR, as well as increased lysoso-mal degradation due to differential internal-ization pathways (6,22,26). However, thereason for ß2-AR refractoriness to down-regulation in HF is not entirely clear since ina number of experimental model systems theß2-AR is actually more profoundly down-regulated (6,22,27).

In summary, chronic HF generates per-sistent adrenergic activation, which becomesindispensable to maintain minimal myocar-dial work necessary to supply organism re-quirements. However, the more the adrener-gic system is activated the higher is its toxic-ity; as a protective mechanism, desensitiza-tion occurs, by changes in the number andthe function of AR. This adaptive pathwaythus stimulates more activation and againmyocardial damage, in a vicious and pro-gressive cycle. This milieu seems to repre-sent an important factor for the progressivestatus of myocardial dysfunction and re-modeling in HF.

Adrenergic receptor polymorphismsand heart failure

A polymorphism is a genetic variant thatoccurs in at least 1% of the population, simi-larly to the human ABO blood groups. Bysetting the cutoff at 1%, it excludes spontane-ous mutations that may have occurred in - andspread through the descendants of - a singlefamily. Since proteins are gene products, poly-morphic versions are simply reflections ofallelic differences in the gene, i.e., allelic dif-

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ferences in DNA (28). Recently, several poly-morphic variants of proteins that constituteAR have been identified and their role in HF isbeing actively investigated.

Since several receptors and regulatorypathways work simultaneously, the finalconsequence of a single mutation is difficultto predict. Genetic studies in animal modelsof HF and in HF patients have explored theconsequences of specific AR polymorphisms(29,30). These studies have shown that poly-morphisms can alter receptor efficiency byregulating G-protein binding, as well as itssensitivity to down-regulatory stimuli. Clini-cal studies have explored the role of thesepolymorphisms in HF risk, progression andeven response to therapy. We will discussthe main AR polymorphisms identified andtheir influence on HF (Table 1).

ß1-Adrenergic receptor polymorphisms

Two main polymorphisms were identifiedfor the ß1-AR, at codons 49 and 389. The ß1-Ser49Gly is an adenine to guanine substitutionat nucleic acid 145, which results in a serine toglycine substitution in the position of aminoacid 49, located in the extracellular region ofthe ß1-AR (31,32). The functional propertiesof this polymorphism were investigated invitro. ß1-49Gly receptors showed higher ac-tivity in addition to a greater response to inhi-

bition by metoprolol, as well as greater desen-sitization and down-regulation when chroni-cally stimulated (31). It has been speculatedthat a higher regulating capacity of the adre-nergic system could be beneficial and protec-tive for patients with HF. In experimentalmodels, despite a similar affinity for agonistsand antagonists of ß1-49Ser and ß1-49Glyvariants, the down-regulation promoted byprolonged stimulation was greater for ß1-49Gly, reinforcing the idea that this can be aprotective mechanism for patients with HF(32).

In order to evaluate the influence of thispolymorphism on HF risk and prognosis, itsprevalence was determined in 184 patientswith idiopathic HF and 77 control subjects.Although the prevalence of the polymor-phism was similar for patients and controls,the long-term prognosis was better for pa-tients with the ß1-49Gly allele (a 5-yearsurvival of 62 vs 39% for patients with ß1-49Ser, P = 0.005) (33). This study agreeswith speculations of experimental studies, inwhich the altered function of the receptorwith the ß1-49Gly allele can result in a myo-cardial protective effect in HF. Moreover,Podlowski and co-workers (34) observedthat the presence of the ß1-49Gly allele ismore prevalent in patients with idiopathiccardiomyopathy. In fact, the role of ß1-Ser49Gly and other AR polymorphisms in

Table 1. Adrenergic receptor polymorphisms and heart failure.

Polymorphism In vitro effects Possible clinical consequences

ß1-Ser49Gly Uncertain Greater regulating capacity of the adrenergic system (31,32)Exaggerated down-regulation? Better prognosis (33)

ß1-Arg389Gly Increased function (acutely) Increased response at the cardiomyocytes (35-37)Increased down-regulation Poor exercise capacity (40)

Increased risk of ventricular arrhythmias (41)Increased response to ß-blockade (37)

ß2-Thr164Ile Decreased affinity for G-protein coupling Worse contractile myocardial function (29)Worse prognosis (42)

α2c-Del322-325 Decreased function Increased norepinephrine release at the synapse level (44)Increased risk of heart failure (38)

References are given in parentheses.

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progression and prognosis of HF representsa rapidly evolving field which needs furtherinvestigation for a more comprehensive un-derstanding.

Another ß1-AR polymorphism is ß1-Arg389Gly, which results from the replace-ment of arginine with glycine at a criticalpoint for G-protein coupling, with less cou-pling affinity for the ß1-389Gly allele (35).The allelic prevalence is approximately 70%for ß1-389Arg and 30% for ß1-389Gly(35,36). In transgenic mice, young Arg389mice had enhanced receptor function andcontractility compared to Gly389 mice. How-ever, older Arg389 mice presented a pheno-typic switch, showing decreased ß-agonistsignaling and cardiac contractility (37). Infact, the ß1-389Arg allele seems to be asso-ciated with an increased and hyperactivesignaling in initial stages, but it reduces sig-naling in later stages, with less receptor bind-ing and ventricular contraction. In addition,Arg389 mice had a better hemodynamic re-sponse and ventricular function improve-ment with ß-blockade, suggesting that thispolymorphism can influence the therapeuticresponse to ß-blockers (37). A retrospectiveanalysis of the MERIT study evaluated theinfluence of the ß1-389Arg allele on thetherapeutic response to ß-blockers in pa-tients with symptomatic HF. However, therewas no association of the ß1-Arg389Glypolymorphism with survival or with responseto ß-blocker therapy in this analysis (36).

To investigate whether this polymor-phism represents a risk for the developmentof HF, Small et al. (38) studied 159 patientswith HF (ischemic and idiopathic) and 189controls. There was no increase in risk withß1-389Arg alone. However, there was amarked increase in risk for HF among blackswho concomitantly had the ß1-389Arg al-lele and another polymorphism related to α-AR (OR = 10.11, 95% CI = 2.11 to 48.53).Among white subjects, allele frequencieswere too low to permit an adequate assess-ment of risk. In another study, the frequency

of ß1-Arg389Gly polymorphism was evalu-ated in 426 patients with idiopathic dilatedcardiomyopathy (39). Although no associa-tion was found with risk or severity of HF,the authors speculated that this polymor-phism may relate to response to ß-blockade.Further studies are needed to clarify thishypothesis.

The association of ß1-Arg389Gly poly-morphism with clinical characteristics of HFwas also studied. In one study, this polymor-phism was a significant determinant of exer-cise capacity (40). Patients with the ß1-389Gly allele had significantly lower peakoxygen consumption than those with ß1-389Arg, suggesting that early detection ofthis polymorphism might be useful to iden-tify patients at risk for depressed exercisecapacity and therefore candidates for specif-ic tailored therapy.

Since ß1-AR appears to be important inthe induction of ventricular arrhythmia, theassociation between the ß1-Arg389Gly poly-morphism and the occurrence of ventriculartachycardia was assessed in Japanese pa-tients with idiopathic dilated cardiomyopa-thy. The ß1-389Gly allele suppressed theoccurrence of this arrhythmia, suggesting apossible decreased sudden death risk associ-ated with this allele (41). Thus, this poly-morphism may represent a tool for the as-sessment of risk and for planning specifictherapies for HF patients.

ß2-adrenergic receptor polymorphisms

Several polymorphisms of ß2-AR havebeen described, but the polymorphic variantin amino acid 164 (ß2-Thr164Ile) is the beststudied. Most individuals are homozygousfor ß2-164Thr (95%), which more stronglyactivates the receptor than the ß2-164Ile vari-ant. In transgenic mice, the presence of theß2-164Ile allele resulted in depressed myo-cardial contractile function (29). Liggett etal. (42) studied the influence of this poly-morphism in 259 patients with idiopathic or

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ischemic HF in relation to risk of death orcardiac transplantation. The 1-year survivalof patients with the ß2-164Ile allele was42% compared with 76% for patients har-boring the wild-type ß2-AR (Figure 2). Theseinvestigators concluded that patients withthe ß2-164Ile allele and HF might be candi-dates for earlier aggressive intervention orcardiac transplantation. Other polymor-phisms of the ß2-AR in this same study (ß2-Arg16Gly and ß2-Gln27Glu) were not asso-ciated with HF risk or prognosis.

ααααα-adrenergic receptor polymorphisms

α-ARs are important receptors whichregulate norepinephrine release into the syn-aptic gap, and variations in their functionmay lead to higher susceptibility to HF (43).One polymorphism of α2c-AR, a deletion of4 amino acids (α2c-Del322-325), results ina decreased function of this receptor, withlower auto-inhibitory activity and highernorepinephrine levels (44). This deletion wasstudied in 159 patients with idiopathic orischemic HF, and was associated with ahigher risk of HF in black patients (38). Thisstudy demonstrated that polymorphisms ofdifferent receptors probably act in a syner-gistic way to influence predisposition to HF.When both the α2c-Del322-325 polymor-phism and the ß1-Arg389 allele were pres-ent in black patients, the risk was increasedby approximately 10-fold. Characterizationof these genotypes may be useful to identifyindividuals at higher risk for HF and, there-fore, candidates for early preventive strate-gies. Racial differences in allele frequenciesremain to be better clarified (38).

Adrenergic receptor polymorphismsand heart failure treatment

A better understanding of the physio-pathological process involved in HF devel-opment and progression has brought dra-matic changes in its treatment over the last

few years. The elucidation of the role of theadrenergic system was one of the most im-portant advances in this regard. Initially seenas a vital compensatory mechanism, the in-cessant activation of the adrenergic systemturned out to be viewed as one of the greatestvillains in HF progression. With this newparadigm, adrenergic system blockade be-came a crucial part of HF treatment. In factthe use of ß-blockers is associated with bet-ter outcomes in several HF clinical trials.This beneficial effect is thought to be due tomultiple mechanisms which include im-proved calcium handling by the sarcoplas-matic reticulum, increased gene expressionof α-myosin heavy chain, and more specifi-cally re-expression and re-coupling of ß1and ß2 receptors by myocytes allowing thereturn of a more physiological response tothe adrenergic drive (45).

However, the results of some clinicaltrials have raised questions related to thisconcept. While the benefit of ß-blockers iswell established, primarily sympatholyticagents seem to have deleterious effects onpatients with HF (46). One example is moxo-nidine, which increased mortality in patientswith HF in the MOXCON study, an effectprimarily attributed to its strong sympatho-

Figure 2. Survival of patients with heart failure with the wild-type ß2-adrenergic receptor(continuous line) or the ß2-164Ile allele (dotted line). Reproduced from Liggett et al. (Ref.42), with permission from the Journal of Clinical Investigation.

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lytic action (47). Another agent, bucindolol(a ß-blocker and a sympatholytic agent),showed no benefit in black patients and inthose in functional class IV, suggesting thatcertain subpopulations may be more suscep-tible to the deleterious effects of adrenergicsuppression (48). One hypothesis for thesefindings is that sympatholytic agents pro-mote removal of adrenergic support, makingunfeasible the adrenergic recruitment whennecessary to keep cardiac function. With theuse of ß-blockers, on the other hand, inhibi-tion can be easily reversed whenever neces-sary through norepinephrine recruitment.

The altered function of AR and its influ-ence on the risk and therapeutic response ofHF patients may represent the link betweenAR polymorphisms and certain characteris-tics in specific populations. An example isthe already mentioned study of Small et al.(38) in which the presence of the ß1-Arg389allele and α2c-Del322-325 polymorphismhad synergistic effects increasing HF risk inblack patients. Through the understandingof the genetics of the adrenergic system itmay be possible to tailor therapy to patientsmore inclined to respond to specific inter-ventions, rather than the current situation(economically unfeasible) of treating a largenumber of patients to effectively benefit aminority. It is possible to speculate, for in-stance, that the black patients who had highermortality with bucindolol were those withα2c-AR polymorphism exposed to muchhigher levels of norepinephrine, and wholost the adjusting capacity due to its abruptinterruption (46). Similarly, the associationof some polymorphisms with the risk of

ventricular tachycardia and survival may helpto select patients for high-cost interventions,such as defibrillator implantation.

The fact that in a MERIT sub-study nodifference related to ß1-Arg398Gly wasfound in response to ß-blockers, and thesynergistic action between polymorphismsof different AR on HF risk, raises the possi-bility that phenotype determination is morelikely a result of the interaction betweenmultiple polymorphisms than the influenceof an individual polymorphism (36,38). Thus,the complex influence of the adrenergic sys-tem on HF must be considered and under-stood so that we can advance in the thera-peutic approach to this syndrome.

Conclusions

The role of the adrenergic system (andspecifically of AR) in the development andprogression of HF has been intensively stud-ied. Genetic studies have provided informa-tion regarding receptor functions and its poly-morphisms in the complex balance of thissystem.

The combination of experimental dataand, recently, studies on HF patients hasprovided information and has raised ques-tions that may help to improve the therapeu-tic approaches for HF. In addition, new in-formation regarding the effects of AR poly-morphisms may be the basis for pharmaco-genetics, which takes into account geneti-cally mediated variability in HF presenta-tion and response to specific medications todefine better individualized approach to HFpatients.

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