Skip Navigation

European Journal of Heart Failure 2008 10(1):3-13; doi:10.1016/j.ejheart.2007.11.008
This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (5)
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Muthumala, A.
Right arrow Articles by Humphries, S. E.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Muthumala, A.
Right arrow Articles by Humphries, S. E.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© 2008 European Society of Cardiology

Role of β adrenergic receptor polymorphisms in heart failure: Systematic review and meta-analysis

Amal Muthumalaa,b,*, Fotios Drenosa, Perry M. Elliottb and Steve E. Humphriesa

a Centre for Cardiovascular Genetics, Rayne Institute, Royal Free and University College Medical School London WC1E 6JF, UK
b Inherited Cardiovascular Diseases Unit, Heart Hospital, Royal Free and University College Medical School London, UK

* Corresponding author. British Heart Foundation Laboratories, Royal Free & University College Medical School, Rayne Building, 5 University Street, London WC1E 6JF, UK. Tel.: +44 20 7679 6964; fax: +44 20 7679 6212. E-mail address: amuthumala{at}aol.com


   Abstract
Top
 Abstract
1. Introduction
 2. β adrenergic receptors...
 3. β adrenergic receptor...
 4. Evidence for functional...
 5. Evidence for functional...
 6. Role of ADRB...
 7. Conclusions
 References
 
Heart Failure (HF) is a common disorder associated with substantial morbidity and mortality. β adrenergic receptors (βAR) are the primary pathway through which cardiac function is influenced. Chronic β1AR activation is implicated in the pathogenesis of HF and βAR blockade improves survival in left ventricular systolic dysfunction. Common functional polymorphisms in β adrenergic receptor genes (ADRB) have been associated with HF phenotypes, and with pharmacogenetic interaction with β adrenergic receptor blockers (β blockers). However, these associations have not been consistently replicated. The evidence for ADRB variant involvement in pathogenesis, progression and response to β blockers in HF is reviewed. In addition, a meta-analysis of three studies analysing the effect of ADRB1 Arg389Gly polymorphism on left ventricular remodelling with the use of β blockers, demonstrating a 5% improvement in left ventricular ejection fraction in Arg389 homozygotes, is presented. There is now accumulating molecular evidence for a different functional response to β blockers associated with this polymorphism. In the future, confirmed genotypic associations may enable patients to be identified who are either at greater risk of developing HF, whose HF may rapidly progress, or who are unlikely to benefit from β blockers, and such patients may benefit from targeted aggressive therapy.

Key Words: β adrenergic receptor • Gene • Polymorphism • Heart failure

Received June 14, 2007; Revised September 18, 2007; Accepted November 19, 2007


   1. Introduction
Top
 Abstract
 1. Introduction
2. β adrenergic receptors...
 3. β adrenergic receptor...
 4. Evidence for functional...
 5. Evidence for functional...
 6. Role of ADRB...
 7. Conclusions
 References
 
Heart failure (HF) is a common syndrome that arises from a variety of cardiovascular disorders, the most common of which are ischaemic heart disease, hypertension and dilated cardiomyopathy. HF is characterised by progressive remodelling of the myocardium, accompanied by worsening symptoms, exercise intolerance and fluid accumulation. The prevalence of HF is increasing, due to the rise in the number of people living to an old age and an increase in the number of individuals who survive myocardial infarction but are left with left ventricular dysfunction. The reported prevalence of HF in a large UK-based study was 1 in 35, for people aged 65-74 years and 1 in 7 in those aged more than 85 years [1]. As a result of the population aging, hospitalisation in the UK due to HF is estimated to rise by 50% over the next 25 years (NICE guidelines [2]). Mortality from HF is high, with more than 50% of patients with severe heart failure dying within 1 year [3]. These mortality figures seem surprisingly high in the context of large heart failure trials; however, most therapeutic trials exclude ‘unstable’ patients, and only recruit patients with a better prognosis, and less comorbidity at diagnosis [4].

Left ventricular systolic dysfunction is accompanied by the activation of compensatory mechanisms which improve cardiac function to a normal range, keeping the patient asymptomatic. These include the adrenergic, renin-angiotensin and cytokine systems [5-7]. Continued stimulation of these systems leads to further myocardial damage, causing worsening ventricular remodelling and an inevitable decline in cardiac performance, with patients developing symptoms of breathlessness and fluid accumulation [5,8]. β adrenergic receptor (βAR) signalling is critical in the progression of HF. Antagonism of this pathway by β adrenergic receptor blockers (β blockers) has been shown to produce a clinical improvement in patients with HF together with an improvement in remodelling and pump function [9,10]. The severity and progression of HF and response to β blockers is variable between patients and this may be attributable to polymorphisms in β adrenergic receptor (ADRB) genes.

The aim of this review paper was therefore to examine the evidence for ADRB variant involvement in pathogenesis, progression and response to β blockers in HF. Due to the scope of this topic, associations with other major diseases where βAR play a central role such as hypertension and asthma, and pharmacogenetic interactions with β blockers (except in the context of HF) will not be discussed.

A PubMed literature search using the terms ‘beta receptor polymorphisms’ and ‘heart failure’ identified 48 studies. Of these, 25 studies reported on 5 SNPs in ADRB1 and ADRB2 genes, looking at phenotypes associated with heart failure. The results of these studies are discussed within this review paper and are summarised in Table 1.


View this table:
[in this window]
[in a new window]

  		Table 1 Summary of association studies involving ADRB SNP in heart failure

 

   2. β adrenergic receptors and their role in HF
Top
 Abstract
 1. Introduction
 2. β adrenergic receptors...
3. β adrenergic receptor...
 4. Evidence for functional...
 5. Evidence for functional...
 6. Role of ADRB...
 7. Conclusions
 References
 
βARs are members of a family of receptors known as G-protein coupled receptors. They have a seven membrane-spanning domain structure, an extracellular amino terminus, three intracellular and three extracellular loops, and an intracellular carboxyl terminus. Ligand binding to these receptors leads to activation of an associated trimeric G protein (GTP-binding protein). This in turn activates or inhibits an enzyme which generates a specific second messenger. All G proteins contain three subunits: G{alpha}, Gβ and G{gamma}. G proteins are localized on the cytosolic face of the plasma membranes and act as ‘on-off’ molecular switches. When bound to GDP, the G protein is in the ‘off’ state. Activation of the receptor causes release of GDP which is exchanged for GTP, converting it to the ‘on’ state. The activated G protein with its bound GTP then dissociates from the receptor and binds to and activates an effector enzyme (e.g. adenylyl cyclase) which in turn catalyses the formation of a second messenger (e.g. cAMP). The G protein then hydrolyses the bound GTP, causing it to revert back to the ‘off’ state.

There are different signalling pathways associated with G protein coupled receptors: (i) the Gs pathway which activates adenylyl cyclase thereby raising cAMP levels; (ii) the Gq/11 pathway which stimulates phosphoinositide metabolism; and (iii) the Gi/o pathway, which inhibits adenylyl cyclase causing a decrease of cAMP levels. βARs activate the Gs pathway but the Gi pathway may also be activated via β2AR [11].

Three βARs have so far been identified in the heart—β1, β2 and β3. The first two subtypes increase contractility and heart rate but the role of the β3AR in the human heart remains unclear. β1ARs and β2ARs are expressed in a ratio of about 60-80%:20-40% [12], with the ratios dependent on β1AR down-regulation. In vascular smooth muscle the majority of βARs are β2ARs.

Stimulation of β1ARs and β2ARs in the heart leads to increased ionotropy, lusitropy and chronotropy via the Gs pathway, causing raised cAMP levels. Protein Kinase A (PKA) is activated by cAMP. PKA phosphorylates proteins important for cardiomyocyte function including L-type calcium channels [13], phospholamban [13,14] and Troponin I [15]. βARs have also been shown to activate PKA independent pathways [16,17].

βAR signalling plays an important role in HF. The degree of increased sympathetic activity is inversely correlated with survival in HF [18]. Potentially harmful effects of β1AR signalling include apoptosis, myocyte growth, fibroblast hyperplasia, myopathy, fetal gene induction and proarrhythmia [19-21]. Cardiac βARs become less responsive in HF, and either downregulate or uncouple from the Gs protein-adenylyl cyclase pathway [22]. These changes are thought to be adaptive to the detrimental persistent βAR signalling, and suggest that inhibition of this pathway could be clinically useful [23,24]. The Gi protein which suppresses activation of adenylyl cyclase is increased in HF [25]—this again may be helpful in protecting against harmful βAR signalling. There is also upregulation of βAR kinase (βark1, also known as GRK2) in HF [26], and these kinases cause receptor desensitization. It is unclear whether this increase in βark1 is beneficial or detrimental in HF.

Blockade of the β1AR is certainly responsible for a large degree of the improvement seen in HF, but it is unlikely that this is the sole mechanism. The pharmacology of the β2AR in the healthy and failing human heart is still unclear. Its activation of the Gi pathway may oppose the harmful effects of β1AR signalling and a β2AR antagonist via Gi coupling has been shown to be negatively ionotropic in cardiomyocytes from failing human hearts [27].


   3. β adrenergic receptor (ADRB) polymorphisms
Top
 Abstract
 1. Introduction
 2. β adrenergic receptors...
 3. β adrenergic receptor...
4. Evidence for functional...
 5. Evidence for functional...
 6. Role of ADRB...
 7. Conclusions
 References
 
The ADRB1 gene is coded by an intronless gene on chromosome 10q24-26. Twelve coding SNPs have been described on the NCBI SNP database, of which eight are non-synonymous and result in an amino acid substitution. Two of these coding SNPs have been studied consistently because they are the most common. These are 145A>G and 1165C>G, resulting in changes in amino acid residues 49 (Ser>Gly) in the amino terminal and 389 (Arg>Gly) in the carboxy terminal, but close to the seventh transmembrane domain in the intracytoplasmic tail. Seven more coding SNPs have also been identified [28]; however, it should be mentioned that apart from the two aforementioned SNPs, the rest are rare and have not been formally verified. These two SNPs are in strong linkage disequilibrium (LD) in Caucasians and African Americans [29], and all Gly 389 homozygotes are also homozygous for Ser 49, while the Gly49Gly389 haplotype is very rare. Reported rare allele frequencies in Caucasians are shown in Fig. 1. For the Arg389Gly polymorphism, because it was the first cDNA cloned, the minor allele Gly389 was initially thought to be the wild-type therefore it has been stated as Gly389Arg in the past.


Figure 01
View larger version (18K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 1 Schematic diagrams of the β1AR with common SNPs and common haplotypes (not to scale). q—rare allele frequency from NCBI. Haplotype frequencies from [29].

 
The ADRB2 gene is coded by an intronless gene on chromosome 5q31-32. There are nine reported coding SNPs of which five are synonymous. Non-synonymous SNPs have been identified at nucleotides 46(A>G), 79(C>G) and 491(C>T) causing changes in amino acid residues 16(Arg>Gly) and 27 (Gln>Glu) of the amino terminus and 164 (Thr>Ile) respectively of the fourth intracellular loop [30]. The SNP at position 100 (Val34Met) is extremely rare and does not convey any functional change [31]. There are another eight SNPs within the 5' flanking sequence some of which are in LD with the above non-synonymous SNPs. The –47(T>C)—19(Arg>Cys)—located within a Beta Upstream Peptide (BUP) or 5'-leader cistron is the most important of these since it affects receptor expression at a translational level [32]. Strong LD exists between codon 16 and codon 27 (D=0.38, chi2 p<0.0001), in that subjects homozygous for Glu27 are nearly always homozygous for Gly16 [33]. Three common haplotypes of these two SNPs exist—Gly16Glu27, Arg16Gln27 and Gly16Gln27. The Arg16Glu27 haplotype is very rare. Rare allele frequencies in Caucasians are shown in Fig. 2. Thirteen SNPs from coding and non-coding regions have been described that are in linkage disequilibrium [34] and only 12 haplotypes were found despite more than 8000 possible combinations. Of these 12 haplotypes, only four were classed as major and their frequency between different races varied considerably.


Figure 02
View larger version (20K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 2 Schematic diagram of the β2AR with common SNPs and common haplotypes (not to scale). q—rare allele frequency from NCBI; 1Arg 16 is rare allele. Haplotype frequencies from [30].

 

   4. Evidence for functional differences in ADRB1 polymorphisms
Top
 Abstract
 1. Introduction
 2. β adrenergic receptors...
 3. β adrenergic receptor...
 4. Evidence for functional...
5. Evidence for functional...
 6. Role of ADRB...
 7. Conclusions
 References
 
4.1. Arg389Gly
4.1.1. In-vitro
This substitution lies within a possible G-protein binding domain and is therefore likely to be functionally important in receptor G-protein coupling. Using human variants recombinantly expressed in rodent cells, the Arg389 receptor had a slightly higher basal and 3-4 fold higher isoprenaline-stimulated adenylyl cyclase activity than the Gly389 variant [35]. Further work using this technique has shown that β1AR Arg389 desensitises more rapidly than the Gly389 variant [36].

4.1.2. Ex-vivo
In human right-atrial preparations, ionotropic and cAMP responses to noradrenaline were greater in subjects carrying the Arg389 receptor compared to the Gly389 variant [35,37]. However, no influence of this polymorphism (or Ser49Gly) was found on the ionotropic effects of noradrenaline in atrial preparations from patients who had undergone coronary artery bypass grafting [38]. There was also no difference in lipolysis between these two polymorphic variants when β1 receptors in human adipocytes were stimulated [39]. Recent data however has demonstrated a clear difference between the β1AR receptor variants from nonfailing ventricular tissue, with Arg389 tissues having greater contractile responses than Gly389 tissues to isoproterenol [40].

4.1.3. In vivo
In view of the clear in-vitro differences within this SNP, in-vivo studies have been carried out to investigate the effects on resting and exercise haemodynamics. In one study looking at genotype-discordant siblings, those that were homozygous for the Arg389 allele had significantly higher resting diastolic blood pressures and heart rates than siblings carrying the Gly389 allele [41]. This was confirmed in another study looking at 142 patients undergoing cardiac screening [42]. However, several studies have found no effect of this polymorphism on resting or exercise haemodynamics [43,44]. Two studies looking at healthy subjects have shown a variation in response to dobutamine within the Arg389Gly polymorphism, with Arg389 β1AR subjects having greater contractility and blood pressure responses [45,46].

4.2. Ser49Gly
4.2.1. In-vitro
Using rodent models, this polymorphism was shown to confer differences in agonist-related downregulation, with the Ser49 variant being more resistant [47]. There is now evidence that receptor coupling is also affected, with the Ser49 variant being less active [48]. When both ADRB1 SNPs were expressed in a human cell line (HEK 293), the coupling efficiency of each haplotype was measured. At basal levels, this was determined by position 49, with Gly49 variants being more active; but at maximal activation by isoprenaline Arg389 variants were more active than Gly389 variants [49].

4.2.2. In-vivo
In a large sample of Chinese and Japanese subjects the Ser49Gly polymorphism was found to be associated with heart rate, with Ser49 homozygotes having the highest rate. In healthy Caucasians, no positive association has been found between this polymorphism and resting or exercise haemodynamics, though the Ser49Gly polymorphism has not been examined extensively.

In summary, there is good in-vitro evidence for functional differences in both ADRB1 polymorphisms but there is still controversy as to how they impact in-vivo. In view of the strong LD that exists between the two, studies attempting to evaluate their role should analyse the effect of both SNPs together.


   5. Evidence for functional differences in ADRB2 polymorphisms
Top
 Abstract
 1. Introduction
 2. β adrenergic receptors...
 3. β adrenergic receptor...
 4. Evidence for functional...
 5. Evidence for functional...
6. Role of ADRB...
 7. Conclusions
 References
 
5.1. Arg16Gly and Gln27Glu
In-vitro: These polymorphisms, occurring in the amino terminal of the receptor, affect agonist-related downregulation (similar to the Ser49Gly ADRB1 polymorphism which also occurs in the amino region terminal) such that the Arg16 and Glu27 variants are resistant to down-regulation [50]. Studies looking at both SNPs, showed that the β2AR Gly16Glu27 protein undergoes even greater agonist-promoted downregulation than Gln27 receptors. The greater downregulation in the double mutant can be attributed to Gly16 effects dominating over the Glu27 effects. Another study in human mast cells however showed that the Gly16 variant was more resistant to downregulation [51]—the fact that Gly16Glu27 exists commonly, implies here, that position 27 is more important in determining desensitization.

In-vivo: These polymorphisms do not affect the β2AR mediated rise in heart rate and contractility in humans confirming the in-vitro data [52]. Differences in vasodilatory responses and response to agonist-induced desensitization between the variants of these two polymorphisms have been studied but the results are conflicting and will not be discussed here [53,54].

5.2. Thr164Ile
Using a rodent model, the Ile164 variant demonstrated impaired receptor coupling and reduced adenylyl cyclase activation [55]. Transgenic mice expressing the Ile164 variant had both lower basal and isoprenaline stimulated adenylyl cyclase activation than mice expressing the Thr164 variant [56]. In support of this, humans heterozygous for the Ile164 variant had lower cardiac and venous β2AR responses compared to those homozygous for the Thr164 variant [57].

There is a clear difference of function for the Thr164Ile polymorphism from both cell, animal and human-based experiments. There are certainly differences within the Arg16Gly and Glu27Gln polymorphisms in-vivo and in-vitro but these are conflicting, and future work should consider the effect of combinations of these SNPs, considering their strong LD. The rarity of the Thr164Ile polymorphism minimises its potential clinical importance.


   6. Role of ADRB polymorphisms in heart failure
Top
 Abstract
 1. Introduction
 2. β adrenergic receptors...
 3. β adrenergic receptor...
 4. Evidence for functional...
 5. Evidence for functional...
 6. Role of ADRB...
7. Conclusions
 References
 
6.1. Experimental evidence
Transgenic mice overexpressing variants of the Arg389Gly SNP in the heart have been used to investigate its direct role in the pathogenesis of HF. Young (3 months old) Arg389 mice had higher receptor activation and cardiac performance than young Gly389 mice, but this was reversed when they became older, with impaired receptor signalling and cardiac contractility in Arg389 mice. The older mice had a heart failure phenotype with abnormal expression of hypertrophy genes, decreased adenylyl cyclase and G{alpha}S, more fibrosis and lower fractional shortening [58]. The same group of researchers also examined myocardial recovery after ischaemia-reperfusion injury in transgenic mice (6 months old) and demonstrated enhanced recovery in Arg389 mice compared to Gly389 mice, due to diminished βAR signalling, enhanced G-protein receptor kinase 2 (βark 1) and increased ERK2 (implicated in cell survival) activation [59]. This group subsequently demonstrated that in ventricular tissue from failing (and normal) human hearts there is however a greater response in Arg389 carriers than Gly389 carriers. They further demonstrated that the β blocker bucindolol was an inverse agonist at Arg389 but not at Gly389 receptors, in failing ventricular tissues. It was also shown to reduce cAMP production to a greater extent in Arg389 cells. Analysis of change in noradrenaline levels in the BEST study, suggested that lowering of noradrenaline (i.e antagonism of adrenergic activity) was the reason for beneficial effects of bucindolol on Arg389 receptors in HF [40]. This advantageous response to βAR blockade in Arg389 compared to Gly389 carriers is supported by previous studies in which the acute and chronic haemodynamic response to infusion of the β blocker propanolol differed by genotype in 4 month old mice, with Arg389 mice showing greater sensitivity and maximal response [58]. A recent study has also demonstrated that carvedilol induced significant inactivation of Arg389 receptors compared to Gly389 receptors [60].

Specifically in experimental models of HF, Arg389 β1AR maybe associated with a greater susceptibility to HF, but there is increasing evidence that these variants paradoxically respond better to βAR blockade.

6.2. Risk of developing HF
If a gene product is strongly involved in the pathogenesis of disease, then there should be differences in allele frequencies of a functional polymorphism of the gene between affected and unaffected cohorts. When this has been looked at for ADRB1 polymorphisms, there have been occasional positive results, but these have not been replicated in other studies. Tesson et al. initially identified the Arg389Gly polymorphism but did not find any difference in allele frequency between a sample of patients with dilated cardiomyopathy (DCM) and matched controls [61]. Small et al. showed that in a sample of 84 black patients with HF, patients who were homozygous for deletion (322-325) in the {alpha}2c receptor gene had a 5.65 fold (p<0.001) higher risk of having HF compared to those who did not have this genotype, and the subjects who were both homozygous for this variant and homozygous for the ADRB1 Arg389 variant had a 10.11 fold (p=0.004) higher risk of HF [62]. There was a multiplicative increase in risk with homozygosity for both alleles but there was no higher risk with only being homozygous for Arg389. The {alpha}2c adrenergic receptor is a postsynaptic receptor that prevents the release of noradrenaline from the sympathetic nerve endings, and the deletion (322-325) variant is hypofunctional and associated with higher levels of noradrenaline [63]. A possible mechanism for the higher risk for the Arg389{alpha}2cdel(322-325) homozygote could be the higher activity of the Arg389 variant receptor, combining with the higher levels of noradrenaline due to the lower activity of the {alpha}2cdeletion(322-325), leading to more persistent and efficient β1AR signalling. In white subjects with HF, there was a similar (non-significant) trend for a higher risk in the {alpha}2cdeletion(322-325) homozygotes and in those who were also Arg389 homozygotes. This could be partly due to much lower frequency of the {alpha}2cdel(322-325) allele in whites, and therefore this study was underpowered to show a significant association. When both polymorphisms were examined in 260 Caucasian patients with HF and a similar number of controls, neither polymorphism either separately or in combination was associated with a higher risk [64]. When the same cohort was also genotyped for two ADRB2 (position 16 and 27) SNPs, there was a higher trend for HF for the Arg389Gly16Gln27 homozygotes, with an odds ratio of 1.4 (95% CI 0.5-3.6) [65]. The enhanced signalling of the Arg389 variant and the possible greater desensitization of the Gly16Gln27 β2AR variant might increase the risk of HF. In a case-control study involving patients with DCM, Podlowski et al. found the Gly49 variant only within the patients [28]; however, the sample numbers were small and this result has not been replicated.

It is clear that ADRB gene variants are not the only factors affecting risk of HF, but this is not surprising because its pathogenesis is multifactorial involving the interaction between the genetic milieu and environment of the individual. However, ADRB gene variants are probably disease modifiers and any risk estimate should be based on interactions with other genes and environmental measures as mentioned above.

6.3. Influence on survival in patients with HF
Consistent with the role of βAR as a disease modifier, ADRB polymorphisms may have more of an impact on survival in patients who have established HF, with persistent β1AR signalling contributing strongly to progressive cardiac dysfunction. A positive association was first found by Liggett et al. in a study of 269 patients with severe HF who had been genotyped for all three ADRB2 polymorphisms and who were prospectively followed [66]. After 1 year, those with the Ile164 variant had a 4.8 fold (p<0.001) higher risk of death or transplantation than Thr164 homozygotes. No such association was found with the other two SNPs. However, because of the low frequency of this variant, only 10 subjects carried the Ile164 variant so the result may not be statistically robust. The same authors demonstrated no effect of the Arg389Gly polymorphism on survival or hospitalisation in HF in a substudy of BEST (in which the selective β1AR blocker, bucindolol, showed no overall mortality benefit in patients with advanced HF) [40] when 525 patients in the placebo arm were genotyped. In another study, 184 patients with HF were genotyped for the ADRB1 Ser49Gly polymorphism [67]. After a 5 year follow-up, Ser49 homozygotes were found to have a risk ratio of 2.34 (p<0.003) of death or transplantation compared to those with Gly49 variants, and after multivariate analysis the risk ratio was reduced to 2.03 with borderline significance (p=0.05). Forleo et al., demonstrated in multivariate analysis that the LC-Cys19, Arg16 and Gln27 alleles were protective against progression of HF in 171 patients with DCM, with HRs of 0.15, 0.12, and 0.15 respectively, using endpoints defined by hospitalisation for HF, cardiac transplantation or death due to HF [68]. The ADRB1 Gly49 allele was protective in univariate analysis and no association was found with the ADRB2 Thre164Ile SNP. However, the small number of events weakened the study. De Groote et al. genotyped the functional ADRB polymorphisms in a cohort of 444 patients with HF followed over 3 years [69]. No SNP was associated with effects on survival, although those patients with the Gly16Gln27 haplotype had a significantly lower rate of cardiac related death or cardiac transplantation compared to the other haplotypes (p=0.05), but only in univariate analysis. Shin et al. have recently shown that in 227 patients with HF, the Arg16Gln27 diplotype conferred an approximately 90% increase in risk of death or cardiac transplantation [70]. Associations have also been reported for arrhythmias in HF; in a study of 160 patients with DCM and 157 controls, the odds ratio for non-sustained VT in Gly389 carriers was significantly less compared with Arg389 homozygotes [71].

One possible reason for the inconsistencies between these studies is the low sample numbers; even when several hundred subjects are included, if the frequency of the polymorphism is sufficiently low, more subjects are required for significant differences to emerge. Another explanation is that the effect of a combination of genotypes rather than just a single genotype is more likely to be related to survival, and therefore haplotype (or combined SNP) analysis is preferred, which also means that even larger sample numbers are needed for meaningful results. However, no study as yet has used complete ADRB2 haplotypes in a HF association study, and, until proven otherwise, it is not known whether a haplotype, one SNP, or several SNPs are the best predictors of a given outcome. It is important to note that other studies looking at the effect of ADRB SNPs on survival in HF have been carried out, but all the patients have been on β blockers, therefore the analysis examines how the pharmacogenetic interaction between β blockers and ADRB genotype may affect survival. These data will be discussed later.

6.4. Exercise capacity
In view of the direct pathway that the cardiac βAR mediates in exercise, and the downregulation of myocardial β1AR in HF, it is certainly likely that functional SNPs will affect exercise performance in HF. A cohort of 230 ambulant patients with HF underwent cardiopulmonary exercise testing and were genotyped for the ADRB2 SNPs [72]. Ile164 carriers had a significantly lower peakVO2 than Thr164 homozygotes (adjusted p<0.0001) and Gly16 homozygotes had a significantly lower peakVO2 than Arg16 homozygotes (adjusted p=0.03). When homozygotes at positions 16 and 27 were combined, Gly16Gln27 homozygotes had the worst performance and Arg16Glu27 the best (p=0.003). The lower peakVO2 in the Ile164 carriers is unsurprising, in view of the cell and animal model evidence for this variant demonstrating lower activity. The reason for lower performance in Gly16 homozygotes may be due to the fact that Gly16 receptors undergo more desensitization than Arg16 variants; this would explain why Gly16Gln27 carriers also had poorer performance. These findings were not supported by data from a smaller study, where Arg16 homozygotes with HF had a lower exercise capacity than Gly16 homozygotes [73].

ADRB1 polymorphisms were also found to predict exercise capacity in subjects with HF. Arg389 homozygotes had a significantly higher peakVO2 than Gly389 homozygotes in 263 patients with DCM [74]. Within the Ser49Gly polymorphism, Gly49 carriers had a higher peakVO2 than Ser49 homozygotes. Haplotype analysis demonstrated that those who were homozygous for Arg389 and were Gly49 carriers had the highest peakVO2 with Gly389Ser49 homozygotes having the lowest peakVO2. These results were supported by data from a sample of 83 patients with severe HF (on a cardiac transplant programme) genotyped for ADRB1 SNPs, which demonstrated significantly higher peakVO2 in Arg389 homozygotes compared to their Gly389 counterparts [75]. No association was found with the Ser49Gly SNP, but the study was not powered to detect a difference for this rarer polymorphism. In a cohort of 900 patients with coronary heart disease (not HF) genotyped for ADRB1 SNPs, Gly49 homozygotes had a higher peakVO2 than the Ser49 homozygotes [76], while Gly49Arg389 homozygotes (and Ser49Gly389/Gly49Gly389 diplotypes) had the highest peakVO2 after haplotype analysis. The Arg389 receptor confers a greater coupling activity than the Gly389 variant in cell studies, transgenic mouse studies and some in-vivo studies. This could lead to a better cardiac performance and thereby support the superior exercise capacity of patients with Arg389 alleles. Similarly, the higher peakVO2 in Gly49 homozygotes can be attributed to the in-vitro evidence for more efficient receptor coupling in the Gly49 receptor.

6.5. Pharmacogenetic interaction with β blockers in patients with HF
6.5.1. Haemodynamic response and effect on LV remodelling
Positive associations between β blockers and ADRB SNPs in influencing resting or exercise haemodynamics have not been reported in patients with HF [77,78].

With respect to the effect on remodelling, in 224 patients with HF who were all treated with the β blocker carvedilol (a non-selective β1AR and β2AR blocker), Arg389 homozygotes had a greater improvement in left ventricular ejection fraction (LVEF) than Gly389 homozygotes [58]. Another study of 61 patients with HF, who were on metoprolol (β1 selective), confirmed that the Arg389 homozygotes had a greater improvement in LVEF than Gly389 carriers and also that Gly49 allele carriers had a significantly greater reduction in left ventricular end diastolic diameter than Ser49 homozygotes [79]. In another study of 80 patients with HF on carvedilol, there was a trend towards a greater improvement in LVEF in Glu27 carriers compared to Gln27 homozygotes [80]. In a cohort of 199 Caucasians with stable HF who were all treated with either carvedilol or bisoprolol (β1AR selective), no association was found between improvement in LVEF and ADRB1 or ADRB2 SNP [77]. More recently in a study of 54 patients with HF, individuals who were both Arg389 homozygotes and {alpha}2cdeletion(322-325) carriers had a greater improvement in LVEF than other diplotypes in response to metoprolol [81]. Fig. 3 demonstrates a fixed effects non-standardised meta-analysis of the three studies [58,77,79] looking at the effect of the Arg389Gly SNP on LV remodelling with β blockers, showing that Arg389 homozygotes benefit, with a significant improvement in LVEF of 5% more than Gly389 carriers (dominant model for Arg389). These results would complement and support the experimental evidence.


Figure 03
View larger version (13K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 3 Forest plot showing the results of a meta-analysis of 3 pharmacogenetic studies looking at the effect of ADRB1 Arg389Gly SNP on left ventricular remodelling with β blockers. The x axis is the mean difference in change in left ventricular ejection fraction (%) (after β blocker use) between Arg homozygotes and Gly carriers [change in left ventricular ejection fraction (%) (after β blocker use) in Arg homozygotes minus change in left ventricular ejection fraction (%) (after β blocker use) in Gly carriers]. The meta-analysis was performed using the "Inter-cooled Stat 9.2 (STB-38:sbe16)" package by Sharp and Sterne. (CI, Confidence Interval).

 
6.5.2. Effect on survival
In a retrospective analysis of a case-control study involving 375 patients with DCM (receiving β blockers) and 492 controls, genotyping for ADRB1 SNPs, revealed a significant association between 5 year survival rate and the Ser49Gly polymorphism [82]. However, this study was limited by some participants not having systolic dysfunction (ejection fraction above 50%) and the details of β blocker treatment were unclear in others. In a substudy of MERIT-HF, in which 307 patients on metoprolol were genotyped for the Arg389Gly ADRB1 SNP and followed for a mean of 12 months, no survival benefit was conferred by genotype [78]. Interestingly in the placebo group who were also genotyped (approximately 300 patients), genotype did not influence survival either. In the BEST study, in which 1040 patients were genotyped for the ADRB SNPs, Arg389 homozygotes treated with bucindolol had a significant reduction in (adjusted) mortality compared to Arg389 homozygotes on placebo whereas there was no difference in outcome between Gly389 carriers on bucindolol and those on placebo [40].

It is important that studies that evaluate pharmacogenetic interactions utilize standard medication regimes. All patients should receive the same β blocker, should be uptitrated to the maximal possible dose and data on dose should be accurately recorded. The same β blocker should be used for all patients because the mechanism of benefit may be different between different β blockers. For example, in addition to blockade of β1AR, metoprolol and bisoprolol are inverse agonists whereas carvedilol has no inverse activity, dissociates slowly from the receptor, is a free radical scavenger and is an {alpha}1 receptor antagonist as well as being a non-selective β blocker.


   7. Conclusions
Top
 Abstract
 1. Introduction
 2. β adrenergic receptors...
 3. β adrenergic receptor...
 4. Evidence for functional...
 5. Evidence for functional...
 6. Role of ADRB...
 7. Conclusions
References
 
The heterogeneity of both the HF phenotype and response to treatment is well recognised and it is likely, that genetic differences form a large component of these differences. βAR mediate both the cardiac response to exercise and the excessive sympathetic activity in HF which contributes to cardiac remodelling. Functional polymorphisms of ADRB cardiac genes, though not causative in human HF, are likely to have a modulatory capacity. They also seem to influence exercise capacity and may have an effect on arrhythmias. A recent study has suggested that ADRB2 variants may be associated with differences in lung function in HF patients [83].

It should be noted that there are faults in the design of many of the studies presented in this review. Most are medium sized (approximately 200-400 subjects) and to detect a modulatory effect a much larger number of subjects are needed. In addition, the sample cohorts are not matched for sex, race and cause and severity of heart failure, therefore it is likely that a genetic effect specific to sex, race or at a particular stage of disease or a combination of above will not be replicated when these parameters are changed. The use of multiple testing (through adjustments and interactions) in these studies tends to generate false-positives and the use of subgroup analysis further reduces the sample size, whilst increasing the number of hypotheses tested. Many of these studies are cross-sectional and not prospective based which would have more power to detect an effect [84]. Given these concerns, further studies that address these issues explicitly, are needed. A meta-analysis was not done on these studies, because for each SNP and associated phenotype there were at the most three studies and in many of the studies the primary data were not presented. In view of their potential modulator role, experimental design and sampling strategies, which allow robust gene-gene and gene-environment interaction, should be utilized. Haplotype (or combined gene SNP) analysis, with other functional SNPs in genes which may have a role in HF pathogenesis should be carried out, such as those that code for sarcometric proteins, cell survival or oxidative stress.

With respect to pharmacogenetics, while ADRB polymorphisms have been shown to interact with different β blockers to influence haemodynamics and survival in patients with HF, results have been inconsistent. Again faults in study design are important. The huge inter-individual variability in response to βAR blockade suggests that a pharmacogenetic interaction exists and if accurately understood could predict who will respond best and worst. Knowledge of the mechanisms underlying the response to pharmacogenetic interaction between β blockers and ADRB polymorphisms is increasing. Putative explanations are seen from the transgenic mice models and other novel studies described earlier [40,60]. The substantial difference in functional response between the Arg389 and Gly389 receptors to certain β blockers is exciting, and the fact that this is mirrored by data from small studies examining effects on LV remodelling, as evidenced by the meta-analysis, is clinically relevant. It is important to state however, that the meta-analysis is limited by small sample sizes, only 3 studies and the inherent limitations of such studies with the tendency for publication of only positive gene association studies. In terms of the 3 studies, the patient cohorts were not identical, there were differences in study design, and different β blockers were used.

Our increasing understanding of βAR signalling pathways and the mechanism of benefit of βAR blockade will provide more information about the impact of ADRB polymorphisms. In order to define the precise role of ADRB polymorphisms in the development and outcome of HF, further large-scale prospective trials involving targeted interactions with other specific genes, environmental factors and β blockers are warranted.


   References
Top
 Abstract
 1. Introduction
 2. β adrenergic receptors...
 3. β adrenergic receptor...
 4. Evidence for functional...
 5. Evidence for functional...
 6. Role of ADRB...
 7. Conclusions
 References
 

  1. Davies M.K., Hobbs F.D.R., Davis R.C., et al. Prevalence of left-ventricular systolic dysfunction and heart failure in the Echocardiographic Heart of England Screening study: a population based study. Lancet (2001) 358:439–444.[CrossRef][Web of Science][Medline]
  2. The National Institute for Clinical Excellence. Management of chronic heart failure in adults in primary and secondary care. NICE Guideline (2003) vol. 5. ed.
  3. Cleland J.G.F., Gemmell I., Khand A., Boddy A. Is the prognosis of heart failure improving? Eur J Heart Fail (1999) 1:229–241.[Abstract/Free Full Text]
  4. Ho K.K.L., Anderson K.M., Kannel W.B., Grossman W., Levy D. Survival after the onset of congestive-heart-failure in Framingham Heart-Study subjects. Circulation (1993) 88:107–115.[Abstract/Free Full Text]
  5. Dzau V.J., Packer M., Lilly L.S., Swartz S.L., Hollenberg N.K., Williams G.H. Prostaglandins in severe congestive heart-failure—relation to activation of the renin-angiotensin system and hyponatremia. N Engl J Med (1984) 310:347–352.[Abstract]
  6. Eichhorn E.J., Bristow M.R. Medical therapy can improve the biological properties of the chronically failing heart: a new era in the treatment of heart failure. Circulation (1996) 94:2285–2296.[Abstract/Free Full Text]
  7. Eisenhofer G., Friberg P., Rundqvist B., et al. Cardiac sympathetic nerve function in congestive heart failure. Circulation (1996) 93:1667–1676.[Abstract/Free Full Text]
  8. Mann D.L., Bristow M.R. Mechanisms and models in heart failure: the biomechanical model and beyond. Circulation (2005) 111:2837–2849.[Free Full Text]
  9. Bristow M.R., Gilbert E.M., Abraham W.T., et al. Carvedilol produces dose-related improvements in left ventricular function and survival in subjects with chronic heart failure. Circulation (1996) 94:2807–2816.[Abstract/Free Full Text]
  10. MERIT-HF Study G. Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in-Congestive Heart Failure (MERIT-HF). Lancet (1999) 353:2001–2007.[CrossRef][Web of Science][Medline]
  11. Kuschel M., Zhou Y.Y., Cheng H.P., et al. G(1) protein-mediated functional compartmentalization of cardiac beta(2)-adrenergic signaling. J Biol Chem (1999) 274:22048–22052.[Abstract/Free Full Text]
  12. Brodde O.E., Michel M.C. Adrenergic and muscarinic receptors in the human heart. Pharmacol Rev (1999) 51:651–689.[Abstract/Free Full Text]
  13. Gerhardstein B.L., Puri T.S., Chien A.J., Hosey M.M. Identification of the sites phosphorylated by cyclic AMP-dependent protein kinase on the subunit of L-type voltage-dependent calcium channels. Biochemistry (1999) 38:10361–10370.[CrossRef][Web of Science][Medline]
  14. Simmerman H.K., Jones L.R. Phospholamban: protein structure, mechanism of action, and role in cardiac function. Physiol Rev (1998) 78:921–947.[Abstract/Free Full Text]
  15. Sulakhe P.V., Vo X.T. Regulation of phospholamban and troponin-I phosphorylation in the intact rat cardiomyocytes by adrenergic and cholinergic roles of cyclic-nucleotides, calcium, protein-kinases and phosphatases and depolarization. Mol Cell Biochem (1995) 149:103–126.[CrossRef][Web of Science][Medline]
  16. Zhu W.Z., Wang S.Q., Chakir K., et al. Linkage of {beta}1-adrenergic stimulation to apoptotic heart cell death through protein kinase A-independent activation of Ca2+/calmodulin kinase II. J Clin Invest (2003) 111:617–625.[CrossRef][Web of Science][Medline]
  17. Sucharov C.C., Mariner P.D., Nunley K.R., Long C., Leinwand L., Bristow M.R. A beta1-adrenergic receptor CaM kinase II-dependent pathway mediates cardiac myocyte fetal gene induction. Am J Physiol, Heart Circ Physiol (2006) 291:H1299–H1308.[Abstract/Free Full Text]
  18. Packer M. Neuro-hormonal interactions and adaptations in congestive heart-failure. Circulation (1988) 77:721–730.[Free Full Text]
  19. Communal C., Singh K., Sawyer D.B., Colucci W.S. Opposing effects of {beta}1- and {beta}2-adrenergic receptors on cardiac myocyte apoptosis : role of a pertussis toxin-sensitive G protein. Circulation (1999) 100:2210–2212.[Abstract/Free Full Text]
  20. Mann D.L., Kent R.L., Parsons B., Cooper G. Adrenergic effects on the biology of the adult mammalian cardiocyte. Circulation (1992) 85:790–804.[Abstract/Free Full Text]
  21. Engelhardt S., Hein L., Wiesmann F., Lohse M.J. Progressive hypertrophy and heart failure in beta 1-adrenergic receptor transgenic mice. Proc Nat Acad Sci (1999) 96:7059–7064.[Abstract/Free Full Text]
  22. Bristow M.R., Ginsburg R., Minobe W., et al. Decreased catecholamine sensitivity and beta-adrenergic-receptor density in failing human hearts. N Engl J Med (1982) 307:205–211.[Abstract]
  23. Tan L.B., Benjamin I.J., Clark W.A. Beta-adrenergic-receptor desensitization may serve a cardioprotective role. Cardiovasc Res (1992) 26:608–614.[Abstract/Free Full Text]
  24. Fowler M.B., Bristow M.R. Rationale for beta-adrenergic blocking-drugs in cardiomyopathy. Am J Cardiol (1985) 55:D120–D124.[CrossRef][Medline]
  25. Neumann J., Scholz H., Doring V., Schmitz W., Vonmeyerinck L., Kalmar P. Increase in myocardial Gi-proteins in heart-failure. Lancet (1988) 2:936–937.[Web of Science][Medline]
  26. Ungerer M., Parruti G., Bohm M., et al. Expression of beta-arrestins and beta-adrenergic-receptor kinases in the failing human heart. Circ Res (1994) 74:206–213.[Abstract/Free Full Text]
  27. Gong H.B., Sun H., Koch W.J., et al. Specific beta(2)AR blocker ICI 118,551 actively decreases contraction through a G(i)-coupled form of the beta(2)AR in myocytes from failing human heart. Circulation (2002) 105:2497–2503.[Abstract/Free Full Text]
  28. Podlowski S., Wenzel K., Luther H.P., et al. Beta1-adrenoceptor gene variations: a role in idiopathic dilated cardiomyopathy? J Mol Med (2000) 78:87–93.[CrossRef][Web of Science][Medline]
  29. Terra S.G., McGorray S.P., Wallace M.R., Picoult-Newberg L., Pepine C.J., Johnson J.A. Linkage disequilibrium of common beta-1 adrenergic receptor polymorphisms. Clin Pharmacol Ther (2002) 71:70.
  30. Brodde O.E., Leineweber K. B eta(2)-adrenoceptor gene polymorphisms. Pharmacogenet Genomics (2005) 15:267–275.[Web of Science][Medline]
  31. Liggett S.B. Molecular and genetic basis of beta(2)-adrenergic receptor function. J Allergy Clin Immunol (1999) 104:S42–S46.[CrossRef][Web of Science][Medline]
  32. Scott M.G.H., Swan C., Wheatley A.P., Hall I.P. Identification of novel polymorphisms within the promoter region of the human beta(2) adrenergic receptor gene. Br J Pharmacol (1999) 126:841–844.[CrossRef][Web of Science][Medline]
  33. Dewar J.C., Wheatley A.P., Venn A., Morrison J.F.J., Britton J., Hall I.P. Beta2-adrenoceptor polymorphisms are in linkage disequilibrium, but are not associated with asthma in an adult population. Clin Exp Allergy (1998) 28:442–448.[CrossRef][Web of Science][Medline]
  34. Drysdale C.M., McGraw D.W., Stack C.B., et al. Complex promoter and coding region beta 2-adrenergic receptor haplotypes alter receptor expression and predict in vivo responsiveness. PNAS (2000) 97:10483–10488.[Abstract/Free Full Text]
  35. Mason D.A., Moore J.D., Green S.A., Liggett S.B. A gain-of-function polymorphism in a G-protein coupling domain of the human beta 1-adrenergic receptor. J Biol Chem (1999) 274:12670–12674.[Abstract/Free Full Text]
  36. Rathz D.A., Gregory K.N., Fang Y., Brown K.M., Liggett S.B. Hierarchy of polymorphic variation and desensitization permutations relative to beta(1)- and beta(2)-adrenergic receptor signaling. J Biol Chem (2003) 278:10784–10789.[Abstract/Free Full Text]
  37. Sandilands A.J., O'Shaughnessy K.M., Brown M.J. Greater inotropic and cyclic AMP responses evoked by noradrenaline through Arg389 [beta]1-adrenoceptors versus Gly389 [beta]1-adrenoceptors in isolated human atrial myocardium (2003) 138:386–392.
  38. Molenaar P., Rabnott G., Yang I., et al. Conservation of the cardiostimulant effects of (–)-norepinephrine across Ser49Gly and Gly389Arg beta1-adrenergic receptor polymorphisms in human right atrium in vitro. J Am Coll Cardiol (2002) 40:1275–1282.[Abstract/Free Full Text]
  39. Ryden M., Hoffstedt J., Eriksson P., Bringman S., Arner P. The Arg 389 Gly beta(1)-adrenergic receptor gene polymorphism and human fat cell lipolysis. Int J Obes (2001) 25:1599–1603.[CrossRef][Web of Science][Medline]
  40. Liggett S.B., Mialet-Perez J., Thaneemit-Chen S., et al. A polymorphism within a conserved beta1-adrenergic receptor motif alters cardiac function and beta-blocker response in human heart failure. PNAS (2006) 103:11288–11293.[Abstract/Free Full Text]
  41. Bengtsson K., Melander O., Orho-Melander M., et al. Polymorphism in the {beta}1-adrenergic receptor gene and hypertension. Circulation (2001) 104:187–190.[Abstract/Free Full Text]
  42. Humma L.M., Puckett B.J., Richardson H.E., et al. Effects of beta(1)-adrenoceptor genetic polymorphisms on resting hemodynamics in patients undergoing diagnostic testing for ischemia. Am J Cardiol (2001) 88:1034–1037.[CrossRef][Web of Science][Medline]
  43. Buscher R., Belger H., Eilmes K.J., et al. In-vivo studies do not support a major functional role for the Gly(389)Arg beta(1)-adrenoceptor polymorphism in humans. Pharmacogenetics (2001) 11:199–205.[CrossRef][Web of Science][Medline]
  44. Xie H.G., Dishy V., Sofowora G., et al. Arg(389)Gly beta(1)-adrenoceptor polymorphism varies in frequency among different ethnic groups but does not alter response in vivo. Pharmacogenetics (2001) 11:191–197.[CrossRef][Web of Science][Medline]
  45. Bruck H., Leineweber K., Ternme T., et al. The Arg389GIy beta(1)-adrenoceptor polymorphism and catecholamine effects on plasma-renin activity. J Am Coll Cardiol (2005) 46:2111–2115.[Abstract/Free Full Text]
  46. La Rosee K., Huntgeburth M., Rosenkranz S., Bohm M., Schnabel P. The Arg389Gly beta(1)-adrenoceptor gene polymorphism determines contractile response to catecholamines. Pharmacogenetics (2004) 14:711–716.[CrossRef][Web of Science][Medline]
  47. Rathz D.A., Brown K.M., Kramer L.A., Liggett S.B. Amino acid 49 polymorphisms of the human beta(1)-adrenergic receptor affect agonist-promoted trafficking. J Cardiovasc Pharmacol (2002) 39:155–160.[CrossRef][Web of Science][Medline]
  48. Levin M.C., Marullo S., Muntaner O., Andersson B., Magnusson Y. The myocardium-protective Gly-49 variant of the beta 1-adrenergic receptor exhibits constitutive activity and increased desensitization and down-regulation. J Biol Chem (2002) 277:30429–30435.[Abstract/Free Full Text]
  49. Sandilands A., Yeo G., Brown M.J., O'Shaughnessy K.M. Functional responses of human beta 1 adrenoceptors with defined haplotypes for the common 389R > G and 49S > G polymorphisms. Pharmacogenetics (2004) 14:343–349.[CrossRef][Web of Science][Medline]
  50. Green S.A., Turki J., Innis M., Liggett S.B. Amino-terminal polymorphisms of the human beta(2)-adrenergic receptor impart distinct agonist-promoted regulatory properties (Vol 33, Pg 9414, 1994). Biochemistry (1994) 33:14368.[Medline]
  51. Chong L.K., Peachell P.T. Influence of genetic polymorphisms in the beta(2)-adrenoceptor on desensitization in human lung mast cells. Br J Pharmacol (2000) 129:U28.
  52. Bruck H., Leineweber K., Buscher R., et al. The Gln(27)Glu beta(2)-adrenoceptor polymorphism slows the onset of desensitization of cardiac functional responses in vivo. Pharmacogenetics (2003) 13:59–66.[CrossRef][Web of Science][Medline]
  53. Bruck H., Leineweber K., Beilfuss A., et al. Genotype-dependent time course of lymphocyte beta(2)-adrenergic receptor down-regulation. Clin Pharmacol Ther (2003) 74:255–263.[CrossRef][Web of Science][Medline]
  54. Dishy V., Sofowora G.G., Xie H.G., et al. The effect of common polymorphisms of the {beta}2-adrenergic receptor on agonist-mediated vascular desensitization. N Engl J Med (2001) 345:1030–1035.[Abstract/Free Full Text]
  55. Green S.A., Cole G., Jacinto M., Innis M., Liggett S.B. A polymorphism of the human beta(2)-adrenergic receptor within the 4Th transmembrane domain alters ligand-binding and functional-properties of the receptor. J Biol Chem (1993) 268:23116–23121.[Abstract/Free Full Text]
  56. Turki J., Lorenz J.N., Green S.A., Donnelly E.T., Jacinto M., Liggett S.B. Myocardial signaling defects and impaired cardiac function of a human beta(2)-adrenergic receptor polymorphism expressed in transgenic mice. Proc Nat Acad Sci U S A (1996) 93:10483–10488.[Abstract/Free Full Text]
  57. Brodde O.E., Buscher R., Tellkamp R., Radke J., Dhein S., Insel P.A. Blunted cardiac responses to receptor activation in subjects with Thr164Ile beta(2)-adrenoceptors. Circulation (2001) 103:1048–1050.[Abstract/Free Full Text]
  58. Perez J.M., Rathz D.A., Petrashevskaya N.N., et al. Liggett SB. [beta]1-adrenergic receptor polymorphisms confer differential function and predisposition to heart failure. Nat Med (2003) 9:1300–1305.[CrossRef][Web of Science][Medline]
  59. Akhter S.A., D'Souza K.M., Petrashevskaya N.N., Mialet-Perez J., Liggett S.B. Myocardial beta(1)-adrenergic receptor polymorphisms affect functional recovery after ischemic injury. Am J Physiol, Heart Circ Physiol (2006) 290:H1427–H1432.[Abstract/Free Full Text]
  60. Rochais F., Vilardaga J.P., Nikolaev V.O., Bunemann M., Lohse M.J., Engelhardt S. Real-time optical recording of {beta}1-adrenergic receptor activation reveals supersensitivity of the Arg389 variant to carvedilol. J Clin Invest (2007) 117:229–235.[CrossRef][Web of Science][Medline]
  61. Tesson F., Charron P., Peuchmaurd M., et al. Characterization of a unique genetic variant in the beta(1)-adrenooeptor gene and evaluation of its role in idiopathic dilated cardiomyopathy. J Mol Cell Cardiol (1999) 31:1025–1032.[CrossRef][Web of Science][Medline]
  62. Small K.M., Wagoner L.E., Levin A.M., Kardia S.L.R., Liggett S.B. Synergistic polymorphisms of beta(1)- and alpha(2C)-adrenergic receptors and the risk of congestive heart failure. N Engl J Med (2002) 347:1135–1142.[Abstract/Free Full Text]
  63. Small K.M., Forbes S.L., Rahman F.F., Bridges K.M., Liggett S.B. A four amino acid deletion polymorphism in the third intracellular loop of the human alpha(2C)-adrenergic receptor confers impaired coupling to multiple effectors. J Biol Chem (2000) 275:23059–23064.[Abstract/Free Full Text]
  64. Metra M., Zani C., Covolo L., et al. Role of beta 1- and alpha 2c-adrenergic receptor polymorphisms and their combination in heart failure: a case-control study. Eur J Heart Fail (2006) 8:131–135.[Abstract/Free Full Text]
  65. Covolo L., Gelatti U., Metra M., et al. Role of beta 1- and beta 2-adrenoceptor polymorphisms in heart failure: a case-control study. Eur Heart J (2004) 25:1534–1541.[Abstract/Free Full Text]
  66. Liggett S.B., Wagoner L.E., Craft L.L., et al. The Ile164 beta(2)-adrenergic receptor polymorphism adversely affects the outcome of congestive heart failure. J Clin Invest (1998) 102:1534–1539.[Web of Science][Medline]
  67. Borjesson M., Magnusson Y., Hjalmarson A., Andersson B. A novel polymorphism in the gene coding for the beta(1)-adrenergic receptor associated with survival in patients with heart failure. Eur Heart J (2000) 21:1853–1858.[Abstract/Free Full Text]
  68. Forleo C., Resta N., Sorrentino S., et al. Association of beta-adrenergic receptor polymorphisms and progression to heart failure in patients with idiopathic dilated cardiomyopathy. Am J Med (2004) 117:451–458.[CrossRef][Web of Science][Medline]
  69. de Groote P., Lamblin N., Helbecque N., et al. The impact of beta-adrenoreceptor gene polymorphisms on survival in patients with congestive heart failure. Eur J Heart Fail (2005) 7:966–973.[Abstract/Free Full Text]
  70. Shin J., Lobmeyer M.T., Gong Y., et al. Relation of [beta]2-adrenoceptor haplotype to risk of death and heart transplantation in patients with heart failure. Am J Cardiol (2007) 99:250–255.[CrossRef][Web of Science][Medline]
  71. Iwai C., Akita H., Shiga N., et al. Suppressive effect of the Gly389 allele of the beta 1-adrenergic receptor gene on the occurrence of ventricular tachycardia in dilated cardiomyopathy. Circulation (2002) 66:723–728.[CrossRef]
  72. Wagoner L.E., Craft L.L., Singh B., et al. Polymorphisms of the beta(2)-adrenergic receptor determine exercise capacity in patients with heart failure. Circ Res (2000) 86:834–840.[Abstract/Free Full Text]
  73. Wolk R., Snyder E.M., Somers V.K., Turner S.T., Olson L.J., Johnson B.D. Arginine 16 glycine [beta]2-adrenoceptor polymorphism and cardiovascular structure and function in patients with heart failure. J Am Soc Echocardiogr (2007) 20:290–297.[CrossRef][Web of Science][Medline]
  74. Wagoner L.E., Craft L.L., Zengel P., et al. Polymorphisms of the [beta]1-adrenergic receptor predict exercise capacity in heart failure. Am Heart J (2002) 144:840–846.[CrossRef][Web of Science][Medline]
  75. Sandilands A.J., Parameshwar J., Large S., Brown M.J., O'Shaughnessy K.M. Confirmation of a role for the 389R>G {beta}-1 adrenoceptor polymorphism on exercise capacity in heart failure. Heart (2005) 91:1613–1614.[Free Full Text]
  76. Defoor J., Martens K., Zielinska D., et al. The CAREGENE study: polymorphisms of the beta(1)-adrenoceptor gene and aerobic power in coronary artery disease. Eur Heart J (2006) 27:808–816.[Abstract/Free Full Text]
  77. de Groote P., Helbecque N., Lamblin N., et al. Association between beta-1 and beta-2 adrenergic receptor gene polymorphisms and the response to beta-blockade in patients with stable congestive heart failure. Pharmacogenet Genomics (2005) 15:137–142.[Web of Science][Medline]
  78. White H.L., de Boer R.A., Maqbool A., et al. An evaluation of the beta-1 adrenergic receptor Arg389Gly polymorphism in individuals with heart failure: a MERIT-HF sub-study. Eur J Heart Fail (2003) 5:463–468.[CrossRef][Web of Science][Medline]
  79. Terra S.G., Hamilton K.K., Pauly D.F., et al. Beta1-adrenergic receptor polymorphisms and left ventricular remodeling changes in response to beta-blocker therapy. Pharmacogenet Genomics (2005) 15:227–234.[Medline]
  80. Kaye D.M., Smirk B., Williams C., Jennings G., Esler M., Holst D. Beta-Adrenoceptor genotype influences the response to carvedilol in patients with congestive heart failure. Pharmacogenetics (2003) 13:379–382.[CrossRef][Web of Science][Medline]
  81. Lobmeyer M.T., Gong Y., Terra S.G., et al. Synergistic polymorphisms of beta(1) and alpha(2c)-adrenergic receptors and the influence on left ventricular ejection fraction response to beta-blocker therapy in heart failure. Pharmacogenet Genomics (2007) 17:277–282.[Web of Science][Medline]
  82. Magnusson Y., Levin M.C., Eggertsen R., et al. Ser49Gly of beta(1)-adrenergic receptor is associated with effective beta-blocker dose in dilated cardiomyopathy. Clin Pharmacol Ther (2005) 78:221–231.[CrossRef][Web of Science][Medline]
  83. Snyder E.M., Turner S.T., Johnson B.D. Beta(2)-adrenergic receptor genotype and pulmonary function in patients with heart failure. Chest (2006) 130:1527–1534.[CrossRef][Web of Science][Medline]
  84. Humphries S.E., Hawe E., Dhamrait S., Miller G.J., Talmud P.J. In search of genetic precision. Lancet (2003) 361:1908–1909.[Web of Science][Medline]

Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 J Am Coll CardiolHome page
A. J. Sehnert, S. E. Daniels, M. Elashoff, J. A. Wingrove, C. R. Burrow, B. Horne, J. B. Muhlestein, M. Donahue, S. B. Liggett, J. L. Anderson, et al.
Lack of Association Between Adrenergic Receptor Genotypes and Survival in Heart Failure Patients Treated With Carvedilol or Metoprolol
J. Am. Coll. Cardiol., August 19, 2008; 52(8): 644 - 651.
[Abstract] [Full Text] [PDF]

Home page
 J Am Coll CardiolHome page
D. L. Mann and D. M. McNamara
Pharmacogenomics and the Failing Heart: Are We Waiting for Godot?
J. Am. Coll. Cardiol., August 19, 2008; 52(8): 652 - 654.
[Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (5)
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Muthumala, A.
Right arrow Articles by Humphries, S. E.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Muthumala, A.
Right arrow Articles by Humphries, S. E.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?