10.1586/14779072.6.2.145 © 2008 Future Drugs Ltd ISSN 1477-9072 145

Editorial

β1-adrenoceptor polymorphisms: deviation of clinical outcome with use of β-blockers in ventricular dysfunctionExpert Rev. Cardiovasc. Ther. 6(2), 145–147 (2008)

Reza Tabrizchi, PhDProfessor of Pharmacology, Division of BioMedical Sciences, Faculty of Medicine, Memorial University of Newfoundland, St. John’s, NL, A1B 3V6, CanadaTel.: +1 709 777 6864Fax: +1 709 777 7010rtabrizc@mun.ca

While the debate continues regarding the role of polymorphisms of β1-adrenoceptors on the clinical

outcomes and beneficial effects of β-blockers in patients with heart failure, we need to step back and examine the

evidence in the peer-reviewed literature more closely.

Currently, it is believed that the most com-mon polymorphisms for the β1-receptorare a serine (Ser) to glycine (Gly) at posi-tion 49 and arginine (Arg) to Gly at posi-tion 389 [1]. The β-receptor is a G-protein-coupled, seven transmembrane-spanningentity in which the amino acid at position49 is located in the extracellular space,while the amino acid at position 389 ispositioned within the intracellulardomain [1]. It has been reported that theintracellular amino acid located at posi-tion 389 is an important site for the acti-vation of adenylyl cyclase [2]. This evi-dence could be taken to support thesuggestion that polymorphisms of theβ1-adrenoceptor at such sites mayaccount for differences in response toβ-blockers in the population.

It is recognized that ejection fraction isan important predictor of survival inpatients with left ventricular dysfunc-tion. Patients treated with β-blockers andwho show marked improvement in leftventricular ejection fraction have anexcellent prognosis [3]. Of special note isan earlier review of the literature thatappears to indicate that the use ofβ-blockers improved left ventricular func-tion in almost all of the studies in whichthis class of drugs was used. Moreover, itappeared that the differences amongβ-blockers in improving left ventricularejection function were small, perhapseven nonsignificant. However, it was alsoapparent that differences exist in survival

rate when various β-blockers were com-pared, leading to the suggestion thatmechanisms other than improvement ofleft ventricular function by these drugsmay have been responsible for the differ-ences in the rate of survival [4]. This couldbe taken as evidence that the clinicaleffects of β-blockers are multifactorialbut, perhaps more importantly, the over-all beneficial effects are most likely linkedto the unique nature of the individualmolecule – the pharmacokinetic andpharmacodynamic considerations.

There have been a number of studieswhich seem to suggest that interindivid-ual differences in response to β-blockersin patients with ventricular dysfunctionare associated with the genetic variationin the β1-adrenoceptor [5,6]. Essentially,the current view is that subjects who areArg homozygous or heterozygous at posi-tion 389 and those who are Serhomozygous or heterozygous at position49 are more likely to respond favorablyto treatment with a β-blocker. By con-trast, subjects who are Gly homozygousat position 389 and Gly homozygous atposition 49 may respond less favorably toa β-blocker. However, it is evident that

“...the use of β-blockers improved left ventricular

function in almost all of the studies in which this class of

drugs was used.”

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146 Expert Rev. Cardiovasc. Ther. 6(2), (2008)

Editorial Tabrizchi

the sample size in most of these studies is small and thisappears to be a major limitation associated with these clinicalinvestigations. In addition, there are also reports that havefailed to show that polymorphisms of β1-adrenoceptors inamino acids 389 and 49 show any significant impact in out-come of treatment with β-blockers [7,8]. Moreover, these reportsalso lack the depth and breadth that is required to purport aclear-cut view that indeed β1-adrenoceptor polymorphisms atposition 389 and 49 have no impact on the responsiveness toβ-blockers, and in the beneficial clinical outcome of patientswith ventricular dysfunction.

Recently, it was reported that bucindolol significantlyincreased the survival rate of patients with left ventricular dys-function who were Arg-389 carriers (hazard ratio [HR]: 0.62;95% confidence interval [CI]: 0.4–0.96; p = 0.03) withoutany beneficial effects in those that were Gly-389 carriers (HR:0.9; 95% CI: 0.62–1.30; p = 0.57) versus placebo. Further-more, bucindolol decreased hospitalization compared withplacebo (HR: 0.64; 95% CI: 0.46–0.88; p = 0.006) in Arg car-riers, while Gly carriers showed no benefits with β-blockertreatment in comparison with placebo (HR: 0.86; 95% CI:0.64–1.15; p = 0.30) [9]. Surprisingly, it seems that there wereno trends by genotype in changes to heart rate or left ventricu-lar ejection fraction during the treatment with bucindolol.This implied that while there appears to be differences in thebeneficial effects of bucindolol based on β1-adrenoceptor poly-morphisms of Arg and Gly, at position 389, improvement inejection fraction did not appear to be the determining factorfor the overall beneficial effects of this molecule [9]. Needless tosay, this finding further complicates the concept that the sig-nificant beneficial effects of β-blockers in the more suitablepolymorphic form of the receptor is the result of improvedejection fraction. Moreover, such a finding seems to be in linewith the view that while there are differences in the beneficialeffects of various β-blockers, the benefits appear not to berelated to the improvement in ejection fraction. This leads tothe conclusion that we do not yet understand the basis bywhich β-blockers produce their beneficial clinical effects inpatients with ventricular dysfunction.

Unfortunately, it also seems that basic scientific experimentaldata have provided limited answers to account for differences inthe behavior of β-blockers with respect to the polymorphicnature of β1-adrenoceptors. For example, in transgenic mice,hearts from animals that were Arg-386 carriers showed protec-tive loss of β1-adrenoceptor-mediated responses compared withGly-386 carriers over time. However, the hearts from Arg-389carriers paradoxically were found to be more sensitive to theactions of the β-blocker, propranolol [10]. This is in contrast tothe evidence provided from explants of right ventricular trabec-ulae tissue of patients with left ventricular dysfunction witheither Arg-389 carriers versus Gly carriers. Essentially, it seemsthat Gly patients have a lower β1-adrenoceptor signaling andlower efficacy exists to the actions of isoprenaline comparedwith Arg carriers [9]. The latter evidence appears to be consistent

with the findings that the maximal isoprenaline-stimulated ade-nylyl cyclase activity levels were markedly higher for Arg-389compared with Gly-389 for β1-adrenoceptor expressed in Chi-nese hamster fibroblast (HW-1102) cells [2]. However, thesefindings seem to be in contrast to the data obtained from trans-genic mice [10]. Site-directed mutagenesis and recombinantexpression studies at position 49 of the β1-adrenoceptor usingthe human embryonic kidney (HEK)-293 cells have revealedthat the Gly form undergoes a significantly higher degree ofdownregulation than the Ser type [11]. It is evident that findingsfrom the bench do not readily provide an adequate answer as towhy β1-adrenoceptor polymorphism at locations 49 and 389would produce either a beneficial, detrimental or no effect inpatients with ventricular dysfunction.

The therapeutic effects of β-blockers in the context ofgenetic make-up are complex. It is also recognized that the ini-tiation of β-blocker therapy can precipitate worsening heartfailure or very limited beneficial effects in certain patients.Nonetheless, there is very little doubt that treatment withβ-blockers should be considered as an important pillar of anystrategy for patients with left ventricular systolic dysfunction.However, there are also challenges to initiating therapy withβ-blockers in patients with ventricular dysfunction. Thus, it isprudent that healthcare professionals who intend to use suchcompounds recognize that demographic factors can have animpact on the outcome of care. At present, there is no simplealgorithm that can easily be employed to distill and crystallizethe beneficial outcome of treatment with a β-blocker based onthe polymorphisms of the β1-adrenoceptors. Notwithstandingthe fact that the occurrence of polymorphisms in β2-adreno-ceptors and α2C-adrenoceptors could also have an impact onthe clinical outcome of treatments with various β-blockers, itis clear that more evidence is needed to establish a meaningfulguide for the use of β-blockers in patients with ventricular dys-function with differing genetic make-up. Until such evidencebecomes available, healthcare professionals must apply due dil-igence and monitor their patients that are treated with thisclass of drugs very carefully to provide the best care and clinicaloutcome for their patients.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement withany organization or entity with a financial interest in or financial conflictwith the subject matter or materials discussed in the manuscript. Thisincludes employment, consultancies, honoraria, stock ownership or options,expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

“...there is no simple algorithm that can easily be employed to distill and crystallize the beneficial outcome of treatment with a β-blocker based on

the polymorphisms of the β1-adrenoceptors.”

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EditorialUse of β-blockers in ventricular dysfunction

www.future-drugs.com 147

References

1 Sandilands AJ, O’Shaughnessy KM. The functional significance of genetic variation within the β1-adrenoceptor. Br. J. Clin. Pharmacol. 60, 235–243 (2005).

2 Mason DA, Moore DJ, Green SA et al. A gain-of-function polymorphism in a G-protein coupling domain of the human β1-adrenergic receptor. J. Biol. Chem. 274, 12670–12674 (1999).

3 Metra M, Nodari S, Parrinello G et al. Marked improvement in left ventricular ejection fraction during long-term β-blockade in patients with chronic heart failure: clinical correlates and prognostic significance. Am. Heart J. 145, 292–299 (2003).

4 Van Campen LC, Visser LC, Visser CA. Ejection fraction improvement by β-blocker treatment in patients with heart failure: an analysis of studies published in the literature. J. Cardiovasc. Pharmacol. 32(Suppl. 1), S31–S25 (1998).

5 Terra SG, Pauly DF, Lee CR et al. β-adrenergic receptor polymorphisms and responses during titration of metoprolol controlled release/extended release in heart failure. Clin. Pharmacol. Ther. 77, 127–137 (2005).

6 Terra SG, Hamilton KK, Pauly DF et al. β1-adrenergic receptor polymorphisms and left ventricular remodeling changes in response to β-blocker therapy. Pharmacogenet. Genomics 15, 227–234 (2005).

7 White HL, de Boer RA, Maqbool A et al. An evaluation of the β-1 adrenergic receptor Arg389Gly polymorphism in individuals with heart failure: a MERIT-HF sub-study. Eur. J. Heart Failure 5, 463–468 (2003).

8 de Groote P, Helbecque N, Lamblin N et al. Association between β-1 and β-2 adrenergic receptor gene polymorphisms and the response to β-blockade in patients with stable congestive heart failure. Pharmacogenet. Genomics 15, 137–142 (2005).

9 Liggett SB, Mialet-Perez J, Thaneemit-Chen S et al. A polymorphism within a conserved β1-adrenergic receptor motif alters cardiac function and β-blocker response in human heart failure. Proc. Natl Acad. Sci. USA 103, 11288–11293 (2006).

10 Mialet Perez J, Rathz DA, Petrashevsskaya NN et al. β1-adrenergic receptor polymorphisms confer differential function and predisposition to heart failure. Nat. Med. 9, 1300–1305 (2003).

11 Rathz DA, Brown KM, Kramer LA et al. Amino acid 49 polymorphisms of the human β1-adrenergic receptor affect agonist-promoted trafficking. J. Cardiovasc. Pharmacol. 39, 155–160 (2002).

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