Abstract
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 common polymorphisms for the β1-receptor are a serine (Ser) to glycine (Gly) at position 49 and arginine (Arg) to Gly at position 389 Citation[1]. The β-receptor is a G-protein-coupled, seven transmembrane-spanning entity in which the amino acid at position 49 is located in the extracellular space, while the amino acid at position 389 is positioned within the intracellular domain Citation[1]. It has been reported that the intracellular amino acid located at position 389 is an important site for the activation of adenylyl cyclase Citation[2]. This evidence could be taken to support the suggestion that polymorphisms of the β1-adrenoceptor at such sites may account for differences in response to β-blockers in the population.
It is recognized that ejection fraction is an important predictor of survival in patients with left ventricular dysfunction. Patients treated with β-blockers and who show marked improvement in left ventricular ejection fraction have an excellent prognosis Citation[3]. Of special note is an earlier review of the literature that appears to indicate that the use of β-blockers improved left ventricular function in almost all of the studies in which this class of drugs was used. Moreover, it appeared that the differences among β-blockers in improving left ventricular ejection function were small, perhaps even nonsignificant. However, it was also apparent that differences exist in survival rate when various β-blockers were compared, leading to the suggestion that mechanisms other than improvement of left ventricular function by these drugs may have been responsible for the differences in the rate of survival Citation[4]. This could be taken as evidence that the clinical effects of β-blockers are multifactorial but, perhaps more importantly, the overall beneficial effects are most likely linked to the unique nature of the individual molecule – the pharmacokinetic and pharmacodynamic considerations.
There have been a number of studies which seem to suggest that interindividual differences in response to β-blockers in patients with ventricular dysfunction are associated with the genetic variation in the β1-adrenoceptor Citation[5,6]. Essentially, the current view is that subjects who are Arg homozygous or heterozygous at position 389 and those who are Ser homozygous or heterozygous at position 49 are more likely to respond favorably to treatment with a β-blocker. By contrast, subjects who are Gly homozygous at position 389 and Gly homozygous at position 49 may respond less favorably to a β-blocker. However, it is evident that the sample size in most of these studies is small and this appears to be a major limitation associated with these clinical investigations. In addition, there are also reports that have failed to show that polymorphisms of β1-adrenoceptors in amino acids 389 and 49 show any significant impact in outcome of treatment with β-blockers Citation[7,8]. Moreover, these reports also lack the depth and breadth that is required to purport a clear-cut view that indeed β1-adrenoceptor polymorphisms at position 389 and 49 have no impact on the responsiveness to β-blockers, and in the beneficial clinical outcome of patients with ventricular dysfunction.
Recently, it was reported that bucindolol significantly increased the survival rate of patients with left ventricular dysfunction who were Arg-389 carriers (hazard ratio [HR]: 0.62; 95% confidence interval [CI]: 0.4–0.96; p = 0.03) without any beneficial effects in those that were Gly-389 carriers (HR: 0.9; 95% CI: 0.62–1.30; p = 0.57) versus placebo. Furthermore, bucindolol decreased hospitalization compared with placebo (HR: 0.64; 95% CI: 0.46–0.88; p = 0.006) in Arg carriers, while Gly carriers showed no benefits with β-blocker treatment in comparison with placebo (HR: 0.86; 95% CI: 0.64–1.15; p = 0.30) Citation[9]. Surprisingly, it seems that there were no trends by genotype in changes to heart rate or left ventricular ejection fraction during the treatment with bucindolol. This implied that while there appears to be differences in the beneficial effects of bucindolol based on β1-adrenoceptor polymorphisms of Arg and Gly, at position 389, improvement in ejection fraction did not appear to be the determining factor for the overall beneficial effects of this molecule Citation[9]. Needless to say, this finding further complicates the concept that the significant beneficial effects of β-blockers in the more suitable polymorphic form of the receptor is the result of improved ejection fraction. Moreover, such a finding seems to be in line with the view that while there are differences in the beneficial effects of various β-blockers, the benefits appear not to be related to the improvement in ejection fraction. This leads to the conclusion that we do not yet understand the basis by which β-blockers produce their beneficial clinical effects in patients with ventricular dysfunction.
Unfortunately, it also seems that basic scientific experimental data have provided limited answers to account for differences in the behavior of β-blockers with respect to the polymorphic nature of β1-adrenoceptors. For example, in transgenic mice, hearts from animals that were Arg-386 carriers showed protective loss of β1-adrenoceptor-mediated responses compared with Gly-386 carriers over time. However, the hearts from Arg-389 carriers paradoxically were found to be more sensitive to the actions of the β-blocker, propranolol Citation[10]. This is in contrast to the evidence provided from explants of right ventricular trabeculae tissue of patients with left ventricular dysfunction with either Arg-389 carriers versus Gly carriers. Essentially, it seems that Gly patients have a lower β1-adrenoceptor signaling and lower efficacy exists to the actions of isoprenaline compared with Arg carriers Citation[9]. The latter evidence appears to be consistent with the findings that the maximal isoprenaline-stimulated adenylyl cyclase activity levels were markedly higher for Arg-389 compared with Gly-389 for β1-adrenoceptor expressed in Chinese hamster fibroblast (HW-1102) cells Citation[2]. However, these findings seem to be in contrast to the data obtained from transgenic mice Citation[10]. Site-directed mutagenesis and recombinant expression studies at position 49 of the β1-adrenoceptor using the human embryonic kidney (HEK)-293 cells have revealed that the Gly form undergoes a significantly higher degree of downregulation than the Ser type Citation[11]. It is evident that findings from the bench do not readily provide an adequate answer as to why β1-adrenoceptor polymorphism at locations 49 and 389 would produce either a beneficial, detrimental or no effect in patients with ventricular dysfunction.
The therapeutic effects of β-blockers in the context of genetic make-up are complex. It is also recognized that the initiation of β-blocker therapy can precipitate worsening heart failure or very limited beneficial effects in certain patients. Nonetheless, there is very little doubt that treatment with β-blockers should be considered as an important pillar of any strategy for patients with left ventricular systolic dysfunction. However, there are also challenges to initiating therapy with β-blockers in patients with ventricular dysfunction. Thus, it is prudent that healthcare professionals who intend to use such compounds recognize that demographic factors can have an impact on the outcome of care. At present, 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. Notwithstanding the fact that the occurrence of polymorphisms in β2-adrenoceptors and α2C-adrenoceptors could also have an impact on the clinical outcome of treatments with various β-blockers, it is clear that more evidence is needed to establish a meaningful guide for the use of β-blockers in patients with ventricular dysfunction with differing genetic make-up. Until such evidence becomes available, healthcare professionals must apply due diligence and monitor their patients that are treated with this class of drugs very carefully to provide the best care and clinical outcome for their patients.
Financial & competing interests disclosure
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes 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.
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