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Pharmacogenomics of β-Adrenergic Receptor Physiology and Response to β-Blockade

von Homeyer, Peter MD*; Schwinn, Debra A. MD*,†

doi: 10.1213/ANE.0b013e31822b887e
Cardiovascular Anesthesiology: Review Articles
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Myocardial β-adrenergic receptors (βARs) are important in altering heart rate, inotropic state, and myocardial relaxation (lusitropy). The β1AR and β2AR stimulation increases cyclic adenosine monophosphate concentration with the net result of myocyte contraction, whereas β3AR stimulation results in decreased inotropy. Downregulation of β1ARs in heart failure, as well as an increased β3AR activity and density, lead to decreased cyclic adenosine monophosphate production and reduced inotropy. The βAR antagonists are commonly used in patients with coronary artery disease and heart failure; however, perioperative use of βAR antagonists is controversial. Individual patient's response to beta-blocker therapy is an area of intensive research, and apart from pharmacokinetics, pharmacodynamics, and ethnic differences, genetic alterations have become more important in the last 20 years. The most common genetic variants in humans are single nucleotide polymorphisms (SNPs). There are 2 clinically relevant SNPs for the β1AR (Ser49Gly, Arg389Gly), 3 for the β2AR (Arg16Gly, Gln27Glu, Thr164Ile), and 1 for the β3AR (Trp64Arg). Although results are somewhat controversial, generally large datasets have the potential to show a relationship between βAR SNPs and outcomes such as development and progression of heart failure, coronary artery disease, vascular reactivity, hypertension, asthma, obesity, and diabetes. Although βAR SNPs may not directly cause disease, they appear to be risk factors for, and modifiers of, disease and the response to stress and drugs. In the perioperative setting, this has specifically been demonstrated for the Arg389Gly β1AR polymorphism with which patients with the Gly variant had a higher incidence of adverse perioperative events. Knowing that genetic variants play an important role, perioperative medicine will likely change from simple therapeutic intervention to a more personalized way of adrenergic receptor modulation.

Published ahead of print September 29, 2011 Supplemental Digital Content is available in the text.

From the *Department of Anesthesiology and Pain Medicine, and the Departments of Genome Sciences and Pharmacology, University of Washington, Seattle.

Funding: Dr. Schwinn's research on the biologic consequences of naturally occurring genetic variability in human a1a-adrenergic receptors is funded by NIH grant #HL49103.

The authors declare no conflict of interest.

Reprints will not be available from the authors.

This report was previously presented, in part, at the International Anesthesia Research Society Annual Meeting, March 2010.

Address correspondence to Peter von Homeyer, MD, Department of Anesthesiology & Pain Medicine, University of Washington, Box 356540, University of Washington, Seattle, WA 98195-6540. Address e-mail to peter2@u.washington.edu.

Accepted April 22, 2011

Published ahead of print September 29, 2011

The purpose of this article is to explore how aspects of the genomic revolution may affect daily anesthetic practice. The main focus of this “state-of-the-field” summary is to describe pharmacogenetics of β-adrenergic receptor (AR) antagonists/blockers and resultant clinical effects.

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ADRENERGIC RECEPTORS

ARs (sometimes referred to as adrenoceptors) are a family of G protein–coupled receptors (GPCRs) that bind stress hormones such as epinephrine and norepinephrine. Changes in the sympathetic nervous system after adrenergic receptor activation have been described as the “fight-or-flight” response, including increased heart rate, pupil dilation, vasoconstriction to nonessential organs with concurrent vasodilation to muscles and brain, enhanced myocardial inotropy, and many other effects.1

Beginning in 1948 with the work of Raymond Ahlquist,2 AR subtypes were classified into 2 major classes (α and β), then further subclassified with the introduction of more specific drugs. There are at least 9 distinct AR subtypes whose cDNAs have been identified as encoding distinct subtype specific receptor proteins37 (Table 1).

Table 1

Table 1

The β1- and β2ARs are functionally active in the human heart,8 providing positive inotropy (increased force of contraction), chronotropy (increased heart rate), and lusitropy (increased rate of relaxation) with receptor stimulation.9 In contrast, β3ARs have been known for years to exist in adipose tissue (both adult white fat and pediatric brown fat),10,11 but their role in the myocardium has only recently been elucidated and remains somewhat controversial.12,13 In general, myocardial β3ARs operate in the opposite direction from β1 and β2ARs, in that β3AR stimulation tends to inhibit inotropy overall.14,15

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βAR FUNCTION: STRUCTURE AND SIGNALING

ARs are GPCRs.5 GPCRs are the largest membrane protein family in the human genome whose cellular structure includes 7-transmembrane–spanning α-helices containing an extracellular component with a protein amino (N) terminus, a ligand binding site, a G protein–binding site, and an intracellular carboxyl (C) terminus.16 In the last few years, several transmembrane GPCRs, including β1- and β2ARs, have been crystallized, and this has led to better understanding of their molecular structure and function17,18 (Fig. 1).

Figure 1

Figure 1

Once stimulated, β1- and β2ARs activate the stimulatory G protein, or Gs, resulting in a dissociation of different G protein subunits, αβ from γ. The αβ subunits activate the intracellular adenylyl cyclase, resulting in conversion of adenosine triphosphate into cyclic adenosine monophosphate (cAMP), which in turn leads to activation of protein kinase A and phosphorylation of several substrates, for example, calcium channels important in myocyte contraction.19,20

In contrast to β1- and β2ARs, β3ARs couple through the inhibitory G protein, Gi, which decreases generation of cAMP (Fig. 2). Also, β3ARs affect biologic function in the heart much less than do other βARs.15,21,22 Interestingly, although clinical βAR antagonists that are currently available effectively block β1- and β2ARs and inhibit their functioning, many simultaneously activate β3ARs, with the overall result being inhibition of inotropic responses.5 This has interesting implications for myocardial diseases such as heart failure,5,23 and upregulation of cardiac β3ARs in heart failure has been shown in humans as well as in animal models.24,25 In animals this pattern of upregulation correlates with the negative inotropy caused by β3AR stimulation.25,26

Figure 2

Figure 2

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BASIC MECHANISMS OF βAR MODULATION

Myocardial βAR expression and function undergo major changes with age as well as in the presence of advanced congestive heart failure (CHF). Both clinical situations are associated with increased sympathetic activity, with aging best characterized by a slow increase in plasma norepinephrine levels over years, whereas a more rapid increase in circulating catecholamines is seen in congestive heart failure.27,28 Functional responsiveness of myocardial βARs to endogenous catecholamines or exogenous drugs is dampened (desensitized) with aging and CHF; this is due to reduction in β1- and β2AR activity and stable or decreased Gs activity, as well as (for CHF) concurrent increased β3AR and Gi density. The net effect is decreased production of cAMP together with reduced inotropy.29,30

In addition to chronic myocardial βAR signaling changes related to aging and CHF, there are also reports of acute changes in myocardial βAR reactivity with extreme stress. Booth et al. investigated βAR signal transduction in patients undergoing heart surgery with cardiopulmonary bypass (CPB).31 Concurrent with robust catecholamine increases during CPB, acutely decreased βAR signaling occurs3133; the underlying mechanism for this acutely dampened βAR efficacy is uncoupling between the receptor and the adenylyl cyclase moiety (Fig. 3). Interestingly, chronic βAR antagonist therapy had no influence on these acute changes in βAR signaling. In 2002, Booth et al. could show in a canine model that the administration of esmolol, a nonselective βAR antagonist, prevented the acute myocardial βAR desensitization process during CPB, thus improving left ventricular function.34 A subsequent study done by the same group observed the effect of IV metoprolol in patients undergoing surgery with CPB. This β1AR-selective antagonist did not reduce βAR desensitization; however, there was a reduction in the incidence of postoperative supraventricular arrhythmias in the patients receiving metoprolol.35

Figure 3

Figure 3

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BENEFITS OF PERIOPERATIVE βAR ANTAGONIST (BETA-BLOCKER) THERAPY

The above findings raise the question of the role of βAR antagonists in the perioperative period. The βAR antagonists are mainstay therapy for patients with coronary artery disease as well as patients with CHF. The use of βAR antagonists in the perioperative period is a topic of intensive research and ongoing discussion. In the late 1990s, 2 studies in high-risk patients undergoing noncardiac surgery showed a beneficial effect of perioperative βAR antagonist treatment.36,37 These results led to widespread application of perioperative βAR antagonists in the following years. However, patients in the DECREASE1 study36 were preselected on the basis of 3 cardiac risk factors. More than 50% of patients had previous myocardial infarction, and all patients had a positive dobutamine stress echocardiogram. Therefore, the response to dobutamine and subsequent response to bisoprolol may have been biased by genetic factors.

New guideline updates on this topic have been published recently,38,39 including the results of the POISE study (PeriOperative Ischemia Study Evaluation trial). This study is one of the largest studies ever performed in perioperative medicine, including almost 9000 patients. It showed that cardiac risks such as myocardial infarction, need for coronary revascularization, and clinically significant atrial fibrillation are decreased in patients receiving perioperative βAR antagonists, but the risk of all-cause mortality and stroke increased as well as the incidence of clinically significant hypotension and bradycardia.40 Two meta-analyses from 2009 supported the POISE results.41,42

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GENETIC VARIABILITY AND βARs

Up to this point, we have presented βARs as monolithic receptors with the same protein structure and pharmacology in every individual. The most common naturally occurring genetic variants in humans are single nucleotide polymorphisms (or variants), called SNPs (Table 2). By the mid-1990s, SNPs in the gene encoding the human β2AR had been shown to occur, and soon thereafter, SNPs were discovered in the gene that encodes the human β1AR as well43 (Fig. 1).

Table 2

Table 2

In the human β1AR, at least 12 SNPs have been described.44,45 Two of these SNPs alter β1AR receptor biology and therefore potentially have clinical relevance. The first SNP occurs in the portion of the gene encoding the protein amino terminus (Ser49Gly), and the second occurs in a region of the gene that encodes the intracellular carboxyl terminus (Arg389Gly); this latter region is also important in G protein binding. There is strong linkage disequilibrium for these SNPs, meaning that they travel together in a block of DNA that is rarely separated during crossing over between chromosomes; such consistent DNA sequences traveling together over cell divisions is called a haplotype.

For the β2AR, at least 19 different SNPs have been described; 4 of these β2AR SNPs seem to have some clinical relevance.44,46 The first is located in the 5-untranslated region, an area of the gene upstream from the translation start codon (Cys-19Arg). This is an important region regulating β2AR expression on the transcriptional level. The Arg-19 genotype has been shown to decrease receptor expression.47 The second and third clinically relevant SNPs are extracellular (Arg16Gly and Gln27Glu), and the fourth is located in the transmembrane section of the receptor (Thr164Ile).27,44,48 There is also strong linkage disequilibrium for β2AR polymorphisms, resulting in common haplotypes containing several β2AR SNPs.49

The β3AR gene is also polymorphic. Although reports are somewhat conflicting,50 the β3AR Trp64Arg SNP has been shown to be associated with diseases such as obesity and type 2 diabetes.51 Associations between βAR SNPs and clinical syndromes are shown in Table 3.

Table 3

Table 3

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βAR SNPS AND MYOCARDIAL FUNCTION

Over the last decade, investigators have performed studies to determine whether βAR SNPs have effects on human disease or alter effectiveness of βAR blocker therapy, and the heart failure population has been a specific focus of these studies.5255 Liggett et al. initially described that the β2AR Ile164 polymorphism in the β2AR is associated with adverse outcome in human heart failure.56 Individuals with this SNP have normal phenotype (appear to have no cardiovascular disease) until their hearts are stressed for the first time with CHF. Subsequently, these individuals develop rapidly worsening heart failure and, if on the heart transplant list, may die within a relatively short (e.g., 3 months) period of time. To explore the mechanisms underlying this unique phenotype, Turki et al. performed a study in transgenic mice and discovered that the Ile164 SNP shows significant dysfunction, with decreased βAR/second messenger (adenylyl cyclase) coupling in receptors present in myocardial membranes as well as evidence of impaired cardiac function in vivo.57

Biolo et al. assessed the 2 previously described clinically relevant β1AR SNPs in Brazilian outpatients. They could not find a direct correlation between certain β1AR polymorphisms and heart failure susceptibility, but they could demonstrate that the Gly389 allele was associated with a lower prevalence of ventricular arrhythmias and better heart failure–related survival. In the conclusion, Biolo et al. suggested a pharmacogenetic effect, because the negative impact on survival in patients with the Arg389 genotype was offset by high-dose βAR blocker therapy58 (Fig. 4). Likewise, Mialet Perez et al. could demonstrate that hearts from mice carrying the Arg389 allele had an enhanced hemodynamic response to βAR antagonist therapy, and being homozygous for the Arg389Arg genotype was an advantage for patients receiving chronic carvedilol treatment for heart failure. They concluded that the Arg389 variant predisposes to heart failure; however, there is a positive pharmacogenomic effect in the response to βAR blockade in these patients.59 That means that a genetic variant that is on one hand a risk factor for disease is on the other hand associated with a better clinical response to treatment with βAR antagonists. Petersen et al., in 2011, evaluated the association of βAR SNPs and mortality in 586 heart failure patients receiving chronic carvedilol therapy.60 A combination of the β1AR Arg389 and the β2AR Gln27 variants was associated with a 2-fold increase in mortality in comparison with other genotypes. The pharmacogenetic effect was, however, not seen in patients chronically treated with metoprolol. This study is one of the few studies showing that genotype combinations have an influence on individual response to therapy with certain βAR antagonists. However, the authors of this study reported that the differences in metoprolol and carvedilol effects may have been biased by small treatment groups, unmatched patients, and confounding indications, because more ill patients were treated with carvedilol. Therefore, the effect of specific βAR antagonists needs to be addressed in randomized trials with matched groups.

Figure 4

Figure 4

With respect to coronary artery disease, Piscione et al. reported that the Ile164 genotype is associated with a more aggressive type of coronary artery disease adversely affecting prognosis in these patients.61 In another study screening patients undergoing cardiac catheterization, Barbato et al. showed that patients carrying the Glu27 genotype had a higher incidence of coronary artery disease and a higher likelihood of later need for coronary revascularization.62

Zee et al., in 2005, used haplotype analysis of the β2AR gene as a means of genetic epidemiology. In a large prospective cohort, they examined different groups of SNPs (haplotypes) to investigate their association with risk of myocardial infarction. The combined Gly16/Gln 27/Ile164 haplotype of the β2AR was found to be protective with respect to myocardial infarction in men.63 The same group conducted a study to replicate these results in women. Their outcome measures were myocardial infarction and stroke. Initially, they found no correlation between the genetic variants and the investigated outcomes. When they specifically looked at Caucasian women, they could show that the Gly16/Gln 27/Thr 164 genotype had an inverse association with the incidence of myocardial infarction, hence being protective. However, they did not find any association between the different genotypes and the incidence of ischemic stroke.64

Other studies have more specifically examined the impact of βAR SNPs and effectiveness of βAR blocker therapy, specifically survival after an acute ischemic event (defined as acute myocardial infarction or crescendo angina with troponin leak). In 2007, Leineweber et al. conducted a study in 82 patients on the impact of chronic metoprolol treatment on catecholamine requirements after coronary artery bypass grafting. They demonstrated that patients with the Arg389 β1AR genotype needed lower doses and shorter duration of inotropic support after CPB,65 concluding that preoperative identification of the β1AR Arg389Gly polymorphism could assist in predicting the need for and response to βAR agonist treatment in patients after CPB.

One of the largest clinical studies on βAR pharmacogenomics (n = 10,911 consecutive patients admitted to 2 Kansas hospitals) was performed by Lanfear et al. They investigated the effect of βAR (β1 and β2) SNPs on mortality (3-year survival) in the 597 patients discharged from the hospital with a diagnosis of acute myocardial infarction and started on βAR blockers.66 The βAR blockers have been shown to have clear benefit after acute coronary syndromes in aggregate. The authors' hypothesis was that this beneficial effect might be attributable to some patient subgroups having significant benefit, whereas others might be without benefit, or even possible harm. Four common β1AR (Arg389Gly 1165C/G and Ser49Gly 145A/G [amino acid and nucleotide changes, respectively]) and β2AR (Gly16Arg 46G/A and Gln27Glu 79C/G) polymorphisms were examined in Lanfear et al.'s study. No effect on mortality was shown for either β1AR SNP. However, mortality was 20% for the AA versus 10% for the GA and GG carriers of the β2AR Gly16Arg 46G/A SNP (P = 0.005). For the Gln27Glu 79C/G SNP, the results showed the worst outcome for patients who were homozygous for the C allele. The 3-year mortality was 16% for the CC, 11% for the CG, and 6% for the GG carriers, respectively (P = 0.03). Interestingly, this was demonstrated only in patients who were taking βAR blockers, not in patients discharged without βAR blocker therapy. To better describe the impact of both β2AR SNPs, the investigators performed composite genotype analysis. They could show that the overall mortality risk increases from 6% (46 GG/79GG) to 20% (46 AA/79 CC) (Fig. 5). Possible mechanisms for these observations include distinctly different lymphocyte and myocardial β-receptor downregulation at baseline. Patients carrying the G alleles in 46GG/79GG encode β2AR protein with impaired downregulation properties; this produces an overall net higher density of βAR. This could explain the beneficial effect of βAR blocker therapy in this subgroup of patients because such medical therapy would decrease heart rate and inotropy, both of which lead to better myocardial oxygen balance. In contrast, patients who carry the A and the C alleles (46 AA/79 CC) have encoded receptor protein with enhanced downregulation; this results in net less cell surface overall βAR density and function at baseline. These patients might not benefit from βAR blocker therapy because they have a “genetic βAR blocker” phenotype already. How adding βAR blocker drugs to this patient subgroup increases mortality, however, remains unknown.

Figure 5

Figure 5

Metra et al. have subsequently reported on 183 patients with chronic heart failure (ischemic and nonischemic cardiomyopathy with an ejection fraction <35%). None of these patients was taking βAR blockers at baseline. They performed hemodynamic measurements as well as exercise testing and nuclear ventriculography studies at baseline and 12 months after initiation of carvedilol therapy, to assess the effect of βAR blocker therapy on a number of βAR SNPs. In summary, the β1AR Arg389Gly and the β2AR Arg16Gly SNPs had no impact on the response to carvedilol, but they were able to show a relationship with the β2AR Gln27Glu polymorphism. Patients homozygous for the Glu27 allele demonstrated a greater increase in left ventricular ejection fraction (13.0% ± 12.2% vs 7.6% ± 9.6%, P = 0.022) and had a more pronounced decrease in pulmonary wedge pressures over the course of the study. Apart from this particular SNP, the study also identified other factors influencing the response to βAR blocker therapy, such as type of cardiomyopathy, systolic blood pressure at baseline, and carvedilol dose.67 Although this study suggests clinical importance of SNPs, it is limited by its small sample size. Despite lack of a statistically significant link between other βAR SNPs and carvedilol response, there was a trend towards better response to the βAR blocker treatment in patients carrying the β1AR Arg389 allele.

Several studies looked at other mechanisms of individual response to βAR antogonists, particularly metoprolol. Metoprolol undergoes hepatic metabolization primarily by cytochrome P450 2D6 (CYP2D6). CYP2D6 is subject to genetic polymorphism, and individuals have been identified to be poor metabolizers, which can lead to excessive plasma levels of βAR antagonists.68 This genetic variability in metoprolol pharmacokinetics also translates into clinically relevant differences among individuals. Poor metabolizers had significantly slower heart rate and diastolic arterial blood pressure, and a higher incidence of bradycardia.69 On the other hand, increased CYP2D6 activity has been shown to be associated with lower trough plasma concentrations, poor heart rate control, and increased risk for developing arrhythmias in patients after myocardial infarction.70

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βAR SNPS AND ETHNICITY

Several studies have been performed focusing on different βAR genotypes and ethnicity, and ample differences in allele frequencies between the Caucasian and the African American population have been demonstrated71,72 (Table 4). A general hypothesis is that the African American population is less responsive to βAR blocker therapy than Caucasian patients because genotypes with poor βAR blocker response are more common in African American patients. When evaluating clinical outcome studies on βAR blockers, the Beta-blocker Evaluation of Survival Trial (BEST) only showed a trend towards better survival in heart failure patients receiving the βAR blocker bucindolol,73 whereas other studies—such as the earlier-mentioned Metoprolol XR/CL Randomized Intervention Trial in Chronic Heart Failure (MERIT-HF), the Carvedilol Prospective Randomized Cumulative Survival Study (COPERNICUS), and the Cardiac Insufficiency Bisoprolol Study II (CIBIS-II)—could demonstrate a more solid survival benefit for the heart failure patients receiving βAR blocker treatment.7477 The BEST trial was done in a more diverse population, including a higher percentage of African American patients.78 Accordingly, researchers considered the comparably smaller effect of βAR blocker treatment in the BEST trial to be a race-linked feature. Post hoc analyses of BEST even demonstrated a trend towards higher mortality for African American patients receiving bucindolol than for those receiving placebo despite having improved myocardial function.79,80 The investigators attributed that outcome to the fact that bucindolol has an intrinsic sympathomimetic effect,81 and because the African American heart failure population appears to have less neurohumoral activation at baseline, they are likely more susceptible to the sympathomimetic activity of this particular βAR antagonist. This effect has proven to be unique to bucindolol because a number of other clinical trials showed equivalent survival benefits when comparing African American and Caucasian patients treated with βAR antagonists, a finding also supported by a larger meta-analysis.82

Table 4

Table 4

Kurnik et al. studied 165 patients (92 Caucasians) under exercise before and after the administration of the β1AR antagonist atenolol. The drug administration resulted in a significantly more pronounced reduction in exercise heart rate in Caucasians than in African Americans. Independently, the Arg389 allele was associated with a greater heart rate reduction as well.83 However, the ethnic differences in heart rate reduction were still apparent even after the investigators adjusted for the different genotype distribution. This brought them to the conclusion that there are further, yet unknown, factors contributing to the ethnic differences in heart rate response to βAR blockers. Conversely, a more recent prospective cohort study in almost 2500 patients evaluating the βAR1 Arg389Gly polymorphism and the Gln41Leu polymorphism of the G protein receptor kinase 5 (GRK5), an enzyme that is closely linked to βAR signaling, concluded that genetic variants rather than race accounted for differences in the response to βAR blocker treatment in patients with heart failure.84

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βAR SNPS AND ASTHMA

Asthma is another common disease in which βAR physiology can be harnessed for potential therapy. In this situation, βAR agonists stimulate bronchial β2ARs to initiate bronchodilation, which helps treat (eliminate) bronchospasm. Excess use of inhaled β2-receptor agonists in patients with asthma has been shown to be associated with detrimental outcome.8587 In addition, the bronchial smooth muscle of patients with severe asthma tends to be less responsive to β2AR treatment.88 This raises the concern that β2AR SNPs may further contribute to less effective treatment of asthma in such individuals.89,90

To examine this hypothesis, Israel et al. performed a study examining a polymorphism at amino acid 16 of the β2AR, addressing whether the SNP encoding of this amino acid is associated with long-term response to albuterol treatment versus placebo in patients with mild asthma.91 The authors demonstrated that patients with β2AR Arg16 had lower peak expiratory flow rates than did patients with the alternative β2AR Gly16 variant. These results suggest that alternative therapies (non-β2AR agonists) might be more appropriate for patients with the β2AR Arg16 genotype for long-term care. A study by Wechsler et al. has confirmed this finding by demonstrating that the response to salmeterol treatment in patients with asthma homozygous for β2AR Arg16 is reduced in comparison with those homozygous for β2AR Gly16, even if the patients had received additional inhaled corticosteroids.92 This suggests an overall dampened bronchial β2AR function in patients with the Arg16 variant (Fig. 6).

Figure 6

Figure 6

In contrast, others studying these β2AR SNPs could not demonstrate a direct relation between β2AR SNPs and responsiveness to β2AR agonist treatment in patients with asthma93,94 or chronic obstructive pulmonary disease.95 In contrast, 2 studies done in pediatric patients with asthma could show a pharmacogenetic effect of βAR variation in the sense that the β2AR Arg1696 and β2AR Gln2797 genotypes were both associated with a less-effective response to β2AR agonist treatment in acute asthma. An interesting recent laboratory analysis showed that there are potentially more downstream regulatory sites with potential impact on response to treatment in respiratory disease. This cell-based study examined the Gln41Leu polymorphism of the GRK5, a protein critical in modulating βAR signaling.98 The authors reported that the Leu41 genotype results in increased loss of function during agonist exposure. The GRK5 Leu41 genotype is much more common in the African American population that shows less asthma control than in Caucasians. Whether this polymorphism is contributing to this fact needs further investigation.99

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βAR SNPS AND BLOOD PRESSURE

In addition to the important role of βARs in terms of myocardial function and asthma, β2ARs are also important in vasculature, where they mediate vasodilation. It is therefore natural to ask whether genetic variability in β2ARs might alter blood pressure. Several research groups have addressed this question. Hoit et al. asked whether the β2AR Arg16 versus Gly16 genotype alter cardiovascular performance in healthy volunteers.100 They measured indicators of cardiac performance as well as hemodynamic variables such as arterial blood pressure and heart rate at baseline, and after infusion of the selective β2AR agonist terbutaline. Baseline measurements showed no difference between the 2 groups. After terbutaline stimulation, individuals with the β2AR Gly16 variant had higher arterial blood pressures, and higher calculated vascular resistance, whereas the heart rate and the left ventricular performance remained unchanged. The authors concluded that the β2AR Gly16 polymorphism is associated with impaired vasodilatory response to agonist stimulation in normotensive subjects and that there likely is a genetic basis of catecholamine-mediated vasodilation.100

In a separate study, forearm vascular reactivity was tested in healthy subjects, specifically examining β2AR Glu27 versus Gln27 polymorphisms. Subjects with the β2AR Gln27 variant had lower-baseline bloodflow as well as attenuated vasodilatory response to an intraarterial infusion of isoproterenol,101 demonstrating lack of effective receptor function for the Gln27 variant. This was particularly clear when dorsal hand veins were preconstricted with norepinephrine (Fig. 7); the β2AR Glu27 variant had much more robust reversal of constriction than did the β2AR Gln27. An additional finding in this study was the attenuation of isoproterenol-mediated vasodilation in healthy African American subjects and in healthy African American subjects with a family history of hypertension. Because of the low prevalence, the authors could not make any definitive conclusions from this subgroup analysis. Another study performed in 136 hypertensive and 81 normotensive African Caribbean patients could also demonstrate an association of the Gly16 β2AR SNP with essential hypertension.102

Figure 7

Figure 7

A large study in almost 6000 patients examined common β1AR and β2AR haplotypes and cardiovascular risk as well as the effectiveness of atenolol versus verapamil in the treatment of hypertension. The investigators showed that after about 3 years, death rates were higher in patients with the β1AR Ser49/Arg389 genotype. This mortality risk was significant in patients randomly receiving the verapamil treatment but not in patients receiving atenolol, thus indicating a protective role of βAR blockade. Their results were consistent with prior studies proving the association with β1AR SNPs and the risk of death. Moreover, βAR blocker therapy seems to be able to offset this mortality risk, suggesting that certain patients are more responsive to the βAR blocker therapy. They concluded that the pharmacogenetic evidence for βAR blockers and βAR SNPs is highly convincing, particularly in the case of the β1AR.103

Most recently, Iwamoto et al. studied the effect of βAR SNPs on the development of cardiovascular disease in 357 hypertensive patients. The investigators were able to show that being homozygous for the β1AR Ser49 and the β3AR Trp64 alleles was associated with a lower event-free survival with respect to cardiovascular outcomes and stroke. However, they did not observe pharmacogenomics in this trial.104

Yuan et al. performed a prospective, observational study in 300 hypertensive Chinese patients evaluating the combined effect of the β1AR Arg389Gly polymorphism and variants of the CYP2D6 gene.105 In their study, the same dose of metoprolol had different treatment effects in relation to the genotype, and different metoprolol doses had the same therapeutic effect in patients with different genotypes. The authors concluded that genotype analysis with respect to β1AR and CYP2D6 polymorphisms can be useful to guide βAR antagonist dosing in hypertensive patients.

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βAR SNPS AND METABOLIC SYNDROMES

A number of studies have shown an association between certain βAR polymorphisms and obesity, higher body fat, and fat cell volume as well as higher fasting insulin levels.51 Large et al. found that the Glu27 β2AR SNP was very common in obese patients (increased body fat and enlarged fat cells), and also that carriers of the Gly16 polymorphism had improved adipocyte receptor function.106 Another group could show a significantly reduced adipocyte receptor function in patients with the β2AR Ile164 SNP.107 Yamada et al., in 1999, suggested a relationship between metabolic syndromes and β2AR gene expression. The β2AR Arg-19 SNP (located in the 5-untranslated region) is accompanied by reduced expression level and was associated with a higher incidence of obesity and type 2 diabetes.108 Finally, a study done in diabetic patients showed that the β1AR Gly49 allele was more frequently associated with a higher body mass index.109 A number of studies demonstrated that β3AR SNPs are also related to obesity110,111 and insulin resistance or type 2 diabetes,50,112 although other studies could not replicate this relationship.113

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βAR SNPS AND PERIOPERATIVE MANAGEMENT

Kim et al. examined the arterial blood pressure response in humans to endotracheal intubation in 92 ASA I and II patients.114 Patients with the β2AR Glu27 polymorphism showed a significant increase in blood pressure 1 minute after endotracheal intubation in comparison with patients with the Gln27 polymorphism. This correlates with results from previous studies101 showing a better vascular reactivity in patients with the Glu27 genotype. Another study investigated β2AR polymorphisms and the vasopressor response in women during cesarean delivery under spinal anesthesia. The investigators found the β2AR Arg16 polymorphism to be the less-functional β-receptor genotype, thus requiring more vasopressor to maintain an adequate perfusion pressure.115 Both of these studies clearly demonstrate that β2AR genetic variants alter normal cardiovascular variables that impact care of the surgical patient.

Zaugg et al., in 2007, performed a double-blind, placebo-controlled study on the effect of bisoprolol on cardiovascular mortality, nonfatal myocardial infarction, unstable angina, CHF, and cerebrovascular insult. The βAR SNPs and safety outcome measures of βAR antagonist therapy were also evaluated. The authors hypothesized that bisoprolol treatment was able to prevent cardiovascular complications in patients undergoing surgery with spinal anesthesia. They were unable to show any significant difference in outcomes between the treatment and the placebo groups. However, they could demonstrate that patients carrying at least 1 Gly allele of the β1AR Arg389Gly polymorphism had a higher incidence of adverse perioperative events.116 This study is another example showing that genetic variants rather than simple therapeutic interventions play a role in perioperative outcomes. More than one third of the patients in this study had preexisting cardiovascular disease. Despite that, they had a low complication rate, and perioperative βAR antagonist therapy did not generate any benefit in terms of clinical outcome. The study is somewhat limited by the relatively small sample size and the fact that the surgical procedures were only intermediate risk class. Nonetheless, the trial of Zaugg et al. is truly a groundbreaking work on the effect of βAR polymorphisms on perioperative outcomes and treatment with βAR antagonists. The β1AR Arg389Gly SNP is of critical relevance in determining cardiovascular outcomes. Patients homozygous for Arg389 were reported to be more prone to hypertension and myocardial infarction.117,118 Interestingly, the β1AR Arg389 genotype has been linked to improved outcomes once heart disease is present. The reason for this advantage in myocardial protection was attributed to enhanced signaling119; in fact in vitro studies showed increased cAMP production of the Arg389 β1AR.120 In addition to that, Bruck et al. could show that the β1AR Arg389Gly SNP plays an important role in the reaction to inotropic stimulation. Dobutamine infusion caused a greater increase in heart rate and contractility as well as higher plasma-renin activity in Arg389Arg homozygous β1AR subjects. These patients also appeared to be more susceptible to bisoprolol pretreatment, because this drug offset the dobutamine-induced effects but was more or less ineffective in Gly alleles carriers.121 The evident genetic variability in the response to dobutamine and bisoprolol might have influenced the results of the DECREASE1 study by Poldermans et al.36 Only patients with a positive dobutamine stress echocardiogram were included in the analysis. This selection may have led to the positive outcomes in patients receiving bisoprolol, and βAR pharmacogenomics may have played the key role.

Taken together, these findings demonstrate the need for a much larger, randomized controlled trial of βAR antagonist pharmacogenomics in the perioperative setting. This future study would need to be conducted on a multinational level, and should also include different ethnicity. Excessive cost of data collection and genotype analysis, and concern for privacy, are limiting factors for performing such a trial.

A meta-analysis by Badgett et al. suggested that differences in βAR antagonist pharmacokinetics might contribute to the conflicting results of perioperative βAR antagonist trials.122 Metoprolol appears to be most dependent on CYP2D6 metabolism, and therefore this particular βAR antagonist is probably not the first choice in the perioperative setting in which slow titration of βAR antagonists is oftentimes not possible. CYP2D6 polymorphisms can further influence βAR antagonist metabolism, leading to very low (ineffective) or excessive (potentially harmful) plasma concentrations. Atenolol and bisoprolol metabolism is much less dependent on CYP2D6; plasma levels were shown to be more stable in patients, and the only perioperative studies with significant results used bisoprolol. Badgett et al. concluded that there is both empirical and theoretical evidence that atenolol and bisoprolol are safer than metoprolol in the perioperative setting.

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CONCLUSIONS

Polymorphisms have been described for genes encoding different βARs. Although genetic variations do not appear to cause diseases per se, they seem to be important risk factors or modifiers of disease. Interindividual and ethnic differences in response to βAR blocker therapy can be accounted for by pharmacogenetic differences of the βAR. This was demonstrated in the variable functional response to treatment with βAR blockers in patients with heart failure. The pharmacogenomic evidence improves our understanding of βAR signaling, and will eventually promote the development of a more “personalized” medicine.123 On the other hand, differences in receptor selectivity and drug metabolism may also be important. Genetic βAR variations provide a unique model for stress response variation and indicate a role for pharmacogenetics in all aspects of clinical medicine, including the important perioperative period. There is early evidence that βAR polymorphisms may affect perioperative outcome. A future study should be adequately powered and should include genotype analysis of the study population. This can help us to develop a “personalized” application of perioperative βAR blockade in the future.

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DISCLOSURES

Name: Peter von Homeyer, MD.

Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.

Attestation: Peter von Homeyer approved the final manuscript.

Name: Debra A. Schwinn, MD.

Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.

Attestation: Debra A. Schwinn approved the final manuscript.

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