β1-ADRENERGIC RECEPTOR POLYMORPHISMS AND RISK OF ATRIAL FIBRILLATION AFTER CARDIAC SURGERY IN IRANIAN POPULATIONHTML Full Text
β1-ADRENERGIC RECEPTOR POLYMORPHISMS AND RISK OF ATRIAL FIBRILLATION AFTER CARDIAC SURGERY IN IRANIAN POPULATION
S. Emami 1, G. Eslami * 2, R. Ghafari 3, A. Hedayatizadeh-Omran 4 and O. Amjadi 4
Pharmaceutical Research Center 1, Cardiovascular Research Center 2, Department of Cardiac Surgery 3, Gastrointestinal Cancer Research Center 4, Mazandaran University of Medical Sciences, Sari, Iran.
ABSTRACT: Postoperative atrial fibrillation (POAF) is a frequent rhythm disturbance after cardiac surgery and is associated with poor cardiovascular outcomes. Beta-blocker therapy is an effective strategy to prevent or decrease the high incidence of POAF and β1-adrenergic receptor (β1AR) polymorphisms that affect the cardiac response to β1AR antagonists. The study objective is to analyze the association between genetic variations in the β1AR gene and the risk of POAF and the prophylactic effect of beta-blockers. Totally, 198 patients undergoing first-time cardiac surgery were examined. The patients after operation were grouped as either with POAF or without POAF according to their continuously electrocardiogram monitoring within ICU and hospital admission period. Subsequently, genotype frequencies of the β1AR gene were determined by polymerase chain reaction-restriction fragment length polymorphism. The results showed that 63 patients (31.8%) of the total study population developed POAF. After the application of a multivariate logistic regression model, the incidence of POAF was associated with Arg389Gly genotype (OR=2.48; 95% CI, 1.06-5.76; p=0.036), Arg389Arg genotype (OR=3.38; 95% CI, 1.28-9.33; p=0.018) and Arg389Ser49 haplotype (OR=1.73; 95% CI, 1.07-2.80; p=0.027) in the whole population. In addition, subgroup analysis showed an association between Arg389Gly (OR=3.09; 95% CI, 1.12-8.52; p=0.03) and Arg389Arg (OR=4.72; 95% CI, 1.07-15.43; p=0.01) genotypes as well as Arg389Ser49 haplotype (OR=2.05; 95% CI, 1.16-3.62; p=0.013) with increased risk for POAF in patients using beta-blocker prophylaxis. These findings indicated that POAF might be related to the Arg389-β1AR variant in the studied Iranian population, and this association appears to be more prominent among patients with beta-blocker prophylaxis.
Atrial fibrillation, β1-adrenergic receptor, Cardiac surgery, Polymorphism
INTRODUCTION: Postoperative atrial fibrilla-tion (POAF) occurs in 15-40% of patients in the first 24-48 postoperative hours after coronary artery bypass graft (CABG) and 62% undergoing valve procedure plus CABG, which is a leading cause of morbidity and mortality 1.
Moreover, it increases the length of intensive care unit (ICU) stays or hospitalization and health care cost 2. Currently, atrial fibrillation (AF) rhythm is the most common indication for readmission within 30 days after hospital discharge 3, 4.
In recent years, the developments in the field of pharmacotherapy and advances in genetic knowledge, including the discovery of novel atrial fibrillation-related genetic variants and extension to new insights into AF mechanisms, have led to patient-specific management and reduced the POAF complications, including the need for a pacemaker, heart failure, venous thromboem-bolism, myocardial infarction and stroke 5, 6. The exact pathophysiology of POAF remains unclear, and its causes are likely multifactorial 7. Inflammation and structural atrial changes occur at the time of surgery and postoperative period, including trauma following cannulation, acute atrial dilatation, ischemic injury, and elevation in atrial pressures or hypertension predisposes patients to POAF 1, 8.
Evidence has revealed that an increase in sinus rate and atrial ectopic activity secondary to an increased sympathetic tone is associated with POAF 2. Hence, beta-blockers have been used extensively for prophylaxis of AF after cardiac surgery, and the efficacy of them as first-line agents for the prevention of POAF has been confirmed in several clinical trials and meta-analysis 9, 10. However, several studies have elucidated that differences in response to β1-adrenergic receptor (β1AR) antagonists could have been influenced by considerable interindividual and interethnic variations 11, 12. These findings suggest that the genetic variation of the β1AR gene may be the basis of interindividual differences in response to beta-blocking medications as prophylaxis for POAF in patients after cardiac surgery. The β1AR is a member of cell surface G protein-coupled receptors expressed on cardio-myocytes. They mediate the increase in cardiac inotropy and chronotropy and modulate sympathetic responses, an increase in intracellular cyclic adenosine monophosphate (cAMP) activity. The β1AR gene is encoded by an intronless gene located on the long arm of chromosome 10q24-26 13.
Two common functional single nucleotide polymorphisms (SNPs) in the human β1AR gene (Arg389Gly and Ser49Gly) have been proved to play a pivotal role in the regulation of the activity of the cardiovascular and sympathetic nervous system 14. In vitro studies have confirmed that the Gly49-β1AR allele enhanced agonist-promoted down-regulation compared to the Ser49 variant, whereas the Arg389-β1AR allele has nearly 2-fold greater basal and 3-fold greater agonist stimulation of the adenylyl cyclase activity than the Gly389-β1AR variant 15. The Arg389-β1AR variant displays an increase in Gs-protein coupling compared to Gly389-β1AR 16. Parvez et al., studied the effects of β1AR gene polymorphisms (Arg389Gly and Ser49Gly) on rate-control therapy in patients with AF. They found that patients carrying Gly389-β1AR variant were associated with an adequate response to rate-control therapy and required the lowest doses of rate-control medications than patients with the Arg389-β1AR allele.
Moreover, they also found that the Ser49Gly polymorphism did not associate with the outcome of rate-control therapy in patients with AF 17. Due to the prominent role of increased sympathetic tone in susceptibility to POAF and the effect of genetic variations of the β1-adrenergic receptor as a mediator of cardiac sympathetic activation on response to beta-blocker therapy, we designed a prospective study to examine the possible association of the SNPs in the β1AR gene with the risk for POAF and influence on the outcome of prophylactic beta-blocker therapy in Iranian patients after cardiac surgery.
MATERIALS AND METHODS:
Study Population: The study protocol was approved by the ethics committee of Mazandaran University of Medical Sciences (approval code: IR. MAZUMS.REC.1397.1810), and voluntary informed consent was obtained from enrolled participants for relevant clinical data gathering and genotyping analysis. Patients aged 18 years or older who indicated elective cardiac surgery were consecutively enrolled in the study between April and September 2018. The exclusion criteria were previous history of AF or other supraventricular and ventricular arrhythmias; those who also needed implanted cardiac devices, including a pacemaker or defibrillator, were excluded from the study. In addition, patients who had bradycardia (heart rate < 60 beats/min) and creatinine clearance < 30 ml/min were excluded. In total, 198 patients were recruited. The patients with an episode of postoperative atrial fibrillation that persisted for more than 15 minutes during the ICU and 5 days post-ICU were defined as POAF group (n=63), and subjects (n=135) without post-operatively AF episodes were classified as the without POAF (control group) 18. In patients with AF rhythm, anti-coagulant agents and amiodarone or cardioversion were used to manage arrhythmia.
Definitions: POAF was defined according to the European Society of Cardiology (ESC) Guidelines for the management of AF, based on no discernible P wave or irregular RR intervals or replacement of sinus P waves by rapid oscillations or fibrillatory waves that vary in size, shape, and timing which continued for at least 30 seconds 19. Postoperative prophylactic beta-blocker treatment was defined as prescription of beta-blocker before the onset of AF rhythm in patients with POAF or during the ICU stay and up to 5 days after ICU discharge in subjects without POAF.
Clinical Data Collection: All the data related to before, during, and after the surgery, including demographic parameters, surgical information, medical and medication history of the patients were obtained from patient’s medical records. All the patients were preoperatively assessed using electrocardiography (ECG) and transthoracic echo-cardiography examination. POAF was detected by continuous telemetry monitoring and a 12-lead ECG recording. Subsequently, all patients were examined at least twice a day by the surgeon and intensive care specialists in ICU and cardiologist on the post-ICU ward. During this time, any AF rhythm was confirmed and documented by the research team.
Anesthesia and Operative Techniques: Similar standard surgical technique with the cardio-pulmonary bypass (CPB) method was utilized in all the patients.
Genotyping: Five milliliters of peripheral venous blood specimens were obtained at the end of the operation for isolation of DNA. Total genomic DNA was extracted from the leukocytes using DNA isolation kit (Denazist Asia Co., Mashhad, Iran). The concentration and purity of the extracted DNA were measured using a Nanodrop spectro-photometer (Biochrom WPA Biowave II+ UV / visible spectrophotometer, Cambridge, UK) 20. The Arg389Gly and Ser49Gly polymorphisms in the β1AR were confirmed by polymerase chain reaction-restriction fragment length polymorphism (RFLP-PCR) methods.
The forward primer for the codon 389 (nucleotide 1165) was 5′-CATC ATGG GCGT CTTCA CGC-3′, and the reverse primer was 5′-T GGGC TTCG AGTT CACC TGC-3′. Primers used for codon 49 (nucleotide 145) had the following sequences: 5'-CCGG GCTT CTGG GGTG TTCC-3′ (forward), 5'-GGCG AGGT GATG GCGA GGTA GC-3' (reverse) 21.
PCR was performed using 200 ng of template DNA, 10 μl Taq DNA polymerase 2x master mix RED (Ampliqon A/S, Odense, Denmark) containing 150 mM Tris-HCl pH 8.5, 40 mM (NH4)2SO4, 3 mM MgCl2, 0.2% Tween 20, 0.4 mM of each dNTP and 0.2 U/μl Ampliqon Taq DNA polymerase, along with 10 pmol of specific primers and 7 µl nuclease-free water.
FIG. 1: SEQUENCE ANALYSIS AND PATTERN OF 2% AGAROSE GEL ELECTROPHORESIS OF DNA SAMPLES FOR ARG389GLY POLYMORPHISM DETECTED BY PCR-RFLP. Lane M shows a 50bp DNA ladder. The Arg389Gly GG genotype was evident as a single 547 bp fragment (Lane 7), GC genotype as 547, 342, 171, and 34 bp fragments (Lanes 2 and 4), and CC genotype as 342, 171, and 34 bp fragments (Lanes 1, 3, 5, 6 and 8). Electrofluorogram was representing all heterozygous and homozygous conditions of the β1-adrenoceptor allele (top).
The PCR conditions were: initial denaturation step at 98 ºC for 3 min followed by 35 cycles of denaturation at 98 ºC for 30 sec, annealing at 60 ºC for 1 min and 72 ºC for 30 sec for β1AR codons 389 and 49, following confirmation of the amplified fragments of the expected size on agarose gel containing DNA green fluorescent dye (DenaZist, Mashhad, Iran).
The expected product lengths were 547 bp and 562 bp for β1AR codons 389 and 49, respectively. The PCR products were restriction-digested with 10 U/µl of BcgI and EcoO109I (Fermentas; Thermo Fisher Scientific, Inc., Waltham, MA, USA) at 37 ºC for 3 h. According to the digestion patterns, two genotypes were determined Fig. 1 and Fig. 2.
FIG. 2: SEQUENCE ANALYSIS AND PATTERN OF 2% AGAROSE GEL ELECTROPHORESIS OF DNA SAMPLES FOR SER49GLY POLYMORPHISM DETECTED BY PCR-RFLP. Lane M shows a 50bp DNA ladder. The Ser49Gly AA genotype was evident as a single 562 bp fragment (Lane 1), AG genotype as 562, 343, and 219 bp fragments (Lane 2) and GG genotype as 343 and 219 bp fragments (Lane 3). Electrofluorogram representing all heterozygous and homozygous conditions of the β1-adrenoceptor allele (top).
PCR Products Sequencing: PCR-RFLP geno-typing results were further confirmed by direct DNA sequencing Fig. 1 and Fig. 2. Genotyping was performed without knowing the population study status. Ten percent of random samples were re-genotyped by Sanger sequencing with forward and reverse primers by ABI 3130XL.
Statistical Analysis: All statistical analyses were carried out using SPSS version 25.0 (IBM Corp., Armonk, NY, USA). All the statistical tests were two-sided, and a P-value of < 0.05 was considered statistically significant. Values are shown as range and mean ± standard deviation (SD). The Differences between means and categorical variables were tested by t-test and Chi-square analysis, respectively. The Chi-square test was used to analyze the differences in distributions of genotypes and alleles between patients with and without POAF. Logistic regression analysis was performed to assess the association of β1AR genotypes with POAF and adjusted for the following clinical covariates: Age ≥ 65 years, male gender, BMI ≥ 30 (kg / m2), reduced left ventricular ejection fraction (LVEF) state (< 50%), valvular surgery, postoperative left atrial diameter (LAD) ≥ 40 mm, cross-clamp time (CCT) and cardiopulmonary bypass time (CPBT). In addition, Multivariate logistic regression analysis was also performed with and without adjustment on the resulting data to determine the interaction between prophylactic beta-blocker use and β1AR genotype on the development of POAF.
RESULTS: The incidence of POAF among our patients was 31.8%, and 155 (78.3%) of 198 patients received postoperative prophylactic beta-blocker therapy. The mean duration of POAF was 20.3 ± 18.1 h (range of 1 to 61 h). The highest prevalence of POAF was recorded on the second and third post-operative days. The results revealed no significant difference between the two groups regarding baseline characteristics Table 1.
The mean age of the study patients was 63.3 ± 9.3 years (range of 36 to 87 years), and 65.7% were men. CABG (87.9%) was the most frequent underlying heart procedure in the study population. As shown in Table 1, surgical and post-operative data were also similar, except for the operation time, which was significantly higher in patients with POAF than those without POAF (4.2 ± 0.9 h vs 3.9 ± 0.9 h, p=0.042).
TABLE 1: BASELINE AND OPERATIVE CHARACTERISTICS OF THE STUDY POPULATION
|Characteristics||With POAF (n=63)||Without POAF (n=135)||P-Value|
Male gender, n
Comorbid features, n
NYHA functional class, n
Medication status, n
Clcr (ml/min/1.73 m2)
Surgery type, n
Operation time (h)
Inotropic support use (Epinephrine), n
Epinephrine - dose (ng/kg/min)
Total inotropic support - time, (h)
Postoperative LAD (mm)
|65.1 ± 9.9
27.1 ± 4.1
2.1 ± 1.5
54 ± 7.5
71 ± 21.1
4.2 ± 0.9
46.8 ± 23.8
16.8 ± 9.1
66.4 ± 35.2
102.7 ± 50.3
43.4 ± 4.1
|62.6 ± 9
26.9 ± 4.2
1.9 ± 1.6
53.3 ± 9.1
73.9 ± 20.8
3.9 ± 0.9
39.8 ± 15.7
15.1 ± 8.9
62.9 ± 31.8
95.8 ± 46.2
42.5 ± 4.1
BMI: Body mass index, MI: Myocardial infarction, COPD: Chronic obstructive pulmonary disease, NYHA: New York heart association, BB: Beta-blocker, ACEI: Angiotensin-converting enzyme inhibitor, ARB: Angiotensin receptor blocker, CABG: Coronary artery bypass graft, MVR: Mitral valve replacement, AVR: Aortic valve replacement, CCT: Cross-clamp time, CPBT: Cardiopulmonary bypass time, LVEF: Left ventricular ejection fraction, LAD: Left atrial diameter, CLcr: Creatinine clearance. Values are mean ± SD where appropriate.
Genotype Analysis: As can be seen from Table 2, the frequencies of alleles and genotypes of Arg389Gly and Ser49Gly polymorphism were similar in both groups, and there was no association between the two polymorphisms studied and the incidence of atrial fibrillation after cardiac surgery in the total population. Multivariate logistic regression analysis showed that heterozygous Arg389Gly variant (OR=2.48; 95% CI, 1.06-5.76; p=0.036), mutant Arg389Arg genotype (OR=3.38; 95% CI, 1.28-9.33; p=0.018) and Arg389-allele (OR=1.72; 95% CI, 1.09-2.72; p=0.02) was significantly associated with POAF compared to the reference group. Genotype analysis revealed that patients with prophylactic beta-blocker therapy and POAF had a higher frequency of mutant Arg389Arg genotype (OR=3.13; 95% CI, 1.11-8.81; p=0.031) compared to control subjects (29.2% vs 17.7%).
TABLE 2: DISTRIBUTION OF GENOTYPES AND ALLELE FREQUENCIES OF THE β1-ADRENERGIC RECEPTOR POLYMORPHISMS AND ITS RELATIONSHIP WITH POAF IN THE WHOLE STUDY POPULATION AND SUBGROUPS SEPARATED BY PROPHYLACTIC BETA-BLOCKER THERAPY
|Allelic Status||With POAF||Without POAF||Unadjusted||P-value||Adjusted*||P-Value|
|OR (95% CI)||OR (95%CI)|
Allele Arg389 vs Gly389
Allele Gly49 vs Ser49
Prophylactic BB use
Allele Arg389 vs Gly389
Allele Gly49 vs Ser49
Allele Arg389 vs Gly389
Allele Gly49 vs Ser49
58 (46%) / 68 (54%)
116 (92.1%) / 10 (7.9%)
42 (43.8%) / 54 (56.2%)
87 (90.6%) / 9 (9.4%)
16 (53.3%) / 14 (46.7%)
29 (96.7%) / 1 (3.3%)
151 (55.9%) / 119 (44.1%)
240 (88.9%) / 30 (11.1%)
122 (57%) / 92 (43%)
187 (87.4%) / 27 (12.6%)
29 (51.8%) / 27 (48.2%)
53 (94.6%) / 3 (5.4%)
1.95 (0.89 - 4.23)
2.39 (0.96 - 5.95)
1.48 (0.97 - 2.28)
0.71 (0.32 - 1.58)
0.69 (0.33 - 1.46)
2.05 (0.83 - 5.04)
3.13 (1.11 - 8.81)
1.71 (1.05 - 2.77)
0.59 (0.06 - 6.28)
0.72 (0.32 - 1.59)
1.56 (0.32 - 7.49)
0.78 (0.09 - 6.32)
0.94 (0.39 - 2.29)
0.75 (0.32 - 1.75)
0.61 (0.06 - 6.12)
2.48 (1.06 - 5.76)
3.38 (1.28 - 9.33)
1.72 (1.09 - 2.72)
0.7 (0.30 - 1.65)
0.7 (0.32 - 1.54)
3.09 (1.12 - 8.52)
4.72 (1.45 - 15.43)
2.03 (1.19 - 3.47)
0.71 (0.28 - 1.78)
0.71 (0.31 - 1.66)
1.69 (0.28 - 10.21)
1.01 (0.09 - 11.07)
1.07 (0.38 - 2.98)
0.22 (0.01 - 13.82)
0.24 (0.01 - 12.52)
Gly: Glycine, Arg: Arginine, Ser: Serine, BB: Beta-blocker, Ref.: Reference category; OR: Odds ratio, CI: Confidence intervals. *Adjusted for age ≥ 65 years, male gender, BMI ≥ 30 (kg/m2), reduced left ventricular ejection fraction (LVEF) state (< 50%), valvular surgery, postoperative left atrial diameter ≥ 40 mm, cross-clamp time (CCT) and cardiopulmonary bypass time (CPBT).
Additionally, the presence of the Arg389-allele was associated with POAF in patients received prophylactic beta-blocker therapy (OR=1.71; 95% CI, 1.05-2.77; p=0.031). Multivariate logistic regression analysis stratified by prophylactic beta-blocker therapy showed a significant association between Arg389-allele (OR=2.03; 95% CI, 1.19-3.47; p=0.009), Arg389Gly (OR=3.09; 95% CI, 1.12-8.52; p=0.03) and Arg389Arg (OR=4.72; 95% CI, 1.45-15.43; p=0.01) genotypes with the risk of POAF after adjustment for clinical covariates Table 2. According to the statistical analysis, in our patients stratified by prophylactic beta-blocker therapy, no influence of the Ser49Gly poly-morphism on the incidence of POAF was found before and after adjustment for clinical previously described covariates.
TABLE 3: HAPLOTYPE ANALYSIS OF THE β1-ADRENERGIC RECEPTOR POLYMORPHISMS AND ITS RELATIONSHIP WITH POAF IN THE WHOLE STUDY POPULATION AND SUBGROUPS SEPARATED BY PROPHYLACTIC BETA-BLOCKER THERAPY
|Haplotypes||With POAF||Without POAF||Unadjusted||P-value||Adjusted*||P-value|
|OR (95% CI)||OR (95% CI)|
Prophylactic BB use
1.50 (0.96 - 2.34)
0.28 (0.03 - 2.24)
1.07 (0.46 - 2.47)
1.75 (1.05 - 2.93)
0.35 (0.04 - 2.87)
1.17 (0.48 - 2.88)
0.91 (0.37 - 2.26)
0.88 (0.07 - 10.43)
1.73 (1.07 - 2.80)
0.22 (0.03 - 1.89)
1.28 (0.52 - 3.15)
2.05 (1.16 - 3.62)
0.25 (0.03 - 2.22)
1.41 (0.54 - 3.69)
1.06 (0.38 - 2.98)
0.41 (0.01 - 27.73)
Gly: Glycine, Arg: Arginine, Ser: Serine, BB: Beta-blocker, Ref.: Reference category, OR: Odds ratio, CI: Confidence intervals. *Adjusted for age ≥ 65 years, male gender, BMI ≥ 30 (kg/m2), reduced left ventricular ejection fraction (LVEF) state (< 50%), valvular surgery, postoperative left atrial diameter ≥ 40 mm, cross-clamp time (CCT), and cardiopulmonary bypass time (CPBT).
Haplotype Analysis: Haplotype analysis revealed that patients with Arg389Ser49 haplotype had 1.73 fold greater risk of POAF (OR=1.73; 95% CI, 1.07-2.80; p=0.027) compared to patients with the Gly389Ser49 reference haplotype Table 3. In patients receiving beta-blocker prophylaxis, the association between Arg389Ser49 haplotype and POAF was statistically significant in the unadjusted (OR=1.75; 95% CI, 1.05-2.93; p=0.027) or adjusted (OR=2.05; 95% CI, 1.16-3.62; p=0.013) models Table 3.
DISCUSSION: β1-adrenergic receptor gene polymorphisms are involved pathophysiologically in cardiovascular diseases. In recent years an increasing number of studies on possible genetic associations with Arg389Gly-β1AR and Ser49Gly-β1AR polymorphisms on hypertension, heart failure, myocardial infarction, and left ventricular remodeling in response to beta-blockade have been reported 15.
The present study found that the Arg389Gly and Arg389Arg genotypes were associated with increased risk of POAF (OR=2.48; p=0.036 and OR=3.38; p=0.018, respectively). A similar association of Arg389Gly (OR=3.09; p=0.03) and Arg389Arg (OR=4.72; p=0.01) variants with POAF was observed in patients with prophylactic beta-blocker therapy. Our results also show that patients who carried Arg389Ser49 haplotype had increased risk for POAF compared to other haplotypes (OR=1.73; p=0.027). Furthermore, the incidence of POAF in subjects with prophylactic beta-blocker was associated with carrying the Arg389Ser49 haplotype (OR=1.75; p=0.032) it was more pronounced after adjustment for previously described clinical covariates (OR=2.05; p=0.013). The Arg389-β1AR variant has a higher basal adenylyl cyclase activity than the Gly389-β1AR variant that was due to reduced G-protein coupling for the Gly389-β1AR 22. In-vitro, isoprenaline-induced adenylyl cyclase activation was three- to fourfold higher in Arg389-β1AR than in Gly389-β1AR variant 23.
Additionally, the Gly49 mutant has been shown to be associated with down-regulated by long-term agonist exposure to a significantly greater extent than the Ser49 mutant 24. Elevated post-operative plasma level of norepinephrine is a well-known risk factor for POAF 25. Sandilands et al., in a study on human right atrial preparations, reported greater inotropic and cAMP responses to norepinephrine at the Arg389-β1AR versus the Gly389-β1AR variant 26. Taken together, our findings and these data indicate that the patients with Arg389-β1AR experienced POAF more frequently than others. Inflammation response and cardiomyocyte damage following cardiac surgery with CPB will lead to an increase in catecholamine release, which has been associated with an increase in stimulation of the β-adrenergic receptors. This results in increased intracellular concentrations of cAMP 27, 28. Iso-prenaline-evoked cAMP levels were significantly higher in Arg389Gly49 and Arg389Ser49 haplo-types than Gly389Ser49 haplotype.
Additionally, recent study reported that the patients with Arg389Gly49, Arg389Ser49, and Gly389Ser 49 haplotypes were more susceptible to idiopathic ventricular arrhythmias 28. As shown in our study patients, the Arg389Ser49 haplotype of the β1AR is associated with increased susceptibility to the provocation of POAF than other haplotypes. This was maybe due to better coupling of the Arg389Ser49 haplotype to the Gs-protein and inducing higher intracellular cAMP levels 29.
Clinical studies examining the influence of β1AR polymorphism on beta-blocker response in patients with AF have met with variable results. Previous studies found a lower rate of new-onset AF in patients with heart failure and treated with bucindolol carrying the Arg389Arg genotype. Furthermore, this treatment effect was not observed in the patients with Gly389Gly variant 30-32. However, in a study by VaglioJr et al., no significant difference between Arg389Gly-β1AR and Ser49Gly-β1AR polymorphisms and modulate response to rate-control therapy (beta-blocker) in AF patients was observed, whereas in other study, Gly389-β1AR was shown to be associated with an adequate response to rate-control therapy in atrial arrhythmias 17, 33.
In our study, when wild-type homozygote genotype (Gly389Gly) was considered as reference, the association between Arg389Gly-β1AR polymorphism and POAF was statistically significant for Arg-β1AR variant among patients receiving prophylactic beta-blocker therapy. It seems that the higher risk of POAF in subjects with the Arg-β1AR variant did not reduce by prophylactic treatment with beta-blockers. However, further studies are needed to validate our findings in the Iranian population. Our results show that Ser49Gly-β1AR poly-morphism was not associated with the development of AF after cardiac surgery and also did not influence the outcome of prophylactic beta-blocker therapy in patients with POAF. However, our results differ from those of Nia et al., who suggested that the Arg389Gly genotype alone was not, and the Ser49Gly genotype slightly associated with the AF prevalence 23. Interestingly, they reported an almost 7-fold higher risk for AF in a combination of both SNPs (Arg389Gly-Ser49Gly). Ethnic differences between the studied populations, sampling, and method differences may account for some of this discrepancy.
The major limitation of our study was the relatively small sample size. In addition, we have genotyped patients only for the β1AR gene polymorphisms and not for the β2AR gene variants. Genetic variation in the β2AR gene might be associated with an increase in susceptibility to POAF because the previous evidence showed that the identification of β2AR gene polymorphisms could be helpful for the prediction of ventricular arrhythmias 28.
CONCLUSION: We have shown that the carriage of the Arg389-β1AR variant as a predictive factor might confer an elevated risk of developing POAF in the Iranian population. The results of this study also suggest that the protective effect of beta-blocker therapy may have no or less influence on the prevention of POAF in patients with the Arg389-β1AR variant. This was the first study in this field conducted on POAF patients in Iran. Further confirmatory studies are needed to determine the clinical significance of these findings.
ACKNOWLEDGEMENT: This paper was financially supported by the Mazandaran University of Medical Sciences (No.1810). The authors greatly appreciate the personnel of Mazandaran Heart Center for their support.
CONFLICTS OF INTEREST: The authors declare that they have no conflict of interest.
- Yadava M, Hughey AB and Crawford TC: Postoperative atrial fibrillation: incidence, mechanisms and clinical correlates. Heart Failure Clinics 2016; 12(2): 299-308.
- Dobrev D, Aguilar M, Heijman J, Guichard JB and Nattel S: Postoperative atrial fibrillation: mechanisms, manifestations and management. Nature Reviews Cardiology 2019; 16(7): 417-36.
- Shah RM, Zhang Q, Chatterjee S, Cheema F, Loor G, Lemaire SA, Wall Jr MJ, Coselli JS, Rosengart TK and Ghanta RK: Incidence, cost and risk factors for readmission after coronary artery bypass grafting. The Annals of thoracic surgery 2019; 107(6): 1782-9.
- Schnaubelt S, Pilz A, Koller L, Kazem N, Hofer F, Fleck T, Laufer G, Steinlechner B, Niessner A and Sulzgruber P: The impact of volume substitution on postoperative atrial fibrillation. European Journal of Clinical Investigation 2020; 20: 13456.
- Huang H and Darbar D: Genetic heterogeneity of atrial fibrillation susceptibility loci across racial or ethnic groups. European Heart Journal 2017; 38: 2595-8.
- Staerk L, Sherer JA, Ko D, Benjamin EJ and Helm RH: Atrial fibrillation: epidemiology, pathophysiology and clinical outcomes. Circulation Research 2017; 120(9): 1501-17.
- Carter-Storch R, Dahl JS, Christensen NL, Pecini R, Søndergård EV, Øvrehus KA and Møller JE: Postoperative atrial fibrillation after aortic valve replacement is a risk factor for long-term atrial fibrillation. Interactive Cardiovascular and Thoracic Surgery 2019; 29(3): 378-85.
- Rezaei Y, Peighambari MM, Naghshbandi S, Samiei1 N, Alizadeh Ghavidel1 A, Dehghani MR, Haghjoo M and Hosseini S: Atrial fibrillation following cardiac surgery: from pathogenesis to potential therapies. American Journal of Cardiovascular Drugs 2020; 20: 19-49.
- O'Brien B, Burrage PS, Ngai JY, Prutkin JM, Huang CC, Xu X, Chae SH, Bollen BA, Piccini JP, Schwann NM and Mahajan A: Society of Cardiovascular Anes-thesiologists/European Association of Cardiothoracic Anaesthetists practice advisory for the management of perioperative atrial fibrillation in patients undergoing cardiac surgery. Journal of Cardiothoracic and Vascular Anesthesia 2019; 33(1): 12-26.
- Zhao BC, Huang TY, Deng QW, Liu WF, Liu J, Deng WT, Liu KX and Li C: Prophylaxis against atrial fibrillation after general thoracic surgery: trial sequential analysis and network meta-analysis. Chest 2017; 151(1): 149-59.
- Okamura K, Shirai K, Okuda T and Urata H: The prevalence of Japanese outpatients with hypertension who meet the definition of treatment resistant hypertension and are eligible for enrolment in clinical trials of endovascular ultrasound renal denervation. Internal Medicine 2018; 57(1): 1-2.
- Van Driest SL, Sleeper LA, Gelb BD, Morris SA, Dietz HC, Forbus GA, Goldmuntz E, Hoskoppal A, James J, Lee TM and Levine JC: Variants in ADRB1 and CYP2C9: Association with Response to Atenolol and Losartan in Marfan Syndrome. The Journal of Pediatrics 2020; 222: 213-20.
- Kumar A, Pandit AK, Vivekanandhan S, Srivastava MV, Tripathi M and Prasad K: Association between beta-1 adrenergic receptor gene polymorphism and ischemic stroke in North Indian population: A case control study. Journal of the Neurological Sciences 2015; 348(1-2): 201-5.
- Wei W, Tian Y, Zhao C, Sui Z, Liu C, Wang C and Yang R: Correlation of ADRB1 rs1801253 polymorphism with analgesic effect of fentanyl after cancer surgeries. Medical Science Monitor: International Medical Journal of Experimental and Clinical Research 2015; 21: 4000-5.
- Thomas CD and Johnson JA: Pharmacogenetic factors affecting β-blocker metabolism and response. Expert Opinion on Drug Metabolism & Toxicology 2020; 16(10): 953-64.
- Rathz DA, Gregory KN, Fang Y, Brown KM and Liggett SB: Hierarchy of polymorphic variation and desensitization permutations relative to β1-and β2-adrenergic receptor signaling. Journal of Biological Chemistry 2003; 278(12): 10784-9.
- Parvez B, Chopra N, Rowan S, Vaglio JC, Muhammad R, Roden DM and Darbar D: A common β1-adrenergic receptor polymorphism predicts favorable response to rate-control therapy in atrial fibrillation. Journal of the American College of Cardiology 2012; 59: 49-56.
- January CT, Wann LS, Calkins H, Chen LY, Cigarroa JE, Cleveland JC, Ellinor PT, Ezekowitz MD, Field ME, Furie KL and Heidenreich PA: 2019 AHA/ACC/HRS focused update of the 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. Journal of the American College of Cardiology 2019; 74(1): 104-32.
- Hindricks G, Potpara T, Dagres N, Arbelo E, Bax JJ, Blomström-Lundqvist C, Boriani G, Castella M, Dan GA, Dilaveris PE, Fauchier L, Filippatos G, Kalman JM, La Meir M, Lane DA, Lebeau JP, Lettino M, Lip GYH, Pinto FJ, Thomas GN, Valgimigli M, Van Gelder IC, Van Putte BP and Watkins CL: ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS). European Heart Journal 2020; 42: 373-498.
- Shokrzadeh M and Mohammadpour A: Evaluation of a modified salt-out method for DNA extraction from whole blood lymphocytes: A simple and economical method for gene polymorphism. Pharmaceutical and Biomedical Research 2018; 4(2): 28-32.
- Kokut S, İnci Meltem AT, Efkan UZ, Akpinar A and DEMİRDAŞ A: The polymorphisms of Ser49Gly and Gly389Arg in beta-1-adrenergic receptor gene in major depression. Nöro Psikiyatri Arşivi 2015; 52(2): 124-7.
- Leineweber K, Bogedain P, Wolf C, Wagner S, Weber M, Jakob HG, Heusch G, Philipp T and Brodde OE: In patients chronically treated with metoprolol, the demand of inotropic catecholamine support after coronary artery bypass grafting is determined by the Arg389Gly-β1-adrenoceptor polymorphism. Naunyn-Schmiedeberg's archives of pharmacology 2007; 375(5): 303-9.
- Nia AM, Caglayan E, Gassanov N, Zimmermann T, Aslan O, Hellmich M, Duru F, Erdmann E, Rosenkranz S and Er F: Beta1-adrenoceptor polymorphism predicts flecainide action in patients with atrial fibrillation. PLoS One 2010; 5(7): 11421.
- Goth CK, Petäjä-Repo UE and Rosenkilde MM: G Protein-Coupled Receptors in the Sweet Spot: Glyco-sylation and other Post-translational Modifications. ACS Pharmacology & Translational Scien 2020; 3(2): 237-45.
- Benzoni P, Campostrini G, Landi S, Bertini V, Marchina E, Iascone M, Ahlberg G, Olesen MS, Crescini E, Mora C and Bisleri G: Human iPSC modelling of a familial form of atrial fibrillation reveals a gain of function of If and ICaL in patient-derived cardiomyocytes. Cardiovascular Research 2019; 116(6): 1147-60.
- Sandilands AJ, O'shaughnessy KM and Brown MJ: Greater inotropic and cyclic AMP responses evoked by noradrenaline through Arg389 β1‐adrenoceptors versus Gly389 β1‐adrenoceptors in isolated human atrial myocardium. British journal of pharmacology 2003; 138(2): 386-92.
- Kim RJ, Iwai S, Markowitz SM, Shah BK, Stein KM and Lerman BB: Clinical and electrophysiological spectrum of idiopathic ventricular outflow tract arrhythmias. J of the American College of Cardiology 2007; 49(20): 2035-43.
- Ulucan C, Cetintas V, Tetik A, Eroglu Z, Kayikcioglu M, Can LH, Payzin S, Aydin M and Hasdemir C: β1 and β2‐adrenergic receptor polymorphisms and idiopathic ventricular arrhythmias. Journal of cardiovascular electrophysiology 2008; 19(10): 1053-58.
- Sandilands A, Yeo G, Brown MJ and O'Shaughnessy KM: Functional responses of human β1 adrenoceptors with defined haplotypes for the common 389R> G and 49S> G polymorphisms. Pharmacogenetics and Genomics 2004; 14(6): 343-49.
- Parikh KS and Piccini JP: Pharmacogenomics of bucindolol in atrial fibrillation and heart failure. Current Heart Failure Reports 2017; 14(6): 529-35.
- Aleong R, Davis G, Sauer W, Robertson AD and Bristow MR: Prevention of atrial fibrillation by bucindolol is completely dependent on the Beta-1 389 Arg/Gly adrenergic receptor polymorphism. Circulation 2011; 124: 10438.
- Aleong RG, Sauer WH, Davis G, Murphy GA, Port JD, Anand IS, Fiuzat M, O'Connor CM, Abraham WT, Liggett SB and Bristow MR: Prevention of atrial fibrillation by bucindolol is dependent on the beta₁389 Arg/Gly adrenergic receptor polymorphism. JACC: Heart Failure 2013; 1(4): 338-44.
- VaglioJr JC, Rowan SB, Kucera G, Stubblefield TD, Carter S, Roden DM and Darbar D: Genetic and clinical predictors of response to rate control therapy in patients with atrial fibrillation. Circulation 2008; 118: 828.
How to cite this article:
Emami S, Eslami G, Ghafari R, Hedayatizadeh-Omran A and Amjadi O: β1-Adrenergic receptor polymorphisms and risk of atrial fibrillation after cardiac surgery in Iranian population. Int J Pharm Sci & Res 2021; 12(7): 3666-75. doi: 10.13040/IJPSR.0975-8232. 12(7).3666-75.
All © 2013 are reserved by the International Journal of Pharmaceutical Sciences and Research. This Journal licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License.
S. Emami, G. Eslami *, R. Ghafari, A. Hedayatizadeh-Omran and O. Amjadi
Department of Clinical Pharmacy, Faculty of Pharmacy, Cardiovascular Research Center, Mazandaran University of Medical Sciences, Sari, Iran.
23 July 2020
26 December 2020
15 May 2021
01 July 2021