Background
Ventricular arrhythmia is a common complication of acute myocardial infarction (AMI). The Arg389Gly polymorphism of the β1-adrenergic receptor genotype may affect AMI patients.
Method
Patients diagnosed with AMI were included in this study. Clinical data were obtained from the patient’s medical history, and genotypes were retrieved from laboratory test reports. ECG data were recorded daily. Data analysis was performed using SPSS 20.0, and differences were deemed statistically significant at P < 0.05.
Result
In the final study, 213 patients were included. The proportions of the Arg389Arg, Arg389Gly, and Gly389Gly genotypes were 65.7%, 21.6%, and 12.7%, respectively. Patients with the Arg389Arg genotype exhibited significantly elevated cardiac troponin T (cTnT) and pro-BNP levels compared to the Arg389Gly and Gly389Gly genotypes [cTnT: 4.00 ± 2.43 ng/ml versus 2.82 ± 1.82 ng/ml, P = 0.012; pro-BNP: 1942.37 (1223.194, 206.59) pg/ml versus 1604.57 (798.05, 1884.79) pg/ml, P = 0.005]. Patients with the Arg389Arg genotype exhibited a lower ejection fraction than those with the Gly389Gly genotype (54.13 ± 4.94% vs. 57.11 ± 2.87%, P < 0.001). Patients homozygous for Arg389Arg exhibited a higher incidence of ventricular tachycardia and a greater proportion of premature ventricular contraction (PVC) compared to patients homozygous for Gly389Gly (ventricular tachycardia: 19.29% vs. 0.00%, P = 0.009; PVC: 70.00% vs. 40.74%, P = 0.003).
Conclusion
The Arg389Arg genotype is associated with greater myocardial damage, impaired cardiac function, and an increased probability of ventricular arrhythmia in AMI patients.
Keywords: 1-adrenergic receptor, myocardial infarction, polymorphisms, ventricular arrhythmias
Introduction
Acute myocardial infarction (AMI) is a prevalent, critical cardiovascular disease worldwide [1]. Following an AMI, ventricular arrhythmia is a frequent consequence that may be associated with a poor prognosis [2]. Most ventricular arrhythmias following AMI occur only in the early stages; however, in some patients, they may persist for an extended period.
The β-adrenergic receptor comprises three subgroups: β1-adrenergic receptor (ADRB1), β2-adrenergic receptor, and β3-adrenergic receptor [3]. ADRB1 is the primary receptor regulating cardiomyocyte contraction [4]. ADRB1 comprises 477 amino acids, and nine nonsynonymous variants have been identified. One of the most common functionally characterized variations occurs at position 389 in the proximal C-terminus, where arginine is substituted by glycine, resulting in tertiary structural alterations in the protein [5]. This is crucial for G-protein coupling and subsequent adenylyl cyclase activation, with the Arg389 receptor having stronger G-protein coupling and three times greater adenylyl cyclase activity than the Gly389 variant [6,7]. Consequently, Arg389 carriers have higher left ventricle contractility [8] and a faster heart rate (HR) [9]. ADRB1 polymorphisms have been linked with multiple cardiovascular disorders, including heart failure [10,11], dilated cardiomyopathy [12], and ventricular remodeling after AMI [13]; however, the influence of ADRB1 polymorphisms on ventricular arrhythmia remains unclear. One European study revealed that Arg389 patients were more susceptible to idiopathic ventricular tachycardia [14]; however, other investigations asserted that ADRB1 polymorphisms are not associated with ventricular arrhythmias [15].
Sympathetic hyperexcitability is one of the causes of ventricular arrhythmias in AMI patients [16]. Clinical therapies for sympathetic hyperexcitability are based on β-blockers [17]. Compared to the Gly389 population, the Arg389 population was more susceptible to β-blockers [18]; however, most of these studies focused primarily on nonselective β-blockers, with few studies investigating the impact of the ADRB1 gene on ventricular arrhythmias after AMI, particularly in the Chinese population. Clinical statistics indicate that the frequency of the Arg389 variant is approximately 70%, whereas the frequency of the Gly389 variant is approximately 30%, suggesting that ADRB1 polymorphisms are also highly prevalent in populations with AMI and may be useful in identifying high-risk populations and personalized medicine. This study aimed to investigate the effect of ADRB1 gene polymorphisms on ventricular arrhythmia following AMI.
Materials and methods
Study population
This study was conducted at Zhongshan Hospital, Fudan University. All patients signed an informed consent statement, and the experiment was approved by the ethical committee. This study included patients admitted to the coronary care unit (CCU) due to AMI between January 2020 and May 2020. The inclusion criteria were as follows: patients diagnosed with MI and admitted to the CCU and patients whose ECGs were routinely monitored while undergoing treatment, and ECG and other medical records provided complete information. The exclusion criteria were as follows: incomplete medical data; age < 18 years; and the diagnosis and cause of death could not be clarified for any reason. Hospital employees ensured the confidentiality of all patients’ genotype information until discharge. The researcher reviewed the ECG monitoring records of the previous day until the patient was discharged from the CCU. An independent collector gathered medical-related data from electronic medical record systems after the patient was discharged from the hospital.
Clinical information was obtained from medical histories, whereas laboratory and echocardiographic data were acquired from a formal report. The ECG monitoring records were reviewed daily. Genotype results were based on the report generated by the PCR laboratory of our hospital.
Ventricular tachycardia was defined as a continuous wide QRS ventricular rhythm of three or more records with a ventricular HR >100 beats/min. Frequent premature ventricular contraction (PVC) was defined as the number of premature beats > 100/24 h. Post-MI mechanical consequences included cardiac rupture, ventricular septal rupture, chord rupture, and papillary muscle dysfunction. Chronic kidney disease (CKD) was defined as an estimated glomerular filtration rate < 60 ml/min * 1.76 m2 on both kidneys, estimated from creatinine levels.
Genotyping
Two tubes of blood samples were drawn from each patient using standard methods, and all samples were sent to the PCR laboratory of Zhongshan Hospital for genotyping. PCR and restriction fragment length polymorphism methods were utilized for genotype analysis; the detailed procedure has been published previously [6].
Data analysis
Normally distributed continuous variables are presented as mean ± SD, abnormally distributed data are shown as median (P25, P75), and the results of categorical variables are expressed as frequency (percentage).
Analysis of variance (ANOVA), Welch, or Brown–Forsythe methods were used to analyze between-group differences for continuous variables where appropriate, and P < 0.05 was considered statistically significant. If the analysis of normal distribution or homogeneity of variance was not met, the Games–Howell method was used to compare the groups.
Using the chi-square test or Fisher’s exact test, the differences between categorical variables and the observed genotype counts were determined. Statistical significance was set at P < 0.05. In further analysis of categorical variables, P < 0.017 was considered statistically significant.
All data were analyzed using the SPSS software (version 20.0; SPSS, Inc., Chicago, USA).
Results
A total of 248 patients were enrolled in the study; 35 were excluded, and the remaining 213 were included in the final analysis.
Genotype distribution
The most prevalent genotype in our study was Arg389Arg, prevalent in 140 individuals and 65.7% of all patients. There were 46 (21.6%) and 27 (12.7%) patients with Arg389Gly and Gly389Gly genotypes, respectively. The allele frequencies for Arg389 and Gly389 in our study were 76.5% and 23.5%, respectively.
Demographic characteristics
Among the 213 patients in this study, 47 (69.01%) were male, with an average age of 56.01 ± 13.38 years. There were no statistically significant differences in sex, age, smoking history, or alcohol use history among the genomes.
Essential hypertension, the most common underlying disease in this study, affected 127 (59.62%) patients. A total of 22 (10.33%) patients had coronary heart disease before enrolling in this study. There were no statistically significant differences in essential hypertension, coronary heart disease, healed MI, diabetes, or CKD between the genotype groups. The average onset time of the disease was 9.57 ± 3.69 h; 53.1% of all patients reported chest pain. A total of 192 patients underwent emergency percutaneous coronary intervention. The distribution of the location of MI and the culprit vessel is presented in the following table. ANOVA analysis revealed no statistically significant difference between the genotypes in the aforementioned data.
Regarding drug application, 170 (79.81%) patients were administered aspirin with ticagrelor. All 210 patients (98.59%) who received statins were treated with atorvastatin or rosuvastatin alone. Metoprolol sustained-release tablet (single dose: 47.5 mg/tablet) was selected as the β receptor blocker drug in our study, and 157 patients (73.71%) were administered metoprolol.
Patients in this study had an average admission HR of 77.85 ± 8.69 beats/min. The ANOVA revealed a statistically significant difference between the groups (P < 0.001). Between the three genome groups, the analysis showed statistical differences in the Arg389Arg versus Arg389Gly genotypes (P = 0.004) and Gly389Gly versus Arg389Arg genotypes (P < 0.001). The average HR while leaving the CCU was 69.62 ± 5.53 beats/min.
In this study, two patients experienced mechanical complications following AMI. All two individuals who developed recurrent MI in the hospital had the Arg389Arg genotype. Thirteen patients (6.10%) were diagnosed with acute cardiac insufficiency while hospitalized.
The mean time of hospital stay in our study population was 10.43 ± 2.97 days. There was no statistically significant difference between the groups in terms of in-hospital mortality, which occurred in 12 patients at a rate of 5.63%.
Table 1 lists the previously mentioned information, and Table 2 displays the genome analysis results. Differences in admission HRs according to genotype are shown in Fig. 2a.
Table 1.
Analysis of general clinical conditions of 213 patients with acute myocardial infarction
| All (n = 213) | Genotype | P value | ||||
|---|---|---|---|---|---|---|
| Arg389Arg (n = 140) | Arg389Gly (n = 46) | Gly389Gly (n = 27) | ||||
| Male | 147 (69.01%) | 100 (71.43%) | 30 (65.22%) | 17 (63.96%) | 0.562 | |
| Age (years) | 56.01 ± 13.38 | 56.11 ± 12.81 | 56.35 ± 13.98 | 54.89 ± 15.53 | 0.893 | |
| Smoking | 115 (53.99%) | 77 (55.00%) | 23 (50.00%) | 15 (55.56%) | 0.827 | |
| Alcohol | 50 (23.47%) | 31 (22.14%) | 10 (21.74%) | 9 (33.33%) | 0.433 | |
| Essential hypertension | 127 (59.62%) | 86 (61.43%) | 28 (60.87%) | 13 (48.15%) | 0.428 | |
| Diabetes | 56 (26.29%) | 40 (28.57%) | 10 (21.74%) | 6 (22.22%) | 0.577 | |
| Coronary heart disease | 22 (10.33%) | 17 (12.14%) | 3 (6.52%) | 2 (7.41%) | 0.590 | |
| Healed myocardial infarction | 7 (3.27%) | 5 (3.57%) | 1 (2.17%) | 1 (3.70%) | >0.999 | |
| CKD | 15 (7.04%) | 10 (7.14%) | 2 (4.35%) | 3 (11.11%) | 0.555 | |
| Onset time | 9.59 ± 3.69 | 9.61 ± 3.68 | 9.35 ± 3.76 | 9.89 ± 3.70 | 0.827 | |
| Chest pain | 113 (53.1%) | 73 (52.1%) | 24 (52.2%) | 16 (59.3%) | 0.787 | |
| Site | Anterior | 57 (26.76%) | 35 (25.00%) | 12 (21.09%) | 10 (37.04%) | 0.541 |
| Inferior | 36 (16.90%) | 26 (18.57%) | 8 (17.39%) | 2 (7.41%) | ||
| High lateral | 13 (6.10%) | 10 (7.14%) | 1 (2.17%) | 2 (7.41%) | ||
| Other | 7 (3.29%) | 3 (2.14%) | 3 (6.52%) | 1 (3.70%) | ||
| NSTEMI | 100 (46.95%) | 66 (47.14%) | 22 (47.83%) | 12 (44.44%) | ||
| Emergency PCI | 192 (90.14%) | 130 (92.86%) | 39 (84.78%) | 23 (85.19%) | 0.161 | |
| Culprit vessel | LM | 3 (1.41%) | 2 (1.43%) | 0 (0.00%) | 1 (3.70%) | 0.155 |
| LAD | 106 (49.77%) | 63 (45.00%) | 25 (54.75%) | 18 (66.67%) | ||
| RCA | 82 (38.50%) | 57 (40.71%) | 19 (41.30%) | 6 (22.22%) | ||
| LCX | 22 (10.33%) | 18 (12.86%) | 2 (4.35%) | 2 (7.41%) | ||
| Antiplatelet | A + T | 170 (79.81%) | 113 (80.71%) | 39 (84.78%) | 18 (66.67%) | 0.254 |
| A + C | 39 (18.31%) | 24 (17.14%) | 6 (13.04%) | 9 (33.33%) | ||
| Other | 4 (1.88%) | 3 (2.14%) | 1 (2.17%) | 0 (0.00%) | ||
| Statin | 210 (98.59%) | 138 (98.57%) | 46 (100.00%) | 26 (96.30%) | 0.436 | |
| Metoprolol | 0 mg | 56 (26.29%) | 38 (28.14%) | 10 (21.74%) | 8 (29.63%) | 0.215 |
| 23.75 mg | 115 (53.99%) | 69 (49.29%) | 29 (63.04%) | 17 (62.96%) | ||
| 47.5 mg | 42 ((19.72%) | 33 (23.59%) | 7 (15.22%) | 2 (7.41%) | ||
| Average dose of metoprolol | 22.19 ± 16.07 | 22.90 ± 16.95 | 22.20 ± 14.51 | 18.47 ± 13.71 | 0.425 | |
| Admission heart rate | 77.85 ± 8.69 | 79.66 ± 9.10 | 75.46 ± 6.98 | 72.6 ± 5.58 | <0.001 | |
| Mechanical complications | 2 (0.94%) | 1 (0.71%) | 1 (2.17%) | 0 (0.00%) | 0.569 | |
| Recurrent MI | 2 (0.94%) | 2 (1.43%) | 0 (0.00%) | 0 (0.00%) | >0.999 | |
| Acute cardiac insufficiency | 13 (6.10%) | 9 (6.43%) | 3 (6.52%) | 1 (3.70%) | 0.923 | |
| Hospital stay time | 10.43 ± 2.97 | 10.36 ± 3.03 | 10.67 ± 3.18 | 10.37 ± 2.22 | 0.824 | |
| Heart rate when out of CCU | 69.62 ± 5.53 | 70.06 ± 6.00 | 69.20 ± 4.50 | 68.07 ± 4.23 | 0.197 | |
| Death | 12 (5.63%) | 9 (6.43%) | 3 (6.52%) | 0 (0.00%) | 0.495 | |
A + C, Aspirin + Clopidogrel; A + T, Aspirin + Ticagrelor; CCU, coronary care unit; CKD, chronic kidney disease; LAD, left anterior descending; LCX, left circumflex; LM, left main; MI, myocardial infarction; NSTEMI, non ST segment elevation myocardial infarction; PCI, percutaneous coronary intervention; RCA, right coronary artery.
Table 2.
Subgroups analysis of results with statistical significance between genotypes
| Genotype | |||
|---|---|---|---|
| Arg389Arg/Arg389Gly | Arg389Gly/Gly389Gly | Gly389Gly/Arg389Arg | |
| Admission heart rate | 0.004 | 0.133 | <0.001 |
| Peak cTnT | 0.005 | 0.845 | 0.012 |
| Peak pro-BNP | 0.513 | 0.193 | <0.001 |
| EF% | 0.389 | 0.137 | <0.001 |
| Ventricular tachycardia | 0.079 | 0.336 | 0.009 |
| PVC | 0.379 | 0.065 | 0.003 |
| Frequent PVC | 0.075 | 0.460 | 0.029 |
cTnT, cardiac troponin T; EF, ejection fraction; PVC, premature ventricular contraction.
Fig. 2.
Differences in heart rate and ventricular arrhythmia by genotype.
Laboratory and echocardiography results
The mean LDL-C level in 213 patients was 2.96 ± 0.69 mmol/l; ANOVA revealed no significant differences between groups (P = 0.585). In our investigation, the average peak level of cardiac troponin T (cTnT) in patients was 3.62 ± 2.27 ng/ml. ANOVA revealed statistically significant differences between the groups (P = 0.003). Further analysis indicated a statistically significant difference between Arg389Arg/Arg389Gly (P = 0.005) and Gly389Gly/Arg389Arg (P = 0.0012).
The median peak pro-BNP level of the study population was 1730.09 (1013.51, 3029.37) pg/ml, with a statistically significant difference between groups (P = 0.047). Furthermore, there was an intragroup difference in the Gly389Gly/Arg389Arg (P < 0.001) group.
The mean ejection fraction value of the study population was 54.7 ± 4.88%. The analysis indicated a significant variation between the groups (P = 0.010), and further analysis showed intragroup differences in the Gly389Gly and Arg389Arg groups (P < 0.001).
Table 3 displays the findings of the laboratory and echocardiogram analyses, and Table 2 includes the analysis of the three genotypes.
Table 3.
The analysis of in-hospital laboratory test, echocardiography, and electrocardiograph monitoring results
| All (n = 213) |
Genotype | P value | |||
|---|---|---|---|---|---|
| Arg389Arg (n = 140) | Arg389Gly (n = 46) | Gly389Gly (n = 27) |
|||
| LDL-C | 2.96 ± 0.69 | 2.93 ± 0.67 | 3.05 ± 0.72 | 2.96 ± 0.77 | 0.585 |
| Peak cTnT | 3.62 ± 2.27 | 4.00 ± 2.43 | 2.92 ± 1.67 | 2.82 ± 1.82 | 0.003 |
| Peak pro-BNP | 1730.09 (1013.51,3029.37) | 1942.37 (1223.19,4206.59) | 1530.47 (798.89,2359.81) | 1604.57 (798.05,1884.79) | 0.047 |
| EF% | 54.76 ± 4.88 | 54.13 ± 4.94 | 55.28 ± 5.21 | 57.11 ± 2.87 | 0.010 |
| Ventricular tachycardia | 33 (15.49%) | 27 (19.29%) | 6 (13.04%) | 0 (0.00%) | 0.017 |
| PVC | 138 (64.79%) | 98 (70.00%) | 29 (63.04%) | 11 (40.74%) | 0.013 |
| Frequent PVC | 74 (34.74%) | 57 (40.71%) | 12 (26.09%) | 5 (18.52%) | 0.031 |
| Bigeminy | 28 (13.15%) | 22 (12.71%) | 4 (8.70%) | 2 (7.41%) | 0.415 |
| Trigeminy | 61 (28.64%) | 42 (30.00%) | 15 (32.61%) | 4 (16.81%) | 0.222 |
| Polymorphic PVC | 7 (3.29%) | 4 (2.86%) | 2 (4.35%) | 1 (3.70%) | 0.613 |
| PVC time >48 h | 28 (13.15%) | 21 (15.00%) | 5 (10.87%) | 2 (7.41%) | 0.565 |
CTnT, cardiac troponin T; EF, ejection fraction; PVC, premature ventricular contraction.
Figure 1a–c depicts the variations in peak cTnT level, pro-BNP level, and ejection fraction values, respectively.
Fig. 1.
Differences in laboratory and echocardiography outcomes in 213 patients with AMI by genotype. AMI, acute myocardial infarction.
The relationship between β1-adrenergic receptor polymorphism and ventricular arrhythmia
Ventricular tachycardia was detected in 33 patients (15.49%) in the study population. The chi-square test revealed a statistically significant difference among the groups (P = 0.017), and an intragroup analysis revealed differences within the Gly389Gly/Arg389Arg group (P = 0.009).
PVC was detected in 138 (64.79%) patients. Fisher’s exact test indicated a statistically significant difference within the groups (P = 0.031) and between the Gly389Gly and Arg389Arg groups (P = 0.003). Frequent PVC was prevalent among 74 (34.74%) patients. The chi-square test revealed a statistically significant difference between Gly389Gly and Arg389Arg (P = 0.029).
The occurrence of premature ventricular bigeminy (28 cases, P = 0.415), trigemini (61 cases, P = 0.222), polymorphic PVC (7 cases, P = 0.613), or present time >48 h (28 cases, P = 0.565) were not statistically significant.
The association between ADRB1 polymorphism and ventricular arrhythmia is displayed in Table 3, and further analysis is presented in Table 2.
Differences in the proportion of patients with ventricular tachycardia, PVC, and frequent PVC depending on genotype subtype are shown in Fig. 2b–d, respectively.
Discussion
The Arg389 genotype may play a role in AMI, a complex cardiovascular emergency caused by environmental and genetic factors. A recent study explored the relationship between ADRB1 polymorphisms and AMI [19], highlighting the higher prevalence of the Arg389 homozygous genotype in patients with AMI than in controls (68.1% vs. 47.2%, P < 0.0001). Another study with 100 AMI patients from a European population found that Arg389 allele carriers had a 3.5 times higher risk of developing AMI than Gly389 allele carriers [20]. In most contemporary populations, Arg389 is a dominant gene; one possible explanation is that carriers of the Arg389 genotype have a competitive advantage due to stronger defense and vigilance responses caused by higher sympathetic reactivity. Because of greater life expectancy and lifestyle changes, this dominant gene has proved deleterious to the cardiovascular system in the contemporary social environment [21].
Liu et al. investigated the effect of Gly389Arg polymorphism on exercise-induced increases in blood pressure and HR in healthy Chinese males. In young Chinese, the Arg389 genotype was associated with a greater response to metoprolol than the Gly389 genotype [22]. In contrast, a study of Chinese patients with chronic heart failure found no link between β-adrenoceptor blockade therapy and the Arg389Gly genotype polymorphism [23]. Our study revealed that patients with the Arg389 allele genotype had a higher HR than patients with the Gly389 genotype at the time of admission; however, there was no significant change in the HR after leaving the CCU. This could be due to a stronger response to β-adrenoceptor blockade therapy in patients with the Arg389 genotype. Another study from the Chinese population demonstrated that patients with the Arg389 allele genotype had lower blood pressure than patients with the Gly389 allele [24]. Similar drug responses can be seen in nonselective β-blockers [25]. All of the above findings were similar to the characteristics of HR changes observed in our study.
The effect of ADRB1 genotype polymorphism on ventricular arrhythmia remains unclear. A European study reported a higher incidence of ventricular arrhythmias in patients with the Arg389 genotype [14]. This finding was consistent with the findings of our study. Cells with the Arg389 genotype have higher cAMP levels than Gly389 genotype cells in response to isoproterenol stimulation [26], which may explain the increased risk of ventricular arrhythmia in patients with the Arg389 genotype. Animal investigations have demonstrated that sympathetic over-activation could enhance ventricular arrhythmia, while intravenous esmolol eliminated inducible ventricular ectopy [27]. In our study, patients with the Arg389 genotype had a significantly reduced incidence of ventricular arrhythmias, which might be due to the stronger sympathetic excitability.
This study reported that patients with the Arg389 genotype have a higher risk of developing ventricular arrhythmia. Clinical research from East Asia also confirmed that the Gly389 allele might prevent ventricular tachycardia in patients with dilated cardiomyopathy. Patients with ventricular tachycardia had a considerably greater frequency of Arg389Arg homozygotes (61% vs. 31%, P = 0.005). Additionally, the frequency of the Gly389 allele was significantly lower in patients with ventricular tachycardia compared to patients without ventricular tachycardia (0.24 vs. 0.46, P = 0.001) [28]. Our findings corroborated the findings of the previous study.
In our study, patients with the Arg389 allele had significantly lower cardiac ejection fractions than patients with the Gly389 genotype. Hakalahti et al. assessed the ADRB1 genotype and echocardiogram data in 452 northern European populations following AMI [29], and the composition of the genotype and time point of echocardiography of the study were similar to our research. In diabetic patients, the Arg389Arg homozygous genotype had a lower ejection fraction than the Gly389Gly homozygous genotype (43.3 ± 9.8% vs. 46.9 ± 9.8%, P = 0.049). Nevertheless, other investigations have determined that the impact of ADRB1 polymorphism on cardiac function varies over time. Perez et al. conducted animal experiments and isolated heart samples of transgenic mice 3, 6, and 9 months after preparing a model of heart failure [11]. Among 3-month mice, the cardiac contractility of Arg389 transgenic mice was considerably higher compared to Gly389 transgenic mice. When comparing cardiac contractility in heart samples of 9-month mice, Arg389 transgenic mice had considerably lower contractility than Gly389 transgenic mice.
Our study had the following limitations: participants in this study were mainly CCU patients, which might have resulted in selection bias; the sample size of this study was relatively small, and several of our findings require additional evidence to be confirmed; because this was a single-center study, and the geographical characteristics of the primary study populations were rather intense, generalization of the population’s characteristics from this study was not possible.
Acknowledgements
This research was supported by the following fund projects: Shanghai Municipal Commission of Economy and Informatization (GYQJ-2018-2-05), Project of Shanghai Science and Technology Committee (21S31906902), and Project of Shanghai Science and Technology Committee (17DZ19030102).
Conflicts of interest
There are no conflicts of interest.
Footnotes
Hu Wei is co-corresponding author.
References
- 1.Gulati M, Levy PD, Mukherjee D, Amsterdam E, Bhatt DL, Birtcher KK, et al. 2021 AHA/ACC/ASE/CHEST/SAEM/SCCT/SCMR guideline for the evaluation and diagnosis of chest pain: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation 2021; 144:e368–e454. [DOI] [PubMed] [Google Scholar]
- 2.McMurray J, Køber L, Robertson M, Dargie H, Colucci W, Lopez-Sendon J, et al. Antiarrhythmic effect of carvedilol after acute myocardial infarction: results of the carvedilol post-infarct survival control in left ventricular dysfunction (CAPRICORN) trial. J Am Coll Cardiol 2005; 45:525–530. [DOI] [PubMed] [Google Scholar]
- 3.Bylund DB, Eikenberg DC, Hieble JP, Langer SZ, Lefkowitz RJ, Minneman KP, et al. International union of pharmacology nomenclature of adrenoceptors. Pharmacol Rev 1994; 46:121–136. [PubMed] [Google Scholar]
- 4.Dorn GW, 2nd. Adrenergic signaling polymorphisms and their impact on cardiovascular disease. Physiol Rev 2010; 90:1013–62. [DOI] [PubMed] [Google Scholar]
- 5.Liggett SB, Mialet-Perez J, Thaneemit-Chen S, Weber SA, Greene SM, Hodne D, et al. A polymorphism within a conserved beta(1)-adrenergic receptor motif alters cardiac function and beta-blocker response in human heart failure. Proc Natl Acad Sci USA 2006; 103:11288–11293. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Maqbool A, Hall AS, Ball SG, Balmforth AJ. Common polymorphisms of beta1-adrenoceptor: identification and rapid screening assay. Lancet 1999; 353:897. [DOI] [PubMed] [Google Scholar]
- 7.Mason DA, Moore JD, Green SA, Liggett SB. A gain-of-function polymorphism in a G-protein coupling domain of the human beta1-adrenergic receptor. J Biol Chem 1999; 274:12670–12674. [DOI] [PubMed] [Google Scholar]
- 8.Kindermann M, Seeland U, Ruhnke P, Böhm M, Maack C. Functional effects of β1-adrenoceptor polymorphisms on the hemodynamic response to dobutamine with and without β-blocker administration. Clin Res Cardiol 2011; 100:129–137. [DOI] [PubMed] [Google Scholar]
- 9.Bengtsson K, Melander O, Orho-Melander M, Lindblad U, Ranstam J, Råstam L, et al. Polymorphism in the beta(1)-adrenergic receptor gene and hypertension. Circulation 2001; 104:187–190. [DOI] [PubMed] [Google Scholar]
- 10.Liu WN, Fu KL, Gao HY, Shang Y-Y, Wang Z-H, Jiang G-H, et al. β1 adrenergic receptor polymorphisms and heart failure: a meta-analysis on susceptibility, response to β-blocker therapy and prognosis. PLoS One 2012; 7:e37659–e37669. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Mialet Perez J, Rathz DA, Petrashevskaya NN, Hahn HS, Wagoner LE, Schwartz A, et al. Beta 1-adrenergic receptor polymorphisms confer differential function and predisposition to heart failure. Nat Med 2003; 9:1300–1305. [DOI] [PubMed] [Google Scholar]
- 12.Jin B, Ge-Shang QZ, Li Y, Shen W, Shi H-M, Ni H-C. A meta-analysis of β1-adrenergic receptor gene polymorphisms in idiopathic dilated cardiomyopathy. Mol Biol Rep 2012; 39:563–567. [DOI] [PubMed] [Google Scholar]
- 13.McLean RC, Hirsch GA, Becker LC, Kasch-Semenza L, Gerstenblith G, Schulman SP. Polymorphisms of the beta adrenergic receptor predict left ventricular remodeling following acute myocardial infarction. Cardiovasc Drugs Ther 2011; 25:251–258. [DOI] [PubMed] [Google Scholar]
- 14.Ulucan C, Cetintas V, Tetik A, Eroglu Z, Kayikcioglu M, Can LH, et al. Beta1 and beta2-adrenergic receptor polymorphisms and idiopathic ventricular arrhythmias. J Cardiovasc Electrophysiol 2008; 19:1053–1058. [DOI] [PubMed] [Google Scholar]
- 15.Ran YQ, Li N, Yang Y, Chen JZ, Feng L, Zhang S, et al. Beta2-adrenoceptor gene variant Arg16Gly is associated with idiopathic ventricular outflow-tract tachycardia. Chin Med J (Engl) 2010; 123:2299–2304. [PubMed] [Google Scholar]
- 16.Marcus GM. Evaluation and management of premature ventricular complexes. Circulation 2020; 141:1404–1418. [DOI] [PubMed] [Google Scholar]
- 17.Lerman BB. Mechanism, diagnosis, and treatment of outflow tract tachycardia. Nat Rev Cardiol 2015; 12:597–608. [DOI] [PubMed] [Google Scholar]
- 18.Si D, Wang J, Xu Y, Chen X, Zhang M, Zhou H. Association of common polymorphisms in β1-adrenergic receptor with antihypertensive response to carvedilol. J Cardiovasc Pharmacol 2014; 64:306–309. [DOI] [PubMed] [Google Scholar]
- 19.Iwai C, Akita H, Kanazawa K, Shiga N, Terashima M, Matsuda Y, et al. Arg389Gly polymorphism of the human beta1-adrenergic receptor in patients with nonfatal acute myocardial infarction. Am Heart J 2003; 146:106–109. [DOI] [PubMed] [Google Scholar]
- 20.Yilmaz A, Kaya MG, Merdanoglu U, Ergun MA, Cengel A, Menevse S. Association of beta-1 and beta-2 adrenergic receptor gene polymorphisms with myocardial infarction. J Clin Lab Anal 2009; 23:237–243. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Julius S. The defense reaction: a common denominator of coronary risk and blood pressure in neurogenic hypertension? Clin Exp Hypertens 1995; 17:375–386. [DOI] [PubMed] [Google Scholar]
- 22.Liu J, Liu ZQ, Tan ZR, Chen X-P, Wang L-S, Zhou G, et al. Gly389Arg polymorphism of beta1-adrenergic receptor is associated with the cardiovascular response to metoprolol. Clin Pharmacol Ther 2003; 74:372–379. [DOI] [PubMed] [Google Scholar]
- 23.Yu WP, Lou M, Deng B, Song H-ming, Wang H-bao. Beta1-adrenergic receptor (Arg389Gly) polymorphism and response to bisoprolol in patients with chronic heart failure. Zhonghua Xin Xue Guan Bing Za Zhi 2006; 34:776–780. [PubMed] [Google Scholar]
- 24.Liu J, Liu ZQ, Yu BN, Xu F-H, Mo W, Zhou G, et al. Beta1-adrenergic receptor polymorphisms influence the response to metoprolol monotherapy in patients with essential hypertension. Clin Pharmacol Ther 2006; 80:23–32. [DOI] [PubMed] [Google Scholar]
- 25.Sofowora GG, Dishy V, Muszkat M, Xie HG, Kim RB, Harris PA, et al. A common beta1-adrenergic receptor polymorphism (Arg389Gly) affects blood pressure response to beta-blockade. Clin Pharmacol Ther 2003; 73:366–371. [DOI] [PubMed] [Google Scholar]
- 26.Sandilands A, Yeo G, Brown MJ, O'Shaughnessy KM. Functional responses of human beta1 adrenoceptors with defined haplotypes for the common 389R>G and 49S>G polymorphisms. Pharmacogenetics 2004; 14:343–349. [DOI] [PubMed] [Google Scholar]
- 27.Zhou J, Scherlag BJ, Yamanashi W, Wu R, Huang Y, Lazzara R, et al. Experimental model simulating right ventricular outflow tract tachycardia: a novel technique to initiate RVOT-VT. J Cardiovasc Electrophysiol 2006; 17:771–775. [DOI] [PubMed] [Google Scholar]
- 28.Iwai C, Akita H, Shiga N, Takai E, Miyamoto Y, Shimizu M, et al. Suppressive effect of the Gly389 allele of the beta1-adrenergic receptor gene on the occurrence of ventricular tachycardia in dilated cardiomyopathy. Circ J 2002; 66:723–728. [DOI] [PubMed] [Google Scholar]
- 29.Hakalahti AE, Tapanainen JM, Junttila JM, Kaikkonen KS, Huikuri HV, Petäjä-Repo UE. Association of the beta-1 adrenergic receptor carboxyl terminal variants with left ventricular hypertrophy among diabetic and non-diabetic survivors of acute myocardial infarction. Cardiovasc Diabetol 2010; 9:42–49. [DOI] [PMC free article] [PubMed] [Google Scholar]