Relationship between genetic variation in the α_2A-adrenergic receptor and the cardiovascular effects of dexmedetomidine in the Chinese Han population

Relationship between genetic variation in the α 2A -adrenergic receptor and the cardiovascular effects of dexmedetomidine in the Chinese Han population 中国汉族人群中肾上腺素α 2A 受体基因多态性与右美托咪定心血管效应的相关性研究 first-author corresp ‡Corresponding Author ‡Corresponding Author †E-mail:smzhu20088@zju.edu.cn †E-mail:smzhu20088@zju.edu.cn smzhu20088@zju.edu.cn Department of Anesthesiology, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China Department of Anesthesiology, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China There are differences in individual cardiovascular responses to the administration of dexmedetomidine, a highly selective α 2A -adrenergic receptor (ADRA2A) agonist. The aim of this study was to investigate ADRA2A gene polymorphisms in the Chinese Han population and their association with the cardiovascular response to intravenous dexmedetomidine infusion. Sixty elective surgery patients of Chinese Han nationality were administered 1 µg/kg dexmedetomidine intravenously over 10 min as a premedication. ADRA2A C-1291G and A1780G polymorphism status was determined in these patients, and their relationships to changes in blood pressure and heart rate after dexmedetomidine administration were analyzed. There were neither significant differences in systolic or diastolic blood pressure changes in individuals with different A1780G and C-1291G genotypes after dexmedetomidine administration, nor in heart rates among the different A1780G genotypes. However, there were significant differences in changes in heart rates in patients with different C-1291G genotypes. There were no significant differences in the sedative effects of dexmedetomidine among different A1780G and C-1291G genotypes. Logistic regression revealed that the C-1291G polymorphism was associated with differential decreases in heart rate after intravenous infusion of dexmedetomidine. These findings indicate that the ADRA2A C-1291G polymorphism can affect heart rate changes in patients after intravenous infusion of dexmedetomidine. 目的 2 通过对右美托咪定静脉输注的临床研究,评价中国汉族人群中肾上腺素α 2A 受体基因多态性与右美托咪定心血管效应的相关性. 创新点 2 探索右美托咪定的心血管系统反应与肾上腺素α 2A 受体基因多态性的关系,期望为临床个体化应用右美托咪定及其他α 2 受体激动剂提供重要的依据. 方法 2 本研究取得单位伦理委员会的批准,所有受试者告知受试内容并签署知情同意书.60例美国麻醉医师协会I-II行择期手术汉族患者根据标准入选本研究.通过静脉输注右美托咪定,记录收缩压、舒张压、心率等心血管效应数据,并用聚合酶链式反应(PCR)法检测 ADRA2A 基因单核苷酸多态性. 结论 2 中国汉族人群中肾上腺素α 2A 受体C-1291G基因多态性与应用右美托咪定后心率变化有相关性. Dexmedetomidine α 2A -Adrenergic receptor Polymorphism Blood pressure Heart rate 右美托咪定 肾上腺素α 2A 受体 多态性 血压 心率 Introduction 1 Dexmedetomidine is a highly selective α 2A- adrenergic receptor (ADRA2A) agonist, which has analgesic, sedative, and sympathetic nervous system (SNS) inhibitory functions. It can reduce the required dosages of other anesthetics, improve hemodynamic stability during surgery, and reduce the incidence of myocardial ischemia; dexmedetomidine has accordingly become a commonly used drug in clinical anesthesia (Mantz et al., 2011 2011 ; Neema, 2012 2012 ). Dexmedetomidine administration can lead to hypotension and bradycardia due to its central SNS inhibition; however, it is also accompanied by an initial increase in blood pressure due to peripheral vasoconstriction (Talke et al., 2003 2003 ; 2005 2005 ). Hypotension and bradycardia are common in patients sedated with dexmedetomidine, causing hemodynamic instability (Ice et al., 2016 2016 ). Obvious inter-individual variability in the effects of dexmedetomidine on intensive care unit (ICU) sedation has been observed (Kohli et al., 2012 2012 ). A given dose of medication can lead to either inadequate sedation or an overdose, resulting in the abovementioned complications. Therefore, individualized dosing is necessary to avoid serious complications. To this end, examining the effects of ADRA2A gene polymorphisms can provide valuable information, enabling personalized clinical administration of dexmedetomidine and other ADRA2A agonists. Studies have shown that the ADRA2A polymorphism can contribute to the different effects of dexmedetomidine, including its sedative effect and changes in blood pressure (Kurnik et al., 2011 2011 ; Yağar et al., 2011 2011 ). However, the minor frequencies of some ADRA2A polymorphisms differ between Asian and Caucasian populations (Small et al., 2006 2006 ). The purpose of this study was to investigate ADRA2A gene polymorphisms in the Chinese Han population and their association with the cardiovascular responses of patients to dexmedetomidine administration. Materials and methods 1 Ethics 2 This study was approved by the Ethics Committee of the First Affiliated Hospital, School of Medicine, Zhejiang University (Hangzhou, China). Written informed consent was obtained from all patients. The study was registered in the Chinese Clinical Trial Registry (ChiCTR) on April 24, 2016, with the registry number ChiCTR-OPC-16008350. Patients 2 Sixty adult patients of Chinese Han nationality who had undergone elective surgery, with American Society of Anesthesiologists physical status I–II and without hypertension, diabetes, or a history of any other major organ diseases, were enrolled in this study between May 1 and September 30, 2016. Exclusion criteria were major organ diseases, obesity (body mass index ≥30), hypertension, arrhythmia, and dexmedetomidine contraindications. Dexmedetomidine administration and determination of its effects 2 After patients entered the preparation room and were awaiting anesthesia and surgery, intravenous dexmedetomidine was administered as a premedication. An intravenous cannula was initially inserted for infusion, and a 5-mL blood sample was drawn in an ethylenediaminetetraacetic acid-coated vacuum tube for DNA extraction. The patients were monitored for electrocardiogram activity, pulse oxygen saturation, and blood pressure, and these parameters served as the baseline parameters (time 0). In addition to routine monitoring, the bispectral index (BIS) was used, which has been shown to correlate with loss of consciousness and increased sedation in patients under anesthesia. Paliwal et al. ( 2015 2015 ) verified the clinical validity and reliability of BIS for monitoring sedation and investigated the correlation with Ramsay sedation score in ICU patients. A 4-µg/mL solution of dexmedetomidine was intravenously infused at a rate of 1 µg/kg over 10 min using a syringe pump (Graseby 3500 Anaesthesia Pump; Graseby Medical Ltd., Watford, Herts, UK). Systolic blood pressure, diastolic blood pressure, heart rate, and BIS were recorded every 5 min from the beginning of infusion until 30 min later. During this time, disturbance of the patient, including dialogue and medical checks, was avoided. We prepared atropine for treatment if the heart rate decreased to < 40 beat per minute (bpm), ephedrine if systolic blood pressure decreased to < 80 mmHg (1 mmHg=133.3 Pa), and urapidil if systolic blood pressure increased to > 180 mmHg. If a patient was treated with one of these drugs, he were excluded from the analysis. Detection of ADRA2A SNPs by PCR and DNA sequencing 2 ADRA2A C-1291G (rs1800544) and A1780G (rs553668) single-nucleotide polymorphisms (SNPs), located in the 5'-promoter region and the 3'-non-coding region, respectively, were examined. We chose these SNPs because genetic variations in rs1800544 were associated with the sedative effect of dexmedetomidine (Yağar et al., 2011 2011 ), and variations in rs553668 were associated with cardiovascular diseases such as hypertension (Kurnik et al., 2006 2006 ). Genomic DNA was extracted from 5 mL of anticoagulant blood using a standard salt precipitation method. Target fragments were amplified by polymerase chain reaction (PCR) using previously described primers (Lima et al., 2007 2007 ): C-1291G forward, 5'-GGAGGTTACTTCCCTCG-3', reverse, 5'-GGTA CCTTGAGCTAGAGAC-3'; A1780G forward, 5'-CA GAGCAGCACTGGACTAC-3', reverse, 5'-TGGAA GGCATCTCTCCCAAG-3'. For genotyping, the PCR products were sequenced on an ABI 7500 sequence detector (Applied Biosystems, Foster City, CA, USA) using the forward primers. Statistical analysis 2 Data are expressed as mean±standard deviation (SD). Analyses were performed using SPSS v.17.0 statistical software. Genotype distribution was assessed for deviation from Hardy-Weinberg equilibrium using a chi-square test. The relationship between ADRA2A gene polymorphisms and cardiovascular system responses to intravenous administration of dexmedetomidine was analyzed using one-way analysis of variance, followed by Student-Newman-Keuls post-hoc multiple comparison test to identify different pairs among groups (for A1780G, with three groups), or Student’s t -test (for C-1291G, with two groups). When there were changes in blood pressure and/or heart rate at any time point between the different genotypes, the patients with the maximal changes of ≥20% and < 20% compared to their baselines were considered different patient groups. Logistic regression was performed to reveal the reason for changes in cardiovascular parameters after dexmedetomidine infusion, by examining variables such as age, sex, weight, height, and genotypes of C-1291G and A1780G. P -values of < 0.05 were considered statistically significant. Results 1 All patients (28 men and 32 women) completed the study. The ages of these patients ranged from 27 to 60 years (mean (44.02±7.94) years). Their weights ranged from 43 to 82 kg (mean (62.15±9.29) kg), and their heights ranged from 151 to 183 cm (mean (164.58±7.03) cm). After intravenous infusion of 1 µg/kg dexmedetomidine, there were no serious adverse cardiovascular reactions. Some patients experienced hypotension, hypertension, or bradycardia, but none required intervention. Two patients experienced short-term oxygen desaturation (88%–90%) but soon recovered. The genotype of the A1780G SNP in the Chinese Han population was A/A in 11 patients (18.33%), A/G in 34 patients (56.67%), and G/G in 15 patients (25.00%). The genotype of the C-1291G SNP was C/C in 3 patients (5.00%), C/G in 31 patients (51.67%), and G/G in 26 patients (43.33%). All genotypes conformed to Hardy-Weinberg equilibrium (all P > 0.05). Because of the low frequency of the C/C genotype of C-1291G, patients were grouped into a CC/CG group with the C/G patients (i.e., with a C allele) and compared to the G/G group (i.e., without a C allele). Systolic blood pressure, diastolic blood pressure, and heart rate changes after dexmedetomidine administration and their relationships with ADRA2A gene polymorphisms are shown in Figs. 1 1 – 3 3 , respectively. For almost all ADRA2A genotypes, systolic and diastolic blood pressures decreased significantly 20–30 min after dexmedetomidineadministration; however, there were no differences between individuals harboring different A1780G and C-1291G gene polymorphisms. The heart rate decreased significantly 5 min after administration and remained low until 30 min after administration in patients with all ADRA2A genotypes. However, although there were no significant differences among the A1780G genotypes, there was a significant difference between the CC/CG and G/G genotypes of the C-1291G polymorphism ( P < 0.05; Fig. 3 3 ). Data are expressed as mean±standard deviation ( n =60) Data are expressed as mean±standard deviation ( n =60) Data are expressed as mean±standard deviation ( n =60). * P < 0.05, comparison between genotype groups The heart rates of patients with CC/CG genotypes in the C-1291G polymorphism were significantly slower than those of patients with the G/G genotype. However, we could not detect differences in sedative effects between patients with the CC/CG and G/G genotypes, because there were no significant differences in BIS values after dexmedetomidine administration (Fig. 4 4 ). Logistic regression showed that the different heart rate changes were significantly related to different C-1291G genotypes ( P < 0.05; Fig. 3a 3a ). Data are expressed as mean±standard deviation ( n =60) Discussion 1 We observed that dexmedetomidine administration caused a significant decrease in heart rates in all patient groups, and that the C-1291G polymorphism of the ADRA2A gene was associated with differential changes in heart rate. In contrast, the A1780G polymorphism had no significant effect on changes in heart rate or blood pressure. The observed minor allele frequencies of the ADRA2A polymorphisms were similar to those reported for Asian (Small et al., 2006 2006 ) and Chinese populations (Li et al., 2012 2012 ; Yin et al., 2016 2016 ), but were different from those reported for a Caucasian population (Small et al., 2006 2006 ). In addition to the effects of physiological factors such as age, sex, and pathological state, genome polymorphisms can contribute to individual responses to drugs. Polymorphisms of metabolic enzymes, for example, can lead to differences in pharmacokinetics, whereas drug receptor polymorphisms can lead to differences in pharmacodynamics (Galley et al., 2005 2005 ). ADRA2A is widely distributed in the central nervous system and peripheral tissues. By inhibiting neuronal excitability and the secretion of norepinephrine and other neurotransmitters, ADRA2A mediates a series of important physiological responses and pharmacological effects (Madsen et al., 2002 2002 ). In humans and other mammals, the receptor can be expressed as three subtypes, namely, α 2A , α 2B , and α 2C , with its main function performed by ADRA2A. Polymorphisms at the ADRA2A locus can lead to differences in a variety of physiological and pharmacological effects. ADRA2A polymorphisms can affect its expression level (Kurnik et al., 2011 2011 ) and its binding affinity for ligands and drugs. Kurnik et al. ( 2006 2006 , 2008 2008 , 2011 2011 ) and Kohli et al. ( 2010 2010 ) investigated ADRA2A polymorphisms in an American population (including individuals of African-descent and those of European-descent) and examined their effects on blood pressure and the pharmacological effects of dexmedetomidine. Yağar et al. ( 2011 2011 ) studied the association between ADRA2A C-1291G gene polymorphisms and the clinical effects of dexmedetomidine and demonstrated that the C-1291G polymorphism was associated with differences in the sedative effect of dexmedetomidine, although no differential effects were observed on the cardiovascular system. We could not determine whether the differential changes in heart rate after dexmedetomidine administration were related to its sedative effect. We chose intravenous infusion of 1 µg/kg dexmedetomidine, because this dosage caused sedation with minimal side effects. BIS values were typically 70–80 after infusion of dexmedetomidine for 10–30 min. Decreases in heart rate likely occurred as a result of both the infusion of dexmedetomidine and sedation itself. Although our study shows a clear relationship between ADRA2A gene polymorphisms and the response to dexmedetomidine administration, it has certain limitations. First, we detected only two SNPs in ADRA2A , and whether SNPs at other sites affect the cardiovascular response to dexmedetomidine will require further study. Second, we did not administer dexmedetomidine in combination with other anesthetics. Third, the statistical analyses were challenging because of the relatively small sample size. Future studies are needed to track the changes in pharmacokinetics. Dexmedetomidine significantly inhibits central SNS release, and has peripheral vasoconstriction effects, and if combined with other anesthetics, these effects can become pronounced (Talke et al., 2003 2003 ). Accordingly, the cardiovascular response, including changes in blood pressure and heart rate, may be different. In addition, our patients were anxious, as they were awaiting surgery, and their heart rates were frequently increased. Therefore, the degree of heart rate reduction was also related to the baseline heart rate. We also found that “younger patients” were more likely to slow their heart rate after dexmedetomidine infusion than “older patients” ((41.74±7.51) years vs. (47.95±7.19) years), possibly because the younger patients were more anxious, and their heart rates were faster before medication. Intravenous infusion of dexmedetomidine generally leads to bradycardia during clinical application. Our results suggest that it is important to consider, prior to the administration of dexmedetomidine, that some patients might be genetically prone to bradycardia. Conclusions 1 We found that the ADRA2A C-1291G polymorphism could affect changes in the heart rates of patients in Chinese Han population after intravenous infusion of dexmedetomidine. References HF Galley , A Mahdy , DA Lowes . 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All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2008 (5). Informed consent was obtained from all patients for being included in the study. Additional informed consent was obtained from all patients for whom identifying information is included in this article. 10.1631/jzus.B1800647 , 2018-12-31 2019-03-26 2022-01-05 Copyright © Zhejiang University and Springer-Verlag GmbH Germany, part of Springer Nature 2019 2019 Journal of Zhejiang University-SCIENCE B (Biomedicine and Biotechnology) 07 20