Study On The Arg389Gly Polymorphism Of β1-adrenergic Receptor Gene And The Therapy Of Vasovagal Syncope

Background:Vasovagal syncope is a kind of neurally mediated reflex, which induced by nervous reflection and displayed hypotension or bradycardia. It accounts for a considerable proportion of syncope cases.The morbidity is about 44% of all syncope patients and 70% of unexplained syncope patients. It is characterized by hypopiesia, bradycardia or appearance of autonomic nerve excitation such as pallor, nausa, sweating, hyperventilate, and so on. The diagnosis of vasovagal syncope is based on case history and confirmed by the head-up tilt table test. The vasovagal syncope is divided into three types according to the head-up tilt table test of character of hemodynamics:type1 mixed, type2:cardioinhibitory, type3:pure vasodep- resssor. Although vasovagal syncope has a good prognosis, it may affect quality of life such as frequent seizures occur in some patients and even lead to serious accidents, such as falls, head trauma and may be the main cause of unexplained falls. Although there are many relative research on vasovagal syncope, its pathogenesis is not completely understood. People tried to explore its pathogenesis from genetics aspect in recent years. As we know, isoproterenol which isβ1 adrenergic receptor agonist can induce vasovagal syncope.So we can speculate thatβ1 adrenergic receptor is related to vasovagal syncope.β1 adrenergic receptor is the majorβ-AR of heart and mediating the cardiac sympathetic-adrenal system of signal transduction.β1-AR gene has two important SNP:first polymorphic locus at nucleic acid 145(Aâ†'G)resulted in substitution of Ser for Gly at position49. second was observed at nucleic acid 1165(Gâ†'C)resulting in substitution of Gly for Arg at position 389.The codon 389 polymorphism is located in the proximal region of the carboxyterminus cytoplasmic tail, and the region is believed to be an important site for receptor coupling to the G-protein. In vitro mutagenesis studies of the codon 389 polymorphism revealed nearly twofold greater basal and threefold greater agonist-mediated adenylyl cyclase activities with the Arg389 receptor form Gly389, so we hypothesized that theβ1-AR genotype Arg389Gly (C1165G) locus may have functional significance in vasovagal syncpe. It is still unclear thatβ1-AR gene locus Arg389Gly (C1165G) SNP have relationship with the pathogenesis of vasovagal syncpe.and racial distribution of the gene is different. Related research is not yet reported in Chinese. The aim of present study was to explore the relationship betweenβ1-AR gene Arg389Gly (C1165G) SNP and the occurrence or development of frequent vasovagal syncpe in Chinese by the technique of polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). We hope to clarify the molecular genetics of vasovagal syncpe and provide a basis for prevention and treatment.There are many therapies of vasovagal syncope such as education, pharmacological therapy and pacing therapy, but the exact effective treatment remains incompletely understood; pacing is reserved for the few patients in whom syncope is accompanied by marked asystole. Many people choose the pharmacological therapy as the main therapy, such asp-adrenergic blockade, but the effect is not sure. Recently, tilt training was proposed to be effective in preventing the recurrence of Vasovagal syncope.Therefore, we conducted a randomized study, designed to explore whether tilt training would be a better therapy for vasoagal syncope. Objectives:To estimateβ1-AR Arg389Gly polymorphism manifestation in vasovagal patients and investigate the effect of tilt training in the prevention of vasovagal syncope.Methods:90 unexplained syncope patients from the Cardiovascular Deparment of nanfang hospital underwent baseline head-up tilt table test (BHUT) and sublingual nitroglycerin (5mg) -provocated head - up tilt table test (SNHUT). Patients with structural heart disease, sick sinus syndrome, intraventricular conduction disturbance, orthostatic hypotension, atrial fibrillation, or other causes of syncope were not enrolled. None was under b-blocker treatment.According to the results of the head-up tilt table test,90 unexplained syncope patients were divided into several groups.66 patients had a positive HUTT (Group A), 22 in the BHUT (Group A1),44 in the SNHUT (Group A2), and 24 were negative to both (Group B). the genomic DNA was extracted from blood and theβ1-AR Arg389Gly (C1165G) polymorphism was diagnosed by restriction of the PCR amplicon with Bcgl.All patients were genotyped forβ1-AR and next analyzed regarding their head-up tilt table test results, We also compared the distribution features of the genotype and allele among the above groups.66 patients with positive HUTT were divided into three groups randomizely:tilt training group, pharmacotherapy group and control group.22 patients of the tilt training group accepted tilt training,22 patients of the pharmacotherapy group accepted metoprolol therapy (25mg bid),22 patients were in the control group.3 groups were examined again with HUTT after treatment for 2 weeks and followed-up. We analyzed the rates of HUTT from positive-to negative and the syncope relapse among the three groups.the statistical analysis of results:SPSS13.0 statistical software was used. Measurement data are presented as mean±standard deviation, the count data of said frequency. Allele and genotype frequencies were obtained by direct counting. Balance of genetic testing utilizes Hardy-Weinberg law of balance. To compare the groups of count data utilize testingχ2. Compared the groups of measurement data by homogeneity of variance test, homogeneity of variance compared using by one-way ANOVA, two-sample comparison between the mean homogeneity from using an independent samples t test, variance from the use of irregular t 'test. Single-variable logistic regression analysis to explore the relationship between gene polymorphism and vasovagal syncope occurred, calculated odds ratio (odds ratio, OR) and 95% confidence interval (95% CI). Statistically significant difference was defined as P<0.05.Results:Baseline characteristics (gender, age, blood pressure, heart rate)were similar in the positive HUTT group and negative HUTT group. Baseline characteristics (gender, age, blood pressure, heart rate) were also similar in the BHUT group, SNHUT group and negative HUTT group. Baseline characteristics of patients with positive HUTT were no significant differences in tilt training group, pharmacotherapy group and control group.The distribution features of the genotype and allele were compared in all groups.All the genotype and allele frequencies were in Hardy-Weinberg equilibrium.The prevalence of genotype Arg389Arg, Arg389Gly, Gly389Gly was 37.8%,45.5%,16.7% respectively in positive HUTT patients. The negative HUTT patients have no genotype Gly389Gly, The prevalence of genotype Arg389Arg, Arg389Gly was 83.3%,16.7% respectively. The Gly389 allele frequency was higher in positive HUTT patients compared with those with negative HUTT patients (39.4% vs 8.3%,χ2= 15.845 P<0.001).The prevalence of genotype Arg389Arg, Arg389Gly, Gly389Gly was 18.2%,50%,31.8% respectively in BHUT patients. And it was 47.7%,43.2%,9.1% in SNHUT patients respectively. The Gly389 allele frequency was higher in BHUT patients compared with those with SNHUT patients (56.8%vs 30.7%,χ2= 4.919 P=0.027). A gradient of allelic frequencies in polymorphism Arg389Gly was found when patients were analysed according to the HUTT responses. The Gly389 allele frequency in subjects of groups BHUT, SNHUT, and negative HUTT was dereased:56.8%,31.7%,8.3%, respectively ((χ2= 19.424, P<0.001)). The heterozygosis Arg389Gly frequency was higher than homozygosis Gly389Gly in every group patients.The presence of Gly389 allele ofβ1-AR gene was found to be a greater risk factor in positive tilted patients than in negative tilted patients. In terms of relative Arg389 allele, OR value (95%CI) was 7.150 (2.425～21.085), P<0.001.After two weeks of treatment, The results of all the patients with positive HUTT were as follow:2 patients had severe bradycardia after taking the metoprolol in the pharmacotherapy group, heart rate was 42 times/min and blood pressure were decreased. So this two cases quitted for bradycardia reasonse.Tilt training group and control group have no adverse reactions.The rate of HUTT from positive to negative was 86.4% for tilt training group,25.0% for pharmacotherapy group, and 18.2% for control group.The former had a statistically significant difference with the latter two (P<0.05). But there was no statistically significant difference between the pharmacotherapy group and control group (P=0.591). After half a year of follow-up,2 patients only adhered to tilt training for two weeks in the tilt training group, but at the end of the experiment, the two patients did not have syncope recurrence.the relapse rates for tilt training group, pharmacotherapy group and control group were 9.1%, 40.0% and 77.3% respectively. There were significant differences among the three groups (P<0.05) (P<0.05), but the relapse rates for tilt training group was the lowest.Conclusion:Theβ1-AR Arg389Gly polymorphism is concerned with the occurrence of vasovagal syncpe.Gly389 allele seems to be susceptibility gene for vasovagal syncpe and it is maintained in the population through heterozygosis. The distribution of Gly389 may be related to the level of the occurrence of syncpe:contributing to susceptibility to faint during orthostatic challenge.Tilt training may be a better therapy for vasoagal syncope.