摘要
特发性室性心律失常是指在目前的诊断技术下未能发现明确器质性心脏病的临床证据,也排除了代谢或电解质紊乱以及长QT间期综合征等的室性心律失常,包括室性心动过速(VT)和频发单形室性早搏(PVCs)。这类心律失常多数来源于右室流出道(RVOT),少数来源于左室流出道(LVOT),性别差异不明显。既往认为PVCs是良性的,近年来发现了室性早搏频发可引起心脏扩大和心动过速型心肌病,导致左室功能不全和充血性心力衰竭;更有甚者,特发性右室流出道室性心律失常可诱发恶性心律失常,导致心脏猝死,因此引起了广大临床医生的重视。但有关其发生机制尚不明确,多数认为与儿茶酚胺所介导的延迟后除极(DAD)和触发活动以及自律性增强(交感神经刺激)有关。心率变异性(HRV)研究分析显示,室性心律失常发作前反应交感神经与迷走神经张力平衡指数LF/HF比率明显增高。动物实验中高频刺激输入到肺动脉近端的交感神经可以诱发出RVOT-VT/PVCs,该反应可被艾司洛尔终止或减弱。交感神经活性增高有助于VT/PVCs的发生。心交感神经末梢释放去甲肾上腺素,作用于心肌细胞膜上的肾上腺素能受体(AR),其中β-肾上腺素能受体(β-AR)在介导心脏功能中起主要作用。G蛋白系统通过受体-G蛋白-效应物信号传导通路在心血管系统中起着非常重要的作用。Gs蛋白α亚单位能够偶联活化的β-AR,通过激活心肌细胞膜上的腺苷酸环化酶(AC)使细胞内环磷酸腺苷(cAMP)增加,后者可以激活蛋白激酶A(PKA),从而引发细胞内一系列分子的级联反应。据报道,人Gs蛋白α亚基基因(GNAS1)定位于染色体20q13.2-13.3,其5号外显子第393位单核苷酸存在一个沉默单核苷酸突变,使编码异亮氨酸密码子由ATT突变成ATC(ATT→ATC,Ile131),从而增强AC活性。因此,我们从信号传导通路出发,大胆假设GNAS1基因T393C位点单核苷酸多态性(SNP)可能是特发性室性早搏发生的可能机制。B-受体阻滞剂(B-Blockade)能有效控制交感神经兴奋相关的室性心律失常包括运动诱发的心律失常,急性心肌梗死、围手术期心律失常和心力衰竭相关的心律失常,并能有效预防心源性死亡。多数B-Blockade能有效减少室性早搏,因此我们进一步探讨特发性室性早搏患者GNAS1基因T393C位点SNP与B-Blockade的疗效的可能关系。
1、分析GNAS1基因T393C位点SNP与中国汉族人群特发性室性早搏的相关性,从分子遗传学水平探讨特发性室性早搏的可能机制。
2、研究GNAS1基因T393C位点SNP与B-Blockade对特发性室性早搏的药效学的可能关系,探讨B-Blockade疗效的基因学基础。
2007年1月至2009年11月从南方医院住院病例和门诊病例中筛查研究对象共318例。
病例组156例,其中男62例,女94例,年龄48.87±14.65(18-75)岁。其纳入标准:①静息12导心电图、24h动态心电图、心电遥测或运动应力测试均提示有频发PVCs,早搏数目≥30个/h;单源呈二联律或三联律,伴或不伴有短阵VT;②经体表心电图、胸部摄片、超声心动图、生化功能、心肌酶谱、部分行冠状动脉血管三维成像和冠状动脉血管造影等排除了高血压、冠心病、扩张型和肥厚型心肌病、致心律失常型右室心肌病、心脏瓣膜病等器质性心脏病;③排除了Brudaga综合征、长QT综合征、短QT综合征等遗传性心律失常;④排除了病态窦房结综合征,房室传导阻滞等缓慢性心律失常;⑤排除了电解质紊乱和代谢性疾病,如风湿性关节炎、糖尿病等。
对照组162例,男65例,女97例,年龄50.39±12.84(18-75)岁。其纳入标准:无室性心律失常或室性早搏数目<30个/h,亦符合上述排除标准,且在性别、年龄、体重指数(BMI)、吸烟、饮酒与病例组相匹配。
两组均建立临床资料观察表,详细记录患者年龄、性别、身高、体重、BMI、吸烟、饮酒等一般情况。
所有研究对象均进行24小时动态心电图检测,记录24小时室性早搏总数、平均心率、SDNN、SDANNindex、SDNNindex、rMSSD、pNN50、LF、HF以及LF/HF。所有受试者清晨空腹抽取静脉血,EDTA抗凝,采用试剂盒从外周血白细胞提取脱氧核糖核苷酸(DNA),采用聚合酶链式反应-限制性片段长度多态性(PCR-RFLP)测定GNAS1基因T393C位点SNP。分别比较两组之间不同基因型及等位基因频率的分布特点以及与HRV的关系。
从病例组中选择无支气管哮喘、慢性阻塞性肺疾病、外周血管病变等适合服用B-Blockade且能规律服药的96例患者。倍他洛克从小剂量开始,逐渐增量至25mg,2次/日。监测血压、心率等指标,观察体位性低血压、窦性心动过缓、房室传导阻滞等不良反应随访4周,比较服药前后患者室性早搏数目,分析GNAS1基因T393C位点SNP与β-Blockade的药效学的可能关系。
1、通过PCR-RFLP对GNAS1基因T393C位点的检测,我们发现中国汉族人群中特发性室性早搏患者存在T393C位点SNP。
2、病例组与对照组GNAS1基因T393C位点TT、TC、CC基因型频数分别为46、78、32和67、77、18,差异有统计学意义(χ2=7.719,P=0.021)。Fokl-等位基因、Fokl+等位基因频率分布为54.5%、45.5%和65.1%、34.9%,差异有统计学意义(χ2=9.487,P=0.006)。Fokl+等位基因频率在病例组中较对照组明显增高。
3、相对TT基因型而言,CC纯合子型、TC+CC基因型能显著增加特发性室性早搏发生的危险性,OR值(95%CI)分别为2.589(1.300-5.156)、1.686(1.059-2.685),P值分别为0.007、0.028,其中杂合子型TC相对于TT来说,OR值为1.475(0.904-2.408),但P值为0.12。
4、LF/HF在病例组、对照组中位数分别为3.01、2.64,平均秩次分别为173.60、145.93;两组比较有统计学差异(P=0.007),病例组中LF/HF较对照组增高。
5、TT、TC、CC三种基因型间的LF/HF差异具有统计学差异(χ2=7.135,P=0.028),其平均秩次分别是158.12、150.55、190.38,即CC>TT>TC。我们可以推断CC基因型的LF/HF增加最明显,其次是TT基因型,再次TC基因型。SDNN、SDANNindex、SDNNindex、rMSSD、pNN50、LF、HF在三种基因型间无显著性差异(P>0.05)。
6、倍他乐克能有效减慢心率和减少室性早搏的数目(P=0.000)。其中疗效显著率、有效率、无效率分别为38.5%、32.3%、29.2%。TT、TC、CC基因型频数在显效组中分别是10、11、16,无效组中分别是15、9、4;T、C等位基因频率在显效组中分别是41.9%、58.1%,无效组中分别是69.6%、30.4%;比较不同基因型及等位基因在显效与无效两组间的差异,χ2值分别为7.294、9.878,P值分别为0.026、0.002,显效组CC基因型明显高于无效组。
1、GNAS1基因编码区第5号外显子中T393C位点SNP存在于中国汉族人群中。
2、特发性室性早搏患者中LF/HF明显高于对照组,交感神经张力增强。
3、GNAS1基因T393C位点SNP与中国汉族人群特发性室性早搏的发生有明显的相关性,Fokl+等位基因可能是其易患基因。
4、GNAS1基因T393C位点SNP与LF/HF的大小有明显的相关性,其与LF/HF的关系为:CC>TT>TC。
5、GNAS1基因T393C位点SNP影响特发性室性早搏发生的可能机制:C等位基因突变导致Gs蛋白功能改变,增加AC活性,使细胞内cAMP含量,从而激活PKA,进而增加其发病风险。
6、β-Blockade通过下调交感神经张力而有效控制特发性室性早搏,CC基因型B-Blockade疗效明显。因此,β-Blockade是CC基因型患者的最好选择。
Idiopathic ventricular arrhythmia is defined as that it failed to find any clinical evidence of organic heart disease under the current diagnostic techniques,but also ruled out metabolic or electrolyte disorders and long QT interal syndrome.It commonly refer to ventricular tachycardia(VT) and/or frequent,monomorphic premature ventricular contractions (PVCs).A majority of these arrhythmias arise from the right ventricular outflow tract(RVOT), and a few from the left ventricular outflow tract(LVOT).This is no significantly difference between genders. In the past,PVCs were considered to be benign. In recent years, We have found that frequent PVCs can induce cardiac enlargement and tachycardia-induced cardiomyopathy and can lead to left ventricular dysfunction and congestive heart failure;What's worse, idiopathic ventricular arrhythmia from RVOT can cause sudden cardiac death.That has aroused the attention of clinical physicians.Up to now,the mechanism of its occurrence is not clear.The two postulated leading arrhythmogenic mechanisms include triggered activity secondary to cyclic adenosine monophosphate(cAMP) -mediated delayed afterdepolarizations and abnormal automaticity(enhanced sympathetic stimulation). Heart rate variablity studies showed sympathetic and vagal tone balance index LF/HF significantly increased prior to the occurrence of ventricular arrhythmias.An animal model has been described that PVCs and VT suggestive of RVOT were induced by high-frequency nerve stimulation of the sympathetic input to the proximal pulmonary artery and can be terminated or reduced by esmolol. Increased sympathetic activity contribute to VT/PVCs.Cardiac sympathetic nerve endings release norepinephrine and act on myocardial cell membrane receptors,namely adrenergic receptors(AR).β-adrenergic receptor(B-AR) plays a major role in mediating the cardiac function. G protein system also plays a very important role in the cardiovascular system by receptor-G protein-effector signal transduction pathway. Gs protein a subunit can be coupled with activatedβ-AR and increase intracellular cyclic adenosine monophosphate (cAMP) by activating adenylate cyclase(AC), the former can activate protein kinase A (PKA) and trigger a series of molecules cascade in the intracellular. As we known, Gs protein a subunit gene (GNAS1) located on chromosome 20q13.2-13.3, there is a silent single-nucleotide mutations in the first 393 nucleotides of exon 5 by ATT mutation into ATC which codon isoleucine(ATT→ATC,Iie131),which led to enhance AC activity.Based on the signal transduction pathway,we dare to assume GNAS1 gene T393C locus single nucleotide polymorphism (SNP) may be the possible mechanism of idiopathic premature ventricular contractions.β-receptor blockade (β-Blockade) can effectively control the sympathetic nerve-related ventricular arrhythmias, including exercise-induced arrhythmia, acute myocardial infarction, perioperative arrhythmia and heart failure related arrhythmia, and can prevent cardiac death. Most ofβ-Blockade are effective in reducing PVCs counts, so we further explore the possible relationship between GNAS1 gene T393C locus SNP and the efficacy ofβ-blockade to patients with idiopathic PVCs.
To determine the association between GNAS1 gene T393C loci SNP and idiopathic PVCs in Chinese Han population,and uncover the possible molecular genetic mechanism. Study the possible relationship between GNAS1 gene T393C loci SNP and the efficacy of B-Blockade on idiopathic PVCs and to exproe the genetic basis of the efficacy of B-Blockade.
318 patients were screened from in-patients and out-patients in the southern hospital from January 2007 to November 2009.
All samples were divided into two study groups. The Case group included 156 subjects,62 males and 94 females,mean age 48.87±14.65 years,range 18-75.The inclusion criteria:①Arrythmias noted on resting 12-lead electrocardiogram (ECG),24-hour Holter monitoring, telemetry monitoring,or during exercise stress testing as well as symptomatic ventricular arrhythmias refractory to medical therapy. The number of PVCs>30/hour, frequent,monomorphic PVCs showed bigeminy or trigeminy, with or without non-sustained ventricular tachycardia.Non-sustained VT was defined as VT≥3 beats and lasting<30 seconds;②Hypertension、Coronary atherosclerotic heart disease(CHD), Dilated cardiomyopathy,Hypertrophic cardiomyopathy,Arrhythmogenic right ventricular cardiomyopathy,Valvular heart disease were excluded by ECG,Chest Radiography,Transthoracic echocardiography, Biochemistry,Myocardial enzyme,and some of by three-dimensional imaging coronary angiography and Coronary angiography;③Hereditary arrhythmia such as Brudaga syndrome,long/short QT syndrome were excluded;④Ruled out sick sinus syndrome, atrioventricular block and other bradyarrhythmias;⑤Ruled out electrolyte disorders and metabolic diseases such as rheumatoid arthritis and diabetes.
The Control group included 162 subjects,65 males and 97 females,mean age 50.39±12.84 years,range 18-75.The inclusion criteria:no ventricular arrhythmias or the number of PVCs<30/hour, Comply with the above exclusion criteria and matched in gender,age,body mass index(BMI),smoking, drinking with the case group.
Both groups were set up clinical data sheet. Basic clinical datas include age, sex, height, weight, BMI, smoking, drinking.24-hour Holter monitoring was tested in all of the subjects and record the total number of 24-hour PVCs,average heart rate,SDNN,SDANNindex, SDNNindex,rMSSD,pNN50, LF, HF and LF/HF. In fasting state, venous blood was collected in all subjects,EDTA anticoagulant. Genomic oligodeoxynucleotide (DNA) in leukocyte extracted by DNA Extraction Kit. T393C locus in exon 5 of GNAS1 gene were analysed by polymerase chain reaction-restriction fragment length polymorphism(PCR-RFLP).Distribution of T393C genotypes and alleles were compared between the two groups,as well as the relation to heart rate variability(HRV).
96 patients from the case group were chosen without bronchial asthma, chronic obstructive pulmonary disease, peripheral vascular disease and suitable forβ-Blockade and can take medicine regularly. Betaloc tablets start at small dose,increase gradually to 25mg,2 times/day.Monitor adverse reactions such as orthostatic hypotension,sinus bradycardia, atrioventricular conduction block and so on. They were followed up for 4 weeks. Compare the number of PVCs after medicine and analysis the possible relationship between GNAS1 gene T393C locus SNP and the efficacy ofβ-Blockade.
1.GNAS1 gene T393C locus SNP exists in Chinese Han population by PCR-RFLP.
2. The frequencies of genotype of TT, TC, CC in case group was 46,78,32 and 67,77,18 in control group. The difference between the two groups was statistically significant (χ2= 7.719, P=0.021). The frequencies of FokI-allele, FokI+allele was 54.5%,45.5% in case group and 65.1%,34.9% in control group, the difference was statistically significant (χ2=9.487,P=0.006).FokI+allele frequencies in case group was higher than control group.
3.Compared to TT genetype, CC homozygous, TC+CC genotype significantly increase the risk of idiopathic PVCs. The odds ratio(OR) are 2.589(1.300-5.156),1.686(1.059-2.685),P values are 0.007,0.028, respectively.The OR values (95% CI) of heterozygous genotype TC is 1.475 (0.904-2.408), but the P value is 0.12.
4. The median of LF/HF between the case group and the control group are 3.01 and 2.64 respectively.The difference between the two groups was significantly(the mean rank of LF/HF are 173.60 vs 145.93, P= 0.007).
5.Among the genotypes TT,TC,CC, the difference of LF/HF is statistically significant (χ2=7.135, P=0.028).The mean rank of them are 158.12,150.55,190.38 respectively,that is CC>TT>TC.But SDNN, SDANNindex, SDNNindex, rMSSD, pNN50, LF and HF among the three genotypes was no significant difference (P>0.05).
6. Metoprolol significantly decreased average heart rate and PVCs counts.The rate of significant effective,effective and ineffective are 38.5%,32.3%,29.2%, respectively. In the significant effective group,the frequencies of genotype TT,TC,CC are 10,11,16 and the frequencies of FokI-allele, FokI+allele are 41.9%, 58.1%;In the ineffective group the frequencies of genotype TT,TC,CC are 15,9,4 and the frequencies of FokI-allele, FokI+allele are 69.6%,30.4%; Comparison of the significant effective group and ineffective group,the distribution of genotypes and alleles are significant.χ2 values are 7.294,9.878 and P values are 0.026,0.002. CC genotype in the significant effective group was significantly higher than ineffective group.
1.GNAS1 gene T393C locus SNP exists in the Chinese Han population.
2.LF/HF is significantly higher in case group than the control group and sympathetic nerve activity increased.
3.The T393C polymorphism of GNAS1 may be associated with idiopathic PVCs in the Chinese Han population, Fokl+allele may be the predisposing factor.
4. There is a clear correlation between GNAS1 gene T393C loci SNP and LF/HF,that is CC>TT>TC.
5.The underlying mechanism of idiopathmic PVCs caused by T393C locus SNP: The Fokl+allele variant of the Gs protein may be associated with a functional variant that enhances activation of AC activity,resulting in increased cAMP production and PKA activity,which increase the risk of its incidence.
6.β-Blockade is effective for idiopathic PVCs by inhibiting the sympathetic tone.Their effectiveness is considerably greater in patients with CC genotype. Therefore,β-Blockade therapy should be the first choice in these patients.
引文
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