心房颤动的遗传学研究

心房颤动多见于老年人,通常伴有器质性心脏病,也可无心脏病基础的称为孤立性房颤或特发性房颤,少部分呈家族遗传倾向。随着分子生物学技术的深入研究,发现家族性房颤的比例较以往增高,现针对心房颤动的遗传学研究作一综述。     

心房颤动的遗传学研究进展

正纵观世界范围内心血管疾病的病谱,心房颤动俨然成为心律失常方面研究的热点及重点,它带给患者的危害不仅仅是心律失常的不适症状,而是其严重威胁患者生命的种种并发症:心力衰竭,脑卒中以及死亡[1]。随心房颤动发病率逐年增加而陡升的巨大社会经济压力,及其加之于整个人类健康事业长久发展的重担,现代药物治疗心房颤动研究的踟躅不前以及至今为止其尚未被医学界参透的详细发病机理使得越来越多的学者将治疗心房颤动的希望寄予基因治疗上。     

心房颤动与单核苷酸多态性

心房颤动是临床上常见的心律失常,多见于老年人。其发病机制目前仍不清楚。随着分子生物学技术的发展,发现基因组中的单核苷酸多态性与房颤的发生有一定关系。现就与房颤发生有关的单核苷酸多态性的研究进展做一综述。     

心房颤动的分子遗传学机制

心房颤动是临床上最常见且危害严重的心律失常,可诱发心力衰竭、导致心动过速性心肌病、增加血栓栓塞的危险。目前房颤的分子遗传学研究成为人们关注的热点,并取得了初步成果,从基因水平探讨房颤的发病机制,为临床工作提供了重要信息,有助于临床诊治和预防。同时,房颤也是一种遗传异质性疾病,存在研究的复杂性和矛盾性。笔者现就目前房颤研究的相关进展作一综述。     

心房颤动分子遗传学研究进展

心房颤动(房颤)是最常见的心律失常之一。房颤是一种多因素疾病,年龄、高血压性心脏病、心肌病、瓣膜疾病和冠心病等是房颤发生的高危因素。近年来研究发现分子遗传因素在该病的发生发展中具有重要作用,房颤的分子遗传机制目前成为研究热点并已取得进展,现对分子遗传学研究中基因变异与房颤发生的相关性进行综述。分子生物学和遗传学研究将推进我们对该疾病的认识和治疗。     

ZFHX3基因rs7193343多态性与心房颤动的相关性

目的:研究ZFHX3基因rs7193343多态性与心房颤动(房颤)的相关性。方法:采用前瞻式病例对照研究,按照相关标准入选202例汉族人群,其中房颤患者102例,无房颤患者100例,收集其临床资料和静脉血标本,分别提取基因组DNA,通过聚合酶链反应-限制性片段长度多态性方法和基因测序法检测所有患者的ZFHX3基因rs7193343多态性的基因型。结果:①2组患者ZFHX3基因rs7193343的CC基因型(P=0.023,OR=0.422,95%CI0.198～0.900)、TT基因型(P=0.024,OR=2.475,95%CI1.106～5.541)及等位基因(P=0.017,OR=1.614,95%CI1.089～2.391)的分布均差异有统计学意义。②房颤患者中,TT基因型患者的超敏C反应蛋白水平较CC基因型患者明显高[1.62(0.90～2.90)mg/L∶0.71(0.34～1.09)mg/L,P=0.014],且TT基因型患者的左房前后径和右房横径大小均较CC基因型患者明显增大[(38.2±4.9)mm∶(33.5±4.1)mm,P=0.026;(38.9±6.0)mm∶(33.1±2.6)mm,P=0.003]。结论:在大陆汉族人群中,ZFHX3基因rs7193343多态性与房颤具有显著的相关性,T等位基因和TT基因型是房颤发生发展的危险因子,可通过影响心房肌的结构重构和炎症性改变为房颤的发生、发展提供基质。     

心房颤动的分子机制

心房颤动是心房快速的无序激动和无效收缩,是临床上最常见的心律失常。早在1850年西方学者Hoffa等就发现心房颤动的存在,然而,150多年过去了,心房颤动的发生机制依然莫衷一是。今天心房颤动依旧是现代医学所面临的一大挑战。20世纪早期产生了心房颤动电生理学的理论框架,认为心房颤动可能起源于三种机制:自律性增加、单环折返和多环折返。1959年以后,由于Moe等和Allessie等的研究工作,多环折返一直是心房颤动发病的主流理论。折返波长是多环折返假说的重要概念,它指在一个不应期中电活动运行的距离。折返波长=不应期×传导速度。折返波长…     

Connexin40基因多态性与心房颤动的相关性研究

目的探讨Connexin40基因多态性与心房颤动的相关性。方法采用等位基因聚合酶链反应（PCR）的方法，对北京地区110例研究对象进行两种Connexin40单核苷酸多态性的检测，其中孤立性房颤组50例，高血压房颤组18例，单纯高血压组12例，健康对照组30例。结果孤立性房颤、高血压房颇、单纯高血压与健康对照组之间Connexin40启动子区域—44位点（G→A）单核苷酸多态等位基因频率和基因型频率存在分布差异显著（p〈0．05）；房颤组与非房颤组相比，在Connexin40启动子区域-44位点A基因型频率及A等位基因频率高于非房颤组（p〈0．05）；孤立性房颤、高血压房颤、单纯高血压与健康对照组之间Connexin40启动子区域（＋71）的基因型频率及等位基因频率的分布差异没有显著性（p〉0．05）.结论Connexin40基因多态性（-44G→A）与心房颤动发生具有相关性。     

心房颤动的治疗

本文回顾了心房颤动的治疗,可供基层医院参考.     

新疆汉族与维吾尔族心房颤动患者钠通道基因多态性与心房颤动易感性的相关性研究

目的 探究新疆汉族与维吾尔族心房颤动(房颤)患者钠通道基因的多态性与房颤易感性的相关性.方法 选取2016年6月至2018年6月在新疆医科大学第一附属医院诊断及治疗的汉族及维吾尔族房颤患者各100例,纳入房颤组;选择同时期非房颤的汉族及维吾尔族健康体检者各100例,纳入对照组.比较两组患者一般资料,包括:性别、年龄、血压、血脂、病史等情况,并进行钠离子通道(SCN5A)H558R位点基因多态性检测,使用多因素Logistic回归模型分析房颤的危险因素.结果 汉族及维吾尔族患者房颤组和非房颤组间年龄、总胆固醇和低密度脂蛋白胆固醇水平(LDL-C)的差异均具有统计学意义(P<0.05);SCN5A H558R位点基因符合Hardy-Weinberg平衡,汉族及维吾尔族房颤患者G等位基因频率均显著高于非房颤组,且基因型频率也与非房颤患者具有显著差异;多因素Logistic回归显示,汉族患者显性模型中(AG+GG)基因型(OR=2.72,P=0.012),共显性模型中AG基因型(OR=2.77,P=0.014)是房颤发生的独立危险因素;维吾尔族患者显性模型中(AG+GG)基因型(OR=2.37,P=0.012),共显性模型中AG基因型(OR=2.65,P=0.006)是房颤发生的独立危险因素;入组总患者显性模型中(AG+GG)基因型(OR=2.19,P=0.001),共显性模型中AG基因型(OR=2.20,P=0.001)是房颤发生的独立危险因素.结论 新疆汉族与维吾尔族房颤患者钠通道基因多态性与房颤均存在显著相关性,值得进一步深入研究.     

Genetic aspects of atrial fibrillation

Atrial fibrillation (AF) occurs predominantly in the elderly and is commonly associated with underlying cardiac diseases. A significant number of patients, however, have early onset AF that is not associated with any underlying disease. At present, it is unknown how often this form of AF is familial and how frequently familial AF is due to genetic causes. Recent data suggest that familial AF occurs more frequently than previously recognized. Also, in AF in the setting of underlying diseases, it is suggested that some form of genetic control may be present. Understanding the molecular mechanisms underlying AF may provide insight into the pathogenesis of AF and eventually may lead to improved, patient-tailored rhythm control strategies.     

Genetic features of atrial fibrillation

Etiology of atrial fibrillation remains largely unknown. Molecular genetics is a powerful tool that may help to identify underlying mechanisms of the arrhythmia. As a matter of fact, a major step forward was the recent identification of the KCNQ1 gene coding a subunit of a potassium channel in IKS current as responsible for idiopathic atrial fibrillation in a familial autosomal dominant form. The KCNQ1 gain-of-function mutation may induce a shortening in action potential and in effective refractory periods leading to the initiation and persistence of atrial fibrillation. In the multifactorial forms of the disease, by far the most frequent, susceptibility genes and modifier genes are also currently being identified. This better understanding of the disease leads to new perspectives, particularly for therapeutists, and would enable them to work with more interest.     

Molecular basis of electrical remodeling in atrial fibrillation

Atrial fibrillation (AF) is the most common cardiac arrhythmia, and is often associated with other cardiovascular disorders and diseases. AF can lead to thromboembolism, reduced left ventricular function and stroke, and, importantly, it is independently associated with increased mortality. AF is a progressive disease; numerous lines of evidence suggest that disease progression results from cumulative electrophysiological and structural remodeling of the atria. There is considerable interest in delineating the molecular mechanisms involved in the remodeling that occurs in the atria of patients with AF. Cellular electrophysiological studies have revealed marked reductions in the densities of the L-type voltage-gated Ca2+ current, I(Ca,L), the transient outward K+ current, I(TO), and the ultrarapid delayed rectifier K+ current, I(Kur), in atrial myocytes from patients in chronic AF. Similar (but not identical) changes in currents are evident in myocytes isolated from a canine model of AF and, in this case, the changes in currents are correlated with reduced expression of the underlying channel forming subunits. In both human and canine AF, the reduction in I(Ca,L) appears to be sufficient to explain the observed decreases in action potential duration and effective refractory period that are characteristic features of the remodeled atria. In addition, expression of the sarcoplasmic reticulum Ca2+ ATPase is reduced, suggesting that calcium cycling is affected in AF. These recent studies suggest that calcium overload and perturbations in calcium handling play prominent roles in AF-induced atrial remodeling. Although considerable progress has been made, further studies focused on defining the detailed structural, cellular and molecular changes that accompany the different stages of AF in humans, as well as in animal models of AF, are clearly warranted. It is anticipated that molecular insights gleaned from these studies will facilitate the development of improved therapeutic approaches to treat AF and to prevent the progression of the arrhythmia.     

心房颤动患者心房纤维化分子基础的临床研究

目的研究风湿性心脏瓣膜病(风心病)心房颤动(房颤)患者心房组织中胶原、基质金属蛋白酶2(matrixmetalloproteinases2,MMP2)及其内源性抑制剂金属蛋白酶组织抑制因子(tissueinhibitorsofmetalloproteinases,TIMPs)的基因转录,探讨房颤患者心房纤维化的分子机制及其在房颤发生、持续中的作用。方法73例风心病接受换瓣手术者分为三组,其中窦性心律组34例,阵发性房颤组9例,持续性房颤组30例。于术中获取右心耳组织,应用半定量逆转录聚合酶链反应(RT PCR)方法,测定心房组织中Ⅰ型胶原、Ⅲ型胶原、MMP2、TIMP1、TIMP2、TIMP3、TIMP4的mRNA水平。结果与窦性心律组比较,Ⅰ型胶原、MMP2的mRNA在阵发性房颤患者(均为P<0.05)、持续性房颤患者(均为P<0.01)心房组织中的表达均明显增加。房颤患者Ⅲ型胶原的mRNA表达虽有增加,但无统计学意义(P>0.05)。持续性房颤组TIMP1、TIMP2、TIMP3的mRNA表达明显下调(均为P<0.01)。TIMP4的mRNA表达水平在各组中差异无统计学意义(P>0.05)。Ⅰ型胶原的mRNA表达水平与左心房内径(r=0.336,P=0.004)、房颤持续时间(r=0.339,P=0.003)呈正相关;MMP2的mRNA表达水平与TIMP2的mRNA表达水平呈负相关(r=-0.326,P=0.006),与Ⅰ型胶原(r=0.322,P=0.006)、左心房内径(r=0.300,P=0.011)、房颤持续时     

心房颤动患者离子重构的分子基础

目的　研究心房颤动 (AF)患者离子重构的分子基础。方法　以先天性心脏病 (CHD)和风湿性心脏病 (RHD)持续窦性心律 (SR)患者为对照 ,应用半定量RT PCR法检测RHD伴阵发性AF(PAF)慢性AF 6个月 (AF 6M )和慢性AF >6个月 (AF >6M )患者心房肌L 型电压依赖钙通道α1c亚基 (LVDCCα1c)、电压依赖KV4 3钾通道α亚基 (VDKV4 3α)和电压依赖钠通道α亚基 (VDSCα)mRNA的表达。结果　SR组内CHD患者与RHD患者LVDCCα1c、VDKV4 3α和VDSCα的mRNA表达差别无明显性 ;与对照组相比 ,各组AF患者VDSCα的表达没有改变 ;LVDCCα1c在AF >6M患者中的表达显著下降 ,而在PAF和AF 6M患者中的表达有不同程度下调 ,但无统计学意义 ;LVDCCα1cmRNA表达与心房率、左、右心房内径成明显负相关 ,并且其表达随AF分数增高逐渐下降 ;单因素协方差分析 (ANOVA)矫正心房内径的影响 ,AF >6M患者α1cmRNA表达仍明显下降 (P <0 0 1)。KV4 3αmRNA在PAF、AF 6M和AF >6M患者中的表达均显著降低。KV4 3钾通道α亚单位mRNA表达与AF分数、左心房内径和平均心房率均成明显负相关 ,经ANOVA剔除左心房内径的影响 ,各组mRNA表达较SR组仍显著下降 (P <0 0 5 )。结论　L 型钙通道和KV4 3钾通道转录水平下调是相应ICaL和Ito1重构的分子基础 ,基因表     

Electrocardiology basis of paroxysmal atrial fibrillation (author's transl)

55 patients (15 subjects in whom a special cardiac disease could be ruled out and 40 patients with paroxysmal atrial fibrillation) were investigated by means of the extrastimulus method at a driving rate of 80 min-1. In 32 of the 40 patients with paroxysmal atrial fibrillation occurred signs of atrial vulnerability. When compared with the healthy subjects and the remaining 8 patients who did not fulfil the criteria for vulnerability, there were significant shorter effective and longer relative refractory periods of the right atrium in the vulnerability group. These findings suggest that the re-entry phenomenon may be the underlying mechanism of paroxysmal atrial fibrillation in the group with atrial vulnerability.     

Mechanisms of disease: Genetic mechanisms of atrial fibrillation

Atrial fibrillation is the most common cardiac arrhythmia, and it increases in prevalence with advancing age to about 6% in people older than 65 years. The chance of developing atrial fibrillation at age 40 years or older is about 25% in men and women. This arrhythmia accounts for about one-third of all strokes, and 30% of all patients with atrial fibrillation have a family history of the disease. In 1997, Brugada et al. identified the first locus for familial atrial fibrillation on chromosome 10q22-24 in three different Spanish families. Since that time, seven further loci have been mapped and four relevant genes identified. All these genes encode potassium-channel subunits. The mechanism of action by which all four genes induce atrial fibrillation is via shortening of the action potential duration and atrial effective refractory period. The consistency of the mechanism of action beckons the development of therapy specifically targeted to prevent these molecular events. In addition to monogenic diseases, patients with structural heart disease are predisposed to atrial fibrillation by inherited DNA polymorphisms. The development of chips with hundreds of thousands of single-nucleotide polymorphisms to perform genome-wide scans will elucidate over the next few years the single-nucleotide polymorphisms that predispose to atrial fibrillation. Within the next decade, most of the genes responsible for atrial fibrillation and the single-nucleotide polymorphisms that confer predisposition will probably be identified, and therapies will be developed on the basis of individuals' genomic profiles. In this review I provide an overview of the understanding of the relevant genetic mutations that have been identified so far, and briefly discuss what implications this information might have for practice.     

心房颤动的基因水平研究与治疗展望

心房颤动（房颤）是临床上仅次于室性早搏的最常见的心律失常，据北美大规模流行病学统计，普通人群的发病率高达0．5％～1％，房颤曾被认为是其他心血管疾病的一个标志，现在则被认为是中风发病甚至死亡的独立的预警因素。虽然房颤是多种因素引起的疾病，且房颤常被看成一种获得性心脏病，但确实有一部分房颤病人特别是那些很早就发病的，并没有其它形式的心脏病，临床上称为“孤立性房颤（lone房颤）”。现在已有学者观察这些患者与基因缺损的关系。在一些家族中，一代或几代的年轻人有着较高的房颤发生率，遗传基因连锁分析表明其易感性具有家族因索。遗传基因相关分析研究也证明了房颤与基因标记有其相关性。基因因素在房颤发生的重要作用已引起人们的重视，它对阐明房颤发生的分子机制和房颤的治疗带来了希望。下面就目前房颤的基因研究做一介绍。