先天性心脏病患者远期并发心律失常的分子遗传学机制

先天性心脏病(congenital heart disease,CHD)是一种最常见的出生缺陷，为自然流产和死胎最常见的原因之一。最近研究提示，在心脏发育中，NKx2.5，SCN5A等基因的异常，不但会导致人类CHD的发生，而且可能会影响成年后心脏的正常功能。CHD患者远期并发的心脏疾患可能与这些基因的异常有关。     

心房颤动患者射频消融术影响TBX5和NKx2.5及其调控微小RNA

目的探讨心房颤动(房颤)患者射频消融术对转录因子TBX5和NKx2.5及其调控微小RNA(miRNA)的影响作用,寻找可能的miRNA调控干预靶点。方法选择行房颤射频消融术患者30例(房颤组),其中阵发性、持续性和永久性房颤各10例,健康体检者10例(对照组)。射频消融术前和术后3个月分别取外周血,使用miRNA芯片进行全基因组miRNA表达谱微阵列分析,实时PCR对调控结构蛋白的主要miRNA表达差异结果进行验证,通过mirbase、miranda、targetscan数据库进行靶基因分析。结果与对照组比较,房颤组术前转录因子TBX5和NKx2.5mRNA表达明显异常;主要参与调控TBX5的miRNA共有hsa-miR-892a等8种,hsa-miR-186-5p等4种主要miRNA术前表达下调,术后显著上调(P<0.05)。与对照组比较,房颤组参与调控NKx2.5的miRNA有hsa-miR-3149等3种,手术前后均有显著性改变(P<0.05)。结论房颤射频消融术逆转了调控转录因子TBX5、NKx2.5的主要miRNA异常,为房颤射频消融术后窦性心律的恢复和维持奠定了基础。这些miRNA有可能成为未来房颤干预的靶点。     

心脏特异转录因子及其对心脏发育和心脏基因的调控

器官的形成需要器官特异细胞的定向分化及形态发育，这些都在特异基因的调控下完成。特异基因的表达由转录因子调控。心脏特异转录因子主要在心肌细胞表达，调节心脏特异基因表达，决定组织特异性，在心脏发育过程中起到了关键的作用。这些基因的突变会导致先天性心脏缺陷。我们感兴趣的是，这些转录因子以及它们所调控的心脏基因，在心脏发育中扮演了什么样的角色，这些基因的突变会有什么样的后果。本文主要综述了目前已经发现的一些转录因子在脊椎动物，尤其是小鼠和人类心脏发育的作用以及它们调控心脏基因表达的方式。     

遗传性房室传导阻滞

遗传性房室传导阻滞分为进行性和非进行性及其他伴有先天性心脏结构异常的房室传导阻滞(AVB)三种类型。分子遗传学研究表明,多种离子通道的基因在心脏传导系统的发生、发育和功能维持方面起到了重要的作用。离子通道编码基因SCN5A,同源框转录因子基因NKX2.5及核纤维层蛋白编码基因LMNA与遗传性AVB发病密切相关。截至目前仍无有效地阻止本病进程的治疗方法 ,因此主要是随访观察和对症治疗。     

转录因子与心脏发育

细胞核转录因子是信号联级调节基因转录的最后环节。许多核转录因子与心脏发育有关。Sp ,GATA ,MEF 2和Nkx2 .5转录因子在胚胎早期心脏的形成及心肌分化的多个环节进行调节 ,MEF 2还与心脏的病理生理有关。     

心脏特异性同源盒基因变异与法洛四联症

心脏特异性同源盒基因，是所有脊椎动物心脏发生中最早表达的转录因子。近年来，大量实验研究表明心脏特异性同源盒基因在心脏发生发育、传导系统及成熟心脏正常功能维持等方面扮演重要角色，其变异影响心脏发育，导致各种先天性心脏病，包括法洛四联症。现对心脏特异性同源盒基因与法洛四联症之间的相关研究作以简单介绍。     

Nkx2.5基因与先天性心脏病的关系

先天性心脏病（以下称先心病）是一类严重危害婴幼儿健康的先天畸形。心脏发育过程中控制发育的基因突变是先心病的常见原因。大量研究表明Nkx2.5作为与发育相关的同源盒基因的一种,在心脏发育过程中起重要的作用,该基因的突变或多态性将影响心脏发育导致先心病。本文系统地阐述了Nkx2.5基因的结构?功能及其与先心病的关系,进而在分子水平上对心脏的发生和先心病发病有更深入的了解。     

Twist1在心脏瓣膜发育与疾病中的研究进展

Twist1属于碱性螺旋-环-螺旋结构转录因子家族,在胚胎中胚层形成和分化中起重要调控作用,与多个器官发育相关.在心脏瓣膜发育中,作为转录因子,Twist1可以促进细胞增殖、迁移及细胞外基质相关基因的表达.Twist1亦可通过作用于其他转录因子,调控相关基因表达.人类病变主动脉瓣膜中其表达可能升高,但这是对瓣膜修复的保护性机制还是导致瓣膜钙化的病理因素,目前尚不明确.     

转录因子Tbx18及Wt1在小鼠心脏发育过程中的时空表达

目的:原位观察转录因子Tbx18及Wt1在胚胎心脏中的表达,及心肌细胞本身是否表达Tbx18及Wt1。方法:收集不同发育阶段小鼠胚胎(E)心脏,冰冻切片后,取不同区域的组织进行免疫荧光染色和DAPI染核,检测Tbx18、Wt1及Nkx2.5的表达。结果:小鼠前体心外膜及不同发育阶段的心外膜可明显表达Tbx18及Wt1蛋白,但未检测到心脏转录因子Nkx2.5的表达。从E10.5~至少E14.5d,Tbx18蛋白明显表达于不同区域的心脏组织中。除E14.5 d少许表达Tbx18的细胞不表达Nkx2.5外,这些表达Tbx18的细胞还同时表达Nkx2.5。从E12.5~至少14.5 d,Wt1表达于不同区域心脏组织中,但这些表达Wt1的细胞都不表达NKx2.5。结论:从E10.5~至少14.5 d,Tbx18表达于小鼠心肌细胞中;从E12.5d~至少E14.5d,Wt1表达于小鼠心脏组织中,但不表达于心肌细胞中。     

TBX5及其网络分子与室间隔发育的相关性

TBX5是一种转录因子,在心脏发育过程中起着重要作用.TBX5转录时点的变化将会导致室间隔发育异常,TBX5-Sall4-Nppa环的网络作用对室间隔的初发、定位有重要意义.Hey2属TBX5的下游调控基因之一,它的表达和TBX5类似,呈现出左侧梯度,故它在室间隔的发生中也有一定的作用.TBX20和TBX5同属T-box家族成员,这两者在表达的方式上呈现类似镜像的关系——一个主要表达于右室,另一个则主要表达于左室,两者的表达界点及相互作用也与室间隔的发生有关.     

Prediction of mortality in heart transplant recipients by stress technetium-99m tetrofosmin myocardial perfusion imaging

Cardiac allograft vasculopathy is a major cause of mortality in heart transplant recipients. The aim of this study was to assess the prognostic value of stress myocardial perfusion imaging in heart transplant recipients. We studied 166 patients (age 54 +/- 10 years, 140 men) by symptom-limited bicycle exercise or dobutamine (up to 40 microg/kg/min) stress myocardial perfusion imaging 7.4 +/- 2.5 years after heart transplantation. An intravenous dose of 370 MBq of technetium-99m tetrofosmin was injected at peak stress and 24 hours after the stress test. An abnormal test was defined as reversible or fixed perfusion defects. Perfusion abnormalities were detected in 55 patients (33%). During a median follow-up of 2.5 years, 54 deaths (33%) occurred, 16 of which were due to cardiac causes. The incidence of perfusion abnormalities was higher in patients with subsequent cardiac death than in patients without subsequent cardiac death (69% vs 29%, p = 0.01). In an incremental multivariate Cox analysis, cardiac death was not predicted by age, gender, duration of transplantation, number of rejection episodes, or cytomegalovirus infection. In the next step, stress test parameters were added. The peak rate-pressure product was the only significant predictor at this step (risk ratio 0.84, 95% confidence interval 0.73 to 0.97, chi-square 7.7, p = 0.006). In the final step, the presence of abnormal myocardial perfusion was an independent predictor of cardiac death (risk ratio 3.5, 95% confidence interval 1.6 to 11.7, chi-square 4.7, incremental to clinical and stress test variables, p = 0.01). It is concluded that stress myocardial perfusion imaging with technetium-99m tetrofosmin single-photon emission computed tomography provides incremental data for the prediction of cardiac death in heart transplant recipients.     

Prediction of sudden cardiac death by fractal analysis of heart rate variability in elderly subjects

OBJECTIVES: The aim of this study was to test the hypothesis that abnormal scaling characteristics of heart rate (HR) predict sudden cardiac death in a random population of elderly subjects. BACKGROUND: An abnormality in the short-term fractal scaling properties of HR has been observed to be related to a risk of life-threatening arrhythmias among patients with advanced heart diseases. The predictive power of altered short-term scaling properties of HR in general populations is unknown. METHODS: A random sample of 325 subjects, age 65 years or older, who had a comprehensive risk profiling from clinical evaluation, laboratory tests and 24-h Holter recordings were followed up for 10 years. Heart rate dynamics, including conventional and fractal scaling measures of HR variability, were analyzed. RESULTS: At 10 years of follow-up, 164 subjects had died. Seventy-one subjects had died of a cardiac cause, and 29 deaths were defined as sudden cardiac deaths. By univariate analysis, a reduced short-term fractal scaling exponent predicted the occurrence of cardiac death (relative risk [RR] 2.5, 95% confidence interval [CI], 1.9 to 3.2, p < 0.001) and provided even stronger prediction of sudden cardiac death (RR 4.1, 95% CI, 2.5 to 6.6, p < 0.001). After adjusting for other predictive variables in a multivariate analysis, reduced exponent value remained as an independent predictor of sudden cardiac death (RR 4.3, 95% CI, 2.0 to 9.2, p < 0.001). CONCLUSIONS: Altered short-term fractal scaling properties of HR indicate an increased risk for cardiac mortality, particularly sudden cardiac death, in the random population of elderly subjects.     

64例老年心源性猝死前的临床分析

本文对６４例老年心源性猝死的临床资料，进行回顾性分析，发现老年心源性猝死之前，有以下特点：（１）多患有冠心病等心脏疾患（７５．０％）；（２）有心律失常和（或）心电图异常、心功能不全、心肌梗塞及先兆症状等高危先兆；（３）多数有明确的诱发因素（７１．９％）；（４）猝死的高峰期多在早晨（５９．４％）。     

Usefulness of an abnormal signal-averaged electrocardiogram for predicting cardiac death in elderly persons without heart disease

We found an abnormal signal-averaged ECG in 7 of 51 elderly patiente (14%) (mean age 83 years) without clinical evidence of heart disease, and in 1 of 25 volunteers (4%) (mean age 31 years [range 17 to 47]) without clinical evidence of heart disease.¹ The data from bur prospective study indicate that at 43-month mean follow-up, elderly patients with an abnormal signal-averaged ECG but no clinical evidence of heart disease do not have an increased incidence of sudden cardiac death, total cardiac death, or total death.     

心源性晕厥或猝死的原因分析

分析 32例在入院时或入院后至少发生 1次或 1次以上心源性晕厥或猝死患者的原因及其发作时与发作前、后的常规 12导联心电图或持续心电监视心电图。结果 :引起心源性晕厥或猝死的基本原因可分为以下几种类型 :①冠心病急性或陈旧性心肌梗死 ;②长QT(U)综合征 ;③Brugada综合征 ;④扩张型和肥厚型心肌病 ;⑤特发性巨大异常J波 ;⑥其他原因。上述各种心源性晕厥或猝死患者有各自不同的心电学特征。结论 :心源性晕厥或猝死是由不同原因、不同心电学特征所致的非单一独立的临床实体     

Gene-trapped mouse embryonic stem cell-derived cardiac myocytes and human genetics implicate AKAP10 in heart rhythm regulation

Sudden cardiac death due to abnormal heart rhythm kills 400,000-460,000 Americans each year. To identify genes that regulate heart rhythm, we are developing a screen that uses mouse embryonic stem cells (mESCs) with gene disruptions that can be differentiated into cardiac cells for phenotyping. Here, we show that the heterozygous disruption of the Akap10 (D-AKAP2) gene that disrupts the final 51 aa increases the contractile response of cultured cardiac cells to cholinergic signals. In both heterozygous and homozygous mutant mice derived from these mESCs, the same Akap10 disruption increases the cardiac response to cholinergic signals, suggesting a dominant interfering effect of the Akap10 mutant allele. The mutant mice have cardiac arrhythmias and die prematurely. We also found that a common variant of AKAP10 in humans (646V, 40% of alleles) was associated with increased basal heart rate and decreased heart rate variability (markers of low cholinergic/vagus nerve sensitivity). These markers predict an increased risk of sudden cardiac death. Although the molecular mechanism remains unknown, our findings in mutant mESCs, mice, and a common human AKAP10 SNP all suggest a role for AKAP10 in heart rhythm control. Our stem cell-based screen may provide a means of identifying other genes that control heart rhythm.     

Prognostic value of an abnormal signal-averaged electrocardiogram in patients with nonischemic dilated cardiomyopathy

The usefulness of an abnormal signal-averaged ECG (SAECG) for the risk stratification of patients with dilated cardiomyopathy was studied prospectively in 76 patients. Multiple analysis showed that an abnormal SAECG predicted cardiac mortality (p = 0.0046), sudden cardiac death, and the need for resuscitation (p = 0.003); however, it did not predict death from heart failure and heart transplantation.