重度子痫前期母胎心脏损害与AT1R基因多态性、AngⅡ、ET浓度的相关性研究
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摘要
子痫前期(preeclampsia)是妊娠期高血压疾病之一,为妊娠期特发的常见并发症,严重威胁母儿健康,尤其是重度子痫前期(severe preeclampsia, S-PE),是导致孕产妇及围生儿死亡的重要原因之一,发病率为9.4%。子痫前期性心脏病是在重度子痫前期基础上发生的以孕妇心肌损害为特征的心力衰竭征候群,约占妊娠合并心脏病的5%左右,临床表现为左心衰竭及肺水肿,是妊娠期高血压疾病孕产妇致死的第二位原因。同时,有报道认为,重度子痫前期可引起胎儿心肌细胞呈均匀性代偿性增大,导致心脏收缩和舒张功能异常。
重度子痫前期基本病理变化为孕妇全身小血管痉挛。子痫前期性心脏病心内膜活检可见心肌细胞肥大,胞浆颗粒样变,心肌间质有局限性纤维变性,重者有点状出血和局灶性坏死;电镜下见心肌纤维有广泛的退行性变、间质水肿、小血管内皮肿胀、管腔狭窄,偶见微血栓存在,表明S-PE患者因心肌供血不足已有不同程度的心肌损害。子痫前期左心室肥厚是全身小血管痉挛的一个重要后果,子痫前期患者心脏前、后负荷均有增加,左室舒张末期内径及左房内径增大,部分患者室间隔增厚,导致左室舒张功能减低。由于小动脉痉挛,外周阻力增加,血压升高,心脏负荷增加,左心室舒张末期压力升高,而心室收缩功能下降。
国内外的大量研究结果显示重度子痫前期具有明显的遗传倾向,子痫前期患者发生心血管疾病的风险很高。肾素-血管紧张素系统在维持机体水盐平衡和调节心血管活动中起着十分重要的作用,尤其是血管紧张素Ⅱ(angiotensinⅡ, AngⅡ)的作用最强,AngⅡ是人体已知的最强的内源性缩血管物质之一,在维持心血管的自身稳定方面及心肌肥厚的形成中起着重要的作用。而AngⅡ又必须通过AngⅡ受体,主要是血管紧张素Ⅱ1型受体(AT1R)发挥作用,这一受体的分子生物学改变可能将影响其功能的变化。AT1R是一种膜受体,它具有激素受体的所有特征,主要分布在血管平滑肌细胞,维持机体代谢平衡及保持血管张力。研究发现AT1R基因的多态位点A1166-C可以导致AT1R密度增加,从而增加了心血管疾病的危险性,与正常对照组相比AT1R基因的多态位点A1166-C在心衰组活性增加。
子痫前期患者较正常妊娠者血管对AngⅡ的反应性显著提高,心脏的心肌细胞和成纤维细胞膜因有AT1R而受AngⅡ作用,增加心肌收缩力,加快心率,促进蛋白合成和间质细胞增生,调节心肌细胞生长发育,表现心肌肥大和增殖。AngⅡ与心肌细胞AT1R结合后,通过Gp调节蛋白激活磷脂酶C,加速细胞膜中的磷酸肌醇水解成三磷酸肌醇和二酰甘油。三磷酸肌醇及二酰甘油促进胞浆内钙增多,激活钙依赖的DNA酶Ⅰ,使DNA断裂,导致心肌细胞死亡。AngⅡ水平的升高,能使血管收缩,促儿茶酚胺的释放和醛固酮分泌,导致心肌凋亡、心肌肥厚,致间质纤维化及心肌重构,从而影响心力衰竭患者的预后。
血管内皮系统形态和功能的异常与重度子痫前期的发病密切相关,而AT1R可使循环中的内皮素(Endothelin ,ET)含量增加。ET是由血管内皮细胞释放的一种生物活性肽,收缩血管作用比AngⅡ强10倍,具有强烈的收缩血管作用和平滑肌细胞增殖作用,参与高血压、动脉粥样硬化、肺心病、哮喘等多种心血管疾病的发病过程,在血管痉挛性组织缺血、缺氧和血管内皮细胞损伤病变中起重要作用;能直接抑制心肌细胞摄取能量代谢底物,干扰细胞能量代谢,还可通过其血流动力学和(或)细胞机制促进组织细胞脂质过氧化损伤,而脂质过氧化又促进ET的大量释放,从而参与心脏缺血-再灌注损伤的过程。ET是血管收缩因子,不但直接刺激或激活多种激素和细胞因子,且广泛参与机体的生理、病理调节、参与心血管疾病的病理生理过程,加强心肌收缩力,并能促进平滑肌增生,促进神经内分泌功能等作用,实验研究显示ET在诱发心力衰竭过程中起着重要作用。
研究背景和目的:
国内外学者认为AT1R基因1166位点腺嘌呤(A)被胞嘧啶(C)替换与原发性高血压有关,已有的较少文献显示AT1R基因多态性与重度子痫前期患者的心脏受累有关。AngⅡ调节血管张力,维持血容量,刺激细胞增殖,细胞外胶原基质合成和堆积,是人体已知的最强的内源性缩血管物质之一,在维持心血管的自身稳定方面起重要作用。有充分的临床和实验室证据表明,AngⅡ与病理性的间质纤维化、心脏重塑和心衰有关。AT1R基因的分子变异可影响机体对AngⅡ的敏感性,使AngⅡ的病理学效应呈现个体差异。ET存在于内皮细胞,是最强的缩血管活性物质之一。许多实验结果证明,S-PE患者血浆ET水平明显高于正常妊娠组,并随患者的病情严重程度增加而升高。但AT1R基因多态性、AngⅡ、ET是否也存在于胎儿,是否对胎儿心脏结构和功能也产生影响,以及其对母体和胎儿心脏结构和功能影响有无相关性,国内外未见报道。我们选取新疆医科大学第一临床医学院产科S-PE患者30例,并选择同期正常晚期妊娠孕妇30例作为对照。采用彩色多普勒超声测定左心室结构指标和收缩功能指标,用放射免疫方法测定血浆AngⅡ及ET浓度,以探讨血浆AngⅡ及ET浓度与子痫前期性心脏病的关系。同时,应用多聚酶链式反应-限制性片段长度多态性(PCR-RFLP)及等位基因特异性PCR(ASP)等现代分子生物学方法,对目前已知的可能涉及子痫前期发病的AT1R基因1166位点多态性进行检测及分析,旨在了解AT1R基因多态性与子痫前期性心脏病的关联情况,从分子水平探索遗传因素在子痫前期性心脏病发病中的作用。
方法:
随机选取2006年4月至2007年9月在新疆医科大学第一临床医学院产科住院患者,重度子痫前期组(病例组)30例,正常妊娠组(对照组)30例,所有受检者由专人通过超声检查测定孕妇和胎儿的左心室心肌重量指数(LVMI)、室壁相对厚度(RWT)、心输出量(CO)、心脏指数(CI)、左室射血分数(EF)和二尖瓣血流的E、A值E/A比值,用于评价心肌损害的严重程度和舒缩功能。采集对照组和病例组的孕妇外周静脉血(母体血样)及胎儿脐带动脉血(胎儿血样)各5ml。
分别测定血浆血管紧张素Ⅱ水平(AngⅡ)、血浆内皮素(ET)和用荧光定量PCR法测定所采集血样的AT1R基因多态性。
分别进行两组间孕妇、胎儿以及母胎间AT1R基因多态性、AngⅡ水平、ET、LVMI、RWT、EF和E/A的比较。
注一:
1.重度子痫前期的纳入和排除标准1)纳入标准:重度子痫前期患者妊娠35-37周,血压≥160/110mmHg,尿蛋白≥300mg/24h或(++)。排除标准:原发性高血压;肾源性高血压。
2)正常对照组的纳入标准是:经产检血压正常、尿常规检查为尿蛋白阴性、心电图及超声心动图检查排除心脏疾患的健康者。
3.血压的测量是用标准的Sphygmomanometric程序,取坐姿,于右臂间隔5min连续3次取其平均值。收缩压<140mmHg,舒张压<90mmHg。
注二:
1.左室结构重构的判断标准
1)左室正常构型:LVMI≤106g/m2,RWT≤0.44;
2)左室向心性重构:LVMI≤106g/m2,RWT>0.44;
3)左室向心性肥厚:LVMI>106g/m2,RWT>0.44;
4)左室离心性肥厚:LVMI>106g/m2,RWT≤0.44。
2.左室功能重构的判断标准以EF、CO、CI作为评价左室收缩功能指标;E/A比值、RFF作为评价左室舒张功能指标。
(1)左室收缩功能异常:EF<50%或CO<3.5L/min或CI<2.2L/ (min·m2)
(2)左室舒张功能异常:E/A<1。
用Devereux公式计算左室心肌重量(LVM)和LVMI,用Simpson法计算EF,用多普勒测定二尖瓣血流的E、A值E/A比值。
实验方案
1.试验及检查技术
1)采用多聚酶链反应(PCR)技术检测AT1R基因A1166位点的多态性。
2)由核医学科资深人员检测血浆AngⅡ水平、ET水平。
3)由心脏超声科专人通过超声检查测定孕妇和胎儿的心脏。
2.统计学方法:
用SPSS 13.0统计软件进行数据分析,采用的统计方法有一般资料的统计描述、蒙特卡罗法单因素方差分析、连续性校正x 2检验、方差齐性检验、两组样本的t检验、协方差分析、Logistic逐步回归线性分析、两个变量间线性相关分析、偏相关分析,以P<0.05为差异有统计学意义。
结果
1.病例组孕妇及胎儿AT1R基因1166位点变异体(AC+CC)频率均高于对照组,差异有统计学意义(P<0.05);两组间C等位基因频率比较差异也均有统计学意义(P<0.05)。
2.孕妇AT1R基因1166位点变异型(AC型+CC型)与野生型(AA型)的比值比(OR)为5.21,95%可信限为2.35～13.52,提示AT1R基因1166位点变异的孕妇发生重度子痫前期的危险性增加5.21倍;胎儿AT1R基因1166位点变异型(AC型+CC型)与野生型(AA型)的比值比(OR)为5.09,95%可信限为2.08～12.95,提示胎儿AT1R基因1166位点变异发生重度子痫前期的危险性增加5.09倍。
3.病例组孕妇的左心室结构指标均显著大于对照组,两组比较差异有非常显著性意义(P<0.01),且病例组左室构型多为向心性肥厚(LVMI>106 g/m2,RWT>0.44)。病例组孕妇的左室舒张末期容积(EDV)及收缩末期容积(ESV)较对照组增加非常明显,比较差异有高度显著性(P<0.01)。病例组孕妇左心室射血(EF)分数明显低于对照组(P<0.01);心脏指数(CI)及E/A指标在组间具有明显统计学差异(P<0.01);心搏出量(SV)及心输出量(CO)在两组间差异无显著性(P>0.05)。
4.孕妇病例组AT1R基因1166位点AA型左心室质量指数(LVMI)>106 g/m2,室壁相对厚度(RWT)0.44±0.06 ,为离心性肥厚;AT1R基因1166位点AC+CC型LVMI>106g/m2,RWT>0.44,为向心性肥厚;左心室超声结构指标利用单因素作组间比较,左心室质量(LVM)及左心室质量指数(LVMI)在AT1R基因1166位点AC+CC型与AA型组间有差异(P均<0.05),室壁相对厚度(RWT)AT1R基因位点AC+CC型与AA型组间有显著性差异(P<0.01)。
5.胎儿左心室舒张末期室间隔厚度(IVST)病例组与对照组比较有显著性差异(P<0.05);胎儿左室后壁厚度(PWT)病例组与对照组比较有差异(P=0.05)。病例组胎儿左心室超声结构指标利用单因素作组间比较,舒张末期室间隔厚度(IVST)、室壁相对厚度(RWT)AT1R基因AC+CC型与AA型组间有显著性差异(P<0.05)。
6.孕妇多因素Logistic回归分析,显示基因型(x1)、家族史(x2)、收缩压(x3)、体重(x5)均参与增加左心室重构的发生概率,OR分别为2.893(95%CI为1.082～8.865)、4.572(95%CI为2.038～14.891)、3.875 (95%CI为1.864～8.518)和2.594(95%CI为1.121～7.816),可看作是重度子痫前期左心室重构的危险因素。
7.病例组孕妇及胎儿的AngⅡ浓度与对照组比较无明显增高,差异无显著性(P>0.05);重度子痫前期孕妇及胎儿左心室结构、功能各指标与AngⅡ浓度无关。
8.重度子痫前期孕妇及胎儿AT1R基因AC+CC型AngⅡ浓度明显高于AA型,差异有显著性(P<0.05)。
9.重度子痫前期孕妇及胎儿血浆ET水平显著高于正常对照组(P<0.01)。
10.重度子痫前期及正常妊娠孕妇血浆ET与IVST,LVSD,PWT,LVM呈正相关关系(P<0.05),与LVMI呈显著正相关关系(P<0.001),与E/A比值呈显著负相关关系(P<0.001);而与LVDD,RWT,EF均无相关性(P>0.05)。
11.病例组中AT1R基因AC+CC型孕妇及胎儿ET浓度明显高于AA型,差异有显著性(P<0.05);
结论
1.AT1R基因A1166C多态性与重度子痫前期呈正相关,提示该位点可能系重度子痫前期发病的危险因子;AT1R基因1166-C等位基因出现增大了患子痫前期的危险性,说明C等位基因是重度子痫前期的易感基因。
2.AT1R基因的多态性变化在重度子痫前期组内孕妇和胎儿之间有相同的表达,可以把AT1R基因A1166-C变异作为一项重要的遗传标志物用于重度子痫前期的预测,并对携带AC和CC基因型的高危人群进行早期预防。
3.重度子痫前期孕妇及胎儿有左室重构;AT1R基因1166位点AC/CC基因型及C等位基因与重度子痫前期孕妇及胎儿左室重构有关。
4.在AngⅡ水平无显著差异的情况下,血管对AngⅡ反应性的提高和AT1R的激活在重度子痫前期左室重构中起着一定的作用。AngⅡ-AT1R可引起孕妇及胎儿左心室心肌细胞肥大和间质重塑。
5.孕妇及胎儿血浆ET浓度是重度子痫前期的敏感指标;重度子痫前期孕妇及胎儿AT1R基因A 1166 C变异与血浆ET的升高有关。
Preeclampsia is one of the hypertension state in pregnancy, which is the special complication of gestation, imperiling the mother and fetus seriously, especially severe preeclampsia (S-PE). Severe preeclampsia is one of the most important reasons of maternal and fetus mortality, the incidence is 9.4%. The onset of the preeclampsia heart disease is severe preeclampsia .The preeclampsia heart disease is character by the heart failure sign group due to the myocardial damage, showing left heart failure and lung edema, which make up 5% of the total heart disease in gestation and is the second leading cause to maternal mortality. Meanwhile, some reports indicate that the fetal cadiocyte present homogenous and compensated hypertrophy due to the severe preeclampsia, at last the systole and diastole function of heart become abnormal.
The primary pathological change of severe preeclampsia is the Small vessels spasmodism all over the body. In the preeclampsia heart disease patient, the endocardium shows cadiocyte hypertrophy, endochylema granulation, stroma focal fibronolysis, in some severe patients there are punctate hemorrhage and focal necrosis. The change of cardiac muscle fibers can be observed under the electron microscope, wide degeneration, interstitial edema, swelling blood vessel endothelium, narrow lumens, microthrombus can be founded sometimes. All signs indicated that myocardial damage has already occurred due to poor supply of blood in the severe preeclampsia. Left ventricular hypertrophy is the severe outcome caused by Small vessels spasmodism, so the preload and afterload of heart may be increased, left ventricular end diastolic period diameter and left atrial diameter should be enlarged, interventricular septum thickening can be observed in some cases, all of these changes lead to the left ventricular diastolic function decreased. in brief, due to small vessels spasmodism, the peripheral resistance increase, the blood pressure step up, cardiac load be added, left ventricular end-diastolic pressure is increased, but the systole function is decreased.
Considerable researches have suggested that severe preeclampsia patients possess conspicuous genetic predisposition and high risk of cardiovascular disease. Renin-angiotensin system play the important role in keeping electrolyte balance and adjusting the cardiovascular activity, especially angiotensinⅡ(AngⅡ) is the most powerful. AngⅡis the one of the most powerful endogenous vasoconstriction substance we have known. It has the significant contribution to maintain cardiovascular homeostasis and to bring about myocardial hypertrophy. Only by the help of AngⅡreceptor can AngⅡwork, especially AngiotensinⅡType 1 Receptor(AT1R), the function of AngⅡmay be changed if the AT1R alter in molecular biology. AT1R as a kind of membrane receptor, it process every characteristic of hormone, distributing on the blood vessel smooth muscle cell, maintaining metabolic balance and the tension of blood vessel. Some results demonstrates that AT1R gene polymorphic site A1166C can lead to the increase of AT1R density, thus, the high risk of cardiovascular disease may be taken place. In comparison to the normal control group, AT1R gene polymorphic site A1166C has high activity in the heart failure patients.
The patients with preeclampsia are more sensitive to AngⅡthan normal pregnant women, due to AT1R, AngⅡcan work on the cadiocyte and desmocyte membrane, thus, the myocardial contractile force and heart rate increased, mesenchymocyte hyperplasia, cadiocyte growth and development, at last, myocardium hypertrophy and proliferation. After binding with AT1R, AngⅡcan accelerate the hydrolysis procedure from phosphoinositide to inositol triphosphate and diglyceride when the phospholipase C are activated by Gp equestron. Inositol triphosphate and diglyceride augment calcium in endochylema, active deoxyribonucleaseⅠdepended by calcium, so the DNA break and cadiocyte die. The level of AngⅡincrease would lead to the blood vessel contraction, catecholamine and aldosterone releasing, so the myocard apoptosis and pachynsis occur, then, the interstitial fibrosis and cadiocyte reconstruction can be observed, these changes can lead to poor prognosis in the heart failure patients.
The abnormal of function and morphous of blood vessel endothelium are closely relation with severe preeclampsia, AT1R increase endothelin(ET) in the blood, which is a kind of biologically active peptide released by vascular endothelial cell. Endothelin has power to contract blood vessel and is ten times powerful than AngⅡ, besides, it can make smooth muscle cell proliferated, by this way, it participate the procedure of hypertension, artherosclerosis, pneumocardial disease, asthma and so on. Endothelin play a important role in the affection of ischemia due to angiospasm and the damage of blood vessel endothelium, it can interfere the energy metabolism of cadiocyte by inhibiting the procedure of intaking energy metabolic substrate, it also can aggravate the damage of cadiocyte lipid peroxidation, which make more much ET released, then, these ET participate the procedure of ischemia-reperfusion. ET is a vasoconstriction factor, which not only stimulate and active many hormones and cytokine but also widely participate the physiological and pathological regulation of body. Meanwhile, it participate the physiopathologic procedure of cardiovascular disease and increase the myocardial contractile force, as well as promote the hyperplasia of smooth muscle and function of neuroendocrine. Some data show that ET plays the important role in the procedure of inducing the heart failure.
Background
Many researcher believe that essential hypertension is closely relation with the adenine be shifted by cytosine on AT1R gene polymorphic site A1166C. A few studies illustrate that the relation of AT1R gene polymorphism with the heart damage in the severe preeclampsia patients. AngⅡas one of the most powerful endogenous vasoconstriction substance can regular angiotasis and maintain blood-volume, stimulate the proliferation of cadiocyte as well as synthesis and cumulate of ecto-cyte collagen, so it play a important part in the maintaining of angiomyocardiac homoeostasis. Sufficient clinic and breadboard findings indicate that AngⅡis relation with pathologic interstitial fibrosis and heart remodeling and failure. AT1R genic mutation can influence the sensitivity of AngⅡ, thus, AngⅡpathologic effect shows individual difference. ET lies in the vascular endothelial cell, which is the one of the most powerful endogenous vasoconstriction substance. A lot of studies confirm that ET is much more in the severe preeclampsia patients than in the normal pregnant women, and would increase with the deterioration. However, no prior work exists on the problem whether AT1R gene polymorphism and AngⅡand ET lie in the fetus and whether they influence the structure and function of maternal and fetal heart or not. Fifty-three severe preeclampsia patients who be treated in the First affiliated hospital of Xinjiang Medical university were included in the present study, meanwhile, forty-eight normal pregnant women were selected as control group. In order to approach the relation of AngⅡand ET level in plasma and the preeclampsia cardiac disease, we measure the index of left ventricle and systolic function by Doppler ultrasound, and obtain the AngⅡand ET level in plasma by radio-immunity. Besides, polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP)and allele-specific PCR(ASP)and many modern molecular biology methods were used to detect and analyses the AT1R gene polymorphic site A1166C related with preeclampsia. In a word, the study is aimed at finding out the relation of AT1R gene polymorphism and preeclampsia cardiac disease, then to explore how the genetic factor contribute to the preeclampsia cardiac disease from molecular level.
Methods
Fifty-three severe preeclampsia patients who be treated in the First affiliated hospital of Xinjiang Medical university were included in the present study, they were chosen completely at random from April, 2006 to September, 2007 (case group). Meanwhile, forty-eight normal pregnant women were selected as control group. The index of left ventricle and systolic function of subjects and their fetus were measured by Doppler ultrasound, the index include left ventricular mass index(LVMI)and relative wall thickness(RWT) ? cardiac output(CO) ? cardiac index(CI) ? ejection factor(EF)and parameter of E and A and E/A of atrioventricular valveblood flow, the indexes be used to evaluate the degree of heart damage and the function of diastole and systole.
5ml mother’s peripheral venous blood and 5ml fetal umbilic blood of all subjects were collected
AngⅡand ET level in plasma were measured by radio-immunity, the AT1R gene polymorphic site A1166C were detected and analyzed with polymerase chain reaction method.(PCR)
Comparison the AT1R gene polymorphism and AngⅡ, ET and LVMI and RWT, EF and E/A between two groups and between mothers and fetus.
Remarks 1
1.selected and eliminated criteria of severe preeclampsia
1) Selected criteria: the pregnant is in the 34-36 gestational week blood pressure≥160/110mmHg Urine protein≥300mg/24h or (++)
2) Eliminated criteria:essential hypertension;renal hypertension
2.Selected criteria of the control group:
The normal pregnant women whose blood pressure and urine analysis are normal were confirmed without heart disease by the examination of electrocardiogram and ultrasonic cardiogram.
3.The blood pressure were measured with sit position by standard Sphygmomano- metric procedure every 5min for 3 times, then get the mean value, systolic pressure<140mmHg, diastolic pressure<90mmHg.
Remarks 2
1.Ultraphonic criteria of left ventricle structure
1) normal:LVMI≤106g/m2, RWT≤0.44;
2) left ventricle inward reconstruction:LVMI≤106g/m2, RWT>0.44;
3) left ventricle inward pachynsis:LVMI >106g/m2, RWT>0.44;
4) left ventricle outward pachynsis::LVMI >106g/m2, RWT≤0.44?
2.Ultraphonic criteria of abnormal cardiac function
EF and CO and CI are the index of evaluating the left ventricle systolic function, E/A and RFF are parameter of evaluating the left ventricle diastolic function.
Abnormal of left ventricle systolic function:EF<50% or CO<3.5L/min or CI<2.2L/ (min·m2)
Abnormal of left ventricle diastolic function:E/A<1 ?
The way to examine the left ventricle inward reconstruction by ultrasound: calculate left ventricular mass(LVM)and left ventricular mass index ( LVMI) with Devereux formula, calculate ejection fraction (EF) with Simpson method, determine E and A and E/A of atrioventricular valveblood flow by Doppler ultrasound.
Program
1.Experiment technique
1) the AT1R gene polymorphic site A1166C were detected and analyzed with polymerase chain reaction method.(PCR)
2) AngⅡand ET level in plasma were measured by senior technician in nuclear medicine department.
3) Maternal and fetal hearts were examined by special doctor.
2.Statistical method:
1) Statistic data was deal with SPSS 13.0, measurement data are described with mean and standard deviation.
2) Comparison of AT1R gene polymorphism between two groups with chi square test
3) Comparison of LVMI and RWT and CO and CI and EF, as well as E and A and E/A of atrioventricular valveblood flow between two groups with t-test?
4) Comparison of the AT1R gene polymorphic site A1166C and left ventricular mass index and relative wall thickness between mothers and fetus in severe preeclampsia group with analysis of covariance.
5) To analyze two variance correlation with Pearson correlation analysis. P<0.05 indicates that contrast are statistical significance
Result
1.The frequency of AT1R gene 1166 polymorphic site variant (AC+CC) in the pregnant women and fetal case group are higher than in the control group, the variation is statistically significant. (P<0.05), the variation between the two groups of C allele frequency is statistically significant too (P<0.05)
2.The ratio of AT1R gene 1166 polymorphic site variant (AC+CC) to the wild type is 5.21(OR) in the pregnant women. 95% confidence interval is 2.35~13.52. It’s means that the risk of severe preeclampsia for those pregnant women whose AT1R gene 1166 polymorphic site variant occur would increase 5.21 times. The ratio of AT1R gene 1166 polymorphic site variant (AC+CC) to the wild type is 5.09 (OR) in the fetus. 95% confidence interval is 2.08~12.95. It’s means that the risk of severe preeclampsia for fetus whose AT1R gene 1166 polymorphic site variant occur would increase 5.09 times.
3. The index of left ventricle structure in the case group is much more than it in the control group, the variation is significant statistically significant (P<0.01), the concentric hypertrophy is most commonly (LVMI>106 g/m2, RWT>0.44). The end-diastolic dimension (EDV) and end-systolic volume (ESV) of left ventricle in the case group are higher obviously then it in the control group (P<0.01), ejection fraction (EF) of left ventricle in the case group are lower obviously then it in the control group (P<0.01), the variation of cardiac index (CI) and E/A is significant statistically significant (P<0.01); the variation of cardiac output (CO) and stroke volume (SV) is no statistically significant (P>0.05).
4. Left ventricular mass index (LVMI) of the pregnant women with AT1R gene 1166 polymorphic site AA-type is more than 106 g/m2, Relative wall thickness (RWT) is 0.44±0.06, it shows eccentric hypertrophy, left ventricular mass index (LVMI) of the pregnant women with AT1R gene 1166 polymorphic site AC+CC-type is more than 106 g/m2, Relative wall thickness (RWT) is more than 0.44, it shows concentric hypertrophy. Compare these index by single factor group comparison, the result shows that the variation of left ventricular mass (LVM) and left ventricular mass index (LVMI) in AT1R gene 1166 polymorphic site AC+CC-type and AT1R gene 1166 polymorphic site AA-type is statistically significant (P<0.05), the variation of relative wall thickness (RWT) in AT1R gene 1166 polymorphic site AC+CC-type and AT1R gene 1166 polymorphic site AA-type is significant statistically significant (P<0.01)
5. Compare the case group and control group, the variation of fetal interventricular septum thickness at enddiastole (IVST) is significant statistically significant (P<0.05), the variation of fetal left ventricular post wall thickness (PWT) is statistically significant (P=0.05). Compare the fetal case group of AT1R gene 1166 polymorphic site AC+CC-type and AT1R gene 1166 polymorphic site AA-type, the variation of the interventricular septum thickness at end diastole (IVST) and Relative wall thickness (RWT) is statistically significant (P<0.05).
6. The result of multiple factor Logistic regression analysis for the pregnant women shows that genetype (x1) and family medical history (x2) and systolic pressure (x3) as well as body mass index (BMI)(x5) are all high risks to increase the incidence of the left ventricle reconstitution, the relative risk (OR) of them are 2.893 (95%CI is 1.082-8.865) and 4.572 (95%CI is 2.038-14.891) and 3.875 (95%CI is 1.864-8.518) and 2.594 (95%CI is 1.121-7.816), they can be take as independent risk factor for left ventricle reconstitution in severe preeclampsia .
7. The concentration of angiotensinⅡin the case groups of pregnant women and fetus are no more than it in the control groups, the variation is no significant (P>0.05). The index of left ventricle structure and function in severe preeclampsia pregnant women and their fetus have nothing to do with the concentration of angiotensinⅡ(AngⅡ).
8. The concentration of angiotensinⅡin the severe preeclampsia women and their fetus who with AT1R gene 1166 polymorphic site AC+CC-type is much more than the fetus who with AT1R gene 1166 polymorphic site AA-type, the variation is statistically significant (P<0.05).
9. The level of ET in case groups both pregnant women and fetus is significant higher than it in the control group (P<0.01).
10. In the both severe preeclampsia and normal pregnant women, the relation of the ET level with IVST, LVSD, PWT, LVM is positive correlation (P<0.05), the relation with LVMI is closely (P<0.001), the relation with the ratio of E/A is negative correlation (P<0.001). The level of ET is no related with LVDD and RWT and EF (P>0.05).
11. The ET level of pregnant women and their fetus with AT1R gene 1166 polymorphic site AC+CC-type is higher than it with AT1R gene 1166 polymorphic site AA-type, the variation is statistically significant (P<0.05).
Conclusion
1. The relation of AT1R gene 1166 polymorphism with severe preeclampsia is positive correlation, indicating that the very site might be a risk factor for severe preeclampsia, the risk of preeclampsia would increase when AT1R gene 1166 C allel occur, it means that AT1R gene 1166 C allel is a predisposing genes for preeclampsia.
2. The expression of AT1R gene 1166 polymorphism in severe pregnant women as same as the expression in their fetus, Gene mutation of AT1R gene 1166 C allel can be take as a important geno-marker to predict severe preeclampsia, the early prophylaxis could be done for the high-risk group with AT1R gene 1166 polymorphic site AC and CC-type.
3. Left ventricle reconstruction occurs in the severe preeclampsia patients and their fetus. AT1R gene 1166 polymorphic site AC/CC-type and C allel are related to the left ventricle reconstruction of severe preeclampsia patients and their fetus.
4. The change of left ventricle configuration in severe preeclampsia patients is related to the poor pregnant outcome and can be observed by echocardiogram, concentric reconstruction and concentric hypertrophy are independent risk factors for predicting poor pregnant outcome.
5. Excluding the factor of AngⅡlevel, the left ventricle reconstruction of severe preeclampsia is affected by the blood vessel reactance to the AngⅡand activation of AT1R. AngⅡand AT1R can cause left ventricle cadiocyte hypertrophy and interstitial remodeling of pregnant women and fetus respectively.
6. The plasma concentration of ET is a sensitive index, gene mutation of AT1R gene 1166 C allel in severe preeclampsia pregnant women and fetus is related to the increase of ET level.
重度子痫前期基本病理变化为孕妇全身小血管痉挛。子痫前期性心脏病心内膜活检可见心肌细胞肥大,胞浆颗粒样变,心肌间质有局限性纤维变性,重者有点状出血和局灶性坏死;电镜下见心肌纤维有广泛的退行性变、间质水肿、小血管内皮肿胀、管腔狭窄,偶见微血栓存在,表明S-PE患者因心肌供血不足已有不同程度的心肌损害。子痫前期左心室肥厚是全身小血管痉挛的一个重要后果,子痫前期患者心脏前、后负荷均有增加,左室舒张末期内径及左房内径增大,部分患者室间隔增厚,导致左室舒张功能减低。由于小动脉痉挛,外周阻力增加,血压升高,心脏负荷增加,左心室舒张末期压力升高,而心室收缩功能下降。
国内外的大量研究结果显示重度子痫前期具有明显的遗传倾向,子痫前期患者发生心血管疾病的风险很高。肾素-血管紧张素系统在维持机体水盐平衡和调节心血管活动中起着十分重要的作用,尤其是血管紧张素Ⅱ(angiotensinⅡ, AngⅡ)的作用最强,AngⅡ是人体已知的最强的内源性缩血管物质之一,在维持心血管的自身稳定方面及心肌肥厚的形成中起着重要的作用。而AngⅡ又必须通过AngⅡ受体,主要是血管紧张素Ⅱ1型受体(AT1R)发挥作用,这一受体的分子生物学改变可能将影响其功能的变化。AT1R是一种膜受体,它具有激素受体的所有特征,主要分布在血管平滑肌细胞,维持机体代谢平衡及保持血管张力。研究发现AT1R基因的多态位点A1166-C可以导致AT1R密度增加,从而增加了心血管疾病的危险性,与正常对照组相比AT1R基因的多态位点A1166-C在心衰组活性增加。
子痫前期患者较正常妊娠者血管对AngⅡ的反应性显著提高,心脏的心肌细胞和成纤维细胞膜因有AT1R而受AngⅡ作用,增加心肌收缩力,加快心率,促进蛋白合成和间质细胞增生,调节心肌细胞生长发育,表现心肌肥大和增殖。AngⅡ与心肌细胞AT1R结合后,通过Gp调节蛋白激活磷脂酶C,加速细胞膜中的磷酸肌醇水解成三磷酸肌醇和二酰甘油。三磷酸肌醇及二酰甘油促进胞浆内钙增多,激活钙依赖的DNA酶Ⅰ,使DNA断裂,导致心肌细胞死亡。AngⅡ水平的升高,能使血管收缩,促儿茶酚胺的释放和醛固酮分泌,导致心肌凋亡、心肌肥厚,致间质纤维化及心肌重构,从而影响心力衰竭患者的预后。
血管内皮系统形态和功能的异常与重度子痫前期的发病密切相关,而AT1R可使循环中的内皮素(Endothelin ,ET)含量增加。ET是由血管内皮细胞释放的一种生物活性肽,收缩血管作用比AngⅡ强10倍,具有强烈的收缩血管作用和平滑肌细胞增殖作用,参与高血压、动脉粥样硬化、肺心病、哮喘等多种心血管疾病的发病过程,在血管痉挛性组织缺血、缺氧和血管内皮细胞损伤病变中起重要作用;能直接抑制心肌细胞摄取能量代谢底物,干扰细胞能量代谢,还可通过其血流动力学和(或)细胞机制促进组织细胞脂质过氧化损伤,而脂质过氧化又促进ET的大量释放,从而参与心脏缺血-再灌注损伤的过程。ET是血管收缩因子,不但直接刺激或激活多种激素和细胞因子,且广泛参与机体的生理、病理调节、参与心血管疾病的病理生理过程,加强心肌收缩力,并能促进平滑肌增生,促进神经内分泌功能等作用,实验研究显示ET在诱发心力衰竭过程中起着重要作用。
研究背景和目的:
国内外学者认为AT1R基因1166位点腺嘌呤(A)被胞嘧啶(C)替换与原发性高血压有关,已有的较少文献显示AT1R基因多态性与重度子痫前期患者的心脏受累有关。AngⅡ调节血管张力,维持血容量,刺激细胞增殖,细胞外胶原基质合成和堆积,是人体已知的最强的内源性缩血管物质之一,在维持心血管的自身稳定方面起重要作用。有充分的临床和实验室证据表明,AngⅡ与病理性的间质纤维化、心脏重塑和心衰有关。AT1R基因的分子变异可影响机体对AngⅡ的敏感性,使AngⅡ的病理学效应呈现个体差异。ET存在于内皮细胞,是最强的缩血管活性物质之一。许多实验结果证明,S-PE患者血浆ET水平明显高于正常妊娠组,并随患者的病情严重程度增加而升高。但AT1R基因多态性、AngⅡ、ET是否也存在于胎儿,是否对胎儿心脏结构和功能也产生影响,以及其对母体和胎儿心脏结构和功能影响有无相关性,国内外未见报道。我们选取新疆医科大学第一临床医学院产科S-PE患者30例,并选择同期正常晚期妊娠孕妇30例作为对照。采用彩色多普勒超声测定左心室结构指标和收缩功能指标,用放射免疫方法测定血浆AngⅡ及ET浓度,以探讨血浆AngⅡ及ET浓度与子痫前期性心脏病的关系。同时,应用多聚酶链式反应-限制性片段长度多态性(PCR-RFLP)及等位基因特异性PCR(ASP)等现代分子生物学方法,对目前已知的可能涉及子痫前期发病的AT1R基因1166位点多态性进行检测及分析,旨在了解AT1R基因多态性与子痫前期性心脏病的关联情况,从分子水平探索遗传因素在子痫前期性心脏病发病中的作用。
方法:
随机选取2006年4月至2007年9月在新疆医科大学第一临床医学院产科住院患者,重度子痫前期组(病例组)30例,正常妊娠组(对照组)30例,所有受检者由专人通过超声检查测定孕妇和胎儿的左心室心肌重量指数(LVMI)、室壁相对厚度(RWT)、心输出量(CO)、心脏指数(CI)、左室射血分数(EF)和二尖瓣血流的E、A值E/A比值,用于评价心肌损害的严重程度和舒缩功能。采集对照组和病例组的孕妇外周静脉血(母体血样)及胎儿脐带动脉血(胎儿血样)各5ml。
分别测定血浆血管紧张素Ⅱ水平(AngⅡ)、血浆内皮素(ET)和用荧光定量PCR法测定所采集血样的AT1R基因多态性。
分别进行两组间孕妇、胎儿以及母胎间AT1R基因多态性、AngⅡ水平、ET、LVMI、RWT、EF和E/A的比较。
注一:
1.重度子痫前期的纳入和排除标准1)纳入标准:重度子痫前期患者妊娠35-37周,血压≥160/110mmHg,尿蛋白≥300mg/24h或(++)。排除标准:原发性高血压;肾源性高血压。
2)正常对照组的纳入标准是:经产检血压正常、尿常规检查为尿蛋白阴性、心电图及超声心动图检查排除心脏疾患的健康者。
3.血压的测量是用标准的Sphygmomanometric程序,取坐姿,于右臂间隔5min连续3次取其平均值。收缩压<140mmHg,舒张压<90mmHg。
注二:
1.左室结构重构的判断标准
1)左室正常构型:LVMI≤106g/m2,RWT≤0.44;
2)左室向心性重构:LVMI≤106g/m2,RWT>0.44;
3)左室向心性肥厚:LVMI>106g/m2,RWT>0.44;
4)左室离心性肥厚:LVMI>106g/m2,RWT≤0.44。
2.左室功能重构的判断标准以EF、CO、CI作为评价左室收缩功能指标;E/A比值、RFF作为评价左室舒张功能指标。
(1)左室收缩功能异常:EF<50%或CO<3.5L/min或CI<2.2L/ (min·m2)
(2)左室舒张功能异常:E/A<1。
用Devereux公式计算左室心肌重量(LVM)和LVMI,用Simpson法计算EF,用多普勒测定二尖瓣血流的E、A值E/A比值。
实验方案
1.试验及检查技术
1)采用多聚酶链反应(PCR)技术检测AT1R基因A1166位点的多态性。
2)由核医学科资深人员检测血浆AngⅡ水平、ET水平。
3)由心脏超声科专人通过超声检查测定孕妇和胎儿的心脏。
2.统计学方法:
用SPSS 13.0统计软件进行数据分析,采用的统计方法有一般资料的统计描述、蒙特卡罗法单因素方差分析、连续性校正x 2检验、方差齐性检验、两组样本的t检验、协方差分析、Logistic逐步回归线性分析、两个变量间线性相关分析、偏相关分析,以P<0.05为差异有统计学意义。
结果
1.病例组孕妇及胎儿AT1R基因1166位点变异体(AC+CC)频率均高于对照组,差异有统计学意义(P<0.05);两组间C等位基因频率比较差异也均有统计学意义(P<0.05)。
2.孕妇AT1R基因1166位点变异型(AC型+CC型)与野生型(AA型)的比值比(OR)为5.21,95%可信限为2.35～13.52,提示AT1R基因1166位点变异的孕妇发生重度子痫前期的危险性增加5.21倍;胎儿AT1R基因1166位点变异型(AC型+CC型)与野生型(AA型)的比值比(OR)为5.09,95%可信限为2.08～12.95,提示胎儿AT1R基因1166位点变异发生重度子痫前期的危险性增加5.09倍。
3.病例组孕妇的左心室结构指标均显著大于对照组,两组比较差异有非常显著性意义(P<0.01),且病例组左室构型多为向心性肥厚(LVMI>106 g/m2,RWT>0.44)。病例组孕妇的左室舒张末期容积(EDV)及收缩末期容积(ESV)较对照组增加非常明显,比较差异有高度显著性(P<0.01)。病例组孕妇左心室射血(EF)分数明显低于对照组(P<0.01);心脏指数(CI)及E/A指标在组间具有明显统计学差异(P<0.01);心搏出量(SV)及心输出量(CO)在两组间差异无显著性(P>0.05)。
4.孕妇病例组AT1R基因1166位点AA型左心室质量指数(LVMI)>106 g/m2,室壁相对厚度(RWT)0.44±0.06 ,为离心性肥厚;AT1R基因1166位点AC+CC型LVMI>106g/m2,RWT>0.44,为向心性肥厚;左心室超声结构指标利用单因素作组间比较,左心室质量(LVM)及左心室质量指数(LVMI)在AT1R基因1166位点AC+CC型与AA型组间有差异(P均<0.05),室壁相对厚度(RWT)AT1R基因位点AC+CC型与AA型组间有显著性差异(P<0.01)。
5.胎儿左心室舒张末期室间隔厚度(IVST)病例组与对照组比较有显著性差异(P<0.05);胎儿左室后壁厚度(PWT)病例组与对照组比较有差异(P=0.05)。病例组胎儿左心室超声结构指标利用单因素作组间比较,舒张末期室间隔厚度(IVST)、室壁相对厚度(RWT)AT1R基因AC+CC型与AA型组间有显著性差异(P<0.05)。
6.孕妇多因素Logistic回归分析,显示基因型(x1)、家族史(x2)、收缩压(x3)、体重(x5)均参与增加左心室重构的发生概率,OR分别为2.893(95%CI为1.082～8.865)、4.572(95%CI为2.038～14.891)、3.875 (95%CI为1.864～8.518)和2.594(95%CI为1.121～7.816),可看作是重度子痫前期左心室重构的危险因素。
7.病例组孕妇及胎儿的AngⅡ浓度与对照组比较无明显增高,差异无显著性(P>0.05);重度子痫前期孕妇及胎儿左心室结构、功能各指标与AngⅡ浓度无关。
8.重度子痫前期孕妇及胎儿AT1R基因AC+CC型AngⅡ浓度明显高于AA型,差异有显著性(P<0.05)。
9.重度子痫前期孕妇及胎儿血浆ET水平显著高于正常对照组(P<0.01)。
10.重度子痫前期及正常妊娠孕妇血浆ET与IVST,LVSD,PWT,LVM呈正相关关系(P<0.05),与LVMI呈显著正相关关系(P<0.001),与E/A比值呈显著负相关关系(P<0.001);而与LVDD,RWT,EF均无相关性(P>0.05)。
11.病例组中AT1R基因AC+CC型孕妇及胎儿ET浓度明显高于AA型,差异有显著性(P<0.05);
结论
1.AT1R基因A1166C多态性与重度子痫前期呈正相关,提示该位点可能系重度子痫前期发病的危险因子;AT1R基因1166-C等位基因出现增大了患子痫前期的危险性,说明C等位基因是重度子痫前期的易感基因。
2.AT1R基因的多态性变化在重度子痫前期组内孕妇和胎儿之间有相同的表达,可以把AT1R基因A1166-C变异作为一项重要的遗传标志物用于重度子痫前期的预测,并对携带AC和CC基因型的高危人群进行早期预防。
3.重度子痫前期孕妇及胎儿有左室重构;AT1R基因1166位点AC/CC基因型及C等位基因与重度子痫前期孕妇及胎儿左室重构有关。
4.在AngⅡ水平无显著差异的情况下,血管对AngⅡ反应性的提高和AT1R的激活在重度子痫前期左室重构中起着一定的作用。AngⅡ-AT1R可引起孕妇及胎儿左心室心肌细胞肥大和间质重塑。
5.孕妇及胎儿血浆ET浓度是重度子痫前期的敏感指标;重度子痫前期孕妇及胎儿AT1R基因A 1166 C变异与血浆ET的升高有关。
Preeclampsia is one of the hypertension state in pregnancy, which is the special complication of gestation, imperiling the mother and fetus seriously, especially severe preeclampsia (S-PE). Severe preeclampsia is one of the most important reasons of maternal and fetus mortality, the incidence is 9.4%. The onset of the preeclampsia heart disease is severe preeclampsia .The preeclampsia heart disease is character by the heart failure sign group due to the myocardial damage, showing left heart failure and lung edema, which make up 5% of the total heart disease in gestation and is the second leading cause to maternal mortality. Meanwhile, some reports indicate that the fetal cadiocyte present homogenous and compensated hypertrophy due to the severe preeclampsia, at last the systole and diastole function of heart become abnormal.
The primary pathological change of severe preeclampsia is the Small vessels spasmodism all over the body. In the preeclampsia heart disease patient, the endocardium shows cadiocyte hypertrophy, endochylema granulation, stroma focal fibronolysis, in some severe patients there are punctate hemorrhage and focal necrosis. The change of cardiac muscle fibers can be observed under the electron microscope, wide degeneration, interstitial edema, swelling blood vessel endothelium, narrow lumens, microthrombus can be founded sometimes. All signs indicated that myocardial damage has already occurred due to poor supply of blood in the severe preeclampsia. Left ventricular hypertrophy is the severe outcome caused by Small vessels spasmodism, so the preload and afterload of heart may be increased, left ventricular end diastolic period diameter and left atrial diameter should be enlarged, interventricular septum thickening can be observed in some cases, all of these changes lead to the left ventricular diastolic function decreased. in brief, due to small vessels spasmodism, the peripheral resistance increase, the blood pressure step up, cardiac load be added, left ventricular end-diastolic pressure is increased, but the systole function is decreased.
Considerable researches have suggested that severe preeclampsia patients possess conspicuous genetic predisposition and high risk of cardiovascular disease. Renin-angiotensin system play the important role in keeping electrolyte balance and adjusting the cardiovascular activity, especially angiotensinⅡ(AngⅡ) is the most powerful. AngⅡis the one of the most powerful endogenous vasoconstriction substance we have known. It has the significant contribution to maintain cardiovascular homeostasis and to bring about myocardial hypertrophy. Only by the help of AngⅡreceptor can AngⅡwork, especially AngiotensinⅡType 1 Receptor(AT1R), the function of AngⅡmay be changed if the AT1R alter in molecular biology. AT1R as a kind of membrane receptor, it process every characteristic of hormone, distributing on the blood vessel smooth muscle cell, maintaining metabolic balance and the tension of blood vessel. Some results demonstrates that AT1R gene polymorphic site A1166C can lead to the increase of AT1R density, thus, the high risk of cardiovascular disease may be taken place. In comparison to the normal control group, AT1R gene polymorphic site A1166C has high activity in the heart failure patients.
The patients with preeclampsia are more sensitive to AngⅡthan normal pregnant women, due to AT1R, AngⅡcan work on the cadiocyte and desmocyte membrane, thus, the myocardial contractile force and heart rate increased, mesenchymocyte hyperplasia, cadiocyte growth and development, at last, myocardium hypertrophy and proliferation. After binding with AT1R, AngⅡcan accelerate the hydrolysis procedure from phosphoinositide to inositol triphosphate and diglyceride when the phospholipase C are activated by Gp equestron. Inositol triphosphate and diglyceride augment calcium in endochylema, active deoxyribonucleaseⅠdepended by calcium, so the DNA break and cadiocyte die. The level of AngⅡincrease would lead to the blood vessel contraction, catecholamine and aldosterone releasing, so the myocard apoptosis and pachynsis occur, then, the interstitial fibrosis and cadiocyte reconstruction can be observed, these changes can lead to poor prognosis in the heart failure patients.
The abnormal of function and morphous of blood vessel endothelium are closely relation with severe preeclampsia, AT1R increase endothelin(ET) in the blood, which is a kind of biologically active peptide released by vascular endothelial cell. Endothelin has power to contract blood vessel and is ten times powerful than AngⅡ, besides, it can make smooth muscle cell proliferated, by this way, it participate the procedure of hypertension, artherosclerosis, pneumocardial disease, asthma and so on. Endothelin play a important role in the affection of ischemia due to angiospasm and the damage of blood vessel endothelium, it can interfere the energy metabolism of cadiocyte by inhibiting the procedure of intaking energy metabolic substrate, it also can aggravate the damage of cadiocyte lipid peroxidation, which make more much ET released, then, these ET participate the procedure of ischemia-reperfusion. ET is a vasoconstriction factor, which not only stimulate and active many hormones and cytokine but also widely participate the physiological and pathological regulation of body. Meanwhile, it participate the physiopathologic procedure of cardiovascular disease and increase the myocardial contractile force, as well as promote the hyperplasia of smooth muscle and function of neuroendocrine. Some data show that ET plays the important role in the procedure of inducing the heart failure.
Background
Many researcher believe that essential hypertension is closely relation with the adenine be shifted by cytosine on AT1R gene polymorphic site A1166C. A few studies illustrate that the relation of AT1R gene polymorphism with the heart damage in the severe preeclampsia patients. AngⅡas one of the most powerful endogenous vasoconstriction substance can regular angiotasis and maintain blood-volume, stimulate the proliferation of cadiocyte as well as synthesis and cumulate of ecto-cyte collagen, so it play a important part in the maintaining of angiomyocardiac homoeostasis. Sufficient clinic and breadboard findings indicate that AngⅡis relation with pathologic interstitial fibrosis and heart remodeling and failure. AT1R genic mutation can influence the sensitivity of AngⅡ, thus, AngⅡpathologic effect shows individual difference. ET lies in the vascular endothelial cell, which is the one of the most powerful endogenous vasoconstriction substance. A lot of studies confirm that ET is much more in the severe preeclampsia patients than in the normal pregnant women, and would increase with the deterioration. However, no prior work exists on the problem whether AT1R gene polymorphism and AngⅡand ET lie in the fetus and whether they influence the structure and function of maternal and fetal heart or not. Fifty-three severe preeclampsia patients who be treated in the First affiliated hospital of Xinjiang Medical university were included in the present study, meanwhile, forty-eight normal pregnant women were selected as control group. In order to approach the relation of AngⅡand ET level in plasma and the preeclampsia cardiac disease, we measure the index of left ventricle and systolic function by Doppler ultrasound, and obtain the AngⅡand ET level in plasma by radio-immunity. Besides, polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP)and allele-specific PCR(ASP)and many modern molecular biology methods were used to detect and analyses the AT1R gene polymorphic site A1166C related with preeclampsia. In a word, the study is aimed at finding out the relation of AT1R gene polymorphism and preeclampsia cardiac disease, then to explore how the genetic factor contribute to the preeclampsia cardiac disease from molecular level.
Methods
Fifty-three severe preeclampsia patients who be treated in the First affiliated hospital of Xinjiang Medical university were included in the present study, they were chosen completely at random from April, 2006 to September, 2007 (case group). Meanwhile, forty-eight normal pregnant women were selected as control group. The index of left ventricle and systolic function of subjects and their fetus were measured by Doppler ultrasound, the index include left ventricular mass index(LVMI)and relative wall thickness(RWT) ? cardiac output(CO) ? cardiac index(CI) ? ejection factor(EF)and parameter of E and A and E/A of atrioventricular valveblood flow, the indexes be used to evaluate the degree of heart damage and the function of diastole and systole.
5ml mother’s peripheral venous blood and 5ml fetal umbilic blood of all subjects were collected
AngⅡand ET level in plasma were measured by radio-immunity, the AT1R gene polymorphic site A1166C were detected and analyzed with polymerase chain reaction method.(PCR)
Comparison the AT1R gene polymorphism and AngⅡ, ET and LVMI and RWT, EF and E/A between two groups and between mothers and fetus.
Remarks 1
1.selected and eliminated criteria of severe preeclampsia
1) Selected criteria: the pregnant is in the 34-36 gestational week blood pressure≥160/110mmHg Urine protein≥300mg/24h or (++)
2) Eliminated criteria:essential hypertension;renal hypertension
2.Selected criteria of the control group:
The normal pregnant women whose blood pressure and urine analysis are normal were confirmed without heart disease by the examination of electrocardiogram and ultrasonic cardiogram.
3.The blood pressure were measured with sit position by standard Sphygmomano- metric procedure every 5min for 3 times, then get the mean value, systolic pressure<140mmHg, diastolic pressure<90mmHg.
Remarks 2
1.Ultraphonic criteria of left ventricle structure
1) normal:LVMI≤106g/m2, RWT≤0.44;
2) left ventricle inward reconstruction:LVMI≤106g/m2, RWT>0.44;
3) left ventricle inward pachynsis:LVMI >106g/m2, RWT>0.44;
4) left ventricle outward pachynsis::LVMI >106g/m2, RWT≤0.44?
2.Ultraphonic criteria of abnormal cardiac function
EF and CO and CI are the index of evaluating the left ventricle systolic function, E/A and RFF are parameter of evaluating the left ventricle diastolic function.
Abnormal of left ventricle systolic function:EF<50% or CO<3.5L/min or CI<2.2L/ (min·m2)
Abnormal of left ventricle diastolic function:E/A<1 ?
The way to examine the left ventricle inward reconstruction by ultrasound: calculate left ventricular mass(LVM)and left ventricular mass index ( LVMI) with Devereux formula, calculate ejection fraction (EF) with Simpson method, determine E and A and E/A of atrioventricular valveblood flow by Doppler ultrasound.
Program
1.Experiment technique
1) the AT1R gene polymorphic site A1166C were detected and analyzed with polymerase chain reaction method.(PCR)
2) AngⅡand ET level in plasma were measured by senior technician in nuclear medicine department.
3) Maternal and fetal hearts were examined by special doctor.
2.Statistical method:
1) Statistic data was deal with SPSS 13.0, measurement data are described with mean and standard deviation.
2) Comparison of AT1R gene polymorphism between two groups with chi square test
3) Comparison of LVMI and RWT and CO and CI and EF, as well as E and A and E/A of atrioventricular valveblood flow between two groups with t-test?
4) Comparison of the AT1R gene polymorphic site A1166C and left ventricular mass index and relative wall thickness between mothers and fetus in severe preeclampsia group with analysis of covariance.
5) To analyze two variance correlation with Pearson correlation analysis. P<0.05 indicates that contrast are statistical significance
Result
1.The frequency of AT1R gene 1166 polymorphic site variant (AC+CC) in the pregnant women and fetal case group are higher than in the control group, the variation is statistically significant. (P<0.05), the variation between the two groups of C allele frequency is statistically significant too (P<0.05)
2.The ratio of AT1R gene 1166 polymorphic site variant (AC+CC) to the wild type is 5.21(OR) in the pregnant women. 95% confidence interval is 2.35~13.52. It’s means that the risk of severe preeclampsia for those pregnant women whose AT1R gene 1166 polymorphic site variant occur would increase 5.21 times. The ratio of AT1R gene 1166 polymorphic site variant (AC+CC) to the wild type is 5.09 (OR) in the fetus. 95% confidence interval is 2.08~12.95. It’s means that the risk of severe preeclampsia for fetus whose AT1R gene 1166 polymorphic site variant occur would increase 5.09 times.
3. The index of left ventricle structure in the case group is much more than it in the control group, the variation is significant statistically significant (P<0.01), the concentric hypertrophy is most commonly (LVMI>106 g/m2, RWT>0.44). The end-diastolic dimension (EDV) and end-systolic volume (ESV) of left ventricle in the case group are higher obviously then it in the control group (P<0.01), ejection fraction (EF) of left ventricle in the case group are lower obviously then it in the control group (P<0.01), the variation of cardiac index (CI) and E/A is significant statistically significant (P<0.01); the variation of cardiac output (CO) and stroke volume (SV) is no statistically significant (P>0.05).
4. Left ventricular mass index (LVMI) of the pregnant women with AT1R gene 1166 polymorphic site AA-type is more than 106 g/m2, Relative wall thickness (RWT) is 0.44±0.06, it shows eccentric hypertrophy, left ventricular mass index (LVMI) of the pregnant women with AT1R gene 1166 polymorphic site AC+CC-type is more than 106 g/m2, Relative wall thickness (RWT) is more than 0.44, it shows concentric hypertrophy. Compare these index by single factor group comparison, the result shows that the variation of left ventricular mass (LVM) and left ventricular mass index (LVMI) in AT1R gene 1166 polymorphic site AC+CC-type and AT1R gene 1166 polymorphic site AA-type is statistically significant (P<0.05), the variation of relative wall thickness (RWT) in AT1R gene 1166 polymorphic site AC+CC-type and AT1R gene 1166 polymorphic site AA-type is significant statistically significant (P<0.01)
5. Compare the case group and control group, the variation of fetal interventricular septum thickness at enddiastole (IVST) is significant statistically significant (P<0.05), the variation of fetal left ventricular post wall thickness (PWT) is statistically significant (P=0.05). Compare the fetal case group of AT1R gene 1166 polymorphic site AC+CC-type and AT1R gene 1166 polymorphic site AA-type, the variation of the interventricular septum thickness at end diastole (IVST) and Relative wall thickness (RWT) is statistically significant (P<0.05).
6. The result of multiple factor Logistic regression analysis for the pregnant women shows that genetype (x1) and family medical history (x2) and systolic pressure (x3) as well as body mass index (BMI)(x5) are all high risks to increase the incidence of the left ventricle reconstitution, the relative risk (OR) of them are 2.893 (95%CI is 1.082-8.865) and 4.572 (95%CI is 2.038-14.891) and 3.875 (95%CI is 1.864-8.518) and 2.594 (95%CI is 1.121-7.816), they can be take as independent risk factor for left ventricle reconstitution in severe preeclampsia .
7. The concentration of angiotensinⅡin the case groups of pregnant women and fetus are no more than it in the control groups, the variation is no significant (P>0.05). The index of left ventricle structure and function in severe preeclampsia pregnant women and their fetus have nothing to do with the concentration of angiotensinⅡ(AngⅡ).
8. The concentration of angiotensinⅡin the severe preeclampsia women and their fetus who with AT1R gene 1166 polymorphic site AC+CC-type is much more than the fetus who with AT1R gene 1166 polymorphic site AA-type, the variation is statistically significant (P<0.05).
9. The level of ET in case groups both pregnant women and fetus is significant higher than it in the control group (P<0.01).
10. In the both severe preeclampsia and normal pregnant women, the relation of the ET level with IVST, LVSD, PWT, LVM is positive correlation (P<0.05), the relation with LVMI is closely (P<0.001), the relation with the ratio of E/A is negative correlation (P<0.001). The level of ET is no related with LVDD and RWT and EF (P>0.05).
11. The ET level of pregnant women and their fetus with AT1R gene 1166 polymorphic site AC+CC-type is higher than it with AT1R gene 1166 polymorphic site AA-type, the variation is statistically significant (P<0.05).
Conclusion
1. The relation of AT1R gene 1166 polymorphism with severe preeclampsia is positive correlation, indicating that the very site might be a risk factor for severe preeclampsia, the risk of preeclampsia would increase when AT1R gene 1166 C allel occur, it means that AT1R gene 1166 C allel is a predisposing genes for preeclampsia.
2. The expression of AT1R gene 1166 polymorphism in severe pregnant women as same as the expression in their fetus, Gene mutation of AT1R gene 1166 C allel can be take as a important geno-marker to predict severe preeclampsia, the early prophylaxis could be done for the high-risk group with AT1R gene 1166 polymorphic site AC and CC-type.
3. Left ventricle reconstruction occurs in the severe preeclampsia patients and their fetus. AT1R gene 1166 polymorphic site AC/CC-type and C allel are related to the left ventricle reconstruction of severe preeclampsia patients and their fetus.
4. The change of left ventricle configuration in severe preeclampsia patients is related to the poor pregnant outcome and can be observed by echocardiogram, concentric reconstruction and concentric hypertrophy are independent risk factors for predicting poor pregnant outcome.
5. Excluding the factor of AngⅡlevel, the left ventricle reconstruction of severe preeclampsia is affected by the blood vessel reactance to the AngⅡand activation of AT1R. AngⅡand AT1R can cause left ventricle cadiocyte hypertrophy and interstitial remodeling of pregnant women and fetus respectively.
6. The plasma concentration of ET is a sensitive index, gene mutation of AT1R gene 1166 C allel in severe preeclampsia pregnant women and fetus is related to the increase of ET level.
引文
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