摘要
目的：
1.研究心肌肥厚大鼠模型的病理形态学与其电生理特性改变之间的关联性。
2.观察参松养心胶囊和扶正化瘀胶囊改善心肌肥厚大鼠病理形态学、电生理学的药效药理学特点。
方法：
1.用部分缩窄大鼠腹主动脉的方法,制作大鼠心肌肥厚的动物模型。应用超声心动技术和病理实验技术,对造模后四周和八周的大鼠心脏进行器官结构形态学比较,并对八周大鼠心肌组织纤维化分析研究。
2.对造模八周后大鼠的心脏,通过在体程控电刺激,引发并测算出大鼠室颤阈值以及引发室颤后的持续时间,通过离体灌流大鼠心脏进行电刺激,观察单相动作电位时程产生的特点。
3.运用统计学中多元线性回归的方法,以电生理指标为应变量,以心脏结构和心肌纤维化数据为自变量研究其多元线性回归关系。
4.以卡托普利作为抗心肌肥厚阳性对照药,将动物分为五组：模型组、假手术组、卡托普利组、参松养心胶囊组、扶正化瘀胶囊组,根据临床等效剂量换算出大鼠给药量,经过八周灌胃给药,研究各药物对心肌肥厚模型大鼠心脏结构形态学变化和对心肌组织纤维化的影响,以及对心肌肥厚模型大鼠心脏电生理的影响。
结果：
1.造模后4和8周,模型组与假手术组比较：室间隔舒张末期厚度(IVSTd),左室后壁舒张末期厚度(LVPWTd),左房收缩末期内径(LADs)非常显著地增厚,P<0.01；左室舒张末期内径(LVDd)非常显著地变小,P<0.01；脏体比值、左室重量(LVM)、左室心肌质量指数(LVMI)非常显著地增大,P<0.01；造模后8周,心肌Ⅰ型胶原、Ⅲ型胶原,胶原总含量非常显著地增多,P<0.O1,Ⅲ胶原／Ⅰ胶原比值非常显著地增大,P<0.01；心肌TGF-β1含量非常显著地增多,P<0.01；CX43含量非常显著地减少,P<0.01；假手术8周组与4周组比较：以上各项指标均无显著变化。模型组8周与模型组4周比较：室间隔舒张末期厚度(IVSTd),左室后壁舒张末期厚度(LVPWTd),左室收缩末期内径(LADs)非常显著地增厚,P<0.01；脏体比值显著增加,P<0.05；左室重量(LVM)、左室心肌质量指数(LVMI)非常显著地增大,P<0.01；左室舒张末期内径(LVDd)、射血分数EF差异无统计学意义。
2.造模后8周,模型组和假手术组比较,诱发室颤的阈值非常显著地降低,(P<0.01)。左室动作电位复极90%(APD90)、左室有效不应期(ERP)非常显著地延长(P<0.01),ERP/APD90比值非常显著地减小,(P<0.01)。
3.将模型组与假手术组LADd、IVSTd、LVDd、LVPWTd、IVSTs、LVDs、LVPWTs与左室室颤阈值、左室ERP/APD90做多元线性回归分析,得到回归方程[1]y=23.85-5.61X3(P<0.01,R=0.78。X3表示LVPWTd,y表示室颤阈值)和回归方程[2]y=1.21-0.18X3(P<0.01,R=0.73。X3表示LVPWTs,y表示左室ERP/APD90);将模型组与假手术组的Ⅰ型胶原含量,Ⅲ型胶原含量,Ⅲ／Ⅰ胶原比值、总胶原含量,与左室室颤阈值、左室ERP／APD90做多元线性回归分析,得到两个回归方程[3]y=23.95-0.004X1-0.1X3(P<0.01,R=0.88。X1表示Ⅰ型胶原,X3表示Ⅲ／Ⅰ胶原比值,y表示室颤阈值)和回归方程[4]y=0.78-186.82 X2(P<0.05,R=0.64。X2表示Ⅲ型胶原,y表示左室ERP/APD90);回归方程[1]显示左心室电刺激室颤阈值与左室后壁舒张末期厚度(LVPWTd)负相关,回归方程[2]显示左室ERP/APD90与左室后壁收缩末期厚度(LVPWTs)负相关；回归方程[3]显示左室室颤阈值与Ⅰ型胶原含量、Ⅲ／Ⅰ胶原比值负相关。回归方程[4]显示左室ERP／APD90与Ⅲ型胶原负相关。
4.各种药物对部分缩窄腹主动脉致心肌肥厚大鼠模型心脏结构的影响：参松养心胶囊组、扶正化瘀胶囊组与模型组相比：室间隔舒张末期厚度(IVSTd),左室后壁舒张末期厚度(LVPWTd),经八周治疗后均非常显著地小于模型组,P<0.01；Ⅰ、Ⅲ型胶原,胶原总含量非常显著地低于模型组,P<0.01；Ⅲ胶原／Ⅰ胶原比值与模型组相比非常显著地减少,P<0.01；阳性对照药卡托普利对心肌肥厚的抑制作用与扶正化瘀胶囊和参松养心胶囊无显著性差异,对于Ⅰ、Ⅲ型胶原的抑制作用卡托普利最强,扶正化瘀胶囊好于参松养心胶囊。对于TGF-p 1的抑制作用卡托普利最强,对于增加CX43含量的作用卡托普利好于扶正化瘀胶囊。
5.各种药物对部分缩窄腹主动脉致心肌肥厚大鼠心脏的电生理影响：参松养心胶囊、扶正化瘀胶囊与模型组相比能非常显著地提高心肌肥厚模型心室重构大鼠室颤的阈值,缩短室颤持续时间,(P<0.01)。参松养心胶囊对于增加左室和右室的ERP、APD90时间,增大ERP/APD90比值的作用好于卡托普利组和扶正化瘀胶囊组。
结论：
1.部分缩窄腹主动脉8周致心肌肥厚的大鼠模型具有向心性肥厚的器官水平特点和组织纤维化特征。
2.部分缩窄腹主动脉大鼠模型发生电生理特点的改变：室颤阈值减小、室颤持续时间延长,左室有效不应期(ERP)和左室动作电位复极90%(APD90)延长,左室ERP/APD90比值减小,心肌肥厚大鼠的心脏电生理离散度增大。
3.随着左室后壁肥厚程度的加重,心肌胶原含量的增多,致心室颤动阈值越小和左室心肌单相动作电位离散度越大,左室ERP/APD90比值降低,更易发生室颤和室性心律失常。本研究经多元线性回归分析建立的四个回归方程反映了向心性心肌肥厚的大鼠的器官、组织结构改变与电生理异常的内在相关规律性。
4.参松养心胶囊和扶正化瘀胶囊能够改变向心性重构大鼠的病理结构形态和减轻心肌纤维化水平,也有各自改善心肌肥厚大鼠电生理作用的特点。
5.在心律失常的治疗中需要重视心律失常疾病中心肌间质和心脏结构的问题。
Objective:
1. To study the correlation between heart structures and electrophysiological parameters in cardiac hypertrophy of model rat.
2. To observe the effects of Shensong Yangxin capsule and Fuzheng Huayu Capsule in improving cardiac hypertrophy in rat.
Method:
1. We made model of cardiac hypertrophy by banding the abdominal aorta of the rat, then we compared the heart structures of four weeks and eight weeks model-operated rat, using echocardiographic and pathologic techniques,we analyse myocardial fibrosis in eight weeks model-operated rat.
2. We assessed the threshold and the duration of ventricular fibrillation of eight weeks model rat through the programmed electrical stimulation in vivo, and observed action potential duration (APD) of eight weeks model rat through electrical stimulation in vitro.
3. We studied the relation between electrophysiological parameters and cardiac structure and myocardial fibrosis using multiple linear regression statistics. Electrophysiological parameters were dependent variables, however cardiac structure and myocardial fibrosis parameters were independent variables.
4. We divided the rats into five groups, including model group, Sham operation group, Captopril group, Shensong Yangxin group, Fuzheng huayu group. Captopril group was considered as a control group for Chinese medicine groups, and then we compared the electrophysiological parameters of medicine groups to model group.
Result:
1. Compared with sham operation group after four and eight weeks operation, IVSTd, LVPWTd, LADs, LVM, LVMI of the model group became significantly thick, P<0.01, and LVDd became significantly decreased, P<0.01; Compared with sham operation group, TypeⅠ, typeⅢ, TGF-β1 andⅢ/Ⅰratio were significantly increased after eight weeks of operation, P<0.01; CX43 was significantly decreased after eight weeks of operation, P<0.01; compared with model-four-week group, IVSTd, LVPWTd, LADs, LVM, LVMI of model-eight-week group were significantly increased, and LVDd had no difference, P>0.05.
2. Compared with sham operation group, APD90, ERP, ERP/APD90 of left ventricular of model-eight-week group became significantly increased, P<0.01;
3. The statistics approach of multiple linear regression showed that threshold and the duration of ventricular fibrillation had negative correlation with LVPWTd andⅢ/Ⅰratio, and ERP/APD90 had negative correlation with LVPWTd typeⅢ.
4. Compared with molde operation group, IVSTd, LVPWTd of Shensong Yangxin group and Fuzheng Huayu group became significantly thinner. Captopril group had the best effect on inhibition of typeⅠ, typeⅢ, and TGF-β1, P<0.01;
5. compared with molde group, the threshold of ventricular fibrillation in Shensong Yangxin group and Fuzheng Huayu group was significantly increased, P<0.01; Shensong Yangxin had significant difference in increasing the time of APD90, ERP, and had better effect in increasing ERP/APD90 ratio than Fuzheng Huayu group and Captopril group, P<0.01;
Conclution:
1. The model hypertrophic cardiac rat induced by coarctation of abdominal aorta after eight weeks have characteristic of concentric hypertrophy and fibrosis.
2. The electrophysiological parameters of the concentric hypertrophy of rat change as the threshold of ventricular fibrillation is decreased, and the duration of ventricular fibrillation, effective refractory period (ERP) and action potential duration (90%) (APD90) all will be prolonged, and ERP/APD90 ratio is decreased.
3. The frequency of Ventricular arrhythmia is increased when thickness of the left ventricular posterior wall (LVPW) and collagen amount is increased. The four equations show that there is a correlation between heart structures and electrophysiological parameters in cardiac hypertrophic model rat.
4. Shensong Yangxin and Fuzheng Huayu can improve concentric hypertrophy, fibrosis and electrophysiological parameters of cardiac hypertrophic model rat.
5. We should pay attention to the relation between hypertrophy of myocardial interstitium and arrhythmia.
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