参松养心胶囊、扶正化瘀胶囊改善大鼠心肌梗死后左室重构及其对电生理影响的研究

【作者】 柴松波；

【导师】 王硕仁；

【作者基本信息】 北京中医药大学 ， 中西医结合临床， 2010， 博士

【摘要】 心肌梗死后心律失常的发生严重威胁人类的健康,尤其是心梗后影响血流动力学的恶性室性心律失常已经成为导致心梗病人近期和远期死亡的主要原因。西药多离子通道阻滞剂已经在心梗急性期的心律失常治疗方面取得了显著的疗效,而由于其长期使用的毒副作用,以及是否真的能够降低猝死率还存在疑问,从而限制了其在心律失常远期防治方面的使用；具有抑制心室重构作用的非离子通道阻滞剂有抗心律失常作用、一些传统不是抗心律失常的药物会产生治疗心律失常的作用启发人们思考发生心律失常的更多成因和由此产生的治疗途径。目的：1、研究大鼠冠状动脉结扎致心室重构及在该病理改变中的电生理异常特点,和两者之间的病理相关性；2、观察参松养心胶囊和扶正化瘀胶囊改善上述心肌梗死后心室重构大鼠病理形态学和心脏电生理作用的药效药理学特点。方法：1、用结扎左冠状动脉的方法,制作大鼠心室重构的动物模型。应用超声心动图技术和病理实验技术,对造模后4周和8周的大鼠心脏进行器官结构形态学和心肌组织纤维化的分析研究。2、通过在体程控电刺激心室重构大鼠心脏,观察引发大鼠室颤阈值以及室颤的持续时间；通过离体心脏灌流并记录心外膜动作电位和有效不应期,观察心肌梗死后心室重构大鼠电生理特性的改变。3、通过对心肌梗死后左室重构大鼠模型的器官水平和组织水平的病理形态学改变与在体发生室颤阈值和离体心脏的ERP/APD90比值之间进行数学多元回归分析,定性、定量地分析大鼠心脏结构与其电的病理生理功能相关性。4、以卡托普利作为抑制心室重构的阳性对照药、胺碘酮作为抗心律失常的阳性对照药。观察扶正化瘀胶囊和参松养心胶囊的作用效果。经过四周和八周灌胃给药,研究各药物(1)对心梗后左室重构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；(2)对大鼠心梗后左室离心性重构模型的室颤阈值和引发室颤后持续时间的影响,以及对离体灌流心脏心外膜动作电位、有效不应期和其离散度的影响。结果1、造模后4周及8周,冠状动脉结扎大鼠模型心脏发生心室重构呈离心性表现,与假手术组比较：IVSd和IVSs显著变薄,P＜0.01, LVDd和LVDs显著增大,P<0.01,EF显著降低,P<0.01；同时伴有LVM和LVMI明显增大及Ⅰ型胶原、Ⅲ型胶原的广泛增生,Ⅲ型胶原／Ⅰ型胶原比值的显著降低,P<0.01；但LVPWd和LVPWs无明显变化,P>0.05。模型组8周与4周比较：LVDd、LVDs进一步增大,P均<0.01；EF进一步降低,P<0.05；ⅣSs进一步变薄,P<0.05；Ⅰ、Ⅲ型胶原含量进一步增多,P<0.01；Ⅲ型胶原／Ⅰ型胶原比值虽有增高的趋势,但未见统计学差异,P>0.05；但IVSd、LVPWd和LVPWs无差异,P>0.05。2、在体电刺激结果显示：造模后4周及8周,冠状动脉结扎大鼠经左室电刺激引发的室颤阈值与假手术组比较均显著降低,P<0.01。而造模后4周,模型组大鼠经右室电刺激引发的室颤阈值与假手术组比较无差异,P>0.05；造模后8周,模型组大鼠经右室电刺激引发的室颤阈值则显著降低,P<0.01。造模后4周,经左、右室电刺激诱发室颤持续时间较假手术组延长,P<0.01或0.05；造模后8周,模型组经左、右室电刺激诱发室颤持续时间在1～10V的低、中电压刺激时较假手术组延长,P<0.01或0.05,11～20V的高电压刺激时虽有延长的趋势,但无差异,P>0.05。模型组8周与4周比较：在体电刺激各项参数均无差异,P>0.05。离体心脏电生理检测结果显示：造模后4周及8周,模型组大鼠左心室和右心室APD20.APD50. APD90、ERP比较假手术组均显著延长,P<0.01或0.05；APD90离散度和ERP离散度增大；但ERP/APD90比值减小,P<0.01或0.05。模型组8周与4周比较：左室和右室APD90、ERP进一步的延长,其离散度进一步增大,ERP/APD90比值进一步减小,P<0.01或0.05。3、对于大鼠模型左室重构的组织、结构改变与其电生理变化进行线性多元回归分析,得到8个回归方程。(1)四周组在体左心室电刺激“室颤阈值”与心脏结构和心肌组织纤维化回归分析,回归方程：y=-20.18+10.86·X1+3.54·X2(P<0.01,R=0.93。X1表示PWd, X2表示IVSs, y表示室颤阈值)和y=18.70-0.016·X(P<0.01,R=0.90。X表示Ⅲ型胶原(μm2),y表示室颤阈值)。(2)八周组在体左心室电刺激“室颤阈值”与心脏结构和心肌组织纤维化回归分析,回归方程：y=1.34+4.12·X(P<0.01,R=0.61。X表示IVSd, y表示室颤阈值)和y=11.30-0.005·X(P<0.01,R=0.59。X表示Ⅲ型胶原(μm2),y表示室颤阈值)。(3)四周组离体灌流“左室ERP/APD90"与心脏结构和心肌组织纤维化回归分析,回归方程：y=0.39+0.025·Xl+0.087·X2(P<0.01,R=0.72。X1表示PWs, X2表示IVSs, y表示左室ERP/APD90)和y=0.84-356.43·X(P<0.01,R=0.66。X表示Ⅲ型胶原(mm2),y表示左室ERP/APD90).(4)八周组离体灌流“左室ERP/APD90"与心脏结构和心肌组织纤维化回归分析,回归方程：y=0.75-0.026·X(P<0.01,R=0.94。X表示LVs, y表示左室ERP/APD90)和y=0.71-137.37·X1+0.002·X2(P<0.01,R=0.90。X1表示Ⅲ型胶原(mm2),X2表示Ⅲ／Ⅰ比值,y表示左室ERP/APD90).4、各药物对冠状动脉结扎致左室重构大鼠模型心脏结构的影响：超声结果显示：药物干预后4周和8周与模型组比较,卡托普利组、扶正化瘀胶囊组IVSd和IVSs明显增厚,LVd、LVs以及LVM和LVMI均明显减小,左室EF值明显提高；参松养心胶囊组与模型组比较IVSd明显增厚,LVd、LVs以及LVM和LVMI均减小,左室EF值明显提高,但IVSs与模型组比较无统计学差异,且参松养心胶囊半量组IVSd明显增厚,LVd, LVM和LVMI减小,但IVSs. LVs、左室EF值与模型组比较无统计学差异；而胺碘酮组、胺碘酮半量组和1／3量胺碘酮组LVM、LVMI及超声心动图检测结果各项参数与模型组比较无统计学差异。8周时1／3量胺碘酮+扶正化瘀胶囊合用组LVM和LVMI也明显减小。病理检测结果显示：药物干预后4周和8周,卡托普利组、扶正化瘀胶囊组、参松养心胶囊组、1／3量胺碘酮+扶正化瘀胶囊合用组左室胶原总面积、Ⅰ、Ⅲ型胶原含量均明显减少,Ⅲ型胶原／Ⅰ型胶原比值明显升高；而胺碘酮组、胺碘酮半量组、1／3量胺碘酮组左室胶原面积与模型组比较无统计学差异。4周时参松养心胶囊半量组左室胶原总面积、Ⅰ型胶原含量也有减少,Ⅲ型胶原／Ⅰ型胶原比值较模型组升高,但左心室Ⅲ型胶原含量与模型组比较无统计学差异。8周组缝隙连接蛋白43(CX43)检测显示：参松养心胶囊对CX43表达的损伤有抑制作用,而胺碘酮对心梗后CX43的损伤无修复性作用。5、各药物对冠状动脉结扎致左室重构大鼠模型心脏电生理的影响：(1)在体电刺激结果显示：四周时左室电刺激引发的室颤阈值、持续时间及八周时左、右室电刺激诱发的室颤阈值、持续时间均与假手术组有差异,各药物对室颤抑制作用的效果是：胺碘酮和1／3量胺碘酮+扶正化瘀胶囊合用效果最好；参松养心胶囊和1／3量胺碘酮效果也非常明显；扶正化瘀胶囊和卡托普利也有部分提高室颤阈值和抑制室颤持续时间的作用。(2)离体心脏电生理检测结果表明：卡托普利和扶正化瘀胶囊缩短APD、增大ERP/APD90比值；胺碘酮和参松养心胶囊延长APD和ERP、增大ERP/APD90比值；1／3量胺碘酮+扶正化瘀胶囊合用不但显著地增大ERP/APD90比值,也使APD90离散度显著减小；而卡托普利、扶正化瘀胶囊、胺碘酮、参松养心胶囊、1／3胺碘酮对心肌梗死后心脏不同部位APD90离散度增加也有一定的抑制作用。(3)胺碘酮、参松养心胶囊、卡托普利、扶正化瘀胶囊、1／3量胺碘酮+扶正化瘀胶囊合用对于电生理实验指标的作用强度大小为：胺碘酮作用效果最强；1／3量胺碘酮+扶正化瘀胶囊合用的效果接近于胺碘酮,参松养心胶囊效果也较强；卡托普利和扶正化瘀胶囊也有部分改善心脏电生理特性的作用,且二者作用效果基本相同。结论：1、结扎左冠状动脉致左室重构模型大鼠心脏,具有左心室离心性改变的器官水平特点和组织纤维化特征；随未经治疗的心肌梗死病程的延长,心肌间质胶原沉积不断增多,造成心室重构地不断进展。2、该模型也发生电生理特性的改变,表现为室颤阈值减小、室颤持续时间延长,单相动作电位离散度增大,具有易于产生电折返传导的基础,引发心律失常。3、心梗后心室重构大鼠室颤阈值和反映心脏单向动作电位离散度的ERP/APD90比值均与左室壁厚度、Ⅲ胶原／Ⅰ胶原比值呈正相关,和左室内径、Ⅲ胶原含量呈负相关。4、卡托普利和扶正化瘀胶囊能够改善左室重构大鼠的离心性病理结构形态和减轻心肌纤维化水平。同时也显著提高了该模型大鼠心脏的室颤阈值、缩短室颤持续的时间；缩短APD时程及其离散度,从而有利于消除折返和各向异性传导,降低心律失常的发生。5、胺碘酮无论大、小剂量均不能够改变左室重构大鼠的离心性病理结构形态和减轻心肌纤维化水平；对心梗后CX43的损伤也无修复性作用。但能够显著提高该模型大鼠的室颤阈值、缩短室颤持续时间；延长APD时程和缩小单向动作电位的离散度。该药的抗心律失常作用与抑制左室重构无关,而是其多离子通道阻滞作用的结果。6、参松养心胶囊能够对离心性左室重构有抑制作用；还能抑制心肌梗死后CX43表达的损伤。但此作用较卡托普利和扶正化瘀胶囊为弱。该药能够显著提高该模型大鼠的室颤阈值、缩短室颤持续时间；延长APD时程、缩小APD各部位离散度、增加ERP/APD90比值。以上作用效果随药量的减小而减弱。参松养心胶囊抗心律失常的作用与其多离子通道阻滞有关,也与其抑制心室重构的非离子通道阻滞作用有关。7、1／3量胺碘酮+扶正化瘀胶囊合用对于心室重构和心肌纤维化的抑制作用等同于扶正化瘀胶囊而强于全量胺碘酮。对于室颤阈值和室颤持续时间的作用接近于胺碘酮全量的效果；对APD作用的效应表现得不甚明显,但对APD90离散度增大的抑制作用效果最显著、有明显增大ERP/APD90比值的作用。其机制可能是合用的两药物从心肌细胞膜离子通道和心肌纤维化两方面均发挥了抗心律失常的作用,从而使单纯西药离子通道阻滞剂在较小剂量使用的情况下,达到了其维持剂量的作用效果。8、对产生心律失常心脏器官、组织水平的长期病理修复性治疗有利于对心律失常的远期防治。更多还原

【Abstract】 Arrhythmia following myocardial infarction which is a serious threat to human health,especially malignant ventricular arrhythmia which affect hemodynamics has become the leading cause of short-term and long-term mortality. Multi-ion channel blockers have gained conspicuous therapeutic effect in arrhythmia at acute stage of myocardial infarction, but because of toxic and side effect and whether or not trully cut down sudden death rate for it’s long-term use,confined it’s usage at arrhythmia long-term prevention; non-ion channel blocker has anti-arrhythmia effect, some untraditional antiarrhythic drugs can bring about treating arrhythmia effect,which evocated us thinking more causes for generating arrhythmia and according this bring out treatment route.Objectives:1.To study the electrophysiological characteristics of coronary artery ligation induced left ventricular remodeling rats model, as well as their patho-relevance.2. Observe Shensongyangxin capsule and Fuzhenghuayu Capsule’s pharmacological effects to improve the pathological morphological characteristics and electrophysiological characteristics of coronary artery ligation induced left ventricular remodeling rats model.Methods:1. With coronary artery ligation rat animal model of ventricular remodeling. After four or eight weeks, application of echocardiography technology and pathology technology, for organ structural morphology and myocard tissue fibrosis pathological s tudy.2.Use program-controlled electricity stimulate coronary artery ligation rat ventricular remodeling model,observe the ventricular fibrillation threshold value and duration of ventricular fibrillation; Through reperfusion isolated heart and recording action potential duration and effective refractory period about epicardium,observe the changes of electrophysiological characteristics after myocardial infarction.3.To establish the Multiple-regression mathematic models between pathological morphological characteristics of organ level and tissue level after myocardial infarction induced ventricular remodeling rats model, and ventricular fibrillation threshold value and ERP/APD90, qualitative and quantitative analyze the cardiac structure and electrophysiological characteristics’patho-relevance.4. Captopril as a positive control myocardial remodeling, amiodarone as a positive control anti-arrhythmic drugs,observe Fuzhenghuayu Capsule and Shensongyangxin capsule’s pharmacological effects. After given medicines four and eight weeks, to study the drug function for (1)the pathological structural morphological characteristics and myocard tissue fibrosis pathological characteristics after myocardial infarction induced left ventricular remodeling; (2) the ventricular fibrillation threshold value and duration of ventricular fibrillation, as well as action potential duration、effective refractory period and dispersions of them at different sites about epicardium after myocardial infarction induced left ventricular remodeling.Results:1. After four or eight weeks of operation, eccentric ventricular remodeling happened in coronary artery ligation rat model, compared with sham operation group: IVSd and IVSs became significantly thinner,P<0.01,LVDd and LVDs dilatated significantly, P<0.01,EF degraded, P<0.01; at the same time accompanied LVM、LVMI and collagenⅠ、Ⅲincreased,Ⅲ/Ⅰratio decreased,P<0.01;while LVPWd and LVPWs had no difference,P>0.05. Compared with model group of eight and four weeks:LVDd、LVDs dilatated the second time,P<0.01, EF degraded the second time,P<0.05; IVSTs thinner the second time, P<0.05; collagenⅠ、Ⅲincreased the second time, P<0.01;Ⅲ/Ⅰratio had increasing tendency,but had no difference, P>0.05; IVSd、LVPWd and LVPWs had no difference, P>0.05.2. Electric stimulation in vivo result showed:At four and eight weeks of operation,compared with sham operation group:ventricular fibrillation threshold value caused by stimulated left ventricle lowed,P<0.01. while at four weeks of operation, ventricular fibrillation threshold value caused by stimulated right ventricle had no difference,P>0.05; at eight weeks of operation, ventricular fibrillation threshold value caused by stimulated right ventricle lowed,P<0.01. At four weeks of operation, duration of ventricular fibrillation caused by stimulated left and right ventricle prolonged, P<0.01 or 0.05; at eight weeks of operation, duration of ventricular fibrillation caused by stimulated left and right ventricle prolonged at 1-10V stimulation, P<0.01 or 0.05, even had prolonged tendency, but had no difference at 11-20V stimulation, P>0.05. Compared with model group of eight and four weeks:Electric stimulation in vivo’s each parameter had no more deteriorate,P>0.05. Isolated cardiac electrophysiology result showed:At four.and eight weeks of operation,compared with sham operation group:APD20、APD50、APD90、ERP of both left and right ventricle prolonged, P<0.01 or 0.05; dispersions of APD90 and ERP enlarged; but ERP/APD90 diminished, P<0.01 or 0.05. Compared with model group of eight and four weeks:APD90、ERP of both left and right ventricle prolonged the second time, dispersions of them enlarged the second time; ERP/APD90 diminished the second time, P<0.01 or 0.05.3.Through multiple regression analysis with left ventricle remodeling between tissue、structural changes and electrophysiological changes, got eight regression equation. (1) regression analysis of ventricular fibrillation threshold value and cardiac structure and myocard tissue fibrosis at four weeks of operation, regression equation:y=-20.18+10.86·X1+3.54·X2(P<0.01, R=0.93. X1 indicated PWd,X2 indicated IVSs,y indicated ventricular fibrillation threshold value)and y=18.70-0.016·X(P<0.01,R=0.90. X indicated collagenⅢ(μm2),y indicated ventricular fibrillation threshold value). (2) regression analysis of ventricular fibrillation threshold value and cardiac structure and myocard tissue fibrosis at eight weeks of operation, regression equation:y=1.34+4.12·X (P<0.01, R=0.61.X indicated IVSd,y indicated ventricular fibrillation threshold value)and y=11.30-0.005·X (P<0.01,R=0.59.X indicated collagenⅢ(μm2),y indicated ventricular fibrillation threshold value). (3) regression analysis of left ventricle ERP/APD90 and cardiac structure and myocard tissue fibrosis at four weeks of operation, regression equation:y=0.39+0.025·X1+0.087·X2 (P<0.01,R=0.72.X1 indicated PWs, X2 indicated IVSs,y indicated left ventricle ERP/APD90)and y=0.84-356.43·X (P<0.01,R=0.66. X indicated collagen III (mm2),y indicated left ventricle ERP/APD90). (4) regression analysis of left ventricle ERP/APD90 and cardiac structure and myocard tissue fibrosis at eight weeks of operation, regression equation:y=0.75-0.026·X (P<0.01,R=0.94. X indicated LVs, y indicated left ventricle ERP/APD90)and y=0.71-137.37·X1+0.002·X2 (P<0.01, R=0.90. X1 indicated collagenⅢ(mm2), X2 indicated collagenⅢ/Ⅰ,y indicated left ventricle ERP/APD90).4. The effect of each medicine on the coronary artery ligation rat model in cardiac structure, Echocardiogram result showed:compared with model group after interfered with medicine for four or eight weeks, captopril group and fuzhenghuayu capsule group: IVSd and IVSs became thicker, LVd、LVs and LVM、LVMI were all diminished, EF% were elevated; shensongyangxin capsule group:IVSd became thicker, LVd、LVs and LVM、LVMI were all diminished, EF% were elevated,but IVSs had no difference than model group; semis shensongyangxin capsule group:IVSd became thicker, LVd、LVM and LVMI were all diminished, but IVSs、LVs and EF% had no difference; amiodarone group、semis amiodarone group and 1/3 amiodarone group:LVM, LVMI and all echocardiogram results had no difference.1/3 amiodarone and fuzhenghuayu capsule combined group:LVM, LVMI were also diminished obviously. Pathological detection showed:after interfered with medicine for four or eight weeks,captopril group、fuzhenghuayu capsule group、shensongyangxin capsule group、1/3 amiodarone and fuzhenghuayu capsule combined group:total collagen area and contents of collagenⅠ、Ⅲdecreased dramatically,whileⅢ/Ⅰincreased dramatically;while amiodarone group、semis amiodarone group and 1/3 amiodarone group:collagen area had no difference with model group. At four weeks, semis shensongyangxin capsule group:total collagen area and contents of collagen I decreased dramatically,andⅢ/Ⅰincreased dramatically; but contents of collagen III had no difference with model group.8 weeks of connexin 43 (CX43) analysis showed:shensongyangxin capsule on the expression of injury CX43 inhibited, and amiodarone on the injury after myocardial infarction CX43 no reparative effect.5. The effect of each medicine on the coronary artery ligation rat model in cardiac lectrophysiology, Electric stimulation in vivo result showed:(1) At four weeks of op-eration, ventricular fibrillation threshold value caused by stimulated left ventricle and duration of ventricular fibrillation caused by stimulated left ventricle, as well as at four and eight weeks of operation, ventricular fibrillation threshold value caused by stimulated left and right ventricle and duration of ventricular fibri-llation caused by stimulated left and right ventricle, compared with model group had difference. The effect of each medicine on ventricular fibrillation:amiodarone group and 1/3 amiodarone and fuzhenghuayu capsule combined group were best; shensongyangxin capsule group and 1/3 amiodarone group were better; captopril group and fuzhenghuayu capsule group also had some of effects on ventricular fibrillation. (2)Isolated cardiac electrophysiology result showed:captopril and fuzhenghuayu capsule shorted APD and increased ERP/APD90; amiodarone and shensongyangxin capsule prolonged APD and ERP, increased ERP/APD90; 1/3 amiodarone and fuzhenghuayu capsule combined both in-creased ERP/APD90 and diminished dispersions of APD90; While captopril、fuzhenghuayu capsule、amiodarone、shensongyangxin capsule、1/3 amiodarone also prohibited the increasing of APD90 dispersions. (3) Amiodarone、shensongyangxin capsule、captopril. fuzhenghuayu capsule、1/3 amiodarone and fuzhenghuayu capsule combined treating effects for electrophysiology were:amiodarone were best; 1/3 amiodarone and fuzheng-huayu capsule combined closed to effect of amiodarone, shensongyangxin capsule group were better; captopril group and fuzhenghuayu capsule group also had some of effects on electrophysiology,and the two medicines’effects were similar.Conclusions:1. Coronary artery ligation rat animal model of left ventricular remodeling, with eccentric left ventricular remodeling organic characteristics and tissue fibrous degeneration characteristics; following time passed after myocardial infarction untreated, cardiac interstitial collagen increased, ventricle remodeling marched unrest.2. The model’s electrophysiological characteristics also changed, displayed:Ven-tricular fibrillation threshold value decreased, duration of ventricular fibrillation prolonged, dispersions of monophasic action potential increased, possessed the foundation of easily created electrical reentry, thus initiate arrhythmia.3. Coronary artery ligation rat animal model of ventricular remodeling, ventricular fibrillation threshold value and ERP/APD90 showed positive correlation with the thickness of left Ventricle wall andⅢ/Ⅰ,while showed negative correlation with the diameter of left ventricle wall and collagen III.4. Captopril and fuzhenghuayu capsule could improve eccentric left ventricular remodeling patho-structure characteristics and lessen tissue fibrous degeneration characteristics. At the same time, elevated ventricular fibrillation threshold value, shortened duration of ventricular fibrillation, shortened APD and dispersions of APD90, increased ERP/APD90, thereby profit to eliminate reentry and anisotropic conduction, thus lower the incidence of arrhythmia.5. Whether large dose or small dose amiodarone could not improve eccentric left ventricular remodeling patho-structure characteristics and lessen tissue fibrous degeneration characteristics. On the injury after myocardial infarction and no rehabilitation CX43 role. while it could elevated ventricular fibrillation threshold value, shortened duration of ventricular fibrillation, prolonged APD and diminished dispersions of APD90, increased ERP/APD90, this anti-arrhythmia effect had nothing to do with prohabit left ventricular remodeling, which was the effect of multi-ion channel blocking. 6. Shensongyangxin capsule could improve left ventricular remodeling, can inhibit the expression of CX43 after myocardial infarction injury. but this effect was weaker than Captopril and fuzhenghuayu capsule. Which also could elevated ventricular fibrillation threshold value, shortened duration of ventricular fibrillation, prolonged APD and diminished dispersions of APD90, increased ERP/APD90, and the above effect was weaken following dosage diminished. Shensongyangxin capsule’s anti-arrhythmia effect both concerned with multi-ion channel blocking and non-ion channel blocking.7.1/3 amiodarone and fuzhenghuayu capsule combined effect of prohabition for ventricular remodeling and tissue fibrous degeneration identificated with fuzhenghuayu capsule, while better than full dosage amiodarone; the effect for ventricular fibrillation threshold value and duration of ventricular fibrillation identificated with full dose amiodarone; the effect for APD was not obvious, while the effect of diminishing dispersions of APD90 was the best; and could dramatically increase ERP/APD90. which mechanism maybe combined medicine played anti-arrhythmia effect from both ion channel blocking and tissue fibrous degeneration prohabiting.8. Given long-term patho-renaturation treatment for arrhythmic heart from organ and tissue levels, profited for long-term prevention and cure of arhythmia.更多还原