Shensong Capsule, Fuzhenghuayu Capsule Improve Left Ventricular Remodeling After Myocardial Infarction And Its Electrophysiological Studies

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.