| Background and ObjectivesCoronary microvasculature dysfunction(CMD)exists in patients with ST-segment elevation myocardial infarction(STEMI)undergoing percutaneous transluminal coronary angioplasty or stent implantation with a high incidence.Current trials have revealed the fact that CMD has a strong negative impact on prognosis and outcomes,including increasing the risk of early post-infarction complications,adverse left ventricular remodeling,late-onset heart failure and mortality.But,currently,it is unclear how to choose optimal treatment strategies for patients with CMD.Patients are in a critical condition and have a high risk of death after acute myocardial infarction.As a result,it is very difficult to carry out a study on assessing methods and interventional strategies for patients of CMD after acute myocardial infarction.So,it plays an important clinical significance to establish a simple,reliable animal model mimicking CMD of patients after acute myocardial infarction.The index of microcirculatory resistance(IMR)is a specific quantitative measurement to assess CMD and shows a high predictive capacity of the extent and severity in patients with STEMI.An accurate calculation of IMR requires a maximal steady state of coronary hyperemia,but the best drug and dosage is unclear administered via intracoronary(IC)bolus for inducing maximal hyperemia in animal experiments.In this study,we will investigate the effectiveness and safety of different agents inducing coronary maximal hyperemia for measuring IMR,explore methods of establishing a proper animal model and study effectiv strategies for treatment CMD after STEMI.This study consists of three parts.1.Explore optimal agents for inducing coronary maximal hyperemia in pig modelObjects and MethodsIMR measurements were induced by seven experimental conditions in sequential order in 21 pigs,namely IC bolus papaverine 18mg,ATP 40 ?g,80 ?g,160 ?g,240?g and nicorandil 2 mg,4 mg,respectively.Next measurement could not be made until blood pressure(BP)and heart rate(HR)recovered from the hyperemia level to the baseline level after several minutes interval Average value of IMR was calculated for analyses.Because of the long hyperemia condition,the measurement of IMR induced by alprostadil 10 ug was in another 7 pigs.IMR were measured in 1,3,5,8,10 minutes after IC bolus.ResultsCompared with IMR induced by papaverine 18 mg(11.5±2.4),IMR induced by ATP 40 ug(22.3±7.9),80 ug(15.6±4.5)and 160 ug(13.4±3.3)were much higher,respectively,all P<0.05,but there was no significant difference in IMR induced by ATP 240 ug(11.6±2.2)(P>0.05).The degree of BP reduction and HR increase induced by ATP 240 ug was less obviously than that of papaverine(both P<0.05).IMR induced by IC bolus nicorandil 2 mg was higher than 18 mg papaverine(13.6±2.1 versus 11.5±2.4,P<0.05),while the effect of nicorandil 4 mg was nearly equal to papaverine(11.3±2.0 versus 11.5±2.4,P=0.999).Unlike IC bolus papaverine,there were fewer changes in the mean BP and HR after nicorandil infusion(both P<0.05).After IC bolus alprostadil 10 ug,IMR decreased gradually and had bottomed out in 5 minutes,and then the value climbed back slowly.No difference of IMR induced by infusion of alprostadil(5 minutes)and papaverine was found(9.6±2.2 versus 11.5±2.4,P>0.05).BP decreased fiercely immediately after alprostadil IC bolus and recoverd to baseline level almost 32 minutes later.ConclusionsIC bolus ATP 240 ug or nicorandil 4 mg is an effective and safe method for measuring IMR in pig model,while alprostadil is not suitable for inducing coronary maximal hyperemia because of BP reduction violently for a long time after IC bolus.2.Establish an animal model of CMD after experimental acute myocardial infarctionObjects and MethodsAnimal model was established by balloon occlusion the left anterior descending artery(LAD)of pig continuously(group 1)or intermittently(group 2)under 4-8 atmosphere.Reperfusion began after 90 minutes persistent occlusion in group 1 in 14 pigs.There were 3 X 30 minutes occlusion in group 2 in 10 pigs,and a 30 minutes reperfusion followed first and second balloon occlusion.Continuous reperfusion began after the total time of balloon inflation up to 90 minutes in both groups.IMR,hemodynamics,echocardiography and blood samples measurements were made in the time points of baseline,continuous reperfusion 0 h,1 h and 2 h in all pigs.ResultsCompared with IMR in group 1 at baseline(11.3±1.8),IMR at reperfusion 0 h(29.7±5.9),1 h(31.6±6.8)and 2 h(34.1±8.2)was higher(all P<0.05).Ingroup 2,IMR at reperfusion 0 h(24.6±4.8),1 h(26.5±5,1)and 2 h(25.3±5.8)was also higher than IMR at baseline(11.8±3.2)(all P<0.05),but fewer change was found in reperfusion period.Meanwhile,IMR in group 1 at reperfusion 0 h,1 h and 2 h was much higher than that of group 2,respectively(P<0.05).Serum cTnI averaged 15.6±2.5 pg/mL in group 1 and 15.4±3.2 pg/mL in group 2 under baseline conditions(P?0.05).As the mass of myocyte infarction increased,cTnI pooled from the bottom in baseline to the top in 24 h in both two groups(nearly increased 73 times,63 times,respectively)(P for trend<0.05).Serum cTnI concentration in group 1 was higher than group 2 in every time point(all P<0.05).Serum BNP concentration under baseline conditions was nearly same(25.3±10.9 pg/mL in group 1 and 28.3±19.2 pg/mL in group 2)(P>0.05),but the top value of BNP in group 1 was higher than group 2 at reperfusion 2 h(P<0.05).Similar to BNP,serum ET-1 concentration increased gradually from baseline to reperfusion period and the top value was observed in reperfusion 2 h.However,serum NO concentration began decreasing gradually from baseline time point and nearly recovered to the baseline level in reperfusion 24 h from the bottom time point in reperfusion 2 h.Baseline value of LV ejection fraction(EF)(60±4%in group 1,61±5%in group 2)was normal in both groups(P>0.05).EF declined violently at reperfusion 0 h(to 37±5%and 47±3%,both P<0.05 vs.baseline)(group 1 first),and maintained a plateau from reperfusion 0 h to 2 h,but EF in group 1 was lower than group 2(P<0.05).Regional left ventricular anterior wall thickening(LVAWT)rose obviously from baseline to reperfusion 2 h in group 1(from 4.43±0.64 mm to 6.71±0.82 mm,P<0.05)and in group 2(from 4.20±0.42 mm to 5.20±0.63 mm,P<0.05).The peak early filling velocity(E-wave)decreased,and late diastolic filling velocity(A-wave)increased.The E/A ratio<1 was measured in reperfusion 2 h in group 1,but E/A ratio?1 in group 2.Left ventricular aneurysms were found in 3 pig hearts in group 1 with the mean area of 13 mm×8 mm in reperfusion 2 h.No ventricular aneurysm was found in group 2.ConclusionsReperfusion followed continuous or intermittent occlusion could result IMR increasing,while ischemia continuously induced higher IMR value than that of intermittent.3.Treatment methods of CMD after experimental acute myocardial infarctionObjects and Methods30 pigs with CMD after acute myocardial infarction were randomly and equally divided into five groups,and different solutions were injected into LAD of each group pigs via IC bolus immediately after IMR measurement at 2 h of reperfusion-Injections included 5 ml of normal saline,10 ug of alprostadil,200 ug of nitroglycerin,2 mg of nicorandil or 200 ug of sodium nitroprusside.IMR was measured 10 minutes after injections.The same doses of each solution were injected into each pig once a day via the jugular vein during the next 6 days.IMR and cardiac function were measured on day 7.Normal areas,infarct areas and areas at risk were differentiated and compared by TTC-Evans blue staining.ResultsIMR decreased sharply 10 minutes after alprostadil,nicorandil or sodium nitroprusside IC injections(allP<0.05),but not after nitroglycerin or normal saline injections(both P>0.05).After 7 days,the IMR of both the alprostadil group and the nicorandil group was much lower than that of the normal saline group,(both P<0.05),but there was no significant difference in the IMR of the nitroglycerin group and the sodium nitroprusside group,(both P>0.05).There was no significant difference in EF or left ventricular end-systolic dimension(LVDs)or left ventricular end-diastolic dimension(LVDd)at baseline and 2 h of reperfusion among five groups(all P>0.05).After 7 days,EF in both the alprostadil group and the nicorandil group was much higher than that of normal saline group(both P<0.05).The differences in LVDd and LVDs among the five groups were similar to the differences in EF.Infarct areas in the alprostadil group and in the nicorandil group were much smaller than that of the normal saline group,(both P<0.05).ConclusionsInfusion of alprostadil or nicorandil improved coronary circulation function,reduced infarct areas and limited left ventricular dilatation in a pig CMD model after STEMI.General conclusionsIC bolus ATP 240 ug or nicorandil 4 mg is an effective and safe method for measuring IMR in the pig model,while alprostadil is not suitable for inducing coronary maximal hyperemia because of BP reduction violently for a long time after IC bolus.Reperfusion followed continuous or intermittent occlusion could result IMR increasing,while ischemia continuously induced higher IMR than that of intermittent.IC bolus alprostadil or nicorandil improved coronary circulation function,reduced infarct areas and limited left ventricular dilatation in a pig CMD model after STEMI. |
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