| For patients with acute myocardial infarction(AMI), rapid, complete and sustained coronary reperfusion with full myocardial tissue perfusion is the effective reperfusion therapy. Percutaneous coronary intervention(PCI) can restore coronary blood flow of epicardial by opening occlusion of infarct related arteries. As an effective means of treatment of AMI, primary PCI reduced the mortality and disability rates significantly. However, studies have found that about 10%-30% patients after primary PCI had no reflow(NR) phenomenon. Coronary angiography(CAG) showed that epicardial blood vessel restored antegrade flow well after relieving coronary artery stenosis or spasm, but myocardium failed to get a good myocardial tissue reperfusion, which greatly reduced the benefits of PCI. How to identify it early, to prevent the occurrence of no reflow and to improve the prognosis of patients, which have important significance for AMI patients and have become an important problem that clinical cardiovascular physicians are facing.Nicorandil can keep the activation of adenosine triphosphate- sensitive K(KATP) channel and induce production of Nitrates-like effects(elevating c GMP without nitric oxide(NO) generation), which lead to dilatation of coronary microcirculation, ischemic preconditioning, antiarrhythmia and reduction of reperfusion injury. The use of intravenous nicorandil in patients with AMI undergoing PCI is effective in improvement of left ventricle systolic function and reduction of no-reflow and slow flow. However, studies of intracoronary nicorandil administration in patients with AMI are rare.Anisodamine, which is a drug with multi-pharmacological effects, can keep stability of the hemodynamic states, dilate the coronary microvascular, improve the microcirculation and increase heart rate, blood pressure, coronary perfusion pressure and heart inotropy. Our previous studies found that intracoronary administration of anisodamine was effective in reversing the NR after primary PCI. However, studies of intracoronary administration anisodamine combined with nicorandil in patients with AMI are rare, the safety, correct method and dosage of administration are unknown.Contrast-induced nephropathy(CIN), as the important side effects, is caused by the application of contrast agent during CAG or PCI process, which has gradually been known at present. For patients with primary PCI, the incidence of CIN is about 10%-20%, which may be higher in the high-risk population. With the incidence of diabetes increased gradually, patients with AMI undergoing PCI were the high risk population. The incidence of CIN post PCI increased than before, but the incidence of CIN was unclear. The effect and possible mechanism of intracoronary administration anisodamine and nicorandil on CIN weren′t exact.The occurrence of NR and CIN after PCI are caused by cardiac and renal microcirculation perfusion injury. Anisodamine and nicorandial, as agents with multi-pharmacological effects, increase tissue micro- circulation perfusion through different ways and mechanisms. We speculate that, for ST segment elevation myocardial infarction(STEMI) patients undergoing PCI, intracoronary administration nicorandil and anisodamine will produce heart and kidney synergistic protective effects.This study is divided into three parts: The first part is main to investigate the preventive effect and possible mechanisms of intracoronary administration of nicorandil with different doses on no reflow in AMI. The objective of the second part is to assess the effect of anisodamine and nicorandil regimens on prevention of NR and amelioration of myocardial reperfusion in patients with AIMI undergoing primary PCI. In the third part, AMI patients combined with diabetes undergoing primary PCI are the research objects, the objective is to explore the incidence of CIN, to assess the preventive effect and possible mechanism of intracoronary administration anisodamine and nicorandil. Part I Beneficial effects of intracoronary administration different doses nicorandil on myocardial reperfusion for patients with STEMI undergoing primary PCIObjectives: To investigate the possible mechanism and whether preventively intracoronary administration of different doses of nicorandil can reduce no reflow(NR) phenomenon and protect myocardial tissue reperfusion for acue myocardial infarction(AMI) patients undergoing primary percutaneous coronary intervention(PCI).Methods: This study adopted prospective and randomized control study method, patients suffering from ST segment elevation myocardial infarction(STEMI) first time within 12 hours undergoing primary PCI were enrolled in this study. Eligible patients were randomly divided into three groups: control group(Group C), intracoronary administration of 3ml saline before opening IRA; the standard dose of nicorandil group(Group SN), preventively intracoronary administration of 2mg/3ml nicorandil before opening IRA; large dose of nicorandil group(Group HN), preventively intracoronary administration of 4mg/3ml nicorandil before opening infarct-related artery(IRA). All patients underwent coronary angiography(CAG) and / or PCI. Coronary systolic, diastolic and mean pressures were recorded before and after nicorandil administration. All quantitative coronary angiography perfusion indexes [including the initial thrombolysis in myocardial infarction(TIMI), corrected TIMI frame count(CTFC), TIMI myocardial perfusion grade(TMPG) and thrombus scores] were judged by two interventional cardiologists. Myocardial infarct size was estimated by peak levels of creatine kinase-MB(CK-MB) and tropnin I(c Tn I) which were determined before and after PCI. Electrocardiography was recorded both on admission and at 90 min after PCI. A decrease in the sum of ST-segment elevation by ≥ 70% was categorized as complete ST-segment resolution(STR). Cardiac function was evaluated left ventricular ejection fraction(LVEF) through echocardialgraphy. The serum levels of high sensitive-C reactive protein(hs-CRP) and mean platelet volume(MPV) were compared in three groups. The incidence of major adverse cardiovascular events(MACEs) was recorded after PCI and during the period of hospitalization. All calculations were computed with the aid of SPSS statistical software(version 16.0). P values of less than 0.05 were considered statistically significant.Results: A total of 121 patients were randomly divided into Group C(n=42), Group SN(n=40) and Group HN(n=39). After PCI, the proportion of TIMI 3 in large dose of nicorandil group and standard dose of nicorandil group was higher than that in control group(73.8% vs. 82.5% vs. 82.1%, P=0.047), so were the TMPG 3 and STR(TMPG 3: 61.9% vs. 77.5% vs. 79.5%, P=0.046; STR: 66.7% vs. 80.0% vs. 82.1%, P=0.042). After PCI, the LVEF of both nicorandil groups is higher than that of control group, they have reached statistical significance(51.9±4.5% vs. 56.3±3.8% vs. 58.1±3.8%, P=0.021). Peak CK-MB and c Tn I after PCI were lower than those of the control group, the differences were statistically significant(CK-MB: 281.9 ± 56.5U/L vs. 188.6±65.5U/L vs. 171.9±42.3U/L, P=0.053; c Tn I: 64.8±19.8 ng/ml vs. 53.4±21.1ng/ml vs. 50.2±18.1ng/ml, P=0.046). After 24 h of PCI, the levels of serum hs-CRP and MPV in both nicorandil groups were significantly lower than those in control group(hs-CRP: 16.1±3.2mg/L vs. 13.2±2.8mg/L vs. 12.6±4.5mg/L, P=0.038; MPV: 9.9±1.7fl vs. 9.2±1.3fl vs. 9.1±1.6fl, P=0.045). But between large dose of nicorandil group and standard dose of nicorandil group, the proportion of TIMI 3 and TMPG 3, the coronary artery pressure, heart rate, indexes of echocardiography and laboratory examination were not significant difference. The incidence of MACE in three groups was not significant difference. Multivariate Logistic regression analysis showed that low coronary diastolic blood pressure and thrombus scores 4/5 were risk factors of poor myocardial perfusion, while different doses of nicorandil administration was the protective factor.Conclusions:1 Preventively intracoronary administration different doses of nicorandil can improve myocardial perfusion, prevent myocardial injury and decrease the incidence of NR;2 Nicorandil can inhibit the inflammatory response after PCI, which should be benifit to protect and improve the myocardial microcirculation in the infarction area;3 Nicorandil can protect myocardium after PCI, so as to improve cardiac function and prognosis of patients;4 Intracoronary administration nicorandil was safe. But in some certain ranges, intracoronary administration nicorandil did not show a significant dose effect relationship. Part Ⅱ Intracoronary administration of anisodamine and nicorandil in individuals undergoing primary percutaneous coronary intervention for acute inferior myocardial infarction: a randomized factorial trialObjectives: To assess the effect of anisodamine and nicorandil regimens on prevention of NR and amelioration of myocardial reperfusion in patients with acute inferior myocardial infarction(AIMI) undergoing primary PCI.Methods: A total of 104 consecutive patients with AIMI presented within 12 h from symptom onset undergoing primary PCI were enrolled into this prospective randomized controlled study. The study population was divided into four groups: Control group(Group A), treated with PCI only; Anisodamine group(Group B), treated with intracoronary anisodamine 2mg/3ml; Nicorandil group(Group C), treated with intracoronary nicorandil 2mg/3ml; Anisodamine and nicorandil group(Group D), treated with intracoronary nicorandil and anisodamine 2mg/3ml respectively. Patients underwent PCI by transradial artery access. The initial TIMI, final TIMI / CTFC and TMPG were evaluated. Coronary systolic, diastolic and mean pressures were recored before and after anisodamine and nicorandil administration. Infarct size was estimated by peak levels of CK-MB and c Tn I, which were determined before and every 4h after the procedure. A decrease in the sum of ST-segment elevation by ≥ 70% was categorized as complete STR and used as an indirect measure of myocardial reperfusion after PCI. The primary end point was the incidence of TMPG 3 after the procedure. MACEs was evaluated during the hospital stay and 30 d after discharge. P values of less than 0.05 were considered statistically significant. All calculations were computed with the aid of SPSS statistical software(version 16.0).Results: A total of 104 patients were randomly divided into four groups. After the procedure, the proportion of TMPG 3 was significantly higher in group D than that in other groups(65.4% vs. 80.8% vs. 76.9% vs. 88.5%, P=0.014); the proportions of postprocedural TIMI 3 and complete STR were the highest in group D, but no statistical differences were achieved, only a trend(TIMI 3: 76.9% vs. 84.6% vs. 80.8% vs. 92.3%, P=0.067; STR: 65.4% vs. 80.8% vs. 80.8% vs. 96.2%, P=0.052). The peak CK-MB and c Tn I were the lowest and LVEF was highest three days after the procedure in group D(CK-MB: 281.9±56.5U/L vs. 243.7±58.1U/L vs. 258.6±65.5U/L vs. 141.9±42.3U/L, P<0.001; c Tn I: 64.8±19.8ng/ml vs. 56.9±18.9ng/ml vs. 61.4±21.1 ng/ml vs. 50.2±18.1 ng/ml, P=0.005; LVEF: 51.9±4.5% vs. 56.8±4.7% vs. 49.3±3.8% vs. 58.1 ±3.8%, P<0.001). Nicorandil had no obvious effect on vital signs during and after the procedure. Anisodamine elevated blood pressure(BP) and heart rate(HR). The MACEs during hospitalization and 30 days follow up after discharge did not differ among these four groups. The result of multivariate Logistic analysis displayed that thrombus scores 4/5 and low DBP before administration of anisodamine and nicorandil were the independent risk factors for poor myocardial reperfusion(expressed as TMPG < 3), while anisodamine and nicorandil 2 mg before PCI were protective for optimal myocardial reperfusion after the procedure.Conclusions:1 Preventively intracoronary administration of anisodamine combined with nicorandil can improve coronary blood flow and myocardial reperfusion, reduce the incidence of NR, narrow myocardial infaction size, protect cardiac function in patients with AIMI undergoing primary PCI;2 Preventively intracoronary administration of anisodamine combined with nicorandil before PCI is protective for optimal myocardial reperfusion after the procedure, which has synergistic effect along with clinical feasibility without serious adverse reaction;3 Intracoronary administration of anisodamine combined with nicorandil can be used as a protective factor, which can improve myocardial reperfusion after PCI, while thrombus scores 4/5 and decreased coronary diastolic blood pressure were independent risk factors for poor myocardial reperfusion. Part ⅢPreventive effect of anisodamine combined with nicorandil on contrast-induced nephropathy in AMI-PCI patients complicated with type 2 diabetesObjectives: To investigate the possible mechanism and whether preventively intracoronary administration of anisodamine and nicorandil can reduce the incidence of contrast-induced nephropathy(CIN) and protect renal function in acute myocardial infarction patients with type 2 diabetes undergoing primary PCI.Methods: Consecutive AMI patients complicated with diabetes presented within 12 h of symptom onset undergoing primary PCI were enrolled into this randomized controlled study. The study population was divided into two groups: Group A(68 cases), treated with intracoronary 2mg/3ml of anisodamine and 2mg/3ml of nicorandil; Group B( 72 cases), treated with intracoronary 2mg/3ml of nicorandil and saline 3ml. The non-ionic contrast agent was used in all patients during operation. The dose of contrast was recorded after PCI. In all enrolled patients, an intravenous infusion of 0.9% saline at a rate of 1ml/kg/h(0.5ml/kg/h for patients with LVEF<40%) was administered at least 8 hours before and after PCI. The primary endpoint was the incidence of CIN, defined as >44.2μmol/L increase or >25% rise in serum creatinine(SCr) concentration within 48 hours of contrast exposure compared to baseline. Blood samples were collected at baseline and 96 h after PCI for the measurement of SCr and the caculation of estimated glomerular filtration rate(e GFR) by using the MDRD study equation. Serum hs-CRP, NT-pro BNP, the neutrophil to lymphocyte ratio(NLR) and the mean platelet volume(MPV) before and after PCI was compared between two groups. All calculations were computed with the aid of SPSS statistical software(version 16.0). P values of less than 0.05 were considered statistically significant.Results: A total of 140 patients were randomly divided into Group A(n=68) and Group B(n=72).The level of SCr in both groups increased gradually at 24 h after PCI, reached the peak at 72 h, and began to recover at 96 h after the operation. The values of SCr in group A at 48 h, 72 h and 96 h after PCI were all significantly lower than those of group B(90.6±12.2μmol/L vs. 95.4±14.8 μmol/L at 48 h, P=0.039; 93.4±14.5μmol/L vs. 113.5±20.6μmol/L at 72 h, P<0.001; 89.3±13.3 μmol/L vs. 99.5±16.7μmol/L at 96 h, P<0.001). The level of e GFR in two groups decreased significantly at 24 h after PCI, reached the trough at 48 h, and began to recover at 72 h after the operation. There were significantly difference of e GFR at 24 h and 48 h after PCI compared with baseline in two groups. The values of e GFR in group A at 24 h, 48 h and 72 h after PCI were significantly higher than those of group B(64.3±14.5 vs. 59.7±12.8 at 24 h, P=0.039; 60.2±11.4 vs. 56.1±11.1 at 48 h, P=0.033; 64.9±13.2 vs. 60.2±13.1 at 72 h, P=0.038). In group B, the incidence of CIN was higher than that in group A(7.4% vs. 19.4%, P=0.037). After primary PCI, the incidence of NR in group A was obviously less than group B(5.9% vs. 16.7%, P=0.045).There was no significant difference in baseline NT-pro BNP levels between the two groups. Compared with the baseline, the level of NT-pro BNP at 24 h after PCI increased, there was statistical significance in group B compared with the baseline(789.7±57.9pg/ml vs. 532.3±52.7 pg/ml, P<0.05), the level of NT-pro BNP in group B at 24 h after PCI was dramaticly higher than that in group A(789.7±57.9pg/ml vs. 612.6±53.2 pg/ml, P<0.001). Compared with baseline before PCI, the levels of inflammatory markers increased at 24 h after PCI, but in group A, they were significantly lower than those in group B(hs-CRP: 14.5±1.8mg/L vs. 22.6±2.3mg/L, P<0.001; NLR: 7.3±2.5 vs. 8.7±2.2, P=0.001; MPV: 9.8± 1.9fl vs. 11.4±1.4fl, P<0.001).Conclusion:1 Preventively intracoronary anisodamine combined with nicorandil can protect renal function in AMI patients complicated with type 2 diabetes after PCI, reduce the incidence of CIN;2 Anisodamine combined with nicorandil can significantly inhibit the inflammatory response after PCI, which may be one of the main mechanisms for protecting renal function and reducing the occurrence of CIN;3 AMI-PCI patients complicated with diabetes are high risk population of CIN. The e GFR is the useful index for accuratly detecting the earlier changes of renal function. |
PDF Full Text Request