| Myocardial reperfusion injury occurs during primary and selective percutaneous coronary intervention(PCI) with acute ST segment elevation myocardial infarction(STEMI). Despite verified opening of the occluded epicardial coronary vessel, the distal flow to the myocardium is severely impaired, resulting in a total loss of microcirculation in some areas. Reperfusion may also cause reversible injury, stunning and arrhythmias, as well as irreversible lethal reperfusion injury. Reperfusion itself has the potential to initiate additional lethal injury. The no-reflow phenomenon and reperfusion arrhythmia are depicted as manifestations of reperfusion injury. Despite improvement in revascularization strategies, myocardial reperfusion injury occurs during PCI with acute STEMI still represents an adverse outcome. How to accurately and rapidly identify the clinical predictors of no reflow, how to fully and effectively reduce the reperfusion arrhythmia, are still need more research. Identifing high risk population by analyzing the clinical, electrical and angiographic factors associated with the no-reflow phenomenon is beneficial to reduce the incidence of no-reflow. However, a fast-track screening tool contains common risk factors and relatively simple to use is not available with STEMI undergoing PCI in Chinese.A lot of drug had been used to reduce no reflow, such as diltiazem, verapamil, adenosine and sodium nitrate might step down heart rate or reduce blood pressure, which inhibited the application. Our previous studies showed that intracoronary administration of anisodamine could reverse the no-reflow phenomenon by increasing coronary perfusion pressure, improving coronary blood flow and myocardial perfusion in STAMI treated with primary PCI. It is especially suitable for patients with bradycardia or hypotension. Whether intracoronary administration of anisodamine and diltiazem might result in synergistic effects and safety in STEMI patients was need to be study.The aim of this study was to access the high risk factors of the no reflow phenomenon during PCI, to establish a bedside available risk scoring system of no reflow at the acute stage of STEMI,and to establish risk stratification for the occurrence of no reflow and analyze the probability and importance of independent risk factors. Moreover, we aimed to discuss the protective effects of intracoronary anisodamine administration in STEMI patients with high risk factors during PCI, and to examine the role of intracoronary anisodamine and diltiazem administration during primary angioplasty on the immediate angiographic results and clinical course.Part I Risk Accessment of the No-reflow Phenomenon in Patients with Acute STEMI undergoing PCIObjectives: To access the high risk factors for the no reflow phenomenon during primary or selective PCI in patients presenting with acute STEMI, to establish a bedside available risk scoring system of no reflow at the acute stage of STEMI and to analyze the probability and importance of independent risk factors.Methods: Between Jan 2012 and Dec 2012, data from patients with STEMI and successfully treated with PCI were analyzed as the model group. According to thrombolysis in myocardial infarction(TIMI) flow grade and TIMI myocardial perfusion grade(TMPG), patients were divided into two groups: no-reflow group and normal blood flow group. The no reflow phenomenon was defined as a final TIMI flow ≤2 or final TIMI flow of 3 with TMPG<2. All clinical data, angiography findings were compared to analyze the risk factors contributing to no-reflow. Multivariable binary logistic regression analysis was used to identify independent no-reflow predictors of the model group. A classification and regression tree(CART) technique was employed in the analysis of independent risk factors for no reflow. Finally, we designed a score according to the odds ratio on logistic regression analysis,established risk stratification and selected no reflow high-risk patients with myocardial infarction. Between Jan 2013 and Jun 2013, data(factors selected by univariate analysis) from patients with STEMI undergoing primary PCI were analyzed as the validation group. The authenticity and reliability of the logistic regression courses were validated using receiver operator characteristic curve(ROC) and Hosmer-Lemeshow goodness-of-fit.Results: The no-reflow phenomenon was found in 199(37.5%) of 530 patients. Univariate analysis showed that the older, female, Killip classification, primary PCI, thrombolysis, infarct-related vessel, preprocedure TIMI flow, thrombus burden pre-PCI and pain to ballon time were correlated with no reflow(P<0.05). Multivessel disease was seen more in normal reflow group(P>0.05). Thrombus aspiration, use of IABP, use of temporary pacemaker were common treatments(P<0.05). The percentage of neutrophi, neutrophil count(109/L) and lymphocyte count(109/L) in the no reflow group were significantly higher than those in the normal flow group(67.1% vs 62.6%, P<0.0001; 6.3 vs 5.3, P=0.0004; 1.6 vs 1.9, P=0.001).Multivariate logistic regression analysis demonstrated that female [odds ratio(OR)=0.639, P=0.045], Killip class of myocardial infarction≥2(OR=3.548, P<0.001), TIMI flow≤2 before primary PCI(OR=0.817, P=0.038), thrombus burden score≥4 on baseline angiography(OR=2.910, P<0.001), pain to ballon time>6 hours(OR=1.485,P=0.083) were independent correlate predictors of no-reflow phenomenon in the STEMI after PCI. The risk score system demonstrated a good risk prediction in the model group with a c-statistic of 0.720 [95% confidence interval(CI): 0.675-0.765] based on ROC analysis. Multivariate logistic regression analysis had no significant difference by Hosmer-Lemeshow goodness-of-fit(X2=1.027, P=0.994).Classification and regression tree analysis showed that the probability of no reflow in patients with Killip class ≥2 was more than twice the probability in patients with Killip class 1(73.2% vs 33.3%). The probability of no occurrence of no reflow in patients with Killip class I was more than two point five times in patients with Killip class ≥2(66.7% vs 26.8%)(P=0.030). The probability of no reflow in patients with Killip class I and thrombus burden score ≥4 was more than twice in patients with Killip class I and thrombus burden score <4(P=0.023). Killip classification is the strongest predictors of no reflow with STEMI undergoing PCI, thrombus burden is important predictors to determine whether no reflow would occur.To establish a no reflow scoring system with STEMI undergoing PCI according to the OR on logistic regression analysis. Risk factors for risk assignment: female counts as 1 point, cardiac function Killip classification ≥2 counts as 4 points, TIMI flow≤2before primary PCI counts as 1 point, thrombus burden score ≥4 on baseline angiography counts as 3 points and pain to ballon time >6 hours counts as 2 points. Risk stratification: total value < 2 was ranked as low risk level, and 2-5 was ranked as the risk level, >5 as high risk level.The risk score system demonstrated a good risk prediction in the validation group with a c-statistic of 0.911(95% CI: 0.86-0.97) based on ROC analysis. Multivariate logistic regression analysis showed no significant difference by Hosmer-Lemeshow goodness-of-fit(X2=2.550, P=0.636). ROC analysis in the validation group was applied to killip class, thrombus burden, the no reflow score and risk stratification in the validation group, the no reflow score was more accurate, with a larger area under the curve( c-statistic=0.890, 95% CI:0.822-0.959).Conclusions:1 Female, Killip classification≥2, preprocedure TIMI flow≤2, score of thrombus burden pre-PCI>4 and pain to balloon time >6 hours were independent predictive factors of no reflow in patients with STEMI undergoing PCI.2 Killip classification was the strongest predictor of no reflow with STEMI undergoing PCI, thrombus burden was important predictor to determine whether no reflow would occur.3 Risk stratification of no reflow according to risk score system was helpful to identify high risk patients with STEMI undergoing PCI.Part II Protective Effects of Anisodamine for High Risk Patients during Primary PCI in Acute STEMIObjectives: To assess the benefit of intracoronary anisodamine administration on myocardial reperfusion as compared with control for high risk patients during PCI in acute STEMI.Methods: This study was a single center, prospective, randomized, placebo control study. Between Jun 2013 and Sep 2014, STEMI patients who underwent successful PCI were randomized to two groups: intracoronary administration of anisodamine 200 ug each time until the total injection to 2 mg or heart rate up to 120 times per minute(anisodamine group, n=122) or saline(5ml)(control group, n=122) before stenting(TIMI>0 before intracoronary injection). Patients in the trial were classified as low, intermediate, and high risk according to the no reflow risk score based on 5 clinical variables. Clinical data, angiography findings and follow-up data were analyzed. The primary endpoint was the incidence of the no reflow phenomenon(which was defined as a final TIMI flow<3) immediately after stenting. The secondary endpoints were the occurrence rates of reperfusion arrhythmia.Results: There was no statistically significant difference in the clinical data including no reflow risk category and coronary radiography between the two groups before the operation. Before reperfusion there were 70-80% patients with TIMI flow grade<3, after reperfusion among 86(35.2%) patients with TIMI flow grade<3. The rates of patients classified as low risk, intermediate risk and high risk were 2.9%, 4.1% and 28.3%(X2=66.6, P=0.000). The rate of TIMI flow grade<3 in the high risk patients randomized to the anisodamine group was significantly lower than that in control group(RR:2.507,95% CI: 1.124 to 5.591, X2=5.157, P=0.023). The risk score system demonstrated a good risk prediction in the model group with a c-statistic of 0.815 based on ROC analysis. Multivariate logistic regression analysis demonstrated no significant difference by Hosmer Lemeshow goodness-of-fit(P=0.529).In the anisodamine and control arms, the rates of ventricular premature contraction were 6.6% and 24.6%, the rates of ventricular tachycardia were 8.2% and 18.0%(X2=15.086, P=0.000; X2=5.179, P=0.023, respectively). There was only one patient occur ventricular fibrillation in the control group. The rates of bradycardia arrhythmia were 9% and 25.4%(X2=11.504, P=0.001). No-reflow risk stratification for patients with intermediate risk was 2 cases(1.6%) in the anisodamine group and 12 cases(9.8%) in the control group(P=0.009). Patients with high risk was 6 cases(4.9%) in the anisodamine group and 14 cases(11.5%)(P=0.046) in the control group. The levels of hs CRP in the anisodamine group was significantly lower than those in the control group(12.1±17.7 vs 19.5±31.7,-2.248, P=0.026). High risk patients in the anisodamine group had the tendency of left ventricular ejection fraction higher than those in the control group(56.4±10.9% vs 53. 2±8.7%, t=-1.699, P=0.092), left ventricular fractional shortening in these two group were 30.2±5.3 vs 28.0±6.4,(t=-2.028, P=0.045). There was no difference in Kaplan–Meier curve of MACEs free survival rate between the two groups at 6 month(log-rank X2=2.515, P=0.113).Conclusions:1 Intracoronary administration of anisodamine contributed to improve immediate coronary epicardium flow and myocardial referfusion, especially in patients with high risk.2 Intracoronary administration of anisodamine prevented arrhythmia rates in patients with STEMI undergoing primary PCI. Patients in high risk category got the most significantly protecive effect of reperfusion arrhythmia and trended to improving heart remodeling.3 Intracoronary administration of anisodamine trended to improving prognosis of patients with STEMI undergoing primary PCI.Part III Protecive Effect of Intracoronary Anisodamine and Diltiazem Administration during Primary PCI in Acute STEMIObjectives: The aim of this study was to examine the role of intracoronary anisodamine and diltiazem administration performed before stenting on the immediate angiographic and clinical outcome in patients with STEMI undergoing primary PCI.Methods: This study was a prospective, randomized, control study. Between Jan 2012 and Dec 2012, STEMI patients who underwent successful primary PCI were randomized to two bolus injections of intracoronary anisodamine(1mg/5m L) and diltiazem(2mg/5m L)(COM group, n=54) or saline(5ml) and diltiazem(2mg/5ml)(diltiazem group, n=54) before stenting(TIMI>0 before intracoronary injection). The primary endpoint was the incidence of the no reflow phenomenon(which was defined as a final TIMI flow<3) immediately after stenting. TMPG and corrected TIMI frame count(c TFC) were assessed. A 12-lead electrocardiogram was assessed at baseline and 90 min after primary PCI. The existing ST-segment deviation in the single ECG had a maximum deviation of 90 min on judging myocardial reperfusion after primary angioplasty. Categorization in ST-segment resolution of the single lead with maximum deviation of ST-segment elevation was used as an indirect measure of myocardial reperfusion. Blood samples were obtained in all patients before and after PCI for creatine kinase-MB, cardiac troponin I, high-sensitivity C-reactive protein(hs CRP) and N-terminal prohormone brain natriuretic peptide(NT-pro BNP). Two-dimensional echocardiography was performed within 7 days of presentation and repeated at the 6-month follow-up. The secondary endpoints were MACEs including death, nonfatal myocardial infarction, and target vessel revascularization. Statistical analysis was carried out using the Statistical Package for IBM SPSS Statistics 19.0 and Med Calc statistical software 12.3.0.Results: There was no significantiy statistical difference in the clinical data between the two groups before the operation. The percent of TIMI flow grade 3 was found to be significantly higher in the COM group than that in the diltiazem group(92.6 vs 75.9%, P=0.032). CTFC was significantly lower in the COM group than that in the diltiazem group immediately after PCI(30 vs 44, P<0.0001). The percent of TMPG 3 observed immediately after PCI was 46.3% in the diltiazem group, which was 68.5% in the COM group(P=0.032).Resolution of single lead ST-segment elevation(>70%) was more frequently observed in the COM group than in the diltiazem group(74.1% vs 46.3%, X2=10.017, P=0.007). The level of hs CRP in the COM group was significantly lower than those in the diltiazem group(7.7±0.8 vs 9.3±1.1, P<0.001). The COM group showed low incidences of bradyarrhythmia and rapid arrhythmia(7.4% vs 24.1%, P=0.032 and 3.7% vs 18.5%, P=0.029, respectively). The rates of heart related complication were basically the same between the two groups. No bleeding events, in hospital death and contrast interralated nephropathy occured.Left ventricular ejection fraction at 6 month after PCI was 59.2±12.3% in patients randomized to intracoronary anisodamine and diltiazem versus 51.2±13.4% in the group with only diltiazem(P=0.002). There were no significant differences in the secondary outcome. There was no difference in Kaplan–Meier curve of MACEs free survival rate between the two groups at 6 month(log-rank X2=2.853, P=0.091).Conclusions:1 Preventively intracoronary administration of anisodamine and diltiazem could significantly improve immediate coronary epicardium flow and myocardial reperfusion, inhibit myocardial necrosis and reduce inflammatory response.2. Anisodamine combined with diltiazem could prevent arrhythmia rates in patients with STEMI undergoing primary PCI, which had good feasibility and safety.3 Medium-term follow-up showed that anisodamine combined with diltiazem could protect cardiac function, and inhibit the ventricular remodeling of patients with STEMI undergoing primary PCI. |
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