| Primary percutaneous coronary intervention (PCI) has become animportant strategy for the opening of the infarct-related artery (IRA) and therestoration of the coronary blood supply within a short period in acutemyocardial infarction (AMI). But still10%to30%of patients present thateven after the opening of the IRA, it also fails to restore effective myocardialperfusion, which means existence of no-perfusion-microcirculatorydisorder (NP-MCD) and ischemia-reperfusion injury-microcirculatorydisorder (IRI-MCD). This causal interaction of the above twopathophysiologic processes leads to the deterioration of myocardial injury,which indicates no-reflow phenomenon after PCI in clinical settings.At present, for the treatment of myocardial NP-MCD/IRI-MCD, themain strategy is “downstream salvage intervention”, that is thepharmaceutical/mechanical intervention during and after PCI. How to adopt“upstream prevention intervention”, referring to the pharmaceuticalintervention before the opening of the IRA and the restoration of the coronaryblood supply, thereby achieve the accommodation of myocardialmicrocirculation in the infarct-related region to the change of reperfusion,relieve and prevent myocardial NP-MCD/IRI-MCD after the opening of theIRA, is an important topic currently uninvolved in interventional cardiology athome and abroad.Anisodamine, an alkaloid with multiple pharmacological effects, isisolated from the Solanaceae tanguticum Belladonna in China. It has beenshown that anisodamine has abilities in the expansion of microvessels,regulation of systolic and diastolic functions of the capillary sphincters andimprovement of microcirculatory perfusion. In addition, large dose of anisodamine is safe without serious side effects. Our previous animalexperiments and clinical studies showed first at home and abroad that:intracoronary administration of anisodamine could effectively reverse theno-reflow phenomenon by increasing coronary perfusion pressure, improvingcoronary blood flow and myocardial perfusion in AMI treated with primaryPCI.Acute inferior myocardial infarction (AIMI) is usually associated withunstable hemodynamic states such as hypotension, bradycardia, high vagustone and so on. Therefore, the circulatory collapse, reperfusion injury andserious arrhythmias like severe atrioventricular block in addition to no-reflowphenomenon possibly happen during primary PCI. As a result, major adversecardiovascular events increase, which severely influences the clinicalprognosis. After comprehensive analysis of the features of AIMI andanisodamine, it is speculated that: anisodamine, a drug withmulti-pharmacological effects, is especially suitable for AIMI.The benefits of statins in acute coronary syndromes (ACS) are seen early,before substantial lipid lowering has occurred. This suggests that pleiotropiceffects of statins, not lipid-lowering effects, are responsible for these earlybenefits. These pleiotropic effects may include improvement in endothelialfunction, anti-inflammatory effects, decrease in oxidative stress, vasodilationof coronary microvessels, and inhibition of thrombogenic response.The growing number of interventional procedures requiring contrastmedia has triggered a parallel increase of contrast-induced nephropathy (CIN).CIN is the third leading cause of hospital-acquired acute renal failure inadmitted patients; it greatly decreases the efficacy of PCI and results inadverse short-and long-term outcomes.This study consists of three parts: part I and II, regarding AIMI as studypopulation, explore the protective effects of preventively intracoronaryadministration of different doses of anisodamine combined with differentdoses of atorvastatin on myocardial reperfusion and cardiac function after PCI;the third part, evaluate the preventive and protective effects of high-dose atorvastatin pretreatment on CIN following PCI, all of which will providevaluable references for the comprehensive heart-kidney protections duringAMI-PCI in clinical settings.Objectives: To investigate whether preventively intracoronaryadministration of anisodamine before the opening of the infarct-related artery(IRA) can reduce/avoid no-reflow phenomenon and improve myocardialreperfusion and heart function in acute inferior myocardial infarction (AIMI)treated with primary percutaneous coronary intervention (PCI).Methods: It was a single-center prospective randomized controlled studywhich enrolled patients suffering from AIMI within12hours undergoingprimary PCI from September2009to June2012. Eligible patients wererandomly divided into two groups: anisodamine group,72cases, preventivelyintracoronary administration of anisodamine1500μg/3ml before the openingof the IRA; control group,71cases, intracoronary administration of saline3ml.All patients underwent coronary angiography (CAG) and/or PCI bytransradial artery approach. All quantitative coronary angiography tissueperfusion indexes [including the initial thrombolysis in myocardial infarction(TIMI), postoperative TIMI, corrected TIMI frame count (CTFC) and TIMImyocardial perfusion grade (TMPG)] were judged by two interventionalcardiologists. Coronary systolic, diastolic and mean pressures were measuredby invasive catheterization before and1min,5min,10min after anisodamineadministration. Myocardial infarct size was estimated by peak levels ofcreatine kinase-MB (CK-MB) and troponin I (cTnI) which were determinedbefore and every4hours after the procedure. Electrocardiography wasrecorded both on admission and at90min after PCI. A decrease in the sum ofST-segment elevation by≥70%was categorized as complete ST-segmentresolution (STR) and used as an indirect measure of myocardial reperfusion and the primary end point of this study. Major adverse cardiovascular events(cardiac death+recurrent MI+target vessel revascularization, MACEs) wereevaluated during the hospital stay and30d after discharge. Repeated measuresanalysis of variance was applied to describe the changes of coronary systolic,diastolic and mean pressures and heart rate over time in anisodamine group.Multivariate logistic regression analysis was used to explore the possiblefactors associated with complete STR. P values (2-sided) of less than0.05were considered statistically significant. All calculations were computed withthe aid of SPSS statistical software (version16.0).Results: After PCI, the proportion of TIMI3in anisodamine group washigher than that in control group (91.7%vs.77.5%, p=0.03), so was theTMPG3(80.6%vs.60.6%, p=0.01). ST segments were significantlyresolved, from10.0±4.2mm to5.8±1.7mm in anisodamine group. Thepercentage of complete STR was statistically different (69.4%vs.50.7%, p=0.03). After intracoronary administration of anisodamine, the coronary bloodpressure and heart rate increased moderately, and there was not any severebradyarrhythmia and tachyarrhythmia. Multivariate Logistic regressionanalysis showed that: low coronary diastolic pressure (p <0.0001, OR=1.298,95%CI=1.155-1.457) and slow heart rate (p=0.002, OR=1.251,95%CI=1.087-1.440) were independent risk factors of incomplete STR, whileanisodamine administration was a protective factor for complete STR (p <0.0001, OR=0.059,95%CI=0.014-0.255). During hospital stay, there wasone patient developing recurrent MI and another patient needing target vesselrevascularization in control group. At the end of30-day follow up, one MACEand5MACEs occurred in anisodamine group and control group respectively(p=0.21).Conclusions:1Preventively intracoronary administration of anisodamine can increasecoronary antegrade blood pressure, regulate and drege INP-MCD, improvemyocardial perfusion and alleviate IRI-MCD as well as no reflow;2Anisodamine can decrease the level of inflammatory mediators, protect and improve myocardial microcirculation;3Anisodamine can save more viable myocardium, reduce infarct size,inhibit ventricular remodeling and protect cardiac function;4Anisodamine has a better feasibility and safety against theINP-MCD/IRI-MCD. Objectives: In acute inferior myocardial infarction (AIMI), many drugsused to improve myocardial microcirculation disorder will significantly reduceblood pressure and coronary perfusion pressure, aggravate bradyarrhythmiaand the hemodynamic states of the whole body, which greatly limits theapplication of these drugs in clinical settings. This study was to assess theefect of various anisodamine (3000μg vs.1500μg) and atorvastatin (80mg vs.20mg) regimens on prevention of no-reflow and amelioration of myocardialreperfusion in patients with AIMI undergoing primary percutaneous coronaryintervention (PCI).Methods: From September2009to June2012, consecutive patients(n=112) with AIMI presented within12hours of symptom onset undergoingprimary PCI were enrolled into this single-center open-label randomizedcontrolled study. Eligible patients were randomly assigned in a1:1ratio toreceive different regimens: Group A (atorvastatin20mg and anisodamine1500μg, n=28); Group B (atorvastatin20mg and anisodamine3000μg, n=28);Group C (atorvastatin80mg and anisodamine1500μg, n=28); Group D(atorvastatin80mg and anisodamine3000μg, n=28). Patients underwentcoronary angiography (CAG) and PCI by transradial artery access. All the angiographic results [initial thrombolysis in myocardial infarction (TIMI),final TIMI/corrected TIMI frame count (CTFC)/TIMI myocardial perfusiongrade (TMPG)] were evaluated by two cardiologists blinded to the clinicalstatus of the patient and the treatment modality. The incidence of TMPG3after the procedure was defined as the primary end point of this study.Coronary systolic, diastolic and mean pressures were determined by invasivecatheterization before and1min,5min,10min after anisodamineadministration. Myocardial infarct size was estimated by peak levels ofcreatine kinase-MB (CK-MB) and troponin I (cTnI) which were determinedbefore and every4hours after the procedure. Electrocardiography wasrecorded both on admission and at90min after PCI. Complete ST-segmentresolution (STR) was defined as a decrease in the sum of ST-segmentelevation by≥70%. The hepatic function was observed within1month of theprocedure to justify the safety of atorvastatin. Major adverse cardiovascularevents (cardiac death+recurrent MI+target vessel revascularization, MACEs)were evaluated during the hospital stay and30days after discharge.Multivariate Logistic regression analysis was used to explore the possiblefactors associated with the optimal myocardial reperfusion (TMPG3). Forpeak CK-MB and left ventricular ejection fraction (LVEF), factorial designanalysis of variance was applied to elucidate the main effects and interactionsof the two drugs. P values (2-sided) of less than0.05were consideredstatistically significant. All calculations were computed with the aid of SPSSstatistical software (version16.0).Results: After PCI, the proportion of TMPG3was significantly higher ingroup D than that in other groups (p=0.011); the proportions of postoperativeTIMI3and complete STR were the highest in group D, but no statisticaldifferences were achieved, only a trend (p=0.073and0.051respectively).The peak CK-MB and cTnI were the lowest and LVEF three days after theprocedure was highest in group D. Targeting the peak CK-MB, anisodaminecombined with atorvastatin had the synergistic effect in reducing the peakCK-MB level, with statistical significance (p=0.001); while targeting LVEF, anisodamine combined with atorvastatin only had the trend of synergisticeffect in elevating LVEF, without statistical significance (p=0.284).Anisodamine elevated blood pressure and heart rate moderately, except thatone case appeared atrial premature beat in group B, no other severebradyarrhythmia and tachyarrhythmia were observed during and after theprocedure. The follow up during hospitalization and30days after dischargedid not differ among these four groups. Multivariate Logistic regressionanalysis displayed: thrombus score3/4(p=0.041, OR=3.492,95%CI=1.055-11.553) and low coronary diastolic pressure before anisodamine (p=0.049, OR=1.085,95%CI=1.000-1.177) were the independent risk factorsfor poor myocardial reperfusion (expressed as TMPG <3), while anisodamine3000μg before PCI was protective for optimal myocardial reperfusion after theprocedure (p=0.038, OR=0.183,95%CI=0.037-0.912).Conclusions:1Preventively intracoronary administration of different doses ofanisodamine combined with different doses of atorvastatin has dose-effectrelationship. High dose of anisodamine (3000μg) combined with high-dose ofatorvastatin (80mg) can be more effective in the improvement of myocardialperfusion, decrease of the incidence of no-reflow and reduction of infarct size,which suggests that these two drugs have a synergistic effect;2Anisodamine combined with atorvastatin can significantly decreaseinflammatory mediators, protect and improve myocardial microcirculationwith dose-related effect, which may be one of the important mechanisms ofthe improvement of myocardial microcirculatory perfusion;3Anisodamine combined with atorvastatin can effectively protectmyocardial microcirculation, increase the number of viable myocardium,reduce infarct size, inhibit ventricular remodeling, protect cardiac function andimprove clinical prognosis. Objectives: To investigate whether preprocedural high-dose atorvastatindecreases the incidence of contrast-induced nephropathy (CIN) and protectsthe renal function in acute ST-segment elevation myocardial infarction(STEMI) undergoing primary percutaneous coronary intervention (PCI).Methods: This randomized controlled study was conducted at the SecondHospital of Hebei Medical University between January1,2009and December31,2011. We enrolled all consecutive patients with acute STEMI presentedwithin12h of symptom onset undergoing primary PCI (door-to-balloon≤1.5h). Patients in current or previous (within3months) statin treatment, with ahistory of renal and hepatic dysfunction and in dialytic treatment wereexcluded. Eligible patients were randomly assigned in a1:1ratio to receiveatorvastatin (in the emergency room, atorvastatin load80mg p.o. wasadministered to patients who were then immediately transferred to cathlab toundergo coronary angiography and PCI. After the procedure, all patients hadlong-term atorvastatin treatment20mg/day. n=78) or placebo (all theprotocols were same as the atorvastatin group except that the atorvastatin loadwas replaced by placebo80mg p.o. n=83). PCI success was defined as TIMI(Thrombolysis in Myocardial Infarction) grade3flow after procedure andresidual stenosis to <20%by quantitative coronary analysis. The nonioniccontrast (Ultravist370, iodine370mg/ml) was used in all patients.Intravenous hydration was administered to all patients with isotonic saline(0.9%) at a rate of1ml/kg/h before the procedure and for12h after theprocedure. Left ventricular function was evaluated by echocardiography in allpatients within24h of admission. Investigators involved in this study were allblinded to the randomized treatment. CIN was defined as an increase in serumcreatinine (SCr) of>0.5mg/dl (>44.2μmol/l) or25%above baseline. SCr concentration was measured upon admission and every day for the following3days after PCI. Serum cystatin C was tested upon admission and24h afterexposure to the contrast medium. The hepatic function was observed within1month of the procedure to justify the safety of atorvastatin. The primary endpoint was the incidence of CIN. Repeated-measures analysis of variance wasapplied to describe the changes of SCr over time between2groups.Multivariate Logistic regression analysis was used to explore the possiblefactors associated with the decreased risk of CIN. A p value <0.05(2-tailed)was considered statistically significant. All calculations were computed withthe aid of SPSS statistical software (version16.0).Results: During the procedure, the incidence of no-reflow was7.7versus10.8%(p=0.69) and the contrast volume was100.0±25.9versus103.6±26.2ml (p=0.38). Compared with the control group, the postprocedural SCrwas significantly lower (93.4±17.1vs112.6±23.3μmol/L at48h and84.2±14.2vs95.3±17.7μmol/L at72h, both p <0.0001) and peak serum cystatin Cwas lower (0.51±0.14vs0.61±0.13mg/L, p <0.0001) in the atorvastatingroup. Finally,2.6%of patients in the atorvastatin group developed CINversus15.7%of those in the control group (p=0.01). Multivariate Logisticregression analysis showed that: peak CK-MB (OR=1.013,95%CI=1.002–1.024, p=0.024) and contrast volume (OR=1.035,95%CI=1.001–1.070, p=0.043) were risk factors of CIN, and atorvastatinpretreatment was independently associated with a decreased risk of CIN (OR=0.084,95%CI=0.015–0.462, p=0.004). The proportion of alanineaminotransferase (ALT)>3×upper limit of normal value (ULN) within1month of the procedure was3.85versus1.20%(atorvastatin group vs. controlgroup, p=0.57), without statistical significance.Conclusions: Preprocedural high-dose atorvastatin load in the emergencyroom prevents CIN and protects the renal function in patients with acuteSTEMI undergoing primary PCI. These results lend further support for the early use of high-dose statins as adjuvant pharmacologic therapy in primaryPCI. |
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