The Study On The Short-term Efficacy And Safety Of Early Digitalis Administration In Reperfused Acute Myocardial Infarction Complicated With Heart Failure

Background:With the economic development, the incidence of AMI is ascending year by year, at least500,000patients suffered with AMI every year in China, which was an important disease threatening human health. According to the World Health Organization, AMI will be the leading cause of death in2020.Acute Heart failure is the most common complication as well as a common cardiovascular emergency, which occurs in about20%AMI patients at admission.AHF was a leading cause of death in AMI patients during hospitalization with the mortality of20.9%reported in recent study. Digitalis,an inotropic agent with a history of more than two centuries in treating HF as well as a history of about one century in treating AHF, always remains controversial since its first use. Its role in the treatment of HF suffered heavy attack when the result of DIG study was published in1997,in which the use of digoxin in patients of heart failure could not change the prognosis, although reduced the readmission rate significantly. Nevertheless, the research subject in DIG study was the patients with chronic heart failure, other than patients with AMI and patients with AHF, or both. At present there is a common opinion that digitalis is a taboo in the acute phase of AMI especially during24hours. The reasons are as follows:(1)digitalis increase the resistance of coronary artery leading to the decrease of coronary flow as a result of myocardial ischemia;(2) Positive inotropic stimulation of surviving myocardium may accentuate the paradoxical systolic excursion in infracted area, increasing idle cardiac work;(3) The maximal stimulation of the noninfarcted area by catecholamines was possible;(4) Increased oxygen consumption lead to extension of infarction;(5)increase the incidence of ventricular arrhythmia due to possible toxic effect of cardiac glycosides;(6)digitalis may possibly increase mortality. But these reasons partly came from the fear of the clinicians, partly from the early research including animal study and clinical study which was performed before1990s.In modern therapy model, the validity of these reasons is questioned. Firstly, the subjective ideas cant take place of evidence-based medicine. secondly, the old experiment design and statistic methods cant meet the modern criterion. lastly, the most importantly, during these two decades the treatment of AMI experienced great changes:(1)Four kinds of evidence-based medicine including aspirin, ACEI, statins, β-blockers,which were proved to decrease the mortality of AMI patients, were widely used.(2)With the development of intervention technique, Primary PCI as a main reperfusion tragedy is widely used in patients with AMI, especially, in recent years the time from the symptom onset to the coronary flow restoration are recommended to be shortened as possible by cardiologist. The guideline of ACCF/AHA AMI in2013recommended the FMC-D time should be within90minutes instead of the D2B time within90minutes by prior guidelines. Therefore, in the reperfusion era, the role of the digitalis in the treatment of acute myocardial infarction complicated with acute heart failure should be reappraised.Part I Animal StudyObjective:1.To establish the Wuzhishan Mini-pig model of the acute myocardial infarction complicated with acute heart failure together with reperfusion model;2.To observe the variation of the hemodynamic parameters and cardiac ultrasound parameters, together with serum markers and pathology, as well as the infarct area after early digitalis administration.Methods:1.Animal Preparation:Whuzhishan Mini-pigs(n=11) recieved aspirin (5mg·kg-1,qn), clopidogrel(5mg·kg-1,qd),enalapril(2.5mg,bid),simvastatin(20mg,qn) daily from three days ago to obtain clinical therapeutic concentration. General anesthesia was induced by intramuscular injection of ketamine200mg,su-mian-xin0.5ml,midazolam5mg and then maintained with ketamine and midazolam intravenously. Under local anesthesia in the inguinal area, the right femoral artery and venous were exposed and isolated after skin incision and separation of subcutaneous tissue.2.Model establishment:A6F size sheath was placed in the artery and7F sheath in venous for Swan-Ganz catheter. A6-French JR3.5guide catheter was put into the left coronary artery through arterial sheath. The baseline angiography was performed to locate the occlusion position. Then a2.0×15mm or2.5×15mmSprinter angioplasty balloon was introduced and directed into the distal point of the first diagonal branch of LAD. After successful ischemic preconditioning, the bloon was inflated for120minutes. At the end of120minutes the bloon was deflated and withdraw from the LAD.TIMI3blood flow was confirmed in all cases after reperfusion. Eight minipigs met the criterion of AMI-AHF(PCWP≥18mmHg).3.Classification and intervention:Eight minipigs were randomized into the treatment group(n=4) and the control group(n=4). The lanatoside C (0.025mg/mg) diluted in20ml0.9%Nacl solution were given intravenously in20min, while the control group received only20ml0.9%Nacl solution.4.Basical vital signs:Electrocardiagraphy,breath,SaO2,HR,invasive blood pressure was recorded before operation, before and0.5h,lh,2h,3h after administration.5.Measurements hemodynamic parameters:Parameters including CVP、RAP、 RVP、PASP、PADP、PCWP were recorded before operation, before and0.5h,1h,2h,3h after administration using Swan-Ganz catheter through the venous sheath. Cardiac output was determined by the thermodilution technique. The parameters including SV、LVSW、TVR were calculated with the special formula by the computer.6.UCG Examination:UCG was performed on the set time point as above. A series of indexes including left ventricular end-systolic dimension, left ventricular end-diastolic dimension, left ventricular septal thickness, posterior wall thickness, ejection fraction and fractional shortening were measured to demonstrate the change in cardiac function.7. Serum Paremeters:Blood samples were collected at baseline, before and after3h、12h、24h、7dand levels of porcine brain natriuretic peptide、Tropnin I、 Neuropeptide Y were measured by ELISA according to the manufacturer’s instructions.8. Histological study and infarcted area assessment:The anesthetized dogs were then killed with10%potassium chloride20ml and the hearts were excised. Hearts were excised and cut into10mm slices from cardiac apex to base. The thicker slices were put on charged slides and stained with hematoxylin and eosin to evaluate for fibrosis. Digital images were obtained for calculation of LV infarct size. The area of the infarcted tissue was measured using imageJ2x special picture analysis system and expressed as a percentage of total left ventricle area.Result:1.General information:A total of3minipigs died during model establishment, the mortality is27.3%,the success rate is72.7%.The malignant arrhythmia occurred frequently during experiment. Ventricular arrhythmia emerged in all experimental minipigs, the rate of ventricular premature beat was 100%,ventricular tachycardia was81.8%,ventricular fibrillation was72.7%.ECG change:ECG demonstrated ST segment raised, T wave was high after the occlusion. Gradually R wave became shorter. All performance resemble that of human beings.2. Hemodynamic parameters:All hemodynamic parameters was not different at baseline. The LVSW was augmented significantly1h、3h after the administration (P <0.05) in digitalis group. While SV increased1h、2h after the administration in digitalis group. PCWP decreased1h and2h after the administration of digitalis compared with the control group(P<0.05). while HR diminished significantly at all set time point except0.5h and1h. No significant changes were observed in SBP、 PASP and CVP after the administration of digoxin. There was a trend for the TVR to decrease, but only significantly at1h after digitalis use (P<0.05)3. Echocardiographic parameters:The result demonstrated the cardiac function was aggravated after the occlusion of the LAD. Although the LVEF、FS、LVEDV did not show significant difference between the digitalis group and the control group(P>0.05),there was an increasing trend of LVEF and FS in the digitalis group.4. Serum markers:The climax concentration of TnI advanced to12h after the digitalis administration, the concentration of TnI did not differ significantly between both groups at the sex time point. The concentration of NPY was lower in the digitalis group compared with the control group at3h after the administration. There was a trend for the BNP concentration to decrease in the digitalis, but not significantly.5.Pathological changes and Infarct area:The infarcted areas represented pale and thin in apex, left ventricular anterior wall. The typical change of acute myocardial necrosis was observed under microscope after HE stain.The noninfarcted myocardium was stained brick red but infarcted myocardium was not stained by TTC. Thus, myocardial infarcts area are detected. The infarction area between digitalis group and control group was not different (27.26%±2.83%vs29.48%±2.99%P>0.05).Conclusion:1.The intervention method to establish the Wuzhishan Mini-pig model of the acute myocardial infarction complicated with acute heart failure was feasible and practical,with a low mortality after learning curve.2.The hemodynamic parameters and echocardiographic parameters were improved as well as the serum NPY concentration decreased after early digitalis administration in experimental reperfused acute myocardial infarction complicated with acute heart failure,without increasing ventricular arrhythmias and mortality.Part Ⅱ Clinical studyObjective:In the animal study, we found that the early use of lanatoside C can improve the cardiac function of the wuzhishan minipigs with AMI-AHF after the early reperfusion without increasing ventricular arrhythmias and mortality. In this study, we aimed to observe the effect and the safety of the early use of digitalis in patients with early reperfused AMI complicated with AHF within24hours from symptom onset.Methods:1.Objects:The enrolled population consisted of39residents hospitalized in the cardiovascular department of Guangzhou General Hospital of Guangzhou Military Command, who entered coronary care units (CCU) from January,2013to December,2013with a definite acute myocardial infarction complicated with acute heart failure after early reperfusion by primary PCI within24h from the onset of symptoms. Exclusion criteria:(1)right ventricular infarction;(2)mechanical complications including free wall rupture and pseudoaneurysm、ventricular septal rupture、papillary muscle displacement or rupture;(3) restrictive cardiomyopathy, Hypertrophic cardiomyopathy or valvular heart disease;(4) Ⅱ°Atrioventricular block or more severe;(5)mechanical ventilation was needed, severe hepatic and kidney function insufficiency;(6) be allergic to digitalis;(7) treatment with other cardiac glycosides.;(8)Do not agree to participate.2.Classification and intervention:All patients were randomized into two groups: digitalis group(n=20) and control group(n=19).Dosage and administration:A dose of of0.2mg lanatoside C diluted in20ml of0.9%Nacl solution were given intravenously in20min, followed by a second dose of0.1-0.2mg lanatoside C was given in the same manner12hours later for three days, while the control group received only20ml of5%glucose solution. Three days later the digitalis group were treated with oral digoxin0.125mg qd. All patients received basic pharmacological treatment consisted of subcutaneous Heparin, dual or triple antiplatelet,statins, ACEI, nitrates, diuretics during hospitalization.3. Basical vital signs:Breath,SaO2,HR,invasive blood pressure was recorded before and lh,2h,3h,12h,24h after administration.4.Hemodynamic parameters:The right heart catheterization was performed using Swan-Ganz7F the catheters being introduced transcutaneously by the Seldinger technique and advanced into the pulmonary artery under fluoroscopic guidance. The following hemodynamic parameters including CVP、RAP、RVP、PASP、PADP、 PCWP were recorded before and lh,2h,3h,12h,24h after administration using Swan-Ganz catheter. Cardiac output was determined by the thermodilution technique. The paraters including CI、LVSWI、SVRI were calculated with the special formula by the computer.5.UCG parameters:UCG was performed before and3h、24h after the administration. A series of indexes including LVEDd、LVEF、FS were measured to demonstrate the change in cardiac function.6.Serum markers:The serum CK-MB、TnI and BNP before and24hours after the digitalis administration. 7.The mortality and ventricular arrhythmia:The mortality within30days was observed in the charge of special person. The electrocardiogram (ECG) was monitored continuously and hourly computation of the number of premature ventricular complexes was obtained by a computerized arrhythmia detection and recall system.Result:1.Basic information:Both groups of patients were similar with regard to demographic characteristics.2.Hemodynamic parameters:HR was significantly lower in the digitalis group at3h、12h、24h after administration compared with the control group. In comparison to the control group, the patients in the digitalis group had an increase of SV at1h after the administration and LVSWI2h after the administration of digitalis (P<0.05).We observed a significant reduction of PCWP in the digitalis group at2h、3h after the administration(19.2±1.0v.s22.9±1.3,.P<0.05;18.6±1.1vs22.4±1.4,P<0.05).The calculated mean SVRI had a decrease trend, but the value was not statistically significant. The CVP and PASP did not differ significantly between two groups.3.Echocardiogram parameters:The baseline parameters was similar in both groups (P>0.05).he statistical analysis of LVEF and FS showed a significant increase in digitalis group in comparison to the control group at3h、24h after the digitalis administration (P<0.05).The difference of LVEDd between two groups was not statistically significant.4.Serum markers:The serum CK-MB and Tn1were not different significantly before and24hours after digitalis administration between the two groups,The BNP concentration was lower in the digitalis group24hours after digitalis administration,but not significantly.5. The mortality and ventricular arrhythmia:The mortality within30days was in a descending trend in the digtitalis group (10.0%vs26.3%,P=0.190).The ventricular arrhythmias between the two groups was not significantly different.Conclusion:In the era of reperfusion therapy, the early use of digitalis plays a benefit role characterized by cardiac function improvement without increasing ventricular arrhythmias and mortality in the treatment of reperfused acute myocardial infarction complicated with acute heart failure in the acute phase.