| BackgroundThe mortality of patients with acute myocardial infarction (AMI) reduced significantly by reperfusion treatment, but the incidence of heart failure (HF) was still high during hospitalization. Heart failure would affect the life quality and long-term survival dramatically. Therefore, it remains one of the main problems to reduce the post-AMI HF incidence in the current cardiovascular field. Left ventricular remodeling plays a key role in the occurrence and development of post-AMI HF. Excessive activation of neurohormonal and inflammatory factors was important mechanism of the left ventricular remodeling after AMI. Ventricular remodeling after AMI mainly includes expansion of infarction area and myocardial hypertrophy in non-infarction area. The extracellular matrix remodeling is one of the important component parts of the ventricular remodeling, mainly represented by the changes of collagen metabolism. Early collagen metabolism after AMI is mainly collagen degradation, especially the degradation of type I collagen, the late is mainly the collagen hyperplasia. The excessive activation of matrix metalloproteinases plays an important role in cardiac collagen metabolism; especially MMP-9plays a crucial role in collagen degradation and left ventricular remodeling after AMI.Digitalis is the traditional medicine treating heart failure. A large number of clinical and experimental research confirmed that it has beneficial effects on hemodynamic, electrophysiological and the neurohormonal improvement. Digitalis has unique vagus nerve excitement effect, suppressing the sympathetic nerve and renin angiotensin system. Therefore it can improve ventricular remodeling after AMI. However, early studies have shown that use of digitalis drugs after AMI have an adverse effect on ventricular remodeling. But the data were from patients or animal models without early reperfusion treatment. It has not been reported the effects of digitalis on left ventricular remodeling on the basis of early reperfusion treatment on post-AMI HF. This study would observe the effect of digitalis on left ventricular remodeling and collagen metabolism on the basis of early reperfusion treatment.Chapter one:Effect of digitalis on left ventricular remodeling and collagen metabolism in a microswine model of acute heart failure after acute myocardial infarctionObjective:To explore the effects of digitalis on left ventricular remodeling and collagen metabolism in a microswine model of acute heart failure after acute myocardial infarction (post-AMI HF).Methods:1. Model establishment:All the animals started taking aspirin, clopidogrel, enalapril and simvastatin after the quarantine period. Acute post-AMI HF was established successfully in8microswines. The animals underwent a percutaneous coronary invention to block blood flow in left anterior descending artery by inflating a balloon for120min. The model were confirmed by observing continuous ST segment elevation in chest leads of electrocardiogram and pulmonary capillaries pressure (PC WP) over or equal to18mmHg.2. Animal grouping and intervention:Animals were randomized to digitalis group(n=4)and control group(n=4)after acute post-AMI HF was confirmed in these animals. Lanatoside C (0.025mg/kg) dissolved in20ml saline was intravenously injected followed by digoxin0.125mg/d in the digitalis group until the end of experiment in the digitalis group. Equivalent saline was injected in control group.3. Outcome measurements:①The changes of left ventricular ejection fraction (EF), left ventricular end diastolic volume (LVEDV), left ventricular end systolic volume (LVESV), left ventricular infarction area wall thickness (WIT), border area wall thickness (WBT) and normal area wall thickness (WNT) walls were measured preoperatively, right after model established and1h,2h,3h,24h,7d and1m after medication.②Serum concentrations of MMP-9was measured by radioimmunoassay preoperatively, right after model established and1h,2h,3h,24h,7d and lm after medication.③The hearts were then harvested to HE stain, TTC stain and the infarction area were measure after executed respectively7d and lm after medication.④Immunohistochemistry staining were performed for detecting Collagen I, Collagen III and MMP-9in infarction area, the border area and normal area.4. Statistical analysis:Using SPSS13.0statistical software, P<0.05for the difference was considered statistically significant. Data were expressed by mean±standard deviation (x±s).Differences between two groups was compared by t-test or χ2-test and differences between over2groups were compared using analysis of variance (ANOVA).Results: 1. The baseline statistics has no statistically significant differences between the two groups.2. Echocardiography results:①Compared with preoperative, the EF decreased significantly after model establishment (P<0.05or P<0.01) and climbed up after reperfusion during the first24h of reperfusion in both groups. The EF went down24h after model establishment in both groups. Bigger elevations were observed in EF of digitalis group compared with control, but the differences were not statistically significant.②The LVEDV and LVESV increased obviously after model establishment in two groups (P<0.05or P<0.01).The two indices maintained enlarged in control group in the first24h after model in control group, while they got reduced in the first3h in digitalis group. They went up at7d and1mon in both groups. The differences between groups did not reach statistical significance at all time points (P>0.05).③The WIT decreased significantly after model establishment and recovered at3h (P<0.05or P<0.01) in control groups. While it recovered at2h in digitalis group. It went down at7d and lmon in both groups.④The WBT decreased significantly after model establishment (P<0.05or P<0.01) in both groups. It climbed up at1h, and then went down gradually, gradually climbed up at the7d and lmon.⑤The WNT decreased significantly after model establishment (P <0.05or P<0.01) in both groups. It climbed up after digitalis treatment at1h,2h and3h in digitalis group, higher than that in control group at equivalent time points. The WNT climbed up to baseline level at the7d and lmon.⑥The thickening rate of infarction wall was remarkably decreased after acute myocardial infarction in both groups (P<0.05), while there were no significant changes in the border area and the non-infarction area (P>0.05) in both groups. No significant differences were observed in the three areas in both groups.(2) Compared with preoperative, the serum level of MMP-9was elevated after model establishment in two groups. It peaked at3h after medication and then gradually declined, and back to normal at the1month in the control group. Compared control group, serum concentration of MMP-9was lower Oh and3h after model establishment, the peak time was prolonged, and the peak concentration was lower in digitalis group (3.44±5.75vs5.43±5.54). There was no statistically significant difference between the two groups (P>0.05).(3) There were no statistically significant differences in infarct areas between two groups (25.53±0.21vs27.93±2.61, P=0.121) and (29.00±3.46vs31.04±3.22, P=0.439) respectively. The infarction area has increased at1m in two groups, but there was no statistically significant difference between groups (P>0.05).(4) Immunohistochemical results:①Compared with normal area, type I and III collagen content decreased in infarction area and bolder area at7th day in two groups. Type III collagen in infarction area and type I and type III collagen in border area were decreased obviously in both groups. Bigger, but not statistically significant, decreases were in control group compared with digitalis group (P>0.05).②The type I collagen content increased in the three regions after7d myocardial infarction in two groups; type III collagen decreased in non-infarct area and increased in border area.③The type I to III collagen content ratio (I/III) decreased at7d in collagen type I and III, and increased at1mon compared with7d, but there was no statistically significant difference between groups (P>0.05).④Compared with control group, the MMM-9content was lower between the three area at7d in digitalis group. MMM-9increased at lmon compared with7d in border area and normal area. There was not significantly different between the two groups(P>0.05).Conclusions:Digitalis might significantly improve the heart function but did not show any adverse impacts on the infarct size, the left ventricular remodeling and collagen metabolism in the microswine model of acute heart failure after acute myocardial infarction.Chapter two:Effect of digitalis on left ventricular remodeling and collagen metabolism in the patients with acute heart failure after acute myocardial infarctionObjective:To observe the effect of digitalis early treatment on left ventricular remodeling and collagen metabolism after the implementation of emergency PCI in patients with acute post-AMI HFMethods:Thirty-nine patients with post-AMI HF, who received emergency PCI with24h after AMI onset from January2013to December2013were selected, and then randomly divided into digitalis group (n=20) and the control group (n=19) after reperfusion. A dose of0.2mg Lanatoside C dissolved in20ml0.9%saline was injected for the first time after reperfusion therapy in digitalis group,0.1or0.2mg was injected4to12hours after the first dose according to the conditions of patients, then followed by digoxin0.125mg/day. Twenty milliliter of0.9%saline was injected at the equivalent time points. Echocardiography was conducted before medication and24h,7d,1mon after medication, measuring EF, left ventricular end diastolic diameter (LVEDD), left ventricular end systolic diameter (LVESD), left ventricular posterior wall thickness (LVPWDD) and ventricular septal end diastolic thickness (IVSD). Serum of the patients were collected before medication and24h,7d, lmon after medication, and concentrations of serum Carboxy-terminal telopeptide of type I collagen (ICTP) and MMP-9were measured by radio immunoassay. Statistical analysis using SPSS13.0statistical software, P<0.05for the difference was statistically significant. Data that obey the normal distribution were expressed with mean±standard deviation (x±s). Differences between two groups was compared by t-test or χ2-test and differences between over2groups were compared using analysis of variance (ANOVA).Results:1. There were not statistically differences in the baseline date, such as age, height, weight and sex,the history of angina, hypertension, diabetes, smoking, renal function, Killip cardiac function level, the use of IABP, whether completely revascularization, STEMI/NSTEM type, area of infarction and the lesion blood vessel (P>0.05).2.Echocardiography results:①The EF was lower than normal after acute myocardial infarction in two groups, climbed up gradually at24h,7d and lmn after randomization. Compared with control group, there was an increasing trend in the EF of digitalis group, especially at24h (51.4±7.9vs48.9±7.3). But the increase was not statistically different (P>0.05).②The LVEDD and LVESD increased continuously with time, peaked at1month in two groups. The LVEDD at1month was significantly increased than the time before medication and24h after medication in control group (P<0.05), here was no statistical difference at all time points in digitalis group (P>0.05). There was no statistically significant difference between the two groups in LVEDD and LVESD (P>0.05).③The IVSD and LVPWDD decreased continuously with time, especially in control group. But the difference between groups was not significant (P>0.05). Compared with control group, the IVSD and LVPWDD did not decreased obviously at24h (IVSD8.86±1.56vs8.64±1.51, LVPWDD9.29±1.33vs9.21±1.31) and7d (IVSD8.79±1.97vs8.07±1.33, LVPWDD9.29±0.99vs8.93±1.27) after medication in digitalis group. There was no statistically significant difference between two groups (P>0.05).3.The serum ICTP and MMP-9concentrations climbed and peaked at24h after medication (P<0.01), then gradually declined back to baseline at7d and lmon. Compared with the control group, the peak concentration was lower in digitalis group(ICTP24895.7±18072.9vs31180.9±18028.6, MMP-937343.6±27109.5vs43978.6±25965.2), but the difference did not reach statistically significance (P>0.05).Conclusions:Digitalis might improve the cardiac function and did not show any adverse impacts on the left ventricular remodeling and collagen metabolism in the patients with acute heart failure after acute myocardial infarction. It may reduce type I collagen degradation at early stage of acute myocardial infarction through the inhibition of MMP-9. General conclusion:The animal experiments and clinical studies have shown that early use of digitalis after reperfusion might improve the failured heart function and does not increase the infarction area, and has no adverse even has beneficial effect on left ventricular remodeling and collagen metabolism after acute myocardial infarction. |
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