| B-type natriuretic peptide has been demonstrated beneficial physiological properties by previous studies, including modulating vasodilation of atery and vein, natriuresis, and inhibition of both the sympathetic nervous system (SNS) and the renin-angiotensin-aldosterone system (RAAS). Recombinant human B-type natriuretic peptide (rhBNP) was admitted to be used on treatment of acute decompensated heart failure by food and drug administration of American. It would be a new treatment for HF, but recently there were controversial results reported of preclinical and clinical trials. Some trial found rhBNP could have adverse effect on renal function, coronary blood flow and even the short-term mortality rate. Simultaneously, other trial got opposite conclusion. There was no enough evidence to clarify this question about the coronary and renal hemodynamics effects of rhBNP.Consequently, this study was designed to evaluate the coronary and renal hemodynamics effect of rhBNP. The York pig model of acute myocardial infarction (AMI) with HF was founded by left anterior decsending (LAD) occluded with balloon combined with injecting of microembolus. And then the blood flow was measured by ComboMap System Model 6800. The clinical trial was designed to clarify the effect and safety of rhBNP on AMI with HF.The detailed methods and results of our study were as follows:Part I Establishment of York pig model of acute myocardial infarction with acute decompensated heart failure by coronary occlusion with balloon and injecting of microembolusObjective:To evaluate the method of York pig model of AMI-HF by coronary occlusion with balloon and injecting of microembolus and to evaluate the changes of coronary and renal hemodynamic parameters on York pig model on AMI-HF.Methods:Ten York pigs were selected in this trial. Coronary angiography and left ventricular angiography were performed and LVEDP were monitored by pigtail catheter. LAD was superselected with 6F guiding catheter and recorded the coronary pressure, and then Doppler guidewire were transferred into coronary distance. 4F pigtail was placed in left ventricular to record the left ventricular end-diastolic pressure (LVEDP). The coronary blood flow was measured with ComboMap System Model 6800. LAD was occluded by balloon which was placed on mid-distal for 30-45 minutes until ST segment elevation for 15min, and then perfused by withdrawing the balloon. After deflating the balloon,the sterile microembolus were injected into LAD intermittently and injecting stopped until LVEDP>18mmHg. The coronary pressure and flow velocity were recorded simultaneously at baseline, instant, 30min and 60min after AMI-HF model success. Average peek velocity (APV), coronary resistance (CR) and coronary flow reserve (CFR) were obtained at basic and maximal hyperemia. The maximal hyperemia was induced by intracoronary bolus of 80ug adenosin. Renal artery angiography was performed and renal artery diameter and pressure were measured. Doppler flowire was placed in renal artery for measure of APV of renal artery (APVra), renal artery vascular resistance (RVR) and renal blood flow (RBF). At the same time ECG was recorded per 15min. CK-MB and cTnI were measured in all York pigs at baseline, 2hr, 4hr, 8hr, 12hr and 24hr after reperfusion. Echo cardiograph was performed to evaluate the heart function.Results : (1) According to the standards of AMI-HF, 8 animals successfully (80%, 8/10). (2) While the model of AMI-HF was established, instant ECG showed that ST segment elevated and formed single-direction curve with high T wave, and R wave was gradually depressed. cTnI and CK-MB were increased significantly. (3) Basic and hyperemia APV were all decreased significantly, they were lower than those of before AMI-HF. CR was increased after AMI-HF model success. CFR was lower than that of baseline. (4) There is no significant difference of renal artery diameter between the model making process. Renal artery pressure has increased trend than baseline. RVR was increased, APVr and RBF was decreased than baseline.Conclusion: A stable experimental method of York pig model of AMI-HF was established successfully by coronary occlusion with balloon and injecting of microembolus in LAD. The method had advantages of closed chest, higher succeed rate and stablility to those of drug induced, tachycardia-pacing induced, coronary artery ligation induced or microsphere injection alone.Part II: The effects of recombinant human B-type natriuretic peptid on coronary circulation and renal hemodynamics in York pigs model of acute myocardial infarction with heart failureObjective:To evaluate the impact of intravenous administration of rhBNP on coronary and renal artery hemodynamics in York pigs model of AMI-HF.Methods: Total of 14 York pigs were included in this study, animals were prepared and anesthetized as previous mentioned in Part I. After the AMI-HF models were established, pigs were randmized into saline group and rhBNP group. Intravenous administration of rhBNP (bolus of 1.5μg/kg followed by a continuous infusion of 0.01μg·kg-1·min-1 for 60minutes, and then the dosage can be increased to 0.02-0.03μg·kg-1·min-1 until LVEDP<12 mmHg, maintaining MBP≥65mmHg) in rhBNP group. The saline group was given equal volume of normal saline using the same method. Coronary pressure (Pc), the average peak velocity (APV), coronary vascular resistance (CR), coronary flow reserve (CFR) and coronary diameter were recorded simultaneously at baseline, instant after the model established, 60min after continuous infusion of 0.01μg·kg-1·min-1 rhBNP and the time point of LVEDP<12mmHg. The coronary blood flow was measured at rest and maximal hyperemia. Renal angiography was performed by 4F catheter and quantitative measurement of diameter was recorded by the computer assisting system. The average peak rate of renal artery (APVra) was recorded, determination of quantitative angiography of renal artery diameter, renal vascular resistance. 4F pigtail was inserted into left ventricular for LVEDP and LVEF was measured by echocardiography.Results: Twelve animals achieved the standard of AMI-HF model successfully, the observation parameters were recorded at baseline before balloon occlusion, instant after the model established, 60min after continuous infusion of 0.01μg·kg-1·min-1 rhBNP and the time point of LVEDP decreased to <12mmHg. 1. Changes of Coronary artery parameters: There is no significant difference of coronary diameter, APV, CR and CFR in saline group. Coronary artery diameter increased after rhBNP administration. According to the intracoronary Doppler flow results, APV and CBF were significantly increased and CR decreased after rhBNP administration. CFR was significant rebound after continuous infusion of 0.01μg·kg-1·min-1 rhBNP for 30min. And compared with the control group at the same observation point, APV and CBF significantly increased and CR significantly decreased at the stage of infusion 0.010μg ? kg-1 ? min-1 rhBNP in rhBNP Group. 2. Renal artery pressure was significantly lower after rhBNP administration. According to the Angiography results, rhBNP exerts renal vasodilator effects in a dose related relationship. According to the Doppler parameters of renal artery, there was no difference of APVra increased after infusion of rhBNP. RBF increased gradually after administration of rhBNP and was significantly higher than that of control group. RVR decreased after administration of rhBNP. LVEF measured by echocardiography was lower than baseline after the models established and tended to increase after administration of rhBNP, but no significance was found compared with that in saline Group and that immediate after models established.Conclusion: It could increase blood flow of injury coronary artery, improve CFR and improve the coronary and renal hemodynamics after intravenous administration of rhBNP in pigs with AMI-HF.Part III The perioperation effect of recombinant human B-type natriuretic peptide for heart failure patients with primary percutaneous coronary interventionObjective: To study the efficacy and safety of recombinant human B-type natriuretic peptide (rhBNP) in AMI-HF patients undergoing PCI, especially changes in renal function and the impact of short-term outcome during BNP treatment.Methods: Choose consecutive patients who happened AMI-HF within 24h in our department. After signing informed consent, all patients were randomly assigned to the rhBNP group and control group. rhBNP was given at 1.5μg?kg-1 intravenously and then infused intravenously (0.0075-0.030μg?kg-1?min-1). The physician can adjust the dose according to patient condition to 0.015 -0.030μg ? kg-1 ? min-1 in the maintenance of systolic blood pressure (SBP)≥85 mm Hg, the average pressure of (MBP)≥65 mmHg. 0.9%Saline was used intravenously in control group as control. Both drugs were administered for 24 hours. Clinical symptoms assessment: dyspnoea was divided into no dyspnoea, dyspnoea after mild activity, supine dyspnea improving condition, killip grade were recorded. 2. Recorded heart rate (HR) and systolic blood pressure (SBP) changes before, after the administration the drug at 1h, 6h and 24h time point. 3. Test the plasma BNP levels with application BNP triage bedside monitor before and after stopping the drug 6h, 14d, 30d. 4. Echocardiography examination were administered before and after stop the medication 24h, 14d and 30d, left ventricular end diastolic diameter (LVEDD) and left ventricular ejection fraction (LVEF) was measured. Serum creatinine (Scr) was measured before and after administered the medication 24h, 48h, 72h, 7d and 14d. Simplified MDRD equation was used to calculate estimated glomerular filtration rate (eGFR). CIN is defined as SCr level is higher than 25% or absolutely increased 44.2umol ? L-1 in SCr before the use of contrast agents. Recording the major adverse cardiac events (MACE) occurrence within 30d, which include recurrent heart failure, myocardial infarction, malignant arrhythmia and sudden death.Results: 1. There were no significant differences between the two groups in baseline characters. 2. clinical effect: rhBNP group has a less dyspnea time than the control group; The heart rate in the two groups both have a decrease trend at the time of immediate withdrawal the medication compared with before treatment, and the statistical differences in rhBNP group was significant; The systolic blood pressure (SBP) level in two groups at different time points after administration was significantly lower than before injection; There was significantly lower after rhBNP administration 1h in systolic blood pressure (SBP) level ,There was no significant differences in SBP at the time point of administration of rhBNP 6h and stopping instantly 3. The plasma BNP levels significantly lower than before treatment at different time point in the two groups. Between the two groups after treatment, after, rhBNP, The plasma BNP levels were significantly lower than the control group at the same time point after treatment 6h and 14d; there was no significant difference between the two groupsafter treatment 30d; 4.There was no significant differences in the level of LVEF and LVEDD in both groups of patients before treatment. The LVEF was significantly higher in treatment group compared with baseline levels after treatment 24h ,while LVEDD significantly decreased even after discontinuation the treatments ,which remain so when the 30d. The LVEF and LVEDD improvements in rhBNP group were significantly better than in the control group after treatment 24h, 14d; 5. The infusion of fluid volume from admission to PCI had higher trend in rhBNP group than in the control group, The SCr significantly increased after PCI, with the peak value at 48h, and then began to decrease. At day 7 after PCI, the SCr had lowered to the baseline level in the rhBNP group, but it failed to do so in the control group. At 48h after PCI, the SCr was lower in the rhBNP group than that in the control group. The eGFR decreased significantly after PCI, with the lowest value at 48h, and then it began to increase. The eGFR after PCI was higher in the rhBNP group than that in the control group. The occurrence of CIN was significantly lower in the rhBNP group than in the control group. The incidence of CIN was 20.69%, which was higher than average incidence of AMI-pPCI, rhBNP groups have lower rate than the control group. 6. The MACE event of 30d in rhBNP group was significantly lower than the control group. Conclusion: rhBNP can promptly and effectively improve the heart function, reduce the incidence of MACE rate in acute myocardial infarction with heart failure patients, which also had a renal function protective effect in patients with and decreased incidence on CIN. |
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