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Remote Ischemic Conditioning and Intermittent Normoxia during Cardioplegia Arrest Reduces Myocardial Reperfusion Injury in Adult Valve Replacement

Author: LiLi
Tutor: ChenShengXi;XuLiaoMei
School: Central South University
Course: Science in cardiothoracic surgery
Keywords: ischemia reperfusion injury myocardial protection cardiac surgery remote preconditioning myocardial inflammation normoxia reactive oxygen radicals cardiopulmonary bypass nuclear factor kB
CLC: R654.2
Type: PhD thesis
Year: 2011
Downloads: 45
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Abstract


Chapter 1 Remote perconditioning reduces myocardial reperfusion injury in adult valve replacementObjectives:Remote perconditioning has been proved to reduce myocardial infarction and improve ventricular function in vivo. This study aims to determine the protection of remote perconditioning against cardiac reperfusion injury in patients undergoing valve replacement.Methods:Eighty-one patients admitted for selective valve replacement were divided into 3 groups with random. Control patients (CON. n=27) underwent sham placement of the tourniquet around the right thigh without inflation; the remote preconditioning group (R-Pre. n=26) received 3 cycles of 4/4 min right thigh ischemia and reperfusion after induction of anesthesia, the limb ischemia was induced by the tourniquet inflated to 600 mmHg; the remote perconditioning group (R-Per. n=28) received the same stimulus immediately after aortic cross-clamping. Venous blood samples were obtained preoperatively, 5 min before aortic de-clamping,30min,4h,12h and 72h after aortic de-clamping for detecting cTnI concentration. The clinical data of inotropes requirement, drainage, ventilation and intensive care time were routinely recorded.Statistical analysis:Statistical analysis was performed with the SPSS statistical software, version 13.0. A value of p<0.05 was regarded as significant. Categorical data were analyzed using chi-square test. Measurement data were compared by one-way analysis of variance. The continuous variables were analyzed with repeated-measures analysis of variance. Multiple comparisons at each time point were made using post hoc least significant difference test. The correlation between two independent parameters was analyzed by Pearson correlation.Results:The remote perconditioning group had significantly lower release of cTnl 5min before aortic de-clamping (CON. vs. R-Pre. vs. R-Per.,0.15±0.10 vs.0.13±0.08 vs.0.10±0.04ng/ml, p=0.05) and 30min after aortic de-clamping (CON. vs. R-Pre. vs. R-Per.,0.40±0.24 vs.0.41±0.40 vs.0.24±0.13ng/ml, p=0.04). The remote pre-and perconditioning treatment abrogated the positive correlation between peak values of cTnl and cardiac ischemic duration in the control group. More incidence of spontaneous resuscitation was observed in the remote perconditioning group(CON. vs. R-Pre. vs. R-Per.,0.44 vs.0.46 vs.0. 75, p=0.04).Conclusions:Remote perconditioning, which is induced by transient lower limb ischemia after aortic cross-clamping, reduces myocardial injury over cardioplegia in adults undergoing selective valve replacement. Chapter 2 Intermittent normoxic cardiopulmonary bypass reduces myocardial reperfusion injury in adult valve replacementObjectives:This study aims to determine the protection of intermittent normoxic cardiopulmonary bypass against myocardial reperfusion injury in adult patients undergoing valve replacement. Controlled oxygenation may reduce both myocardial and systemic inflammation during cardiopulmonary bypass by decreasing production of ROS and inhibiting activation of NFkB pathway.Methods:One hundred and two patients were admitted in our department for selective valve replacement from June to September,2010. Seventy patients of them were included and divided into 2 groups with random. The control group (hyperoxic cardiopulmonary bypass, H-CPB, n=35) received continued hyperoxic reperfusion (PaO2 180-250mmHg) throughout CPB; the treatment group (intermittent normoxic cardiopulmonary bypass, IN-CPB, n=35) underwent 3 cycles of 5/5 min normal/high oxygenation (PaO2 80-150/180-250mmHg) during cardioplegia arrest, and maintained the same hyperoxic status as the control group in the rest time of CPB. Venous blood samples were collected preoperatively,5min before aortic de-clamping,30min,4h,12h and 24h after aortic de-clamping for detecting concentration of cTnI, TNF-α, IL-6, IL-8, IL-10 and MDA. The clinical data of inotropes requirement, drainage, ventilation and intensive care time were routinely recorded. Fifteen patients in either group received biopsies of right atrial tissue during venous cannulation and 30min after aortic de-clamping. The level of MPO was measured to determine the extent of neutrophil infiltration. Activation of NFkB was detected by EMSA method and patterned by immunohistochemistry of NFkB p65. RT-PCR was used to quantify expression of genes (TNF-α, IL-6 and IL-10) regulated by NFkB.Statistical analysis:Statistical analysis was performed with the SPSS statistical software, version 13.0. A value of p<0.05 was regarded as significant. Categorical data were analyzed using chi-square test. Measurement data were compared by independent-t-test. The continuous variables were analyzed with repeated-measures analysis of variance.Results:The IN-CPB group had significantly lower release of cTnl 5min before aortic de-clamping (H-CPB vs. IN-CPB,0.15±0.09 vs.0.11±0.05ng/ml, p=0.04) and 30min (H-CPB vs. IN-CPB,0.37±0.19 vs.0.25±0.18ng/ml, p=0.04), 4h (H-CPB vs. IN-CPB,0.34±0.20 vs.0.23±0.14ng/ml, p=0.03) after aortic de-clamping. Level of plasma MDA and inflammatory factors TNF-a, IL-6, IL-8, and IL-10 markedly increased during cardiopulmonary bypass and reached peak 4h later (p<0.001). Except that plasma TNF-αwas significantly decreased in the IN-CPB group 30min and 4h (H-CPB vs. IN-CPB,857.65±65.82 vs.766.19±59.24ng/l, p=0.004) after myocardial reperfusion, there were no difference between groups in plasma concentration of inflammatory factors (IL-6, IL-8 and IL-10) at any detected time point. The total MDA released, expressed as the area under the curve over the 24h after aortic de-clamping, was reduced in the IN-CPB group (H-CPB vs. IN-CPB,715.37±84.49 vs.339.53±46.03nmol/ml*24h, p<0.001). Less myocardial inflammation was observed in the IN-CPB group with decreased MPO activity (H-CPB vs. IN-CPB,5.78±0.51 vs.5.21±0.55, p=0.03) and gene expression of TNF-α(H-CPB vs. IN-CPB,0.69±0.08 vs.0.56±0.12, p=0.01) and IL-6 (H-CPB vs. IN-CPB,0.40±0.09 vs.0.27±0.05, p=0.001). Myocardial gene expression of IL-10 had no significant difference between groups. Meanwhile, activity of NFkB binding to DNA was remarkably lower in the IN-CPB group (H-CPB vs. IN-CPB,968.61±128.70 vs.857.69±89.09, p=0.04), which was consistent with the immunohistochemistry measurement of NFkB p65 (H-CPB vs. IN-CPB,0.35±0.05 vs.0.30±0.04, p=0.03).Conclusions:Intermittent normal oxygenation during cardioplegia arrest reduces myocardial reperfusion injury in adults undergoing selective valve replacement. The protective mechanism may be related to decreased myocardial inflammation due to less formation of ROS and inhibition of NFkB pathway, the latter sequencely downregulates gene expression of some detrimental inflammatory factors.

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