| Objective: The cardiac function refreshment can be delayed or preventedseriously by ischemia reperfusion injury (IRI). Previous study has alreadydemonstrated that a short term statins preconditioning showed a similarprotection as ischemic preconditioning (IPC) against myocardial IRI. Whetherdoes the protection of the second window of the preconditioning also exist inthis situation is seldom reported. Our study aims to investigate the effect ofloading dose fluvastatin (80mg/kg) pretreatment on myocardial IRI, andcompare it with IPC.Methods:84SD rats were randomly divided into12groups (n=7). Onerat was selected to be used for HE staining and electron microscopy in eachgroup. Dissolved fluvastatin in saline (20mg/ml), then treated rats orally withfluvastatin of80mg/kg (about1.1ml per rat).(1) Sham group: Treated with the same amount of saline orally as thefluvastatin group, and then exposed the heart by a thoracotomy. Rest for150min after threaded the left coronary artery (LCA)2-3mm away from itsorigin.(2) I/R (ischemic/reperfusion) group: Treated with the same amount of salineorally as the fluvastatin group, and then exposed and threaded as the shamgroup. Made them into models of I/R.(3) Fluvastatin preconditioning groups (F-1~F-8group): Treated with loadingdose fluvastatin (80mg/kg)1h,2h,4h,6h,12h,24h,48h or72h before amyocardial ischemia, and then exposed and threaded as the sham group. Madethem into models of I/R.(4) IPC (Ischemic preconditioning) group (IPC-1group and IPC-2group):Treated with the same amount of saline orally as the fluvastatin group.Exposed and threaded as the sham group. Reproduced the IPC-1group into models of IPC，and the IPC-2group into models of delayed IPC.Produced the model of I/R by30min occlusion and120min reperfusionon LCA, and the model of IPC by3cycles of5min ischemia and5minreperfusion before30min occlusion and120min reperfusion on LCA. Themodel of delayed IPC was the same as the model of IPC but add a24h’s restbefore an occlusion. Weight (W), weight of Left ventricular (LV), heart rate(HR) and arrhythmia score (AS) were all recorded. CK-MB activity and LDHactivity were measured after120min of reperfusion respectively. Myocardialischemia/infracted range were measured using area and weight measurementmethods by Evans blue and TTC double staining. Light microscope andtransmission electron microscope were used to examine cardiomyocytestructures．Results:1Inclusions and exclusionsNo significant ECG change appeared in the sham group throughout thesurgery. ST segment elevated and merged with T-wave were seen in othergroups after ischemic or reperfusion. The refractory ventricular fibrillation orcardiac arrest ones were picked out.2Basic indexesNo significant difference was found within each group in W, LV and HR(P＞0.05).3The influence of loading dose fluvastatin pretreatment in myocardial IRIFor fluvastatin preconditioning groups, as to the myocardial infractedarea ratio, each group was effectively lower than the I/R group besides theF12h and F24h group (P＜0.05), and the F4h group was lower than F1h, F12h,F24h, F48h, F72h group (P＜0.05), but compared with the F2h group and theF6h group, there were only decreasing trends, no significant difference wasfound (P>0.05). The significant decrease was also seen among the F48h groupand F12h, F24h group (P＜0.05), but compared to the F-8group, there wasonly a decreasing trend, no significant difference was found (P>0.05). Thetime course of loading dose fluvastatin preconditioning against myocardial infraction shows double window of protection to myocardial IRI: the earlyphase is an immediate, powerful but short-lived protection, turns up1h later,reaches a maximumand at4h, and last at least5h;24h later, a second,weaker, sustained window of protection appears, reaches a maximumand at48h and last at least24h. The changing trends of other indicators were almostaccordant. So F4h group and F48h group were chosen into further compare.4The comparation between loading dose fluvastatin pretreatment and IPC inmyocardial IRI protection4.1The myocardial infracted area/weight ratioCompared with the I/R group, the myocardial infracted area/weight ratiosof the F-3group, the F-7group and the IPC group were significantly reduced(P＜0.05), and so was the IPC-1group with the F-3group (P＜0.05).Compared with the F-7group in the myocardial infracted weight ratio, theIPC-2group was significantly reduced (P＜0.05), but when comes to themyocardial infracted area ratio, there was only a decreasing trend (P>0.05).4.2The myocardial ischemia area/weight ratioCompared with the I/R group, the myocardial ischemia area/weight ratiosof the F-3group, the F-7group and the IPC group were significantly reduced(P＜0.05), and so was the IPC-1group with the F-3group (P＜0.05).Compared with the F-7group in the myocardial ischemia weight ratio, theIPC-2group was significantly reduced (P＜0.05), but no significant differencewas foung in the myocardial ischemia area ratio (P>0.05).4.3The arrhythmia scoresCompared with the I/R group, the arrhythmia scores of the F-3group, theF-7group and the IPC group were significantly reduced (P＜0.05). Betweenthe IPC-1and the F-3group, no significant difference was foung in thearrhythmia scores (P>0.05), so was the IPC-2and the F-7group (P>0.05).4.4LDH and CK-MBCompared with the I/R group, the LDH and CK-MB of the F-3group,the F-7group and the IPC group were significantly reduced (P＜0.05), and sowas the IPC-1group with the F-3group (P＜0.05). But no significant difference was foung between the IPC-2group and the F-7group (P>0.05).5Myocardial changes under the light microscopeThe appearance of cardiomyocytes in sham group seemed regularwithout swollen, while atrophy and denaturation in controul groups.6Myocardial changes under the transmission electron microscopyCardiomyocytes in sham group seemed regular, while terriblely destroiedin the I/R group. Both of the F-3group and the IPC-1group showed apowerful myocardial protective effect against cardiac IRI, and the F-3groupwas better in some sort. For the F-7group and the IPC-2group, result seemedbetter than the I/R group similarly, but comparatively severe than the F-3group and the IPC-1group.Conclusions:1The time course of loading dose fluvastatin preconditioning showsdouble window of protection to myocardial IRI: the early phase is animmediate, powerful but short-lived protection, turns up1h later, reaches amaximumand at4h, and last at least5h;24h later, a second, weaker,sustained window of protection appears, reaches a maximumand at48h andlast at least24h.2As to the protective effect of loading dose fluvastatin preconditioningto myocardial IRI, the early phase is less potent than IPC in reducingmyocardial infarction/ischemia, cardiac arrhythmia, serum LDH and CK-MB,and maintaining cardiomyocytes micro structural integrity, while the latephase seemed similar. But the protective effect loading dose fluvastatinpreconditioning seemed better than IPC in reducing myocardial infarction. |
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