| Clinically,patients with cardiovascular disease,especially heart failure,are often associated with significant cognitive impairment or anxiety depression.This cognitive impairment is mainly manifested in executive function,attention,and memory.Heart failure associated with cognitive impairment tends to increase mortality and rehospitalization rates and decrease quality of life.The theory of traditional Chinese medicine holds that "The heart controls mental activities",and modern medicine also holds that the function of the heart will affect the physiological function of the brain.However,the pathophysiological mechanism of cognitive impairment after heart failure remains unclear.This study bases on the perspective of cognitive dysfunction after heart failure,with heart failure after myocardial infarction model rats as the research object,includes heart failure rats behavior evaluation scheme,change and molecular mechanism of the cerebral blood flow,cerebral energy metabolism changes and molecular mechanism and to explore the pathological mechanism of cognitive dysfunction after heart failure and Qiliqiangxin capsules intervention effect of cognitive function after capsule for heart failure.Aims1.The cognitive function of rats with heart failure was evaluated by various protocols of Morris water maze experiment.The characteristics of cognitive impairment in rats with heart failure were studied,and the most sensitive evaluation scheme of water maze was selected.2.Through detecting cerebral blood flow,electron microscopy and molecular mechanism in rats with heart failure,the change and mechanism of cerebral blood flow in cognitive impairment after heart failure were studied.3.Through the detection of PET-CT and molecular biology in heart failure rats,the changes of brain energy metabolism and related molecular mechanisms of cognitive impairment in heart failure were observed.4.Through the intervention of qiliqiangxin in heart failure rats,the intervention effect and related mechanism of qiliqiangxin capsule on cognitive impairment rats after heart failure were researched.Methods1.The heart failure model were made by ligation of left anterior descending coronary artery,and the rats were distributed model group,Qiliqiangxin group,Enalapril group.2.The ECG was detected at 24h and 60 days postoperatively,respectively,and the ultrasonic echocardiography was performed at 60 days postoperatively.In addition,heart tissues of heart failure rats were stained with HE and NBT.3.The cognitive function of rats with heart failure was evaluated by Morris water maze acquisition trial,probe trial,reversal experiment and matching-to-sample test after 60 days of the operation.4.Cerebral blood flow changes in heart failure rats were detected by laser doppler flowmetry 60 days after surgery,vascular and endothelial functions in heart failure rats were observed by transmission electron microscopy,and eNOS and iNOS expressions in brain of heart failure rats were detected by Western Blot.5.The changes of cerebral glucose metabolism in rats with heart failure were detected by pet-ct 60 days after the operation,and the expression levels of cerebral cortex GLUT1,GLUT4,AMPK,CaMK and CPT-1 were detected by Western Blot.6.After 60 days of intragastric administration,ultrasound,water maze,cerebral blood flow and electron microscopy results were detected in the sham operation group,model group and qiliqiangxin capsule group.Results1.Results of cardiac function:Compared with control group,model group electrocardiogram had V1-V6,I and aVL apparent pathologic Q wave.The EF and FS values of the model group were significantly lower than those of the sham group and there was a statistical difference(P<0.05).Compared with the sham group,the anterior wall thickness and posterior wall thickness of the model group at end-diastolic/end-systolic period were smaller than that of the sham group,and the left indoor diameter at end-diastolic and end-systolic period were larger than that of the sham group,with statistical differences(P<0.01).HE staining revealed a wide range of myocardial cell necrosis in the model group,with disordered arrangement of myocardial cells and a large amount of fibrous connective tissue.2.Results of Morris water maze:In the probe trial,the times of rats in the model group crossing the original platform were significantly reduced compared with those in the sham group(P<0.01),and the percentage of marching distance and time to total distance and total time in the quadrant of the original platform was significantly reduced(P<0.01).In the reversal experiment,the mean latency and total swimming distance of the first time in the sham group were significantly greater than that in the model group(P<0.05).The ratio of time/distance to total time/distance of the original quadrant(SW)of the sham group was higher than that of the model group,while the results of the new target quadrant were reversed.The total latency and swimming distance of the second reversal experiment in the model group were significantly higher than those in the sham group,and the time ratio and distance ratio of the new target quadrant were significantly lower than those in the sham group(P<0.05).In the matching-to-sample test,the time to find the platform in Trial 2 was significantly shorter in both the sham group and the model group than in Trial l.At day 5,the difference between the mean latency of Trial 1 and Trial 2 in the model group was significantly greater than that in the sham group(P<0.05),and the mean latency of Trial 1 in the model group on day 5 was significantly greater than that in the sham group(P<0.05),but there was no significant difference between the two groups in the mean latency of Trial 2 on day 5.3.Results of cerebral blood flow and vascular endothelial structure and function:Compared with the sham operation group,there was no statistically significant difference in the cerebral perfusion volume of rats in the model group.Compared with the sham group,the relative expression of eNOS in the cerebral cortex of rats in the model group showed a decreasing trend(P=0.089),but the difference was not statistically significant(P>0.05),while the relative expression of iNOS showed no significant change.Comparing the relative expression of eNOS and iNOS in the brain tissues of rats,it was found that the relative expression of eNOS/iNOS in rats with heart failure was significantly lower than that in the sham group(P<0.05).In the rats with heart failure,the endothelial cells and basement membrane were seriously damaged and the boundaries were blurred,and the organelles were swollen around the blood vessels,the structural damage was blurred,and the astrocyte processes were edema.4.Results of cerebral glucose metabolism and expression of its related regulatory proteins:Glucose uptake and absorption decreased significantly in rats with heart failure for 60 days,which mainly included the prefrontal cortex sublimbic area,prefrontal cortex,lateral prefrontal cortex,medial prefrontal cortex and ventral prefrontal cortex.Compared with the sham group,there was no statistical difference in the content of glucose transporter 1 in the cerebral cortex of rats in the model group,but the mean value of the sham group was higher than that in the model group.There was no significant difference in the expression of glucose transporter 4 in the cerebral cortex between the sham group and the model group.Compared with control group,the heart failure rat cerebral cortex AMPK expression and CaMK Ⅱexpress no statistical differences.However,the expression of cpt-1 in the cerebral cortex of heart failure rats decreased significantly compared with that of the sham group(P<0.05).5.Results of Qiliqiangxin capsule drug efficacy and mechanism:The EF and FS values of qiliqiangxin group were greater than those of model group and were statistically significant.The anterior wall thickness of left ventricular end diastolic period in qiliqiangxin group and enalapril group was significantly higher than that in model group(P<0.05).The frequency and target quadrant time ratio of qiliqiangxin group were significantly higher than that of model group.Compared with model group,qiliqiangxin group and enalapril group had no statistical difference in cerebral blood flow.Compared with the model group,the electron microscopy performance of qiliqiangxin group and enalapril group was improved,with clear endothelial cells and basement membrane,but there was still edema of perivascular organelles and slight edema of astrocytes.Conclusions1.According to the results of electrocardiogram,echocardiography,HE staining and NBT staining,the heart morphology and function were damaged,and the model met the diagnostic criteria for heart failure.2 HF rats have cognitive dysfunction,mainly manifested in long-term memory ability,spatial learning ability and reverse learning ability.Although the matching-to-sample test can also assess the memory function of heart failure rats,however,the reversal test and probe trial may be more sensitive and desirable.3.Although the rats with chronic heart failure had abnormal NOS system and endothelial function was impaired under electron microscopy,the changes in brain blood flow were not obvious.These results suggest that the effect of the heart on brain function is a complex process,and blood flow is only one of the factors that affect the function.4.The cognitive decline of rats with heart failure may be related to the disorder of brain energy metabolism.There is a significant decrease in glucose uptake in the frontal cortex and a decrease in the expression of key enzymes for fatty acid oxidation in the cerebral cortex.5 Qiliqiangxin capsules has a significant therapeutic effect on patients with clinical heart failure and can improve the cognitive function of rats with heart failure,which may be related to the improvement of endothelial function. |
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