| Heart failure(HF),with high mortality and disability,is the end stage of many cardiovascular diseases.Patients with HF are often associated with cognitive dysfunction.Early manifestations of heart failure are mild cognitive dysfunction,and late stage of heart failure can develop into dementia,but the pathological mechanism is unknown.Heart failure combined with cognitive dysfunction increases the hospitalization rate and mortality of patients,which seriously affects the quality of life of patients.Chinese medicine has the views of "heart governing blood and vessels" and "heart controlling mental activities",the"heart" of the concept of Chinese medicine is "functional heart","systematic heart",and there is a close relationship between "heart" and other systems.The understanding of "heart" by Chinese medicine not only includes the concept of "heart" of Western medicine,but also the function of "brain" which is part of modern medicine.Its connotation is richer and its extension is broader.Cognitive dysfunction after heart failure not only reflects the close relationship between the heart and the brain,but also fits well with the theory of "heart controlling mental activities" in Chinese medicine.Brain natriuretic peptide(BNP)is mainly secreted by the ventricle and positively correlated with the occurrence of cognitive dysfunction after heart failure,which provides a new research entry point for heart and brain correlation.Ischemic heart disease is the most important factor in the pathogenesis of HF.Therefore,we simulated the clinical phenomenon by ligating the anterior descending coronary artery of the rat to cause a heart failure model after myocardial infarction.By establishing a model of murine brain natriuretic peptide(BNP)injected into the lateral ventricle,we can directly observe how the BNP secreted by the heart will affect brain tissue.Through model evaluation,cognitive behavioral evaluation,radionuclide-labeled glucose(18F-fluorodeoxyglucose,18F-FDG)metabolism imaging technology(Positron emission tomography-Computed tomography,PET-CT),ultrastructure of brain neurons,glycolipid energy metabolism,etc.we explored the possible mechanisms by which HF is susceptible to cognitive impairment.Our research provides a basis for the theory of "heart controlling mental activities" in Chinese medicine,and it sounds an alarm for early prevention and treatment of such diseases.Objectives:1.Morris water maze test to clarify the evolution and characteristics of cognitive dysfunction in rats with heart failure.2.Through the PET-CT and pathomorphological examination of brain tissue,the evolution and characteristics of glucose metabolism and local brain neurons in different brain regions were elucidated.3.Intraventricular injection of mouse-derived BNP was used to directly observe the effects of BNP secreted by the heart on brain cognitive function and systemic glucose and lipid metabolism.4.To explore the effect and possible mechanism of Chinese medicine qiliqiangxin capsule on cognitive dysfunction after heart failure.Methods:1.The heart failure model after myocardial infarction was established by ligation of the anterior descending coronary artery in rats,and designed at two time points of 10/60 days.Rats with successful modeling were randomly divided into sham group and model group at 10 days.The 60-day time points were randomly divided into sham group,model group,qiliqiangxin group and enalapril group.The electrocardiogram was measured before rats were sacrificed to assess the cardiac structure and function.2.Morris water maze was used to evaluate the cognitive function of rats with heart failure,Morris water maze test was divided into spatial acquisition trial,probe trial and spatial working memory trial.Test indicators include average latency,path length,number of times of passing over,and swimming speed,and so on.3.Screening 5-6 rats each group with heart failure at 10/60 days by cognitive behavioral test results,PET-CT was detected by tail vein injection of radionuclide-labeled 18F-FDG,and the whole brain standard brain region was divided according to the atlas in Paxinos and Watson space by SPM8 software,and all brain regions were statistically analyzed.4.Screening 3 rats each model group and sham group with heart failure at 10/60 days were detected by Nissl staining to observe neuron and Nissl body changes;screening 3 rats each group with heart failure at 60 days by cognitive behavioral test results were examined by transmission electron microscopy to observe the ultrastructure of neurons and count the number of synapses.5.The rat brain-derived BNP channel was established by inserting a trocar into the cerebral ventricle.The experiment was divided into sham operation group and BNP group,and the administration time was 15 days.Morris water maze(spatial acquisition trial,probe trial and reverse platform test)was used to detect the effect of BNP on brain cognitive function.6.Serum samples of heart failure rats and lateral ventricle injection of Murine BNP rats were tested for blood glucose,insulin,non-esterified fatty acid and ?-HB.Results:1.The ischemic necrosis of the left ventricular anterior wall of the model group was pale in heart failure rats after myocardial infarction for 10 days;in the 60-day model group,the left ventricular wall collapsed and thinned to form ventricular aneurysm.The model group showed obvious pathological Q wave changes on the electrocardiogram on the 2nd day after surgery(including I lead,AVL lead and V1-V6 lead).Left ventricular end-diastolic diameter(LVDd),left ventricular end-systolic diameter(LVDs),left ventricular end-diastolic volume(LVEDV),and left ventricular end-systolic volume(LVESV)were significantly increased in the 10/60-day model group were significantly higher than those in the sham group(P<0.01);left ventricular end-diastolic anterior wall thickness(LVAWd),left ventricular end-systolic anterior wall thickness(LVAWd),and left ventricular posterior end-systolic wall thickness(LVPWs)were significantly lower in the model group than in the sham group(P<0.01);left ventricular posterior end-diastole wall thickness(LVPWd)was not statistically different(P>0.05).At the same time,left ventricular ejection fraction(EF)and fraction Shortening(FS)were significantly lower(P<0.01).The drug group can improve the morphological parameters of the heart(LVDd,LVDs,LVEDV,LVESV,LVAWd,LVAWs,LVPWd,LVPWs)(P<0.01 or P<0.05),but the functional indicators(EF,FS)are not effective(P>0.05).The improvement of morphological indexes by qiliqiangxin capsule was comprehensive and the effect was better than that of enalapril;enalapril only played a role in LVPWd and LVPWs(P<0.01),and the other indicators showed no significant relief.2.Compared with the sham group,the 10-day model group of heart failure after myocardial infarction,there were no statistical differences in all data of spatial acquisition trial and probe trial(P>0.05),well,all the test indicators showed 1-2 statistical differences in the spatial working memory trial(P<0.05).There was a statistical difference(P<0.05)in the 4th/8th percentage length in target quadrant in the 60-day model group of heart failure after myocardial infarction,there was no statistical difference in the other indicators;the number of times of passing over platform in the model group was significantly lower than that of the sham group(P<0.05);all indicators showed 1-7 statistical differences in the spatial working memory trial(P<0.05 or P<0.01),on the first and third days of the experiment(the platform was changed to the opposite side and tested 3 times a day),when the platform is replaced to the opposite side,the average latency and path length traveled by the sham group to find the platform is higher than the model group:high-low-low;the average latency and path length spent in the original target quadrant:high-low-low;the average latency and path length spent in the target quadrant:low-high-high,the model group results are opposite or the regularity is not obvious.There was no significant difference in the swimming speed between the model group and the sham group at two time points(P>0.05).The probe trial of the qiliqiangxin group was significantly higher than that of the model group(P<0.05),but lower than the sham group.The baseline of the drug group was basically within the upper and lower limits of the sham group and the model group.The trend of the average latency and path length indicator on the 1/3 day(high-low-low)in the drug group was basically consistent with the sham group.3.The glucose uptake of Midbrain and Pontine in the 10-day model group was lower than that in the sham group,well,in the prefrontal cortex(PFC),medial prefrontal cortex(mPFC),cingulate gyrus(CG),and basal ganglia(BG)increased compared with the sham group.At this time point,the cerebral glucose metabolism in the model group was manifested by local enhancement.The glucose uptake of PFC and BG in the 60-day model group of heart failure was reduced compared with the sham group,and the brain glucose metabolism in the model group was manifested as local decrease.4.In the 10-day model group of heart failure,a small number of neurons in the frontal lobe and hippocampus were irregular in shape,a small amount of Nissl was unevenly stained;in the 60-day model group,the multiple neurons in the frontal lobe and hippocampus were pyknosis and deep-stained,the number of Nissl bodies is reduced,a large number of dyeing is uneven,and the neurons in the hippocampal CA1 area were disordered.Transmission electron microscopy of frontal lobe of heart failure in 60 days of rats:The model group had multiple neuronal pyknosis,edema of the foot of astrocytes surrounding the neuron,organelle swelling,swollen mitochondria with crista fragmentation,endoplasmic reticulum expansion,polyribosome depolymerization;the number of synapses in the model group was significantly lower than that in the sham operation group(P<0.01).The drug group can improve the above-mentioned damaged neuronal 'structure,eliminate astrocytes edema,improve microcirculation,and restore the number of synapses(P<0.01).5.The spatial acquisition trial of the lateral ventricle injection of the murine BNP model group:the single average latency of the first time,the path length of the first day,and the summary average latency and path length of the BNP group were lower than the sham group and had statistical difference(P<0.05).Probe trial:The number of times of passing over in the model group was more than that in the sham group,but there was no statistical difference(P>0.05),In the reverse platform trial,the average latency of the first time,the path length of the first time,and the summary average latency and path length of the BNP group were lower than the sham group and had statistical difference(P<0.05 or P<0.01).6.There were no significant differences in blood glucose,insulin,non-esterified fatty acid and ?-HB between the model group and the sham group in 10/60-day HF rats(P>0.05).There was no significant difference in blood glucose and ?-HB between the BNP group and the sham group(P>0.05).The insulin and non-esterified fatty acid of model group was significantly higher than the sham group(P<0.05 or P<0.01).In the 60-day heart failure group,the blood glucose level of enalapril was higher than that of the other groups(P<0.05).The other indexes of insulin,non-esterified fatty acid and ?-HB were not significantly different among the four groups(P>0.05).Conclusion:1.The rat model of heart failure after myocardial infarction induced by ligating the anterior descending coronary artery is a reliable model for studying clinical HF with cognitive dysfunction.The cognitive impairment of heart failure was not obvious for 10 days.The heart failure was characterized by mild cognitive dysfunction for 60 days.The sensitivity of Morris water maze method was:spatial working memory trial>probe trial>spatial acquisition trial.2.Heart failure for 10 days is mainly characterized by compensatory increase in cerebral glucose metabolism,and 60 days is characterized by decreased brain glucose metabolism.The frontal lobe and basal ganglia are the key brain regions for studying cognitive impairment after heart failure.Abnormal brain glucose metabolism is an important cause of cognitive impairment in heart failure rats.3.Neurons and organelles with heart failure for 10 days are not significantly damaged.A large number of neurons were condensed and degenerated in 60 days,organelles were damaged,and synaptic counts were significantly reduced.These changes are the structural basis for the occurrence of cognitive impairment.4.Injecting murine BNP into the lateral ventricle can enhance the spatial learning and memory ability of rats,but it can't break the highest threshold.BNP can regulate the metabolism of glycolipids.5.qiliqiangxin capsule not only has significant improvement in cardiac structure and cognitive function(better than enalapril),but also improves brain glucose metabolism and neuronal ultrastructure,and restores the number of synapses.6.This study shows that cardiac dysfunction can affect the cognitive function of the brain,and there is a close relationship between the heart and the brain.At the same time,it also provides some evidence to support the theory of "heart controlling mental activities" in Chinese medicine.The traditional Chinese medicine qiliqiangxin capsule has good curative effect,and it should pay sufficient attention to the cognitive dysfunction after heart failure in clinical practice,and carry out early prevention and treatment. |
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