| Objective:To investigate the changes and mechanisms of myocardial energy metabolism with aging.Method:Male SD Rats of 2 months old were choosed into the young group while those of 14 months old were choosed into the aging group. Intragastric administration of Trimetazidine,L-carnitine and Physiological Saline for 4 weeks. 6 groups were recorded as YT(Young & Trimetazine), YL(Young & L-carnitine), YC(Young & control);AT(Aging & Trimetazine), AL(Aging & L-carnitine), AC(Aging & control).(1)4 weeks later,Evaluate cardiac systolic and diastolic function by Echocardiography.(2)Determinate ATP content in the apical tissue by high performance liquid chromatography(HPLC).(3)Observe myocardial tissue by HE staining.(4)Observe the myocardial ultrastructure under transmission electron microscope.(5)Detect GLUT-4 and CPT-1 expression by Western blot.(6)Detect serum MDA, SOD, Glu, TG, TC, LDL-c, HDL-c, AST, ALT, ALP, BUN, Cr, LDH content by biochemical method.Result:(1)The echocardiography: LVEF of all the rats were normal,but LVEF of aging control group is lower than that of the young control group; Both Trimetazidine and L-carnitine can significantly improve LVEF and FS, Trimetazidine was better in aging rats while L-carnitine was better in the young group.(2)Detection of ATP content in the apical tissue of rats in HPLC: ATP in aging rats was significantly lower than that in young rats, Both Trimetazidine and L-carnitine can enhance the ATP productivity in aged heart, and trimetazidine is better. However,the young medication group produced less ATP than the control group.(3)The myocardial tissue HE staining: aging & control group: muscle fiber fracture,dissolution, evacuation, disorder, interstitial hyperplasia, inflammatory cell infiltration. Trimetazidine and L-carnitine improved the aging tissue damage.The muscle fibers of the young group were arranged more closely, in order to have no fracture, dissolution, and no inflammatory cell infiltration.(4)Observe myocardial ultrastructure by transmission electron microscope: With the age increasing,the arrangement disorder and abruption of myocardiac cells,the swelling of mitochondria and adecrease in mitochondrial cristaes,and anincrease in intercellular connective tissue were found in the aging rats. The application of trimetazidine and L-carnitine in young rats showed mild mitochondrial injury lesions, while the application of these two drugs in aging rats improved mitochondrial swelling and vacuolization obviously.(5)Detecte the expression of GLUT-4 and CPT-1 by Western blot: GLUT-4 and CPT-1 expression decreased in aging rats. GLUT-4 / CPT-1 increased in aging than that in young.Both Trimetazidine and L-carnitine decreased the expression of GLUT-4 and CPT-1 in young rats, but inhanced the expression in aging rats.(6)Serum:The content of serum MDA significantly increased in the aging, while there is no obvious difference of SOD activity between the aging and the young. Both Trimetazidine and L-carnitine improved the activity of SOD.No significantly differences was found in the function of heart, liver or kidney in all the rats.Conclusion:Both glucose metabolism and fatty acid metabolism decreased with aging. The main substrate of myocardial metabolism in young was fatty acids, while in the aging rats that was glucose,which is also called “the recapitulation of fetal energy metabolism”.If this compensation can't effectively improve the productivity of energy, then the peroxide material may accumilated,ATP concentration decreased,and the quantity and structure of mitochondria changes including mitochondria swelling, mitochondria ridge sparsed, and vacuolar degeneration. As a result,the oxidation ability of myocardium decreased seriously,which finally caused the heart contract and diastole function decreased and even the structure was also damaged. Both Trimetazidine and L-carnitine can improve myocardial energy metabolism, reduce tissue injury, enhance the antioxidant capacity by regulating substrates of cardiac energy metabolism in aging rats, and Trimetazidine is better.This maybe related with the optimization of glucose which produce more energy with less oxygen. The application of drugs in the myocardial energy metabolism in young rats may reduce the myocardial capacity, damage mitochondria structure and thus harmful.,which suggests that we should fully consider the influence of age on the metabolism in the drug treatment of energy metabolism.Background:Heart failure is the end stage of all kinds of heart disease, with the aging society, the incidence and prevalence rate of heart failure is increasing year by year. Currently the diagnosis of heart failure relies on ejection fraction(LVEF) as the "gold standard". At the same time, the guidelines also recommend application of NTpro BNP as a supporting serum marker in the diagnosis and monitoring of heart failure. However, in clinical practice, a simple application of LVEF and NT-pro BNP do not always reflect the progression precisely.Therefore, clinicians hope to have a more comprehensive, more accurate assessment system of heart failure to reflect the severity of the disease and guide clinical diagnosis and treatment. We believe that serological biomarkers will be suitable because of different pathophysiological mechanisms.Phosphocreatine, Levosimendan and Recombinant human brain natriuretic peptide are used in the clinical therapy of acute heart failure and chronic decompensated heart failure with their good therapeutic effect. But there is no clear application standards for these 3 drugs at present. As these three drugs have different pharmacological mechanisms, it is possible to use biomarkers to search for the more suitable drugs for different subsetsObjective :(1)To assess the disease condition and monitor the effect of treatment with the help of a number of serological biomarkers which mean different pathophysiological mechanisms in heart failure;(2)To classify patients with heart failure into subgroups on basis of biomarkers, to search for the more suitable drugs for different subsets,to promote individual medical and precise medical implementation, and ultimately to contribute to the rational use of clinical resources.Methods :160 patients were arranged into this Random parallel positive controlled clinical studies,with 40 cases in each group.1)Control group(Con group):These patient received routine medication treatment according to the China Heart Failure Guidelines.2)Phosphocreatine group(PCr group):These patients received Phosphocreatine in addition to routine medication.3)Levosimendan group(Lev group) :These patients received Levosimendan in addition to routine medication.4)Recombinant Human Brain Natriuretic Peptid group(rh BNP group) :These patients received Recombinant Human Brain Natriuretic Peptid in addition to routine medication.The usage,dosage and course of the above drugs were in accordance with instructions.The vital signs and clinical manifestations of heart failure were monitored, echocardiography was performed to measure the cardiac functional parameters of left ventricular ejection fraction(LVEF), ELISA was conducted to examine the serum levels of NT-pro BNP, Copeptin, ST2, and Galectin-3 before and 1 week after treatment.Results :150 patients were included in the results of the analysis. 1)Clinical efficacy rate:Con group was62.5%(25/40), PCr group is 84.2%(32/38, lev group was 89.2%(33/37) and rh BNP group was 85.7%(30/35)(x2=10.744,P=0.013). All experimental groups were better than the control group(P=0.042,0.008,0.035),while there was no statistical difference among the experimental groups(P>0.05). 2) serum biomarkers before and after treatment: All the biomarkers before treatment of each group are homogeneous(P>0.05).(1)NT-pro BNP level was decreased in all groups after treatment(Con t=5.643,P<0.001;PCr t=7.633,P<0.001;Lev t=5.794,P<0.001;rh BNP t=8.820,P<0.001), There were significant differences between the groups(F=2.998, P=0.039), every experimental group were better than the control group(P = 0.041, 0.029, 0.011). There was no statistical difference in all the experimental groups(P>0.05).(2)Copeptin levels was decreased in all groups after treatment(Con t=5.044,P<0.001;PCr t=5.057,P=0.001;Lev t=3.95,P=0.006;rh BNP t=6.669,P=0.001). There were significant differences between the groups(F=3.131,P=0.035), every experimental group were better than the control group(P=0.039,0.035,0.018). There was no statistical difference in all the experimental groups(P>0.05).(3)ST2 decreased in All the groups(Con t=3.741,P=0.004;PCr t=4.137,P=0.003;Lev t=6.04,P<0.001)except the rh BNP group(rh BNPt=0.549,P=0.595>0.05). There were significant differences between the groups(F=7.452,P=0.001),and the Lev group is more significant than the control group( P=0.045)and rh BNP(P<0.001). There is no statistical significance between Lev group and PCr group(P = 0.084). There no significant difference between PCr group and control group(P = 0.856). The rh BNP group ST2 decreased significantly lower than the other groups(rh BNP vs Con P = 0.015, rh BNP vs PCr P = 0.014, rh BNP vs Lev P < 0.001).(4) Galectin-3 was significantly decreased(P<0.05) in Levosimendan group, while the else groups have no signifident change(P>0.05). 3) safety observation: There was no significant defference in the incidence of adverce reaction among all the groups(P>0.05). 4)NT-pro BNP and ST2 were positively correlated by spearman method(r=0.326, P=0.003).Both ST2( r=-0.378,P=0.004) and NT-pro BNP( r=-0.273,P=0.042) were negitively correlated with LVEF.NT-pro BNP was positively correlated with age,while Copeptin? Galectin-3?ST2 have no relation with age, gender, Primary disease category. Conclusions: 1. Application of NT-pro BNP, Copeptin, ST2, Galectin-3 can assess the condition of patients with heart failure more comprehensively, and Galectin-3 can be used as a secondary index in cardiac function classification. NT-pro BNP, Copeptin, ST2 can monitor the treatment effect immediately, and ST2 is more sensitive, because it is not affected by age, gender, the incidence of the disease, and have a good correlation with LVEF, NT-pro BNP. 2. Detecting the serum biological markers can be as a reference index for clinical use: Patients with NT-pro BNP, copeptin elevated are more suitable to choose phosphocreatine, Levosimendan, Recombinant Human Brain Natriuretic Peptide. Patients with elevated galectin-3 is particularly suitable for the treatment of levosimendan. Patients with elevated ST2 should avoid the use of recombinant human brain natriuretic peptide. |
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