Clinical Study Of The Relationship Between Soluble Receptor For Advanced Glycation End Products And The Heart Failure

1.BackgroundHeart failure is the end stage of the development of cardiovascular disease,as well as the ultimately death reason for many other diseases.The abnormalmyocardial energy metabolism,disorder of cardiac excitation contraction cou-pling,and the loss of myocardial cells and contractile protein resulted in cardiac the abnormalities of systolic function.The delayed calcium reset,obstacle of myosin-actin complex dissociation,uncoordinated ventricular diastole,all of this resultingin cardiac diastolic dysfunction. At present, the treatment of heart failure mainly includes the cardiotonic drug,diuresis,vasodilation and cardiac resyn-chronization therapy.Mortality of5years is still higher than60%,with a systematic treat. Itsuggests that there are some unknown factors in occurrence and development of heart failure.Soluble receptor for advanced glycation end products (sRAGE)has become the new breakthrough point of heart failure analyzing.sRAGE is the free RAGE, produced by shearing endogenous secretory RAGE (es-RAGE) and matrix metalloproteinase. The expression of sRAGE in vascular endothelial cells vascular smooth muscle cells,myocardial cells,macrophages, Tlymphocytes,dendritic cells, is higher in elderly,high glucose,high angiotensin II. RAGE has three isoforms:full length RAGE, dominant negative RAGE (DN-RAGE),endogenous secretory RAGE(es-RAGE).By activating extensive signal transduction pathways、inducing tissue factor release、regulating an abnormal gene expression of myocardial cells,full length RAGE is related to the occurrence and development of atherosclerosis, hypertension, cardiomyopathies. By neutralizing advanced glycation end products(Advanced glycation end products, AGEs), sRAGE can inhibited the direct damage to vascular endothelial cells, caused by AGEs, with protein cross-linking.There is a lot of molecular biology research and animal experiments confirmed that sRAGE takes part in heart failure;however there is little clinical evidence for the relationship between sRAGE and heart failure.This study focuses on the relationship between serum sRAGE level and heart failure as well as the malignant arrhythmia after heart failure, and demonstrates the feasibility and accuracy of serum sRAGE in clinical evaluation, treatment and prognosis of heart failure.2.Purpose(1) To analyzing the difference of serum sRAGE between heart failure patients with or without diabetes, and healthy people.(2) To explore the relationship between serum sRAGE and heart function, in heart failure with or without diabetes:①the correlation between serum sRAGE level and NYHA grade;②the relationship between serum level of sRAGE and and cardiac ultrasound (left ventricular ejection fraction LVFE, E/A ratio);③the correlation between serum sRAGE level and serum B type natriuretic peptide (BNP).(3)To explore the relationship between serum sRAGE levels and the arrhythmia in patients of heart failure patients with and without diabetes:①the correlation between serum sRAGE level and atrial fibrillation episodes;②the relation between the levels of serum sRAGE and frequent ventricular premature attack.3.Methods3.1Collection of clinical data52patients with definite diagnosis of heart failure (NYHA grade Ⅱ-Ⅳ) and10cases without heart failure in the control group were collected, in Department of Cardiology, provincial hospital affiliated to Shandong University, during2013.1.1- 2013.12.30. There are45men,17women, with an average age for79.3years old, from age60to80years old.3.2The separation of serum samplesAll the individuals are extracted10ml elbow venous blood, after fasting6-8hours, then added into inert separation gel tube. After15min static, we centrifuge the sample in2000bpm for20min, and then pick up the supernatant into EP tube.3.3Enzyme linked immunosorbent assay (ELISE) for human soluble receptor for advanced glycation end products (sRAGE).The double antibody sandwich method is applied to determinate the sRAGE level in test serum. The sRAGE is combined with sRAGE antibody, marked by HRP, on the microplate samples. Then forming the antibody-antigen-antibody complex, which is colored by TMB, after thoroughly washing. The TMB convert into blue with the HRP catalytic enzyme, then turns into yellow under the action of acid. Measure the absorbance (OD) in the450nm wavelength, then use the standard curve to calculate the concentration of sRAGE in samples.3.4Statistical analysisWith SPSS Statistics V19.0, the Comparison for samples basic statistics and serum average levels of sRAGE is made, in group of heart failure with or with-out diabetes, health crowd, using variance analysis, chi-square test, independent sample meant test. Using the chi-square test and linear Pearson correlation test, the correlation of serum levels of sRAGE is evaluated, between NYHA, LVEF, E/A ratio, the BNP, ventricular premature beat, atrial fibrillation.4.Results4.1The serum level of sRAGE in heart failure patients with diabetes, heart failure, with non-diabetes, healthy people were0.172±0.073μg/L、0.170±0.055μg/L>0.140±0.011μg/L. The serum level of sRAGE in group of heart failure with or without diabetes is significantly higher than those in healthy population (mean t test p<0.05), there was no significant difference of serum sRAGE between heart failure with and without diabetes. 4.2The relationship between serum sRAGE and heart function, in heart failure with or without diabetesThere is a significant correlation between serum sRAGE levels and NYH-A(chi square test, P=0.024),in groups of heart failure with non-diabetes,Pearsonlinear test(r=-0.231,p=0.101)also shows a negative correlation for the trend;there is a positive linear correlation between serum sRAGE and E/A ratio (Pearson linear test r=0.800,p<0.001).In group of heart failure patients with diabetes, the level of serum sRAGE and left ventricular ejection fraction LVEF)ave a significantly positive correla-tion (Pearson linear test r=0.456p=0.033).While, there is no obvious correlation between serum sRAGE levels and BNP.Generally,there is a positive correlation between serum sRAGE level and cardiac function; the serum sRAGE level wil1be higher when heart function is better.4.3The relationship between serum sRAGE and arrhythmia, in heart failure with or without diabetesIn heart failure without diabetes group, the serum level of sRAGE and ventricular premature beat have a negative correlation (Pearson linear test r=-0.469, p=0.033).A significant correlation is found between the level of serum sRAGE and atrial fibrillation (chi square test between P=0.046) Generally speaking, in the group of non-diabetic heart failure, the level of sRAGE in serum and cardiac arrhythmia are significantly correlated, and therefore it can be inferred that, the serum sRAGE level can predict the occurrence of arrhythmia and heart failure.5.ConclusionThere is clinical significance of evaluation for cardiac function, in heart failure patients with and without diabetes, using serum sRAGE levels. High levels of serum sRAGE can protect cardiac function, delaying the ventricular remodeling, reducing the incidence of arrhythmia and heart failure. The serum sRAGE level is an independent risk factor for heart failure, occurred in non-diabetic patients, so as to improve the level of serum sRAGE can be used as new breakthrough point for the treatment of non-diabetic chronic heart failure.