Increased Serum Levels Of Tumor Necrosis Factor Alpha And Matrix Metalloproteinase-9 In Patients With Chronic Heart Failure

BackgroundIt is recognized that the fundamental mechanism responsible for the regression of chronic heart failure is myocardial remodeling caused by long-time neurohumoral activation.We have made sure that such factors as norepinephrine(NE), angiotensin Ⅱ (Ang Ⅱ ),aldosterone(Ald),endothelin(ET),pro-inflammatory cytokines such as tumor necrosis factor alpha(TNF- α ),interleukin-6(IL-6) and interleukin-1 beta(IL-1 3 ),matrix metalloproteinases(MMPs),oxidant stress,growth factor can induce cardiac remodeling. Of these, TNF- α and MMPs are research hotspots at present. Serum levels of TNF- α and MMPs are higher in patients with heart failure. They are involved in myocardial remodeling and contribute to myocardial fibrosis, left ventrical dilatation and failure of eject function. TNF- α regulates MMP gene expression and animal experimental studies have shown that TNF- α stimulates MMP activity in cardiac fibroblasts.Foreign researchs had shown that increased serum TNF-α were accompanied by elevated MMP levels in CHF patients whereas the reduction in serum TNF- α resulted in reduced serum MMP. However,few domestic studies of change of serum TNF- ct and MMP and their relation in CHF patients have beenconducted up to day. Aminoterminal propeptide of type Ⅲ procollagen(PⅢNP) has been used to evaluate myocardial fibrosis in patients with hypertension and CHF. TNF- a and MMP both promote myocardial fibrosis,but the relations between either of them and PⅢNP are not known. ObjectiveMatrix metalloproteinase-9(MMP-9) is a gelatinase of MMPs.The study aims at observing serum levels of TNF- α and MMP-9 in CHF patients and clarifying their relation, the relation between either of them and PⅢNP(the marker of myocardial fibrosis), the relation between either of them and heart disfunction,and evaluating their functions in promotion of systolic heart failure. Methods63 patients with chronic heart failure(concluded 25 cases of hypertension,23 cases of coronary heart disease, 10 cases of idiopathic dilated cardiomyopathy and 5 cases of rheumatic heart disease) were divided into New York Heart Association functional class Ⅱ,Ⅲ and Ⅳ groups and were again divided into diastolic heart failure(DHF) group and systolic heart failure(SHF) group according to the parameters of 2-DE. 31 health people acted as control group.The additional factors which may influence serum levels of TNF- α , MMP-9 or PIIINP were excluded,such as acute or chronic infective disease, diabetes, acute heart failure, serious liver or kidney disfunction,autoimmune disease,cancer,chronic respiratory tract disease,and unstable angina pectoris,myocardial infaction,rheumatic activity, taking immune-related medicine of late three month.Serum samples each about 4ml were collected on a empty stomach in the morning and were stored at -80℃. Serum samples of 26 CHF patients that accepted three months'conventional therapy were collected again. Serun levels of TNF- α and PIIINP were measured by specific radioimmunoassay and those of MMP-9 were measured by enzyme-linked immunosorbent assays.Doppler echocardiographic studies were performed and the left ventricular(LV) eject fraction(EF),the early rapid filling velocity(E) and atrial contraction velocity(A),E/A ratio,LV end-diastolic dimension (LVIDd), end-diastolic interventricular septal wall thickness (IVST) and end-diastolic LV posterior wall thickness(LVPWT) wererecorded.The diagnosis standard of DHF is EF≥50% and E/A<1, and that of SHF isEF≤40% and LVIDd enlarges.Results1. Serum levels of TNF- a in the control subjects was 12.64 ± 2.58pg/ml,in CHF patients 27.14 ±5.29pg/ml, in NYHA functional class II patients23.75 ± 3.61pg/ml, class III 26.73 ±4.00pg/ml and class IV 31.64 ± 5.41 pg/ml;Serum levels of MMP-9 in the control subjects was 28.25 ± 5.32ng/ml, in CHF patients 82.08 ± 14.59ng/ml,in NYHA functional class II patients 62.29 ± 7.68ng/ml,class Ⅲ 80.64 ± 9.05ng/ml,and class IV 87.12 ± 9.50 ng/ml;Serum levels of PⅢNP in the control subjects was 2.42 ± 0.35 μg/ml,in CHF patients 5.30 ± 1.16 μ g/ml,in NYHA functional class Ⅱ 4.67± 0.92 μ g/ml,classⅢ5.41 ± 1.13 μ g/ml,classⅣ 5.82±1.18 μ g/ml.Serum levels of TNF- α ,MMP-9 and PⅢNP were all significantly higher in CHF patients than in control subjects(p<0.01). Serum levels of TNF- α increased with the increase of NYHA functional class(p<0.01). Serum levels of MMP-9 and PⅢNP were significantly higher in NYHA functional classⅢthan in class II (p<0.01 and p<0.05 respectively),but their difference between classⅢand Ⅳ are not significant.2. Serum levels of TNF- α ,MMP-9 and PⅢNP in DHF patients were 24.35 ±3.25 pg/ml,67.39 ± 10.36ng/ml,4.58 ± 0.92 μ g/l respectively; Those in SHF patients were 31.99 ± 4.64 pg/ml, 88.46 ± 10.73 ng/ml, 6.02 ± 1.17 μ g/l respectively.Every parameter was higher in SHF patients than in the control subjects(p<0.01).3. Serum levels of TNF- α ,MMP-9 and PⅢNP in 26 CHF patients accepted conventional therapy were 28.57 ±5.68 pg/ml, 81.40 ± 14.63 ng/ml, 5.53 ± 1.28 μ g/l respectively before therapy and 18.90 ±4.20 pg/ml, 52.75±11.24 ng/ml, 4.30 ±0.88 μ g/l after therapy. Every parameter after therapy was much more lower than those before therapy(p<0.01).4. In CHF patients,there was a significant positive correlation between serum levels of TNF- α and MMP-9(r=0.750, p<0.001) and they all positively correlated with serum levels of PⅢNP (r1=0.362, p1=0.004; r2=0.406, p2=0.001). Serum levels ofPIIINP negatively correlated with E values(r=-0.603, p<0.001) and E/A ratio(r= -0.637, p<0.001).Serum levels of TNF- α negatively correlated with EF values( r=-0.633, p=0.005) and had no correlation with other parameters of 2-DE. Serum levels of MMP-9 had no significant correlations with any parameters of 2-DE. Conclusion1. TNF- α and MMP-9 can be indirect markers evaluating the extent of heart disfunction and myocardial fibrosis in CHF patients.2. TNF- α and MMP-9 may both play an important role in the development and progression of chronic heart failure especially systolic heart failure.The blockade of them may partially reverse pathological changes of cardiac remodeling and prevent the progression of heart failure.3. In CHF patients,there was a significant positive correlation between serum levels of TNF- α and MMP-9,therefore we can inhibit MMP-9 indirectly by reducing the level of TNF- α to prevent myocardial remodling.4. Checking serum levels of TNF- α and MMP-9 in CHF patients may indirectly understand the status of cardiac remodeling and contribute to evaluate the effect of the treatment and guide the latter clinical treatment.