Correlative Research Of Serum Levels Of Hepatocyte Growth Factor In Patiens With Congestive Heart Failure

Purpose Congestive Heart failure(CHF) is a complex clinical syndrome which may occur as a consequence of most forms of heart disease.Moreover,the incidence rates of CHF are high and the five-year survival rates are similar to malignant tumor Nowadays,CHF is one of the major public health problems and appears to be increasing in prevalence and incidence.It is often characterized by a progressive remodeling of the left ventricular chamber. Activation of endogenous neurohormonal systems and cytokines appears to be involved in ventricular remodeling and thereby the progression of CHF.Ventricular remodeling is related to various processes such as cardiomyocytes loss due to necrosis or to apoptosis,hypertrophic responses of cardiomyocytes in the surviving regions,angiogenesis,and anarchitectural rearrangemen of the extracellular matrix.Apoptosis ,the independent and important factor of the ventricular remodeling , is the turning point at which CHF enters into the disompensated stage.Recent studies have shown that HGF is a potential antia- poptotic cytokine,which plays a role in the pathogenesis of CHF.Moreover,clinical studies also suggest a beneficial role of HGF in ventricular remodeling of CHF. HGF acts an antiapoptotic effect via the MEK/ERK-dependent GATA-4 phosphorylated signaling pathway and phosphatidyl inositolkinase pathway. Rescent foreign studies have suggested that serum HGF levels on stable CHF are correlated with the severity of CHF.Recent years, though many circulatory biologic markers have been demonstrated in assessing and diagnosing the prognosis of patients with CHF,the relationships between the serum HGF levels and CHF severity are rarely reported in domestic or foreign studies.In our study,we determine the HGF levels by NYHA classification and demonstrate their correlations so as to assess the prognosis of CHF via serum HGF levels and represent a novel mode therapy for CHF.Methods Eighty-eight patients with CHF were studied(57 men and 31women).Their age averaged 46-88years (70.1±5.6years),and mean CHF history was 0.7-8.1years(3.2±2.0years).Eighteen patients were in NYHA functional classⅡ,thirty-nine patients were in NYHA functional classⅢ,and the remaining thirty-one patients were in functional classⅣ.Fifty-eight had ischemic heart disease,six had rheumatic heart disease,nineteen had hypertensive heart disease,and five had dilated cardiomyopathy.Thirty-eight were complicated by hypertension.Eleven were complicated by diabetes mellitus.No patients had Acute cardiac sydrome,Acute cerebral vescular diease, trauma, malignant tumor, severe liver or kidney dysfunction, and percutaneous intracoronary stent implantation history within six months.The control group included 40 subjects,admitted for the non-heart disease patients(29 men,11women;69.3±4.1 years old).Sixteen had a history of hypertension,five had a history of diabetes mellitus.The excluded conditions were upon upfront standards.Left vemtricular ejection fraction(LVEF) were routinely measured by dopplar echocardiography,while the serum HGF levels were determined with bi-antibody enzyme-linked immuno-analytic method when all patients were hospitalized within 24 hours. Results In patients with NYHA classⅢandⅣ, serum HGF levels were 835.84 34.28ng/L, 1279.25 34.03ng/L respectively,which were significantly higher than that in the classⅡ(626.96±33.55ng/L) and control group (617.86±34.06g/L, P<0.01).The HGF levels in the classⅣgroup were marked increased compared with that in the classⅢgroup(P<0.01),while there were no significant differences between the classⅡgroup and the control group(P>0.05).In patients with NYHA classⅡ,Ⅲ,andⅣ,LVEF were 48.39±3.33%,36.13±4.26%,26.74±3.22%,respectively,which were lower compared with the control group(61.73±4.96%, P<0.01). Differences were considered statistically significant. The serum HGF levels were associated inversely with LVEF(r=-0.961,P<0.01).Discussion Subsequent studies have demonstrated that HGF possesses multipotent activities such as mitogenic,motogenic, morphogenic and antiopoptotic activities.HGF has also been shown to induce tissue regeneration in a variety of organs.Ueno et al. have found that in patiets with CHF,the serum HGF concentration was marked increased ,while gradually decreased when the patients were stable.The present study indicates that elevated levels of CHF are associated with CHF severity.In NYHA classⅢand NYHA classⅣ, levels of HGF are dramatically increased compared with the classⅡand control group.It shows that increased HGF levels are likely a compensated reaction of human body,but also as a warning of adverse prognosis,which share the same view of Ueno et al.In Lamblin et al. studies, 529 patients followed-up for 988 days,the similar conclusions were demonstrated.The survival curve suggested that elevation of baseline HGF levels were correlated with adverse clinical outcome.Left ventricular ejection fraction(LVEF), provides a practical means of LV systolic function. Ejection fraction is related with contractility of cardiomyocytes,thus increased contractility exhibits a greater stroke volume and ejection fraction.Despiste the oretical limitations,LVEF provides a simple and useful clinical indicator of overall LV contractile strength,whereas there would exist a certain deviation according to different measurements methods.At present, NYHA classification is a general standard for roughly assessing CHF severity,however, the subjectivity of patients'complaints cannot be avoided and the symptoms may deflect from laboratory examinations sometimes.Our results demonstrate that HGF levels are significantly increased in NYHA classⅢandⅣmeanwhile,the elevated levels of serum HGF are associated with a reduction of LVEF,which indicates that changes in the levels of HGF may predict the ventricular loads and cardiac function. Because its objectivity,the subjective judges in NYHA classification and deviations in determination of LVEF can be avoided.So the levels of HGF may index cardiac function more objectively and play a more important role in assessing the prognosis and clinical prognosis in the patients of CHF.In HGF gene treated animal models of CHF,either the human recombinant HGF therapy or adenovirus encoding human HGF administration can greatly reduce myocardial apoptosis and remodeling,preserve left ventricular geometry, as well as improve cardiac function.Several mechanisms appear to underline these beneficial effects, including anti-apoptosis , angiogenesis, anti-fibrosis,and/or myocardial hypertrophy.Our study suggests that marked increased HGF levels are associated with CHF severity which is a compensated reaction in severe CHF.As a potent antiapoptotic and cardioprotective factor,HGF gene or protein treatment is a possible novel alternative to conventional therapy in patients with CHF.Conclusion The elevated serum levels of HGF are correlated with higher NYHA class of CHF.In addition,LVEF is negatively related with serum HGF levels which are the more powerful predictors of cardiac function in the patients with CHF.Furthermore, HGF is an attractive option for treating CHF,such as HGF gene or protein therapy and our data may provide some basis for it.