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Usefulness of the Hepatocyte Growth Factor as a Predictor of Mortality in Patients Hospitalized With Acute Heart Failure Regardless of Ejection Fraction

      Hepatocyte growth factor (HGF) plays a role in the improvement of cardiac function and remodeling. Their serum levels are strongly related with mortality in chronic systolic heart failure (HF). The aim of this study was to study prognostic value of HGF in acute HF, interaction with ejection fraction, renal function, and natriuretic peptides. We included 373 patients (age 76 ± 10 years, left ventricular ejection fraction [LVEF] 46 ± 14%, 48% men) consecutively admitted for acute HF. Blood samples were obtained at admission. All patients were followed up until death or close of study (>1 year, median 371 days). HGF concentrations were determined using a commercial enzyme-linked immunosorbent assay (human HGF immunoassay). The predictive power of HGF was estimated by Cox regression with calculation of Harrell C-statistic. HGF had a median of 1,942 pg/ml (interquartile rank 1,354). According to HGF quartiles, mortality rates (per 1,000 patients/year) were 98, 183, 375, and 393, respectively (p <0.001). In Cox regression analysis, HGF (hazard ratio1SD = 1.5, 95% confidence interval 1.1 to 2.1, p = 0.002) and N-terminal pro b-type natriuretic peptide (NT-proBNP; hazard ratio1SD = 1.8, 95% confidence interval 1.2 to 2.6, p = 0.002) were independent predictors of mortality. Interaction between HGF and LVEF, origin, and renal function was nonsignificant. The addition of HGF improved the predictive ability of the models (C-statistic 0.768 vs 0.741, p = 0.016). HGF showed a complementary value over NT-proBNP (p = 0.001): mortality rate was 490 with both above the median versus 72 with both below. In conclusion, in patients with acute HF, serum HGF concentrations are elevated and identify patients at higher risk of mortality, regardless of LVEF, ischemic origin, or renal function. HGF had independent and additive information over NT-proBNP.
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      References

        • Nakamura T.
        • Nishizawa T.
        • Hagiya M.
        • Seki T.
        • Shimonishi M.
        • Sugimura A.
        • Tashiro K.
        • Shimizu S.
        Molecular cloning and expression of hepatocyte growth factor.
        Nature. 1989; 342: 440-443
        • Matsumoto K.
        • Nakamura T.
        Emerging multipotent aspects hepatocyte growth factor.
        J Biochem. 1996; 119: 591-600
        • Nakamura Y.
        • Morishita R.
        • Higaki J.
        • Kida I.
        • Aoki M.
        • Moriguchi A.
        • Yamada K.
        • Hayashi S.
        • Yo Y.
        • Nakano H.
        • Matsumoto K.
        • Nakamura T.
        • Ogihara T.
        Hepatocyte growth factor is a novel member of the endothelium specific growth factors: additive stimulatory effect of hepatocyte growth factor with basic fibroblast growth factor but not with vascular endothelial growth factor.
        J Hypertens. 1996; 14: 1067-1072
        • Montesano R.
        • Schaller G.
        • Orci L.
        Induction of epithelial tubular morphogenesis in vitro by fibroblast-derived soluble factors.
        Cell. 1991; 66: 697-711
        • Lokker N.A.
        • Mark M.R.
        • Luis E.A.
        • Bennett G.L.
        • Robbins K.A.
        • Baker J.B.
        • Godowski P.J.
        Structure-function analysis of hepatocyte growth factor: identification of variants that lack mitogenic activity yet retain high affinity receptor binding.
        EMBO J. 1992; 11: 2503-2510
        • Huh C.G.
        • Factor V.M.
        • Sanchez A.
        • Uchida K.
        • Conner E.A.
        • Thorgeirsson S.S.
        Hepatocyte growth factor/c-met signalling pathway is required for efficient liver regeneration and repair.
        Proc Natl Acad Sci U S A. 2004; 101: 4477-4482
        • Morishita R.
        • Aoki M.
        • Hashiya N.
        • Yamasaki K.
        • Kurinami H.
        • Shimizu S.
        • Makino H.
        • Takesya Y.
        • Azuma J.
        • Ogihara T.
        Therapeutic angiogenesis using hepatocyte growth factor (HGF).
        Curr Gene Ther. 2004; 4: 199-206
        • Borowiak M.
        • Garratt A.N.
        • Wustefeld T.
        • Strehle M.
        • Trautwein C.
        • Birchmeier C.
        Met provides essential signals for liver regeneration.
        Proc Natl Acad Sci U S A. 2004; 101: 10608-10613
        • Hamanoue M.
        • Kawaida K.
        • Takao S.
        • Shimazu H.
        • Noji S.
        • Matsumoto K.
        • Nakamura T.
        Rapid and marked induction of hepatocyte growth factor during liver regeneration after ischemic or crush injury.
        Hepatology. 1992; 16: 1485-1492
        • Balkovetz D.F.
        • Lipschutz J.H.
        Hepatocyte growth factor and the kidney: it is not just for the liver.
        Int Rev Cytol. 1999; 186: 225-260
        • Igawa T.
        • Matsumoto K.
        • Kanda S.
        • Kanda S.
        • Saito Y.
        • Nakamura T.
        Hepatocyte growth factor may function as a renotropic factor for regeneration in rats with acute renal injury.
        Am J Physiol. 1993; 265: F61-F69
        • Nakamura Y.
        • Morishita R.
        • Nakamura S.
        • Aoki M.
        • Moriguchi A.
        • Matsumoto K.
        • Nakamura T.
        • Higaki J.
        • Ogihara T.
        A vascular modulator, hepatocyte growth factor, is associated with systolic pressure.
        Hypertension. 1996; 28: 409-413
        • Nishimura M.
        • Ushiyama M.
        • Nanbu A.
        • Ohtsuka K.
        • Takahashi Y.
        • Yoshimura M.
        Serum hepatocyte growth factor as a possible indicator of arteriosclerosis.
        J Hypertens. 1997; 15: 1137-1142
        • Matsumori A.
        • Furukawa Y.
        • Hashimoto T.
        • Ono K.
        • Shioi T.
        • Okada M.
        • Iwasaki A.
        • Nishio R.
        • Sasayama S.
        Increased circulating hepatocyte growth factor in the early stage of acute myocardial infarction.
        Biochem Biophys Res Commun. 1996; 221: 391-395
        • Ueno S.
        • Ikeda U.
        • Hojo Y.
        • Arakawa H.
        • Nonaka M.
        • Yamamoto K.
        • Shimada K.
        Serum hepatocyte growth factor levels are increased in patients with congestive heart failure.
        J Card Fail. 2001; 7: 329-334
        • Lamblin N.
        • Susen S.
        • Dagorn J.
        • Mouquet F.
        • Jude B.
        • Van Belle E.
        • Bauters C.
        • de Groote P.
        Prognostic significance of circulating levels of angiogenic cytokines in patients with congestive heart failure.
        Am Heart J. 2005; 150: 137-143
        • Rychli K.
        • Richter B.
        • Hohensinner P.J.
        • Kariem Mahdy A.
        • Neuhold S.
        • Zorn G.
        • Berger R.
        • Mörtl D.
        • Huber K.
        • Pacher R.
        • Wojta J.
        • Niessner A.
        • Hülsmann M.
        Hepatocyte growth factor is a strong predictor of mortality in patients with advanced heart failure.
        Heart. 2011; 97: 1158-1163
        • Richter B.
        • Koller L.
        • Hohensinner P.J.
        • Zorn G.
        • Brekalo M.
        • Berger R.
        • Mörtl D.
        • Maurer G.
        • Pacher R.
        • Huber K.
        • Wojta J.
        • Hülsmann M.
        • Niessner A.
        A multi-biomarker risk score improves prediction of long-term mortality in patients with advanced heart failure.
        Int J Cardiol. 2013; 168: 1251-1257
        • Bussolino F.
        • Di Renzo M.F.
        • Ziche M.
        • Bocchietto E.
        • Olivero M.
        • Naldini L.
        • Gaudino G.
        • Tamagnone L.
        • Coffer A.
        • Comoglio P.M.
        Hepatocyte growth factor is a potent angiogenic factor which stimulates endothelial cell motility and growth.
        J Cell Biol. 1992; 119: 629-641
        • Nieminen M.S.
        • Böhm M.
        • Cowie M.R.
        • Drexler H.
        • Filippatos G.S.
        • Jondeau G.
        • Hasin Y.
        • Lopez-Sendon J.
        • Mebazaa A.
        • Metra M.
        • Rhodes A.
        • Swedberg K.
        • Priori S.G.
        • Garcia M.A.
        • Blanc J.J.
        • Budaj A.
        • Cowie M.R.
        • Dean V.
        • Deckers J.
        • Burgos E.F.
        • Lekakis J.
        • Lindahl B.
        • Mazzotta G.
        • Morais J.
        • Oto A.
        • Smiseth O.A.
        • Garcia M.A.
        • Dickstein K.
        • Albuquerque A.
        • Conthe P.
        • Crespo-Leiro M.
        • Ferrari R.
        • Follath F.
        • Gavazzi A.
        • Janssens U.
        • Komajda M.
        • Morais J.
        • Moreno R.
        • Singer M.
        • Singh S.
        • Tendera M.
        • Thygesen K.
        • ESC Committee for Practice Guideline (CPG)
        Executive summary of the guidelines on the diagnosis and treatment of acute heart failure: the Task Force on Acute Heart Failure of the European Society of Cardiology.
        Eur Heart J. 2005; 26: 384-416
        • Januzzi J.L.
        • van Kimmenade R.
        • Lainchbury J.
        • Bayes-Genis A.
        • Ordonez-Llanos J.
        • Santalo-Bel M.
        • Pinto Y.M.
        • Richards M.
        NT-proBNP testing for diagnosis and short-term prognosis in acute destabilized heart failure: an international pooled analysis of 1256 patients: the International Collaborative of NT-proBNP Study.
        Eur Heart J. 2006; 27: 330-337
        • Nakamura T.
        • Mizuno S.
        • Matsumoto K.
        • Sawa Y.
        • Matsuda H.
        • Nakamura T.
        Myocardial protection from ischemia/reperfusion injury by endogenous and exogenous HGF.
        J Clin Invest. 2000; 106: 1511-1519
        • Ono K.
        • Matsumori A.
        • Shioi T.
        • Furukawa Y.
        • Sasayama S.
        Enhanced expression of hepatocyte growth factor/c-Met by myocardial ischemia and reperfusion in a rat model.
        Circulation. 1997; 95: 2552-2558
        • Zhu Y.
        • Hojo Y.
        • Ikeda U.
        • Shimada K.
        Production of hepatocyte growth factor during acute myocardial infarction.
        Heart. 2000; 83: 450-455
        • Ueda H.
        • Nakamura T.
        • Matsumoto K.
        • Sawa Y.
        • Matsuda H.
        • Nakamura T.
        A potential cardioprotective role of hepatocyte growth factor in myocardial infarction in rats.
        Cardiovasc Res. 2001; 51: 41-50
        • Cotter G.
        • Milo O.
        • Davison B.A.
        Increased mortality after an acute heart failure episode: new pathophysiological insights from the RELAX-AHF study and beyond.
        Curr Heart Fail Rep. 2014; 11: 19-30