Serum hepatocyte growth factor levels predict long-term clinical outcome after percutaneous coronary revascularization

Sophie Susen2,4,{dagger}, Karine Sautière1,4,{dagger}, Frédéric Mouquet1,4, François Cuilleret1, Akram Chmaït1, Eugène P. McFadden1, Bernadette Hennache3, Florence Richard5, Pascal de Groote1, Jean-Marc Lablanche1, Jean Dallongeville5, Christophe Bauters1,5, Brigitte Jude2,4 and Eric Van Belle1,4,*

1Department of Cardiology, University Hospital, Lille, France
2Department of Hematology, University Hospital, Lille, France
3Department of Biochemistry, University Hospital, Lille, France
4INSERM-ESPRI 2004–EA 2693, Lille II University, Lille, France
5INSERM-U508, Institut Pasteur, Lille, France

Received 9 May 2005; revised 18 June 2005; accepted 7 July 2005; online publish-ahead-of-print 16 August 2005.

* Corresponding author: Service de Cardiologie B et Hémodynamique, Hôpital Cardiologique, Centre Hospitalier Régional, 59037 Lille Cedex, France. Tel: +33 3 20 44 50 08; fax: +33 3 20 44 51 30. E-mail address: ericvanbelle{at}aol.com


    Abstract
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Study limitations
 Clinical implications
 References
 
Aims To evaluate, in patients referred for elective percutaneous coronary revascularization (PCR) without heparin pre-treatment, the relationship between baseline serum levels of the angiogenic growth factors, vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF), and clinical outcome.

Methods and results In 488 consecutive patients undergoing elective coronary angioplasty, hsC-reactive protein, HGF, and VEGF levels were measured before heparin administration. The primary endpoint, a composite of death and myocardial infarction, occurred in 44 patients at a median follow-up of 14.9 months. At baseline, VEGF levels were related to C-reactive protein levels and inversely related to age; HGF levels were related to C-reactive protein levels, diabetes, and recent clinical instability. In the univariate analysis, HGF had a significant positive relationship (P=0.003) with the primary endpoint. A similar trend was observed for VEGF (P=0.11). The only three variables significantly associated with the primary endpoint in the multivariable Cox model were HGF (P=0.004), C-reactive protein (P=0.007), and diabetes (P=0.04).

Conclusion Our results demonstrate that in patients, without heparin pre-treatment, referred for PCR, a high serum level of HGF is an independent predictor of clinical events during follow-up and is correlated with other surrogate measures of the activity of atherosclerosis.

Key Words: Angioplasty • Growth factors • Diabetes mellitus • C-reactive protein • Clinical outcome


    Introduction
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Study limitations
 Clinical implications
 References
 
Vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) are angiogenic growth factors, with important roles in tissue and vascular repair,13 whose potential clinical benefit in patients with myocardial or peripheral ischaemia is currently under evaluation.4 It has also been suggested that serum levels of such growth factors, by reflecting the extent or activity of atherosclerosis,57 might be useful in risk stratification.

VEGF and HGF are heparin-binding growth factors, whose synthesis is induced by heparin administration in vivo.8 HGF levels are increased 5–50-fold after heparin administration in humans,9,10 and it is considered that ‘heparin-released’ serum levels reflect the capability and the functional reserve of the organism to produce HGF.11

Conflicting results regarding the predictive value of angiogenic growth factors, specifically HGF, have recently been published. One study showed that, in patients with an acute coronary syndrome (ACS) treated with intravenous heparin, high serum levels of HGF were associated with a lower rate of subsequent adverse clinical events,12 whereas another showed that, in patients with renal failure, high levels of HGF were associated with carotid atherosclerosis and an increased rate of death and cardiovascular events.13

No study has addressed the predictive value of serum VEGF and HGF levels in patients with coronary artery disease (CAD) not treated by heparin. In consecutive patients referred for percutaneous coronary revascularization (PCR) who were not receiving heparin, we studied the relationship between VEGF and HGF levels and clinical outcome. We also examined the clinical and biological covariates of baseline serum levels of VEGF and HGF.


    Methods
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Study limitations
 Clinical implications
 References
 
Patients
From June 2000 to September 2001, 1209 patients were scheduled for PCR in our institution. Consecutive patients scheduled for PCR between 8 AM and 4 PM were enrolled in a cardiovascular registry (n=802). Patients referred for acute myocardial infarction (MI) and patients who were receiving low-molecular weight or unfractioned heparin within 48 h of blood sampling were excluded for this analysis (n=314). The study population comprised 488 patients. Plasma and serum samples were drawn and stored at –80°C until analysis. The Ethics Committee of the ‘Centre Hospitalier Régional de Lille’ approved the study, and each subject gave written informed consent.

Hypertension was defined as a known blood pressure >140/90 mmHg or use of antihypertensive drugs. Smoking was defined as acknowledged ceased/unceased smoking. Diabetes mellitus was defined as a fasting glucose ≥126 mg/dL, use of hypoglycaemic agents, or a history of physician-diagnosed diabetes mellitus. Obesity was defined as body mass index >30 kg/m2. Family history of premature CAD was defined as CAD in a male first-degree relative <55 years or CAD in a female first-degree relative <65 years.14

Angioplasty procedure
Balloon angioplasty and coronary stenting were performed according to the standard technique in our laboratory.15 All patients received aspirin 300 mg/day; a bolus dose of heparin (5000–10 000 IU) was administered just before PCR. The use of stents was left to the discretion of the operator. Patients who had conventional balloon angioplasty received aspirin alone, whereas patients who had coronary stent implantation received aspirin (325 mg) and clopidogrel (300 mg loading dose and 75 mg daily) for 4 weeks followed by aspirin alone.

Clinical follow-up
Long-term clinical follow-up beginning at the time of the index procedure was accomplished by a questionnaire completed by the patient or by telephone contact. Review of hospital records and contact with the referring physician enabled us to complete missing information. Information obtained included death, occurrence of MI, and target vessel revascularization (TVR) since the initial PCR procedure. In the peri-procedural period, MI was defined as the development of new pathological Q-waves or creatine kinase-MB (or total CK if CK-MB not available) more than three times normal. During the follow-up period, MI was defined as the occurrence of new pathological Q-waves, or onset of ischaemic symptoms or ischaemic ECG changes with total CK-MB (or total CK if CK-MB not available) more than two times normal.16 Angiographic follow-up was performed only in patients with recurrent angina and/or positive stress testing. TVR was defined as the percutaneous or bypass revascularization of any segment of the epicardial coronary artery containing the target lesion. The clinical follow-up was intended to be performed after 12 months. The median follow-up period was 14.9 months (interquartile: 12.0–18.5 months). The primary endpoint of our study was a composite of death and non-fatal MI.

Analysis of biological markers
Blood samples were drawn from the arterial sheath immediately after puncture under sterile conditions and before heparin administration. Plasma and serum samples were divided into aliquots and stored at –80°C until analysis. To determine C-reactive protein, HGF, and VEGF, blood was collected into a Vacutainer (Terumo, Venoject) tube with no additive as recommended by the manufacturer. HGF and VEGF were measured by enzyme-linked immunosorbent assay (R&D systems). C-reactive protein was measured by nephelometry (Dade-Behring). For each parameter, all samples were analysed in the same run on the same day. The detection limit for HGF was 40 pg/mL and 5 pg/mL for VEGF. Inter-assay variation in our laboratory was 8% for HGF and 7% for VEGF, and intra-assay variation was 4.5% for both techniques within the limits given by the manufacturer. Inter-assay and intra-assay variation for C-reactive protein were 7.28 and 2.65%, respectively, for low levels and 3.77 and 2%, respectively, for high levels within the limits given by the manufacturer.

Statistical analysis
Continuous variables with little to mild skewness were presented as mean±SD and continuous variables with skewed distribution were presented as median values (interquartile range). Discrete variables were presented as absolute number and percentages. The association between angiogenic growth factors (HGF, VEGF) and continuous variables were assessed using Spearman's correlation coefficient; for discrete variables, the association was assessed with a logistic regression analysis using the discrete variable as dependent variable and growth factors as independent variable. To study the relation between angiogenic growth factors and multiple categorical and continuous determinants, a multiple regression analysis was performed. Categorical independent variables were encoded as 0 (absent) or 1 (present). Continuous independent variables were incorporated without any change.

Event-free survival was estimated with the Kaplan–Meier method. Differences were tested with a log-rank test. For presentation purpose, angiogenic growth factors were incorporated as tertiles.

Hazard ratios were calculated using simple (univariate) and multiple (multivariable) Cox models. Three multivariable Cox regression models were established. In the first model, the relation was assessed adjusting on age and gender; in the second model, usual factors related to prognosis [diabetes, hypertension, smoking, obesity, family history of CAD, clinical symptoms, left ventricular ejection fraction (LVEF), C-reactive protein levels, LDL-cholesterol levels, use of statins] were added; and in the final model, medications associated with survival in univariate analysis [use of glycoprotein IIb/IIIa inhibitors or angiotensin-converting enzyme (ACE)-inhibitors] were added. Because these three models yield similar results, only values of the third model are presented. Because of skewness, log transformation of HGF, VEGF, and C-reactive protein, were used.

For each variable, the proportional hazards assumption was tested visually using Kaplan–Meier curves and by examining a plot of –ln(–ln(survival time)) against the ln(time). The assumption was tested statistically using the stphtest command in Strata, which is based on fitting a simple linear regression model with the Schoenfield residuals as the dependent variable and time as the independent variable and then testing whether the slope of the regression line is equal to zero. In addition, the proportional hazard was assessed and satisfied by including an interaction time-dependent term in the multivariable Cox regression analysis. All hypothesis were two-tailed with a 0.05 type I error rate.


    Results
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Study limitations
 Clinical implications
 References
 
Characteristics of the study population
The characteristics of the study population are presented in Table 1. Most (78%) were men, with mean age 61 years, and 29% had diabetes. Among the 142 diabetic patients, 70 were treated with oral hypoglycaemic drugs, 39 were treated with insulin, and 33 were on diet alone. Because patients were included at the time of the angioplasty procedure and because patients with heparin treatment before blood sampling were excluded, neither there were patients with an ongoing ACS nor there were patients treated with glycoprotein IIb/IIIa inhibitors in the population. However, 31% of the population had angioplasty within 1 month of an acute coronary event (unstable angina or MI). These patients were patients in whom the ACS was initially treated using a conservative approach leading to medical stabilization and in whom the heparin was already stopped at the time of the procedure.


View this table:
[in this window]
[in a new window]
 
Table 1 Baseline characteristics of the study population and covariates of VEGF and HGF levels by univariate analysis
 
Stent implantation was performed in 447 patients (91%), and 162 patients (33%) received glycoprotein IIb/IIIa inhibitors during the procedure (Table 1).

Median C-reactive protein level was 2.60 mg/L (1.20–7.09), median VEGF level was 445 pg/mL (291–676), and median HGF level was 1585 pg/mL (1287–2113).

Angiogenic growth factor levels and cardiovascular risk factors
Correlates of VEGF and HGF levels by univariate analysis as a function of baseline patient characteristics are presented in Table 1.

By multivariable analysis, higher VEGF levels were associated with higher C-reactive protein levels (P=0.0001) and were inversely correlated with age (P=0.02). Higher HGF levels were associated with diabetes mellitus (P=0.03), clinical instability (P=0.007), and with higher C-reactive protein levels (P=0.003).

Angiogenic growth factor levels and clinical outcome
Clinical follow-up was obtained in all patients at a median interval of 14.9 (12.0–18.6) months after inclusion. During follow-up, 24 patients died, 26 had an acute MI, and 49 had a TVR. A major coronary event (death or MI) occurred in 44 patients.

Higher HGF levels were associated with a higher risk of major coronary event during follow-up (death or MI, {chi}2=8.62, HR=5.91 for one log increase, 95% CI=1.81–19.25; P=0.003) (Table 2) and a similar trend was observed for VEGF levels (P=0.11, Table 2). A separate analysis was performed in patients with or without an ACS during the last 4 weeks. Among patients with a recent ACS, higher HGF levels were associated with a higher risk of major coronary event ({chi}2=4.82, HR=4.23 for one log increase, 95% CI=1.11–23.12; P=0.03). Similarly, among patients without a recent ACS, higher HGF levels were associated with a higher risk of major coronary event ({chi}2=3.95, HR=6.63 for one log increase, 95% CI=1.05–44.08; P=0.04).


View this table:
[in this window]
[in a new window]
 
Table 2 Univariate relationship between baseline characteristics of the study population and the risk of clinical event (Cox model)
 
Among other parameters, diabetes mellitus, a low ejection fraction, the use of ACE-inhibitors at baseline, the use of glycoprotein IIb/IIIa during the procedure, and C-reactive protein levels were associated with the occurrence of a major coronary event on univariate analysis (Table 2).

In multivariable analysis; with adjustment for age, gender, hypertension, smoking, obesity, family history of CAD, clinical symptoms, LDL cholesterol levels, LVEF, use of glycoprotein IIb/IIIa during the procedure, VEGF serum levels, and treatment with statins and ACE-inhibitors; three predictors of major coronary events were identified: diabetes mellitus (P=0.04), C-reactive protein levels (P=0.007), and HGF levels (P=0.004) (Table 3). Figure 1 illustrates the occurrence of events according to diabetic status, tertiles of C-reactive protein levels, and tertiles of HGF levels, and Figure 2 illustrates the combined prognostic value of tertiles of C-reactive protein and HGF levels.


View this table:
[in this window]
[in a new window]
 
Table 3 Multivariable correlates of death and MI by Cox model analysis
 


View larger version (18K):
[in this window]
[in a new window]
 
Figure 1 Occurrence of events (death or MI) according to diabetic status (A), tertiles of C-reactive protein levels (B), and tertiles of HGF levels (C).

 


View larger version (27K):
[in this window]
[in a new window]
 
Figure 2 Hazard ratio of events (death or MI) according to combined tertile levels of C-reactive protein and HGF.

 
Higher HGF levels were also associated with a higher risk of TVR during follow-up ({chi}2=4.00, HR=2.59 for one log increase, 95% CI=1.02–6.53; P=0.04). Apart from a trend towards a higher rate of TVR in diabetics vs. non-diabetics (HR=1.62, P=0.09), no other baseline characteristics of our study population was predictive of the need for subsequent TVR.

Effects of CAD and heparin on angiogenic growth factor levels
Additional patients had plasma and serum samples and were used for ancillary analyses. Forty-one consecutive patients with suspected stable angina but a normal angiogram (no stenosis >30% diameter by visual assessment) and no heparin treatment were used to confirm the effect of CAD on biological markers. Eighteen consecutive patients with an abnormal angiogram (at least one stenosis >50% diameter by visual assessment) but without recent (<30 days) unstable symptoms and treated with IV heparin for at least 24 h before blood sampling were used to confirm the effect of heparin on angiogenic growth factor levels.

In patients with stable angina and CAD from our study population (n=338), C-reactive protein [2.45 mg/L (0.99–5.93) vs. 1.86 mg/L (0.57–4.43)] and HGF [1538 pg/mL (1265–1928) vs. 402 pg/mL (230–577)] levels were higher than that in 41 consecutive patients with suspected stable angina but a normal angiogram (P=0.03 and P=0.0001, respectively). There was no difference in VEGF [439 pg/mL (273–660) vs. 402 pg/mL (230–577)] levels between the two groups (P=0.16). Other major baseline characteristics were not different between the two groups (data not shown).

HGF and VEGF levels were also compared between a group of patients with CAD and stable angina pre-treated with heparin (n=18) with the subgroup of patients with stable angina in our study population (n=338). In patients receiving heparin, median HGF level [3622 pg/mL (1711–8701)] was 2.5-fold higher than in patients without heparin pre-treatment [1538 pg/mL (1265–1928), P=0.0001], whereas median VEGF level [481 pg/mL (428–852)] was only slightly higher than in patients without heparin pre-treatment [439 pg/mL (273–660), P=0.04]. Other major baseline characteristics were not different between the two groups (data not shown).


    Discussion
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Study limitations
 Clinical implications
 References
 
A previous study, in a highly selected population with refractory unstable angina who were receiving unfractionated heparin, showed that high HGF levels were associated with a decreased rate of subsequent events, whereas the converse was true for high levels of VEGF. The major finding of the present study, in consecutive patients referred for PCR who were not receiving heparin pre-treatment, was that high HGF levels were an independent predictor of adverse clinical outcome at 15 months.

Clinical and biological correlates of VEGF and HGF levels
Very few studies, in relatively small cohorts, have investigated the correlates of VEGF and HGF in patients with cardiovascular disease.1719

In our study, VEGF levels were positively correlated with C-reactive protein levels and were inversely related to age. No relation was found between VEGF levels and other risk factors. The observed relation between VEGF and C-reactive protein levels is consistent with previous reports that demonstrated a similar relationship between VEGF levels and inflammatory markers, including C-reactive protein, in diverse clinical conditions.20 The observed relationship between VEGF and C-reactive protein could reflect the fact that both are regulated by interleukin 6.21

The inverse relationship between VEGF levels and age confirms previous observations in animals that VEGF expression decreases with age.22 A similar relationship was described in a recent study in 50 patients referred for coronary artery bypass surgery.23

As previously reported, HGF levels were higher in obese24 and smokers18 as well as in patients with CAD than in patients without CAD.5 Higher HGF levels were also observed in patients with a low ejection fraction. The latter finding could reflect induction of HGF production by myocardial injury.3

In multivariable analysis, HGF levels were related to C-reactive protein levels. As for VEGF, this relationship was previously reported in other clinical situations25 and was suggested to be related to induction by interleukin 6.26 Of importance, multivariable analysis demonstrated that HGF levels were related to two clinical situations, diabetes mellitus and a recent episode of ‘unstable’ symptoms. It has been shown that, in patients with CAD, intra-arterial thrombus is more frequent in diabetic patients27 and can persist for weeks following an acute coronary event.28 Such arterial thrombus formation could increase circulating HGF as previously demonstrated in animal models8 and in humans.29 The mechanism suggested for this induction is thought to be related to the release of endogenous heparin during mast cell degranulation.8

The lack of relationship between HGF levels and thrombus, as detected by angiography, in the CAPTURE trial12 is not inconsistent with this hypothesis. Indeed, because of the poor sensitivity of angiography to detect thrombus, the study by Heeschen et al.12 was largely underpowered in that aspect. Although the frequency of thrombus in patients with ACS has been reported to be very high (65–75%) using a very sensitive method such as angioscopy,27,30 it was detected in only 6% of cases by angiography in the CAPTURE trial.12

Predictive value of C-reactive protein level in our population
Elevated C-reactive protein has been identified as a strong predictor of prognosis in healthy individuals, in patients with stable or unstable angina, and in patients after an acute MI.31 More recent studies have demonstrated that C-reactive protein was also an independent predictor of events in patients referred for PCR.3234 Our study confirms these recent reports and extend their findings in a different patient population. Indeed, whereas in our study, a high proportion of patients were treated with coronary stents (91%), it was the case in only 30% of patients in the study by de Winter et al.32 Among studies in which the use of coronary stents was more liberal (>80%), it is also interesting to notice that, because patients with an acute MI or unstable symptoms requiring heparin treatment were excluded, our study confirms the results by Walter et al.33 and by Chan et al.34 in a population at lower ‘risk’ where the median C-reactive protein level (2.6 mg/L) was much lower than in the populations studied by Walter et al. (6 mg/L) or Chan et al. (4.2 mg/L).

Predictive value of VEGF and HGF levels in our population
Because it is considered that angiogenic growth factors are involved in the vascular injury/repair process, it has been suggested that the serum levels of these growth factors could predict clinical outcome in patients with atherosclerosis.

Our study demonstrates that in patients with CAD referred for PCR, serum VEGF levels were a weak predictor of clinical events, whereas serum HGF levels were a strong and independent predictor of clinical events. Our findings on HGF are concordant with the results of a study performed in patients with renal insufficiency showing that patients with serum HGF levels >1475 pg/mL had a shorter survival.13

A recently published ancillary study of the CAPTURE trial reported the impact of VEGF and HGF levels on clinical outcome in patients with an ACS.12 This study differed significantly from our study with respect to patient selection. All patients in the CAPTURE trial had refractory unstable angina; in the present study, only one-third of the population had a history of an acute coronary event in the month preceding the PCR procedure. Similarly, in the CAPTURE trial, half of the population received glycoprotein IIb/IIIa inhibitors for 18–24 h before coronary angioplasty, whereas no patient in our population was pre-treated with glycoprotein IIb/IIIa inhibitors before blood sampling and the start of the angioplasty procedure. Among other differences are the higher proportion of diabetic patients (29 vs. 10%) and patients treated with ACE-inhibitors (42 vs. 20%) in our study compared with the CAPTURE trial.

Another key difference between the two studies is the use of heparin. Indeed, blood samples were tested during heparin treatment in all patients in the CAPTURE trial, whereas they were tested in patients free of heparin in our study. The latter observation is of great importance because VEGF and HGF are heparin-binding growth factors and are known to be inducible by heparin administration in vivo.8 It has been reported that administration of unfractioned or low molecular weight heparin in humans can induce a 50-fold increase in serum levels of HGF after intravenous injection9,10 and a four- to five-fold increase following subcutaneous injection.9,10 This probably explains why the median HGF level was three-fold higher in the CAPTURE trial than in our study group or than in the study by Malatino et al.13 The 2.5-fold higher HGF level observed in an ancillary group of 18 patients pre-treated with heparin in our study is also consistent with this explanation.

Administration of heparin has already been employed as a test to evaluate the functional reserve of the organism to produce HGF, a growth factor involved in vascular and myocardial repair.11 This may explain the apparently conflicting observation in the CAPTURE study that ‘stimulated’ HGF levels were associated with a protective effect on prognosis, whereas ‘naturally’ circulating HGF, as measured in the present study and in the study by Malatino et al.,13 was a marker of poor prognosis. This prognostic value is probably related to the fact that naturally circulating HGF is produced in response to the atherothrombotic process and to myocardial damage as demonstrated by the analysis of correlates of HGF levels.

Finally, an alternative explanation could be that the study by Heeschen et al.12 and our study represent a continuum with low HGF levels reflecting the extent of the inflammatory process and thus events in a stable population, whereas high levels in an unstable population have therapeutic benefits (i.e. angiogenesis) and thus exert a protective effect.


    Study limitations
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Study limitations
 Clinical implications
 References
 
As VEGF is partly released from platelets,35 measurement of circulating VEGF in serum samples rather than in plasma samples might be considered a limitation. Nevertheless, we choose to analyse serum samples rather than plasma samples because performing analysis of serum rather than plasma samples allowed us to compare our results with those reported by Heeschen et al.12 In addition, it is currently unclear whether serum (total) or plasma (without release of platelet) VEGF levels are better predictors of clinical outcome. Furthermore, in 26 selected patients, analyses performed in both serum and plasma (EDTA) samples demonstrated a high degree of correlation (r=0.94, P=0.0001). Finally, it has also been suggested that an alternative method to account for platelet-released VEGF is to normalize serum VEGF on the basis of platelet count.36 Using this method did not improve the value of VEGF level to predict clinical events (P=0.18 instead of 0.11).

This was a single-centre study, and patient referral, PCR technique, and medical management may have influenced the results. However, the consecutive nature of the population and the exclusion of patients treated with heparin provide a unique insight into ‘baseline’ levels of VEGF and HGF and of their biological and clinical correlates in patients with CAD. Finally, these characteristics in conjunction with the high rate of clinical follow-up (100%) allowed us to accurately evaluate the prognostic value of baseline levels of VEGF and HGF after PCR.


    Clinical implications
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Study limitations
 Clinical implications
 References
 
The present study provides important information on the clinical significance of baseline levels of angiogenic growth factor in patients with CAD. More specifically, it demonstrates that in patients with established CAD, high circulating levels of HGF are a marker of the atherothrombotic process and independently predict the risk of subsequent death or MI following PCR. This suggests that serum HGF levels may provide incremental prognostic information over that provided by classical markers such as C-reactive protein levels or diabetes in patients with CAD. In addition, our results in conjunction with the previously published literature suggest that the clinical significance of serum levels of angiogenic growth factors may be critically different in patients with or without heparin treatment. Some caution needs to be applied, however, before generalizing the use of ‘HGF level’ as a risk factor for clinical management. In particular, additional studies are needed in patients managed with medical or surgical therapy.


    Footnotes
 
{dagger}The first two authors contributed equally to this work. Back


    References
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Study limitations
 Clinical implications
 References
 

  1. Van Belle E, Tio FO, Chen D, Maillard L, Kearney M, Isner JM. Passivation of metallic stents after arterial gene transfer of phVEGF165 inhibits thrombus formation and intimal thickening. J Am Coll Cardiol 1997;29:1371–1379.[Abstract]
  2. Van Belle E, Witzenbichler B, Chen D, Silver M, Chang L, Schwall R, Isner JM. Potentiated angiogenic effect of scatter factor/hepatocyte growth factor via induction of vascular endothelial growth factor: the case for paracrine amplification of angiogenesis. Circulation 1998;97:381–390.[Abstract/Free Full Text]
  3. Nakamura T, Mizuno S, Matsumoto K, Sawa Y, Matsuda H. Myocardial protection from ischemia/reperfusion injury by endogenous and exogenous HGF. J Clin Invest 2000;106:1511–1519.[Abstract/Free Full Text]
  4. Isner JM, Vale PR, Symes JF, Losordo DW. Assessment of risks associated with cardiovascular gene therapy in human subjects. Circ Res 2001;89:389–400.[Abstract/Free Full Text]
  5. Nishimura M, Ushiyama M, Ohtsuka K, Nishida M, Inoue N, Matsumuro A, Mineo T, Yoshimura M. Serum hepatocyte growth factor as a possible indicator of vascular lesions. J Clin Endocrinol Metab 1999;84:2475–2480.[Abstract/Free Full Text]
  6. Tateishi J, Waku S, Masutani M, Ohyanagi M, Iwasaki T. Hepatocyte growth factor as a potential predictor of the presence of atherosclerotic aorto-iliac artery disease. Am Heart J 2002;143:272–276.[CrossRef][ISI][Medline]
  7. Cotton JM, Mathur A, Hong Y, Brown AS, Martin JF, Erusalimsky JD. Acute rise of circulating vascular endothelial growth factor-A in patients with coronary artery disease following cardiothoracic surgery. Eur Heart J 2002;23:953–959.[Abstract/Free Full Text]
  8. Kinoshita M, Miyamoto T, Ohashi N, Sasayama S, Matsumori A. Thrombosis increases circulatory hepatocyte growth factor by degranulation of mast cells. Circulation 2002;106:3133–3138.[Abstract/Free Full Text]
  9. Okada M, Matsumori A, Ono K, Miyamoto T, Takahashi M, Sasayama S. Hepatocyte growth factor is a major mediator in heparin-induced angiogenesis. Biochem Biophys Res Commun 1999;255:80–87.[CrossRef][ISI][Medline]
  10. Salbach PB, Bruckmann M, Turovets O, Kreuzer J, Kubler W, Walter-Sack I. Heparin-mediated selective release of hepatocyte growth factor in humans. Br J Clin Pharmacol 2000;50:221–226.[CrossRef][ISI][Medline]
  11. Yasuda S, Goto Y, Sumida H, Noguchi T, Baba T, Miyazaki S, Nonogi H. Angiotensin-converting enzyme inhibition restores hepatocyte growth factor production in patients with congestive heart failure. Hypertension 1999;33:1374–1378.[Abstract/Free Full Text]
  12. Heeschen C, Dimmeler S, Hamm CW, Boersma E, Zeiher AM, Simoons ML. Prognostic significance of angiogenic growth factor serum levels in patients with acute coronary syndromes. Circulation 2003;107:524–530.[Abstract/Free Full Text]
  13. Malatino LS, Mallamaci F, Benedetto FA, Bellanuova I, Cataliotti A, Tripepi G, Zoccali C. Hepatocyte growth factor predicts survival and relates to inflammation and intima media thickness in end-stage renal disease. Am J Kidney Dis 2000;36:945–952.[ISI][Medline]
  14. Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001;285:2486–2497.[Free Full Text]
  15. Van Belle E, Perie M, Braune D, Chmait A, Meurice T, Abolmaali K, McFadden EP, Bauters C, Lablanche JM, Bertrand ME. Effects of coronary stenting on vessel patency and long-term clinical outcome after percutaneous coronary revascularization in diabetic patients. J Am Coll Cardiol 2002;40:410–417.[Abstract/Free Full Text]
  16. Bhatt D, Marso S, Lincoff M, Wolski K, Ellis S, Topol E. Abciximab reduces mortality in diabetics following percutaneous coronary intervention. J Am Coll Cardiol 2000;35:922–928.[Abstract/Free Full Text]
  17. Yamamoto Y, Kohara K, Tabara Y, Igase M, Nakura J, Miki T. Plasma hepatocyte growth factor and the relationship between risk factors and carotid atherosclerosis. Hypertens Res 2002;25:661–667.[CrossRef][ISI][Medline]
  18. Yoshitomi Y, Kojima S, Umemoto T, Kubo K, Matsumoto Y, Yano M, Sugi T, Kuramochi M. Serum hepatocyte growth factor in patients with peripheral arterial occlusive disease. J Clin Endocrinol Metab 1999;84:2425–2428.[Abstract/Free Full Text]
  19. Blann AD, Belgore FM, Constans J, Conri C, Lip GY. Plasma vascular endothelial growth factor and its receptor Flt-1 in patients with hyperlipidemia and atherosclerosis and the effects of fluvastatin or fenofibrate. Am J Cardiol 2001;87:1160–1163.[CrossRef][ISI][Medline]
  20. Drouart M, Saas P, Billot M, Cedoz JP, Tiberghien P, Wendling D, Toussirot E. High serum vascular endothelial growth factor correlates with disease activity of spondylarthropathies. Clin Exp Immunol 2003;132:158–162.[CrossRef][ISI][Medline]
  21. Nakahara H, Song J, Sugimoto M, Hagihara K, Kishimoto T, Yoshizaki K, Nishimoto N. Anti-interleukin-6 receptor antibody therapy reduces vascular endothelial growth factor production in rheumatoid arthritis. Arthritis Rheum 2003;48:1521–1529.[CrossRef][ISI][Medline]
  22. Rivard A, Fabre JE, Silver M, Chen D, Murohara T, Kearney M, Magner M, Asahara T, Isner JM. Age-dependent impairment of angiogenesis. Circulation 1999;99:111–120.[Abstract/Free Full Text]
  23. Scheubel RJ, Zorn H, Silber RE, Kuss O, Morawietz H, Holtz J, Simm A. Age-dependent depression in circulating endothelial progenitor cells in patients undergoing coronary artery bypass grafting. J Am Coll Cardiol 2003;42:2073–2080.[Abstract/Free Full Text]
  24. Rehman J, Considine RV, Bovenkerk JE, Li J, Slavens CA, Jones RM, March KL. Obesity is associated with increased levels of circulating hepatocyte growth factor. J Am Coll Cardiol 2003;41:1408–1413.[Abstract/Free Full Text]
  25. Okamoto T, Takatsuka H, Fujimori Y, Wada H, Iwasaki T, Kakishita E. Increased hepatocyte growth factor in serum in acute graft-versus-host disease. Bone Marrow Transplant 2001;28:197–200.[CrossRef][ISI][Medline]
  26. de Jong KP, van Gameren MM, Bijzet J, Limburg PC, Sluiter WJ, Slooff MJ, de Vries EG. Recombinant human interleukin-6 induces hepatocyte growth factor production in cancer patients. Scand J Gastroenterol 2001;36:636–640.[ISI][Medline]
  27. Silva JA, Escobar A, Collins TJ, Ramee SR, White CJ. Unstable angina. A comparison of angioscopic findings between diabetic and nondiabetic patients. Circulation 1995;92:1731–1736.[Abstract/Free Full Text]
  28. Van Belle E, Lablanche JM, Bauters C, Renaud N, McFadden EP, Bertrand ME. Coronary angioscopic findings in the infarct-related vessel within 1 month of acute myocardial infarction: natural history and the effect of thrombolysis [see comments]. Circulation 1998;97:26–33.[Abstract/Free Full Text]
  29. Matsumori A, Takano H, Obata JE, Takeda S, Tsuyuguchi N, Ono K, Okada M, Miyamoto T, Ohnishi T, Daikuhara Y, Sasayama S. Circulating hepatocyte growth factor as a diagnostic marker of thrombus formation in patients with cerebral infarction. Circ J 2002;66:216–218.[CrossRef][ISI][Medline]
  30. White C, Ramee S, Collins T, Escobar A, Karsan A, Shaw D, Jain S, Bass T, Heuser R, Teirstein P, Bonan R, Walter P, Smalling R. Coronary thrombi increase PTCA risk. Angioscopy as a clinical tool. Circulation 1996;93:253–258.[Abstract/Free Full Text]
  31. Willerson JT, Ridker PM. Inflammation as a cardiovascular risk factor. Circulation 2004;109:II2–II10.[Medline]
  32. de Winter RJ, Heyde GS, Koch KT, Fischer J, van Straalen JP, Bax M, Schotborgh CE, Mulder KJ, Sanders GT, Piek JJ, Tijssen JG. The prognostic value of pre-procedural plasma C-reactive protein in patients undergoing elective coronary angioplasty. Eur Heart J 2002;23:960–966.[Abstract/Free Full Text]
  33. Walter DH, Fichtlscherer S, Sellwig M, Auch-Schwelk W, Schachinger V, Zeiher AM. Preprocedural C-reactive protein levels and cardiovascular events after coronary stent implantation. J Am Coll Cardiol 2001;37:839–846.[Abstract/Free Full Text]
  34. Chan AW, Bhatt DL, Chew DP, Reginelli J, Schneider JP, Topol EJ, Ellis SG. Relation of inflammation and benefit of statins after percutaneous coronary interventions. Circulation 2003;107:1750–1756.[Abstract/Free Full Text]
  35. Caine GJ, Lip GY, Stonelake PS, Ryan P, Blann AD. Platelet activation, coagulation and angiogenesis in breast and prostate carcinoma. Thromb Haemost 2004;92:185–190.[ISI][Medline]
  36. George ML, Eccles SA, Tutton MG, Abulafi AM, Swift RI. Correlation of plasma and serum vascular endothelial growth factor levels with platelet count in colorectal cancer: clinical evidence of platelet scavenging? Clin Cancer Res 2000;6:3147–3152.[Abstract/Free Full Text]




This Article
Abstract
Full Text (PDF)
All Versions of this Article:
26/22/2387    most recent
ehi436v1
Alert me when this article is cited
Alert me if a correction is posted
Services
Email this article to a friend
Similar articles in this journal
Similar articles in ISI Web of Science
Similar articles in PubMed
Alert me to new issues of the journal
Add to My Personal Archive
Download to citation manager
Request Permissions
Google Scholar
Articles by Susen, S.
Articles by Van Belle, E.
PubMed
PubMed Citation
Articles by Susen, S.
Articles by Van Belle, E.