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European Journal of Heart Failure 2008 10(4):380-387; doi:10.1016/j.ejheart.2008.02.012
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© 2008 European Society of Cardiology

Biomarkers of endothelial dysfunction are elevated and related to prognosis in chronic heart failure patients with diabetes but not in those without diabetes

Caroline Kistorpa,*, Aun Y. Chongb, Finn Gustafssonc, Søren Galatiusd, Ilan Raymondd, Jens Fabera, Gregory Y.H. Lipb and Per Hildebrandte

a Department of Endocrinology, Herlev University Hospital Copenhagen, Denmark
b Haemostasis Thrombosis and Vascular Biology Unit, University Department of Medicine, City Hospital Birmingham, United Kingdom
c Department of Cardiology, State University Hospital (Rigshospitalet) Copenhagen, Denmark
d Department of Cardiology, Gentofte University Hospital Denmark
e Department of Medicine, Roskilde University Hospital Denmark

* Corresponding author. Department of Endocrinology, Herlev University Hospital, Herlev Ringvej 75, DK-2730, Herlev, Denmark. Tel.: +45 22475699; fax: +45 39633634. E-mail address: cnkistorp{at}dadlnet.dk (C. Kistorp).


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 References
 
Background: Biomarkers of endothelial dysfunction, such as soluble E-selectin, and von Willebrand factor (vWf) are elevated in patients with chronic heart failure (CHF). The impact of diabetes mellitus (DM) on these biomarkers, and their relation to prognosis remains unknown.

Aims: to investigate the impact of DM on plasma levels and the prognostic value of E-selectin and vWf in patients with CHF.

Methods and results: Plasma levels of E-selectin and vWf were measured in 195 CHF patients with (n = 48, 24.5%), and without DM, and in 116 age-matched healthy controls. Compared with controls, median plasma E-selectin levels were higher in CHF patients with DM (P = 0.012), but not in CHF patients without DM (P = 0.45); vWf levels were also higher in CHF patients with DM (P < 0.001), but not without DM (P = 0.108). E-selectin was associated with risk of recurrent ischaemic cardiovascular events among CHF patients with DM (HR 2.60; P = 0.009), but not among patients without DM (HR 1.09; P = 0.60) per 1 SD increment in log transformed variable. vWf was not related with outcome in CHF patients with or without DM.

Conclusions: Plasma levels of E-selectin and vWf are elevated in CHF patients with DM but not in those without DM. High E-selectin levels may be associated with ischaemic events in patients with DM.

Key Words: Endothelial dysfunction • Diabetes • Prognosis

Received June 25, 2007; Revised December 30, 2007; Accepted February 19, 2008


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 References
 
An increasing interest in the relation between endothelial dysfunction, low grade inflammation and chronic heart failure (CHF) is emerging [1]. Elevated plasma levels of various cellular adhesion molecules (CAMs), and other markers of abnormal endothelial function have been reported in patients with CHF [1-4]. Recent studies have suggested that abnormal activity of CAMs, and of endothelial dysfunction are involved in the pathogenesis of thromboembolic and ischaemic cardiovascular events in patients with CHF [1,5]. E-selectin is a leukocyte adhesion molecule specific to endothelial cells, and soluble E-selectin is a marker of endothelial activation. Elevated plasma levels of soluble E-selectin have been observed in patients with CHF, but also in other disorders related to inflammation, such as ischaemic heart disease (IHD), and type 2 diabetes mellitus (DM) [6]. Furthermore, high E-selectin levels are associated with hyperglycaemia and insulin resistance (IR) in patients with type 2 DM [7]. von Willebrand factor (vWf) is a glycoprotein that is important for platelet aggregation and adhesion to the endothelium, and is considered as a marker of endothelial dysfunction. Elevated plasma levels of vWf have been reported in patients with CHF [2,4,8].

It is well recognized that DM is frequent in patients with CHF, and in the majority of clinical and cohort studies, the prevalence is between 20% to more than 30% [9,10]. Diabetes mellitus has been associated with an increased risk of overall and cardiovascular mortality, independent of traditional factors reflecting severity of CHF [10,11]. The mechanisms underlying this finding remain unexplained, but a possible connection with abnormal endothelial function and chronic low grade inflammation in patients with type 2 DM may be of importance. Previous cross-sectional CHF studies, comparing plasma levels of various CAMs and vWf with healthy controls, have not addressed the influence of DM [2-5,8]. Thus, it is possible that the diabetic subgroups may influence the measurements of these markers.

We aimed to test the hypothesis, that the presence of DM has an impact on the plasma levels of these biomarkers associated with endothelial function in patients with CHF, and that high levels of E-selectin and vWf have prognostic implications in CHF patients with diabetes.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 5. Conclusions
 References
 
2.1. Study population
All CHF patients in the study were recruited from our specialized heart failure clinic at Frederiksberg University Hospital, Copenhagen, Denmark. [12]. A total of 195 consecutive CHF patients with confirmed chronic systolic heart failure were included. Systolic CHF was defined as left ventricular ejection fraction (LVEF)≤45% by echocardiography in combination with symptoms. Diabetes mellitus was defined as history of diabetes which was confirmed by medical records, and according to the recommended diagnostic criteria of the WHO, as fasting blood glucose above 6.1 mmol/L measured on two occasions on two different days. A total of 39 patients (21%) had a previous history of DM, and 9 (4.6%) patients had newly diagnosed DM, 95% were classified as type 2 [13].

At the baseline visit, all patients were examined by a physician and the following was obtained: medical history including medications, a physical examination, NYHA classification based on patient information, measurements of height and weight, resting blood pressure and heart rate. A standard transthoracic echocardiography (with a Sonos-5500 machine, Hewlett Packard, Andover, Mass) was performed by a physician with training in cardiology at a specialist level. All CHF patients were followed with respect to mortality and recurrent cardiovascular events for a median of 2.6 years (range 0.5-3.9 years). None of the CHF patients were lost to follow-up.

All patients were registered in our heart failure database "HJERTER +". The database is a Microsoft Access program which serves as a combined medical record and database [12]. A total of 116 healthy controls were included from a population study previously conducted in our department [14]. These subjects were matched with the CHF patients by age, and were selected from the following criteria: Normal LVEF defined as ≥60%, and no prior history of cardiovascular disease including hypertension or DM. The investigations conformed to the principles outlined in the Declaration of Helsinki. The study was approved by the central local ethics committee of Copenhagen, and all patients and controls provided written informed consent.

2.2. Measurements and laboratory procedures
Following a minimum 8 h overnight fast and 20 min of supine rest, venous blood was obtained for measurement of fasting insulin, fasting blood glucose, HbA1c and lipids. Blood was drawn into EDTA tubes, promptly centrifuged at 4 °C, and frozen at –80 °C in aliquots until laboratory analyses. Levels of soluble E-selectin were estimated in plasma by using a monoclonal antibody based ELISA assay from R&D Systems (Europe) Ltd., Abingdon, UK. The inter- and intra-assay coefficients of variation (CV) were below 5% and 10%, respectively. von Willebrand factor levels were measured by ELISA (R&D Systems and Dako-Platts. C-reactive protein was measured with a highly sensitive, latex-particle-enhanced immunoassay (Roche Diagnostics, Germany), measuring range: 0.1-300 mg/L, with a lower detection limit: 0.03 mg/L. The plasma concentration of NT-proBNP was measured using a double antibody sandwich assay with an ElectroChemiLuminescense as signal (Elecsys 2010, Roche Diagnostics). The sensitivity of the assay is <5.9 pmol/L, and the inter- and intra-assay CV were both <5.0% [15]. Plasma fasting insulin was measured using a double sandwich immunoassay (Elecsys 2010, Roche Diagnostics). Both the inter- and intra-assay CVs were below 3%, with a lower detection limit of 1.39 pmol/L for this assay. Urine was collected as first morning spot urine samples. Urinary albumin excretion was determined as the urinary albumin/creatinine (A/C) ratio, upper limit of normal range was 30 mg/g. The creatinine clearance rate was calculated with the Cockcroft-Gault equation: (140–age)xweight (kg))/serum creatinine (µmol/L) [16].

2.3. Outcomes
All CHF patients were followed with respect to mortality status and major cardiovascular events on a regular basis. To meet the criteria for a major cardiovascular event, a hospitalisation was required. The hospitalisations were recorded by the discharge registry of the Danish National Board of Health, which records all primary hospital discharge diagnoses in Denmark. The register has previous been described in detail [17]. The codes of diagnosis for the cardiovascular events were prespecified. Codes were assigned according to the International Classification of Diseases, 10th Revision (ICD-10). Cardiovascular events were defined according to the following ICD-10 codes: I20.0-I22, I24, I25-I29, I42.0, I46, I50, I63, I65, I66. The cardiovascular events were analyzed as either admission because of worsening of heart failure, or as an ischaemic cardiovascular event, including non-fatal myocardial infarction, stable and unstable angina pectoris, stroke and transient ischaemic attack. All deaths were confirmed by the Danish Central Personal Register, which records all deaths in Denmark within two weeks. Deaths from cardiovascular disease were ascertained from central registers in the Danish National Board of Health, and verified by study physicians from death certificates. The members of the Danish National board of Health, and the study physicians were blinded to the data on the biomarkers.

2.4. Statistical analysis
Comparisons between the groups were performed by one-way ANOVA or Kruskal-Wallis test for continuous variables, according to whether or not their distribution was Gaussian. The Chi-square test was used for categorical data. Due to skewed distributions, E-selectin, vWf, CRP, and NT-proBNP were logarithmically transformed in all analyses. Analyses of differences in E-selectin and vWf levels between DM, non-DM CHF patients and controls, were performed using ANOVA with LSD post hoc analyses on log transformed variables. Multivariable linear regression analyses, examining the determinants of plasma E-selectin and vWf levels, included all baseline variables that were associated with the biomarkers at the P<0.10 level in univariate analyses. Standardized coefficient (β) is shown for the linear regression analysis. Using Cox proportional hazard regression models, hazard ratios (HR) for E-selectin, vWf, and CRP with each outcome were assessed. Multivariable Cox proportional hazard analyses were performed as stepwise regression with backward elimination. The best fitted models were found using Likelihood ratio tests. Hazard ratios and 95% confidence intervals (CI) were calculated in unadjusted analyses and in multivariable models including relevant baseline variables. We specifically tested whether there was interaction between DM status, and the biomarkers examined, as well as the parameters of metabolism. The assumption of proportionality with regards to E-selectin, vWf, CRP, NT-proBNP was met. All values are two tailed, and a P value below 0.05 was considered statistically significant. The statistical software package SPSS version 11.5 was used for all analyses.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 5. Conclusions
 References
 
3.1. Characteristics of the study population
Baseline characteristics of the CHF patients, according to DM status, and of the healthy control subjects are shown in Table 1. The diabetic CHF patients were younger than the non-diabetic, they were more often male, and had higher mean BMI (29.6 versus 26.5 kg/m2, P=0.001).


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  		Table 1 Baseline characteristics of CHF patients with and without DM, and controls

 
Ischaemic heart disease was more often considered as the aetiology of CHF in the diabetic patients than in the non-diabetic CHF patients. There were no differences in severity of CHF between the diabetic and the non-diabetic patients, as plasma NT-proBNP levels, LVEF and NYHA classification were similar between the two groups. Furthermore, no difference in the use of active cardiovascular medication such as beta-blockers, ACE-inhibitors, statins, acetylsalicylic acid or warfarin was found between the two groups. Only 4 patients were treated with clopidogrel at the time of enrolment, and no one received low-molecular weight heparin. Of the diabetic CHF patients, 11 (22.9%) were treated with metformin, either in combination with a sulfonylurea (n=8, 16.6%), or with insulin (n=2, 4.2%), and one patient received metformin alone (2.1%). Fourteen patients (29.2%) were treated with a sulfonylurea alone, 5 (10.4%) with insulin alone, and 18 (37.5%) were on diet therapy or had newly diagnosed DM.

Plasma CRP concentrations were higher among CHF patients than controls, but no impact of DM status was found on CRP levels (Table 1). Furthermore, CRP levels were similar in patients with ischaemic and non-ischaemic heart failure (P=0.61).

3.2. Comparisons of plasma E-selectin and vWF levels among CHF patients with and without DM and healthy controls
Plasma soluble E-selectin and vWf levels were higher in the diabetic CHF patients compared with the non-diabetic CHF patients, and the healthy controls. In contrast, no significant difference in E-selectin and vWf plasma levels between non-diabetic CHF patients and the healthy controls was observed (Fig. 1, panels A and B). In the total pooled CHF population vWf levels were higher than among controls [95.5 (65.0-149.0) versus 81 (55-132) IU/L, P=0.017), median (inter-quartile range)], whereas there was no difference in soluble E-selectin levels 37.0 (26.0-52.0) versus 36.0 (25.25-46.75) ng/ml, P=0.48.


Figure 01
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  		Fig. 1 Plasma soluble E-selectin (panel A), and vWf (panel B) in CHF patients with and without DM, and controls. Panel A: *significantly higher in diabetic versus non-diabetic CHF patients (P=0.002), and versus controls (P=0.012). No significant difference between non-diabetic CHF patients and controls (P=0.46). Panel B: *significantly higher in diabetic versus non-diabetic CHF patients (P=0.010), and versus controls (P<0.001). No significant difference between non-diabetic CHF patients and controls (P=0.11). ANOVA and LSD post hoc analyses on log transformed variables.

 
3.3. Predictors of E-selectin and vWf levels among CHF patients
Among the patients with CHF, increasing levels of E-selectin (β=0.22, P=0.002) were associated with higher NYHA-class, and a trend towards a relation between NYHA-class and vWf (β=0.13, P=0.079) was observed. E-selectin, but not vWf or CRP, was associated with age (β=–0.15, P=0.036). In addition, E-selectin levels were associated with diastolic blood pressure (β=0.184, P=0.057) and with heart rate (β=0.184, P=0.012). Neither E-selectin, vWf nor CRP were associated with the clinical parameters: BMI, presence of IHD, systolic blood pressure, LVEF, NT-proBNP, TG, LDL-cholesterol or HDL-cholesterol (data not shown).

Table 2 demonstrates the associations between E-selectin, vWf, CRP and indices of glucose metabolism. E-selectin levels were significantly related with fasting blood glucose, fasting plasma insulin, and urinary A/C ratio. von Willebrand factor did not correlate with urinary A/C ratio, or the parameters reflecting glucose metabolism, and none of the biomarkers measured were inter-correlated. Multivariable linear regression analyses of E-selectin levels, with relevant variables (age, gender, NYHA-class, heart rate, diastolic blood pressure, DM status, fasting blood glucose, fasting plasma insulin, and urinary A/C ratio), demonstrated that age (β=–0.18, P=0.021), NYHA-class (β=0.21, P=0.005), urinary A/C ratio (β=0.18, P=0.024), and fasting blood glucose (β=0.19, P=0.015) were independent predictors of plasma E-selectin levels. Only presence of DM was independently associated with vWf in multivariable analyses (β=0.19, P=0.020).


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  		Table 2 Univariate associations in patients with chronic heart failure (n=195)

 
3.4. Predictors of mortality and cardiovascular events among CHF patients with and without diabetes
During the 2.6 years of follow-up, 46 (23.5%) of the 195 CHF patients died, of these 29 (63.0%) were categorized as cardiovascular death. A total of 45 (23.1%) of the patients developed an ischaemic cardiovascular event, of these 8 (17.7%) had a stroke or transient ischaemic attack, 9 (20.1%), a myocardial infarction or unstable angina, and 28 (62.2%) were admitted due to angina pectoris. Almost half of the patients (92 (47.2%)) were admitted to hospital because of worsening of heart failure during the follow-up period.

Table 3 shows the age and sex adjusted associations between baseline parameters, mortality and ischaemic cardiovascular events. Diabetes mellitus per se was not related to increased risk of mortality, or to ischaemic events in the current CHF population. With respect to mortality, neither elevated concentrations of soluble E-selectin, nor vWf were associated with an increased risk. In contrast, in multivariable Cox analysis, high levels of CRP were predictive of mortality, independent of age, sex, NYHA-class, and LVEF<25%, the HR being 1.36 (95% CI, 1.02-1.83; P=0.038).


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  		Table 3 Age and sex adjusted hazard ratios of mortality, and ischaemic events in patients with chronic heart failure (n=195)

 
With respect to ischaemic cardiovascular events, high levels of several of the parameters examined were associated with an increased risk in the total CHF population. Hence, soluble E-selectin (P=0.088), urinary A/C ratio (P=0.012), and indices of metabolic control: increasing HbA1c (P=0.04), fasting blood glucose (P=0.004), and fasting plasma insulin (P=0.003) were all associated with an increased risk of ischaemic cardiovascular event, after adjustment for age and sex. In contrast, no association between vWf, CRP, or NT-proBNP and ischaemic cardiovascular events was observed (Table 3). The effect of DM on the predictive ability of E-selectin, and indices of metabolic control was tested by entering interaction terms in the models. There was a significant interaction between DM and E-selectin (P=0.004), fasting blood glucose (P=0.040), and urinary A/C ratio (P=0.012). Therefore, the prognostic value of these parameters was examined in DM subgroup analyses.

Among the diabetic CHF patients, plasma E-selectin, fasting blood glucose and urinary A/C ratio were associated with increased risk of ischaemic events. For E-selectin the age and sex adjusted risk increased 2.6 fold per 1 SD increase in log transformed value (P=0.009), while there was a 15% increase in risk per 1 mmol/L increase in fasting blood glucose (P=0.008), and for urinary A/C ratio the age and sex adjusted HR was 2.35 (P=0.012) per 1 SD increment in log transformed variable (Table 4). There were only 13 ischaemic events in the diabetic subgroup, therefore we only performed bivariate Cox proportional hazard analyses with E-selectin versus fasting blood glucose, and versus urinary A/C ratio. E-selectin predicted ischaemic events independently of both fasting blood glucose (P=0.038), and of urinary A/C ratio (P=0.023). In the non-diabetic CHF patients, no association between E-selectin, fasting blood glucose, or urinary A/C ratio and future ischaemic events was observed (Table 4).


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  		Table 4 Age and sex adjusted associations between E-selectin, fasting blood glucose, urinary A/C ratio, and ischaemic events in CHF patients with and without DM

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
5. Conclusions
 References
 
To our knowledge, the present study is the first to address the influence of DM on plasma levels of soluble E-selectin and vWf in patients with CHF, and to examine the prognostic value of E-selectin and vWf in these patients. We showed that among patients with CHF, only those with DM had elevated E-selectin and vWf levels, and that soluble E-selectin may have prognostic implications regarding cardiovascular events in CHF patients with DM.

Previous studies examining CAMs and vWf in patients with heart failure, have found elevated levels compared with healthy controls [2-5,8,18,19]. However, only a minority of these studies have reported on the prevalence of DM among the CHF patients [2,18], and none of them have addressed the influence of DM on the plasma levels of these biomarkers, despite the high prevalence of DM in CHF populations [9,10,13]. Type 2 DM per se, is associated with chronic low grade inflammation and endothelial dysfunction; and elevated levels of E-selectin, inter-cellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and vWf have been demonstrated in these patients [6,20,21]. Thus, the high prevalence of diabetic patients may influence the measurements of CAMs and of vWf in cohorts of patients with CHF. The current findings underline the fact that it appears to be the presence of DM rather than CHF that results in elevated levels of these two biomarkers.

In the present study, plasma concentrations of soluble E-selectin were associated with fasting blood glucose, fasting plasma insulin and urinary A/C ratio among the CHF patients. This finding is in accordance with previous studies, reporting on the relation between soluble E-selectin and metabolic control in type 2 DM patients with and without cardiovascular disease [20,22]. Our study extends these findings to include diabetic patients with CHF. There are several possible mechanisms behind these observations. For instance, a direct effect of hyperglycaemia on plasma levels of soluble adhesion molecules, including E-selectin, in patients with type 2 DM has been demonstrated [23]. We found a relationship between increased levels of vWf and the presence of DM, which was independent of hyperglycaemia and fasting plasma insulin levels. This observation is in line with the notion that vWf levels are abnormal in diabetic subjects, but are unrelated to factors of glucose metabolism both in patients with and without DM [24]. Plasma levels of vWf were not significantly related to any of the variables reflecting severity of heart failure. This finding is in contrast to previous studies that have shown a relation between NYHA-class and vWf levels [8,25], whereas, no association between LVEF and CAMs, or vWf has been reported [2].

Diabetes mellitus per se was not related to an increased risk of mortality, or of cardiovascular events in our population of patients with CHF, excluding patients with newly diagnosed DM did not change this observation. Our finding contradicts most previous heart failure studies, reporting that DM has an independent prognostic impact on mortality and cardiovascular events [11,26,27]. The diabetic and non-diabetic patients in our study were treated equally with evidence based cardiovascular drugs. In addition, the diabetic patients were younger and had higher BMI, factors that have been shown to be beneficial in patients with CHF [28]. Furthermore, no data on metabolic control of the diabetic patients, or of urinary albumin excretion levels have been reported in previous heart failure trials. The diabetic patients in our study were relatively well controlled with a mean HbA1c of 7.5% which, in part, might help to explain the lack of association between DM and outcome. This was supported in our analyses on future ischaemic cardiovascular events, which suggested that poor metabolic control and increasing urinary albumin levels were related with an increased risk among the diabetic CHF patients. Achievement of glycaemic control with different anti-diabetic agents in patients with diabetes and CHF is controversial, and a strong warning against the use of metformin still exists. However, interestingly, treatment with metformin decreases plasma levels of both vWf and E-selectin [29], and observational data suggest, that metformin is associated with lower morbidity and mortality in these populations [30]. Unfortunately, the population size of the present study did not permit any subgroup analyses on the impact of metformin treatment on outcome.

Soluble E-selectin levels were associated with major cardiovascular events in the diabetic, but not in the non-diabetic CHF patients. This association was not explained by the association between E-selectin and glucose metabolism. Thus, plasma E-selectin was predictive of cardiovascular events, independently of fasting blood glucose and urinary A/C ratio. In contrast, no relation between vWf and mortality or cardiovascular events was observed. Injury of the vascular endothelium is considered to be an early step in atherogenesis, and CAMs seem to play an important role in the pathophysiological mechanisms behind the development and progression of the atherosclerotic plaque [31]. Activation of endothelial cells leads to expression of various adhesion molecules, including E-selectin, which mediate rolling and adhesion of leucocytes on the endothelium. E-selectin is a CAM of particular interest, since it is exclusively expressed on endothelial cells and therefore differs from other members of the selectin family and from ICAM-1 and VCAM-1 [32]. Hence, soluble E-selectin may be a more specific biomarker of endothelial activation. Hyperglycaemia is a known stimulus of the expression of E-selectin, it could therefore be hypothesized that E-selectin, in part, may explain some of the increased risk of atherosclerosis among patients with DM.

Previous studies of the prognostic value of CAMs in CHF patients have not been consistent, some have reported on a relationship between the cellular adhesion molecules ICAM-1, P-selectin and outcome [5,18], and one study observed a possible association between vWf levels and prognosis [4]. However, given the relatively small population sizes, and especially the limited number of events in these studies, the prognostic value of biomarkers of endothelial dysfunction in patients with CHF is yet to be determined. Chronic heart failure is a complex condition characterized by immune activation with pro-inflammatory cytokines; plasma levels of CAMs and vWf have been shown to be affected by these inflammatory cytokines [32]. They could therefore be elevated in the absence of endothelial dysfunction in patients with CHF. This may account for some of the apparent discrepancy between the prognostic value of CAMs and vWf in different populations. The inflammatory response in CHF was supported in our study, since plasma CRP levels were markedly elevated and related to prognosis in patients with CHF, which was independent of DM status and presence of IHD.

Some limitations of the present study need to be considered. First, the CHF patients and the healthy controls were primarily matched by age, hence other parameters such as gender, BMI and smoking may have influenced endothelial function. We did not include lifestyle factors such as smoking and BMI, since these data unfortunately were not available in detail, lack of information on smoking should be noted, since smoking is known to influence endothelial function. However, the presence of DM and indices of glucose metabolism were the most important determinants of E-selectin and vWf levels among the CHF patients, suggesting that further adjustment for these factors would not change the main result of the present study. Second, the small number of events in the DM subgroup analyses should be considered when interpreting the present results on prognosis. Finally, it should be noted that fasting glucose, insulin and lipids were not available for the control group.


   5. Conclusions
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
References
 
The present study suggests for the first time, that the elevated plasma levels of E-selectin and vWf in CHF are dependent on the presence or absence of DM. Furthermore, the study indicates that soluble E-selectin, but not vWf, may have a role as a predictor of future ischaemic cardiovascular events in CHF patients with a diagnosis of diabetes mellitus. Our data strengthen the hypothesis that endothelial dysfunction plays a key role in cardiovascular events especially in diabetic patients.


   Acknowledgements
 
Dr. Caroline Kistorp has been supported by research grant 10/02s from the Copenhagen Hospital Corporation, Denmark and by the Danish Diabetes Association. The study was also supported by a grant from Grosserer A.V. Lykfeldt and wife's foundation. We would like to acknowledge the laboratory assistance of Inger Wätjen and Lisbet Hansson, Department of Clinical Chemistry, Frederiksberg University Hospital, Frederiksberg, Denmark.


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 References
 

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M. Shechter, S. Matetzky, M. Arad, M. S. Feinberg, and D. Freimark
Vascular endothelial function predicts mortality risk in patients with advanced ischaemic chronic heart failure
Eur J Heart Fail, June 1, 2009; 11(6): 588 - 593.
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