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European Journal of Heart Failure 2003 5(5):629-637; doi:10.1016/S1388-9842(03)00110-7
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© 2003 European Society of Cardiology

Enhanced levels of CD154 (CD40 ligand) on platelets in patients with chronic heart failure{star}

Christian Stumpfa,*, Christoph Lehnera, Saeed Eskafia, Dorette Raaza, Atilla Yilmaza, Susanne Ropersa, Alexander Schmeisserb, Joseph Ludwiga, Werner G. Daniela and Christoph D. Garlichsa

a Laboratory for Molecular Cardiology, Medical Clinic II, University of Erlangen-Nuremberg Schwabachanlage 10, Ostfluegel, UG, Erlangen 91054, Germany
b Heart Center Dresden, University of Dresden Dresden, Germany

* Corresponding author. Tel.: +49-91-31-853-5896; fax: +49-91-31-533-165. E-mail address: ch.stumpf{at}web.de


   Abstract
Top
 Notes
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Background: Inflammation plays a significant contributory role in the pathogenesis of chronic heart failure (CHF). Previous data have shown enhanced plasma levels of proinflammatory cytokines, i.e. TNF-{alpha} and IL-6, as well as a persistent immune activation in patients with CHF. Furthermore, the immune modulator CD154 has been receiving increased attention, since it plays a key role in the pathophysiology of multicellular vascular events such as thrombosis, inflammation and atherosclerosis. Since CD154 intitiates and maintains the release of proinflammatory cytokines from endothelial cells, its potential role for the development and progression of CHF is of interest.

Methods: Fifty patients with CHF (aged 66.9±12.6 years, mean ejection fraction 22.1±9.2%, NYHA II–IV, 39 of ischemic origin, 11 with idiopathic dilated cardiomyopathy) and 15 healthy controls (aged 62.5±9.8 years) were examined. Thirty-two patients were taking aspirin (100 mg/day). Blood was drawn from a peripheral vein and immediately fixed with 1% paraformaldehyde, incubated with anti-CD154, anti-P-selectin, and anti-CD61 and thereafter analyzed by flow cytometry.

Results: Patients with CHF showed significantly enhanced expression of platelet-bound CD154 and P-selectin as compared to controls (CD154: median 35.6 25th percentile: 26.3; 75th percentile: 44.6 vs. 12.8; 25th: 6.8; 75th: 15.6 mean fluorescence intensity [MFI], P<0.001; P-selectin: median 3.2 25th percentile: 1.9; 75th percentile: 5.9 vs. 1.4; 25th: 1.2; 75th: 1.9, MFI, P<0.001). CD154 expression on platelets positively correlated with increasing NYHA-class. In contrast, no significant differences in serum levels of soluble CD154 or CD40 expression on monocytes were detected in the study groups. Antiplatelet-therapy with aspirin did not influence CD154 or P-selectin expression on platelets.

Conclusion: Our pilot study demonstrates significantly enhanced levels of CD154 on platelets in patients with CHF. This suggests that the CD40–CD154 axis may contribute to the proinflammatory milieu, which exists in CHF and thus may play a pathogenic role in the development and progression of CHF.

Key Words: Heart failure • Inflammation • Platelets

Received December 31, 2002; Revised March 6, 2003; Accepted June 12, 2003


   1. Introduction
Top
 Notes
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
Over the past decade there has been an increasing interest in the potential role of inflammatory mediators in cardiac diseases, such as CHF. Elevated circulating levels of cytokines, in particular TNF-{alpha} and IL-6, have consistently been identified in patients with CHF [1]. Several studies have suggested that the extent of cytokine production directly correlates to the severity of the disease process [2]. Furthermore, studies such as the SOLVD database showed an increased rate of mortality associated with increasing levels of TNF-{alpha} in patients with CHF [3]. Interestingly, many aspects of the syndrome of CHF can be explained by the known biological effects of these inflammatory mediators: serum concentrations of TNF-{alpha} equal to those found in CHF induce progressive left ventricular dysfunction, LV remodeling, fetal gene expression, and cardiomyopathy [4]. Thus, analogous to the well known elevation of neurohormones in CHF, TNF-{alpha} can predict the functional class and the clinical outcome in patients with CHF.

The emerging link between inflammatory cytokines and the pathogenesis and progression of CHF has already resulted in the development of anti-cytokine strategies that might be used as adjunctive therapy in patients with CHF. But although inflammatory mediators have become the focus of interest in leading heart failure trials, their cellular and molecular interactions in CHF are far from being clearly understood. In this context, the immune modulator pair CD40–CD154 has attracted considerable attention with regard to its role in the pathogenesis of chronic inflammatory diseases. So far, an upregulation of the CD40–CD154 axis has been shown for chronic inflammatory diseases such as autoimmune disorders, [5] arthritis, atherosclerosis, [6] and even cancer [7].

Interestingly, the CD40 receptor and its ligand CD154 (formerly CD40L) belong to the TNF-receptor family and thus share some biological features with TNF-{alpha}. However, considering this background, there is little known about the role of CD40–CD154 in the development and progression of CHF.

The CD40 receptor was first identified and functionally characterized on B lymphocytes. It plays a pivotal role as a mediator of T-cell-dependent B cell activation, proliferation and differentiation [8]. Its ligand, CD40L (recently renamed CD154), a type-II transmembrane protein, was originally considered to be restricted to activate CD4 positive helper T lymphocytes [9]. In lymphocytes, two forms of CD154 are described: a cell bound full-length form (CD154, 30 kD) and a truncated soluble form (sCD154, 18 kD). During recent years, it has become obvious that CD40 is expressed on many cells other than B cells (e.g. endothelial cells, monocytes, dendritic cells), and that CD154 is also expressed on vascular cells [10]. This broadened spectrum of CD40–CD154 expression has established a new role of the CD40–CD154 dyad as a central mediator for immunity and inflammation. It is now known that the CD40–CD154 axis upregulates proinflammatory mediators, such as the expression of adhesion molecules (i.e. ICAM-1, VCAM-1), proinflammatory cytokines (i.e. TNF-{alpha}, IL-6), activates matrix-metalloproteinases, and induces chemokines such as MCP-1 [11]. All of these mediators have already been described as being elevated in CHF and potentially contribute to the development and progression of CHF [2,12–14].

Furthermore, recent research has described upregulation of CD40 and CD154 on activated platelets thus enabling these cells to induce a potent inflammatory reaction of endothelial cells [15]. This finding suggests a pathophysiological role of platelets in triggering not only thrombosis, but also vascular inflammation [16].

Given this background it is of interest whether the CD40–CD154 system also plays a role in CHF. To clarify this possible role of CD40–CD154, we analyzed the levels of membrane-bound and soluble CD154 in patients with CHF. We particularly focused on the emerging role of CD154-bearing platelets as inflammation-inducing cells [17].


   2. Methods
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
2.1. Patients and control subjects
Fifty patients (38 men, 12 women) with symptomatic CHF, defined as dyspnea, fatigue at rest or on exertion for more than 3 months, were studied, 40 as in-patients and 10 as out-patients (Table 1). The severity of the CHF ranged from New York Heart Association functional class II to IV (Table 1). Thirty-nine patients had CHF of ischemic origin and 11 patients had an idiopathic dilated cardiomyopathy. All patients underwent echocardiography. Their clinical and hemodynamic situations were stable, with no changes in medication during the month prior to study entry. Blood was sampled before any new medications or interventions were prescribed which might have influenced platelet activation. None of the patients had hemodynamic support devices.


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  		Table 1 Baseline characteristics of CHF patients and age- and sex-matched control subjects

 
CHF medication consisted of ACE-inhibitors, beta-blockers, diuretics, digitalis and AT1-blockers. 32 patients were taking aspirin and 18 were without aspirin. All patients had serum creatinine levels lower than 150 µmol/l and none had any concomitant diseases such as fever, infection, myocarditis, malignancies, collagen vascular disease, pulmonary disease or thyrotoxicosis. Control subjects were 15 healthy sex- and age-matched blood donors (nine men, six women). In addition, 10 patients (seven men, three women) with stable coronary artery disease (CAD) without CHF were recruited as controls for comparison with the ischemic cardiomyopathy group.

Informed consent for participation in the study was obtained from all individuals.

2.2. Blood sampling protocol
Peripheral venous blood was drawn into blood collection tubes, containing 106 mmol/l sodium citrate, in a highly standardized manner. All blood samples were collected under minimal tourniquet pressure from the antecubital vein using a wide calibre puncture needle (21-gauge) under resting conditions (subjects had rested for more than 15 min). For fixation, 1% paraformaldehyde in PBS (without Ca2+/Mg2+) was added immediately to one tube of blood (1:1 v/v) [18]. All blood tubes were immediately transferred to the laboratory. Platelets were stained within 30 min of blood collection. A third separate aliquot of blood without any additives was allowed to clot for 1 h before centrifugation (1500xg and 4 °C for 10 min). The serum supernatant was stored at –80 °C until analysis. Samples were thawed only once.

2.3. Flow cytometric analysis of platelets
Platelet immunostaining was performed as previously described [19]. Fixed blood was diluted 1:25 with PBS. Aliquots were mixed 1:8 with fluorescein isothiocyanate (FITC)-conjugated anti-CD154 (B-B29, mouse IgG2a, Dianova, Germany), FITC-conjugated anti-CD62P (AK-4, mouse IgG1, Dianova), or FITC-conjugated anti-CD40 (5C3, mouse IgG1, PharMingen, Germany) as well as phycoerythrin (PE)-conjugated anti-CD61 resp. anti-CD41 (PM6, mouse IgG1, Dianova) and incubated for 30 min at room temperature. FITC-conjugated mouse-IgG (Dianova and Pharmingen) served as isotype-matched control. Platelets were identified with anti-CD61 resp. anti-CD41, which labeled all platelets. After incubation time, 1 ml PBS was added to the samples and analyzed as described below.

Platelets were identified by gating on CD61-PE resp. CD41-PE positivity and their characteristic light scatter. The platelet population evaluated was found to be ≥98% positive for CD61 resp. CD41.

2.4. Culture of HUVEC and activation by platelets
Primary cultures of human umbilical vein endothelial cells (HUVEC) were obtained by dispase treatment of umbilical cord veins and cultured in endothelial cell growth medium (PromoCell, Heidelberg). For co-incubation experiments, platelets were pre-stimulated with 2 U/ml {alpha}-thrombin (Sigma, Germany) for 20 min followed by antagonization of thrombin by 5 U/ml hirudin (Roche, Germany). Thereafter, 250 µl of the platelet suspension was added to 250 µl complete endothelium cell growth medium (final platelet count 2x108/ml) and transferred to 24-well plates covered with confluent monolayers of HUVEC. HUVEC were left untreated or were incubated for 10 min at 37 °C with a-thrombin-stimulated platelets. For blocking engagement of CD40 on HUVEC, anti-CD154 (IgG1, PharMingen) or MOPC-21 (isotype control; both 10 µg/ml) were added to some portions of a-thrombin-stimulated platelets before incubation with HUVEC. Thereafter, the supernatants of coculture experiments were analyzed for MCP-1 (see below).

2.5. Enzyme-linked immunosorbent studies
Serum levels of sCD154 and monocyte chemoattractant peptide-1 (MCP-1) in the supernatant of cultured HUVEC treated with activated platelets were determined by EIA (sCD154: detection limit 95 pg/ml; Bender MedSystems, Austria; MCP-1: detection limit 5 pg/ml, R&D, Germany) according to the manufacturers’ instructions.

2.6. Statistical analysis
The data were analyzed by non-parametric methods to avoid assumptions about the distribution of the measured variables. Comparisons between groups were made with the Mann–Whitney U test. The differences between baseline and post-treatment values were analyzed with the Wilcoxon signed-rank test. The association of measurements with other biochemical parameters was assessed by the Spearman rank correlation test. Statistical significance was considered to be indicated by a value of P<0.05.


   3. Results
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
The patients’ characteristics are shown in Table 1.

Patients with CHF showed significantly enhanced expression of platelet-bound CD154 compared to healthy control subjects (Fig. 1). The expression of CD154 positively correlated with increasing NYHA functional class. Accordingly, the highest levels were found in patients with NYHA class IV (Fig. 2a). The expression of membrane-bound CD154 in the ischemic cardiomyopathy group was also significantly enhanced compared to the group of patients with stable CAD without CHF (median 35.6 25th percentile: 26.3; 75th percentile: 44.6 vs. 13.4; 25th: 12.0; 75th: 20.5 MFI, P<0.001, Fig. 3a).


Figure 1
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  		Fig. 1 Expression of CD154 (a) and P-selectin (b) on platelets in 15 healthy controls and 50 CHF patients. Values represent the mean fluorescence intensity.

 


Figure 2
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  		Fig. 2 Expression of CD154 (a) and P-selectin (b) on platelets in CHF patients as a function of the severity of symptoms. Data are given as mean fluorescence intensity.

 


Figure 3
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  		Fig. 3 Expression of CD154 (a) and P-selectin (b) on platelets in 15 healthy controls, 10 patients with stable coronary artery disease, 39 patients with ischemic cardiomyopathy and 11 patients with idiopathic dilated cardiomyopathy. Data are given as mean fluorescence intensity.

 
There were no significant differences in CD154 expression on platelets from in-patients with CHF as compared to those from out-patients with CHF (median 38.6 25th percentile: 23.2; 75th percentile: 43.6 vs. 39.7; 25th: 22.3; 75th: 44.6, P=ns).

Since some medications, particularly those with well known effects on platelet function such as aspirin, modulate platelet function, we investigated whether or not any influence of aspirin on CD154 expression was detectable in our study groups. Interestingly, we could not find a significant difference between the CD154 expression on platelets in CHF patients taking aspirin as compared to those patients without aspirin (median 35.6 25th percentile: 26.9; 75th percentile: 46.8 vs. 36.2; 25th: 22.6; 75th: 44.0, P=ns) (Fig. 4a). In addition, our data did not show any significant link between the cause of CHF and the degree of CD154 expression on platelets.


Figure 4
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  		Fig. 4 Expression of CD154 (a) and P-selectin (b) on platelets in CHF patients who were taking aspirin compared to non-aspirin users. Data are given as mean fluorescence intensity.

 
In contrast to membrane-bound CD154, patients with CHF did not show significantly altered serum levels of sCD154 as compared to healthy controls (3.3+1.7 vs. 3.5+1.6 ng/ml, P=ns). There was no correlation between serum levels of sCD154 and the severity of CHF.

Next to CD154 on platelets, patients with CHF showed significantly enhanced expression of platelet-bound P-selectin as compared to healthy control subjects (median 3.4 25th percentile: 1.9; 75th percentile: 6.2 vs. 1.1; 25th: 1.0; 75th: 1.4 MFI, P<0.001, Fig. 1b). The expression of P-selectin also positively correlated with increasing NYHA functional class. Again, the highest levels were found in patients with NYHA class IV (Fig. 2b). The expression of P-selectin in the ischemic cardiomyopathy group was also significantly enhanced as compared to the group of patients with stable CAD without CHF (median 3.2 25th percentile: 1.9; 75th percentile: 5.9 vs. 1.4; 25th: 1.2; 75th: 1.9, P<0.001, Fig. 3b).

Similarly to the CD154 expression, aspirin had no significant influence on P-selectin expression (median 3.6 25th percentile: 1.8; 75th percentile: 5.0 vs. 3.2; 25th: 1.9; 75th: 6.6 MFI, P=ns) (Fig. 4b).

In addition to platelets, monocytes play an important role in chronic inflammatory processes. Therefore, we examined the expression levels of CD40 on monocytes in CHF patients. In our study groups, no significant differences in CD40 expression on monocytes were seen between CHF patients and healthy controls (median 5.4 25th percentile: 3.1; 75th percentile: 9.6 vs. 5.2; 25th: 2.9; 75th: 8.6 MFI, P=ns). Again, there was no correlation between the expression levels of CD40 on monocytes and the severity of CHF.

To further evaluate the pathophysiological relevance of enhanced expression of CD154 on platelets in CHF, we stimulated HUVEC with activated platelets in an established in vitro model. In this coculture model platelets activated by physiological concentrations of human thrombin (2 U/ml) were able to significantly induce MCP-1 release from endothelial cells (control 111+6 pg/ml vs. unstimulated platelets 260+37 pg/ml vs. stimulated platelets 492+42 pg/ml, n=3, Fig. 5), an effect which was significantly blocked by pretreatment of stimulated platelets with a specific monoclonal anti-CD154 antibody, but not with the control antibody MOPC-21 (stimulated platelets 492+42 pg/ml vs. pretreatment with anti-CD154, 293+31 pg/ml vs. pretreatment with MOPC-21 421+15 pg/ml, Fig. 5).


Figure 5
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  		Fig. 5 In-vitro model of activated platelets and endothelial cells, showing CD154-induced production of MCP-1. This effect was blocked by pre-treatment with a specific monoclonal anti-CD154 antibody but not by the control antibody (MOPC-21). +P=ns vs. activated platelets.

 

   4. Discussion
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
This pilot study shows a significant upregulation of CD154 in patients with CHF. The degree of CD154 upregulation closely correlated with severity, but was independent of the origin of heart failure.

Our results about the involvement of the CD40 system in CHF, support the theory of a contributory role of inflammation in the process of CHF. Since engagement of the CD40 system on monocytes or vascular cells such as endothelial or smooth muscle cells induces a broad spectrum of proinflammatory mediators, a considerable role for upregulated CD154 may be assumed for the pathophysiology of CHF.

In our study, we concentrated on platelets as CD154 bearing cells. The new finding of CD154 expression together with other platelet-derived substances reveal platelets as potent inflammation-modulating circulating blood cells. Thereby, a strong line of evidence has recently shown the close interrelation between inflammation and thrombosis [16].

In CHF, increased serum levels of platelet-derived inflammation-modulating mediators have been shown previously [20]. Their release is accompanied by an activation of platelets, as shown by O'Connor et al. [21]. In our present study, we confirmed the activation of platelets using P-selectin as an activation marker. In addition, our data show a positive correlation between expression of P-selectin and the severity of CHF. On the basis of these studies, platelet activation seems to be an integral, but rather unknown pathophysiological element of CHF. The exact cause of platelet activation in CHF, however, still remains to be elucidated in further studies. One possible explanation is the activation of platelets through sympthoadrenal stimulation and enhanced catecholamine release [22].

Interestingly, we could not find any significant differences in serum levels of sCD154 in patients with CHF as compared to healthy controls in our study. Obviously, the chronic inflammatory process of heart failure differs pathophysiologically from acute inflammatory situations, where upregulation of soluble CD154 has been described (i.e. acute coronary or cerebral ischemia) [23]. Under acute inflammatory settings the binding of the membrane-bound CD154 to coexpressed CD40 on platelets can lead to a cleavage of the membrane-bound CD154 and the release of the soluble (18 kD) form of this molecule (sCD154) [24]. Surface CD154 thus rapidly becomes deactivated. In contrast to transmembrane CD154, the released sCD154 does not induce an inflammatory reaction on endothelial cells [24]. After the acute phase, serum levels of sCD154 return to the normal range.

In contrast to acute inflammatory states, platelet activation in CHF seems to be a chronic process, with significant upregulation of membrane-bound, but not soluble CD154. These results correspond to another study, where patients with hypercholesterolemia with its known chronic proinflammatory and prothrombotic milieu, showed upregulation of membrane-bound CD154, but not sCD154 [25]. On the basis of these studies, it seems, that in chronic inflammatory disorders the released form of CD154 is rapidly bound to CD40 on many vascular cells leading to ‘normal’ levels of sCD154 in chronic inflammatory states.

An interesting finding in our study was that aspirin did not suppress the upregulation of CD154 on platelets. This result is in accordance with a study by Hermann et al., in which newer antithrombotic substances such as clopidogrel, but not aspirin, significantly inhibited upregulation of CD154 upon platelet activation [26]. As a consequence, patients with CHF could benefit from therapy with modern antithrombotic substances such as clopidogrel since CD154-mediated proinflammatory pathways become suppressed.

The pathophysiological relevance of our finding of highly upregulated CD154 on platelets was underlined by a coculture model of activated platelets and endothelial cells, where CD154-induced production of MCP-1 was observed. This result is in accordance with in-vitro data from Henn et al. [15]. Moreover, CD154-induced release of MCP-1 may be one cause for elevated serum levels of MCP-1 found in patients with CHF [12] and suggests the induction of vascular inflammation by platelets.

Our findings of the raised expression of CD154 on platelets may not be specific for CHF, but we believe that these data support the theory that immunologic and inflammatory processes are important features of CHF. Meanwhile, it has been proven, that statins are capable of downregulating the CD40–CD154 system thus suppressing CD40–CD154-induced inflammation [25]. Interestingly, other scientific data suggest that patients with severe CHF benefit from statin treatment [27–29]. According to our results, this observation may be partially due to the downregulation of the CD40 system by statins.

In summary, elevated levels of CD154 may contribute to the proinflammatory milieu existing in CHF and may be both a cause and a consequence of immune activation in this disease. However, further investigation is required to clarify its role in CHF progression and to test whether substances that downregulate the CD40–CD154 interaction may represent a new therapeutic option in patients with CHF.


   Acknowledgements
 
This study was supported by the ELAN programme of the medical faculty of the university of Erlangen-Nuremberg, Germany.


   Notes
Top
 Notes
Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
{star} Supported by grants from the ELAN programme of the medical faculty of the university of Erlangen-Nuremberg, Germany. Back


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

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