Published online before print July 1, 2002, doi: 10.1161/01.CIR.0000025419.95769.F0
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
(Circulation. 2002;106:399.)
© 2002 American Heart Association, Inc.
Brief Rapid Communications |
Association Between Enhanced Soluble CD40L and Prothrombotic State in Hypercholesterolemia
Effects of Statin Therapy
From the Center of Excellence on Aging (E.P., C.D.F., M.N., A.F., F.C., G.D.), Center for the Prevention of Atherosclerosis (F.C., A.M., M.F.), University of Chieti "G. D’Annunzio" School of Medicine, Chieti, Italy.
Correspondence to Giovanni Davì, MD, Dipartimento di Medicina e Scienze dell’Invecchiamento, via dei Vestini 31, 66013 Chieti, Italy. E-mail gdavi{at}unich.it
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
Background— Hypercholesterolemia is associated with inflammation and the prothrombotic state. CD40-CD40 ligand (CD40L) interactions promote a prothrombotic response in nucleated cells. The aim of this study was to characterize the in vivo expression of soluble CD40L (sCD40L) in hypercholesterolemia, to correlate it with the extent of the prothrombotic state, and to investigate whether it may be modified by statins.
Methods and Results— We studied 80 hypercholesterolemic patients and 80 matched healthy subjects. Hypercholesterolemic subjects had enhanced levels of sCD40L, factor VIIa (FVIIa), and prothrombin fragment 1+2 (F1+2) compared with healthy subjects. sCD40L correlated with total cholesterol and LDL cholesterol. Moreover, sCD40L was positively associated with in vivo platelet activation, as reflected by plasma P-selectin and urinary 11-dehydro-thromboxane B2, and with procoagulant state, as reflected by FVIIa and F1+2. Inhibition of cholesterol biosynthesis by pravastatin or cerivastatin was associated with comparable, significant reductions in sCD40L, FVIIa, and F1+2.
Conclusions— This study suggests that sCD40L may represent the molecular link between hypercholesterolemia and the prothrombotic state and demonstrates that statin therapy may significantly reduce sCD40L and the prothrombotic state.
Key Words: risk factors • atherosclerosis • hypercholesterolemia • inflammation
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
A high incidence of thrombotic complications has been associated with hypercholesterolemia. This may be related to enhanced thrombotic risk. In fact, we have previously documented persistent platelet activation1 and increased thrombin generation2 in hypercholesterolemic subjects, as well as the ability of simvastatin to reverse these abnormalities.2,3
The CD40 ligand (CD40L) has been found expressed on CD4+ T cells and on activated platelets.4 Both membrane-bound and soluble CD40L (sCD40L) interact with CD40 expressed on vascular cells, resulting in inflammatory and prothrombotic responses.4,5 Thus, CD40L-CD40 interaction may be the molecular mechanism that links inflammation and the prothrombotic state in the setting of hypercholesterolemia. According to this hypothesis, inhibition of CD40 signaling would prevent the initiation6 and progression7 of atherosclerosis. Moreover, sCD40L has been implicated in acute coronary syndromes,8 and elevated sCD40L predicts an increased risk of future cardiovascular events in healthy subjects.9 Interestingly, Garlichs et al10 showed that hypercholesterolemia is associated with an ex vivo activation of the CD40 system that can be downregulated by cerivastatin. However, they did not provide any direct evidence suggesting the intervention of this mechanism in vivo or its contribution to the prothrombotic state observed in hypercholesterolemia.
Therefore, in the present study, we investigated whether upregulation of the CD40 system in hypercholesterolemia is associated with in vivo platelet activation and the procoagulant state. Moreover, we investigated whether the sCD40L-associated prothrombotic state may be normalized by statins and whether this effect is a function of cholesterol reduction or is due to pleiotropic effects of statins.
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Subjects
Eighty consecutive hypercholesterolemic patients and 80 matched healthy normocholesterolemic subjects were asked to participate in the study. Patient recruitment was completed when predetermined groups with laboratory evidence of hypercholesterolemia were formed. The local Ethics Committee approved the study, and patients provided written informed consent. The baseline characteristics of patients and controls are shown in Table 1.
|
Design of the Studies
First, a cross-sectional comparison of circulating sCD40L, interleukin-2 receptor (sIL2-R), factor VIIa (FVIIa), and prothrombin fragment 1+2 (F1+2) was performed between all patients and controls. Furthermore, urinary 11-dehydro-thromboxane (TX) B2 and plasma P-selectin were evaluated in 27 of the 80 hypercholesterolemic patients compared with 27 of the 80 healthy controls. Both groups were chosen randomly.
Second, to ascertain whether statin therapy could influence sCD40L, we investigated the effects of 2 structurally different statins (cerivastatin and pravastatin) on sCD40L. Thus, in a first study (study A), we randomly assigned 10 of the 80 hypercholesterolemic patients to 8-week treatment with either cerivastatin (0.2 mg/d) or placebo in a double-blind fashion. In a second study (study B), 16 of the 80 hypercholesterolemic patients were randomly assigned to 8-week treatment with either pravastatin (40 mg/d) or placebo in a double-blind fashion. All patients were given the American Heart Association step I diet.
Sample Collection
Serum, plasma, and urine samples were obtained after a 12-hour fast. Samples were frozen and stored at -20°C until analysis.
Biochemical Measurements
Total cholesterol (TC) and triglycerides were determined by an enzymatic method. HDL cholesterol was measured after phosphotungstic acid/MgCl2 precipitation on fresh plasma. LDL cholesterol (LDL-C) was calculated by the Friedewald formula.
Enzyme Immunoassays
Serum sCD40L and plasma P-selectin, sIL2-R, F1+2, and FVIIa were determined by ELISA (sCD40L: Bender Medsystems; P-selectin and sIL2-R: R&D Systems; F1+2: Behringwerke AG; and FVIIa: Diagnostica Stago).
11-Dehydro-TXB2 Assay
Immunoreactive 11-dehydro-TXB2 was extracted from 20-mL urine aliquots and measured by a previously described radioimmunoassay.1–3
Statistical Analysis
Comparisons between groups were made with the Mann-Whitney U test. The differences between baseline and posttreatment values were analyzed with the Wilcoxon test. Correlations were assessed by Spearman test. All values are reported as mean±SD. Statistical significance was indicated by P<0.05. All calculations were made with the Stat View II program (Abacus Concepts).
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Patients had significantly higher TC and LDL-C than controls. No differences were observed with respect to HDL cholesterol and triglycerides (Table 1).
Inflammatory and Prothrombotic State
sCD40L was significantly increased in hypercholesterolemic versus normocholesterolemic subjects (8.3±5.2 versus 2.4±1.3 ng/mL, n=80, P<0.0001; Figure 1A). Fifty-eight (72.5%) of 80 patients had sCD40L in excess of 2 SD above the control mean (Figure 1A). Hypercholesterolemic patients also had higher FVIIa and F1+2 with respect to controls (37±13 versus 24±4.8 mU/mL, P<0.001, and 1.52±0.95 versus 0.55±0.22 nmol/L, P<0.001, respectively; n=80). Finally, hypercholesterolemic patients had enhanced 11-dehydro-TXB2 (1319±547 versus 350±164 pg/mg creatinine, n=27, P<0.001) and P-selectin (115±55 versus 60±15 ng/mL, n=27, P<0.001) compared with controls.
|
) and after (
) cumulative statin treatment (n=13) are represented. Box shows correlation in normocholesterolemic subjects.
Associations
In hypercholesterolemic patients and in control subjects, sCD40L showed a correlation with TC (r=0.353, P=0.0018, and r=0.231, P=0.04, respectively) and LDL-C (r=0.379, P=0.0008, and r=0.292, P=0.0094, respectively; Figure 1B). Moreover, sCD40L was correlated with the intensity of platelet activation, as reflected by 11-dehydro-TXB2 (Figure 2a) and P-selectin (Figure 2b), both in hypercholesterolemic patients (r=0.443, P=0.024, and r=0.455, P=0.0204, respectively) and in normocholesterolemic subjects (r=0.514, P=0.0087, and r=0.402, P=0.0403, respectively). sCD40L was also correlated with the procoagulant state, as reflected by FVIIa (Figure 2c) and F1+2 (Figure 2d) levels, both in hypercholesterolemic patients (r=0.799, P<0.0001, and r=0.789, P<0.0001, respectively) and in controls (r=0.343, P=0.0023, and r=0.273, P=0.0154, respectively). In contrast, sCD40L was not correlated with T-lymphocyte activation, as reflected by sIL2-R (data not shown).
|
Effect of Statin Therapy
Placebo administration was not associated with any change in blood lipids, sCD40L, or procoagulant state in the 2 intervention studies (Table 2). In contrast, both pravastatin and cerivastatin therapy were associated with comparable, significant reductions in TC and LDL-C (Table 2). More interestingly, patients randomized to both statins showed a significant reduction in sCD40L, FVIIa, and F1+2 (Figure 1B; Table 2). When we compared the effect of cerivastatin and pravastatin on sCD40L, we observed that both drugs produced a reduction in sCD40L comparable to the effects on lipid profile (Table 2). Notably, the correlation between sCD40L and TC (r=0.389, P<0.05), LDL-C (r=0.41, P<0.05), FVIIa (r=0.871, P=0.0001), and F1+2 (r=0.733, P=0.0002) remained significant after statin therapy.
|
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Despite ex vivo evidence of CD40L upregulation on activated platelets that has been reported recently in the setting of hypercholesterolemia,10 no double-bind, randomized studies have yet demonstrated whether statins are able to reduce circulating sCD40L in vivo, thus improving the prothrombotic state associated with hypercholesterolemia.11 Furthermore, little is still known regarding the cellular sources of sCD40L in humans. The present study is the first to (1) provide in vivo evidence that enhanced sCD40L is associated with platelet activation in the setting of hypercholesterolemia, (2) relate the increase in sCD40L to the prothrombotic state previously described in hypercholesterolemia, and (3) provide in vivo evidence that statins may significantly reduce sCD40L and the CD40L-associated prothrombotic state.
In the present study, the association between enhanced sCD40L and platelet activation is supported by the relationship between sCD40L and both 11-dehydro-TXB2 and P-selectin. In contrast, the nonsignificant correlation between sCD40L and sIL2-R suggests that T cells are unlikely to be a major source of sCD40L in this setting.
In addition to the association with platelet activation, increased sCD40L showed a positive correlation with FVIIa and F1+2, which are in vivo indices of coagulative activation. This could suggest that hypercholesterolemia stimulates the release of sCD40L from activated platelets in vivo and that it may subsequently induce a procoagulant response in endothelial and mononuclear cells through interaction with CD40.4,5 Interestingly, because CD40L is a stimulus for cyclooxygenase-2 expression and activated platelets may induce cyclooxygenase-2 in mononuclear cells,12 we can speculate that sCD40L might also contribute to this transcellular mechanism of aspirin-insensitive TXA2 biosynthesis.
In the present study, increased sCD40L in hypercholesterolemic patients showed a correlation with TC and LDL-C; in contrast, a nonsignificant (P=0.06) trend was observed in the study from Garlichs et al.10 It is likely that the significantly different sample size between the 2 studies (80 versus 15 patients) may be responsible for this discrepancy.
In the present study, statins decreased sCD40L and coagulative activation, 2 effects that could contribute to explain the reduction in cardiovascular events observed in clinical trials with statins. In contrast, Garlichs et al10 reported that a short-term (21 day) treatment with cerivastatin 0.3 mg/d did not significantly affect sCD40L. The most plausible explanation for this discrepancy might be the different period of treatment. Thus, adequately long treatment periods with statin might be necessary to significantly downregulate sCD40L. Notably, the comparable reduction in sCD40L obtained with both cerivastatin and pravastatin argues against any molecule-specific pleiotropic effect and suggests that a reduction in sCD40L and the sCD40L-associated prothrombotic state is a class feature of statins.
In conclusion, the present study addresses the missing link between hypercholesterolemia and the prothrombotic state by demonstrating the association between enhanced sCD40L and platelet and coagulative activation in this setting and by providing evidence that sCD40L suppression by statins is associated with the prothrombotic state reduction in vivo. These findings are potentially important from a fundamental standpoint because they demonstrate the decisive role of sCD40L in all steps of thrombus formation. From a practical standpoint, statins might provide a novel therapy for high-risk patients with a thrombophilic pattern.
Received March 22, 2002; revision received May 23, 2002; accepted May 23, 2002.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Davì G, Averna M, Catalano I, et al. Increased thromboxane biosynthesis in type IIa hypercholesterolemia. Circulation. 1992; 85: 1792–1798.
2. Davì G, Ganci A, Averna M, et al. Thromboxane biosynthesis, neutrophil and coagulative activation in type IIa hypercholesterolemia. Thromb Haemost. 1995; 74: 1015–1019.[Medline] [Order article via Infotrieve]
3. Notarbartolo A, Davì G, Averna M, et al. Inhibition of thromboxane biosynthesis and platelet function by simvastatin in type IIa hypercholesterolemia. Arterioscler Thromb Vasc Biol. 1995; 15: 247–251.
4. Henn V, Slupsky JR, Grafe M, et al. CD40 ligand on activated platelets triggers an inflammatory reaction of endothelial cells. Nature. 1998; 391: 591–594.[CrossRef][Medline] [Order article via Infotrieve]
5. Lindmark E, Tenno T, Siegbahn A. Role of platelet P-selectin and CD40 ligand in the induction of monocytic tissue factor expression. Arterioscler Thromb Vasc Biol. 2000; 20: 2322–2328.
6. Mach F, Schonbeck U, Sukhova GK, et al. Reduction of atherosclerosis in mice by inhibition of CD40 signaling. Nature. 1998; 394: 200–203.[CrossRef][Medline] [Order article via Infotrieve]
7. Schonbeck U, Sukhova GK, Shimizu K, et al. Inhibition of CD40 signaling limits evolution of established atherosclerosis in mice. Proc Natl Acad Sci U S A. 2000; 97: 7458–7463.
8. Aukrust P, Muller F, Ueland T, et al. Enhanced levels of soluble and membrane-bound CD40 ligand in patients with unstable angina. Circulation. 1999; 100: 614–620.
9. Schonbeck U, Varo N, Libby P, et al. Soluble CD40L and cardiovascular risk in women. Circulation. 2001; 104: 2266–2268.
10. Garlichs CD, John S, Schmeiber A, et al. Upregulation of CD40 and CD40 ligand (CD154) in patients with moderate hypercholesterolemia. Circulation. 2001; 104: 2395–2400.
11. Davì G, Romano M, Mezzetti A, et al. Increased levels of soluble P-selectin in hypercholesterolemic patients. Circulation. 1998; 97: 953–957.
12. Goppelt-Struebe M, Wiedemann T, Heusinger-Ribeiro J, et al. Cox-2 and osteopontin in cocultured platelets and mesangial cells: role of glucocorticoids. Kidney Int. 2000; 57: 2229–2238.[CrossRef][Medline] [Order article via Infotrieve]
This article has been cited by other articles:
 |
|
 |
|
  A. Natarajan, A. G Zaman, and S. M Marshall Platelet hyperactivity in type 2 diabetes: role of antiplatelet agents Diabetes and Vascular Disease Research, June 1, 2008; 5(2): 138 - 144. [Abstract] [PDF]
|
|
|
|
 |
|
 S. Chakrabarti, P. Blair, and J. E. Freedman CD40-40L Signaling in Vascular Inflammation J. Biol. Chem., June 22, 2007; 282(25): 18307 - 18317. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Prontera, N. Martelli, V. Evangelista, E. D'Urbano, S. Manarini, A. Recchiuti, A. Dragani, C. Passeri, G. Davi, and M. Romano Homocysteine Modulates the CD40/CD40L System J. Am. Coll. Cardiol., June 5, 2007; 49(22): 2182 - 2190. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Martino, P. Pignatelli, E. Martino, F. Morrone, R. Carnevale, S. Di Santo, B. Buchetti, L. Loffredo, and F. Violi Early Increase of Oxidative Stress and Soluble CD40L in Children With Hypercholesterolemia J. Am. Coll. Cardiol., May 15, 2007; 49(19): 1974 - 1981. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Santilli, G. Davi, A. Consoli, F. Cipollone, A. Mezzetti, A. Falco, T. Taraborelli, E. Devangelio, G. Ciabattoni, S. Basili, et al. Thromboxane-Dependent CD40 Ligand Release in Type 2 Diabetes Mellitus J. Am. Coll. Cardiol., January 17, 2006; 47(2): 391 - 397. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. W Clarke, N. C Ward, J. H. Wu, J. M Hodgson, I. B Puddey, and K. D Croft Supplementation with mixed tocopherols increases serum and blood cell {gamma}-tocopherol but does not alter biomarkers of platelet activation in subjects with type 2 diabetes Am. J. Clinical Nutrition, January 1, 2006; 83(1): 95 - 102. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Pignatelli, V. Sanguigni, B. Buchetti, L. Lenti, F. Violi, A. Undas, and K. G. Mann Early Anticoagulant Effect of Atorvastatin Arterioscler Thromb Vasc Biol, December 1, 2005; 25(12): e145 - e146. [Full Text] [PDF]
|
|
|
|
|
|
C. Heeschen Biomarkers in acute coronary syndromes and their role in diabetic patients Diabetes and Vascular Disease Research, October 1, 2005; 2(3): 122 - 127. [Abstract] [PDF]
|
|
|
|
|
|
J. A. de Lemos, A. Zirlik, U. Schonbeck, N. Varo, S. A. Murphy, A. Khera, D. K. McGuire, G. Stanek, H. S. Lo, R. Nuzzo, et al. Associations Between Soluble CD40 Ligand, Atherosclerosis Risk Factors, and Subclinical Atherosclerosis: Results from the Dallas Heart Study Arterioscler Thromb Vasc Biol, October 1, 2005; 25(10): 2192 - 2196. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G Davi and A Falco Oxidant stress, inflammation and atherogenesis Lupus, September 1, 2005; 14(9): 760 - 764. [Abstract] [PDF]
|
|
|
|
|
|
A. Pfutzner, N. Marx, G. Lubben, M. Langenfeld, D. Walcher, T. Konrad, and T. Forst Improvement of Cardiovascular Risk Markers by Pioglitazone Is Independent From Glycemic Control: Results From the Pioneer Study J. Am. Coll. Cardiol., June 21, 2005; 45(12): 1925 - 1931. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. Sanguigni, P. Pignatelli, L. Lenti, D. Ferro, A. Bellia, R. Carnevale, M. Tesauro, R. Sorge, R. Lauro, and F. Violi Short-Term Treatment With Atorvastatin Reduces Platelet CD40 Ligand and Thrombin Generation in Hypercholesterolemic Patients Circulation, February 1, 2005; 111(4): 412 - 419. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. Sanguigni, D. Ferro, P. Pignatelli, M. Del Ben, T. Nadia, M. Saliola, R. Sorge, and F. Violi CD40 ligand enhances monocyte tissue factor expression and thrombin generation via oxidative stress in patients with hypercholesterolemia J. Am. Coll. Cardiol., January 4, 2005; 45(1): 35 - 42. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Pleiner, G. Schaller, F. Mittermayer, S. Zorn, C. Marsik, S. Polterauer, S. Kapiotis, and M. Wolzt Simvastatin Prevents Vascular Hyporeactivity During Inflammation Circulation, November 23, 2004; 110(21): 3349 - 3354. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Li, S.-P. Zhao, D.-q. Peng, Z.-m. Xu, and H.-n. Zhou Early Effect of Pravastatin on Serum Soluble CD40L, Matrix Metalloproteinase-9, and C-Reactive Protein in Patients with Acute Myocardial Infarction Clin. Chem., September 1, 2004; 50(9): 1696 - 1699. [Full Text] [PDF]
|
|
|
|
 |
|
 D. Vishnevetsky, V. A Kiyanista, and P. J Gandhi CD40 Ligand: A Novel Target in the Fight Against Cardiovascular Disease Ann. Pharmacother., September 1, 2004; 38(9): 1500 - 1508. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Kinlay, G. G. Schwartz, A. G. Olsson, N. Rifai, W. J. Sasiela, M. Szarek, P. Ganz, P. Libby, and for the Myocardial Ischemia Reduction with Aggress Effect of Atorvastatin on Risk of Recurrent Cardiovascular Events After an Acute Coronary Syndrome Associated With High Soluble CD40 Ligand in the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) Study Circulation, July 27, 2004; 110(4): 386 - 391. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. S. Lim, A. D. Blann, and G. Y.H. Lip Soluble CD40 Ligand, Soluble P-Selectin, Interleukin-6, and Tissue Factor in Diabetes Mellitus: Relationships to Cardiovascular Disease and Risk Factor Intervention Circulation, June 1, 2004; 109(21): 2524 - 2528. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
U. Schonbeck and P. Libby Inflammation, Immunity, and HMG-CoA Reductase Inhibitors: Statins as Antiinflammatory Agents? Circulation, June 1, 2004; 109(21_suppl_1): II-18 - II-26. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Nomura, A. Shouzu, S. Omoto, M. Nishikawa, and T. Iwasaka Effects of Losartan and Simvastatin on Monocyte-Derived Microparticles in Hypertensive Patients With and Without Type 2 Diabetes Mellitus Clinical and Applied Thrombosis/Hemostasis, April 1, 2004; 10(2): 133 - 141. [Abstract] [PDF]
|
|
|
|
 |
|
 V. L.M. Herrera, T. Didishvili, L. V. Lopez, R. H. Myers, and N. Ruiz-Opazo Genome-Wide Scan Identifies Novel QTLs for Cholesterol and LDL Levels in F2[Dahl RxS]-Intercross Rats Circ. Res., March 5, 2004; 94(4): 446 - 452. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. W. Sommeijer, M. R. MacGillavry, J. C.M. Meijers, A. P. Van Zanten, P. H. Reitsma, and H. T. Cate Anti-Inflammatory and Anticoagulant Effects of Pravastatin in Patients With Type 2 Diabetes Diabetes Care, February 1, 2004; 27(2): 468 - 473. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Roselli, T. C. Mineo, S. Basili, F. Martini, S. Mariotti, S. Aloe, G. Del Monte, V. Ambrogi, A. Spila, R. Palmirotta, et al. Soluble CD40 Ligand Plasma Levels in Lung Cancer Clin. Cancer Res., January 15, 2004; 10(2): 610 - 614. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
O. A. Belton, A. Duffy, S. Toomey, and D. J. Fitzgerald Cyclooxygenase Isoforms and Platelet Vessel Wall Interactions in the Apolipoprotein E Knockout Mouse Model of Atherosclerosis Circulation, December 16, 2003; 108(24): 3017 - 3023. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Cipollone, C. Ferri, G. Desideri, L. Paloscia, G. Materazzo, M. Mascellanti, M. Fazia, A. Iezzi, C. Cuccurullo, B. Pini, et al. Preprocedural Level of Soluble CD40L Is Predictive of Enhanced Inflammatory Response and Restenosis After Coronary Angioplasty Circulation, December 2, 2003; 108(22): 2776 - 2782. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Ferroni, F. Martini, C. M. Cardarello, P. P. Gazzaniga, G. Davi, and S. Basili Enhanced Interleukin-1{beta} in Hypercholesterolemia: Effects of Simvastatin and Low-Dose Aspirin Circulation, October 7, 2003; 108(14): 1673 - 1675. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Mulhaupt, C. M Matter, B. R Kwak, G. Pelli, N. R Veillard, F. Burger, P. Graber, T. F Luscher, and F. Mach Statins (HMG-CoA reductase inhibitors) reduce CD40 expression in human vascular cells Cardiovasc Res, September 1, 2003; 59(3): 755 - 766. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Varo, D. Vicent, P. Libby, R. Nuzzo, A. L. Calle-Pascual, M. R. Bernal, A. Fernandez-Cruz, A. Veves, P. Jarolim, J. J. Varo, et al. Elevated Plasma Levels of the Atherogenic Mediator Soluble CD40 Ligand in Diabetic Patients: A Novel Target of Thiazolidinediones Circulation, June 3, 2003; 107(21): 2664 - 2669. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Weng, L. Zemany, K. N. Standley, D. V. Novack, M. La Regina, C. Bernal-Mizrachi, T. Coleman, and C. F. Semenkovich {beta}3 integrin deficiency promotes atherosclerosis and pulmonary inflammation in high-fat-fed, hyperlipidemic mice PNAS, May 27, 2003; 100(11): 6730 - 6735. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Marx, A. Imhof, J. Froehlich, L. Siam, J. Ittner, G. Wierse, A. Schmidt, W. Maerz, V. Hombach, and W. Koenig Effect of Rosiglitazone Treatment on Soluble CD40L in Patients With Type 2 Diabetes and Coronary Artery Disease Circulation, April 22, 2003; 107(15): 1954 - 1957. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Desideri and C. Ferri Effects of Obesity and Weight Loss on Soluble CD40L Levels JAMA, April 9, 2003; 289(14): 1781 - 1782. [Full Text] [PDF]
|
|
|
|
 |
|
 C. Heeschen, S. Dimmeler, C. W. Hamm, M. J. van den Brand, E. Boersma, A. M. Zeiher, M. L. Simoons, and the CAPTURE Study Investigators Soluble CD40 Ligand in Acute Coronary Syndromes N. Engl. J. Med., March 20, 2003; 348(12): 1104 - 1111. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. J. Lefer Statins as Potent Antiinflammatory Drugs Circulation, October 15, 2002; 106(16): 2041 - 2042. [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||