Christopher Heeschen, M.D., Stefanie Dimmeler, Ph.D., Christian W. Hamm, M.D., Marcel J. van den Brand, M.D., Eric Boersma, Ph.D., Andreas M. Zeiher, M.D., Maarten L. Simoons, M.D., for the CAPTURE Study Investigators
Background CD40 ligand is expressed on platelets and releasedfrom them on activation. We investigated the predictive valueof soluble CD40 ligand as a marker for clinical outcome andthe therapeutic effect of glycoprotein IIb/IIIa receptor inhibitionin patients with acute coronary syndromes.
Methods Serum levels of soluble CD40 ligand were measured in1088 patients with acute coronary syndromes who had previouslybeen enrolled in a randomized trial comparing abciximab withplacebo before coronary angioplasty and in 626 patients withacute chest pain.
Results The levels of soluble CD40 ligand were elevated (above5.0 µg per liter) in 221 patients with acute coronarysyndromes (40.6 percent). Among patients receiving placebo,elevated soluble CD40 ligand levels indicated a significantlyincreased risk of death or nonfatal myocardial infarction duringsix months of follow-up (adjusted hazard ratio as compared withpatients with low levels of the ligand [5.0 µg per liter],2.71; 95 percent confidence interval, 1.51 to 5.35; P=0.001).The prognostic value of this marker was validated in the patientswith chest pain, among whom elevated soluble CD40 ligand levelsidentified those with acute coronary syndromes who were at highrisk for death or nonfatal myocardial infarction (adjusted hazardratio as compared with those with low levels of the ligand,6.65; 95 percent confidence interval, 3.18 to 13.89; P<0.001).The increased risk in patients with elevated soluble CD40 ligandlevels was significantly reduced by treatment with abciximab(adjusted hazard ratio as compared with those receiving placebo,0.37; 95 percent confidence interval, 0.20 to 0.68; P=0.001),whereas there was no significant treatment effect of abciximabin patients with low levels of soluble CD40 ligand.
Conclusions In patients with unstable coronary artery disease,elevation of soluble CD40 ligand levels indicated an increasedrisk of cardiovascular events. Elevation of soluble CD40 ligandidentifies a subgroup of patients at high risk who are likelyto benefit from antiplatelet treatment with abciximab.
Establishing the correct diagnosis and initiating the appropriatetreatment in patients with acute coronary syndromes who do nothave ST-segment elevation can be challenging. Sensitive andspecific markers of myocardial-cell necrosis, notably cardiactroponins, have become valuable tools in the evaluation of patientswith acute coronary syndromes.1 However, troponins are not activelyinvolved in the pathophysiology of acute coronary syndromesand, instead, represent a surrogate marker for the formationof fragile thrombi.2,3,4 Markers of platelet activation thatcan be used to identify disease activity even before myocardialnecrosis occurs may provide important supplementary informationfor the diagnostic and therapeutic stratification of patientswith acute coronary syndromes.
Increasing evidence suggests that CD40 ligand plays an importantpart in disease progression and plaque destabilization.5,6 TheCD40–CD40 ligand system is widely distributed on a varietyof leukocytic and nonleukocytic cells, including endothelialand smooth-muscle cells,7 and on activated platelets.8 CD40ligand also occurs in a soluble form that is fully active biologically,termed soluble CD40 ligand,9 which is shed from stimulated lymphocytesand is actively released after platelet stimulation.10,11 SolubleCD40 ligand is proinflammatory for endothelial cells and promotescoagulation by inducing expression of tissue factor on monocytes12and endothelial cells.13 Moreover, soluble CD40 ligand containsa KGD sequence,9 a known binding motif that is specific forthe major platelet integrin IIb3.14 Indeed, CD40 ligand hasbeen demonstrated to be an IIb3 (glycoprotein IIb/IIIa) ligandand a platelet agonist and to be necessary for the stabilityof arterial thrombi.15
These data suggest that soluble CD40 ligand plays an importantpart in the pathophysiology of acute coronary syndromes. Apparentlyhealthy women with increased plasma levels of soluble CD40 ligandhave been shown to be at increased risk for cardiovascular events.16Elevation of soluble CD40 ligand levels is detectable in theserum of patients with acute coronary syndromes.17 Accordingly,we investigated the predictive value of serum levels of solubleCD40 ligand with respect to cardiac events and the effects ofthe glycoprotein IIb/IIIa inhibitor abciximab in patients withacute coronary syndromes who were enrolled in the c7E3 Fab AntiplateletTherapy in Unstable Refractory Angina (CAPTURE) study.18
Methods
Patients with Acute Coronary Syndromes
The CAPTURE trial enrolled 1265 patients with acute coronarysyndromes who had recurrent chest pain at rest in associationwith electrocardiographic changes. Before randomization, allpatients were documented by coronary angiography to have substantialcoronary artery disease, with stenosis of at least 70 percentof the coronary-artery diameter at a culprit lesion that wassuitable for angioplasty. The patients were randomly assignedto receive abciximab or placebo, and coronary angioplasty wasscheduled 18 to 24 hours after the study treatment was begun.The combined primary end point was death or nonfatal myocardialinfarction during 30 days and 6 months of follow-up.18
Patients with Acute Chest Pain
A separate validation sample consisted of 626 consecutive patients(465 men and 161 women; mean [±SD] age, 62±12years) who presented with acute chest pain lasting less than12 hours (mean, 5.1±3.6) and had no ST-segment elevationon electrocardiography. The presence of coronary artery diseasewas documented by one of the following criteria: electrocardiographicevidence of myocardial ischemia (new ST-segment changes or T-waveinversions) or a history of coronary heart disease (myocardialinfarction, coronary revascularization, a positive exercisestress test, or stenosis of more than 50 percent of the luminaldiameter of a major coronary artery on a previous angiogram).All patients were followed for 30 days for the occurrence ofdeath or nonfatal myocardial infarction. The study protocolwas approved by the ethics committee of the Hamburg MedicalBoard, and written informed consent was obtained from each patient.
Biochemical Analysis
Soluble CD40 ligand, soluble P-selectin, high-sensitivity tumornecrosis factor , and soluble intracellular adhesion molecule1 were measured by enzyme-linked immunosorbent assay (R&DSystems). Troponin T was measured with an electrochemiluminescenceenzyme-linked immunosorbent assay (Elecsys 2010, Roche Diagnostics),and C-reactive protein was measured by nephelometry (BehringBN II Nephelometer, Dade–Behring).
In Vivo Platelet Activation
In a subgroup of 161 patients with chest pain (131 patientswith acute coronary syndromes, 20 patients with stable coronaryheart disease, and 10 patients without coronary heart disease),platelet activation was assessed by flow cytometry with theuse of phycoerythrin-conjugated glycoprotein IIb–specificmonoclonal antibodies (CD41, Dako) and fluorescein isothiocyanate(FITC)–conjugated, P-selectin–specific monoclonalantibodies (BD Pharmingen). Circulating monocyte–plateletaggregates were stained with FITC-conjugated, glycoprotein IIIa–specificmonoclonal antibody (CD61, Dako) and phycoerythrin-conjugatedmonoclonal antibodies against CD14 (BD Pharmingen). Monocyte–plateletaggregates were defined as monocytes positive for glycoproteinIIIa, and values are expressed as the percentage of aggregatedmonocytes.19
Statistical Analysis
To distinguish between patients with different degrees of cardiacrisk, an exploratory data analysis was chosen. The Cox proportional-hazardsregression model was used to estimate the relative risk of cardiovascularevents, and patients were categorized according to quintilesof soluble CD40 ligand levels.20 We analyzed the effect of base-linecharacteristics and other biochemical markers on any observedassociations between soluble CD40 ligand levels and cardiovascularevents, using stepwise Cox proportional-hazards models (witha value of P=0.10 necessary to enter a variable into the model).All results for continuous variables are expressed as means±SD. Comparisons between groups were analyzed with atwo-sided t-test. Categorical variables were compared by thePearson chi-square test. Post hoc analysis was performed byusing the Cox proportional-hazards regression model, with thequintile for soluble CD40 ligand as a categorical variable andthe quintile group with the lowest levels of soluble CD40 ligandserving as the reference group. P values under 0.05 were consideredto indicate statistical significance. All analyses were performedwith SPSS software (version 11.0).
Results
Patients with Acute Coronary Syndromes
Base-line samples were available for 1088 of the 1265 patientswith acute coronary syndromes (86 percent).21 The level of solubleCD40 ligand did not correlate with measured levels of troponinT (r=0.14) or C-reactive protein (r=0.11).
Soluble CD40 Ligand and Cardiovascular Risk
The 544 patients in the placebo group of the study were classifiedaccording to their measured levels of soluble CD40 ligand atbase line, as follows: 100 in the first quintile (<1.93 µgper liter), 102 in the second quintile (1.93 to 3.50 µgper liter), 121 in the third quintile (3.51 to 5.00 µgper liter), 115 in the fourth quintile (5.01 to 6.30 µgper liter), and 106 in the fifth quintile (>6.30 µgper liter). For the initial 24-hour period before coronary angioplasty,the incidence of the combined end point of death or nonfatalmyocardial infarction did not differ significantly among patientsin these groups (P=0.13). For the later follow-up times (72hours, 30 days, and 6 months), the rates of events were significantlyhigher in both the fourth quintile (P=0.01, P=0.02, and P=0.003,respectively) and the fifth quintile (P=0.009, P=0.005, andP=0.002, respectively) (Figure 1).
Figure 1. Association between Soluble CD40 Ligand Levels and the Rate of Cardiac Events (Death or Nonfatal Myocardial Infarction) at 24 Hours, 72 Hours, 30 Days, and 6 Months among 544 Patients Receiving Placebo.
The patients were divided into quintiles according to the serum level of soluble CD40 ligand, as follows: first quintile, below 1.93 µg per liter; second quintile, 1.93 to 3.50 µg per liter; third quintile, 3.51 to 5.00 µg per liter; fourth quintile, 5.01 to 6.30 µg per liter; and fifth quintile, above 6.30 µg per liter. P values are for trend at each time point.
Accordingly, the patient sample was divided into two groupswith soluble CD40 ligand levels of greater than 5.0 µgper liter or 5.0 µg per liter or less; 221 patients (40.6percent) were thus classified as having high levels of solubleCD40 ligand and 323 patients as having low levels. There wereno significant differences in the base-line characteristicsof the two groups (Table 1). The incidence of death or nonfatalmyocardial infarction was higher in patients who had elevatedsoluble CD40 ligand levels before coronary angioplasty (4.1percent, vs. 0.9 percent among patients with low levels; P=0.02),after 72 hours, a period during which coronary angioplasty wasperformed in all patients (13.1 percent vs. 4.3 percent, P<0.001),after 30 days (14.5 percent vs. 5.3 percent, P<0.001), andafter 6 months (18.6 percent vs. 7.1 percent, P<0.001) (Figure 2and Figure 3). The predictive value of soluble CD40 ligandwas independent of the presence or absence of myocardial necrosisas evidenced by the troponin T level (Table 2). Among the patientswho were negative for troponin T, high levels of soluble CD40ligand identified a subgroup with an increased risk of cardiacevents (13.6 percent) that was not significantly different fromthe risk in troponin T–positive patients (14.0 percent,P=1.00).
Table 1. Base-Line Characteristics of Patients with Acute Coronary Syndromes Who Were Randomly Assigned to the Placebo Group, According to the Level of Soluble CD40 Ligand.
Figure 2. Kaplan–Meier Curves Showing the Cumulative Incidence of Death or Nonfatal Myocardial Infarction during 72 Hours of Follow-up, According to the Base-Line Level of Soluble CD40 Ligand in the Placebo Group (544 Patients) and the Abciximab Group (544 Patients).
High levels of soluble CD40 ligand were defined as levels greater than 5.0 µg per liter, and low levels as 5.0 µg per liter or less.
Figure 3. Kaplan–Meier Curves Showing the Cumulative Incidence of Death or Nonfatal Myocardial Infarction during Six Months of Follow-up, According to the Base-Line Level of Soluble CD40 Ligand in the Placebo Group (544 Patients) and the Abciximab Group (544 Patients).
High levels of soluble CD40 ligand were defined as levels greater than 5.0 µg per liter, and low levels as 5.0 µg per liter or less.
Table 2. Hazard Ratios for Death or Nonfatal Myocardial Infarction during Six Months of Follow-up among Patients Receiving Placebo.
Abciximab Treatment and Soluble CD40 Ligand
Among patients in the first three quintiles for soluble CD40ligand, no significant differences in cardiac risk were observedbetween those receiving placebo and those receiving abciximab(Figure 4). Among patients in the highest two quintiles, a significantreduction in cardiac risk, which did not differ between thetwo quintiles, was documented for those receiving abciximab.The abrupt change in the hazard ratio from 1.12 in the thirdquintile to 0.35 in the fourth suggests a threshold level ofbenefit in this range of soluble CD40 ligand levels. Accordingly,curves for the incidence of death or nonfatal myocardial infarctionwere generated with a threshold level of 5.0 µg of solubleCD40 per liter. Among patients with low levels of soluble CD40ligand, no significant difference in incidence was observedbetween patients receiving abciximab and those receiving placebo(1.2 percent vs. 0.9 percent at 24 hours, and 3.8 percent vs.4.3 percent at 72 hours) (Figure 2). In contrast, the ratesof death or nonfatal myocardial infarction were significantlyhigher among patients with high levels of soluble CD40 ligandwho were receiving placebo and were effectively reduced by treatmentwith abciximab before coronary angioplasty (hazard ratio, 0.12;95 percent confidence interval, 0.01 to 0.92; P=0.01); the samewas true for angioplasty-related events (hazard ratio, 0.19;95 percent confidence interval, 0.08 to 0.49; P<0.001). Thisbenefit persisted during six months of follow-up (hazard ratio,0.37; 95 percent confidence interval, 0.20 to 0.68; P=0.001)(Figure 3). Among troponin T–negative patients, high levelsof soluble CD40 ligand identified a subgroup whose risk of cardiacevents was significantly reduced by treatment with abciximab(5.5 percent, vs. 13.6 percent for those receiving placebo;P=0.03).
Figure 4. Adjusted Hazard Ratios (Solid Squares) and 95 Percent Confidence Intervals (Vertical Lines) Associated with Treatment with Abciximab, as Compared with Placebo, According to Quintiles of Soluble CD40 Ligand.
The levels of soluble CD40 ligand were as follows: first quintile, <1.93 µg per liter; second quintile, 1.93 to 3.50 µg per liter; third quintile, 3.51 to 5.00 µg per liter; fourth quintile, 5.01 to 6.30 µg per liter; and fifth quintile, more than 6.30 µg per liter. The effect of treatment with abciximab was measured as the reduction in the rate of death or nonfatal myocardial infarction during six months of follow-up. Hazard ratios below 1.0 indicate a benefit of treatment with abciximab as compared with placebo. Hazard ratios have been adjusted for base-line characteristics.
Patients with Acute Chest Pain
Of the 626 patients with acute chest pain, 308 had acute coronarysyndromes (117 of whom had myocardial infarction without ST-segmentelevation). Of the remaining patients stable angina was diagnosedin 91, pulmonary embolism in 10, congestive heart failure in11, and myocarditis in 7. No evidence of heart disease was foundin 199. Soluble CD40 ligand levels were significantly higherin the 308 patients with acute coronary syndromes (mean, 4.53µg per liter; 95 percent confidence interval, 3.19 to5.87) than in patients with stable angina (mean, 2.41 µgper liter; 95 percent confidence interval, 1.99 to 3.52; P<0.001)and patients without evidence of heart disease (mean, 1.57 µgper liter; 95 percent confidence interval, 0.88 to 1.76; P<0.001).The 97.5th percentile for the soluble CD40 ligand level in patientswithout evidence of heart disease was 4.7 µg per liter,and the 99th percentile was 6.2 µg per liter. SolubleCD40 ligand levels did not correlate with markers of necrosis(troponin T levels), markers of inflammation (levels of C-reactiveprotein and tumor necrosis factor ), or adhesion molecules (solubleintracellular adhesion molecule 1).
Among the 308 patients with acute coronary syndromes, 43.5 percenthad soluble CD40 ligand levels above the 97.5th-percentile upperreference limit. When the prespecified threshold value for solubleCD40 ligand of 5.0 µg per liter was used, patients withelevated levels were at significantly higher risk for deathor nonfatal myocardial infarction than those with lower levels(adjusted hazard ratio, 3.00; 95 percent confidence interval,1.35 to 6.71; P=0.009). Among the entire heterogeneous populationof 626 patients with chest pain, the threshold value of 5.0µg per liter also reliably identified patients who wereat highest risk for death or nonfatal myocardial infarction(adjusted hazard ratio, 6.65; 95 percent confidence interval,3.18 to 13.89; P<0.001).
Association of Soluble CD40 Ligand Levels with Platelet Activation
In a subgroup of 161 patients with chest pain, we observed astrong correlation between platelet activation, as evidencedby the percentage of monocytes that were aggregated with platelets(monocyte–platelet aggregates), and soluble CD40 ligandlevels (r=0.75, P<0.001) (Figure 5). Similar results wereobtained for P-selectin expression on platelets (P<0.001;data not shown). Patients were divided into three roughly equalgroups according to their measured levels of soluble CD40 ligand:55 with levels below 2.5 µg per liter, 50 with levelsof 2.5 to 4.5 µg per liter, and 56 with levels above 4.5µg per liter. For patients in the group with the lowestlevels, the mean percentage of monocyte–platelet aggregateswas 11.3±6.1 percent. For those in the other two groups,platelet activation was significantly higher, with monocyte–plateletaggregates of 22.3±8.9 percent (P<0.001) and 34.1±15.6percent (P<0.001), respectively.
Figure 5. Correlation between the Level of Soluble CD40 Ligand and Platelet Activation in 161 Patients with Chest Pain.
Platelet activation is expressed as the percentage of monocytes that were aggregated with platelets (monocyte–platelet aggregates). Dotted lines indicate the classification of patients into three roughly equal groups according to the degree of platelet activation (<15 percent, 15 to 30 percent, and >30 percent) and according to soluble CD40 ligand levels (<2.5 µg per liter, 2.5 to 4.5 µg per liter, and >4.5 µg per liter).
Discussion
The present study demonstrates that soluble CD40 ligand is apowerful biochemical marker of inflammatory thrombotic activityin patients with acute coronary syndromes. Elevated levels ofsoluble CD40 ligand reliably identify the subgroup of patientswith acute coronary syndromes who are at highest risk for cardiacevents and who receive substantial benefit from treatment withthe glycoprotein IIb/IIIa receptor antagonist abciximab. Thus,soluble CD40 ligand not only contributes importantly to thepathophysiology of acute coronary syndromes but also representsa reliable and powerful clinical marker for use in identifyingpatients with high-risk atherosclerotic lesions, coronary thrombosis,or both.15,22
Soluble CD40 ligand was a powerful prognostic marker that providedinformation beyond the evidence provided by troponin T, theinflammatory marker C-reactive protein, tumor necrosis factor, and the soluble intracellular adhesion molecule 1. In a multivariateCox regression model, troponin T, C-reactive protein, and solubleCD40 ligand provided independent and incremental prognosticinformation (Table 2). Troponins are markers of myocardial necrosis;they are not actively involved in the pathophysiology of acutecoronary syndromes but, rather, are surrogate markers for theformation of fragile thrombi.2,3,4 Postmortem studies in patientswith acute coronary syndromes identified erosion or ruptureof the fibrous cap of the atherosclerotic plaque, leading toplatelet activation, as the underlying pathophysiological feature.5,6,23,24,25Coronary arterial thromboembolism, with altered microvascularperfusion and necrosis, is an integral part of acute coronarysyndromes.3,4 Accordingly, sensitive markers for the detectionof minor myocardial injury, notably troponins, serve as surrogatemarkers for arterial thromboembolism originating from an activethrombotic process in the culprit lesion.
In contrast, soluble CD40 ligand may be directly involved inmultiple ways in the pathophysiology of acute coronary syndromes.Recent evidence suggests that soluble CD40 ligand contributesimportantly to the progression of atherosclerosis and, consequently,to the destabilization of atherosclerotic plaques5,6 by inducingthe expression of cytokines, chemokines, growth factors, matrixmetalloproteinases, and procoagulant factors in a variety ofatheroma-associated cell types.7,8,11,12,26,27 Activated plateletsproduce and release large amounts of soluble CD40 ligand.11A recent study demonstrated that cardiopulmonary bypass causesan increase in the plasma level of soluble CD40 ligand, witha corresponding decrease in platelet CD40 ligand content, suggestingthat soluble CD40 ligand is derived primarily from plateletsand may contribute to the thrombotic complications associatedwith cardiopulmonary bypass.28 Soluble CD40 ligand levels correlatepositively with plasma levels of soluble P-selectin and urinarylevels of 11-dehydro-thromboxane B2.29 In addition, experimentalstudies demonstrate that CD40 ligand is required for arterialthrombus stabilization.15
Our results provide further evidence that soluble CD40 ligandis a marker of inflammatory thrombotic activity. Platelet activation,as determined by flow cytometry in patients with acute coronarysyndromes, correlated closely with soluble CD40 ligand levels(Figure 5). These findings are supported by the fact that inhibitionof glycoprotein IIb/IIIa receptors by abciximab abrogated theincreased risk in patients with acute coronary syndromes andelevated levels of soluble CD40 ligand. Thus, whereas positivityfor troponins may indicate the propensity of the thrombus toembolize, leading to myocardial necrosis, elevated soluble CD40ligand levels in patients with acute coronary syndromes appearto reflect the inflammatory thrombotic activity of the culpritlesion in recruiting and activating platelets.
In a previous subgroup analysis of data from the CAPTURE trial,we demonstrated that additional treatment with the glycoproteinIIb/IIIa receptor antagonist abciximab reduced the elevatedrisk of death or nonfatal myocardial infarction among troponin-positivepatients to the risk level among troponin-negative patients.21Such patients represent about one third of those with acutecoronary syndromes.1,30,31,32,33 Similar findings for troponinT and troponin I have emerged from other trials,34,35,36 andmeasurement of troponins was subsequently incorporated intothe new guidelines as part of risk stratification of patientswith acute coronary syndromes.37,38 Here, we demonstrate thata pronounced benefit of antiplatelet therapy is also evidentin patients with elevated levels of soluble CD40 ligand. Ourfindings suggest that patients with acute coronary syndromeswho have elevated levels of soluble CD40 ligand are effectivelyprotected from adverse cardiac events by the glycoprotein IIb/IIIareceptor antagonist abciximab (Figure 2 and Figure 3).
Troponin T and soluble CD40 ligand have independent predictivevalue with respect to both the risk of ischemic events and thebenefit of glycoprotein IIb/IIIa receptor inhibition by abciximab.Patients without evidence of myocardial injury (i.e., with noelevation of troponin levels), but with increased soluble CD40ligand levels, were at increased risk for cardiovascular eventsand derived substantial benefit from treatment with the glycoproteinIIb/IIIa inhibitor abciximab. Accordingly, patients at highrisk for coronary thrombosis, as evidenced by elevation of eithersoluble CD40 ligand or troponin T levels, who represented 54percent of the patients enrolled in the CAPTURE trial, deriveda marked benefit from abciximab treatment, as compared withthe placebo group, with an adjusted hazard ratio for death ormyocardial infarction of 0.38 (95 percent confidence interval,0.21 to 0.72; P<0.001) (data not shown). Thus, the measurementof both troponins and soluble CD40 ligand, which are separatebut interacting components of the underlying pathophysiologicalprocess in patients with acute coronary syndromes, providesimportant insights into disease activity, cardiac risk, andthe effect of inhibition of glycoprotein IIb/IIIa with abciximabthat are superior to those obtained with the use of a singlemarker.
Supported by a research grant from the University of Frankfurt,Frankfurt, Germany.
Dr. Heeschen reports having received lecture fees from Merck,Roche Diagnostics, and Abbott Laboratories.
We are indebted to Sylvia Rhiel and Christiane Mildner-Rihmfor their expert technical assistance. A list of the principalinvestigators and committee members of the CAPTURE Study Investigatorshas been published previously.18
Source Information
From the c7E3 Fab Antiplatelet Therapy in Unstable Refractory Angina (CAPTURE) Study (C.H., S.D., C.W.H., M.J.B., E.B., A.M.Z., M.L.S.); Molecular Cardiology, Department of Internal Medicine IV, University of Frankfurt, Frankfurt, Germany (C.H., S.D., A.M.Z.); the Kerckhoff Heart Center, Bad Nauheim, Germany (C.W.H.); and the Thoraxcentre, Erasmus University, Rotterdam, the Netherlands (M.J.B., E.B., M.L.S.).
Address reprint requests to Dr. Heeschen at the Department of Molecular Cardiology, Internal Medicine IV, University of Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany, or at c.heeschen{at}em.uni-frankfurt.de.
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5.0 µg per liter], 2.71; 95 percent confidence interval, 1.51 to 5.35; P=0.001). The prognostic value of this marker was validated in the patients with chest pain, among whom elevated soluble CD40 ligand levels identified those with acute coronary syndromes who were at high risk for death or nonfatal myocardial infarction (adjusted hazard ratio as compared with those with low levels of the ligand, 6.65; 95 percent confidence interval, 3.18 to 13.89; P<0.001). The increased risk in patients with elevated soluble CD40 ligand levels was significantly reduced by treatment with abciximab (adjusted hazard ratio as compared with those receiving placebo, 0.37; 95 percent confidence interval, 0.20 to 0.68; P=0.001), whereas there was no significant treatment effect of abciximab in patients with low levels of soluble CD40 ligand. 
IIb
3.14 Indeed, CD40 ligand has been demonstrated to be an 
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