Complement component C5a predicts future cardiovascular events in patients with advanced atherosclerosis

Walter S. Speidl1,2, Markus Exner3, Jasmin Amighi1, Stefan P. Kastl1,2, Gerlinde Zorn1,2, Gerald Maurer1,2, Oswald Wagner3, Kurt Huber4, Erich Minar1, Johann Wojta1,2 and Martin Schillinger1,*

1Department of Internal Medicine II, Medical University of Vienna, Waehringer Guertel 18–20, A-1090 Vienna, Austria
2Ludwig Boltzmann Foundation for Cardiovascular Research, Vienna, Austria
3Department of Laboratory Medicine, Medical University of Vienna, Austria
4Third Medical Department, Wilhelminenhospital, Vienna, Austria

Received 10 February 2005; revised 9 April 2005; accepted 28 April 2005; online publish-ahead-of-print 25 May 2005.

* Corresponding author. Tel: +43 1 40400 4670; fax: +43 1 40400 4665. E-mail address: martin.schillinger{at}meduniwien.ac.at


    Abstract
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusion
 Acknowledgements
 References
 
Aims Complement activation occurs in atherosclerotic lesions, and particularly complement component C5a exerts potent chemotactic and proinflammatory effects. However, it is yet unknown, whether plasma levels of C5a may predict cardiovascular risk. The aim of this study was to examine whether plasma levels of the complement component C5a may predict cardiovascular risk in patients with advanced atherosclerosis.

Methods and results We studied 173 patients with symptomatic peripheral artery disease (median age 72, 82 male). Cardiovascular risk profile, levels of the complement factor C5a, and other non-specific inflammatory parameters [high sensitivity C-reactive protein, serum amyloid A (SAA), and fibrinogen] were obtained at baseline, and patients were followed for median 22 months [interquartile range (IQR) 13–27] for the occurrence of major adverse cardiovascular events (MACE: myocardial infarction, percutaneous coronary interventions, coronary artery bypass graft, carotid revascularization, stroke, and death). We observed 65 MACE in 49 patients (28%). Cumulative event rates (95% confidence interval (CI)) within quartiles of C5a at 24 months were 16 (5–27), 26 (13-39), 36 (21–51), and 37% (23–51), respectively (P=0.0077). Adjusted hazard ratios for the occurrence of a first MACE according to increasing quartiles of C5a were 1.81, 2.23, and 2.66, respectively, as compared to the lowest quartile (P=0.038), irrespective of the level of other inflammatory parameters.

Conclusion Complement activation, indicated by the elevation of C5a, seems to be associated with increased cardiovascular risk in patients with advanced atherosclerosis. Clinically, determination of C5a may add to the predictive value of other non-specific inflammatory parameters.

Key Words: Atherosclerosis • Complications • Complement factor • Inflammation


    Introduction
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusion
 Acknowledgements
 References
 
Inflammation within the vascular wall plays an important role in the pathogenesis of atherosclerosis.1 Recent studies demonstrated that elevation of proinflammatory cytokines like tumour necrosis factor-{alpha} (TNF-{alpha}),2 chemokines like monocyte chemoattractant protein-1 (MCP-1),3 soluble adhesion molecules, e.g. soluble intercellular cell adhesion molecule-1 (sICAM-1),4 and systemic inflammatory markers like the acute phase component C-reactive protein57 are associated with an increased risk for acute cardiovascular events.

The complement system, a family of enzymes and bio-regulators, has multiple biological activities and plays a central role in many inflammatory states like immune responses to microbial pathogens or immune-mediated diseases. It has been suggested that the complement system may also be involved in the pathogenesis of atherosclerosis. Deposition of the complement components C1q, C3, and C4 and generation of the terminal complement complex C5b-9 in atherosclerotic lesions were shown by immunohistochemistry.8 The extent of C5b-9 deposition correlated with the severity of the lesions9 and the deposition of iC3b was higher in vulnerable and ruptured plaques.10 In addition, it has also been demonstrated that messenger RNA of complement genes are expressed locally within atherosclerotic plaques.11

Among the factors of the complement cascade, the anaphylatoxin C5a exhibits proinflammatory effects by binding to the respective receptors present in atherosclerotic lesion. C5a is one of the most potent chemotactic factor for monocytes, mast cells and T-lymphocytes,12,13 and induces the expression of adhesion molecules on endothelial cells14 and enhances the release of TNF-{alpha} and interleukin-1 (IL-1) from macrophages and the generation of reactive oxygen species.15

In humans, plasma levels of the complement factors C3 and C4 were associated with the presence of atherosclerosis16,17 and C3 predicted the risk for myocardial infarction (MI) in a population-based cohort study.18 However, no data are available about any effects of activation of the complement system on cardiovascular risk. We hypothesized that elevated levels of the highly proinflammatory complement component C5a would increase the risk for adverse cardiovascular outcome in patients with advanced atherosclerotic disease, independently of non-specific markers of inflammation. Therefore, the aim of the present study was to analyse the association between C5a levels, other inflammatory parameters, and the occurrence of future cardiovascular adverse events in patients with symptomatic peripheral artery disease.


    Methods
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusion
 Acknowledgements
 References
 
Study design
We prospectively enrolled all consecutive patients with symptomatic peripheral artery disease (PAD) and intermittent claudication due to superficial femoral artery (SFA) obstructions, who were admitted to the inpatient ward of an angiology department of a tertiary care university hospital during a 12-month period. We decided to include this specific subgroup of patients with peripheral artery disease to obtain a homogenous patient sample. All patients were clinically stable and patients with critical limb ischaemia were not eligible for inclusion, because of the potential confounding effect of infections and inflammation at the sites of necrosis. Of 454 patients with peripheral artery disease, 105 were excluded due to critical limb ischaemia, and 164 patients due to pelvic artery obstructions or tibio-peroneal disease, leaving 185 patients with intermittent claudication due to SFA disease who were potentially eligible for the analysis. Of these, 12 patients refused to participate in the follow-up examinations and could not be included. The remaining 173 patients had complete baseline and follow-up data.7

Patient data
At admission, patients' demographic data, clinical characteristics, and current medication were recorded by two independent observers. Data were evaluated for inter-observer agreement at the day of patients' discharge. In case of discrepancies, the patient was re-evaluated by both investigators in consensus. Efforts to detect undiagnosed diabetes at admission were routine measurement of overnight fasting blood glucose and HbA1c levels. During the hospital stay, repetitive blood pressure measurements were applied two to four times daily to detect undiagnosed hypertensive patients.

Laboratory parameters
To avoid complement activation, blood samples for determination of C5a were collected directly into serum tubes, immediately centrifuged (4°C; 3000g for 15 min) and stored at –70°C until further use. C5a was measured by ELISA using monoclonal antibodies specific for human C5a-desArg (BD Biosciences, San Diego, CA, USA) with a lower detection level of 0.06 ng/mL and coefficient of variation of 6.3%, cross-reactivity to C3a and C5 was 0.15 and 0.7%, respectively. We used high-sensitivity assays for measurement of serum high sensitivity C-reactive protein (N Latex CRP Mono®, DADE Behring, Vienna, Austria) and serum amyloid A (SAA; N Latex SAA®, DADE Behring, Vienna, Austria) with lower detection levels of 0.03 and 3.8 mg/dL, and coefficients of variation of 4.6 and 6.4%, respectively. For measurement of fibrinogen Fibrinogen Clauss (Stago/Roche) was used (detection level 20 mg/dL, coefficient of variation 5.2%).

Study endpoint
The study endpoint was the occurrence of a first major adverse cardiovascular event (MACE), a composite of MI, percutaneous coronary interventions (PCI), coronary artery bypass graft (CABG), stroke, carotid revascularization (carotid stenting or carotid endarterectomy), and death.

Surveillance protocol
Patients were clinically re-evaluated routinely at 3, 6, and 12 months after hospital discharge and then annually at the outpatient ward of our department until December 2002. A follow-up questionnaire was then sent to each patient during December 2002 re-evaluating the occurrence of MACE. Information from the follow-up questionnaire was validated by reviewing the original hospital discharge reports of corresponding re-admissions due to MACE. If the follow-up questionnaire was not returned, personal telephone contact to the patients, their relatives, or to the treating physicians was established. Further information was obtained by reviewing the hospital discharge reports of any other re-admission during the follow-up period. The performance of PCI, CABG, carotid stenting, and carotid endarterectomy was validated by review of the original procedure protocols. Outcome was assessed by two independent observers, who were blinded with respect to patients' baseline, clinical, and laboratory data.

Definitions
The diagnosis of PAD was confirmed by lower limb angiography and classified according to Fontaine.19 MI was defined based on the consensus document of The Joint European Society of Cardiology/American College of Cardiology Committee for the redefinition of MI.20 Stroke was defined as a neurological deficit that persisted longer than 24 h evaluated by a neurologist according to the modified Rankin stroke scale.21 Mandatory cranial computed tomography or, if available, magnetic resonance imaging was used for the confirmation of the diagnosis.

Statistical analysis
Data are given as the median and the IQR (range from the 25th to 75th percentile), or as counts and per cent values. We used {chi}2 tests, Mann–Whitney U tests, Spearman's correlation coefficient, and log rank test for univariate analyses, as adequate. Event-free survival rates until the first cardiovascular adverse event are presented as Kaplan–Meier curves and compared by means of the log rank test. A multivariable Cox proportional hazards model was applied to assess the effect of C5a on event-free survival until the occurrence of first MACE, giving hazard ratios (HRs) and 95% CI. We adjusted the multivariable model for confounding effects of baseline variables, which were (a) established risk factors for coronary artery disease or (b) associated with C5a levels by a P-value <0.2. We tested for interaction with the following variables using multiplicative interaction terms and log-likelihood ratio tests: gender, age, diabetes, smoking, hyperlipidaemia, and hypertension. For none of these factors significant interaction was observed, suggesting that C5a was an equally effective prognostic factor irrespective of these variables. We assessed the overall model fit using the Cox–Snell residuals. We tested the proportional hazard assumption for all covariates using Schoenfeld residuals (overall test) and the scaled Schoenfeld residuals (variable-by-variable testing). On the basis of the tests, the proportional hazards assumption was not violated. A two sided P-value <0.05 was considered as statistically significant. Calculations were performed with SPSS for Windows (Version 12.0, SPSS Inc., Chicago, IL, USA).


    Results
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusion
 Acknowledgements
 References
 
Patients
We studied 173 patients, who were admitted with symptomatic PAD due to obstructions in the superficial femoral artery during the study period. Twelve patients (6%) had to be excluded due to missing follow-up data. These 12 patients with missing data were closely resembling patients with complete data with respect to baseline demographic and clinical characteristics without significant differences (data not shown). Follow-up data were derived from follow-up examinations in 155 patients (90%), in the remaining 18 patients (10%) follow-up was based on information from the follow-up questionnaire (n=18), personal phone calls (n=8) and review of hospital discharge letters from other institutions (n=9).

The median age of the 173 patients, who were eligible for the final analysis, was 72 years (IQR 61–78) and 82 patients were male (47%). Median levels of C5a, high sensitivity C-reactive protein, SAA, and fibrinogen were median 39.7 ng/mL (IQR 27.7–55.4), 0.59 mg/dL (IQR 0.23–1.18), 8.2 mg/L (IQR 4.8–17.4), and 418 mg/dL (IQR 353–480), respectively. C5a plasma levels were not associated with the established risk factors: age, sex, smoking, hypertension, and diabetes (Table 1). However, patients with a history of MI showed increased C5a levels. C5a was weakly associated with high sensitivity C-reactive protein, SAA, and fibrinogen.


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Table 1 Association between C5a levels and demographic data and traditional cardiovascular risk factors in 173 patients with advanced atherosclerosis
 
Follow-up for MACE
During the median follow-up period of 22 months (IQR 13–27) 65 MACE occurred in 49 patients: 6 MIs, 16 PCIs, 2 CABGs, 10 carotid revascularization procedures, 8 strokes, and 23 deaths. Of 23 case fatalities, 19 patients died of cardiovascular causes. Cumulative event-free survival rates (freedom from MACE) at 6, 12, and 24 months were 93, 85, and 71%, respectively.

Complement factor C5a and MACE
Higher levels of C5a were indicative of an increased cardiovascular risk (Figure 1). Cumulative event rates (95 % CI) within quartiles of C5a at 24 months were 16 (5–27), 26 (13–39), 36 (21–51), and 37% (23–51), respectively (P=0.0077). Being aware of several potential confounders, we then applied a multivariable Cox proportional hazards model adjusting for age, sex, diabetes, smoking, hyperlipidaemia, hypertension, serum creatinine, history of stroke, history of MI, ankle brachial index, use of statins, and high sensitivity C-reactive protein (Table 2). Adjusted HRs for the occurrence of a first MACE according to the increasing quartiles of C5a were 1.81, 2.23, and 2.66, respectively, as compared to the lowest quartile (P=0.038). Re-calculating the fully-adjusted multivariable model and including C5a as a continuous parameter rather than in quartiles, increase in C5a (per ng/mL) was associated with an increased adjusted risk for poor outcome (adjusted HR 1.015, 95% CI 1.003–1.026, P=0.010). Adjusting the multivariable model for the type of diabetes (no/IDDM/NIDDM) revealed no relevant changes of the effect sizes and model fit, and, therefore, was not included in the final model. Owing to collinearity, we did not include high sensitivity C-reactive protein, SAA, and fibrinogen simultaneously into a multivariable model. However, consistent results were found when adjusting the final model for SAA (HR per ng/mL C5a 1.013, 95% CI 1.002 to 1.024) or fibrinogen (HR per ng/mL C5a 1.013, 95% CI 1.003–1.025) instead of high sensitivity C-reactive protein, indicating that C5a may add to the predictive value of other inflammatory parameters.



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Figure 1 Cumulative cardiovascular event-free survival (freedom from MI, PCI, CABG, stroke, carotid revascularization, and death) in 173 patients with advanced PAD based on the levels of the complement factor C5a.

 

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Table 2 Multivariable Cox proportional hazards model assessing the association between complement factor C5a (in quartiles) and MACE (MI, PCI, CABG, stroke, carotid revascularization, and death) in 173 patients with PAD
 

    Discussion
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusion
 Acknowledgements
 References
 
We found that elevated levels of C5a in the third (39.7–55.4 ng/mL) and fourth quartile (>55.4 ng/mL) were associated with a significantly increased risk for poor cardiovascular outcome in patients with pre-existent atherosclerotic disease. This association was independent of non-specific markers of inflammation like high sensitivity C-reactive protein, SAA, and fibrinogen, and thus determination of C5a may add to clinical risk prediction in these patients.

Accumulating evidence indicates that inflammation plays a major role in progression of atherosclerosis and in the pathogenesis of acute cardiovascular events. The complement cascade is a pivotal player in the mammalian inflammatory system, and thus has been previously suggested to be involved in atherogenesis. In particular, the complement component C5a exerts proinflammatory effects by binding to its receptor. C5a seems to play a role in the initiation and progression of atherosclerosis as a potent chemotactic agent for monocytes, mast cells, and T-lymphocytes, and induces the expression of adhesion molecule on monocytes as well as endothelial cells.12,13,15 C5a may also promote acute vascular events such as destabilization of arterial plaques or thrombus formation by the generation of reactive oxygen species and by increasing the production of TNF-{alpha}, IL-1,15 and tissue factor.22

Within atherosclerotic lesions, activation of the complement cascade, leading to the formation of C5a, may be induced either by the classical or the alternative pathway. Auto-antibodies specific for oxidized LDL may trigger the classical pathway of complement activation.23 C-reactive protein has been found co-localized to complement components and C-reactive protein bound to enzymatically modified LDL (E-LDL) may activate the classic complement pathway. Recent evidence, however, indicates that the binding of C-reactive protein to factor H may restrict the activation to the C3 level.24 However, statistically, C-reactive protein showed no interaction with C5a and its effect on cardiovascular outcome. Activation of the alternative pathway could be initiated by unesterified cholesterol,25 cell debris and E-LDL.26

In our study, plasma levels of C5a showed a weak correlation to high sensitivity C-reactive protein, SAA, and fibrinogen indicating that complement activation and generation of C5a are associated with a proinflammatory state. The fact, however, that C5a predicts risk independently from these non-specific markers of inflammation suggests that measurement of plasma levels of C5a may add prognostic value beyond markers of acute phase response in patients with advanced atherosclerosis.

The increase in risk for a poor cardiovascular outcome correlated with increasing plasma levels of C5a suggesting a biological gradient that further strengthens our results. However, it is virtually unknown whether enhanced activation of complement only reflects a more active state of disease, or alternatively, if elevated C5a levels may causally affect the course of the disease. Assuming the possible proatherogenic effects of C5a together with its capacity to predict risk independently from markers of acute phase response draws attention to a potential causative role of complement activation and generation of C5a for progression of atherosclerosis independently from other inflammatory pathways. It should also be emphasized that auto-immune diseases like rheumatoid arthritis or systemic lupus erythematosus are known to be associated with the activation of complement27 and that these patients are at increased risk for cardiovascular events.28,29 Interestingly, recent studies that investigated the effects of pexelizumab, an anti-C5 complement antibody, showed promising effects after administration as adjunctive therapy to primary PCI in acute MI and to CABG by reducing the incidence of MI and death after 30 days.3032 Although, these studies evaluated, in contrast to our study, mostly patients with acute coronary events, taken the results together, the role of complement activation in patients with CAD may warrant further investigations.

Limitations
Some limitations of the present study have to be acknowledged. We do not believe that selection bias plays a major role as complete baseline and follow-up data were available in the majority of patients and patients with missing follow-up data were comparable with the remaining patients. Information bias is unlikely as outcome assessors were blinded to baseline and laboratory data. Further, our study is of an exploratory nature. Accordingly, our results may arise from multiple testing or be explained by unmeasured confounding factors. Therefore, we tried to control for baseline imbalances by multivariable modelling. The possibility of residual or undetected confounding is small but cannot be ruled out. Owing to the low rate of single endpoints, we used a composite endpoint of MI, PCI, CABG, stroke, carotid revascularization (carotid stenting or carotid endarterectomy), and death. Therefore, we cannot rule out that there may be differing effects on different single endpoints.


    Conclusion
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusion
 Acknowledgements
 References
 
Complement activation, indicated by elevation of C5a seems to be associated with increased cardiovascular risk in patients with advanced atherosclerosis. The role of complement activation in the progression of atherosclerosis and possible effects of C5a need further investigation. Determination of complement factor C5a may add to the predictive value of other inflammatory parameters.


    Acknowledgements
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusion
 Acknowledgements
 References
 
This work was supported by the Ludwig Boltzmann Foundation for Cardiovascular Research, by the Association for Promotion of Research in Arteriosclerosis, Thrombosis, and Vascular Biology, and by the Hans and Blanca Moser Foundation.


    References
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusion
 Acknowledgements
 References
 

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