Distinct associations of complement C3a and its precursor C3 with atherosclerosis and cardiovascular disease. The
Elisabeth Hertle1, Marleen M van Greevenbroek, Ilja C Arts
1Elisabeth Hertle, MSc, PhD candidate, Department of Internal Medicine and CARIM School for Cardiovascular Diseases, Maastricht University Medical Centre, Universiteitssingel 50, P.O. Box 616, 6200 MD Maastricht, The Netherlands, Tel.: +31 43 388 2462, Fax: +31 43 387 5006,
Insights
Complement C3a is linked to atherosclerosis, while both C3a and C3 are associated with cardiovascular disease (CVD) in heavy smokers. These factors may have distinct roles in CVD development, with C3a potentially promoting atherosclerosis.
Area of Science:
- Cardiovascular research
- Immunology
- Medical science
Background:
- Complement C3 is a newly identified risk factor for cardiovascular disease (CVD).
- The specific mechanisms linking C3 to CVD remain largely unknown.
- Understanding the role of C3 and its activation product, C3a, is crucial for elucidating CVD pathogenesis.
Purpose of the Study:
- To determine the associations of C3a and C3 with atherosclerosis markers and CVD.
- To investigate the potential modifying effect of smoking on these associations.
- To explore the mediating role of inflammation in the observed relationships.
Main Methods:
- Cross-sectional analysis of 545 participants from the Cohort on Diabetes and Atherosclerosis Maastricht (CODAM) study.
- Assessment of associations between C3a, C3, carotid intima-media thickness (cIMT), ankle-arm blood pressure index (AAIx), and CVD.
- Linear and logistic regression analyses adjusted for multiple covariates, with stratification for smoking behavior.
Main Results:
- C3a was independently associated with increased cIMT and decreased AAIx.
- Neither C3a nor C3 showed associations with cIMT or AAIx in the general cohort.
- Both C3a and C3 were independently associated with CVD in heavy smokers, with C3's association being independent of C3a.
- Inflammation partially mediated the C3a-AAIx association but not others.
Conclusions:
- C3a and C3 appear to have distinct roles in CVD development.
- C3a may contribute to atherosclerosis and advance CVD, particularly in heavy smokers.
- C3 may be linked to CVD in heavy smokers through mechanisms independent of atherosclerosis and C3a.
Abstract:
Complement C3 is a novel risk factor for cardiovascular disease (CVD), but the underlying mechanism is currently unknown. We determined the associations of the anaphylatoxin C3a, the activation product of C3, and of C3 itself with estimates of atherosclerosis and CVD. We studied associations of C3a and C3 with carotid intima-media thickness (cIMT), ankle-arm blood pressure index (AAIx) and CVD in cross-sectional analyses among 545 participants of the Cohort on Diabetes and Atherosclerosis Maastricht (CODAM) study (62% men, 59.4 ± 6.9 years) and examined effect modification by smoking. We conducted linear and logistic regression analyses with adjustments for age, sex, glucose metabolism status, lipids, adiposity, renal function, blood pressure, pack-years smoked, physical activity, use of medication and investigated mediation by inflammation. C3a was independently associated with cIMT (β=0.032 mm, [95% confidence interval: 0.004; 0.060]) and AAIx (β=-0.022, [-0.043; -0.001]), but C3 was not. Effect modification by smoking was only observed for CVD (P(smoking*C3a)=0.008, P(smoking*C3)=0.018), therefore these associations were stratified for smoking behaviour. Both C3a (odds ratio [OR] =2.96, [1.15; 7.62]) and C3 (OR =1.98, [1.21; 3.22]) were independently associated with CVD in heavy smokers. The association of C3 with CVD was independent of C3a. Low-grade inflammation did partially explain the association of C3a with AAIx, but not the other observed associations. This suggests that C3a and C3 have distinct roles in pathways leading to CVD. C3a may promote atherosclerosis and additionally advance CVD in heavy smokers. Conversely, C3 may be associated with CVD in heavy smokers via pathways other than atherosclerosis.
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