TY - JOUR
T1 - Distinct Longitudinal Associations of MBL, MASP-1, MASP-2, MASP-3, and MAp44 With Endothelial Dysfunction and Intima-Media Thickness The Cohort on Diabetes and Atherosclerosis Maastricht (CODAM) Study
AU - Hertle, Elisabeth
AU - Arts, Ilja C. W.
AU - van der Kallen, Carla J. H.
AU - Feskens, Edith J. M.
AU - Schalkwijk, Casper G.
AU - Hoffmann-Petersen, Ingeborg T.
AU - Thiel, Steffen
AU - Stehouwer, Coen D. A.
AU - van Greevenbroek, Marleen M. J.
PY - 2016/6
Y1 - 2016/6
N2 - Objective-Previous studies suggested that the lectin-complement pathway plays a complex role in cardiovascular disease (CVD). To date, no prospective human studies have investigated the relationship between the initiating factor of the lectin pathway, that is, mannose-binding lectin (MBL), and low-grade inflammation, endothelial dysfunction, or carotid intima-media thickness (cIMT). Moreover, MBL-associated proteases (MASPs) and MBL-associated proteins (MAps), which mediate downstream complement activation, have not been studied in the development of CVD. Approach and Results-In a prospective cohort (n=574; age 60 +/- 7 years; 7-year follow-up), we investigated longitudinal associations of plasma MBL, MASP-1, MASP-2, MASP-3, and MAp44 with biomarker scores that reflect low-grade inflammation and endothelial dysfunction, respectively, and with cIMT. We also investigated their associations with incident CVD (n=73). In adjusted analyses, low-grade inflammation was lowest in the middle tertile (T-Middle) of MBL, that is, T-Middle was 0.19 SD (0.03 to 0.34) lower than T-Low, and 0.15 SD (-0.02 to 0.31) lower than T-High. cIMT was 28 mu m (-50 to -5) lower in the highest MBL tertile (T-High) than in T-Middle and did not differ between T-Low and T-Middle. MBL was not associated with endothelial dysfunction or CVD. MASP-1 and MASP-2 were not associated with any cardiovascular outcomes. MASP-3 and MAp44 were, independently of MBL levels, associated with endothelial dysfunction (per 1 SD higher MASP-3: beta=0.10 SD [0.02 to 0.18]; per 1 SD higher MAp44 beta=0.12 SD [0.04 to 0.20]) but not with low-grade inflammation, cIMT, or CVD. Conclusions-High MBL may contribute to low cIMT, whereas the association of MBL with low-grade inflammation was nonlinear. MASP-1 and MASP-2 were not associated with adverse cardiovascular outcomes. MASP-3 and MAp44 may play a role in endothelial dysfunction, potentially independent of lectin-pathway activation.
AB - Objective-Previous studies suggested that the lectin-complement pathway plays a complex role in cardiovascular disease (CVD). To date, no prospective human studies have investigated the relationship between the initiating factor of the lectin pathway, that is, mannose-binding lectin (MBL), and low-grade inflammation, endothelial dysfunction, or carotid intima-media thickness (cIMT). Moreover, MBL-associated proteases (MASPs) and MBL-associated proteins (MAps), which mediate downstream complement activation, have not been studied in the development of CVD. Approach and Results-In a prospective cohort (n=574; age 60 +/- 7 years; 7-year follow-up), we investigated longitudinal associations of plasma MBL, MASP-1, MASP-2, MASP-3, and MAp44 with biomarker scores that reflect low-grade inflammation and endothelial dysfunction, respectively, and with cIMT. We also investigated their associations with incident CVD (n=73). In adjusted analyses, low-grade inflammation was lowest in the middle tertile (T-Middle) of MBL, that is, T-Middle was 0.19 SD (0.03 to 0.34) lower than T-Low, and 0.15 SD (-0.02 to 0.31) lower than T-High. cIMT was 28 mu m (-50 to -5) lower in the highest MBL tertile (T-High) than in T-Middle and did not differ between T-Low and T-Middle. MBL was not associated with endothelial dysfunction or CVD. MASP-1 and MASP-2 were not associated with any cardiovascular outcomes. MASP-3 and MAp44 were, independently of MBL levels, associated with endothelial dysfunction (per 1 SD higher MASP-3: beta=0.10 SD [0.02 to 0.18]; per 1 SD higher MAp44 beta=0.12 SD [0.04 to 0.20]) but not with low-grade inflammation, cIMT, or CVD. Conclusions-High MBL may contribute to low cIMT, whereas the association of MBL with low-grade inflammation was nonlinear. MASP-1 and MASP-2 were not associated with adverse cardiovascular outcomes. MASP-3 and MAp44 may play a role in endothelial dysfunction, potentially independent of lectin-pathway activation.
KW - carotid intima-media thickness
KW - complement system proteins
KW - inflammation
KW - lectin-complement pathway
KW - METABOLIC SYNDROME
KW - MYOCARDIAL-INFARCTION
KW - MANNOSE-BINDING LECTIN
KW - COMPLEMENT ACTIVATION
KW - RISK
KW - INSULIN-RESISTANCE
KW - SERUM-LEVELS
KW - CARDIOVASCULAR-DISEASE
KW - LOW-GRADE INFLAMMATION
KW - CORONARY-ARTERY-DISEASE
U2 - 10.1161/ATVBAHA.115.306552
DO - 10.1161/ATVBAHA.115.306552
M3 - Article
C2 - 27055907
SN - 1079-5642
VL - 36
SP - 1278
EP - 1285
JO - Arteriosclerosis Thrombosis and Vascular Biology
JF - Arteriosclerosis Thrombosis and Vascular Biology
IS - 6
ER -