TY - JOUR
T1 - Elevated Levels of Circulating DNA and Chromatin Are Independently Associated With Severe Coronary Atherosclerosis and a Prothrombotic State
AU - Borissoff, Julian I.
AU - Joosen, Ivo A.
AU - Versteylen, Mathijs O.
AU - Brill, Alexander
AU - Fuchs, Tobias A.
AU - Savchenko, Alexander S.
AU - Gallant, Maureen
AU - Martinod, Kimberly
AU - ten Cate, Hugo
AU - Hofstra, Leonard
AU - Crijns, Harry J.
AU - Wagner, Denisa D.
AU - Kietselaer, Bas L. J. H.
PY - 2013/8
Y1 - 2013/8
N2 - Objective Aberrant neutrophil activation occurs during the advanced stages of atherosclerosis. Once primed, neutrophils can undergo apoptosis or release neutrophil extracellular traps. This extracellular DNA exerts potent proinflammatory, prothrombotic, and cytotoxic properties. The goal of this study was to examine the relationships among extracellular DNA formation, coronary atherosclerosis, and the presence of a prothrombotic state. Approach and Results In a prospective, observational, cross-sectional cohort of 282 individuals with suspected coronary artery disease, we examined the severity, extent, and phenotype of coronary atherosclerosis using coronary computed tomographic angiography. Double-stranded DNA, nucleosomes, citrullinated histone H4, and myeloperoxidase-DNA complexes, considered in vivo markers of cell death and NETosis, respectively, were established. We further measured various plasma markers of coagulation activation and inflammation. Plasma double-stranded DNA, nucleosomes, and myeloperoxidase-DNA complexes were positively associated with thrombin generation and significantly elevated in patients with severe coronary atherosclerosis or extremely calcified coronary arteries. Multinomial regression analysis, adjusted for confounding factors, identified high plasma nucleosome levels as an independent risk factor of severe coronary stenosis (odds ratio, 2.14; 95% confidence interval, 1.26-3.63; P=0.005). Markers of neutrophil extracellular traps, such as myeloperoxidase-DNA complexes, predicted the number of atherosclerotic coronary vessels and the occurrence of major adverse cardiac events. Conclusions Our report provides evidence demonstrating that markers of cell death and neutrophil extracellular trap formation are independently associated with coronary artery disease, prothrombotic state, and occurrence of adverse cardiac events. These biomarkers could potentially aid in the prediction of cardiovascular risk in patients with chest discomfort.
AB - Objective Aberrant neutrophil activation occurs during the advanced stages of atherosclerosis. Once primed, neutrophils can undergo apoptosis or release neutrophil extracellular traps. This extracellular DNA exerts potent proinflammatory, prothrombotic, and cytotoxic properties. The goal of this study was to examine the relationships among extracellular DNA formation, coronary atherosclerosis, and the presence of a prothrombotic state. Approach and Results In a prospective, observational, cross-sectional cohort of 282 individuals with suspected coronary artery disease, we examined the severity, extent, and phenotype of coronary atherosclerosis using coronary computed tomographic angiography. Double-stranded DNA, nucleosomes, citrullinated histone H4, and myeloperoxidase-DNA complexes, considered in vivo markers of cell death and NETosis, respectively, were established. We further measured various plasma markers of coagulation activation and inflammation. Plasma double-stranded DNA, nucleosomes, and myeloperoxidase-DNA complexes were positively associated with thrombin generation and significantly elevated in patients with severe coronary atherosclerosis or extremely calcified coronary arteries. Multinomial regression analysis, adjusted for confounding factors, identified high plasma nucleosome levels as an independent risk factor of severe coronary stenosis (odds ratio, 2.14; 95% confidence interval, 1.26-3.63; P=0.005). Markers of neutrophil extracellular traps, such as myeloperoxidase-DNA complexes, predicted the number of atherosclerotic coronary vessels and the occurrence of major adverse cardiac events. Conclusions Our report provides evidence demonstrating that markers of cell death and neutrophil extracellular trap formation are independently associated with coronary artery disease, prothrombotic state, and occurrence of adverse cardiac events. These biomarkers could potentially aid in the prediction of cardiovascular risk in patients with chest discomfort.
KW - atherosclerosis
KW - coagulation
KW - blood
KW - chromatin
KW - DNA
KW - neutrophils
KW - nucleosomes
KW - thrombin
KW - thrombophilia
U2 - 10.1161/ATVBAHA.113.301627
DO - 10.1161/ATVBAHA.113.301627
M3 - Article
C2 - 23818485
SN - 1079-5642
VL - 33
SP - 2032
EP - 2040
JO - Arteriosclerosis Thrombosis and Vascular Biology
JF - Arteriosclerosis Thrombosis and Vascular Biology
IS - 8
ER -