for the AtheroGene InvestigatorsBackground-Matrix metalloproteinase (MMP)-9 secretion by macrophages and other inflammatory cells accelerates atherosclerotic progression and destabilizes vulnerable plaque in animal models. However, epidemiological data evaluating the prognostic impact of circulating concentrations and functional genetic variations of MMP-9 are lacking. Methods and Results-In a prospective study of 1127 patients with documented coronary artery disease, we measured baseline plasma MMP-9 levels and determined the MMP-9/C-1562T and MMP-9/R279Q genotypes. During the follow-up period (mean of 4.1 years), 97 patients died from cardiovascular (CV) causes. Median concentrations of MMP-9 were significantly higher among patients who experienced a fatal CV event than among those who did not (62.2 versus 47.8 ng/mL; PϽ0.0001). The crude hazard risk ratio of CV death associated with increasing quartiles of MMP-9 was 1.4 (95% CI, 1.2 to 1.8; PϽ0.0001), and after adjustment for clinical and therapeutic confounders, it was 1.3 (95% CI, 1.1 to 1.6; Pϭ0.005). Additional adjustment for highly sensitive CRP, interleukin-6, fibrinogen, and interleukin-18 revealed a hazard risk ratio to 1.2 (95% CI, 0.9 to 1.6; Pϭ0.15). The T allele of the C-1562T polymorphism was associated with increased MMP-9 levels in a fairly codominant fashion (Pϭ0.004). Although none of the polymorphisms was significantly related with future CV death, there was a significant association (Pϭ0.02) between the R279Q polymorphism and CV events in patients with stable angina. Conclusions-Plasma MMP-9 concentration was identified as a novel predictor of CV mortality in patients with coronary artery disease. Whether it provides independent prognostic information compared with other inflammatory markers will have to be additionally assessed.

No abstract

MD; for the AtheroGene InvestigatorsBackground-Vascular cell adhesion molecule (VCAM)-1, intercellular adhesion molecule (ICAM)-1, and E-selectin mediate adhesion and transmigration of leukocytes to the vascular endothelial wall and may promote plaque growth and instability. In a prospective study, we evaluated the effect of soluble adhesion molecules on the risk of future cardiovascular events among patients with angiographically documented coronary artery disease (CAD). Methods and Results-We obtained baseline samples from a prospective cohort of 1246 patients with CAD. Besides various markers of inflammation, soluble VCAM-1 (sVCAM-1), sICAM-1, and sE-selectin were determined. Follow-up information on cardiovascular events was obtained (mean, 2.7; maximum, 4.1 years). Independently higher levels of sVCAM-1 (1932 versus 1128 ng/mL; PϽ0.0001), sICAM-1 (353 versus 287 ng/mL; Pϭ0.015), and sE-selectin (81 versus 63 ng/mL; Pϭ0.003) were observed in patients with future death from cardiovascular causes. In a multivariate model, fatal risk was 2.1-fold (1.1 to 4.0) higher in patients within the top quartile of baseline sVCAM-1 concentrations compared with lower quartiles. This association was present independent of general inflammatory response as reflected by low or high C-reactive protein (hs-CRP) levels. In a model that simultaneously controlled for all inflammatory and soluble adhesion markers determined, only sVCAM-1 remained independently significant for future fatal cardiovascular events, with a 2.8-fold increase in risk (Pϭ0.003). Conclusions-Soluble adhesion molecules sVCAM-1, sICAM-1, and sE-selectin were significantly related to future death from cardiovascular causes among patients with documented CAD. Especially sVCAM-1 added to the predictive value of classic risk factors and hs-CRP in determining the risk of future cardiovascular death.

In patients with coronary artery disease, a low level of activity of red-cell glutathione peroxidase 1 is independently associated with an increased risk of cardiovascular events. Glutathione peroxidase 1 activity may have prognostic value in addition to that of traditional risk factors. Furthermore, increasing glutathione peroxidase 1 activity might lower the risk of cardiovascular events.

No abstract

Background —The number of infectious pathogens to which an individual has been exposed (infectious burden) may correlate with coronary artery disease (CAD). In a prospective study, we evaluated the effect of 8 pathogens and the aggregate pathogen burden on the risk for future fatal cardiac events among patients with angiographically documented CAD. Methods and Results —In 1018 patients, IgG or IgA antibodies to herpes simplex virus types 1 and 2, cytomegalovirus, Epstein-Barr virus, Haemophilus influenzae , Chlamydia pneumoniae , Mycoplasma pneumoniae , and Helicobacter pylori were determined. Moreover, highly sensitive C-reactive protein was measured. Follow-up information on cardiovascular events was obtained (mean 3.1 years, maximum 4.3 years). Seropositivities to Epstein-Barr virus ( P =0.001), H pylori ( P =0.002), and herpes simplex virus type 2 ( P =0.045) were independently associated with the future risk of cardiovascular death. An increasing number for pathogen burden was significantly predictive of the long-term prognosis ( P <0.0001). Infectious burden divided into 0 to 3, 4 or 5, and 6 to 8 seropositivities was associated with an increasing mortality of 3.7%, 7.2%, and 12.6%, respectively. Patients seropositive to >5 pathogens compared with those seropositive to <4 pathogens had a 5.1 (1.4 to 18.3) higher risk of future cardiac death. This result was mainly driven by the pathogen burden of seropositivities to Herpesviridae ( P <0.0001). The prognostic impact of total or viral pathogen burden was independent of the C-reactive protein level. Conclusions —These results support the hypothesis that the number of infectious pathogens to which an individual has been exposed independently contributes to the long-term prognosis in patients with documented CAD.

The potential use of autologous thrombocytic growth factors to accelerate bone regeneration requires improved methods of isolating platelet-rich plasma (PRP). In addition to discontinuous cell separation, a second method by which PRP is produced at the point-of-care has now become available. In this study, growth factor levels in PRP from these two sources were compared. Whole blood was drawn from 115 healthy donors (73 males, 42 females) aged 21 - 62 years (mean 36, SD 10). The PRP was separated by the blood bank (BB) using the discontinuous cell separation method or at the 'point-of-care' by the so-called 'buffy coat' method (analogous to the Curasan PRP Kit). Growth factor content differed significantly for TGF-beta1 (BB 268.65+/-70.77 ng/ml, Curasan 95.02+/-60.67 ng/ml (sign test P<0.001)) and PDGF-AB (BB 133.59+/-46.26 ng/ml, Curasan 233.70+/-111.86 ng/ml (P<0.001)), while the content of IGF-I (BB 85.37+/-25.58 ng/ml, Curasan 101.72+/-47.7 ng/ml (P<0.160)) showed no significant difference. The higher thrombocyte count in the BB PRP (BB 1434300+/-351960/ microl, Curasan 908.500+/-492.30/microl) seems to result in higher TGF-beta1 levels, while the higher leukocyte count in the Curasan PRP (BB 160+/-320/ microl, Curasan 30130+/-12500/microl) seems to result in higher PDGF-AB levels. The similar IGF-I levels in the two preparations might merely reflect similar amounts of plasma in the PRP produced by each approach.

MD; for the AtheroGene InvestigatorsBackground-Recent findings suggest a causative role of infections in the pathogenesis of atherosclerosis. In hypothesizing an association between infectious agents and the development of atherosclerosis, we would expect a correlation to the extent of atherosclerosis. Moreover, this effect could be multiplied by the number of pathogens to which an individual had been exposed. Methods and Results-In 572 patients, IgG or IgA antibodies to herpes simplex virus 1 and 2, cytomegalovirus, Epstein-Barr virus, Hemophilus influenzae, Chlamydia pneumoniae, Mycoplasma pneumoniae, and Helicobacter pylori were measured. The extent of atherosclerosis was determined by coronary angiography, carotid duplex sonography, and evaluation of the ankle-arm index. Elevated IgA antibodies against C pneumoniae (PϽ0.04) and IgG antibodies against H pylori (PϽ0.02), cytomegalovirus (PϽ0.05), and herpes simplex virus 2 (PϽ0.01) were associated with advanced atherosclerosis (Ն2 vascular regions), adjusted for age, sex, cardiovascular risk factors, and highly sensitive C-reactive protein.Infectious burden divided into 0 to 3, 4 to 5, and 6 to 8 seropositivities was significantly associated with advanced atherosclerosis, with an odds ratio (95% CI) of 1.8 (1.2 to 2.6) for 4 to 5 (PϽ0.01) and 2.5 (1.2 to 5.1) for 6 to 8 seropositivities (PϽ0.02) (adjusted). After a mean follow-up of 3.2 years, cardiovascular mortality rate was 7.0% in patients with advanced atherosclerosis and seropositive for 0 to 3 pathogens compared with 20.0% in those seropositive for 6 to 8 pathogens. Conclusions-Our results support the hypothesis that infectious agents are involved in the development of atherosclerosis.We showed a significant association between infectious burden and the extent of atherosclerosis. Moreover, the risk for future death was increased by the number of infectious pathogens, especially in patients with advanced atherosclerosis.