BACKGROUND:The cause of lacunar ischemic stroke, a clinical feature of cerebral small vessel disease (SVD), is largely unknown. Inflammation and endothelial dysfunction have been implicated. Plasma biomarkers could provide mechanistic insights but current data are conflicting. White matter hyperintensities (WMHs) are an important imaging biomarker of SVD. It is unknown if plasma biomarkers add predictive capacity beyond age and vascular risk factors in explaining WMH.METHODS:We prospectively recruited patients presenting with non-disabling ischemic stroke, classifying them clinically and with the help of MRI as lacunar or cortical. We measured biomarkers of inflammation, endothelial dysfunction and hemostasis for >1 month after stroke and compared biomarker levels between stroke subtypes. We quantitatively calculated WMH. We used multiple linear regression analysis to model WMH as a function of age, sex, hypertension and smoking (the baseline model). We fitted exploratory models using plasma biomarkers as predictor variables to assess model improvement over baseline.RESULTS:We recruited 125 patients. The lacunar group (n = 65) had lower tissue plasminogen activator (t-PA) levels in unadjusted (7.39 vs. 8.59 ng/ml, p = 0.029) and adjusted (p = 0.035) analyses compared with the cortical group (n = 60). There were no significant differences in the other plasma biomarkers. The results for t-PA were consistent with an updated meta-analysis, although the effect remains non-significant (standardized mean difference -0.08 (95% CI -0.25 to 0.09)). The baseline regression model explained 29% of the variance in quantitative WMH (R2 0.289). Inflammatory biomarkers showed minor improvement over baseline (R2 0.291), but the other plasma biomarkers did not improve the baseline model.CONCLUSION:Plasma t-PA levels appear to differ between lacunar and cortical stroke subtypes, late after stroke, independent of age, sex and vascular risk factors and may reflect endothelial dysfunction. Except for a minor additional predictive effect of inflammatory markers, plasma biomarkers do not relate to WMH severity in this small stroke population.

Objective Mortality rates reported by the National Joint Registry for England and Wales (NJR) were higher following cemented total knee replacement (TKR) compared with uncemented procedures. The aim of this study is to examine and compare the effects of cemented and uncemented TKR on the activation of selected markers of inflammation, endothelium, and coagulation, and on the activation of selected cytokines involved in the various aspects of the systemic response following surgery. Methods This was a single centre, prospective, case-control study. Following enrolment, blood samples were taken pre-operatively, and further samples were collected at day one and day seven post-operatively. One patient in the cemented group developed a deep-vein thrombosis confirmed on ultrasonography and was excluded, leaving 19 patients in this cohort (mean age 67.4, (sd 10.62)), and one patient in the uncemented group developed a post-operative wound infection and was excluded, leaving 19 patients (mean age 66.5, (sd 7.82)). Results Both groups had a similar response with regards to the levels of C-reactive protein (CRP), interleukin 6 (IL-6) and tumour necrosis factor-alpha (TNFα). CD40 levels rose significantly on the cemented group over day one to day seven compared with that of the uncemented group, which occurred over the first 24 hours. The CD14/42a levels demonstrated a statistically significant increase in the cemented group (p < 0.001 first 24 hours and p = 0.02 between days one and seven). Conclusions The uncemented and cemented groups demonstrated significant changes in the various parameters measured at various time points but apart from CD14/42a levels, there was no significant difference in the serum markers of inflammation, coagulation and endothelial dysfunction following cemented TKR. Cite this article: Bone Joint Res 2014;3:108–16.

Purpose: There are few data assessing the relationship between circulating levels of C-reactive protein (CRP), fibrinogen, and interleukin-6 (IL-6) and the risk of vascular complications in individuals with type 2 diabetes mellitus (T2DM). We studied the associations between these inflammatory markers and the risk of major CV events (CV death, myocardial infarction or stroke), microvascular complications and death in patients T2DM who participated in the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial. Methods: Baseline high sensitivity CRP, fibrinogen and IL-6 levels were determined in a case-cohort study (n=3,865), nested within the ADVANCE trial. Results: During 5 years of follow-up, 709 patients suffered a major CV event, 439 a microvascular complication and 706 died. All 3 markers were associated with an increased risk of CV events and death in analyses adjusting for age, sex and treatment groups. After further adjustment, for other potential confounders and for each other, only IL-6 was an independent predictor of these outcomes (hazard ratio [HR] for CV events 1.37 per 1 standard deviation [SD] increase in log IL-6, 95% confidence interval [CI] 1.24-1.51; HR for death 1.35, 95% CI 1.23-1.49). This increased hazard was seen in patients with and without prior CV disease (figure, HR per 1 SD increase in log IL-6). IL-6 significantly improved the prediction of CV events and death using reclassification statistics (net reclassification improvement in continuous models 23% for CV events and 30% for death). After adjustment, none of the markers predicted microvascular complications. Death stratified by prior CV disease Conclusions: IL-6, but not CRP or fibrinogen, levels add significantly to the prediction of CV events and mortality in individuals with T2DM.

. Background: In England and Wales, approximately 20% extra deaths from coronary heart disease (CHD) occur between December and March, among older people. Circulating concentrations of tissue plasminogen activator (t-PA), von Willebrand factor (VWF) and fibrin D-dimer are associated with arterial disease, and tend to peak in winter. The potential contributions of these hemostatic activation measures to excess winter mortality are unknown. Objectives: To estimate contributions of hemostatic factors to excess winter mortality. Methods: Seasonal patterns in t-PA, VWF and D-dimer were investigated in 4088 men aged 6079 years from 24 British towns. Data on established coronary risk factors were collected by questionnaire, physical examination and blood sampling. The adjusted mean increase in hemostatic markers during winter months, after adjustment for a range of coronary risk factors, was combined with associations of each marker with CHD mortality obtained from 9 years follow-up of participants, to predict degree of excess CHD winter mortality. Associations of hemostatic markers with CHD incidence from large meta-analyses were also used. Results: All three markers showed peaks in winter; the adjusted mean increases during winter months were 0.21, 0.15 and 0.12 standard deviations for t-PA, VWF and log(D-dimer), respectively. Predicted excess hazard ratios for winter CHD mortality were 3.0%, 2.4% and 3.1%, respectively, in combination, representing an 8.6% excess. This increased to 14% when applying meta-analysis estimates. Conclusions: Seasonal patterns in three hemostatic markers predict at least 8.6% excess CHD mortality in winter in Great Britain, potentially accounting for over half the excess observed in recent years.

Aim: To examine the effects of glibenclamide and repaglinide on glucose stimulated insulin release, incretins, oxidative stress and cell adhesion molecules in patients with type 2 diabetes suboptimally treated with metformin.Methods: A randomized clinical trial was performed recruiting 27 subjects (HbA(1c) between 7.5 and 10.5%) free from cardiovascular and renal disease. Glucose, insulin, C-peptide, glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic peptide (GIP), total antioxidant status, F-2-isoprostane, interleukin-6 and cell adhesion molecules were measured during an oral glucose load at baseline and after eight weeks of treatment. The areas under the curve were analysed at 45, 60 and 120 min (AUC(45), AUC(60), AUC(120)).Results: Significant improvements in glucose were observed with repaglinide (HBA(1c): -1.5%, fasting glucose: -2.8 mmol/L, 2-h glucose: -3.7 mmol/L, AUC(120): -18.9%) and glibenclamide (-1.0%, -2.2 mmol/L, -2.5 mmol/L, -17.5%). Repaglinide was also associated with an increase in the AUC(60) and AUC(120) for insulin (+56%, +61%) and C-peptide (+41%, +36%). GLP-1, GIP, IL-6, ICAM-1 and E-selectin levels did not change in either group. No association was observed between GLP-1, GIP-1 and plasma markers of oxidative stress.Conclusion: Repaglinide is associated with improved postprandial glycaemic control via insulin and C-peptide release. We observed no direct effects of glibenclamide or repaglinide on plasma levels of GLP-1 or GIP. We observed no associations of GLP-1 and GIP with plasma markers of oxidative stress. (C) 2011 Elsevier Ireland Ltd. All rights reserved.

Background: CD40 ligand(CD40L) is implicated in atherosclerotic plaque formation. Objectives: We investigated prospective associations between circulating soluble CD40L and myocardial infraction (MI) or stroke in an older general population cohort, accounting for established and novel cardiovascular risk factors. Methods: Baseline serum CD40L (sCD40L) was measured in incident MI (n = 368) and stroke (n = 304) cases and two controls per case, 'nested' in prospective UK studies of 4252 men and 4286 women aged 60-79 years, sampled from general practices in Britain in 1998-2000, with 7-year follow-up for fatal and non-fatal MI and stroke. Results: sCD40L was higher in smokers and negatively associated with lung function and positively associated with total cholesterol and markers of inflammation, but not with other established cardiovascular disease (CVD) risk factors. Geometric mean sCD40L levels did not differ between MI cases and controls (5.94 ng mL(-1) vs. 5.82 ng mL(-1); P = 0.5) or between stroke cases and controls (5.61 ng mL(-1) vs. 5.28 ng mL(-1), P = 0.1). There was no strong evidence for elevated risk of MI or stroke in multivariable models comparing participants in the top to those in the bottom third of sCD40L. Age-adjusted odds ratios (ORs) were 1.39 [95% confidence interval (CI) 0.98, 1.96] for MI and 1.16 (0.78, 1.73) for stroke. These attenuated to 1.24 (95% CI 0.86, 1.79) and 1.18 (0.78, 1.78), respectively, after adjustment for established and novel CVD risk factors. Conclusions: sCD40L is associated with other inflammatory markers but is not itself a strong independent risk marker for either stroke or MI.

Aims/Purpose To determine the prevalence of age-related maculopathy (ARM) and age-related macular degeneration (AMD) in men aged 65–83 years living in the Speedwell region of Bristol, United Kingdom and identify modifiable risk factors. Methods A total of 2348 men recruited to the Speedwell prospective cohort study in 1979 were followed up in 1997 with an eye questionnaire and had retinal photographs that were assessed using the International Classification System for ARM. Results In all, 934 men (66.8% response rate) attended with a mean of 17.9 years (15.3–20.6 years) follow-up. Early ARM (grades 2–3) was found in 9.2% (95% confidence interval (CI) 7.4%, 11.4%) and late age-related maculopathy (grade 4, AMD) in 0.5% (95% CI 0.2%, 1.2%). The risk of ARM (grades 2–4) was increased with raised C-reactive protein and consumption of lard and solid fats, whereas triglyceride levels were associated with a lower risk. The latter were confirmed in multivariable analyses and in addition, haemodynamic measures also predicted risk (eg mean arterial pressure odds ratio (OR) per z-score 1.37, 95% CI 1.04, 1.79). Conclusions In a representative cohort of men aged 65–83 from Bristol, United Kingdom, many had macular changes that put them at higher risk of developing AMD. Various modifiable exposures were associated with an increased risk ARM/AMD. Opportunities for screening and undertaking secondary prevention interventions need to be explored to prevent progression of the disease and blindness.

BACKGROUND:Circulating levels of C-reactive protein (CRP), fibrinogen, fibrin D-dimer, tissue plasminogen activator antigen (t-PA) and von Willebrand factor (VWF) are associated with incident coronary heart disease (CHD). However, their associations with metabolic syndrome and its components in large populations of men and women have not been well defined. OBJECTIVES:We compare the sex associations of these biomarkers with established CHD risk factors, metabolic syndrome and its components in a large cohort. PATIENTS AND METHODS:8302 men and women aged 45 years from the British 1958 birth cohort provided a blood sample. Analyses were restricted to 3457 men and 3464 women with complete data on all risk factors and no history of cardiovascular disease. Multiple regression analyses adjusted for smoking, social class, alcohol consumption and variables related to biomarker measurement error. RESULTS:Adjusted sex differences in levels of all biomarkers (except VWF) varied according to presence/absence of metabolic syndrome, its components and obesity (BMI ≥30 kg m(-) (2)). Associations in women were up to twice as strong for CRP, fibrinogen and t-PA with markers of obesity (body mass index, waist circumference), blood pressure, blood lipids and metabolic syndrome. D-dimer showed weaker associations and less heterogeneity by sex. There was no evidence of sex interaction in associations with VWF. CONCLUSIONS:Associations between CRP, fibrinogen and t-PA and metabolic syndrome and its components were stronger in women than in men. Understanding the reasons for these differences across sex will be important in understanding the pathophysiology of cardiovascular and metabolic disease in men and women.

Background Biomarkers might add to clinical measures of neurological impairment and age to predict poor outcome after stroke. Methods We recruited symptomatic patients <24 h after stroke or TIA from an emergency department. We drew blood for markers of inflammation, thrombosis, thrombolysis, cardiac dysfunction and cerebral damage. We measured outcome at 3 months with the modified Rankin Scale (mRS). We used logistic regression, calculated measures of discrimination and reclassification and adjusted for multiple comparisons. Results We drew blood from 285 patients (230 ischaemic strokes, 40 TIA, 15 haemorrhagic strokes) at a median of 7 h (IQR 3–19 h) after symptom onset and contacted 99% at 3 months: 160 (57%) had mRS 0–2 and 123 (43%) had mRS 3–6. After adjusting for neurological impairment and age, only IL-6 (OR 2.4 (95% CI 1.4 to 4.2), 75th to 25th centile) and Ln NT pro BNP (OR 2.2 (1.2 to 4.0)) were significantly associated with poor outcome. A clinical model containing the NIHSS score and age had an area under a receiver operator curve of 0.84 (95% CI 0.79 to 0.88); neither IL-6 nor Ln NT pro-BNP improved this significantly. There was no net reclassification improvement across clinically important boundaries after adding IL-6 or Ln NT pro-BNP to the clinical model. Conclusion It is unlikely that the biomarkers measured in this study improve the clinical prediction of death or disability when measured at a uniform and early point after stroke or TIA.

Aims: Secondhand smoke (SHS) exposure is associated with elevated CHD risks. Yet the pathways through which this may operate have not been investigated in epidemiologic studies with objective SHS exposure measures and a wide range of CHD risk factors associated with active smoking. Therefore we investigate associations between SHS exposure and CHD risk factors, to clarify how SHS exposure may raise risk of CHD.Methods: Cross-sectional population-based study of 5029 men and women aged 59-80 years from primary care practices in Great Britain. Smoking, behavioural and demographic information was reported in questionnaires; nurses made physical measurements and took blood samples for analysis of serum cotinine and markers of inflammation, hemostasis and endothelial dysfunction.Results: Active cigarette smokers had lower albumin and higher triglycerides, CRP, IL-6, white cell count, fibrinogen, blood viscosity, factor VIII, VWF and t-PA than non-smokers. Among non-smokers, serum cotinine levels were independently positively associated with CRP, fibrinogen, factor VIII, VWF and t-PA and inversely associated with albumin, after adjustment for age, gender, social and behavioural factors. The differences in CRP, fibrinogen and albumin between cotinine <= 0.05 and >0.7 ng/ml were one-third to one half the size of differences between cotinine <= 0.05 ng/ml and current smokers, but were of similar magnitude for VWF and t-PA.Conclusions: Endothelial, inflammatory and haemostatic markers related to CHD risk showed independent associations with SHS exposure in the same direction as those for active smoking. Results aid understanding of the associations between SHS exposure and elevated CHD risks. (C) 2009 Elsevier Ireland Ltd. All rights reserved.

Background. A lack of longitudinal studies has made it difficult to establish the direction of associations between circulating concentrations of low-grade chronic inflammatory markers, such as C-reactive protein and interleukin-6, and cognitive symptoms of depression. The present study sought to assess whether C-reactive protein and interleukin-6 predict cognitive symptoms of depression or whether these symptoms predict inflammatory markers.Method. In a prospective Occupational cohort study of British white-collar civil servants (the Whitehall II study), serum C-reactive protein, interleukin-6 and cognitive symptoms of depression were measured at baseline in 19911993 and at follow-up in 2002-2004, an average follow-up of 11.8 years. Symptoms of depression were measured with four items describing cognitive symptoms of depression from the General Health Questionnaire. The number of participants varied between 3339 and 3070 (mean age 50 years, 30% women) depending on the analysis.Results. Baseline C-reactive protein (beta=0.046, p=0.004) and interleukin-6 (beta=0.046, p=0.005) predicted cognitive symptoms of depression at follow-up, while baseline symptoms of depression did not predict inflammatory markers at follow-up. After full adjustment for sociodemographic, behavioural and biological risk factors, health conditions, medication use and baseline cognitive systems of depression, baseline C-reactive protein (beta=0.038, p=0.036) and interleukin-6 (beta=0.041, p=0.018) remained predictive of cognitive symptoms of depression at follow-up.Conclusions. These findings suggest that inflammation precedes depression at least with regard to the cognitive symptoms of depression.

Background: Evidence on socioeconomic inequalities in coronary heart disease (CHD) and their pathways in the elderly is limited. Little is also known about the contributions that novel coronary risk factors (particularly inflammatory/hemostatic markers) make to socioeconomic inequalities in CHD. Objectives: To examine the extent of socioeconomic inequalities in CHD in older age, and the contributions (relative and absolute) of established and novel coronary risk factors. Methods: A population-based cohort of 3761 British men aged 60-79 years was followed up for 6.5 years for CHD mortality and incidence (fatal and non-fatal). Social class was based on longest-held occupation recorded at 40-59 years. Results: There was a graded relationship between social class and CHD incidence. The hazard ratio for CHD incidence comparing social class V (unskilled workers) with social class I (professionals) was 2.70 [95% confidence interval (CI) 1.37-5.35; P-value for trend = 0.008]. This was reduced to 2.14 (95% CI 1.06-4.33; P-value for trend = 0.11) after adjustment for behavioral factors (cigarette smoking, physical activity, body mass index, and alcohol consumption), which explained 38% of the relative risk gradient (41% of absolute risk). Additional adjustment for inflammatory markers (C-reactive protein, interleukin-6, and von Willebrand factor) explained 55% of the relative risk gradient (59% of absolute risk). Blood pressure and lipids made little difference to these estimates; results were similar for CHD mortality. Conclusions: Socioeconomic inequalities in CHD persist in the elderly and are at least partly explained by behavioral risk factors; novel (inflammatory) coronary risk markers made some further contribution. Reducing inequalities in behavioral factors (especially cigarette smoking) could reduce these social inequalities by at least one-third.

AIMS:The extent to which hemostatic and inflammatory biomarkers are related to angina pectoris as compared with myocardial infarction (MI) remains uncertain. We examined the relationship between a wide range of inflammatory and hemostatic biomarkers, including markers of activated coagulation, fibrinolysis and endothelial dysfunction and viscosity, with incident myocardial infarction (MI) or coronary heart disease (CHD) death and incident angina pectoris uncomplicated by MI or CHD death in older men. METHODS:A prospective study of 3217 men aged 60-79 years with no baseline CHD (angina or MI) and who were not on warfarin, followed up for 7 years during which there were 198 MI/CHD death cases and 220 incident uncomplicated angina cases. RESULTS:Inflammatory biomarkers [C-reactive protein (CRP), interleukin-6, fibrinogen], plasma viscosity and hemostatic biomarkers [von Willebrand factor (VWF) and fibrin D-dimer] were associated with a significant increased risk of MI/CHD death but not with uncomplicated angina even after adjustment for age and conventional risk factors. Adjustment for CRP attenuated the relationships between VWF, fibrin D-dimer and plasma viscosity with MI/CHD death. Comparisons of differing associations with risk of MI/CHD deaths and uncomplicated angina were significant for the inflammatory markers (P < 0.05) and marginally significant for fibrin D-dimer (P = 0.05). In contrast, established risk factors including blood pressure and high-density lipoprotein (HDL)-cholesterol were associated with both MI/CHD death and uncomplicated angina. CONCLUSION:Circulating biomarkers of inflammation and hemostasis are associated with incident MI/CHD death but not incident angina uncomplicated by MI or CHD death in older men.

We establish the connection between a paper by Kartner et al. [F.X. Kartner, D.M. Zumbuhl, N. Matuschek, Phys. Rev. Lett. 82 (1999) 4428] entitled “Turbulence in mode-locked lasers”, and earlier work on the role of noise in mode-locked laser systems. We present numerical results that broadly support the analytical results of Kartner et al.

We agree with Buimeret al. [1Buimer M. Lok C.A.R. Nieuwland R. Ris C. Van Der Post J.A.M. Placental corticotrophin‐releasing hormone mRNA and microparticles in maternal plasma are not measures of placental shedding of debris: a rebuttal.J Thromb Haemost. 2008; 6: 1837Abstract Full Text Full Text PDF Google Scholar] that the total number of microparticles in maternal plasma is not a measure of placental shedding of debris. We made our view clear in the discussion of our article [2Freeman D.J. Tham K. Brown E.A. Rumley A. Lowe G.D. Greer I.A. Fetal corticotrophin‐releasing hormone mRNA, but not phosphatidylserine‐exposing microparticles, in maternal plasma are associated with factor VII activity in pre‐eclampsia.J Thromb Haemost. 2008; 6: 421-7Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar] that ‘the total microparticle population (in maternal plasma) comprises a mixture of fetal and maternal‐derived microparticles and is not a specific marker of placental debris.’ We did not claim that the overall procoagulant activity of total microparticles was specific for placenta‐derived microparticles and stated ‘our prothrombinase assay would detect total PS‐exposing microparticles and would be unable to distinguish between fetal and maternal‐derived material.’ While the letter of Buimeret al. [1Buimer M. Lok C.A.R. Nieuwland R. Ris C. Van Der Post J.A.M. Placental corticotrophin‐releasing hormone mRNA and microparticles in maternal plasma are not measures of placental shedding of debris: a rebuttal.J Thromb Haemost. 2008; 6: 1837Abstract Full Text Full Text PDF Google Scholar] refers to our study as measuring the number or concentration of microparticles, this is not the case. Our interest in microparticle prothrombinase activity, and fetal CRH mRNA, in maternal plasma was in their interaction with the maternal coagulation system. We did not suggest that either measure would be a useful marker for placental dysfunction. Proteins are not the only molecules of interest with biological activity on the microparticle membrane. In the process of apoptosis, phosphatidyl serine molecules, which normally reside in the inner leaflet of the cell membrane, flip over to the outer leaflet. This alerted us to the possibility that the exposed PS could act as a platform for assembly for coagulation factors. Rather than using FACS to identify the number of microparticles, we used the prothrombinase assay, which is dependent on the expression of PS molecules on the surface of the microparticles; hence our reference in the article to ‘phosphatidylserine‐exposing microparticles’ and our unit of measurement of nm PS equivalents [2Freeman D.J. Tham K. Brown E.A. Rumley A. Lowe G.D. Greer I.A. Fetal corticotrophin‐releasing hormone mRNA, but not phosphatidylserine‐exposing microparticles, in maternal plasma are associated with factor VII activity in pre‐eclampsia.J Thromb Haemost. 2008; 6: 421-7Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar]. Because we are not measuring actual numbers of microparticles but relating their biological activity to measures of coagulation activation in the same sample, hemoconcentration is not a concern. These phosphatidylserine‐exposing microparticles may represent yet another subset of the total microparticle population but one that can be identified by its biological activity. We do state that we consider fetal CRH mRNA levels in maternal blood to be one measure of placental debris. CRH is made by cytotrophoblasts. Placental CRH mRNA is subject to upregulation in situations of fetal stress and placental dysfunction. There appears to be little doubt that fetal CRH mRNA expression is upregulated in pre‐eclampsia, as indicated by a number of cDNA array experiments; see, for example, Nishizawaet al. [3Nishizawa H. Pryor‐Koishi K. Kato T. Kowa H. Kurahashi H. Udagawa Y. Microarray analysis of differentially expressed fetal genes in placental tissue derived from early and late onset severe pre‐eclampsia.Placenta. 2007; 28: 487-97Crossref PubMed Scopus (0) Google Scholar]. Therefore, as Buimeret al. point out, we cannot discount the possibility that our observation of increased fetal CRH mRNA levels may result from no change in shedding of placental debris but that each ‘package’ of debris contains more copies of CRH transcript. This could potentially confound our observed relationship between fetal CRH mRNA and factor VIIa activity. However, if fetal CRH mRNA was merely a non‐specific marker for the presence of a pre‐eclamptic placenta, we might have expected to observe a relationship between fetal CRH mRNA and other circulating markers that are well known to be associated with pregnancies complicated by pre‐eclampsia, such as markers of endothelial activation. We did not observe this. The authors state that they have no conflict of interest.

BACKGROUND:Matrix metalloproteinase-9 (MMP-9) has a potential role in arterial plaque rupture, but its relation to risk of coronary heart disease (CHD) is uncertain.AIM:To determine whether circulating levels of serum MMP-9 are prospectively related to the risk of CHD in the general population.METHODS:We measured baseline MMP-9 levels in stored serum samples of subjects in a case-control study nested within a prospective study of 5661 men followed up for 16 years for CHD events (465 cases, 1076 controls).RESULTS:MMP-9 values were associated with cigarette smoking, and with several inflammatory and haemostatic markers, but not with age, body mass index, blood pressure or lipid measurements. Men in the top third of baseline MMP-9 levels had an age-adjusted odds ratio (OR) for CHD of 1.37 (95% CI 1.04-1.82) compared with those in the bottom third. Adjustment for conventional risk factors (smoking in particular) reduced the odds ratio to borderline significance: OR 1.28 (95% CI 0.95-1.74), while additional adjustment for two markers of generalized inflammation, interleukin-6 and C-reactive protein, further attenuated the association: OR 1.13 (0.82-1.56).CONCLUSION:Serum MMP-9 has a modest association with incident CHD in the general population, which is not independent of cigarette smoking exposure and circulating markers of generalized inflammation. MMP-9 is unlikely to be a clinically useful biomarker of CHD risk, but may still play a role in the pathogenesis of CHD.