Inflammation plays a pivotal role in all stages of atherosclerosis. Numerous inflammatory, lipid, and cytokines markers have been associated with coronary artery disease (CAD) risk but data directly comparing their predictive value are limited. Studies were carried to elucidate the role of high-sensitivity C-reactive protein (hsCRP), other inflammatory as well as lipid markers and their associations. Among 1021 subjects, comprising 774 CAD affected members from Indian Atherosclerosis Research Study (IARS), plasma hsCRP levels showed strong correlation with inflammatory markers, namely, IL6 (r = .373; P = <.0001), sPLA2 (r = .544; P = <.0001) as also with fibrinogen (r = .579; P = <.0001). Levels of hsCRP were higher among subjects affected by CAD who suffered a repeat coronary event as compared to those who remained event free and subjects in the top quartile of hsCRP (>3.58 mg/L) were found to have a fourfold higher risk. In conclusion, hsCRP appears to be an independent predictor of recurrent CAD events in Asian Indian population.
Objective: Inflammation plays a key role in the pathogenesis of atherosclerosis. This study aimed to assess the relationship of serum inflammatory marker high sensitivity C Reactive protein (hsCRP), with the presence and severity of angiographically evaluated coronary artery disease (CAD).
Methods: This study was conducted at departments of physiology and cardiology, College of Medicine & King Khalid University Hospital, King Saud University, Riyadh from August 2009 to March 2012. Eighty seven patients (57 males and 30 females) with angiographically evaluated CAD were studied. In all these patients CAD severity was assessed by Gensini scoring and vessel scoring. Control group consisted of 29 healthy subjects (17 males and 12 females). Fasting venous blood samples were analyzed for lipid profile and high sensitivity C-reactive protein (hsCRP).
Results: There were non-significant differences in age, weight and BMI among healthy subjects and CAD patients. Comparison of lipid profile between control and CAD patients showed that CAD patients had significantly higher TG and significantly lower HDL levels compared to control subjects. CAD patients presented with significantly higherhsCRP levels than controls. Linear regression analysis between hsCRP and CAD severity determined by Gensini scores showed a significant positive correlation (r=0.423, p=0.018). Triple vessel disease patients had significantly higher hsCRP levels than one vessel and two vessel disease, while the difference was non significant between one and two vessel disease groups.
Conclusions: These results suggest that patients with angiographically evaluated CAD have significantly higher levels of hsCRP levels compared to healthy individuals and are correlated with the presence & severity of CAD.
High sensitivity C-reactive protein; Coronary artery disease; Gensiniscore; Vessel scores; Angiography
Background & objectives:
The association between adiponectin and risk of cardiovascular disease is well known. The aim of the present study was to evaluate adiponectin and certain inflammatory markers and to determine the correlations between them in angiographically proven coronary artery disease (CAD) in subjects with and without diabetes.
A total of 180 subjects who underwent coronary angiography for symptoms suggestive of CAD were categorised into groups based on their diabetes and/or CAD status: group1 (non-diabetic non-CAD); group2 (non-diabetic CAD); group3 (diabetic non-CAD) and group4 (diabetic CAD). Adiponectin, tumour necrosis factor α (TNF-α) and soluble form of E-selectin (sE-selectin) were estimated using quantitative sandwich enzyme immunoassay and high sensitive C-reactive protein (hsCRP) by particle enhanced immunoturbidimetric method.
Adiponectin levels were significantly lower in subjects with either diabetes or CAD and were much lower in subjects who had both. hsCRP was elevated in CAD and diabetes but did not differ significantly between groups. sE-selectin and TNF-α levels were elevated in CAD. Adiponectin negatively correlated with age, glucose, sE-selectin, total and LDL cholesterol. hsCRP correlated with BMI, sE-selectin and urea. sE-selectin correlated with BMI, triglycerides and VLDL cholesterol, whereas TNF-α correlated with fasting plasma glucose. In the logistic regression analysis, adiponectin had a significant inverse association with CAD. sE-selectin and TNF-α also showed significant independent association with CAD.
Interpretation & conclusions:
Adiponectin and other inflammatory markers such as sE-selectin and TNF-α showed a significant association with CAD. Hence, early assessment of such markers can help to identify high risk patients, and to reduce the inflammatory component of diabetes and CAD.
Adiponectin; angiography; coronary artery disease; diabetes mellitus; India; inflammatory markers; TNF-α
Inflammatory processes are implicated in the etiology of cardiovascular disease (CVD). Data on the association of inflammatory markers with cardiovascular risk factors in Indian patients with CVD are limited.
This study was conducted with the aim to evaluate the association of inflammatory markers with traditional and nontraditional cardiovascular risk factors in angiographically proven coronary artery disease (CAD) patients.
Subjects and Methods:
We studied the association of serum highly sensitive C-reactive protein (hsCRP) (0.1-37.9 mg/l), interleukin-6 (IL-6) (2-253.2 pg/ml) and tumor necrosis factor-alpha (TNF-α) (8-525.8 pg/ml) with cardiovascular risk factors in 300 (M: 216, F: 84; mean age: 60.9 (12.4) years) CAD patients. All patients were evaluated for anthropometry and cardiovascular risk factors, and blood samples were collected for biochemical and inflammatory markers. Statistical analysis was carried out using SPSS Version 20.
Mean hsCRP, IL-6 and TNF-α in study population were 11.7 (9.7) mg/l, 64.5 (75.2) pg/ml, and 25.3 (40.9) pg/ml respectively. A total of 73.6% (221/300) patients had hsCRP levels >3.0 mg/l. All inflammatory markers were significantly higher and showed a positive correlation with dyslipidemia, diabetes mellitus, and/or hypertension (HTN). TNF-α had a negative correlation with age and positive correlation with smoking. Only IL-6 and hsCRP had a positive correlation with insulin resistance and negative correlation with insulin secretion. Among lipid parameters, triglyceride had a positive correlation, and high density lipoprotein had a negative correlation with all inflammatory markers. There was a progressive increase in the percentage of subjects with diabetes, HTN, and dyslipidemia with increasing levels of inflammatory markers.
Indian patients with CAD had significantly high levels of inflammatory markers, which were related to cardiovascular risk factors.
C-reactive protein; Coronary artery disease; Inflammatory markers; Interleukin-6; Tumor necrosis factor-α
Myeloid-related protein 8/14 (MRP8/14) is a stable heterodimer formed by two different calcium-binding proteins (MRP8 and MRP14). Studies have identified that MRP8/14 regulates vascular inflammation and serves as a novel marker of acute coronary syndrome. In this study, we evaluated the correlation between serum levels of MRP8/14, hsCRP, endogenous secretory receptor for advanced glycation end-products (esRAGE) and the occurrence of coronary artery disease (CAD), or carotid intima-media thickness (IMT) when CAD was not yet developed in diabetic patients.
Serum levels of MRP8/14, esRAGE and hsCRP were measured in 375 diabetic patients. Then the results of those who had CAD were compared against who had not. Also, we investigated the associations between above-mentioned indicators and IMT of subjects without CAD in both diabetic group and non-diabetic one.
Serum MRP8/14 was significantly higher in CAD than in non-CAD group (9.7 ± 3.6 ug/ml vs. 8.2 ± 3.0 ug/ml, P < 0.001). It was associated with severity of CAD (r = 0.16, P = 0.026). In non-CAD group, MRP8/14 was associated with IMT in patients with (r = 0.30, P < 0.001) or without diabetes (r = 0.26, P = 0.015). The areas under the curves of receiver operating characteristic for CAD were 0.63 (95% CI 0.57-0.68) for MRP8/14, 0.76 (95% CI 0.71-0.81) for hsCRP and 0.62 (95% CI 0.56 -0.67) for esRAGE.
In summary, we report that diabetic patients with CAD had elevated plasma MRP8/14 levels which were also positively correlated with the severity of CAD and carotid IMT in patients without clinically overt CAD.
MRP8/14; Diabetes mellitus; Coronary artery disease; Intima media thickness
Background & objectives:
Studies on cardiovascular diseases (CVD) in India have shown about 10-20 per cent of cases with no obvious risk factors, raising a suspicion of infections as a cause. There is a paucity of data on this possible role of infections. This study was, therefore, undertaken to find out the association between infection due to Chlamydia pneumoniae and other organisms and coronary artery disease (CAD).
Patients with CAD were selected in group I (acute myocardial infarction, AMI) and group III (patients undergoing coronary artery bypass graft (CABG) surgery), and normal controls in group II. Routine biochemical, haematological and inflammatory tests [C-reactive protein (CRP), total leucocyte count (TLC), fibrinogen, ESR], serodiagnostic tests for IgA and IgG antibodies to C. pneumoniae, Helicobacter pylori, cytomegalovirus (CMV), Mycoplasma pneumoniae and Parvovirus B-19 by ELISA kits, C. pneumoniae antigen by microimmunofluorescence and PCR from endothelial tissue obtained at CABG were carried out. Aortic punch biopsies were done in patients who underwent CABG.
Acute MI patients had a significantly higher association with accepted cardiac risk factors, lipid profile, inflammatory and thrombogenic tests. IgG and IgA antibodies levels against C. pneumoniae were not significantly different in the controls as against the AMI group. However, C. pneumoniae antigen seropositive group had significant association with HDL cholesterol, lipid tetrad index (P<0.001) and with triglycerides. Parvovirus B antigen was detected in 8.3 per cent of tissue specimens by PCR and of 44 patients with AMI (6.8%) were also positive for parvovirus B-19 IgG antibodies.
Interpretation & conclusions:
There was no direct evidence of the involvement of C. pneumoniae and other infective agents and viruses in CAD. It is possible that such infections produce an indirect adverse effect on the lipid profile.
Chlamydia pneumoniae; chronic infections; coronary artery disease
To assess the relationship of levels of inflammatory risk markers to presence of clinical coronary artery disease (CAD) in patients with treated heterozygous familial hypercholesterolaemia.
A cross-sectional study of patients on the Simon Broome Familial Hyperlipidaemia Register.
Six hospital outpatient clinics in the UK.
A total of 211 men and 199 women with heterozygous familial hypercholesterolaemia.
Main outcome measures
Analysis of conventional risk factors and concentrations of high-sensitivity C-reactive protein (hsCRP), lipoprotein(a), serum intercellular adhesion molecule (sICAM), interleukin-6 (IL-6) and lipoprotein-associated phospholipase A2 (LpPLA2) mass.
CAD was present in 104 men and in 55 women; the mean ages of onset were 43.1 and 46.5 years, respectively. On univariate analysis there was a positive relationship of CAD with age, male sex, smoking, IL-6 and sICAM, and an inverse relationship with low-density lipoprotein (LDL) and LpPLA2. On multivariate analysis, age, smoking, low LDL and low LpPLA2 were associated with CAD. When LpPLA2 values were adjusted for apoB and aspirin usage, there was no significant difference between those with and without CAD. Only age and smoking were independently associated with CAD in men, and IL-6 and lipoprotein(a) in women.
Although on univariate analysis inflammatory marker levels were associated with CAD in these patients, the majority of the associations, including that for hsCRP, disappeared when corrected for smoking and apoB. This may be because atherosclerotic plaques in these statin-treated patients were quiescent or an effect of aspirin usage. In this observational study newer risk markers were not usefully associated with the presence or absence of symptomatic CAD.
Chronic inflammatory stimuli such as cytomegalovirus (CMV) infection and various genetic polymorphisms determining the inflammatory response are assumed to be important risk factors in atherosclerosis. We investigated whether patients with stable coronary artery disease (CAD) and homozygous for allele 2 of the interleukin 1 receptor antagonist (IL-1RA) gene and seropositive for CMV represent a group particular susceptible for recurrent cardiovascular events.
In a series of 300 consecutive patients with angiographically defined CAD a prospective follow-up was conducted (mean age 57.9 years, median follow-up time 38.2 months).
No statistically significant relationship was found between CMV serostatus and IL-1RN*2 (alone or in combination) and risk for future cardiovascular events (CVE). The hazard ratio (HR) for a CVE given positive CMV-serology and IL-1RN*2 was 1.07 (95% confidence interval (CI) 0.32–3.72) in the fully adjusted model compared to seronegative CMV patients not carrying the IL-1RN*2 allele. In this prospective cohort study involving 300 patients with angiographically defined CAD at baseline, homozygousity for allele 2 of the IL-1 RA and seropositivity to CMV alone and in combination were not associated with an increased risk for cardiovascular events during follow-up; in addition, combination of the CMV-seropositivity and IL-1RN*2 allele were not associated with a proinflammatory response
Our study suggests that seropositivity to CMV and IL-1RA*2 genotype alone or in combination might not be a strong risk factor for recurrent cardiovascular events in patients with manifest CAD, and is not associated with levels of established inflammatory markers.
The association between TGF-β1 levels and long-term major adverse cardiovascular events (MACE) in patients with coronary artery disease (CAD) is controversial. No study specifically addressed patients with CAD and diabetes mellitus (DM). The association between TGF-β1 levels and long-term major adverse cardiovascular events (MACE) in patients with coronary artery disease (CAD) is controversial. No study specifically addressed patients with CAD and diabetes mellitus (DM).
Patients (n = 135, 30–80 years) referred for coronary angiography were submitted to clinical and laboratory evaluation, and the coronary angiograms were evaluated by two operators blinded to clinical characteristics. CAD was defined as the presence of a 70% stenosis in one major coronary artery, and DM was characterized as a fasting glycemia > 126 mg/dl or known diabetics (personal history of diabetes or previous use of anti-hyperglycemic drugs or insulin). Based on these criteria, study patients were classified into four groups: no DM and no CAD (controls, C n = 61), DM without CAD (D n = 23), CAD without DM (C-CAD n = 28), and CAD with DM (D-CAD n = 23). Baseline differences between the 4 groups were evaluated by the χ2 test for trend (categorical variables) and by ANOVA (continuous variables, post-hoc Tukey). Patients were then followed-up during two years for the occurrence of MACE (cardiac death, stroke, myocardial infarction or myocardial revascularization). The association of candidate variables with the occurrence of 2-year MACE was assessed by univariate analysis.
The mean age was 58.2 ± 0.9 years, and 51% were men. Patients with CAD had a higher mean age (p = 0.011) and a higher percentage were male (p = 0.040). There were no significant baseline differences between the 4 groups regarding hypertension, smoking status, blood pressure levels, lipid levels or inflammatory markers. TGF-β1 was similar between patients with or without CAD or DM (35.1 ×/÷ 1.3, 33.6 ×/÷ 1.6, 33.9 ×/÷ 1.4 and 31.8 ×/÷ 1.4 ng/ml in C, D, C-CAD and D-CAD, respectively, p = 0.547). In the 2-year follow-ip, independent predictors of 2-year MACE were age (p = 0.007), C-reactive protein (p = 0.048) and systolic blood pressure (p = 0.008), but not TGF-β1.
Serum TGF-β1 was not associated with CAD or MACE occurrence in patients with or without DM.
Plasma inflammatory markers have been shown to be predictors for cardiovascular risk, however, there is no study where the levels of plasma circulatory markers have been evaluated in coronary artery disease patients (CAD pts) positive for C. pneumoniae IgA and high sensitive C-reactive protein (hsCRP) which may help in better understanding of disease pathogenesis. A total of 192 patients and 192 controls attending the Cardiology Outpatient Department of Safdarjung Hospital were enrolled. The levels of plasma circulatory inflammatory markers were evaluated by ELISA. The levels of circulatory plasma markers (IL-4, IL-8, IL-13, ICAM-1, and VCAM-1) were significantly higher, whereas, levels of IL-10 and IFN-γ
were significantly lower in CAD pts compared to healthy controls. The levels of IL-4, IL-8, and ICAM-1 (P = .007, .015, and .048) were significantly higher, however, IL-10 and IFN-γ
were significantly lower (P < .001, < .001) in C. pneumoniae IgA positive CAD pts. The levels of IL-4, IL-8, IL-13, ICAM-1, and VCAM-1 were higher but not significant and levels of IL-10 and IFN-γ
were significantly (P < .001, < .001) lower in hsCRP positive CAD pts. Our study suggested that circulatory cytokines, namely, IL-4, IL-8, and adhesive molecules like ICAM-1 were enhanced after infection with C. pneumoniae whereas in contrast to this IL-10 and IFN-λ
were lowered. Suggesting the important role of these cytokines in progression of CAD.
Platelet-activating factor acetylhydrolase (PAF-AH) is a circulating enzyme that has an important role in the development of coronary artery disease (CAD). The correlations between PAF-AH and CAD are controversial. Furthermore, the differences of the enzyme levels between patients with stable and unstable CAD are not fully determined. The purpose of this study was to evaluate plasma PAF-AH levels and its association with the presence of CAD and some clinical risk factors in the patients.
This case-control study included 50 control subjects without CAD, 50 stable CAD patients and 50 unstable CAD patients with angiographically documented CAD. Plasma PAF-AH activity was determined by a commercial kit. The inflammatory markers, high sensitivity C-reactive protein (hsCRP) and oxidized low density lipoprotein (ox-LDL), and lipid profile were also measured. Comparisons of biochemical risk factors among all groups were performed by one way ANOVA. The association of PAF-AH activity with the presence of CAD was analyzed by multiple logistic regression.
Plasma PAF-AH activity levels were higher in unstable CAD patients (0.040 ± 0.012 μmol/min/ml) than in stable CAD patients (0.032 ± 0.010 μmol/min/ml) and control subjects (0.026 ± 0.009 μmol/min/ml) (p < 0.01). Plasma PAF-AH activity was also independently associated with the presence of CAD (p< 0.01).
Plasma PAF-AH activity levels were highly increased in unstable and stable CAD patients as compared to control subjects and may be a useful biomarker for CAD prediction.
Platelet-Activating Factor Acetylhydrolase; Stable Coronary Artery Disease; Unstable Coronary Artery Disease
The interplay between the novel adipokine retinol-binding protein-4 (RBP4) and coronary artery disease (CAD) is still obscure. We investigated the relationship between RBP4 levels and the presence and severity of angiographically proven CAD and determined its possible role in acute myocardial infarction (AMI).
305 individuals with angiographically proven CAD (CAD-patients), were classified into 2 subgroups: 1) acute myocardial infarction (AMI, n = 141), and 2) stable angina (SA, n = 164). Ninety-one age- and sex-matched individuals without CAD, but with at least 2 classical cardiovascular risk factors, served as controls (non-CAD group). RBP4 serum levels were measured at hospital admission and were analyzed in relation to the coronary severity stenosis, assessed by the Gensini-score and the number of coronary narrowed vessels. Other clinical parameters, including insulin levels, HOMA-IR, hsCRP, glycaemic and lipid profile, and left-ventricular ejection fraction were also assessed.
Serum RBP4 levels were significantly elevated in patients with CAD compared to non-CAD patients (39.29 ± 11.72 mg/L vs. 24.83 ± 11.27 mg/L, p < 0.001). We did not observe a significant difference in RBP4 levels between AMI and SA subgroups (p = 0.734). Logistic regression analysis revealed an independent association of CAD presence with serum RBP4 (β = 0.163, p = 0.006), and hsCRP (β = 0.122, p = 0.022) levels, in the whole study group. Among variables, hsCRP (β = 0.220), HDL (β = −0.150), and RBP4 (β = 0.297), correlated in both univariate and multivariate analysis with CAD severity (R2 = 0.422, p < 0.001). Similarly, RBP4 concentrations increased with the number of coronary narrowed vessels (p < 0.05).
Patients with CAD, both SA and AMI, showed elevated RBP4 serum levels. Notably, increased RBP4 concentration seemed to independently correlate with CAD severity, but no with AMI.
The ClinicalTrials.gov Identifier is: NCT00636766
Retinol-Binding Protein-4; Myocardial infarction; Coronary artery disease; Adipokines
Basic and clinical research provide evidence that inflammatory mechanisms play a central role in the pathogenesis and progression of atherosclerosis, plaque rupture, thrombosis, and stroke. Inflammatory biomarkers such as high-sensitivity C-reactive protein (hsCRP) have been identified as predictors of first stroke and prognosis after stroke. The value of hsCRP and other markers may depend on the characteristics of the study population; their utility may be less among populations with high vascular risk. A recent randomized clinical trial suggests that the use of rosuvastatin therapy in otherwise healthy patients with hsCRP > 2 mg/dl can reduce the risk of a first stroke by 50%. The prognostic role of hsCRP among patients after a stroke, however, is less clear, and other biomarkers, including lipoprotein-associated phospholipase A2, may provide complementary information about risk of stroke recurrence. Infections, moreover, may contribute to inflammation and stroke risk. While no single infectious organism is likely to be identified as the direct cause of atherosclerosis, summary measures of multiple chronic infectious exposures, or “infectious burden,” have been associated with risk of stroke and atherosclerosis affecting carotid arteries. Acute infections have also been found to serve as stroke triggers in epidemiological studies. Recommendations to vaccinate patients with cardiovascular disease against influenza represent the first specific anti-infective strategy to be employed in vascular prophylaxis. Further studies are needed to determine the role of treatment of inflammation and infection in stroke prevention.
atherosclerosis; inflammation; infection; infectious burden; statins; stroke; cerebral thrombosis; risk factors
In present day atherosclerosis is perceived as a chronic inflammatory vascular condition and infectious diseases are believed to contribute to its pathophysiology. In this context, the microorganisms which are believed to play a role in the pathophysiology include Chlamydia pneumoniae, cytomegalovirus (CMV), and Helicobacter pylori.
A case control study (retrospective) was conducted over a two-year period. The study population was divided into two groups with 200 individuals in each group. The first group comprised cases of coronary artery disease (CAD) and the second comprised healthy controls selected from the general population after matching for age and sex. Enzyme-linked immunosorbent assay (ELISA) was done for immunoglobulin (IgG) antibodies to H. pylori, C. pneumonia, and CMV. They were also evaluated for conventional risk factors including hypertension, diabetes, obesity, and dyslipidaemia. Epi Info™ version 6 six software was used for analysis of data. Odds ratio, χ2 for trend and multiple logistic regression analysis were used to find out statistically significant results.
Seropositivity for H. pylori was present in 119 patients of CAD (59.5%) but it was present in only 76 controls (38%) (P = 0.001). There was a statistically significant association between seropositivity for H. pylori and CAD. There was no statistically significant association between C. pneumoniae and CMV seropositivity with CAD. Multiple logistic regression analysis was done with CAD as the outcome (dependent variable). The predictor covariates (independent) variables were seropositivity to H. pylori, C. pneumoniae, and CMV, hypertension, obesity, diabetes, and dyslipidaemia. It was found that seropositivity to H. pylori, hypertension, obesity, and dyslipidaemia were significant risk factors for CAD.
Our study shows an association between IgG antibody response to H. pylori and CAD. Multiple logistic regression analysis showed that this association was retained even on comparison with the other risk factors.
Chlamydia pneumoniae; coronary artery disease; cytomegalovirus; Helicobacter pylori
More than a million diagnostic cardiac catheterizations are performed annually in the US for evaluation of coronary artery anatomy and the presence of atherosclerosis. Nearly half of these patients have no significant coronary lesions or do not require mechanical or surgical revascularization. Consequently, the ability to rule out clinically significant coronary artery disease (CAD) using low cost, low risk tests of serum biomarkers in even a small percentage of patients with normal coronary arteries could be highly beneficial.
Serum from 359 symptomatic subjects referred for catheterization was interrogated for proteins involved in atherogenesis, atherosclerosis, and plaque vulnerability. Coronary angiography classified 150 patients without flow-limiting CAD who did not require percutaneous intervention (PCI) while 209 required coronary revascularization (stents, angioplasty, or coronary artery bypass graft surgery). Continuous variables were compared across the two patient groups for each analyte including calculation of false discovery rate (FDR ≤ 1%) and Q value (P value for statistical significance adjusted to ≤ 0.01).
Significant differences were detected in circulating proteins from patients requiring revascularization including increased apolipoprotein B100 (APO-B100), C-reactive protein (CRP), fibrinogen, vascular cell adhesion molecule 1 (VCAM-1), myeloperoxidase (MPO), resistin, osteopontin, interleukin (IL)-1β, IL-6, IL-10 and N-terminal fragment protein precursor brain natriuretic peptide (NT-pBNP) and decreased apolipoprotein A1 (APO-A1). Biomarker classification signatures comprising up to 5 analytes were identified using a tunable scoring function trained against 239 samples and validated with 120 additional samples. A total of 14 overlapping signatures classified patients without significant coronary disease (38% to 59% specificity) while maintaining 95% sensitivity for patients requiring revascularization. Osteopontin (14 times) and resistin (10 times) were most frequently represented among these diagnostic signatures. The most efficacious protein signature in validation studies comprised osteopontin (OPN), resistin, matrix metalloproteinase 7 (MMP7) and interferon γ (IFNγ) as a four-marker panel while the addition of either CRP or adiponectin (ACRP-30) yielded comparable results in five protein signatures.
Proteins in the serum of CAD patients predominantly reflected (1) a positive acute phase, inflammatory response and (2) alterations in lipid metabolism, transport, peroxidation and accumulation. There were surprisingly few indicators of growth factor activation or extracellular matrix remodeling in the serum of CAD patients except for elevated OPN. These data suggest that many symptomatic patients without significant CAD could be identified by a targeted multiplex serum protein test without cardiac catheterization thereby eliminating exposure to ionizing radiation and decreasing the economic burden of angiographic testing for these patients.
atherosclerosis; biomarkers; cardiac catheterization; coronary angiography; coronary stenosis; multiplex proteomics
Cardiovascular (CV) risk markers, including high-sensitivity C-reactive protein (hsCRP), are increasingly important in predicting cardiac events. A favorable CV risk profile might be expected in anorexia nervosa (AN) due to low body weight and dietary fat intake. However, women with AN have decreased IGF-I levels reflecting decreased GH action, and IGF-I deficiency is associated with elevated hsCRP. Moreover, oral estrogens, known to increase hsCRP in other populations, are commonly prescribed in AN. To date, hsCRP levels and their physiological determinants have not been reported in women with AN.
We examined the relationship between CV risk markers, undernutrition, IGF-I, and oral estrogens, specifically hypothesizing that in the setting of undernutrition, AN would be associated with low hsCRP despite low IGF-I levels and that those women taking oral contraceptive pills (OCPs) would have higher hsCRP and lower IGF-I levels.
Design and Setting
We conducted a cross-sectional study at a clinical research center.
Subjects included 181 women: 140 women with AN [85 not receiving OCPs (AN-E) and 55 receiving OCPs (AN+E)] and 41 healthy controls [28 not receiving OCPs (HC-E) and 13 receiving OCPs (HC+E)].
Main Outcome Measures
We assessed hsCRP, IL-6, IGF-I, low-density lipoprotein (LDL), and high-density lipoprotein (HDL).
Despite low weight, more than 20% of AN+E had high-risk hsCRP levels. AN+E had higher hsCRP than AN-E. AN-E had lower mean hsCRP levels than healthy controls (HC+E and HC-E). IL-6 levels were higher in AN+E with elevated hsCRP (>3 mg/liter) than in AN+E with normal hsCRP levels. IGF-I was inversely associated with hsCRP in healthy women, suggesting a protective effect of GH on CV risk. However, this was not seen in AN. Few patients in any group had high-risk LDL or HDL levels.
Although hsCRP levels are lower in AN than healthy controls, OCP use puts such women at a greater than 20% chance of having hsCRP in the high-CV-risk (>3 mg/liter) category. The elevated mean IL-6 in women with AN and high-risk hsCRP levels suggests that increased systemic inflammation may underlie the hsCRP elevation in these patients. Although OCP use in AN was associated with slightly lower mean LDL and higher mean HDL, means were within the normal range, and few patients in any group had high-risk LDL or HDL levels. IGF-I levels appear to be important determinants of hsCRP in healthy young women. In contrast, IGF-I does not appear to mediate hsCRP levels in AN.
Apolipoprotein E (apoE) has been implicated as conveying increased risk for coronary artery disease (CAD). Previous studies suggest a role of apoE as a modulator of immune response and inflammatory properties. We hypothesized that the presence of apo E4 is associated with an increased inflammatory burden in subjects with CAD as compared to subjects without CAD.
ApoE genotypes, systemic (C-reactive protein [CRP], fibrinogen, serum amyloid-A [SAA]) and vascular inflammatory markers (Lipoprotein-associated phospholipase A2 [Lp-PLA2] and pentraxin-3 [PTX-3]) were assessed in 324 Caucasians and 208 African Americans, undergoing coronary angiography.
For both ethnic groups, Lp-PLA2 index, an integrated measure of Lp-PLA2 mass and activity, increased significantly and stepwise across apoE isoforms (P=0.009 and P=0.026 for African Americans and Caucasians respectively). No differences were found for other inflammatory markers tested (CRP, fibrinogen, SAA and PTX-3). For the top cardiovascular score tertile, apo E4 carriers had a significantly higher level of Lp-PLA2 index in both ethnic groups (P=0.027 and P=0.010, respectively).
The presence of the apo E4 isoform was associated with a higher level of Lp-PLA2 index, a marker of vascular inflammation. Our results suggest that genetic variation at the apoE locus may impact cardiovascular disease risk through enhanced vascular inflammation.
ApoE genotype; inflammation; coronary artery disease; ethnicity
Inflammatory markers such as high-sensitivity C-reactive protein (hsCRP) are associated with an increased risk of cardiovascular events and with the severity of peripheral arterial disease. The effects of inflammation on the development of vein graft disease remain speculative. We hypothesized that high levels of inflammatory markers would identify patients at increased risk for adverse events (graft failure, major cardiovascular events) after lower extremity bypass surgery.
Patients (n = 91) scheduled to undergo lower extremity bypass using autogenous vein were enrolled into a prospective study at two institutions. Exclusion criteria included the presence of major infection. A baseline plasma sample was obtained on the morning of lower extremity bypass. Biomarkers for inflammation included hsCRP, fibrinogen, and serum amyloid A (SAA). Values between patients with and without critical limb ischemia were compared. Proportions of events among dichotomized populations (upper limit of normal of each laboratory assay) were compared by log-rank test.
Of the patients undergoing lower extremity bypass, 69% were men, 53% were diabetic, 81% were smokers, and their mean ankle-brachial index was 0.51 ± 0.19. The indication for lower extremity bypass was critical limb ischemia in 55%. There were no perioperative deaths and two early graft occlusions. During a mean follow-up of 342 days (range, 36–694 days) there were four deaths, 27 graft-related events, and 10 other cardiovascular events. No relationships were found between events and demographics, comorbidities, baseline ankle-brachial index, or statin use. High-sensitivity CRP (P = .005), fibrinogen (P < .001), and SAA (P = .0001) levels were associated with critical limb ischemia at presentation. Among patients with an elevated hsCRP (>5 mg/L) immediately before surgery, major postoperative vascular events occurred in 60% (21/35), compared with a 32% (18/56) rate in those with a baseline CRP <5 mg/L (P = .004, log-rank test). On multivariable analysis, only elevated hsCRP correlated with adverse graft-related or cardiovascular events (P = .018).
The inflammatory biomarkers of hsCRP, fibrinogen, and SAA correlate with peripheral arterial disease severity at presentation in patients undergoing lower extremity bypass. Patients with elevated hsCRP are at increased risk for postoperative vascular events, most of which are related to the vein graft. These findings suggest a potential relationship between inflammation and outcomes after lower extremity vein bypass surgery.
The role of inflammation in atherosclerosis is widely appreciated. High mobility group box 1 (HMGB1), an injury-associated molecular pattern molecule acting as a mediator of inflammation, has recently been implicated in the development of atherosclerosis. In this study, we sought to investigate the association of plasma HMGB1 with coronary plaque composition in patients with suspected or known coronary artery disease (CAD).
HMGB1, high sensitive troponin T (hsTnT) and high sensitive C-reactive protein (hsCRP) were determined in 152 consecutive patients with suspected or known stable CAD who underwent clinically indicated 256-slice coronary computed tomography angiography (CCTA). Using CCTA, we assessed 1) coronary calcification, 2) non-calcified plaque burden and 3) the presence of vascular remodeling in areas of non-calcified plaques.
Using univariate analysis, hsCRP, hsTnT and HMGB1 as well as age, and atherogenic risk factors were associated with non-calcified plaque burden (r = 0.21, p = 0.009; r = 0.48, p<0.001 and r = 0.34, p<0.001, respectively). By multivariate analysis, hsTnT and HMGB1 remained independent predictors of the non-calcified plaque burden (r = 0.48, p<0.01 and r = 0.34, p<0.001, respectively), whereas a non-significant trend was noticed for hs-CRP (r = 0.21, p = 0.07). By combining hsTnT and HMGB1, a high positive predictive value for the presence of non-calcified and remodeled plaque (96% and 77%, respectively) was noted in patients within the upper tertiles for both biomarkers, which surpassed the positive predictive value of each marker separately.
In addition to hs-TnT, a well-established cardiovascular risk marker, HMGB1 is independently associated with non-calcified plaque burden in patients with stable CAD, while the predictive value of hs-CRP is lower. Complementary value was observed for hs-TnT and HMGB1 for the prediction of complex coronary plaque.
Inflammation, as measured by the circulating inflammatory marker high sensitivity C-reactive protein (hsCRP), has been associated with cardiovascular disease. However, data regarding CRP and risk of colorectal cancer have been conflicting. The Adenoma Prevention with Celecoxib (APC) trial demonstrated that the anti-inflammatory drug celecoxib prevents recurrence of colorectal adenoma but increases risk of cardiovascular events. We examined if serum hsCRP modified these results.
We measured hsCRP from serum specimens provided at study entry by patients enrolled in the APC trial. Patients were stratified according to use of low-dose aspirin, randomized to receive three years of treatment with placebo, 200-mg-bid celecoxib, or 400-mg-bid celecoxib, and underwent follow-up colonoscopies at Year 1 and 3.
Among 1,680 patients, the estimated three-year cumulative incidence of adenoma was 42% for patients with hsCRP <1mg/L, compared with 43% (RR=1.02; 95% confidence interval (CI)=0.85–1.22) for hsCRP 1–3mg/L, and 41% (RR=1.1; CI=0.90–1.34) for hsCRP >3mg/L. The effect of celecoxib on adenoma recurrence did not vary among patients with high (>3mg/L) compared with low (≦3mg/L) hsCRP. However, among patients with high hsCRP, the RR of cardiovascular events compared with placebo was 2.27 (95%CI=0.72–7.14) for those randomized to celecoxib 200-mg-bid and 3.28 (CI=1.09–9.91) for 400-mg-bid. In contrast, among patients with low hsCRP, the corresponding RRs were 0.99 (CI=0.53–1.83) and 1.11 (CI=0.61–2.02).
HsCRP may predict risk of celecoxib-associated cardiovascular toxicity, but not adenoma recurrence or celecoxib treatment efficacy. Patients with low hsCRP may be a subgroup with a favorable risk-benefit profile for celecoxib chemoprevention.
Adenoma; celecoxib; c-reactive protein; inflammation; chemoprevention
It was reported that C-reactive protein (CRP) levels increase in parallel with the progression of chronic liver diseases, such as chronic hepatitis and liver cirrhosis. Inflammatory markers, such as high sensitive C-reactive protein (hsCRP), ferritin, transferrin, albumin, alpha-1 acid glycoprotein (AAG), alpha-2 macroglobulin (AMG), alpha-1 anti-trypsin (AAT) and lipoprotein a [Lp(a)] were measured in coronary artery disease patients (CAD) and CAD patients with non-alcoholic steatohepatitis (NASH). In the present preliminary study an attempt was made to study whether there is an increase in the levels of CRP in CAD patients associated with NASH. CAD patients showed an increase in CRP and serum ferritin levels. In CAD patients with NASH along with an increase in the levels of serum ferittin (p<0.001), the levels of serum AMG and ceruloplasmin (CP) were also increased (p<0.01). The CAD patients with NASH had a higher proportion of diabetes, hypertension and dyslipidaemia compared to CAD patients. But how this difference contributes to the elevation in acute inflammatory markers particularly AMG and CP levels in CAD patients with NASH cannot be explained. This study shows that a substantial number of CAD patients may be associated with NASH. Non-invasive simple parameters that reflect the degree of inflammation and fibrosis of the liver in patients with NASH would facilitate improved understanding and treatment of the disease. Further studies may be necessary to evaluate the percentage of NASH patients progressing to CAD.
C-reactive protein; alpha-1 acid glycoprotein; alpha 2 macroglobulin; alpha 1 anti trypsin; lipoprotein a; coronary artery disease; non-alcoholic steatohepatitis
High-sensitivity C-reactive protein (hsCRP) has been previously linked to different forms of vascular disease. However, some studies have not found any relationship between hsCRP and atherosclerosis. Also, studies investigating correlation between hsCRP and ankle brachial index (ABI) are scarce. We studied hsCRP in a cardiovascular risk population with a special interest in correlation between hsCRP and ABI. All men and women aged 45 to 70 years from a rural town Harjavalta, Finland were invited to participate in a population survey. Diabetics and people with known vascular disease were excluded. Seventy-three percent (n = 2085) of the invited persons participated and 70% of the respondents (n = 1496) had at least one risk factor to cardiovascular diseases. These subjects were invited to further examinations. From them we measured ABI, hsCRP, leukocyte count, glucose tolerance, systemic coronary risk evaluation (SCORE), body mass index (BMI), and waist circumference. Mean hsCRP was 1.9 mg/L. Smokers had higher hsCRP (mean 2.2 mg/L) than nonsmokers (mean 1.8 mL/L). hsCRP in women was higher than in men (mean 2.0 mg/L versus 1.8 mg/L). Mean ABI was 1.10, and the prevalence of peripheral arterial disease was 3.1%. ABI correlated weakly with hsCRP (r = −0.077, p = 0.014), leukocyte count (r = −0.107, p = 0.001), and SCORE (r = −0.116, p = 0.001). It did not have correlation between age, weight, BMI, or waist circumference. hsCRP correlated with BMI (r = 0.208, p < 0.0001) and waist circumference (r = 0.325, p < 0.0001). When we excluded subjects with hsCRP >10 mg/L, ABI no longer correlated with hsCRP. In a cardiovascular risk population, hsCRP has only a weak correlation with ABI, and this correlation disappeared when we excluded subject with hsCRP >10 mg/L. Instead, hsCRP was correlated to the measures of obesity (waist circumference and BMI), indicating its role as a marker of adipose tissue–driven inflammation. hsCRP does not seem to be a suitable screening method for peripheral arterial disease.
High sensitivity C-reactive protein; ankle brachial index; cardiovascular risk factors
Abacavir (ABC) treatment has been associated with an increased incidence of myocardial infarction. The pathophysiological mechanism is unknown. In this study markers of inflammation and coagulation in HIV-infected patients using antiretroviral therapy with or without ABC were examined to pinpoint a pathogenic mechanism. Given the important role of high sensitivity C-reactive protein (hsCRP) levels in predicting cardiovascular risk, patient groups were also analyzed according to hsCRP levels.
Patients treated with ABC and a matched control group treated without ABC were selected retrospectively. Vascular endothelial growth factor (VEGF) and markers of endothelial cell activation (von Willebrand factor (vWF), factor VIII), fibrin formation (fibrinogen, D-dimer, prothrombin fragment 1+2 (F1+2), endogenous thrombin potential (ETP)), anticoagulation markers (protein C and S, activated protein C sensitivity ratio (APCsr)) and inflammation markers (IL-6, hsCRP) were measured in citrated plasma.
A total of 81 patients were included of whom 27 patients used an ABC-containing regimen and 54 used a non-ABC-containing regimen. Patient characteristics were not significantly different between the groups except for longer duration of use of the current antiretroviral regimen in the ABC group (p = 0.01). The median time on ABC was 68 months (interquartile range 59-80 months). No differences in coagulation and inflammation markers according to ABC use were observed. For the whole patient group elevated vWF and F1+2 levels were observed in 23% and 37%, respectively. Compared to the reference ranges for the general population increased APCsr was found in 79% and lower protein C and VEGF levels in 40% and 43%, respectively. Patients in the high-risk category for cardiovascular disease with hsCRP levels > 3 mg/L had significantly higher fibrinogen, D-dimer, F1+2 and ETP levels compared to patients from the low-risk category with hsCRP levels < 1 mg/L.
HIV-infected patients using ABC showed no specific abnormalities in coagulation or inflammation markers that might explain the increased risk of myocardial infarction. For the whole group, regardless of ABC use, evidence of a prothrombotic state was observed. Thirty-three percent of patients with long-term use of antiretroviral treatment had hsCRP levels above 3 mg/L, which is strongly associated with cardiovascular disease in HIV-uninfected individuals.
C-reactive protein (CRP) may play an anti-inflammatory role during the acute phase of inflammation, and is also used as a marker of inflammation associated with cardiovascular disease. In the present study, we investigated the association between high-sensitivity CRP (hsCRP) and systemic lupus erythematosus (SLE) manifestations, autoantibodies, and organ damage.
In this cross-sectional study, 610 SLE patients from a prospective cohort had more than one hsCRP measurement. Organ damage was assessed using the Systemic Lupus International Collaborating Clinics (SLICC)/American College of Rheumatology (ACR) Damage Index. Multiple linear regression models were used to adjust for age, gender, ethnicity, disease duration, body mass index, education, disease activity, current prednisone dose, statin use, and estrogen use.
After adjusting for confounders, hsCRP was associated with myocarditis, cardiac murmur, interstitial pulmonary fibrosis, pulmonary hypertension, gastrointestinal lupus manifestations, and anemia. Anti-dsDNA antibodies and lupus anticoagulant were associated with hsCRP in unadjusted models, and these associations remained significant after adjustment for confounders. hsCRP levels were significantly higher in patients with pulmonary, musculoskeletal, and endocrine damage, and a total SLICC Damage Index score ≥1. After adjustment, hsCRP was associated with pulmonary, musculoskeletal, and total damage, but no longer with endocrine damage.
hsCRP is associated with a broad range of clinical features and organ damage in SLE, particularly in the pulmonary and musculoskeletal systems. This association holds true independent of sociodemographic, disease activity, and treatment factors, and may be useful to identify high-risk SLE patients who would benefit from additional screening and surveillance studies.
Cardiovascular risk factors; C-reactive protein; systemic lupus erythematosus; inflammation
This multisite prospective trial, Stress Echocardiography in Menopausal Women At Risk for Coronary Artery Disease (SMART), aimed to evaluate the prognostic value of contrast stress echocardiography (CSE), coronary artery calcification (CAC), and cardiac biomarkers for prediction of cardiovascular events after 2 and 5 years in early menopausal women experiencing chest pain symptoms or risk factors. This report describes the study design, population, and initial test results at study entry.
From January 2004 through September 2007, 366 early menopausal women (age 54±5 years, Framingham risk score 6.51%±4.4 %, range 1%–27%) referred for stress echocardiography were prospectively enrolled. Image quality was enhanced with an ultrasound contrast agent. Tests for cardiac biomarkers [high-sensitivity C-reactive protein (hsCRP), atrial natriuretic protein (ANP), brain natriuretic protein (BNP), endothelin (ET-1)] and cardiac computed tomography (CT) for CAC were performed.
CSE (76% exercise, 24% dobutamine) was abnormal in 42 women (11.5%), and stress electrocardiogram (ECG) was positive in 22 women (6%). Rest BNP correlated weakly with stress wall motion score index (WMSI) (r=0.189, p<0.001). Neither hsCRP, ANP, endothelin, nor CAC correlated with stress WMSI. Predictors of abnormal CSE were body mass index (BMI), diabetes mellitus, family history of premature coronary artery disease (CAD), and positive stress ECG. Twenty-four women underwent clinically indicated coronary angiography (CA); 5 had obstructive (≥50%), 15 had nonobstructive (10%–49%), and 4 had no epicardial CAD.
The SMART trial is designed to assess the prognostic value of CSE in early menopausal women. Independent predictors of positive CSE were BMI, diabetes mellitus, family history of premature CAD, and positive stress ECG. CAC scores and biomarkers (with the exception of rest BNP) were not correlated with CSE results. We await the follow-up data.