Oxidized low-density lipoprotein, iron stores, and haptoglobin polymorphism

BACKGROUND: In vitro experimental studies demonstrated that iron promotes free radical-induced low-density lipoprotein (LDL) oxidation. OBJECTIVE: To test the hypothesis that circulating oxidized LDL (oxLDL) levels might be associated with body iron stores (serum ferritin) and iron-related genetic markers (hemochromatosis gene C282Y mutation, haptoglobin polymorphism). METHODS: We investigated 381 (176 males, 205 females, age 45 +/- 6 years) healthy Caucasians. Serum oxLDL, assayed by a mAb-4E6-based enzyme-linked immunosorbent assay (ELISA), was expressed as oxLDL/LDL ratio to adjust for serum LDL-cholesterol concentration. Hemochromatosis gene C282Y mutation analysis was performed by a Taqman-based polymerase chain reaction (PCR) assay. Haptoglobin (Hp) phenotypes (Hp 1-1, Hp 2-1, Hp 2-2) were determined by starch gel electrophoresis. RESULTS: In stepwise multivariate regression analysis, gender (P < 0.0001), current smoking (P < 0.0001), HDL-cholesterol (P = 0.0001), ferritin (P = 0.0051), body mass index (BMI) (P = 0.0063), and Hp phenotype (P = 0.0331) independently predicted oxLDL/LDL ratio in the total group. In men, smoking (P < 0.0001), ferritin (P = 0.0052), Hp phenotype (P = 0.0063), and HDL-cholesterol (P = 0.0127) were independent determinants of oxLDL/LDL ratio. In women, only body mass index (P < 0.0001), HDL-cholesterol (P = 0.0005), and smoking (P = 0.0025) were significantly associated with oxLDL/LDL ratio. The C282Y mutation (wild-type versus C282Y heterozygotes) was not associated with oxLDL/LDL ratio in both sexes. CONCLUSION: Serum ferritin concentration and Hp polymorphism are independently associated with circulating oxLDL levels in males.     

The etiology of 'smoker's paradox' in acute myocardial infarction with special emphasis on the association with inflammation

Despite increased risk for coronary artery disease and acute myocardial infarction (AMI), prior studies have found that smokers with AMI have lower mortality rates than nonsmokers, a phenomenon often termed 'smoker's paradox'. The present study was designed to examine the etiology of 'smoker's paradox', especially with respect to the association with inflammation. The subjects included 528 consecutive AMI patients who were admitted within 24 hours of onset and underwent successful coronary intervention. Of the 528 subjects, 232 (44%) were smokers. The cardiac mortality rates over a 6 month period was significantly lower in the smoking group than the nonsmoking group (3% versus 9%, P = 0.01). There were significantly more male patients in the smoking group, and the smoking group was significantly younger than the nonsmoking group (P < 0.0001). The value of high sensitivity C-reactive protein (hs-CRP) on admission and 24 hours after onset, and serum amyloid A protein (SAA) were significantly higher, and acute phase BNP was significantly lower (hs-CRP on admission 1.36 +/- 1.03 mg/dL versus 0.75 +/- 0.82 mg/dL, P = 0.02, hs-CRP at 24 hours 3.86 +/- 4.32 mg/dL versus 2.90 +/- 3.46 mg/dL, P = 0.008, SAA; 288 +/- 392 microg/dL versus 176 +/- 206 microg/dL, P < 0.05, BNP; 248 +/- 342 pg/mL versus 444 +/- 496 pg/mL, P = 0.0002) in the smoking group than in the nonsmoking group. The early ST-segment resolution rate was higher in the smoking group compared with the nonsmoking group (80% versus 66%, P = 0.003). The reason why smokers with AMI have lower mortality rates than nonsmokers, the so-called 'smoker's paradox', is believed to be because smoking induces inflammation and smokers may have less damage to microvascular function after primary percutaneous coronary intervention.     

Incidence, clinical findings, and outcome of women with left ventricular apical ballooning syndrome

Left ventricular apical ballooning syndrome (LVABS) is a clinical condition that may mimic ST-elevation acute myocardial infarction (AMI). To assess incidence, clinical findings, and outcome of white women with LVABS, we reviewed 305 consecutive women with chest pain and anterior ST-elevation AMI referred for potential mechanical revascularization; 36 (12%) patients met the diagnostic criteria for LVABS and were compared with the remaining 269 women with angiographic evidence of coronary artery disease (CAD). Patients with LVABS showed a lower incidence of diabetes mellitus (5% vs 21%, p = 0.023), a higher rate of antecedent stressful events (26% vs 3%, p <0.0001), and a higher heart rate at admission (91 +/- 20 vs 82 +/- 19, p = 0.018) than women with CAD. Urgent angiography showed no significant CAD in patients with LVABS and an average of 1.6 +/- 0.7 diseased coronary arteries (>50% stenosis) in the 269 control women (p = 0.0001). Peak creatine kinase-MB value was lower in patients with LVABS (21 +/- 26 mU/ml) than in women with CAD (307 +/- 302 mU/ml, p = 0.0001). The only independent predictors of LVABS among women with anterior AMI were peak creatine kinase-MB value (p = 0.0001) and the presence of an antecedent stressful event (p = 0.001). LV systolic function at admission was similar between women with LVABS and those with CAD (echocardiographic ejection fraction 35.6 +/- 8.4% vs 35.5 +/- 8.0%, p = 0.944) but was significantly different at discharge (ejection fraction 50.1 +/- 9.6% vs 45.2 +/- 13.5%, p = 0.021). Moreover, at 6-month follow-up, women with LVABS showed a better survival rate (97% vs 86%, p = 0.055) and freedom from major cardiac events (death, reinfarction, or rehospitalization 92% vs 69%, p = 0.001) than women with CAD. In conclusion, few women presenting with clinical features of anterior AMI have LVABS. Despite a favorable outcome, LVABS should be considered in the differential diagnosis of women with chest pain and ST-segment elevation in the precordial leads. Peak creatine kinase-MB value and the presence of an antecedent stressful event are strong predictors of LVABS in women with anterior AMI.     

Lipoprotein(a), apolipoprotein(a) polymorphism and coronary atherosclerosis severity in type 2 diabetic patients

BACKGROUND: Few and conflicting data are available in the literature on the association between Lp(a) levels and the severity of coronary artery disease (CAD) in diabetic patients. In addition, no studies took into account the role of apo(a) polymorphism. The purpose of the present study was to analyse the association of the degree of coronary atherosclerosis with Lp(a) levels and apo(a) polymorphism in a large group of type 2 diabetic patients. METHODS: The study population consisted of 227 consecutive type 2 diabetic patients undergoing a routine coronary angiography to evaluate chest pain or suspected CAD. The patients were subdivided into four subgroups according to the number of coronary arteries diseased: normal arteries (n=26), mono-vessel disease (n=67), bi-vessel disease (n=54) and multi-vessel disease (n=80). RESULTS: Lp(a) levels (normal arteries: 14.6+/-19.6 mg/dl; mono-vessel disease: 19.0+/-16.4 mg/dl; bi-vessel disease: 19.3+/-15.1 mg/dl; multi-vessel disease: 26.5+/-16.8 mg/dl; p<0.001) and the percentages of patients with at least one isoform of low molecular weight (normal arteries: 23.1%; mono-vessel disease: 38.8%; bi-vessel disease: 75.9%; multi-vessel disease: 81.2%; p<0.001) were significantly correlated with increasing number of coronary vessels diseased. Multiple logistic regression analysis showed that both Lp(a) levels (OR: 1.31; 95% CI: 1.02-4.11) and apo(a) polymorphism (OR: 3.43; 95% CI: 1.67-7.05) were independent predictors of CAD severity. CONCLUSIONS: Our data suggest that Lp(a) levels and apo(a) polymorphism may be reliable predictors of CAD severity in type 2 diabetic patients.     

C-reactive protein and coronary artery disease

Evidence suggests that inflammation plays a key role in the pathogenesis of atherosclerosis. The chronic inflammatory process can develop to an acute clinical event by the induction of plaque rupture and therefore cause acute coronary syndromes. The aim of this study was to determine the serum levels of the circulating acute-phase reactant C-reactive protein (CRP), which is a sensitive indicator of inflammation, in patients with chronic stable coronary artery disease (CAD) and acute coronary syndromes (ACS). We studied 56 subjects: 1) 25 consecutive patients (18 men, 7 women; mean age, 68.5 +/- 14.3 years, range, 40-86) with unstable angina (UA) or acute myocardial infarction (AMI); 2) 31 consecutive patients (25 men, 6 women; mean age 64 +/- 12.7; range, 47-83, years) with signs and symptoms of clinically stable CAD. High-sensitivity-C-reactive protein (hs-CRP) levels were determined with a commercially available enzyme-linked immunoassay method. In patients with unstable angina and AMI before reperfusion therapy, CRP levels were not significantly different to those in patients with stable CAD (5.96 +/- 2.26 versus 4.35 +/- 2.6 mg/L; P = 0.12), but tended to be higher in patients with unstable angina and AMI. Baseline CRP levels in the subgroup of patients with AMI (6.49 +/- 2.28 mg/L) were significantly higher than levels in patients with stable CAD (4.35 +/- 2.6 mg/L; P = 0.02). CRP levels in patients with unstable angina and AMI were measured four times during a 72-hour period (0, 12, 24, and 72 hours). The lowest value was observed at baseline and differed significantly from values measured at any other time of the observation period (P < 0.001; 5.96 +/- 2.26; 9.5 +/- 9.04, 18.25 +/- 11.02; 20.25 +/- 10.61). CRP levels after 12, 24, and 72 hours were also significantly different to the initial values for patients with stable CAD (P < 0.01). There was no correlation between CRP and creatine kinase (CK), CK-MB isoenzyme, or troponin I positivity as markers for the extent of the myocardial injury during the observation period. Baseline levels of serum CRP tended to be higher in patients with unstable angina or AMI but were not significantly different from levels in patients with chronic stable CAD. In the subgroup of patients with AMI, baseline CRP levels were significantly higher than the levels in patients with stable CAD. CRP as a marker of inflammation is significantly increased in patients with AMI and unstable angina shortly after the onset of symptoms (after a period of 12 hours), supporting the hypothesis of an activation of inflammatory mechanisms in patients with an acute coronary syndrome or AMI.     

South-to-North gradient in lipid peroxidation in men with stable coronary artery disease in Europe.

AIMS: A South-to-North gradient across Europe exists for the incidence of coronary artery disease (CAD) rates. Low-density lipoprotein (LDL) oxidation is a hallmark of atherosclerosis and CAD development. The aim of our study was to determine whether differences exist in the degree of LDL oxidation in stable CAD patients from different regions of Europe. METHODS AND RESULTS: A cross-sectional multicentre study included 790 stable CAD male subjects aged 35-79 years (61.4 +/- 9.5) from six European countries in three regions by latitude: Northern (Finland and Sweden), Central (Germany), and Southern (Greece, Spain, and Italy). Plasma oxidized LDL (oxLDL) levels were determined. Alcohol intake and lipid profile were significantly associated with oxLDL. The Italian participants had the highest oxLDL levels. A sensitivity analysis showed the models yielded higher adjusted oxLDL values in Northern (63.8 U/L) than in Central (57.6 U/L) and Southern populations (56.5 U/L), P < 0.001, after excluding Italian subjects. The probability of Southern Europe scoring the lowest oxLDL levels was >71% in all fitted models. CONCLUSION: Our findings suggest a gradient in LDL oxidation from Southern to Northern Europe that consistently holds for all levels of LDL, except for Italy; this country displays the highest levels in Europe, for unknown reasons.     

Diabetes mellitus has an additional effect on coronary artery disease

We investigated whether plasma levels of adiponectin in patients with both coronary artery disease (CAD) and diabetes mellitus (DM) are lower than in patients with CAD alone. We examined plasma adiponectin levels in 113 patients, 82 with CAD (40 of whom had both CAD and type 2 DM) and 31 normal controls. We found differences in plasma adiponectin levels between CAD patients with and without DM (7.8 +/- 4.75 versus 12.1 +/- 6.87 microg/mL, P = 0.002), between patients with CAD and controls (10.0 +/- 6.27 versus 15.3 +/- 5.38 microg/mL, P < 0.0001), and between men and women (10.2 +/- 6.41 versus 13.1 +/- 6.22 microg/mL, P = 0.017). Plasma adiponectin levels were correlated negatively with body mass index, triglyceride, total cholesterol, hemoglobin A1c, and fibrinogen levels (r = -0.456, P < 0.0001; r = -0.355, P < 0.0001; r = -0.286, P = 0.002; r = -0.299, P < 0.0001; r = -0.400, P < 0.0001, respectively), but were not significantly correlated with high sensitivity C-reactive protein or low density lipoprotein levels (r = -0.088, P = 0.352; r = -0.167, P = 0.077, respectively). Plasma adiponectin levels correlated positively with high density lipoprotein levels (r = 0.410, P < 0.0001). Our study demonstrates that plasma adiponectin levels in patients with both CAD and DM are lower than in patients with CAD alone. We speculate that people who have very low plasma adiponectin levels may be at increased risk of developing both CAD and DM.     

Clinical evaluation of coronary lesion characteristics in acute myocardial infarction

Coronary lesion instability at the onset of acute myocardial infarction (AMI) was evaluated. The mechanism of AMI has been considered to be coronary lesion instability with occlusive thrombus, although more than one half of AMI occurs in clinically stable patients. A total of 313 AMI patients treated by primary percutaneous transluminal coronary angioplasty with provisional stenting (rate, 41%) were studied. They were divided into 2 groups: group 1A (n = 211), without unstable angina before AMI onset, and group 1B (n = 102), with unstable angina before onset. Moreover, angina patients treated similarly were studied: group 2A (n = 180), with stable angina, and group 2B (n = 204), with unstable angina. Coronary lesion instability at AMI onset was also predicted by C-reactive protein (CRP) levels within 6 hours after onset, before they were affected by myocardial damage. The incidence of repeated AMI and/or target vessel revascularization was 1.9% in group 1A, 7.8% in 1B (p=0.035), 1.7% in 2A, and 5.9% in 2B (p=0.043). Event-free survival curves were consistent with each other in groups 1A and 2A and in groups 1B and 2B. CRP levels on admission were 2.0 +/- 1.7 mg/L in group 1A, 3.3 +/- 4.8 mg/L in group 1B (p<0.001), 2.1 +/- 1.7 mg/L in group 2A, and 3.4 +/- 4.7 mg/L in group 2B (p<0.001). Thus coronary lesion characteristics at AMI onset appeared to be similar in groups 1A and 2A and in groups 1B and 2B. A substantial number of patients have stable culprit lesions at the onset of AMI.     

Oxidative stress and the mitochondrial theory of aging in human skeletal muscle

According to the mitochondrial theory of aging, an age-related increase in oxidative stress is responsible for cellular damage and ultimately cell death. Despite compelling evidence that supports the mitochondrial theory of aging in some tissues, data regarding aging skeletal muscle are inconsistent. We collected resting muscle biopsies from the vastus lateralis, and 24 h urine samples from, young (N = 12, approximately 22 yr), and older (N = 12 approximately 72 yr) men. Urinary 8-OHdG was significantly higher in older as compared to younger men (Old: 7714 +/- 1402, Young: 5333 +/- 1191 ng g(-1) creatinine: p = 0.005), as were levels of protein carbonyls (Old: 0.72 +/- 0.42, Young: 0.26 +/- 0.14 nmol mg(-1) protein: p = 0.007). MnSOD activity (Old: 7.1 +/- 0.8, Young: 5.2 +/- 1.8 U mg(-1) protein: p = 0.04) and catalase activity (Old: 8.5 +/- 2.0, Young: 6.2 +/- 2.4 micro mol min(-1) mg(-1) protein: p = 0.03) were significantly higher in old as compared to young men, respectively, with no differences observed for total or CuZnSOD. Full-length mtDNA appeared lower in old as compared to young men, and mtDNA deletions were present in 6/8 old and 0/6 young men (p = 0.003). The maximal activities of citrate synthase, and complex II+III, and IV were not different between young and old men, however, complex I+III activity was marginally higher in older as compared to younger men (Old: 2.5 +/- 0.5, Young: 1.9 +/- 0.5 micromol min(-1) g(-1) w.w: p = 0.03) respectively. In conclusion, healthy aging is associated with oxidative damage to proteins and DNA, a compensatory up-regulation of antioxidant enzymes, and aberrations of mtDNA, with no reduction in electron transport chain maximal enzyme activity.     

C-Reactive protein as a risk factor for left ventricular thrombus in patients with acute myocardial infarction

BACKGROUND: Elevated C-reactive protein (CRP) has been found to correlate with higher risk for cardiac events in patients with acute myocardial infarction (AMI). It has been suggested that CRP may be involved in initiation process of coagulation; however, the role of CRP level in the formation of left ventricular (LV) thrombus has not been studied. HYPOTHESIS: This study investigated whether CRP is a risk factor for LV thrombus in patients with AMI. METHODS: Clinical, echocardiographic, and biochemical data were analyzed in 141 consecutive patients (aged 57 +/- 13 years; 33 women) with first anterior AMI. Two-dimensional and Doppler echocardiographic examinations were performed on Days 1, 3, 7, 15, and 30. Blood samples were obtained every day during hospitalization. Serum CRP concentrations were measured by an ultrasensitive immunonephelometry method. RESULTS: Left ventricular thrombus was detected in 33 (23.4%) patients. Univariate analysis showed that patients with LV thrombus had a higher peak creatine kinase (CK) level (2,879 +/- 742 vs. 1,693 +/- 1,210 I/U, p = 0.001), higher peak CRP level (14.9 +/- 7.1 vs. 9.2 +/- 6.8 mg/dl, p = 0.001), higher wall motion score index (1.8 +/- 0.2 vs. 1.5 +/- 0.3, p = 0.002), higher apical wall motion score index (2.35 +/- 0.72 vs. 2.07 +/- 0.70, p = 0.001), larger end-diastolic volume (145.2 +/- 43.7 vs. 116.5 +/- 44.2 ml, p = 0.002), larger end-systolic volume (85.4 +/- 37.2 vs. 62.9 +/- 31.6 ml, p = 0.003), and lower ejection fraction (42.1 +/- 12 vs. 47.3 +/- 13, p = 0.04). In multivariate analyses, only peak CK level (p = 0.0001), LV apical wall motion score index (p = 0.001), and CRP levels (p = 0.001) were independent predictors of LV thrombus formation. CONCLUSIONS: These results suggest that CRP is a risk factor for LV thrombus in patients with AMI.     

Levels and values of serum high-sensitivity C-reactive protein within 6 hours after the onset of acute myocardial infarction

BACKGROUND: C-reactive protein (CRP), which has been suggested to directly enhance inflammation in plaques, is rapidly synthesized and secreted in the liver 6 h after an acute inflammatory stimulus. Therefore, serum levels of CRP within 6 h after the onset of acute myocardial infarction (AMI) merely reflect a chronic and persistent inflammatory process and are not due to acute myocardial damage. We hypothesized that the serum CRP level, which would abnormally elevate thereafter, is followed by a plaque rupture in the clinical setting of AMI. METHODS AND RESULTS: CRP was prospectively measured by high-sensitivity CRP assay (hs-CRP) in 157 consecutive patients (106 patients within 6 h, and 51 patients >/= 6 h but < 12 h after the onset of AMI) with ST-segment elevation AMI undergoing primary percutaneous coronary intervention (PCI). Serum levels of hs-CRP were also measured in 30 patients with stable angina undergoing elective PCI and in 30 healthy control subjects. The serum level of hs-CRP was significantly higher in patients with an onset of AMI < 6 h than in patients with angina pectoris (2.7 +/- 2.3 mg/L vs 1.4 +/- 0.7 mg/L, p < 0.0001 [mean +/- SD]) and in healthy subjects (2.7 +/- 2.3 mg/L vs 1.0 +/- 0.6 mg/L, p < 0.0001). There were no significant differences in serum levels of hs-CRP in patients with an onset of AMI 3 h but < 6 h (2.7 +/- 2.5 mg/L vs 2.7 +/- 2.2 mg/L, p = 0.87). However, the serum level of hs-CRP was significantly higher in patients with an onset >/= 6 h than in patients with an onset < 6 h (14.1 +/- 16.5 mg/L vs 2.7 +/- 2.3 mg/L, p < 0.0001). CONCLUSIONS: Serum levels of hs-CRP were significantly higher in patients with an onset of AMI < 6 h than in healthy subjects and in patients with angina pectoris undergoing PCI. The inflammatory process has been proved as one of the mechanisms causing plaque rupture. Elevated serum hs-CRP levels in patients with AMI < 6 h may portend vulnerable plaque rupture.     

Serum interleukin-6 levels, not genotype, correlate with coronary plaque complexity

An increased serum interleukin-6 (IL-6) level is associated with an increased risk of cardiovascular events in healthy subjects. However, it is unknown whether the level of serum IL-6 or genetic IL-6 polymorphism is correlated with the complexity of coronary plaque in patients with stable coronary artery disease (CAD). Patients with stable CAD (n = 135) were divided into 3 groups: insignificant coronary plaque (n = 77), simple coronary plaque (n = 15), and complex coronary plaque (n = 43). IL-6-174G > C polymorphism and serum levels of IL-6 and C-reactive protein (CRP) were investigated. No significant difference in the distribution of IL-6 genotypes was found among the groups. The presence of complex coronary plaque was associated with higher serum concentrations of IL-6 (P = 0.026) and CRP (P < 0.0001). To predict the presence of complex lesions, IL-6 > 5.8 ng/L and CRP > 2.6 mg/L had sensitivities of 86% and 74%, and specificities of 61% and 62%, respectively. By multivariate analysis, IL-6 > 5.8 ng/L and CRP > 2.6 mg/L were independently related to the presence of complex coronary plaque (P = 0.0002 and 0.004, respectively). IL-6 > 5.8 ng/L and CRP > 2.6 mg/L were associated with a 4.5-fold increase in the odds of having complex coronary plaque (P < 0.005). A simple measurement of the serum IL-6 level in patients with CAD can potentially identify subjects with complex coronary lesions and provide the option of aggressive medical strategies in a clinical setting.     

Association of serum MMP-9 with autoantibodies against oxidized LDL.

Monocyte-derived macrophages in atherosclerotic plaques secrete matrix metalloproteinases (MMPs), which may contribute to plaque rupture. There has been much speculation as to which factors precipitate in the arterial inflammation. Oxidized low density lipoprotein (oxLDL) has been suggested to have proinflammatory properties, and it has been shown to increase matrix metalloproteinase-9 (MMP-9) secretion by macrophages in vitro. We determined serum MMP-9 concentration and autoantibodies against oxLDL by ELISA in men with angina pectoris (n=243) and age-matched controls (n=238). The association between serum MMP-9 concentration and autoantibodies against oxLDL was evaluated. Autoantibody level against oxLDL, expressed in optical density units, was significantly higher in subjects with angina pectoris compared to controls (0.100+/-0.064 versus 0.088+/-0.051, respectively, P=0.030), but serum levels of MMP-9 did not differ significantly between these groups (54.2+/-29.9 versus 50.6+/-23.1 microg/l). However, autoantibodies against oxLDL correlated positively with serum MMP-9 (r=0.21, P<0.001). In a multiple regression model (including age, diastolic blood pressure, cholesterol, HDL cholesterol, triglycerides, BMI, smoking and MMP-9) serum MMP-9 (beta=0.200, P<0.001) and smoking (beta=0.179, P<0.001) were significantly associated with autoantibodies against oxLDL. In conclusion, autoantibodies against oxLDL were positively associated with angina pectoris and serum MMP-9. Since autoantibody level against oxLDL could be expected to reflect the degree of oxLDL in the vessel wall, our results suggest that oxLDL is associated with MMP-9 in vivo.     

Comparison of high-density and low-density lipoprotein cholesterol subclasses and sizes in Asian Indian women with Caucasian women from the Framingham Offspring Study

BACKGROUND: Asian Indian women have a higher rate of coronary artery disease (CAD) than do other ethnic groups, despite similar conventional risk factors and lipid profiles. Smaller high-density lipoprotein cholesterol (HDL-C) particle size is associated with reduced cardiac protection or even an increased risk of CAD. Exceptional longevity correlates better with larger HDL-C particle sizes. HYPOTHESIS: Higher rates of CAD among Asian Indian women may partly be explained by the differenes in the prevalence of atherogenic HDL-C and low-density lipoprotein cholesterol (LDL-C) sizes and their subclass concentrations among Asian Indian women compared with Caucasian women. METHODS: We measured HDL-C concentrations and sizes by nuclear magnetic resonance spectroscopy in 119 relatively healthy Asian Indian women and compared them with those of 1752 Caucasian women from the Framingham Offspring Study (FOS). RESULTS: Asian Indian women were significantly younger (47.9 +/- 11.2 vs. 51.0 +/- 10.1 years, p = 0.0001), leaner (body mass index 24.0 +/- 4.7 vs. 26.0 +/- 5.6, p = < 0.0002), less likely to be postmenopausal (32 vs. 54%, p = < 0.0001), or smoke (< 1 vs. 20%, p = < 0.0001); nevertheless, prevalence of CAD was higher in Asian Indian women (4.2 vs. 1%, p = 0.0006). Asian Indian women had similar HDL-C (53 +/- 13 vs. 53 +/- 13 mg/dl, p = 0.99), smaller HDL-C particle size (8.9 +/- 0.35 vs. 9.4 +/- 0.44 nm, p = < 0.0001), higher total cholesterol (209 +/- 40 vs. 199 +/- 42 mg/dl, p = 0.01), and similar triglyceride (120 +/- 77 vs. 108 +/- 110 mg/d, p = 0.24) levels. Low-density lipoprotein cholesterol, particle concentrations and sizes, as well as prevalence of pattern B were similar. CONCLUSIONS: Compared with the FOS, Asian Indian women have significantly smaller overall HDL particle size and similar levels of HDL-C, which may reflect impaired, reverse cholesterol transport. Total cholesterol was higher, whereas triglyceride and LDL-C levels were similar. This may partly explain the higher CAD rates in Asian Indian women. Further large scale, prospective, long-term studies are warranted.     

Circulating oxidized low-density lipoprotein is an independent predictor for cardiac event in patients with coronary artery disease

Oxidized low-density lipoprotein (oxLDL) plays a crucial role in the development of atherosclerosis, however, the predictive value of circulating oxLDL for cardiac events (CE) in patients with coronary artery disease (CAD) has remained poorly understood. We prospectively studied 238 consecutive patients with documented CAD for up to 52 months until the occurrence of one of the following cardiac events: cardiac death, nonfatal myocardial infarction (MI), and refractory angina requiring revascularization. The plasma levels of oxLDL were measured by an enzyme-linked immunosorbent assay (ELISA) using the monoclonal antibody, DLH3. The levels of circulating oxLDL were significantly higher in patients with CE than in patients without CE (median 20.3 U/ml versus 17.6 U/ml, P = 0.002). Multivariate Cox models showed that higher level of oxLDL was an independent predictor of developing CE. The adjusted hazard ratios for CE were 3.15 (95% CI 1.47-6.76, P = 0.003) times higher in patients with the highest quartile of oxLDL levels and 1.88 (95% CI 0.90-3.95, P = 0.09) times higher in patients with the third quartile than in those within the lowest quartile. Thus, measurement of circulating oxLDL may be helpful in the assessment of future CE in patients with CAD.     

Mitochondrial DNA oxidation and manganese superoxide dismutase activity in peripheral blood mononuclear cells from type 2 diabetic patients

AIM: To investigate the balance between parameters of oxidative stress and antioxidant defences in the mitochondria of peripheral blood mononuclear cells (PBMCs) of type 2 diabetic patients with late complications. METHODS: Ten type 2 diabetic patients with late diabetic complications and 10 age-matched healthy volunteers (controls) were prospectively recruited. Mitochondrial DNA (mtDNA) oxidative damage and mtDNA content were measured as indices of oxidative stress. Manganese superoxide dismutase (MnSOD) activity has been used as an index of mitochondrial antioxidant defence. Mitochondrial respiratory-chain function (cytochrome C oxidase activity) was also assessed. RESULTS: Mitochondrial DNA (mtDNA) oxidation was significantly higher in the PBMCs of diabetic patients than in control subjects (P<0.0001) and, although mtDNA content was lower in the diabetic group, this was not statistically significant. MnSOD activity was significantly increased in PBMCs of type 2 diabetic patients compared with healthy controls (1366+/-187 versus 686+/-167 U/g of protein; P=0.01), and was related to mtDNA oxidative damage. No differences in mitochondrial respiratory-chain function were found between diabetic patients and controls. CONCLUSION: PMBCs from type 2 diabetic patients with late diabetic complications exhibit high mtDNA oxidative damage. The degree of mtDNA oxidation was associated with an increase in MnSOD as an adaptive response to oxidative stress. The consequences of mtDNA oxidative damage on PBMC function and the progression of diabetic complications remain to be elucidated.     

Serum levels of YKL-40 increases in patients with acute myocardial infarction

OBJECTIVES: YKL-40 is secreted by macrophages, including those in atherosclerotic plaques, neutrophils, and vascular smooth muscle cells. Circulating YKL-40 is elevated in patients with inflammation and increased tissue remodeling. The aim was to examine the sequential changes in serum YKL-40 in patients with acute myocardial infarction (AMI), with and without thrombolytic therapy, as compared with patients with stable coronary artery disease (CAD). METHODS: YKL-40 was measured by radioimmunoassay in serum from 63 patients. A total of 47 patients had their first AMI [30 with ST segment elevation myocardial infarction (STEMI) were thrombolyzed, 17 with non-STEMI were not thrombolyzed] and 16 patients had CAD. RESULTS: Serum YKL-40 at the time of admission was higher in patients with AMI (median: 156 microg/l, range: 40-3000 microg/l) than in patients with CAD (median: 106 microg/l, range: 54-300 microg/l, P=0.048) and healthy participants (median: 102 microg/l, range: 38-514 microg/l, P<0.001). No difference in serum YKL-40 between CAD patients and healthy participants (P=0.89) was observed. No difference in serum YKL-40 between the AMI patients with or without ST-elevations (P=0.12) was observed. The maximum serum YKL-40 during the first 24 h after admission was higher in thrombolyzed STEMI patients than in the nonthrombolyzed, non-STEMI patients (P=0.01) and the CAD patients (P<0.0001). Serum YKL-40 declined consistently from the maximum value just after the AMI and during follow-up. Serum YKL-40 at 90, 180, and 360 days after AMI were significantly higher in nonthrombolyzed than in thrombolyzed patients (P=0.004, P=0.008, P=0.017, respectively). CONCLUSION: These results demonstrated that serum concentrations of YKL-40 are greatly increased in AMI patients with and without thrombolytic therapy.     

High oxidative stress in patients with stable coronary heart disease

Oxidized low density lipoprotein (oxLDL) plays a pivotal role in the development of atherosclerosis. The aim of the study was to investigate the relationship between oxLDL and other oxidative stress biomarkers with stable coronary heart disease (CHD). We compared the degree of oxidative stress in patients with CHD and sex-matched healthy control subjects in a case-control study. The study included 64 male subjects: 32 patients with stable CHD and 32 normal control subjects. Levels of circulating oxLDL were measured by a monoclonal antibody 4E6-based competition ELISA. Comparison of oxidative stress marker levels between cases and controls, adjusted for age, revealed significantly higher plasma oxLDL levels (63.32+/-25.49 vs. 37.73+/-20.58 U/l, P=0.001), lower serum levels of autoantibodies against oxLDL (341.53+/-350.46 vs. 796.45+/-1034.2 mU/ml, P=0.021), higher activities of the antioxidant enzymes superoxide dismutase in erythrocytes (951+/-70.2 vs. 771.6+/-191.2 U/g, P=0.032) and glutathione peroxidase in whole blood (GSH-Px: 10714.4+/-3705.4 vs. 5512.2+/-1498.1 U/l, P<0.001). The risk of having CHD was 20.6-fold greater (95% CI, 1.86-228.44, P=0.014) in the highest tertile of the oxLDL distribution than in the lowest, determined by logistic regression analysis on the combined study population after adjustment for age and other potential confounding factors. When the risk associated with GSH-Px levels was calculated, the odds ratio was 305.3 (95% CI, 5.07-18369.95, P=0.006) in the highest tertile compared with the lowest. Our results showed that an oxidative stress occurs in patients with CHD despite being clinically stable and under medical treatment. The combination of oxLDL levels and GSH-Px activity may be useful for the identification of patients with stable CHD.     

Genetic polymorphism of heparan sulfate proteoglycan (perlecan, HSPG2), lipid profiles and coronary artery disease in the Australian population

Perlecan is one of the three major classes of heparan sulfate proteoglycans (HSPGs) within the cardiovascular system; it interacts with lipid metabolism by binding to lipoprotein lipase (LpL) and apolipoprotein B (apo B) and may be related to vascular disease. We explored interactions between an HSPG2 polymorphism (BamHI marker), and apo B and coronary artery disease (CAD) in patients undergoing coronary angiography. The frequencies of the HSPG2 BamHI +/+, +/-, and -/- genotypes were 4.7, 31.7 and 63.6%, respectively, with a '+' allele frequency of 20.6%. The genotype distribution was in Hardy-Weinberg equilibrium (chi(2)=0.669, P0.05). The +/+homozygotes had the lowest apo B levels (0.74+/-0.06 g/l, n=36) compared to +/- (0.89+/-0.03 g/l, n=241) and -/- (0.93+/-0.02 g/l, n=480) genotypes. Although plasma apo B concentration was the strongest lipid risk factor for significant CAD, the HSPG2 genotypes were not independently associated with the presence of CAD (P=0.640 in males; P=0.224 in females), with significant CAD (P=0.764; P=0.110) or with the number of significantly stenosed coronary arteries (P=0.945; P=0. 335). In Australian Caucasians undergoing coronary angiography the HSPG2 BamHI polymorphism is associated with lower circulating apo B but not with the occurrence or severity of CAD. This may be due to HSPG2-mediated alterations in the HSPG2-apo B-LpL system and requires further exploration.