Post-challenge hyperglycaemia is strongly associated with future macrovascular events and total mortality in angiographied coronary patients.

AIMS: The prevalence of post-challenge hyperglycaemia in coronary patients is high. Until now, it is unclear whether post-challenge hyperglycaemia is associated with an increased risk for future macrovascular events in this clinically important patient population. METHODS AND RESULTS: We enrolled 1040 patients undergoing coronary angiography for the evaluation of suspected or established coronary artery disease. In patients without previously established diabetes mellitus, an oral glucose tolerance test (oGTT) was performed. Prospectively, mortality and macrovascular events were recorded over a mean follow-up period of 3.8 years. From our patients, 394 had normal glucose tolerance (NGT), 280 post-challenge hyperglycaemia (this subgroup includes both impaired glucose tolerance and post-challenge diabetes) and 366 had conventional diabetes. The incidence of macrovascular events was significantly higher in patients with post-challenge hyperglycaemia as well as in patients with conventional diabetes than in subjects with NGT (23.6 and 29.5% vs. 18.5%; P = 0.013 and P < 0.001, respectively). Adjusted hazard ratios were 1.46 (95% CI 1.03-2.07, P = 0.033) for patients with post-challenge hyperglycaemia and 1.73 (1.25-2.37, P = 0.001) for patients with conventional diabetes. CONCLUSION: Post-challenge hyperglycaemia is associated with future macrovascular events in patients undergoing coronary angiography for the evaluation of stable coronary artery disease (CAD). Oral glucose tolerance tests in this high-risk population thus identify patients with a particularly unfavourable prognosis.

Diabetes as a coronary artery disease risk equivalent: before a change of paradigm?

BACKGROUND: Current guidelines consider diabetes per se as a coronary artery disease (CAD) risk equivalent. We aimed at investigating the contribution of baseline coronary atherosclerosis to the risk of diabetic patients for future vascular events. DESIGN: Prospective cohort study. METHODS: Vascular events were recorded over 4 years in 750 consecutive patients undergoing coronary angiography for the evaluation of stable CAD. RESULTS: From our patients, 244 had neither type 2 diabetes (T2DM) nor significant CAD (i.e. coronary stenoses >or=50%) at the baseline angiography, 50 had T2DM but not significant CAD, 342 did not have T2DM but had significant CAD, and 114 had both T2DM and significant CAD. Nondiabetic patients without significant CAD had an event rate of 9.0%. The event rate was similar in T2DM patients without significant CAD (8.0%, P = 0.951), but higher in nondiabetic patients with significant CAD (24.9%, P<0.001). Patients with T2DM and significant CAD had the highest event rate (43.0%). Importantly, T2DM patients without significant CAD had a significantly lower event rate than nondiabetic patients with significant CAD (P = 0.008). CONCLUSION: T2DM per se is not a CAD risk equivalent. Moderate-risk diabetic patients without significant CAD and very high-risk diabetic patients with significant CAD add up to a grand total of high-risk diabetic patients, this is why diabetes seems to be a CAD risk equivalent in many epidemiological studies.

Factors predicting cardiovascular events in statin-treated diabetic and non-diabetic patients with coronary atherosclerosis.

OBJECTIVE: We aimed at identifying which lipid factors drive vascular risk in statin-treated patients with coronary artery disease (CAD). METHODS: We recorded vascular events over 5.6 years in 491 consecutive statin-treated patients with angiographically proven stable CAD, covering 2750 patient-years. RESULTS: In the total population, low high-density lipoprotein (HDL) cholesterol (standardized adjusted HR 0.73 [0.60-0.89]; p=0.001), low apolipoprotein A1 (0.77 [0.65-0.92]; p=0.003), a small low-density lipoprotein (LDL) particle diameter (0.76 [0.64-0.91]; p=0.002), and high triglycerides (1.20 [1.05-1.38]; p=0.007) predicted vascular events, but not total cholesterol, LDL cholesterol, or apolipoprotein B. Factor analysis in the lipid profiles of our patients revealed an HDL-related factor and an LDL-related factor. Concordant with the results for individual lipid parameters, the HDL-related factor (0.69 [0.58-0.83]; p<0.001) but not the LDL-related factor (p=0.455) predicted vascular events. Patients with type 2 diabetes (T2DM; n=116) were at a higher vascular risk than non-diabetic subjects (38.6% vs. 24.1%; p<0.001), and like in the total population the HDL-related factor (0.59 [0.44-0.77]; p<0.001) but not the LDL-related factor (p=0.591) predicted vascular risk in diabetic patients. CONCLUSIONS: The pattern of low HDL cholesterol, low apolipoprotein A1, small LDL particles, and high triglycerides drives vascular risk in statin-treated coronary patients, particularly in those with T2DM.

Effectiveness of atrial fibrillation as an independent predictor of death and coronary events in patients having coronary angiography.

The impact of atrial fibrillation (AF) on future coronary events is uncertain. In particular, the prognostic impact of AF in the clinically important population of coronary patients who undergo angiography is unknown. The aim of this study was to investigate (1) the prevalence of AF, (2) its association with coronary atherosclerosis, and (3) its impact on future coronary events in patients who undergo angiography. Electrocardiograms were evaluated in a consecutive series of 613 patients who underwent coronary angiography. Prospectively, death and cardiovascular events were recorded over 4.0 +/- 0.6 years. Among these patients, 37 (6%) at baseline had AF, and 576 (94%) were in sinus rhythm. The presence of AF was associated with a lower prevalence of coronary artery disease and of coronary diameter narrowing >or=50% on baseline angiography. However, prospectively, patients with AF were at a strongly increased risk for all-cause mortality (adjusted hazard ratio 5.15, 95% confidence interval 2.36 to 11.26, p <0.001), coronary death (hazard ratio 8.16, 95% confidence interval 2.89 to 23.09, p <0.001), and major coronary events (hazard ratio 3.80, 95% confidence interval 1.45 to 9.94, p = 0.007). In conclusion, although inversely associated with the presence of angiographically determined coronary atherosclerosis, AF is a strong predictor of death and future coronary events in patients with coronary artery disease who undergo coronary angiography.

Key role of postchallenge hyperglycemia for the presence and extent of coronary atherosclerosis: an angiographic study.

BACKGROUND: The associations between impaired glucose tolerance (IGT) and postchallenge diabetes with the presence and extent of angiographically characterized coronary atherosclerosis are unclear. MATERIALS AND METHODS: We enrolled 1040 consecutive Caucasian patients undergoing coronary angiography for the evaluation of coronary artery disease (CAD). An oral 75-g glucose tolerance test was performed in patients without previously diagnosed diabetes. RESULTS: From our patients, 394 had normal glucose tolerance (NGT), 190 impaired glucose tolerance (IGT), 90 isolated postchallenge diabetes (postchallenge glucose >or=200 mg/dl), and 366 type 2 diabetes previously established or newly diagnosed on the basis of fasting glucose (conventional diabetes). Coronary atherosclerosis was more frequent in patients with IGT, isolated postchallenge diabetes, or conventional diabetes when compared to NGT subjects (87.9, 95.6, 89.1 versus 80.7%; p=0.030, 0.001, 0.043, respectively). The prevalence of significant coronary stenoses >or=50%, compared to NGT subjects (57.4%), was similar in IGT patients (59.5%; p=0.628), but significantly higher in patients with isolated postchallenge diabetes (77.8%; p=0.001) or conventional diabetes (68.0%; p=0.002). Also the number of significant stenoses compared to NGT subjects was similar in IGT patients, but significantly higher in those with isolated postchallenge or conventional diabetes. These results were confirmed after multivariate adjustment. CONCLUSIONS: Abnormal glucose tolerance is strongly and independently associated with angiographically characterized coronary atherosclerosis. In IGT, non-significant coronary atherosclerosis is more frequent than in NGT; the prevalence and number of significant stenoses increases when postchallenge diabetes evolves.

Low serum adiponectin is independently associated with both the metabolic syndrome and angiographically determined coronary atherosclerosis.

BACKGROUND: We aimed at investigating serum adiponectin in patients with the metabolic syndrome (MetS), in patients with angiographically diagnosed coronary artery disease (CAD), and in patients who had both, the MetS and CAD. METHODS: We enrolled 687 consecutive patients undergoing coronary angiography for the evaluation of CAD. RESULTS: From our patients, 178 had neither the MetS (Adult Treatment Panel III definition) nor significant CAD (MetS-/CAD-), 91 had the MetS, but not significant CAD (MetS+/CAD-), 251 did not have the MetS but had significant CAD (MetS-/CAD+), and 167 had both, the MetS and significant CAD (MetS+/CAD+). Serum adiponectin was highest (12.1+/-8.3 microg/ml) in MetS-/CAD- subjects. It was significantly lower in MetS+/CAD- (9.5+/-7.3 microg/ml; p=0.001) and in MetS-/CAD+ patients (9.2+/-5.3 microg/ml; p<0.001) and lowest in MetS+/CAD+ patients (6.7+/-3.8 microg/ml) in whom it was significantly lower than in MetS-/CAD-, MetS+/CAD-, and MetS-/CAD+ patients (p<0.001 for all comparisons). In analysis of covariance the MetS and significant CAD proved associated with serum adiponectin in a mutually independent manner. CONCLUSIONS: Low serum adiponectin is independently associated with both the MetS and coronary atherosclerosis.

The -11377 C>G promoter variant of the adiponectin gene, prevalence of coronary atherosclerosis, and incidence of vascular events in men.

No prospective data demonstrating an association between the -11377 C > G adiponectin gene promoter variant and cardiovascular risk are available. We therefore prospectively evaluated the cardiovascular risk associated with adiponectin gene single nucleotide polymorphisms (SNPs) including SNP -11377 in a consecutive series of men undergoing coronary angiography. We recorded vascular events over four years in 402 men undergoing coronary angiography for the evaluation of coronary artery disease. No significant associations of SNPs +276 G > T and +45 T > G with serum adiponectin, with significant coronary stenoses >50%, or with vascular events were observed. However, for SNP -11377 C > G, serum adiponectin levels significantly decreased (p(trend) = 0.003), and the prevalence of significant coronary stenoses significantly increased from the CC over the GC to the GG genotype (p(trend) = 0.004). Prospectively, the risk of vascular events significantly increased from the CC over the CG to the GG genotype of this SNP (adjusted hazard ratios 1.555 [0.957 - 2.525] and 2.309 [1.067 - 4.998], respectively; p(trend) = 0.014). The -11377 C > G adiponectin gene promoter variant is i) associated with decreased serum adiponectin levels, ii) correlated with the presence of coronary atherosclerosis and iii) significantly predictive of vascular events among men undergoing coronary angiography.

Relationship between glomerular filtration rate and the adipokines adiponectin, resistin and leptin in coronary patients with predominantly normal or mildly impaired renal function.

BACKGROUND: Due to their molecular weight, it is possible that the adipokines adiponectin, resistin and leptin accumulate when glomerular filtration rate (GFR) is decreased. In reduced renal clearance, altered serum concentrations of these proteins might affect cardiovascular risk. The objective of the study was to investigate the relationship between adipokine concentrations and GFR. METHODS: The association between GFR, as determined by the abbreviated MDRD equation, and the concentrations of the adipokines adiponectin, resistin and leptin was assessed in a cohort of coronary patients (n=538; 363 male, 165 female). After calculation of correlations between GFR and adipokine concentrations, the association was further assessed by analysis of covariance following adjustment for age, gender, BMI, presence of type 2 diabetes, presence of hypertension, history of smoking as well as for serum lipid concentrations. RESULTS: Mean GFR in our study population was 68.74+/-15.27 ml/min/1.73 m(2). 74.3% of the patients had a GFR >60 ml/min/1.73 m(2), 24% of the patients had a GFR between 30 and 60 ml/min/1.73 m(2), and 1.7% of the patients had a GFR <30 ml/min/1.73 m(2). There were significant inverse correlations between adiponectin (r=-0.372; p<0.001), resistin (r=-0.227; p<0.001) and leptin (r=-0.151; p=0.009) concentrations and GFR. After multivariate adjustment, the associations remained significant for adiponectin and resistin. Subgroup analysis in patients with GFR >60 ml/min/1.73 m(2) showed a significant correlation between GFR and adiponectin as well as leptin concentrations. However, after adjustment, these associations no longer were significant. CONCLUSIONS: There is an independent association between GFR and the serum concentrations of adiponectin and resistin. However, this association is not present at GFR >60 ml/min/1.73 m(2). This finding suggests that adipokine concentrations in mildly impaired and normal renal function are influenced by factors other than GFR.

Evaluation of two fully automated novel enzyme-linked immunosorbent assays for the determination of human adiponectin in serum.

BACKGROUND: In contrast to RIA, recently available ELISAs provide the potential for fully automated analysis of adiponectin. To date, studies reporting on the diagnostic characteristics of ELISAs and investigating on the relationship between ELISA- and RIA-based methods are rare. METHODS: Thus, we established and evaluated a fully automated platform (BEP 2000; Dade-Behring, Switzerland) for determination of adiponectin levels in serum by two different ELISA methods (competitive human adiponectin ELISA; high sensitivity human adiponectin sandwich ELISA; both Biovendor, Czech Republic). Further, as a reference method, we also employed a human adiponectin RIA (Linco Research, USA). Samples from 150 patients routinely presenting to our cardiology unit were tested. RESULTS: ELISA measurements could be accomplished in less than 3 h, measurement of RIA had a duration of 24 h. The ELISAs were evaluated for precision, analytical sensitivity and specificity, linearity on dilution and spiking recovery. In the investigated patients, type 2 diabetes, higher age and male gender were significantly associated with lower serum adiponectin concentrations. Correlations between the ELISA methods and the RIA were strong (competitive ELISA, r=0.82; sandwich ELISA, r=0.92; both p<0.001). However, Deming regression and Bland-Altman analysis indicated lack of agreement of the 3 methods preventing direct comparison of results. The equations of the regression lines are: Competitive ELISA=1.48 x RIA-0.88; High sensitivity sandwich ELISA=0.77 x RIA+1.01. CONCLUSIONS: Fully automated measurement of adiponectin by ELISA is feasible and substantially more rapid than RIA. The investigated ELISA test systems seem to exhibit analytical characteristics allowing for clinical application. In addition, there is a strong correlation between the ELISA methods and RIA. These findings might promote a more widespread use of adiponectin measurements in clinical research.

Adult Treatment Panel III 2001 but not International Diabetes Federation 2005 criteria of the metabolic syndrome predict clinical cardiovascular events in subjects who underwent coronary angiography.

OBJECTIVE: The International Diabetes Federation (IDF) has recently established a worldwide consensus definition of the metabolic syndrome. No prospective data are available on the cardiovascular risk associated with this new metabolic syndrome definition. RESEARCH DESIGN AND METHODS: In a prospective study of 750 coronary patients, we recorded vascular events over 4 years. RESULTS: From our patients, 37.3% (n = 280) had the metabolic syndrome according to the Adult Treatment Panel III (ATPIII) definition and 45.5% (n = 341) according to the IDF definition. The metabolic syndrome as defined by the ATPIII criteria significantly predicted vascular events (adjusted hazard ratio 1.745 [95% CI 1.255-2.427]; P = 0.001), but the metabolic syndrome as defined by IDF criteria did not (1.189 [0.859-1.646]; P = 0.297). Accordingly, event-free survival was significantly lower among patients who fulfilled the ATPIII but not the IDF criteria than among those who met the IDF but not the ATPIII criteria (P = 0.012). The metabolic syndrome as defined by ATPIII criteria remained significantly predictive of vascular events after adjustment for type 2 diabetes but not after additional adjustment for the metabolic syndrome components high triglycerides and low HDL cholesterol. These lipid traits in turn proved significantly predictive of vascular events even after adjustment for the metabolic syndrome. CONCLUSIONS: The ATPIII definition of the metabolic syndrome confers a significantly higher risk of vascular events than the IDF definition. However, among angiographied coronary patients, even the ATPIII definition of the metabolic syndrome does not provide prognostic information beyond its dyslipidemic features.

The metabolic syndrome, insulin resistance, and cardiovascular risk in diabetic and nondiabetic patients.

CONTEXT: The contribution of insulin resistance per se to the vascular risk conferred by the metabolic syndrome (MetS) is not known; conversely, it is uncertain whether insulin resistance confers vascular risk beyond the entity of the MetS. OBJECTIVE: The objective of this study was to investigate the impact of the MetS (Adult Treatment Panel III criteria) and insulin resistance (as estimated by the homeostasis model assessment index) on the incidence of vascular events. DESIGN AND PATIENTS: This was a prospective cohort study enrolling 750 consecutive patients undergoing coronary angiography for the evaluation of coronary artery disease. SETTING: The study was performed at a tertiary care clinical research center. MAIN OUTCOME MEASURE: The main outcome measure was the incidence of vascular events over 2.3 yr. RESULTS: Both the MetS and insulin resistance predicted vascular events after controlling for non-MetS risk factors [hazard ratio (HR), 2.74 (95% confidence interval, 1.71-4.39; P < 0.001) and 1.51 (1.24-1.84; P < 0.001), respectively]. After additional adjustment for insulin resistance, the MetS remained significantly predictive of vascular events [HR, 2.69 (1.57-4.64); P < 0.001], and conversely, insulin resistance remained significantly predictive of vascular events despite adjustment for the MetS [standardized HR, 1.41 (1.14-1.75); P = 0.002]. Additional adjustment for the presence of type 2 diabetes revealed that both the MetS [adjusted HR, 2.57 (1.47-4.51); P = 0.001] and homeostasis model assessment of insulin resistance [standardized adjusted HR, 1.37 (1.09-1.73); P = 0.007] significantly predicted vascular events independent from diabetes status. CONCLUSIONS: Both the MetS and insulin resistance are strong and mutually independent predictors of vascular risk among angiographed coronary patients.

Is atherosclerosis in diabetes and impaired fasting glucose driven by elevated LDL cholesterol or by decreased HDL cholesterol?

OBJECTIVE: To evaluate the atherogenicity of lipids in coronary patients with normal fasting glucose (NFG), impaired fasting glucose (IFG), and type 2 diabetes. RESEARCH DESIGN AND METHODS: Serum lipid values, the presence of angiographic coronary artery disease (CAD) at baseline, and the incidence of vascular events over 2.3 years were recorded in 750 consecutive patients undergoing coronary angiography. RESULTS: Triglycerides significantly (P < 0.001) increased and HDL cholesterol (P < 0.001) as well as LDL particle diameter (P < 0.001) significantly decreased from subjects with NFG <5.6 mmol/l (n = 272) over patients with IFG > or =5.6 mmol/l (n = 314) to patients with type 2 diabetes (n = 164). Factor analysis revealed two factors in the lipid profiles of our patients: triglycerides, HDL cholesterol, apolipoprotein A1, and LDL particle diameter loaded high on an HDL-related factor, and total cholesterol, LDL cholesterol, and apolipoprotein B loaded high on an LDL-related factor. In patients with type 2 diabetes, the HDL-related factor (odds ratio 0.648 [95% CI 0.464-0.904]; P = 0.011), but not the LDL-related factor (0.921 [0.677-1.251]; P = 0.597), was associated with significant coronary stenoses > or =50%. Consistently, in the prospective study, the HDL-related factor (0.708 [0.506-0.990]; P = 0.044), but not the LDL-related factor (1.362 [0.985-1.883]; P = 0.061), proved significantly predictive for vascular events in patients with type 2 diabetes. CONCLUSIONS: The low HDL cholesterol/high triglyceride pattern is associated with the degree of hyperglycemia. In coronary patients with type 2 diabetes, this pattern correlates with the prevalence of CAD and significantly predicts the incidence of vascular events.