Altan Onat

Interleukin-6 receptor pathways in coronary heart disease: a collaborative meta-analysis of 82 studies.

Summary Background Persistent inflammation has been proposed to contribute to various stages in the pathogenesis of cardiovascular disease. Interleukin-6 receptor (IL6R) signalling propagates downstream inflammation cascades. To assess whether this pathway is causally relevant to coronary heart disease, we studied a functional genetic variant known to affect IL6R signalling. Methods In a collaborative meta-analysis, we studied Asp358Ala (rs2228145) in IL6R in relation to a panel of conventional risk factors and inflammation biomarkers in 125 222 participants. We also compared the frequency of Asp358Ala in 51 441 patients with coronary heart disease and in 136 226 controls. To gain insight into possible mechanisms, we assessed Asp358Ala in relation to localised gene expression and to postlipopolysaccharide stimulation of interleukin 6. Findings The minor allele frequency of Asp358Ala was 39%. Asp358Ala was not associated with lipid concentrations, blood pressure, adiposity, dysglycaemia, or smoking (p value for association per minor allele ≥0·04 for each). By contrast, for every copy of 358Ala inherited, mean concentration of IL6R increased by 34·3% (95% CI 30·4–38·2) and of interleukin 6 by 14·6% (10·7–18·4), and mean concentration of C-reactive protein was reduced by 7·5% (5·9–9·1) and of fibrinogen by 1·0% (0·7–1·3). For every copy of 358Ala inherited, risk of coronary heart disease was reduced by 3·4% (1·8–5·0). Asp358Ala was not related to IL6R mRNA levels or interleukin-6 production in monocytes. Interpretation Large-scale human genetic and biomarker data are consistent with a causal association between IL6R-related pathways and coronary heart disease. Funding British Heart Foundation; UK Medical Research Council; UK National Institute of Health Research, Cambridge Biomedical Research Centre; BUPA Foundation.

Metabolic syndrome: major impact on coronary risk in a population with low cholesterol levels—a prospective and cross-sectional evaluation

UNLABELLED The prevalence and the excess coronary heart disease (CHD) risk of the metabolic syndrome (MS) and its components were investigated in the Turkish Adult Risk Factor Study in both a prospective and a cross-sectional manner. In a population sample, representative of Turkish adults who have low levels of high- and low-density lipoprotein-cholesterol (HDL-C and LDL-C), MS was identified in conformity with the definition used in the recent NCEP guidelines. Prospective analysis was based on 2398 men and women (mean age at baseline 49.1+/-13 years) who had a baseline examination in 1997/98 and were followed-up for a mean of 3 years. CHD was diagnosed based on clinical findings and Minnesota coding of resting electrocardiograms. Fatal and nonfatal CHD developed in 126 subjects. 27% of men and 38.6% of women were found to have MS at baseline examination. When adjusted for age, MS was an independent predictor of subsequent overall fatal and nonfatal CHD in both genders, displaying an RR of 1.71. At the final cross-sectional evaluation, coronary risk associated with MS in men was primarily accounted for by standard MS components (largely inherent in glucose intolerance, hypertension and in a surrogate of small, dense LDL particles), in addition to a minor independent contribution by C-reactive protein (CRP). In women with MS, a substantial residual coronary risk remained after controlling for five components, which was partly accounted for by levels of LDL-C and CRP. It was estimated that MS was the culprit in just over half the cases of CHD in Turkey. CONCLUSION MS was the major determinant of CHD risk in a population having generally low levels of HDL-C and LDL-C in middle-aged and elderly adults, extending to three out of every eight adults, and imposing an overall excess CHD risk of approximately 70%. In contrast to men, a substantial residual coronary risk is retained in Turkish women after controlling for five MS components.

Lipid-related markers and cardiovascular disease prediction.

CONTEXT The value of assessing various emerging lipid-related markers for prediction of first cardiovascular events is debated. OBJECTIVE To determine whether adding information on apolipoprotein B and apolipoprotein A-I, lipoprotein(a), or lipoprotein-associated phospholipase A2 to total cholesterol and high-density lipoprotein cholesterol (HDL-C) improves cardiovascular disease (CVD) risk prediction. DESIGN, SETTING, AND PARTICIPANTS Individual records were available for 165,544 participants without baseline CVD in 37 prospective cohorts (calendar years of recruitment: 1968-2007) with up to 15,126 incident fatal or nonfatal CVD outcomes (10,132 CHD and 4994 stroke outcomes) during a median follow-up of 10.4 years (interquartile range, 7.6-14 years). MAIN OUTCOME MEASURES Discrimination of CVD outcomes and reclassification of participants across predicted 10-year risk categories of low (<10%), intermediate (10%-<20%), and high (≥20%) risk. RESULTS The addition of information on various lipid-related markers to total cholesterol, HDL-C, and other conventional risk factors yielded improvement in the models discrimination: C-index change, 0.0006 (95% CI, 0.0002-0.0009) for the combination of apolipoprotein B and A-I; 0.0016 (95% CI, 0.0009-0.0023) for lipoprotein(a); and 0.0018 (95% CI, 0.0010-0.0026) for lipoprotein-associated phospholipase A2 mass. Net reclassification improvements were less than 1% with the addition of each of these markers to risk scores containing conventional risk factors. We estimated that for 100,000 adults aged 40 years or older, 15,436 would be initially classified at intermediate risk using conventional risk factors alone. Additional testing with a combination of apolipoprotein B and A-I would reclassify 1.1%; lipoprotein(a), 4.1%; and lipoprotein-associated phospholipase A2 mass, 2.7% of people to a 20% or higher predicted CVD risk category and, therefore, in need of statin treatment under Adult Treatment Panel III guidelines. CONCLUSION In a study of individuals without known CVD, the addition of information on the combination of apolipoprotein B and A-I, lipoprotein(a), or lipoprotein-associated phospholipase A2 mass to risk scores containing total cholesterol and HDL-C led to slight improvement in CVD prediction.

Risk factors and cardiovascular disease in Turkey

Cardiovascular risk factors as well as morbidity and mortality from coronary heart disease among Turkish adults are herein reviewed. Lipids and lipoproteins are in focus, but other relevant risk factors are also discussed. Turks have distinctively low levels of total and high-density lipoprotein (HDL)-cholesterol, associated with high levels of hepatic lipase and fasting triglycerides. In addition, physical inactivity is common in both genders; close to 60% of men have the smoking habit, while obesity is common among Turkish women leading to a high prevalence of hypertension and diabetes in them. These factors probably account for the unanticipated fact that Turkish adults have the pattern of causes of death similar to a developed population, although the process of industrialization is ongoing, the structure of its population is young and overall cholesterol levels are comparatively low. The age-standardized coronary heart disease death rate is estimated to rank among the highest in Europe. The leading independent predictors of coronary events and death [systolic blood pressure, total/HDL-cholesterol ratio, followed by diabetes and (central) obesity] are related to the metabolic syndrome, estimated to prevail in 3-4% of adults aged 30 or over, and to underlie one-eighth of cases of coronary disease. Since several adverse factors exhibit a rising trend, primary and secondary prevention of cardiovascular disease must assume a much higher priority in various issues in Turkey than it currently does.

Association of Cardiometabolic Multimorbidity With Mortality.

IMPORTANCE The prevalence of cardiometabolic multimorbidity is increasing. OBJECTIVE To estimate reductions in life expectancy associated with cardiometabolic multimorbidity. DESIGN, SETTING, AND PARTICIPANTS Age- and sex-adjusted mortality rates and hazard ratios (HRs) were calculated using individual participant data from the Emerging Risk Factors Collaboration (689,300 participants; 91 cohorts; years of baseline surveys: 1960-2007; latest mortality follow-up: April 2013; 128,843 deaths). The HRs from the Emerging Risk Factors Collaboration were compared with those from the UK Biobank (499,808 participants; years of baseline surveys: 2006-2010; latest mortality follow-up: November 2013; 7995 deaths). Cumulative survival was estimated by applying calculated age-specific HRs for mortality to contemporary US age-specific death rates. EXPOSURES A history of 2 or more of the following: diabetes mellitus, stroke, myocardial infarction (MI). MAIN OUTCOMES AND MEASURES All-cause mortality and estimated reductions in life expectancy. RESULTS In participants in the Emerging Risk Factors Collaboration without a history of diabetes, stroke, or MI at baseline (reference group), the all-cause mortality rate adjusted to the age of 60 years was 6.8 per 1000 person-years. Mortality rates per 1000 person-years were 15.6 in participants with a history of diabetes, 16.1 in those with stroke, 16.8 in those with MI, 32.0 in those with both diabetes and MI, 32.5 in those with both diabetes and stroke, 32.8 in those with both stroke and MI, and 59.5 in those with diabetes, stroke, and MI. Compared with the reference group, the HRs for all-cause mortality were 1.9 (95% CI, 1.8-2.0) in participants with a history of diabetes, 2.1 (95% CI, 2.0-2.2) in those with stroke, 2.0 (95% CI, 1.9-2.2) in those with MI, 3.7 (95% CI, 3.3-4.1) in those with both diabetes and MI, 3.8 (95% CI, 3.5-4.2) in those with both diabetes and stroke, 3.5 (95% CI, 3.1-4.0) in those with both stroke and MI, and 6.9 (95% CI, 5.7-8.3) in those with diabetes, stroke, and MI. The HRs from the Emerging Risk Factors Collaboration were similar to those from the more recently recruited UK Biobank. The HRs were little changed after further adjustment for markers of established intermediate pathways (eg, levels of lipids and blood pressure) and lifestyle factors (eg, smoking, diet). At the age of 60 years, a history of any 2 of these conditions was associated with 12 years of reduced life expectancy and a history of all 3 of these conditions was associated with 15 years of reduced life expectancy. CONCLUSIONS AND RELEVANCE Mortality associated with a history of diabetes, stroke, or MI was similar for each condition. Because any combination of these conditions was associated with multiplicative mortality risk, life expectancy was substantially lower in people with multimorbidity.

Association of Cardiometabolic Multimorbidity With Mortality The Emerging Risk Factors Collaboration

IMPORTANCE The prevalence of cardiometabolic multimorbidity is increasing. OBJECTIVE To estimate reductions in life expectancy associated with cardiometabolic multimorbidity. DESIGN, SETTING, AND PARTICIPANTS Age- and sex-adjusted mortality rates and hazard ratios (HRs) were calculated using individual participant data from the Emerging Risk Factors Collaboration (689,300 participants; 91 cohorts; years of baseline surveys: 1960-2007; latest mortality follow-up: April 2013; 128,843 deaths). The HRs from the Emerging Risk Factors Collaboration were compared with those from the UK Biobank (499,808 participants; years of baseline surveys: 2006-2010; latest mortality follow-up: November 2013; 7995 deaths). Cumulative survival was estimated by applying calculated age-specific HRs for mortality to contemporary US age-specific death rates. EXPOSURES A history of 2 or more of the following: diabetes mellitus, stroke, myocardial infarction (MI). MAIN OUTCOMES AND MEASURES All-cause mortality and estimated reductions in life expectancy. RESULTS In participants in the Emerging Risk Factors Collaboration without a history of diabetes, stroke, or MI at baseline (reference group), the all-cause mortality rate adjusted to the age of 60 years was 6.8 per 1000 person-years. Mortality rates per 1000 person-years were 15.6 in participants with a history of diabetes, 16.1 in those with stroke, 16.8 in those with MI, 32.0 in those with both diabetes and MI, 32.5 in those with both diabetes and stroke, 32.8 in those with both stroke and MI, and 59.5 in those with diabetes, stroke, and MI. Compared with the reference group, the HRs for all-cause mortality were 1.9 (95% CI, 1.8-2.0) in participants with a history of diabetes, 2.1 (95% CI, 2.0-2.2) in those with stroke, 2.0 (95% CI, 1.9-2.2) in those with MI, 3.7 (95% CI, 3.3-4.1) in those with both diabetes and MI, 3.8 (95% CI, 3.5-4.2) in those with both diabetes and stroke, 3.5 (95% CI, 3.1-4.0) in those with both stroke and MI, and 6.9 (95% CI, 5.7-8.3) in those with diabetes, stroke, and MI. The HRs from the Emerging Risk Factors Collaboration were similar to those from the more recently recruited UK Biobank. The HRs were little changed after further adjustment for markers of established intermediate pathways (eg, levels of lipids and blood pressure) and lifestyle factors (eg, smoking, diet). At the age of 60 years, a history of any 2 of these conditions was associated with 12 years of reduced life expectancy and a history of all 3 of these conditions was associated with 15 years of reduced life expectancy. CONCLUSIONS AND RELEVANCE Mortality associated with a history of diabetes, stroke, or MI was similar for each condition. Because any combination of these conditions was associated with multiplicative mortality risk, life expectancy was substantially lower in people with multimorbidity.

Neck circumference as a measure of central obesity: Associations with metabolic syndrome and obstructive sleep apnea syndrome beyond waist circumference

BACKGROUND & AIMS To investigate the relationship of neck circumference (NC) to metabolic syndrome (MetS) and obstructive sleep apnea syndrome (OSAS) and whether it adds information to that provided by waist circumference. METHODS Cross-sectional analysis of a population sample of 1,912 men and women, aged 55.1 +/- 12 years, representative of Turkish adults. MetS was identified based on modified criteria of the ATP-III, OSAS when habitual snoring and episodes of apnea were combined with another relevant symptom. RESULTS NC measured 36.7 (+/- 3.5) cm in the total sample. It was significantly correlated with numerous risk factors, above all body mass index and waist girth (r > or = 0.6), homeostatic model-assessed insulin resistance, blood pressure and, inversely, with smoking status and sex hormone-binding globulin. Sex- and age-adjusted NC was associated significantly with MetS, at a 2-3-fold increased likelihood for 1 standard deviation (SD) increment. After further adjustment for waist circumference and smoking status, a significant residual odds ratio (OR, 1.13 [95% CI 1.08; 1.19]) persisted, corresponding to ORs of 1.53 and 1.27 in males and females, respectively, for 1 SD increment. Even when adjusted for all MetS components, a residual OR (1.08 [95% CI 1.000; 1.17]) remained. Sex- and age-adjusted NC was associated significantly also with OSAS in genders combined, independent of waist girth, yielding an added OR of 1.3 for 1 SD increment. CONCLUSIONS NC contributes to MetS likelihood beyond waist circumference and the MetS components. Regarding association with OSAS, NC is of greater value than WC among Turkish men, not women.

Apolipoprotein C-III, a strong discriminant of coronary risk in men and a determinant of the metabolic syndrome in both genders

AIMS Apolipoprotein C-III (apoC-III) has been recognized as a useful marker of triglyceride-rich lipoproteins (TRLs) metabolism and proposed as an indicator of prognosis for coronary risk in healthy subjects. We studied cross-sectionally in a population having low cholesterol levels, but a high prevalence of the metabolic syndrome, whether serum levels of total apoC-III or its sub-fractions were independent markers of prevalent coronary heart disease (CHD) or were related to variables reflecting the metabolic syndrome. METHODS AND RESULTS In 857 unselected participants of the representative population sample of the Turkish Adult Risk Factor Survey in 2001, apoC-III as well as other risk variables were evaluated, and CHD was diagnosed based on clinical findings and Minnesota coding of resting electrocardiograms. The sample consisted of men and women, aged 33-82 years, having a mean waist circumference of 89.4 and 92.9 cm, respectively, 42% of whom had the metabolic syndrome identified by criteria of the ATP III. ApoC-III values were measured by turbidimetric immunoassay. Mean concentrations for non-high-density lipoprotein (nonHDL) apoC-III in men and women were 6.4 and 6.2 mg/dl, respectively, and for apoC-III in HDL were 6.2 and 6.3 mg/dl, respectively. NonHDL apoC-III was similar to, and apoC-III in HDL was higher than that in Western populations. Both fractions of apoC-III were significantly correlated with lipids, lipoproteins, apoB, anthropometric measures, and blood pressures in both genders. Correlations for both were high with serum triglycerides (r(s)=around 0.70) and apoB (r(p)=around 0.37). Total apoC-III as well as both fractions were significantly correlated in women also with levels of inflammatory risk markers: strongly (r=0.40-0.45, P<0.001) with complement C3, and weakly (r(s)=around 0.20, P<0.001) with C-reactive protein. A cutoff of >7.0 mg/dl as opposed to lower levels of nonHDL apoC-III indicated the presence of hypertriglyceridemic hyperapo B with an age-adjusted odds ratio (OR) of 13.8; it indicated the presence of metabolic syndrome with 4.66-fold likelihood. Total apoC-III and nonHDL apoC-III proved to be significantly (P-trend <0.05 and 0.002) and strongly associated with prevalent CHD in men even after adjustment for age, low-density lipoprotein-cholesterol (LDL-C) and high-density lipoprotein-cholesterol (HDL-C): OR gradients across upper and lower quartiles were 3.88-fold (CI: 1.3; 11.4) and 8.8-fold (CI: 2.6; 29.8), respectively. CONCLUSIONS In a population among whom the metabolic syndrome prevails, total- and nonHDL apoC-III are each a determinant in both genders of the metabolic syndrome and of hypertriglyceridemic hyperapo B. Each is a powerful significant marker of prevalent CHD in men independent of LDL- and HDL-C levels. In women, despite being correlated with inflammatory risk markers, the significant association of elevated levels of apoC-III with CHD did not prove to be independent of age.

Glycated Hemoglobin Measurement and Prediction of Cardiovascular Disease

IMPORTANCE The value of measuring levels of glycated hemoglobin (HbA1c) for the prediction of first cardiovascular events is uncertain. OBJECTIVE To determine whether adding information on HbA1c values to conventional cardiovascular risk factors is associated with improvement in prediction of cardiovascular disease (CVD) risk. DESIGN, SETTING, AND PARTICIPANTS Analysis of individual-participant data available from 73 prospective studies involving 294,998 participants without a known history of diabetes mellitus or CVD at the baseline assessment. MAIN OUTCOMES AND MEASURES Measures of risk discrimination for CVD outcomes (eg, C-index) and reclassification (eg, net reclassification improvement) of participants across predicted 10-year risk categories of low (<5%), intermediate (5% to <7.5%), and high (≥ 7.5%) risk. RESULTS During a median follow-up of 9.9 (interquartile range, 7.6-13.2) years, 20,840 incident fatal and nonfatal CVD outcomes (13,237 coronary heart disease and 7603 stroke outcomes) were recorded. In analyses adjusted for several conventional cardiovascular risk factors, there was an approximately J-shaped association between HbA1c values and CVD risk. The association between HbA1c values and CVD risk changed only slightly after adjustment for total cholesterol and triglyceride concentrations or estimated glomerular filtration rate, but this association attenuated somewhat after adjustment for concentrations of high-density lipoprotein cholesterol and C-reactive protein. The C-index for a CVD risk prediction model containing conventional cardiovascular risk factors alone was 0.7434 (95% CI, 0.7350 to 0.7517). The addition of information on HbA1c was associated with a C-index change of 0.0018 (0.0003 to 0.0033) and a net reclassification improvement of 0.42 (-0.63 to 1.48) for the categories of predicted 10-year CVD risk. The improvement provided by HbA1c assessment in prediction of CVD risk was equal to or better than estimated improvements for measurement of fasting, random, or postload plasma glucose levels. CONCLUSIONS AND RELEVANCE In a study of individuals without known CVD or diabetes, additional assessment of HbA1c values in the context of CVD risk assessment provided little incremental benefit for prediction of CVD risk.

Cardiovascular Disease Mortality in Europeans in Relation to Fasting and 2-h Plasma Glucose Levels Within a Normoglycemic Range

OBJECTIVE To study mortality in relation to fasting plasma glucose (FPG) and 2-h plasma glucose levels within the normoglycemic range. RESEARCH DESIGN AND METHODS Data from 19 European cohorts comprising 12,566 men and 10,874 women who had FPG <6.1 mmol/l and 2-h plasma glucose <7.8 mmol/l at baseline examination were analyzed. Multivariate-adjusted hazard ratios (HRs) and 95% CIs for deaths from cardiovascular disease (CVD), non-CVD, and all causes were estimated for individuals whose 2-h plasma glucose > FPG (group II) compared with those whose 2-h plasma glucose ≤ FPG (group I). RESULTS A total of 827 (246) CVD and 611 (351) non-CVD and 1,438 (597) all-cause deaths occurred in men (women). Group II was older and had higher BMI, blood pressure, and fasting insulin than group I. The multivariate-adjusted HRs (95% CIs) for CVD, non-CVD, and all-cause mortality were 1.22 (1.05–1.41), 1.09 (0.92–1.29), and 1.16 (1.04–1.30) in men and 1.40 (1.03–1.89), 0.99 (0.79–1.25), and 1.13 (0.94–1.35) in women, respectively, for group II as compared with group I. HRs were 1.25 (1.05–1.50), 1.09 (0.89–1.34), and 1.18 (1.03–1.35) in men and 1.60 (1.03–2.48), 1.05 (0.78–1.42), and 1.18 (0.93–1.51) in women, respectively, after additional adjustment for fasting insulin in a subgroup of individuals. CONCLUSIONS In individuals with both FPG and 2-h plasma glucose within the normoglycemic range, high 2-h plasma glucose was associated with insulin resistance and increased CVD mortality.