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1.  Comprehensive analysis of circulating adipokines and hsCRP association with cardiovascular disease risk factors and metabolic syndrome in Arabs 
Background
Cardiovascular diseases (CVD) are a leading cause of death worldwide including the Middle East. This is caused in part by the dysregulation of adipose tissue leading to increased production of pro-inflammatory adipokines and reduction in cardio-protective adipokines such as adiponectin. Ethnicity has been recognized as a major factor in the association between CVD risk factors and the different circulating adipokines. In this study, for the first time, the relationship between traditional cardiovascular risk factors, Metabolic Syndrome (MetS) and circulating level of adipokines in Arab ethnicity was investigated.
Methods
We conducted a population-based cross-sectional survey on 379 adult Arab participants living in Kuwait. Traditional cardiovascular risk factors such as blood pressure (BP), low density lipoprotein (LDL) and triglyceride (TG) were measured. Plasma levels of circulating Leptin, Plasminogen Activator Inhibitor (PAI-1) visfatin, adiponectin, resistin and adipsin were assessed using the multiplexing immunobead-based assay.
Results
Circulating levels of High sensitivity C-Reactive Protein (hsCRP), Leptin, PAI-1 and adiponectin were significantly higher in Arab women than men (p < 0.0001). In multi-variate analysis, the homeostasis model assessment-insulin resistance (HOMA-IR) and body mass index (BMI) showed strong association with most of the biomarkers (p < 0.05). HsCRP showed significant association with all risk factors (p < 0.05). Leptin, PAI-1 and adipsin showed significant positive correlation with BMI, unlike adiponectin which showed inverse correlation (p < 0.05). Subjects in the highest tertile of leptin, PAI-1 and hsCRP had higher odds of having Metabolic Syndrome (MetS) (odd ratio [OR] = 3.02, 95% confidence interval [CI] = 1.47 – 6.19) and (OR = 2.52, 95% CI = 1.45 – 4.35), (OR = 4.26, 95% CI = 2.39 – 7.59) respectively. On the other hand subjects with highest tertile of adiponectin had lower odds of having MetS (OR = 0.22, 95% CI = 0.12 – 0.40). Leptin, PAI-1 and hsCRP showed significant positive association with increased MetS components (P-trend <0.05), while adiponectin was negatively associated with increased MetS components (P-trend <0.0001).
Conclusion
Our results show positive association between hsCRP, leptin, PAI-1 with increased MetS components and increase the odds of having MetS. Adiponectin on the other hand showed inverse correlation with MetS components and associated with reduction in MetS. Overall, our data highlights the significant clinical value these markers have in MetS especially hsCRP which can be used as good marker of low grade inflammation in Arabs.
doi:10.1186/1475-2840-13-76
PMCID: PMC3997236  PMID: 24716628
Adipokine; Arab; Metabolic syndrome; Cardiometabolic risk factors; Lipid profile; hsCRP; Leptin; Adiponectin; Visfatin; Resistin; Adipsin; Low grade inflammation
2.  C-Reactive Protein Modifies the Association of Plasma Leptin With Coronary Calcium in Asymptomatic Overweight Individuals 
Obesity (Silver Spring, Md.)  2011;20(4):856-861.
Evidence suggests putative interactions of leptin and C-reactive protein (CRP) in the pathogenesis of adiposity-related atherosclerotic cardiovascular disease (CVD). Therefore, we investigated whether CRP levels modify the relationship of leptin levels with coronary artery calcium (CAC). We examined 1,460 asymptomatic individuals from two community-based cross-sectional studies coordinated at a single, university-based research center. We focused on subjects who were overweight or obese (BMI ≥25) given greater biologic plausibility in this setting. In multivariable CAC models, we analyzed the interaction of log-transformed plasma leptin levels with higher CRP levels as defined by three cut-points: two clinically based (2 mg/l, 3 mg/l) and one dataset specific (sex-specific upper quartile). The association of plasma leptin with CAC was modified by higher CRP regardless of cut-point (interaction term P values all <0.01 in fully adjusted models). Leptin levels were associated with CAC in those with high, but not low CRP levels (e.g., tobit ratio for a 1 unit increase in ln(leptin) (95% CI): 2.18 (1.29–3.66) if CRP level ≥3 mg/l; N = 461 vs. 0.94 (0.67–1.31) if CRP levels <3 mg/l; N = 999) in fully adjusted models. No interaction with CRP was present in control analyses with adiponectin, BMI and waist circumference. In conclusion, in asymptomatic overweight and obese adults, increased leptin levels were independently associated with increased CAC in the presence of high, but not low CRP levels, supporting a leptin-CRP interface in atherosclerosis risk.
doi:10.1038/oby.2011.164
PMCID: PMC4005808  PMID: 21738237
3.  Lipoprotein(a) is strongly associated with coronary artery calcification in type-2 diabetic women 
Background
Lp(a), implicated in both atherogenesis and thrombosis pathways, varies significantly by demographic and metabolic factors, providing challenges for its use in Coronary Heart Disease (CHD) risk. The purpose of this study was to investigate whether type-2 diabetic subjects, relative to non-diabetics, might benefit more from Lp(a) measurement in the prediction of CHD risk, as measured by coronary artery calcium (CAC).
Methods
We performed cross sectional analyses in two community-based studies: the Penn Diabetes Heart Study [N=1299 with type-2 diabetes] and the Study of Inherited Risk of Coronary Atherosclerosis [N=860 without diabetes].
Results
Blacks had 2–3 fold higher Lp(a) levels than whites in diabetic and non-diabetic samples. There was significant difference by gender (interaction p<0.001), but not race, in the association of Lp(a) with CAC in type-2 diabetic subjects. In age and race adjusted analysis of diabetic women, Lp(a) was associated with CAC [Tobit regression ratio 2.76 (95% CI 1.73–4.40), p<0.001]. Adjustment for exercise, medications, Framingham risk score, metabolic syndrome, BMI, CRP and hemoglobin A1c attenuated this effect, but the association of Lp(a) with CAC remained significant [2.25, (1.34–3.79), p=0.002]. This relationship was further maintained in women stratified by race, or by the use of HRT or lipid lowering drugs. In contrast, Lp(a) was not associated with CAC in diabetic men, nor in non-diabetic men and women.
Conclusions
Lp(a) is a strong independent predictor of CAC in type-2 diabetic women, regardless of race, but not in men. Lp(a) does not relate to CAC in men or women without type-2 diabetes.
doi:10.1016/j.ijcard.2010.02.021
PMCID: PMC3132301  PMID: 20303190
Coronary artery calcium; Lipoprotein(a); Gender; Subclinical atherosclerosis
4.  Gender Differences in the Association of C-Reactive Protein with Coronary Artery Calcium in Type-2 Diabetes 
Clinical endocrinology  2011;74(1):44-50.
Objective
Plasma C-reactive protein (CRP) is associated with cardiovascular disease (CVD) but effects may vary by gender and degree of CVD risk. Whether CRP has value as a CVD risk marker in type-2 diabetes (T2DM) is unclear. We examined whether CRP has gender differences in the association of coronary artery calcium (CAC) in diabetic and non diabetic samples without clinical CVD.
Methods
We performed cross-sectional analyses of gender influence on CRP association with CAC in the Penn Diabetes Heart Study (N = 1299 with T2DM), the Study of Inherited Risk of Coronary Atherosclerosis (N = 860 non diabetic subjects), and a combined sample.
Results
Female gender was associated with higher plasma CRP in diabetic and non-diabetic samples after adjustment for covariates. There was a strong interaction by gender in the association of CRP with CAC (interaction p < 0.001). In diabetic women, CRP was associated with higher CAC even after further adjustment for age, race, medications, metabolic syndrome, Framingham risk score, and body mass index [Tobit ratio 1.60, 95% CI (1.03-2.47)]. Although this relationship was attenuated in non diabetic women, the combined sample maintained this association in fully adjusted models [1.44, 95% CI (1.13-1.83)]. There was no association of CRP with CAC in either diabetic or non diabetic men.
Conclusions
CRP may be a useful marker of cardiovascular risk in women, particularly in diabetic women who otherwise have no known CVD. Prospective studies are needed to better assess gender differences in CRP utility and the use of CRP in T2DM.
doi:10.1111/j.1365-2265.2010.03879.x
PMCID: PMC3005137  PMID: 20874770
Coronary artery calcium; C-reactive protein; Diabetes; Gender
5.  Coronary Calcium Score and Prediction of All-Cause Mortality in Diabetes  
Diabetes Care  2011;34(5):1219-1224.
OBJECTIVE
In diabetes, it remains unclear whether the coronary artery calcium (CAC) score provides additional information about total mortality risk beyond traditional risk factors.
RESEARCH DESIGN AND METHODS
A total of 1,051 participants, aged 34–86 years, in the Diabetes Heart Study (DHS) were followed for 7.4 years. Subjects were separated into five groups using baseline computed tomography scans and CAC scores (0–9, 10–99, 100–299, 300–999, and ≥1,000). Logistic regression was performed adjusting for age, sex, race, smoking, and LDL cholesterol to examine the association between CAC and all-cause mortality. Areas under the curve with and without CAC were compared. Natural splines using continuous measures of CAC were fitted to estimate the relationship between observed CAC and mortality risk.
RESULTS
A total of 17% (178 of 1,051) of participants died during the follow-up. In multivariate analysis, the odds ratios (95% CIs) for all-cause mortality, using CAC 0–9 as the reference group, were CAC 10–99: 1.40 (0.57–3.74); CAC 100–299: 2.87 (1.17–7.77); CAC 300–999: 3.04 (1.32–7.90); and CAC ≥1,000: 6.71 (3.09–16.87). The area under the curve without CAC was 0.68 (95% CI 0.66–0.70), and the area under the curve with CAC was 0.72 (0.70–0.74) (P = 0.0001). Using splines, the estimated risk (95% CI) of mortality for a CAC of 0 was 6.7% (4.6–9.7), and the risk increased nearly linearly, plateauing at CAC ≥1,000 (20.0% [15.7–25.2]).
CONCLUSIONS
In diabetes, CAC was shown to be an independent predictor of mortality. Participants with CAC (0–9) were at lower risk (0.9% annual mortality). The risk of mortality increased with increasing levels of CAC, plateauing at approximately CAC ≥1,000 (2.7% annual mortality). More research is warranted to determine the potential utility of CAC scans in diabetes.
doi:10.2337/dc11-0008
PMCID: PMC3114476  PMID: 21398528
6.  Blood Pressure and Fasting Plasma Glucose Rather Than Metabolic Syndrome Predict Coronary Artery Calcium Progression 
Diabetes Care  2009;32(1):141-146.
OBJECTIVE—To examine the association of the metabolic syndrome, defined by World Health Organization (WHO) and Adult Treatment Panel III (ATP-III) criteria, and its components with coronary artery calcium (CAC) progression.
RESEARCH DESIGN AND METHODS—Participants were 338 older community-dwelling men and women without known heart disease who had measurements of heart disease risk factors and CAC at two clinic visits within an average interval of 4.5 years. Progression was defined as an increase in total CAC volume score ≥2.5 mm3.
RESULTS—At baseline, mean age was 67.6 years; metabolic syndrome was present in 15.1% by WHO criteria and in 11.8% by ATP-III criteria, and 5.3% met both criteria. Participants with WHO-defined metabolic syndrome had a greater change in total CAC volume score than those without (P = 0.001). There was no significant difference in CAC volume change by ATP-III–defined metabolic syndrome status (P = 0.69). Overall, 46.4% of participants were CAC progressors. In logistic regression analyses adjusted for age, sex, smoking status, and LDL cholesterol, neither WHO–nor ATP-III–defined metabolic syndrome predicted CAC progression. Among metabolic syndrome components, only hypertension was independently associated with CAC progression (odds ratio 2.11 [95% CI 1.33–3.3], P = 0.002). Fasting blood glucose (>100 mg/dl) was an independent predictor of CAC progression, but only for the 118 participants younger than age 65 years (2.3 [1.01–5.5], P = 0.04).
CONCLUSIONS—In older adults without known heart disease, blood pressure levels and fasting plasma glucose were better independent determinants of CAC progression than metabolic syndrome itself.
doi:10.2337/dc08-1360
PMCID: PMC2606850  PMID: 18852333
7.  Resistin gene variation is associated with systemic inflammation but not plasma adipokine levels, metabolic syndrome or coronary atherosclerosis in nondiabetic Caucasians 
Clinical endocrinology  2008;70(5):698-705.
Summary
Objective
Resistin causes insulin resistance and diabetes in mice whereas in humans it is linked to inflammation and atherosclerosis. Few human genetic studies of resistin in inflammation and atherosclerosis have been performed. We hypothesized that the −420C>G putative gain-of-function resistin variant would be associated with inflammatory markers and atherosclerosis but not with metabolic syndrome or adipokines in humans.
Design and methods
We examined the association of three resistin polymorphisms, −852A>G, −420C>G and +157C>T, and related haplotypes with plasma resistin, cytokines, C-reactive protein (CRP), adipokines, plasma lipoproteins, metabolic syndrome and coronary artery calcification (CAC) in nondiabetic Caucasians (n = 851).
Results
Resistin levels were higher, dose-dependently, with the −420G allele (CC 5·9 ± 2·7 ng/ml, GC 6·5 ± 4·0 ng/ml and GG 7·2 ± 4·8 ng/ml, trend P = 0·04) after age and gender adjustment [fold higher for GC + GG vs. CC; 1·07 (1·00–1·15), P < 0·05)]. The −852A>G single nucleotide polymorphism (SNP) was associated with higher soluble tumour necrosis factor-receptor 2 (sol-TNFR2) levels in fully adjusted models [1·06 (95% CI 1·01–1·11), P = 0·01)]. The estimated resistin haplotype (GGT) was associated with sol-TNFR2 (P = 0·04) and the AGT haplotype was related to CRP (P = 0·04) in the fully adjusted models. Resistin SNPs and haplotypes were not associated with body mass index (BMI), fasting glucose, insulin resistance, metabolic syndrome, adipokines or CAC scores.
Conclusions
Despite modest associations with plasma resistin and inflammatory biomarkers, resistin 5′ variants were not associated with metabolic parameters or coronary calcification. This suggests that resistin is an inflammatory cytokine in humans but has little influence on adiposity, metabolic syndrome or atherosclerosis.
doi:10.1111/j.1365-2265.2008.03375.x
PMCID: PMC3108432  PMID: 18710472
8.  Usefulness of Insulin Resistance Estimation and the Metabolic Syndrome in Predicting Coronary Atherosclerosis in Type 2 Diabetes Mellitus 
The American journal of cardiology  2011;107(3):406-411.
Metabolic syndrome (MS) definitions predict cardiovascular events beyond traditional risk factors in type 2 diabetic (DM) as well as non-diabetics subjects. We and other have shown that apolipoprotein B (apoB) and non-HDL cholesterol (non-HDL-C) are associated with coronary artery calcification (CAC) in DM. However, the relative value of MS, apoB lipoproteins and estimates of insulin resistance is unknown in predicting atherosclerosis in DM. We performed cross sectional analyses of white subjects in 2 community based studies (N= 611 type 2 diabetic subjects, N= 803 non-diabetic subjects) using multivariate analysis of traditional risk factors and then adding MS, apoB and homeostatic model assessment for insulin resistance (HOMA-IR). Incremental value was tested with likelihood ratio testing. Beyond traditional risk, HOMA-IR [Tobit regression ratio 1.86 (p=0.002)], apoB [1.55 (p=0.001)] and MS [2.37 (p=0.007)] were independently associated with CAC. In nested models, HOMA-IR added value to apoB [1.72 (p=0.008)], MS [1.72 (p=0.011)] and both apoB and MS [1.64 (p=0.021)]. ApoB showed a similar pattern when added to HOMA-IR [1.51 (p=0.004)], MS [1.46 (p=0.005)] and both HOMA-IR and MS [1.48 (p=0.006)]. MS added to apoB [1.99 (p=0.032)], but not HOMA-IR [1.54 (p=0.221)] or both apoB and HOMA-IR [1.32 (p=0.434)]. In conclusion, insulin resistance estimates add value to MS and apoB in predicting CAC scores in DM and warrant further evaluation in clinic for identification of DM patients at higher risk for atherosclerotic cardiovascular disease.
doi:10.1016/j.amjcard.2010.09.035
PMCID: PMC3040419  PMID: 21257006
insulin resistance; apolipoprotein B; coronary artery calcification; type 2 diabetes
9.  Metabolic Risk Susceptibility in Men Is Partially Related to Adiponectin/Leptin Ratio 
Journal of Obesity  2013;2013:409679.
Background. High adiponectin/leptin ratio may be protective from metabolic risks imparted by high triglyceride, low HDL, and insulin resistance. Methods. This cross-sectional study examines plasma adipokine levels in 428 adult men who were subgrouped according to low (<6.5 μg/mL)and high (≥6.5 μg/mL)adiponectin levels or a low or high ratio of adiponectin/leptin. Results. Men with high adiponectin/leptin ratio had lower plasma triglyceride and higher HDL cholesterol than those with low ratio. Similarly, those with high adiponectin/leptin ratio had lower TG/HDL cholesterol ratio and HOMA2-IR than those with low ratio. In contrast, levels of adiponectin or the ratio of adiponectin/leptin did not associate with systolic blood pressure. But the ratio of adiponectin/leptin decreased progressively with the increase in the number of risk factors for metabolic syndrome. Conclusion. Adipokine levels may reflect adipose tissue triglyceride storage capacity and insulin sensitivity. Leptin is an index of fat mass, and adiponectin is a biomarker of triglyceride metabolism and insulin sensitivity. Men with high adiponectin/leptin ratios have better triglyceride profile and insulin sensitivity than men with a low ratio regardless of waist girth.
doi:10.1155/2013/409679
PMCID: PMC3606776  PMID: 23533722
10.  Calcification of coronary arteries and abdominal aorta in relation to traditional and novel risk factors of atherosclerosis in hemodialysis patients 
BMC Nephrology  2013;14:10.
Background
Process of accelerated atherosclerosis specific for uremia increases cardiovascular risk in patients with chronic kidney disease (CKD) and may be influenced by the different structure of arteries. The study assesses the influence of traditional and novel risk factors on calcification of coronary arteries (CAC) and abdominal aorta (AAC) in hemodialysis patients (HD).
Methods
CAC and AAC were assessed by CT in 104 prevalent adult HD and 14 apparently healthy subjects with normal kidney function (control group). Mineral metabolism parameters, plasma levels of FGF-23, MGP, osteoprotegerin, osteopontin, fetuin-A, CRP, IL-6 and TNF-α were measured.
Results
CAC and AAC (calcification score ≥ 1) were found in 76 (73.1%) and 83 (79.8%) HD respectively, more frequent than in the control group. In 7 HD with AAC no CAC were detected. The frequency and severity of calcifications increased with age. Both CAC and AAC were more frequently detected in diabetics (OR = 17.37 and 13.00, respectively). CAC score was significantly greater in males. CAC and AAC scores were correlated significantly with pack-years of smoking and plasma osteoprotegrin levels. However the independent contribution of plasma osteoprotegerin levels was not confirmed in multiple regression analysis. Age (OR = 1.13) and hemodialysis vintage (OR = 1.14) were the independent risk factor favoring the occurrence of CAC; while age (OR = 1.20) was the only predictor of AAC occurrence in HD.
Conclusions
1. AAC precedes the occurrence of CAC in HD patients. 2. The exposition to uremic milieu and systemic chronic microinflammation has more deteriorative effect on the CAC than the AAC.
doi:10.1186/1471-2369-14-10
PMCID: PMC3556324  PMID: 23317172
Atherosclerosis; Risk factors; Hemodialysis
11.  Yield of Screening for Coronary Artery Calcium in Early Middle-Age Adults Based on the 10-Year Framingham Risk Score 
JACC. Cardiovascular imaging  2012;5(9):923-930.
OBJECTIVES
The purpose of this study was to assess the prevalence and distribution of coronary artery calcium (CAC) across Framingham Risk Score (FRS) strata and therefore determine FRS levels at which asymptomatic, young to early middle-age individuals could potentially benefit from CAC screening.
BACKGROUND
High CAC burden is associated with increased risk of coronary events beyond the FRS. Expert panel recommendations for CAC screening are based on data obtained in middle-age and older individuals.
METHODS
We included 2,831 CARDIA (Coronary Artery Risk Development in Young Adults) study participants with an age range of 33 to 45 years. The number needed to screen ([NNS] number of people in each FRS stratum who need to be screened to detect 1 person with a CAC score above the specified cut point) was used to assess the yield of screening for CAC. CAC prevalence was compared across FRS strata using a chi-square test.
RESULTS
CAC scores >0 and ≥100 were present in 9.9% and 1.8% of participants, respectively. CAC prevalence and amount increased across higher FRS strata. A CAC score >0 was observed in 7.3%, 20.2%, 19.1%, and 44.8% of individuals with FRSs of 0 to 2.5%, 2.6% to 5%, 5.1% to 10%, and >10%, respectively (NNS = 14, 5, 5, and 2, respectively). A CAC score of ≥100 was observed in 1.3%, 2.4%, and 3.5% of those with FRSs of 0 to 2.5%, 2.6% to 5%, and 5.1% to 10%, respectively (NNS = 79, 41, and 29, respectively), but in 17.2% of those with an FRS >10% (NNS = 6). Similar trends were observed when findings were stratified by sex and race.
CONCLUSIONS
In this young to early middle-age cohort, we observed concordance between CAC prevalence/amount and FRS strata. Within this group, the yield of screening and possibility of identifying those with a high CAC burden (CAC score of ≥100) is low in those with an FRS of ≤10%, but considerable in those with an FRS >10%.
doi:10.1016/j.jcmg.2012.01.022
PMCID: PMC3664953  PMID: 22974805
coronary artery calcium; coronary heart disease; Framingham Risk Score; number needed to screen; risk factors
12.  Comparison of salivary and plasma adiponectin and leptin in patients with metabolic syndrome 
Background
The relationship of saliva with plasma protein levels makes saliva an attractive diagnostic tool. Plasma levels of adiponectin and leptin in healthy individuals or diabetes mellitus patients have been previously reported. Nevertheless, salivary levels of these adipocytokines in patients with metabolic syndrome (MS) have never been investigated. This study was aimed to determine adiponectin and leptin levels in saliva and plasma from patients with metabolic syndrome, and evaluate any correlation of these levels with MS.
Methods
Forty-six healthy and 82 MS patients were enrolled. Demographic data and blood biochemistries were recorded. Saliva and plasma adiponectin and leptin levels were analyzed by enzyme-linked immunosorbent assay (ELISA).
Results
Adiponectin and leptin were higher in plasma than in saliva (p < .001). Plasma adiponectin was decreased and plasma leptin increased in patients with MS (p < .001). Salivary adiponectin and salivary leptin were not different between healthy subjects and MS patients (p = .619 and p = .523). Correlation between salivary and plasma adiponectin showed significant association (r = .211, p = .018) while salivary and plasma leptin had no correlation (r = -.161, p = .069). Significant correlation was observed between the salivary adiponectin/salivary leptin ratio and plasma adiponectin (r = .371, p < .001), but not with any component of MS. Increased triglyceride and waist circumference were associated with risk of having a low level of plasma adiponectin (OR = 1.009; 95% CI 1.002–1.015 and OR = 1.125; 95% CI 1.029–1.230). For leptin, body mass index and high-density lipoprotein cholesterol (HDL-C) were associated with a high level of plasma leptin (OR = 1.621; 95% CI 1.212–2.168 and OR = .966; 95% CI .938–.996). The OR for MS as predicted by plasma adiponectin was .928 (95% CI .881-.977).
Conclusions
This study showed that salivary adiponectin and leptin do not correlate with MS. Although correlation between salivary and plasma adiponectin was observed, no association with MS was observed. Only plasma adiponectin may be useful for the prediction of MS.
doi:10.1186/1758-5996-6-19
PMCID: PMC3926677  PMID: 24528653
Saliva; Plasma; Adiponectin; Leptin; Metabolic syndrome
13.  Fatty Liver, Insulin Resistance, and Features of Metabolic Syndrome 
Diabetes Care  2012;35(11):2359-2364.
OBJECTIVE
Nonalcoholic fatty liver disease (NAFLD) coexists with insulin resistance (IR), but it is uncertain whether NAFLD and IR contribute independently to atherosclerosis. We tested whether fatty liver, IR, and metabolic syndrome (MetS) features (waist, glucose, triglyceride, HDL cholesterol [HDL-C], and blood pressure) were associated with a marker of atherosclerosis (coronary artery calcium [CAC] score >0), independently of cardiovascular risk factors and cardiovascular disease (CVD).
RESEARCH DESIGN AND METHODS
Data were analyzed from a South Korean occupational cohort of 10,153 people who all received ultrasound measurements of fatty liver and a cardiac computed tomography CAC score. IR was defined by homeostasis model assessment of IR (HOMA-IR) ≥75th percentile. Odds ratios (ORs) (95% CIs) for the presence of a CAC score >0 were estimated using logistic regression.
RESULTS
There were 915 people with a CAC score >0. MetS features were increased (glucose, blood pressure, triglyceride, and waist) or decreased (HDL-C) among people with a CAC score >0 (all comparisons against CAC score ≤0; P < 0.0001). Of subjects with a CAC score >0, 55% had fatty liver and 33.7% were insulin resistant. Fatty liver (OR 1.21 [95% CI 1.01–1.45]; P = 0.04) and HOMA-IR (1.10 [1.02–1.18]; P = 0.02) were associated with CAC score >0, independently of all MetS features, conventional cardiovascular risk factors, and prior evidence of CVD. The presence of IR and fatty liver combined was associated with CAC score >0 (1.53 [1.20–1.95]; P = 0.001).
CONCLUSIONS
Fatty liver and HOMA-IR are both associated with a CAC score >0 (independently of each other), features of MetS, conventional cardiovascular risk factors, and existing CVD.
doi:10.2337/dc12-0515
PMCID: PMC3476919  PMID: 22829522
14.  Association of serum adipocytokine levels with cardiac autonomic neuropathy in type 2 diabetic patients 
Background
Cardiac autonomic neuropathy (CAN) is a common complication of diabetes associated with poor prognosis. In addition, the autonomic imbalance is associated with cardiovascular disease (CVD) in diabetes. It is thought that adipocytokines contribute to the increased risk of vascular complications in patients with type 2 diabetes mellitus (T2DM). However, literature data on the association between CAN with adipocytokines such as leptin, tumor necrosis factor-alpha (TNF-alpha), adiponectin in subjects with T2DM is limited.
Therefore, in the present study, we examined the relationship between fasting serum leptin, TNF- alpha and adiponectin and CAN in Korean T2DM patients.
Methods
A total of 142 T2DM patients (94 males, 48 females) were recruited. CAN was assessed by the five tests according to the Ewing's protocol and the time and frequency domain of the heart rate variability (HRV) was evaluated. Serum TNF-alpha and adiponectin levels were measured using enzyme-linked immunosorbent assay and serum leptin levels were measured using radioimmunoassay.
Results
Although, the mean levels of leptin, TNF-alpha and adiponectin were not significantly different between the groups with and without CAN, the levels of leptin and adiponectin had a tendency to increase as the score of CAN increased (p = 0.05, p = 0.036). Serum leptin levels demonstrated a negative correlation with low frequency (LF) in the upright position (p = 0.037). Regarding TNF-alpha, a significant negative correlation was observed with SDNN and RMSSD in the upright position (p = 0.023, p = 0.019). Adiponectin levels were not related to any HRV parameters. Multivariate logistic regression analysis demonstrated that the odds of CAN increased with a longer duration of diabetes (1.25, [1.07-1.47]) and higher homeostatic model of assessment-insulin resistance (HOMA-IR) (5.47, [1.8-16.5]). The relative risks for the presence of CAN were 14.1 and 51.6 for the adiponectin 2nd, 3rd tertiles when compared with first tertile (p-value for trend = 0.022).
Conclusions
In the present study, the higher serum adiponectin levels and HOMA-IR were associated with an increased risk for the presence of CAN. Also, the CAN score correlated with the serum adiponectin. Serum adipocytokines such as leptin and TNF-alpha were significantly correlated with parameters of HRV, representative markers of CAN. Future prospective studies with larger number of patients are required to establish a direct relationship between plasma adipocytokine concentrations and the development or severity of CAN.
doi:10.1186/1475-2840-11-24
PMCID: PMC3353195  PMID: 22413919
Cardiac autonomic neuropathy; heart rate variability; leptin; TNF- alpha; adiponectin; type 2 diabetes mellitus
15.  Risk Factors for Coronary Artery Calcium Among Patients with Chronic Kidney Disease (From the Chronic Renal Insufficiency Cohort Study) 
The American journal of cardiology  2012;110(12):1735-1741.
Cardiovascular disease is the leading cause of death in patients with chronic kidney disease (CKD). We examined the cross-sectional association between novel risk factors and coronary artery calcium (CAC) measured by electron-beam computed tomography or multidetector computed tomography among 2,018 patients with CKD. Based on total Agatston scores, participants were classified as no (0), moderate (>0–100) or high (>100) CAC. After adjustment for age, sex, race, study sites, cigarette smoking, prior cardiovascular disease, hypertension, and diabetes, use of lipid-lowering drugs, body-mass index, waist circumference, and cystatin C, several novel risk factors were significantly associated with high CAC. For example, odds ratios (95% confidence interval) of high CAC associated with one standard deviation higher levels of risk factors were 1.20 (1.04, 1.38) for serum calcium, 1.21 (1.04, 1.41) for serum phosphate, 0.83 (0.71, 0.97) for log (total parathyroid hormone), 1.21 (1.03, 1.43) for log (HOMA-insulin resistance), and 1.23 (1.04, 1.45) for hemoglobin A1c. Additionally, the multivariable-adjusted odds ratio for one standard deviation higher level of cystatin C was 1.31 (1.14, 1.50). Serum high-sensitive C-reactive protein, interleukin-6, tumor necrosis factor-α, and homocysteine were not statistically significantly associated with high CAC. In conclusion, these data indicate that abnormal calcium and phosphate metabolism, insulin resistance, and declined kidney function were associated with the prevalence of high CAC independent of traditional risk factors in patients with CKD. Further studies are warranted to examine the causal effect of these risk factors on CAC in CKD patients.
doi:10.1016/j.amjcard.2012.07.044
PMCID: PMC3511639  PMID: 22980963
calcium; chronic kidney disease; coronary artery calcium; cystatin C; insulin-resistance; phosphate; total parathyroid hormone
16.  Factors Associated with Presence and Extent of Coronary Calcium in Individuals Predicted to be at Low Risk Based on Framingham Risk Score (From The Multi-Ethnic Study of Atherosclerosis) 
The American journal of cardiology  2011;107(6):879-885.
Even among asymptomatic people at low risk (<10%) by Framingham Risk Score (FRS), high coronary artery calcium (CAC) scores signify higher predicted risk of coronary heart disease (CHD) events. We sought to determine non-invasive factors (without radiation exposure) significantly associated with CAC in low-risk, asymptomatic persons. In a cross-sectional analysis, we studied 3046 participants from MESA at low 10-year predicted risk (FRS <10%) for CHD events. Multivariable logistic regression was used to assess the association of novel markers with presence of any CAC (CAC >0) and advanced CAC (CAC ≥ 300). CAC >0 and CAC ≥ 300 were present in 30% and 3.5% of participants, respectively. Factor VIIIc, fibrinogen and sICAM were each associated with CAC presence (P ≤ 0.02); and C-reactive protein, D-dimer and carotid intima-media thickness (CIMT) with advanced CAC (P ≤ 0.03). The base model combining traditional risk factors had excellent discrimination for advanced CAC (C-statistic, 0.808). Addition of the 2 best-fit models combining biomarkers plus/minus CIMT improved the c-statistics to 0.822 and 0.820, respectively. All 3 models calibrated well, but were similar in estimating individual risk probabilities for advanced CAC (prevalence = 9.97%, 10.63% and 10.10% in the highest quartiles of predicted probabilities versus 0.26%, 0.26% and 0.26% in the lowest quartiles, respectively). In conclusion, in low risk individuals, traditional risk factors alone predicted advanced CAC with high discrimination and calibration. Biomarker combinations +/− CIMT were also significantly associated with advanced CAC, but improvement in prediction and estimation of clinical risk were modest compared to traditional risk factors alone.
doi:10.1016/j.amjcard.2010.10.072
PMCID: PMC3182475  PMID: 21376929
coronary calcium; biomarkers; novel markers; low-risk; risk factors
17.  Adipocytokine Profile and Insulin Resistance in Childhood Obesity 
Mædica  2012;7(3):205-213.
ABSTRACT
Background: Adipose tissue is a veritable "endocrine organ" due to its adipocytokines secretion implied in insulin sensitivity modulation and cardiovascular complications.
Objective: To identify the adipocytokines' plasmatic profile (adiponectin, leptin, resistin, IL-6, TNFα) in obese children and adolescents and to assess their relationship with "classic" clinical/paraclinical markers of metabolic syndrome and insulin resistance.
Material and Methods: A case-control study comparing a study group of 38 obese children and adolescents (age 13.5±2.3 years) to a normal weight age matched control group of 24 children.
We measured body mass index (BMI) and waist circumference (WC), systolic and diastolic blood pressure (BP). The classical metabolic parameters (fasting glycemia, total cholesterol and its fractions, serum triglycerides) were measured in both groups. Insulin sensitivity was evaluated using fasting insulinemia, HOMA-index and insulin-resistance summary score (IRS). Adiponectin, leptin, resistin, IL-6 and TNFα were measured using ELISA method.
Outcomes: Serum levels of leptin, resistin and IL-6 were signficantly higher (42.42±22.58 ng/ml versus 14.4±14.49 ng/ml, p <0.001; 9.69±3.47 ng/ml versus 7.92±2.13ng/ml, p = 0.029 and 2.66 ±2.87 pg/ml versus 0.89 ± 1.16 pg/ml, p = 0.006 respectively), while adiponectin levels were significantly lower (9.05±4.61 µg/ml versus 15.93±9.24 μg/ml, p <0.001) in the obese group compared to control group. TNFα was not statistical different between groups.
In multivariate regression analysis adiponectin was negatively and significantly correlated with WC (r = - 0.463, p = 0.003); leptin was positively and significantly related to WC, diastolic BP, fasting insulinemia and resistin (r = 0.775, p <0.001); resistin was positively related to leptin and IL-6 (r = 0.499, p <0.001), IL-6 was positively and significantly related to diastolic blood pressure (r = 0.333, p = 0.008).
Conclusions: Serum levels of adiponectin, leptin, resistin and IL-6 are significantly different in obese children compared to normal weight controls; leptin was the only adipokine correlated with insulin resistance in children. There are significant correlations between plasmatic levels of leptin, resistin and IL-6.
Simple plasmatic determination of TNFα is not a marker of the degree of obesity or its metabolic complications in pediatric population.
PMCID: PMC3566883  PMID: 23400230
adipokine; cytokine; obesity; children
18.  Sepsis induced changes of adipokines and cytokines - septic patients compared to morbidly obese patients 
BMC Surgery  2010;10:26.
Background
Hyperglycemia and insulin resistance frequently occur in critically ill and in morbidly obese (MO) patients. Both conditions are associated with altered serum levels of cytokines and adipokines. In addition, obesity related alterations in adipokine expression contribute to insulin resistance in metabolic syndrome. In this study we examined the serum adipocytokine profile in critically ill patients, MO patients, and healthy blood donors.
Methods
33 patients who fulfilled the clinical criteria for severe sepsis or septic shock (SP) were prospectively enrolled in this study. A multiplex analysis was performed to evaluate plasma levels of adiponectin, resistin, leptin, active PAI-1, MCP-1, IL-1 alpha, IL-6, IL-8, IL-10, and TNF-alpha in 33 critically ill patients, 37 MO patients and 60 healthy blood donors (BD).
Results
In SP, adiponectin was significantly lowered and resistin, active PAI-1, MCP-1, IL-1 alpha, IL-6, IL-8, IL-10, and TNF-alpha were significantly elevated compared to BD. Leptin levels were unchanged. In MO, adiponectin and IL-8 were significantly lowered, leptin, active PAI-1, MCP-1, IL-1 alpha, IL-6, and IL-10 significantly elevated, whereas resistin was unaltered.
In SP, adiponectin correlated negatively with BMI, SAPS II and SOFA scores, while resistin correlated positively with SAPS II and SOFA scores and leptin correlated positively with the BMI. Adiponectin was approximately equally diminished in SP and MO compared to BD. With the exception of active PAI-1, cytokine levels in SP were clearly higher compared to MO.
Conclusion
A comparable adipocytokine profile was determined in critically ill and MO patients. As in MO, SP showed reduced adiponectin levels and elevated MCP-1, active PAI-1, IL-1 alpha, IL-6, and IL-10 levels. Leptin is only elevated in MO, while resistin, IL-8, and TNF-alpha is only elevated in SP. As in MO patients, increased levels of proinflammatory cytokines and altered levels of adipokines may contribute to the development of insulin resistance in critically ill patients.
doi:10.1186/1471-2482-10-26
PMCID: PMC2944119  PMID: 20825686
19.  Type 2 diabetes does not attenuate racial differences in coronary calcification 
Aims
Coronary artery calcification (CAC) is a strong predictor of atherosclerotic cardiovascular disease (CVD). Whites appear to have a higher prevalence of CAC than African-Americans (AAs), but it is unknown if type 2 diabetes, a major cardiovascular risk factor, attenuates this difference. We investigated the relationship of race and CAC in a sample of patients with type 2 diabetes without clinical CVD.
Methods
Multivariable analyses of self-reported ethnicity and CAC scores, stratified by gender, in 861 subjects [32% AA, 66.9% male] with type 2 diabetes.
Results
AA race was associated with lower CAC scores in age-adjusted models in males [Tobit ratio for AAs vs. Whites 0.14 (95% CI 0.08–0.24, p < 0.001)] and females [Tobit ratio 0.26 (95% CI 0.09–0.77, p = 0.015)]. This persisted in men after adjustment for traditional, metabolic and inflammatory risk factors, but adjustment for plasma triglycerides [0.48 (95% CI 0.15–1.49, p = 0.201)] and HOMA-IR [0.28 (95% CI 0.08–1.03, p = 0.055)] partially attenuated the association in women.
Conclusions
Relative to African-Americans, White race is a strong predictor of CAC, even in the presence of type 2 diabetes. The relationship in women appears less robust possibly due to gender differences in metabolic risk factors.
doi:10.1016/j.diabres.2010.07.004
PMCID: PMC3092471  PMID: 21067835
Race; Coronary artery calcification; Atherosclerosis; Type 2 diabetes
20.  Metabolic Health Is More Closely Associated with Coronary Artery Calcification than Obesity 
PLoS ONE  2013;8(9):e74564.
Background
Recent studies have suggested that metabolic health may contribute more to the atherosclerosis than obesity. The aim of this study is to compare coronary artery calcium scores (CACS) among patients with different metabolic health and obesity status.
Methods
A health-screening program of 24,063 participants (mean age 41 years) was conducted, and CACS was assessed by multi-detector computerized tomography (MDCT). Being metabolically healthy was defined as having fewer than two of the following risk factors: high blood pressure, high fasting blood glucose, high triglyceride, low high-density lipoprotein cholesterol, highest decile of homeostasis model assessment-insulin resistance (HOMA-IR) index, and highest decile of high-sensitivity C-reactive protein (hs-CRP). Obesity status was defined as body mass index (BMI) higher than 25 kg/m2. Analyses were performed in four groups divided according to metabolic health and obesity: metabolically healthy non-obese (MHNO), metabolically healthy obese (MHO), metabolically unhealthy non-obese (MUHNO), and metabolically unhealthy obese (MUHO).
Results
Mean values of CACS in the four groups were significantly different, except those between MHNO and MHO and between MUHNO and MUHO. When multinomial logistic regression analysis was performed with five CACS categories as the dependent variables and after adjusting for age, sex, and smoking status, the MHO, MUHNO, and MUHO groups showed significantly increased odds ratio for increasing CACS categories compared with no calcification status (5.221 for CACS >400 in MUHO group with 95% CI 2.856∼5.032 with MHNO group as the reference). When other variables including the metabolic parameters were included in the same model, the risks were attenuated.
Conclusion
Metabolic health is more closely associated with subclinical atherosclerosis than obesity as assessed by CACS.
doi:10.1371/journal.pone.0074564
PMCID: PMC3770589  PMID: 24040286
21.  The Relationship Between Insulin Resistance and Incidence and Progression of Coronary Artery Calcification 
Diabetes Care  2011;34(3):749-751.
OBJECTIVE
We sought to determine whether insulin resistance predicts the incidence and progression of coronary artery calcification (CAC).
RESEARCH DESIGN AND METHODS
We studied 5,464 participants not on hypoglycemic therapy from the Multi-Ethnic Study of Atherosclerosis (MESA). Each had baseline homeostasis model assessment of insulin resistance (HOMA-IR) and baseline and follow-up CAC scores. Incident CAC was defined as newly detectable CAC; progression was defined as advancing CAC volume score at follow-up.
RESULTS
Median HOMA-IR was 1.2 (0.8–2.0). Across all ethnicities, there was a graded increase in CAC incidence and progression with increasing HOMA-IR. When compared with those in the 1st quartile, participants in the 2nd–4th quartiles had 1.2, 1.5, and 1.8 times greater risk of developing CAC. Median annualized CAC score progression was 8, 14, and 17 higher, respectively. However, HOMA-IR was not predictive after adjustment for metabolic syndrome components.
CONCLUSIONS
HOMA-IR predicts CAC incidence and progression, but not independently of metabolic syndrome.
doi:10.2337/dc10-1681
PMCID: PMC3041221  PMID: 21292863
22.  Soluble CD14 is independently associated with coronary calcification and extent of subclinical vascular disease in treated HIV infection 
AIDS (London, England)  2014;28(7):969-977.
Objective
To use multimodality imaging to explore the relationship of biomarkers of inflammation, T-cell activation and monocyte activation with coronary calcification and subclinical vascular disease in a population of HIV-infected patients on antiretroviral therapy (ART).
Design
Cross-sectional.
Methods
A panel of soluble and cellular biomarkers of inflammation and immune activation was measured in 147 HIV-infected adults on ART with HIV RNA less than 1000 copies/ml and low-density lipoprotein cholesterol (LDL-C) 130 mg/dl or less. We examined the relationship of biomarkers to coronary calcium (CAC) score and multiple ultrasound measures of subclinical vascular disease.
Results
Overall, median (interquartile range, IQR) age was 46 (40–53) years; three-quarters of participants were male and two-thirds African-American. Median 10-year Framingham risk score was 6%. Participants with CAC more than 0 were older, less likely to be African-American and had higher current and lower nadir CD4+ T-cell counts. Most biomarkers were similar between those with and without CAC; however, soluble CD14 was independently associated with CAC after adjustment for traditional risk factors. Among those with a CAC score of zero, T-cell activation and systemic inflammation correlated with carotid intima–media thickness and brachial hyperemic velocity, respectively. Compared with normal participants and those with CAC only, participants with increasing degrees of subclinical vascular disease had higher levels of sCD14, hs-CRP and fibrinogen (all P<0.05).
Conclusion
Soluble CD14 is independently associated with coronary artery calcification, and, among those with detectable calcium, predicts the extent of subclinical disease in other vascular beds. Future studies should investigate the utility of multimodality imaging to characterize vascular disease phenotypes in this population.
doi:10.1097/QAD.0000000000000158
PMCID: PMC4097603  PMID: 24691204
carotid intima–media thickness; coronary artery calcium; endothelial function; HIV; inflammation; microbial translocation; soluble CD14
23.  Unacylated Ghrelin is associated with the isolated low HDL-cholesterol obese phenotype independently of insulin resistance and CRP level 
Background
Low plasma high-density lipoprotein-cholesterol (HDL-c) level is commonly present in obesity and represents an independent cardiovascular risk factor. However, obese patients are a very heterogeneous population and the factors and mechanisms that contribute to low HDL-c remain unclear. The aim of this study was to investigate the association between plasma HDL-c levels and plasma hormonal profiles (insulin, adiponectin, resistin, leptin and ghrelin) in subsets of class II and III obese patients.
Methods
Fasting plasma levels of glucose, total cholesterol, LDL-c, HDL-c, triglycerides, free fatty acids, apoproteins A-I, B-100, B-48, C-II, C-III, insulin, hs-CRP, adipocytokines (adiponectin, resistin, leptin), unacylated ghrelin, body composition (DXA) and resting energy expenditure were measured in three subsets of obese patients: 17 metabolically abnormal obese (MAO) with metabolic syndrome and the typical metabolic dyslipidaemia, 21 metabolically healthy obese (MHO) without metabolic syndrome and with a normal lipid profile, and 21 isolated low HDL-c obese patients (LHO) without metabolic syndrome, compared to 21 healthy lean control subjects.
Results
Insulin resistance (HOMA-IR) increased gradually from MHO to LHO and from LHO to MAO patients (p < 0.05 between MHO and MAO and between LHO and MAO). In multiple regression analysis, serum unacylated ghrelin levels were only positively and independently associated with HDL-c levels in the LHO group (p = 0.032).
Conclusions
These results suggest that, in class II and III obese patients with an isolated low HDL-c phenotype, unacylated ghrelin is positively associated with HDL-c level independently of insulin resistance and CRP levels, and may contribute to the highly prevalent low HDL-c level seen in obesity.
doi:10.1186/1743-7075-9-17
PMCID: PMC3317856  PMID: 22413940
Adiponectin; Apolipoprotein; Cardiovascular risk; Ghrelin; HDL-cholesterol; Inflammation; Insulin resistance; Lipids; Obesity
24.  Distribution of Coronary Artery Calcium Scores by Framingham 10-Year Risk Strata in the Multi-Ethnic Study of Atherosclerosis (MESA): Potential Implications for Coronary Risk Assessment 
Objectives
By examining the distribution of CAC across FRS strata in a large, multi-ethnic, community-based sample of men and women, we sought to determine if lower risk persons could potentially benefit from CAC screening.
Background
The 10-year Framingham risk scores (FRS) and coronary artery calcium (CAC) are predictors of coronary heart disease (CHD). CAC ≥300 is associated with the highest risk for CHD even in low risk (FRS <10%) persons; however expert groups have suggested CAC screening only in intermediate risk (FRS 10–20%) groups.
Methods
We included 5660 MESA participants. The number needed to screen [number of people that need to be screened to detect one person with CAC above the specified cut-point (NNS)] was used to assess the yield of screening for CAC. CAC prevalence was compared across FRS strata using chi-square tests.
Results
CAC >0, ≥100 and ≥300 were present in 46.4%, 20.6% and 10.1% of participants, respectively. Prevalence and amount of CAC increased with higher FRS. CAC ≥300 was observed in 1.7% and 4.4% of those with FRS 0–2.5% and 2.6–5%, respectively (NNS =59.7 and 22.7). Likewise, CAC ≥300 was observed in 24% and 30% of those with FRS 15.1–20% and >20%, respectively (NNS =4.2 and 3.3). Trends were similar when stratified by age, gender and race/ethnicity.
Conclusions
Our study suggests that in very low risk individuals (FRS ≤5%), the yield of screening and probability of identifying persons with clinically significant levels of CAC is low, but becomes greater in low and intermediate risk persons (FRS 5.1–20%).
doi:10.1016/j.jacc.2010.11.053
PMCID: PMC3268231  PMID: 21527159
Framingham risk score; coronary calcium; coronary heart disease; number needed to screen; risk factors; population; atherosclerosis; low risk
25.  Coronary Calcium Score Predicts Cardiovascular Mortality in Diabetes 
Diabetes Care  2013;36(4):972-977.
OBJECTIVE
In type 2 diabetes mellitus (T2DM), it remains unclear whether coronary artery calcium (CAC) provides additional information about cardiovascular disease (CVD) mortality beyond the Framingham Risk Score (FRS) factors.
RESEARCH DESIGN AND METHODS
A total of 1,123 T2DM participants, ages 34–86 years, in the Diabetes Heart Study followed up for an average of 7.4 years were separated using baseline computed tomography scans of CAC (0–9, 10–99, 100–299, 300–999, and ≥1,000). Logistic regression was performed to examine the association between CAC and CVD mortality adjusting for FRS. Areas under the curve (AUC) with and without CAC were compared. Net reclassification improvement (NRI) compared FRS (model 1) versus FRS+CAC (model 2) using 7.4-year CVD mortality risk categories 0% to <7%, 7% to <20%, and ≥20%.
RESULTS
Overall, 8% of participants died of cardiovascular causes during follow-up. In multivariate analysis, the odds ratios (95% CI) for CVD mortality using CAC 0–9 as the reference group were, CAC 10–99: 2.93 (0.74–19.55); CAC 100–299: 3.17 (0.70–22.22); CAC 300–999: 4.41(1.15–29.00); and CAC ≥1,000: 11.23 (3.24–71.00). AUC (95% CI) without CAC was 0.70 (0.67–0.73), AUC with CAC was 0.75 (0.72–0.78), and NRI was 0.13 (0.07–0.19).
CONCLUSIONS
In T2DM, CAC predicts CVD mortality and meaningfully reclassifies participants, suggesting clinical utility as a risk stratification tool in a population already at increased CVD risk.
doi:10.2337/dc12-1548
PMCID: PMC3609509  PMID: 23230101

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