The Effects of an Obesogenic Diet on Liver Oxysterol Metabolism in C57BL/6J Mice

Oxysterols are key regulators of lipid metabolism and play a role in the etiology of atherosclerosis; however, our current understanding of tissue levels of oxysterols during different disease states such as obesity is limited. The purpose of this study was to quantify the effects of obesity induced by a high fat-cholesterol (HFC) diet on liver oxysterol metabolism. Male C57BL/6J mice were fed either a standard control diet (5.0% w/w fat, 0.03% w/w chol) or a HFC (21.0% w/w fat, 0.15% w/w chol) diet for 24 weeks. Comparisons between dietary groups were made with independent sample t-tests. Total body mass and liver tissue mass of the HFC group was greater (33.2±5.2 vs. 49.0±3.6 g and 1.4±0.3 vs. 3.9±0.8 g, respectively; P\u3c0.05) than the control group. In the HFC group, a 3.3 fold increase in lipid mass of the liver tissue was due to increased levels of cholesterol (0.10±0.01 vs. 0.33±0.06 mg/mg protein; P\u3c0.05) and triglyceride (0.37±0.05 vs. 1.49±0.12 mg/mg protein; P\u3c0.05). In the HFC diet, 4β-OH, 5,6β-epoxy, and 27-OH were greater and 7-keto was lower when compared to the control diet. Post-dietary liver 4β-OH, 5,6β-epoxy, and 27-OH were increased in the HFC diet group. Interestingly, despite increased oxysterol levels no significant changes in mRNA levels were observed for oxysterol-related enzymes CYP3A11, CYP27A1 or CYP7A1. The 24-week HFC diet was effective at promoting obesity and hepatic steatosis in mice. Due to the low concentration of oxysterols in the diet, it is unlikely that the oxysterols in the diet had a significant impact on liver oxysterols. Furthermore, our results suggest that the increased hepatic oxysterol levels observed in mice on the obesogenic diet were not due to increased rates of oxysterol synthesis

Cardiac Biomarkers and Subsequent Risk of Hospitalization With Bleeding in the Community: Atherosclerosis Risk in Communities Study

Background hs-cTnT (high-sensitivity cardiac troponin T), but not NT-proBNP (N-terminal pro-B natriuretic peptide), has been shown to predict bleeding in patients with atrial fibrillation. Whether these biomarkers are independently associated with bleeding in the general population is unknown. Methods and Results We used Cox proportional hazards models to examine the association of hs‐cTnT and NT‐proBNP with incident bleeding (defined by International Classification of Diseases, Ninth Revision [ICD‐9] codes) among 9550 middle‐aged men and women without a history of cardiovascular disease or bleeding. There were 847 hospitalizations with bleeding (92% from gastrointestinal bleeding) during a median follow‐up of 9.0 years. Serum levels of hs‐cTnT were associated with bleeding in a graded fashion, with a hazard ratio of 1.28 (95% CI, 1.06–1.59) for 6 to \u3c 9 ng/L, 1.52 (1.21–1.91) for 9 to \u3c 14, and 2.05 (1.56–2.69) for ≥14 versus \u3c 3 ng/L. For NT‐proBNP, the highest category (≥264 versus \u3c 42 pg/mL) showed a hazard ratio of 2.00 (1.59–2.61), and the remaining 3 categories had hazard ratios ranging from 1.2 to 1.3. Individuals in the highest category of both hs‐cTnT and NT‐proBNP had a hazard ratio of 3.03 (1.97–4.68) compared with those in the lowest categories. Conclusions In a community‐based population, elevated hs‐cTnT and NT‐proBNP were associated with bleeding‐related hospitalizations. These biomarkers may have a high utility in identifying people at high risk for bleeding. There is a need for research on the underlying mechanisms linking subclinical cardiac abnormalities and bleeding

Association of rs780094 in \u3ci\u3eGCKR\u3c/i\u3e with Metabolic Traits and Incident Diabetes and Cardiovascular Disease: The ARIC Study

Objective: The minor T-allele of rs780094 in the glucokinase regulator gene (GCKR) associates with a number of metabolic traits including higher triglyceride levels and improved glycemic regulation in study populations of mostly European ancestry. Using data from the Atherosclerosis Risk in Communities (ARIC) Study, we sought to replicate these findings, examine them in a large population-based sample of African American study participants, and to investigate independent associations with other metabolic traits in order to determine if variation in GKCR contributes to their observed clustering. In addition, we examined the association of rs780094 with incident diabetes, coronary heart disease (CHD), and stroke over up mean follow-up times of 8, 15, and 15 years, respectively. Research Design and Methods: Race-stratified analyses were conducted among 10,929 white and 3,960 black participants aged 45–64 at baseline assuming an additive genetic model and using linear and logistic regression and Cox proportional hazards models. Results: Previous findings replicated among white participants in multivariable adjusted models: the T-allele of rs780094 was associated with lower fasting glucose (p = 10-7) and insulin levels (p = 10-6), lower insulin resistance (HOMA-IR, p=10-9), less prevalent diabetes (p = 10-6), and higher CRP (p = 10-8), 2-h postprandial glucose (OGTT, p = 10-6), and triglyceride levels (p = 10-31). Moreover, the T-allele was independently associated with higher HDL cholesterol levels (p = 0.022), metabolic syndrome prevalence (p = 0.043), and lower beta-cell function measured as HOMA-B (p = 0.011). Among black participants, the T-allele was associated only with higher triglyceride levels (p = 0.004) and lower insulin levels (p = 0.002) and HOMA-IR (p = 0.013). Prospectively, the T-allele was associated with reduced incidence of diabetes (p = 10-4) among white participants, but not with incidence of CHD or stroke. Conclusions: Our findings indicate rs780094 has independent associations with multiple metabolic traits as well as incident diabetes, but not incident CHD or stroke. The magnitude of association between the SNP and most traits was of lower magnitude among African American compared to white participants

Biomarkers and degree of atherosclerosis are independently associated with incident atherosclerotic cardiovascular disease in a primary prevention cohort: The ARIC study

Biomarkers and atherosclerosis imaging have been studied individually for association with incident cardiovascular disease (CVD); however, limited data exist on whether the biomarkers are associated with events with a similar magnitude in the presence of atherosclerosis. In this study, we assessed whether the presence of atherosclerosis as measured by carotid intima media thickness (cIMT) affects the association between biomarkers known to be associated with coronary heart disease (CHD) and incident cardiovascular disease (CVD) in a primary prevention cohort

Diabetes medication use and blood lactate level among participants with type 2 diabetes : the atherosclerosis risk in communities carotid MRI study

Background: The objective of this study is to compare lactate levels between users and non-users of diabetes medications under the hypothesis that the level of lactate is a marker of oxidative capacity. Methods: The cross-sectional data of 493 participants aged 61–84 with type 2 diabetes who participated in the Atherosclerosis Risk in Communities Carotid MRI study were analyzed using survey weighted linear regression. Results: Median plasma lactate level was 8.58 (95% CI: 8.23, 8.87) mg/dl. Comparing users of diabetic medications with nonusers, thiazolidinedione use was significantly associated with lower lactate level (7.57 (6.95–8.25) mg/dL vs. 8.78 (8.43–9.14) mg/dL), metformin use with a slightly higher lactate level (9.02 (8.51–9.58) mg/dL vs. 8.36 (7.96–8.77) mg/dL), and sulfonylurea and insulin use were not associated with lactate level. After adjustment for demographic and lifestyle factors, the plasma lactate level for thiazolidinedione users was 15.78% lower than that for non-users (p,0.001). Considering use of each medication separately and in combination did not change the results. Conclusion: In conclusion, thiazolidinedione use was associated with lower plasma lactate level compared to non-use and metformin use was only marginally associated with a slightly higher lactate level. These results are consistent with the previously demonstrated effects of diabetes medications on oxidative metabolism. Further investigation of the role that diabetes medications play in improvement of oxidative metabolism is warrante

Myocardial Injury, Obesity, and the Obesity Paradox

To examine whether pre-heart failure (HF) myocardial injury explains the differential mortality after HF across weight categories

Lipoprotein-associated phospholipase A2 and venous thromboembolism: A prospective study

Plasma lipoprotein-associated phospholipase A2 (Lp-PLA2) is an inflammatory marker associated positively with atherothrombotic risk. Whether Lp-PLA2 is related to risk of venous thromboembolism (VTE) is incompletely studied

Recalibration of Blood Analytes over 25 Years in the Atherosclerosis Risk in Communities Study: Impact of Recalibration on Chronic Kidney Disease Prevalence and Incidence

BACKGROUND: Equivalence of laboratory tests over time is important for longitudinal studies. Even a small systematic difference (bias) can result in substantial misclassification. METHODS: We selected 200 Atherosclerosis Risk in Communities Study participants attending all 5 study visits over 25 years. Eight analytes were remeasured in 2011-2013 from stored blood samples from multiple visits: creatinine, uric acid, glucose, total cholesterol, HDL cholesterol, LDL cholesterol, triglycerides, and high-sensitivity C-reactive protein. Original values were recalibrated to remeasured values with Deming regression. Differences >10% were considered to reflect substantial bias, and correction equations were applied to affected analytes in the total study population. We examined trends in chronic kidney disease (CKD) pre- and postrecalibration. RESULTS: Repeat measures were highly correlated with original values [Pearson r > 0.85 after removing outliers (median 4.5% of paired measurements)], but 2 of 8 analytes (creatinine and uric acid) had differences >10%. Original values of creatinine and uric acid were recalibrated to current values with correction equations. CKD prevalence differed substantially after recalibration of creatinine (visits 1, 2, 4, and 5 prerecalibration: 21.7%, 36.1%, 3.5%, and 29.4%, respectively; postrecalibration: 1.3%, 2.2%, 6.4%, and 29.4%). For HDL cholesterol, the current direct enzymatic method differed substantially from magnesium dextran precipitation used during visits 1-4. CONCLUSIONS: Analytes remeasured in samples stored for approximately 25 years were highly correlated with original values, but 2 of the 8 analytes showed substantial bias at multiple visits. Laboratory recalibration improved reproducibility of test results across visits and resulted in substantial differences in CKD prevalence. We demonstrate the importance of consistent recalibration of laboratory assays in a cohort study

Lipoprotein associated phospholipase A2 activity, apolipoprotein C3 loss-of-function variants and cardiovascular disease: The Atherosclerosis Risk In Communities Study

Lipoprotein-associated phospholipase A2 (LpPLA2) activity was associated with higher CHD risk in a meta-analysis, which was partly dependent on circulating lipid levels. Apolipoprotein C3 loss-of-function (ApoC3 LOF) mutations were related with reduced postprandial lipemia and CHD risk. However, the association of LpPLA2 activity with ApoC3 LOF is not known

Association of High-Density Lipoprotein-Cholesterol Versus Apolipoprotein A-I With Risk of Coronary Heart Disease: The European Prospective Investigation Into Cancer-Norfolk Prospective Population Study, the Atherosclerosis Risk in Communities Study, and the Women's Health Study.

BACKGROUND: The contribution of apolipoprotein A-I (apoA-I) to coronary heart disease (CHD) risk stratification over and above high-density lipoprotein cholesterol (HDL-C) is unclear. We studied the associations between plasma levels of HDL-C and apoA-I, either alone or combined, with risk of CHD events and cardiovascular risk factors among apparently healthy men and women. METHODS AND RESULTS: HDL-C and apoA-I levels were measured among 17 661 participants of the EPIC (European Prospective Investigation into Cancer)-Norfolk prospective population study. Hazard ratios for CHD events and distributions of risk factors were calculated by quartiles of HDL-C and apoA-I. Results were validated using data from the ARIC (Atherosclerosis Risk in Communities) and WHS (Women's Health Study) cohorts, comprising 15 494 and 27 552 individuals, respectively. In EPIC-Norfolk, both HDL-C and apoA-I quartiles were strongly and inversely associated with CHD risk. Within HDL-C quartiles, higher apoA-I levels were not associated with lower CHD risk; in fact, CHD risk was higher within some HDL-C quartiles. ApoA-I levels were associated with higher levels of CHD risk factors: higher body mass index, HbA1c, non-HDL-C, triglycerides, apolipoprotein B, systolic blood pressure, and C-reactive protein, within fixed HDL-C quartiles. In contrast, HDL-C levels were consistently inversely associated with overall CHD risk and CHD risk factors within apoA-I quartiles (P<0.001). These findings were validated in the ARIC and WHS cohorts. CONCLUSIONS: Our findings demonstrate that apoA-I levels do not offer predictive information over and above HDL-C. In fact, within some HDL-C quartiles, higher apoA-I levels were associated with higher risk of CHD events, possibly because of the unexpected higher prevalence of cardiovascular risk factors in association with higher apoA-I levels. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00000479