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1.  Aortic Valve Calcium Independently Predicts Coronary and Cardiovascular Events in a Primary Prevention Population 
Jacc. Cardiovascular Imaging  2012;5(6):619-625.
This study aimed to test whether aortic valve calcium (AVC) is independently associated with coronary and cardiovascular events in a primary-prevention population.
Aortic sclerosis is associated with increased cardiovascular morbidity and mortality among the elderly, but the mechanisms underlying this association remain controversial and it is unknown if this association extends to younger individuals.
We performed a prospective analysis of 6,685 participants in the Multi-Ethnic Study of Atherosclerosis. All subjects, aged 45-84 years and free of clinical cardiovascular disease at baseline, underwent computed tomography for AVC and coronary artery calcium (CAC) scoring. The primary, pre-specified combined endpoint of cardiovascular events included myocardial infarctions, fatal and non-fatal strokes, resuscitated cardiac arrest and cardiovascular death, while a secondary combined endpoint of coronary events excluded strokes. The association between AVC and clinical events was assessed using Cox proportional hazards regression with incremental adjustments for demographics, cardiovascular risk factors, inflammatory biomarkers and subclinical coronary atherosclerosis.
Over a median follow up of 5.8 [IQR 5.6, 5.9] years, adjusting for demographics and cardiovascular risk factors, subjects with AVC (n=894, 13.4%) had higher risks of cardiovascular (HR, 1.50; 95% CI, 1.10-2.03) and coronary (HR, 1.72; 95% CI, 1.19-2.49) events compared to those without AVC. Adjustments for inflammatory biomarkers did not alter these associations, but adjustment for CAC substantially attenuated both cardiovascular (HR, 1.32; 95% CI: 0.98-1.78) and coronary (HR, 1.41; 95% CI, 0.98-2.02) event risk. AVC remained predictive of cardiovascular mortality even after full adjustment (HR, 2.51; 95% CI, 1.22-5.21).
In this multiethnic MESA cohort, free of clinical cardiovascular disease, AVC predicts cardiovascular and coronary event risk independent of traditional risk factors and inflammatory biomarkers, likely due to the strong correlation between AVC and subclinical atherosclerosis. The association of AVC with excess cardiovascular mortality beyond coronary atherosclerosis risk merits further investigation.
PMCID: PMC3376353  PMID: 22698532
2.  Inflammatory proteins on HDL: What are we measuring? 
Translational Research  2007;150(3):150-152.
PMCID: PMC3380078  PMID: 17761366
glycophosphotidylinosital-specific phospholipase D; high density lipoprotein; atherosclerosis; macrophage; obesity; inflammation
3.  Plasma glycosylphosphatidylinositol-specific phospholipase D predicts the change in insulin sensitivity in response to a low fat but not a low carbohydrate diet in obese women 
Metabolism: clinical and experimental  2008;57(4):10.1016/j.metabol.2007.11.007.
Although circulating glycosylphosphatidylinositol-specific phospholipase D, a minor high density lipoprotein-associated protein, is elevated in patients with insulin resistance or high triglycerides, no information is available on the effect of weight loss or changes in insulin sensitivity on circulating glycosylphosphatidylinositol-specific phospholipase D levels.
Determine the effect of weight loss and changes in insulin sensitivity on plasma glycosylphosphatidylinositol-specific phospholipase D levels.
Forty two non-diabetic obese women.
Three month dietary intervention randomizing patients to a low fat or a low carbohydrate diet.
Main outcome measures
Plasma glycosylphosphatidylinositol-specific phospholipase D levels and insulin sensitivity as estimated by the homeostasis model assessment.
The very low carbohydrate diet group lost more weight after 3 months (−7.6 ± 3.2 vs. −4.2 ± 3.5 kg, P < 0.01) although the decrease in insulin resistance was similar between groups. Weight loss with either diet did not alter plasma glycosylphosphatidylinositol-specific phospholipase D levels. However, baseline glycosylphosphatidylinositol-specific phospholipase D levels correlated with the change in insulin sensitivity in response to the low fat diet while baseline insulin sensitivity correlated the change in insulin sensitivity in response to the low carbohydrate diet.
Plasma GPI-PLD may serve as a clinical tool to determine the effect of a low fat diet on insulin sensitivity.
PMCID: PMC3857163  PMID: 18328347
glycosylphosphatidylinositol phospholipase D; diet; obesity; insulin sensitivity; women
4.  Risk Factors Associated with the Incidence and Progression of Mitral Annulus Calcification: The Multi-Ethnic Study of Atherosclerosis 
American heart journal  2013;166(5):904-912.
Significant cardiovascular morbidity has been associated with mitral annulus calcification (MAC), but limited data exist regarding its progression. The purpose of this study was to examine the natural history of and risk factors for MAC progression.
The Multi-Ethnic Study of Atherosclerosis (MESA) is a longitudinal cohort study of participants aged 45–84 years without clinical cardiovascular disease who underwent serial cardiac computed tomography studies with quantification of MAC. Regression models were used to identify risk factors associated with MAC incidence and progression.
Prevalent MAC was observed in 534 of 5,895 (9%) participants. Over a median 2.3 years, 280 (5%) developed incident MAC. After adjustment, age was the strongest predictor of incident MAC (adjusted OR, 2.25 per 10 yrs; 95% CI, 1.97 to 2.58; P<0.0001). Female gender, white ethnicity, body mass index, diabetes, hypertension, hyperlipidemia, serum cholesterol, smoking, and interleukin-6 were also significant predictors of incident MAC. In participants with prevalent MAC, the median rate of change was 10.1 [IQR, −6.7, 60.7] Agatston units (AU)/year. Baseline MAC severity was the predominant predictor of rate of MAC progression (β-coefficient per 10 AU, 0.88; 95% CI, 0.85 to 0.91; P<0.0001), although ethnicity and smoking status possessed modest influence.
Several cardiovascular risk factors predicted incident MAC, as did female gender. Severity of baseline MAC was the primary predictor of MAC progression, suggesting that, while atherosclerotic processes may initiate MAC, they are only modestly associated with its progression over these time frames.
PMCID: PMC3978772  PMID: 24176447
calcification; mitral valve; progression; risk factors; gender
5.  Relationship of Apolipoproteins A-1 and B, and Lipoprotein (a) to Cardiovascular Outcomes in the AIM-HIGH Trial 
The aim was to examine the relationship between baseline and on-study apolipoproteins (apo) A-1 and B and lipoprotein(a) [Lp(a)] levels and the development of subsequent cardiovascular (CV) events in the AIM-HIGH Trial.
Niacin has been reported to lower apoB and Lp(a) and to raise apoA-1.
Individuals with CV disease and low baseline levels of HDL-C were randomized to simvastatin plus placebo or simvastatin plus extended-release niacin (ERN, 1500–2000 mg/day), with ezetimibe added, as needed, in both groups to maintain an on-treatment LDL-C in the range of 40–80 mg/dL. Hazard ratios (HR) were used to evaluate the relationship between levels of apo A-1, apoB and Lp(a) and CV events in each treatment group.
Baseline apoB and the apoB/apoA-I ratio were significantly predictive of CV events only for the placebo group (HR=1.17, p=0.018 and HR=1.19, p=0.016). Baseline and on-study Lp(a) were predictive of CV events in both simvastatin+placebo (baseline HR= 1.24, p=0.002 and on-study HR=1.21, p=0.017) and the simvastatin+ERN group (baseline HR=1.25, p=0.001 and on-study HR=1.18 p=0.028). ERN modestly increased 1-year apoA-1 (7%), decreased apoB (13%), decreased the ApoB/ApoA-1 ratio (19%), and decreased Lp(a) 21%, but did not reduce CV events.
Lp(a) was associated with increased CV risk in both treatment groups indicating that it contributes to residual CV risk. However, there was no evidence that ERN reduced CV risk despite favorable lipoprotein changes.
PMCID: PMC3800510  PMID: 23973688
6.  Relationship of Lipoproteins to Cardiovascular Events in the Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides and Impact on Global Health Outcomes (AIM-HIGH) Trial 
Journal of the American College of Cardiology  2013;62(17):10.1016/j.jacc.2013.07.023.
In this secondary analysis of the AIM-HIGH trial, the objectives were to examine the relationship between niacin treatment, lipoproteins, and cardiovascular (CV) outcomes.
During 3-year follow-up in 3,414 patients with established CV disease and low HDL-C, combined niacin + LDL-lowering therapy did not reduce CV events versus LDL-lowering therapy alone.
Subjects taking simvastatin + ezetimibe were randomized to extended-release (ER) niacin 1500–2000 mg or minimal immediate-release niacin (<150 mg) as placebo at bedtime. LDL-C in both groups was maintained from 40 to 80 mg/dL. Hazard ratios (HR) were estimated by Cox proportional hazards for relationships between lipoproteins and the composite endpoint of CV death, myocardial infarction, acute coronary syndrome, ischemic stroke, or symptom-driven revascularization.
CV outcomes were not associated with ER niacin in any baseline lipoprotein tertile. In a subset of patients in both the highest triglyceride (>198 mg/dl) and lowest HDL-C (<33 mg/dl) tertiles, ER niacin showed a trend toward benefit (HR=0.74, p=0.073). In-trial LDL-C, nonHDL-C, and TC/HDL-C ratio were positively associated with CV events in the control group, but these relationships were absent in the ER niacin group.
Baseline lipoprotein tertiles did not predict differential benefit or harm with ER niacin added to LDL-lowering therapy, but a small dyslipidemic subgroup may benefit. ER niacin attenuated expected relationships of lipoprotein risk factors with CV events, raising the possibility that nonlipoprotein actions of niacin could impact risk.
Clinical trial info
AIM-HIGH; NCT00120289
PMCID: PMC3862446  PMID: 23916935
niacin; cardiovascular events; clinical trial; lipoproteins; GPR109A
7.  Deletion of Serum Amyloid A3 Improves High Fat High Sucrose Diet-Induced Adipose Tissue Inflammation and Hyperlipidemia in Female Mice 
PLoS ONE  2014;9(9):e108564.
Serum amyloid A (SAA) increases in response to acute inflammatory stimuli and is modestly and chronically elevated in obesity. SAA3, an inducible form of SAA, is highly expressed in adipose tissue in obese mice where it promotes monocyte chemotaxis, providing a mechanism for the macrophage accumulation that occurs with adipose tissue expansion in obesity. Humans do not express functional SAA3 protein, but instead express SAA1 and SAA2 in hepatic as well as extrahepatic tissues, making it difficult to distinguish between liver and adipose tissue-specific SAA effects. SAA3 does not circulate in plasma, but may exert local effects that impact systemic inflammation. We tested the hypothesis that SAA3 contributes to chronic systemic inflammation and adipose tissue macrophage accumulation in obesity using mice deficient for Saa3 (Saa3−/−). Mice were rendered obese by feeding a pro-inflammatory high fat, high sucrose diet with added cholesterol (HFHSC). Both male and female Saa3−/− mice gained less weight on the HFHSC diet compared to Saa3+/+ littermate controls, with no differences in body composition or resting metabolism. Female Saa3−/− mice, but not males, had reduced HFHSC diet-induced adipose tissue inflammation and macrophage content. Both male and female Saa3−/− mice had reduced liver Saa1 and Saa2 expression in association with reduced plasma SAA. Additionally, female Saa3−/− mice, but not males, showed improved plasma cholesterol, triglycerides, and lipoprotein profiles, with no changes in glucose metabolism. Taken together, these results suggest that the absence of Saa3 attenuates liver-specific SAA (i.e., SAA1/2) secretion into plasma and blunts weight gain induced by an obesogenic diet. Furthermore, adipose tissue-specific inflammation and macrophage accumulation are attenuated in female Saa3−/− mice, suggesting a novel sexually dimorphic role for this protein. These results also suggest that Saa3 influences liver-specific SAA1/2 expression, and that SAA3 could play a larger role in the acute phase response than previously thought.
PMCID: PMC4177399  PMID: 25251243
8.  Associations between Aspirin and other non-steroidal anti-inflammatory drugs and aortic valve or coronary artery calcification: The Multi-Ethnic Study of Atherosclerosis and the Heinz Nixdorf Recall Study 
Atherosclerosis  2013;229(2):310-316.
The association between non-steroidal anti-inflammatory drugs (NSAIDs) and the incidence of valvular and arterial calcification is not well established despite known associations between these drugs and cardiovascular events.
To compare the association between the baseline use of aspirin with other NSAID class medications with the incidence and prevalence of aortic valve calcification (AVC) and coronary artery calcium (CAC).
The relationship of NSAID use to AVC and CAC detected by computed tomography was assessed in 6,814 participants within the Multi-Ethnic Study of Atherosclerosis (MESA) using regression modeling. Results were adjusted for age, sex, ethnicity, study site, anti-hypertensive medication use, education, income, health insurance status, diabetes, smoking, exercise, body mass index, blood pressure, serum lipids, inflammatory markers, fasting glucose, statin medication use, and a simple diet score. Medication use was assessed by medication inventory at baseline which includes the use of non-prescription NSAIDs. MESA collects information on both incident and prevalent calcification. The 4,814 participants of the Heinz Nixdorf Recall (HNR) Study, a German prospective cohort study with similar measures of calcification, were included in this analysis to enable replication.
Mean age of the MESA participants was 62 years (51% female). After adjustment for possible confounding factors, a possible association between aspirin use and incident AVC (Relative Risk(RR): 1.60; 95%Confidence Interval (CI): 1.19–2.15) did not replicate in the HNR cohort (RR: 1.06; 95%CI: 0.87–1.28). There was no significant association between aspirin use and incident CAC in the MESA cohort (RR 1.08; 95%CI: 0.91–1.29) or in the HNR cohort (RR 1.24; 95%CI: 0.87–1.77). Non-aspirin NSAID use was not associated with either AVC or CAC in either cohort. There were no associations between regular cardiac dose aspirin and incident calcification in either cohort.
Baseline NSAID use, as assessed by medication inventory, appears to have no protective effect regarding the onset of calcification in either coronary arteries or aortic valves.
PMCID: PMC3724227  PMID: 23880181
Non-steroidal anti-inflammatory drugs; aspirin; aortic valve calcification; coronary artery calcification; Multi-Ethnic Study of Atherosclerosis; Heinz Nixdorf Recall Study
9.  Scan-rescan reproducibility of quantitative assessment of inflammatory carotid atherosclerotic plaque using dynamic contrast-enhanced 3T CMR in a multi-center study 
The aim of this study is to investigate the inter-scan reproducibility of kinetic parameters in atherosclerotic plaque using dynamic contrast-enhanced (DCE) cardiovascular magnetic resonance (CMR) in a multi-center setting at 3T.
Carotid arteries of 51 subjects from 15 sites were scanned twice within two weeks on 3T scanners using a previously described DCE-CMR protocol. Imaging data with protocol compliance and sufficient image quality were analyzed to generate kinetic parameters of vessel wall, expressed as transfer constant (Ktrans) and plasma volume (vp). The inter-scan reproducibility was evaluated using intra-class correlation coefficient (ICC) and coefficient of variation (CV). Power analysis was carried out to provide sample size estimations for future prospective study.
Ten (19.6%) subjects were found to suffer from protocol violation, and another 6 (11.8%) had poor image quality (n = 6) in at least one scan. In the 35 (68.6%) subjects with complete data, the ICCs of Ktrans and vp were 0.65 and 0.28, respectively. The CVs were 25% and 62%, respectively. The ICC and CV for vp improved to 0.73 and 28% in larger lesions with analyzed area larger than 25 mm2. Power analysis based on the measured CV showed that 50 subjects per arm are sufficient to detect a 20% difference in change of Ktrans over time between treatment arms with 80% power without consideration of the dropout rate.
The result of this study indicates that quantitative measurement from DCE-CMR is feasible to detect changes with a relatively modest sample size in a prospective multi-center study despite the limitations. The relative high dropout rate suggested the critical needs for intensive operator training, optimized imaging protocol, and strict quality control in future studies.
PMCID: PMC4237824  PMID: 25084698
Carotid artery; Atherosclerosis; Reproducibility; Dynamic contrast-enhanced cardiovascular magnetic resonance
10.  Apolipoprotein A-I and HDL Have Anti-Inflammatory Effects on Adipocytes via Cholesterol Transporters: ATP-Binding Cassette (ABC) A-1, ABCG-1 and Scavenger Receptor B-1(SRB-1) 
Circulation research  2013;112(10):1345-1354.
Macrophage accumulation in adipose tissue associates with insulin resistance and increased cardiovascular disease risk. We previously have shown that generation of reactive oxygen species (ROS) and monocyte chemotactic factors after exposure of adipocytes to saturated fatty acids (SFAs) such as palmitate occurs via translocation of NADPH oxidase 4 (NOX4) into lipid rafts (LRs). The anti-inflammatory effects of apolipoprotein A-I (apoA-I) and HDL on macrophages and endothelial cells appears to occur via cholesterol depletion of LRs. However, little is known concerning anti-inflammatory effects of HDL and apoA-I on adipocytes.
To determine whether apoA-I and HDL inhibit inflammation in adipocytes and adipose tissue, and whether this is dependent on LRs.
Methods and Results
In 3T3L-1 adipocytes, apoA-I, HDL and methyl-β-cyclodextrin inhibited chemotactic factor expression. ApoA-I and HDL also disrupted LRs, reduced plasma membrane cholesterol content, inhibited NOX4 translocation into LRs, and reduced palmitate-induced ROS generation and monocyte chemotactic factor expression. Silencing ABCA-1 abrogated the effect of apoA-I, but not HDL, while silencing ABCG-1 or SRB-1 abrogated the effect of HDL but not apoA-I. In vivo, apoA-I transgenic mice fed a high fat, high sucrose, cholesterol-containing diet showed reduced chemotactic factor and pro-inflammatory cytokine expression and reduced macrophage accumulation in adipose tissue.
ApoA-I and HDL have anti-inflammatory effects in adipocytes and adipose tissue similar to their effects in other cell types. These effects are consistent with disruption and removal of cholesterol from LRs, which are regulated by cholesterol transporters such as ABCA-1, ABCG-1 and SRB-1.
PMCID: PMC3767575  PMID: 23501697
Adipocytes; ABC transporters; cholesterol; HDL; Apolipoprotein A-I
11.  Genetic Associations with Valvular Calcification and Aortic Stenosis 
The New England journal of medicine  2013;368(6):503-512.
Limited information is available regarding genetic contributions to valvular calcification, which is an important precursor of clinical valve disease.
We determined genomewide associations with the presence of aorticvalve calcification (among 6942 participants) and mitral annular calcification (among 3795 participants), as detected by computed tomographic (CT) scanning; the study population for this analysis included persons of white European ancestry from three cohorts participating in the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium (discovery population). Findings were replicated in independent cohorts of persons with either CT-detected valvular calcification or clinical aortic stenosis.
One SNP in the lipoprotein(a) (LPA) locus (rs10455872) reached genomewide significance for the presence of aorticvalve calcification (odds ratio per allele, 2.05; P = 9.0×10−10), a finding that was replicated in additional white European, African-American, and Hispanic-American cohorts (P<0.05 for all comparisons). Genetically determined Lp(a) levels, as predicted by LPA genotype, were also associated with aorticvalve calcification, supporting a causal role for Lp(a). In prospective analyses, LPA genotype was associated with incident aortic stenosis (hazard ratio per allele, 1.68; 95% confidence interval [CI], 1.32 to 2.15) and aortic-valve replacement (hazard ratio, 1.54; 95% CI, 1.05 to 2.27) in a large Swedish cohort; the association with incident aortic stenosis was also replicated in an independent Danish cohort. Two SNPs (rs17659543 and rs13415097) near the proinflammatory gene IL1F9 achieved genomewide significance for mitral annular calcification (P = 1.5×10−8 and P = 1.8×10−8, respectively), but the findings were not replicated consistently.
Genetic variation in the LPA locus, mediated by Lp(a) levels, is associated with aorticvalve calcification across multiple ethnic groups and with incident clinical aortic stenosis. (Funded by the National Heart, Lung, and Blood Institute and others.)
PMCID: PMC3766627  PMID: 23388002
12.  Toll-like Receptor 4 Deficiency Decreases Atherosclerosis but Does Not Protect against Inflammation in Obese LDL Receptor-Deficient Mice 
Obesity is associated with insulin resistance, chronic low-grade inflammation and atherosclerosis. Toll-like receptor 4 (TLR4) participates in the cross-talk between inflammation and insulin resistance, being activated by both lipopolysaccharide and saturated fatty acids. This study was undertaken to determine whether TLR4 deficiency has a protective role in inflammation, insulin resistance and atherosclerosis induced by a diabetogenic diet.
Methods and Results
TLR4 and LDL receptor double knockout (Tlr4−/−Ldlr−/−) mice and Ldlr−/− mice were fed either a normal chow or a diabetogenic diet for 24 weeks. Tlr4−/−Ldlr−/− mice fed a diabetogenic diet showed improved plasma cholesterol and triglyceride levels but developed obesity, hyperinsulinemia and glucose intolerance equivalent to obese Ldlr−/− mice. Adipocyte hypertrophy, macrophage accumulation and local inflammation were not attenuated in intra-abdominal adipose tissue in Tlr4−/−Ldlr−/− mice. However, TLR4 deficiency led to markedly decreased atherosclerosis in obese Tlr4−/−Ldlr−/− mice. Compensatory up-regulation of TLR2 expression was observed both in obese TLR4 deficient mice and in palmitate-treated TLR4-silenced 3T3-L1 adipocytes.
TLR4 deficiency decreases atherosclerosis without affecting obesity-induced inflammation and insulin resistance in LDL receptor deficient mice. Alternative pathways may be responsible for adipose tissue macrophage infiltration and insulin resistance that occurs in obesity.
PMCID: PMC3748807  PMID: 22580897
Toll-like receptor 4; insulin resistance; atherosclerosis; inflammation; diabetogenic diet
13.  Associations of Left Ventricular Hypertrophy with Prevalent and Incident Valve Calcification: The Multi-Ethnic Study of Atherosclerosis 
JACC. Cardiovascular imaging  2012;5(8):781-788.
We aim to evaluate the relationship between percent of predicted left ventricular mass (%PredLVM) and valve calcification in the Multi-Ethnic Study of Atherosclerosis (MESA).
Cardiac valve calcification has been associated with left ventricular hypertrophy (LVH), which portends cardiovascular events. However, this relationship and its mediators are poorly understood.
MESA is a longitudinal cohort study of men and women aged 45-84 years without clinical cardiovascular disease in whom serial cardiac magnetic resonance and computed tomography imaging were performed. The relationships between baseline %PredLVM and the prevalence, severity, and incidence of aortic valve (AVC) and mitral annulus calcification (MAC) were determined by regression modeling.
Prevalent AVC was observed in 630 and MAC in 442 of 5,042 subjects (median 55.9 and 71.1 Agatston units, respectively). After adjustment for age, gender, body mass index, ethnicity, socioeconomic status, physical activity, diabetes, cholesterol levels, blood pressure, smoking, kidney function, serum lipids, and antihypertensive and statin medications, %PredLVM was associated with prevalent AVC (OR=1.18 per SD increase in %PredLVM [95%CI 1.08 – 1.30]; p=0.0004) and MAC (OR=1.18 [95%CI 1.06 – 1.32]; p=0.002). Similarly, %PredLVM was associated with increased severity of prevalent AVC (risk difference = 0.26 [95%CI 0.15 – 0.38]; p<0.0001) and MAC (risk difference = 0.20 [95%CI 0.03 – 0.37]; p=0.02). During follow-up (mean 2.4±0.9 years), 153 subjects (4%) developed AVC and 198 (5%) MAC. %PredLVM was associated with incident AVC (OR=1.24 [95%CI 1.04 – 1.47]; p=0.02) and MAC (OR=1.18 [1.01-1.40]; p=0.04). Further adjustment for inflammatory markers and coronary artery calcification did not attenuate these associations. Specifically, concentric LVH most strongly predicted incident valve calcification.
Within the MESA cohort, LVH was associated with prevalence, severity, and incidence of valve calcification independent of hypertension and other identified confounders.
PMCID: PMC3426868  PMID: 22897991
aortic valve; calcification; left ventricular mass; mitral valve annulus
14.  T Cell Activation Inhibitors Reduce CD8+ T Cell and Pro-Inflammatory Macrophage Accumulation in Adipose Tissue of Obese Mice 
PLoS ONE  2013;8(7):e67709.
Adipose tissue inflammation and specifically, pro-inflammatory macrophages are believed to contribute to insulin resistance (IR) in obesity in humans and animal models. Recent studies have invoked T cells in the recruitment of pro-inflammatory macrophages and the development of IR. To test the role of the T cell response in adipose tissue of mice fed an obesogenic diet, we used two agents (CTLA-4 Ig and anti-CD40L antibody) that block co-stimulation, which is essential for full T cell activation. C57BL/6 mice were fed an obesogenic diet for 16 weeks, and concomitantly either treated with CTLA-4 Ig, anti-CD40L antibody or an IgG control (300 µg/week). The treatments altered the immune cell composition of adipose tissue in obese mice. Treated mice demonstrated a marked reduction in pro-inflammatory adipose tissue macrophages and activated CD8+ T cells. Mice treated with anti-CD40L exhibited reduced weight gain, which was accompanied by a trend toward improved IR. CTLA-4 Ig treatment, however, was not associated with improved IR. These data suggest that the presence of pro-inflammatory T cells and macrophages can be altered with co-stimulatory inhibitors, but may not be a significant contributor to the whole body IR phenotype.
PMCID: PMC3699637  PMID: 23844072
15.  How to Best Manage Glycemia and Non-Glycemia During the Time of Acute Myocardial Infarction 
Diabetes Technology & Therapeutics  2012;14(Suppl 1):S-22-S-32.
Acute myocardial infarction (AMI) is common in patients with diabetes. Reasons for this are multifactorial, but all relate to a variety of maladaptive responses to acute hyperglycemia. Persistent hyperglycemia is associated with worse left ventricular function and higher mortality during AMI, but intervention data are far from clear. Although there is a theoretical basis for the use of glucose-insulin-potassium infusion during AMI, lack of outcome efficacy (and inability to reach glycemic targets) in recent randomized trials has resulted in little enthusiasm for this strategy. Based on the increasing understanding of the dangers of hypoglycemia, while at the same time appreciating the role of hyperglycemia in AMI patients, goal glucose levels of 140–180 mg/dL using an intravenous insulin infusion while not eating seem reasonable for most patients and hospital systems. Non-glycemic therapy for patients with diabetes and AMI has benefited from more conclusive data, as this population has greater morbidity and mortality than those without diabetes. For ST-elevation myocardial infarction (STEMI), reperfusion therapy with primary percutaneous coronary intervention or fibrinolysis, antithrombotic therapy to prevent acute stent thrombosis following percutaneous coronary intervention or rethrombosis following thrombolysis, and initiation of β-blocker therapy are the current standard of care. Emergency coronary artery bypass graft surgery is reserved for the most critically ill. For those with non-STEMI, initial reperfusion therapy or fibrinolysis is not routinely indicated. Overall, there have been dramatic advances for the treatment of people with AMI and diabetes. The use of continuous glucose monitoring in this population may allow better ability to safely reach glycemic targets, which it is hoped will improve glycemic control.
PMCID: PMC3388496  PMID: 22650221
16.  Reduced vascular nitric oxide-cGMP signaling contributes to adipose tissue inflammation during high-fat feeding 
Obesity is characterized by chronic inflammation of adipose tissue, which contributes to insulin resistance and diabetes. Although nitric oxide (NO) signaling has anti-inflammatory effects in the vasculature, whether reduced NO contributes to adipose tissue inflammation is unknown. We sought to determine whether 1) obesity induced by high-fat (HF) diet reduces endothelial nitric oxide signaling in adipose tissue, 2) reduced endothelial nitric oxide synthase (eNOS) signaling is sufficient to induce adipose tissue inflammation independent of diet, and 3) increased cGMP signaling can block adipose tissue inflammation induced by HF feeding.
Methods and results
Relative to mice fed a low-fat diet, HF diet markedly reduced phospho-eNOS and phospho-VASP, markers of vascular NO signaling. Expression of pro-inflammatory cytokines was increased in adipose tissue of eNOS−/− mice. Conversely, enhancement of signaling downstream of NO by phosphodiesterase 5 (PDE-5) inhibition using sildenafil attenuated HF-induced pro-inflammatory cytokine expression and the recruitment of macrophages into adipose tissue. Finally, we implicate a role for Vasodilator- stimulated phosphoprotein (VASP), a downstream mediator of NO-cGMP signaling in mediating eNOS-induced anti-inflammatory effects since VASP−/− mice recapitulated the pro-inflammatory phenotype displayed by eNOS−/− mice.
These results imply a physiological role for endothelial NO to limit obesity-associated inflammation in adipose tissue and hence identifies the NO-cGMP-VASP pathway as a potential therapeutic target in the treatment of diabetes.
PMCID: PMC3342311  PMID: 21903940
18.  The neuroimmune guidance cue netrin-1 promotes atherosclerosis by inhibiting macrophage emigration from plaques 
Nature Immunology  2012;13(2):136-143.
Atherosclerotic plaque formation is fueled by the persistence of lipid-laden macrophages in the artery wall. The mechanisms by which these cells become trapped, thereby establishing chronic inflammation, remain unknown. Netrin-1, a neuroimmune guidance cue, was secreted by macrophages in human and mouse atheroma, where it inactivated macrophage migration to chemokines implicated in their egress from plaques. Acting via its receptor UNC5b, netrin-1 inhibited CCL2- and CCL19-directed macrophage migration, Rac1 activation and actin polymerization. Targeted deletion of netrin-1 in macrophagesseverely diminished atherosclerosis progression in Ldlr−/− mice and promoted macrophage emigration from plaques. Thus, netrin-1 promotes atherosclerosis by retaining macrophages in the artery wall and establish a causative role for negative regulators of leukocyte migration in chronic inflammation.
PMCID: PMC3262880  PMID: 22231519
19.  Association of Serum Phosphate Levels with Aortic Valve Sclerosis and Annular Calcification: the Cardiovascular Health Study 
To evaluate mineral metabolism markers as potential risk factors for calcific aortic valve disease.
Mineral metabolism disturbances are common among older people and may contribute to cardiac valvular calcification. Associations of serum mineral metabolism markers with cardiac valvular calcification have not been evaluated in a well-characterized general population of older adults.
We measured serum levels of phosphate, calcium, parathyroid hormone, and 25-hydroxyvitamin D in 1,938 Cardiovascular Health Study participants who were free of clinical cardiovascular disease and who underwent echocardiography measurements of aortic valve sclerosis (AVS), mitral annular calcification (MAC), and aortic annular calcification (AAC). We used logistic regression models to estimate associations of mineral metabolism markers with AVS, MAC, and AAC after adjustment for relevant confounding variables, including kidney function.
The respective prevalences of AVS, MAC, and AAC were 54%, 39%, and 44%. Each 0.5 mg/dl higher serum phosphate concentration was associated with a greater adjusted odds of AVS (odds ratio 1.17, 95% confidence interval 1.04 to 1.31, p = 0.01), MAC (odds ratio 1.12, 95% confidence interval 1.00 to 1.26, p =0.05), and AAC (odds ratio 1.12, 95% confidence interval 0.99 to 1.25, p = 0.05). In contrast, serum calcium, parathyroid hormone, and 25-hydroxyvitamin D concentrations were not associated with aortic or mitral calcification.
Higher serum phosphate levels within the normal range are associated with valvular and annular calcification in a community-based cohort of older adults. Phosphate may be a novel risk factor for calcific aortic valve disease and warrants further study.
PMCID: PMC3147295  PMID: 21737022
Phosphate; Aortic Valve; Mitral Valve; Calcification; Epidemiology
20.  Stages of Systemic Hypertension and Blood Pressure as Correlates of Computed Tomography-Assessed Aortic Valve Calcium (From the Multi-Ethnic Study of Atherosclerosis) 
Hypertension has been identified as a risk factor for aortic valve calcium (AVC) but the magnitude of the risk relation with hypertension severity or whether age affects the strength of this risk association has not been studied. The relationship of hypertension severity, as defined by JNC-7 hypertension stages or blood pressure (BP), to CT-assessed AVC prevalence and severity was examined in 4,274 participants in the Multi-Ethnic Study of Atherosclerosis (MESA) without treated hypertension. Analyses were stratified by age < or ≥ 65 years, were adjusted for common cardiovascular risk factors, and excluded those on antihypertensive medications. In age-stratified, adjusted analyses, Stage I/II hypertension was associated with prevalent AVC in those <65 but not in those ≥65 years of age [OR (95% CI): 2.31 (1.35, 3.94) vs. 1.33 (0.96, 1.85), P-interaction = 0.041]. Similarly, systolic BP and pulse pressure (PP) were more strongly associated with prevalent AVC in those <65 than those ≥65 years of age [OR (95% CI): 1.21 (1.08, 1.35) vs. 1.07 (1.01, 1.14) per 10 mmHg increase in systolic BP, Pinteraction = 0.006] and [OR (95% CI): 1.41 (1.21, 1.64) vs. 1.14 (1.05, 1.23) per 10 mmHg increase in PP]. No associations were found between either hypertension stage or BP and AVC severity. In conclusion, stage I/II hypertension, as well as higher systolic pressure and pulse pressure were associated with prevalent AVC. These risk associations were strongest in participants younger than age 65 years.
PMCID: PMC3032359  PMID: 21146685
Blood Pressure; Aortic Valve; Calcification
21.  Bisphosphonate use and the Prevalence of Valvular and Vascular Calcification in Women: The Multi-Ethnic Study of Atherosclerosis 
To determine whether nitrogen-containing bisphosphonate (NCBP) therapy is associated with the prevalence of cardiovascular calcification.
Cardiovascular calcification correlates with atherosclerotic disease burden. Experimental data suggest that NCBP may limit cardiovascular calcification, which has implications for disease prevention.
The relationship of NCBP use to the prevalence of aortic valve, aortic valve ring, mitral annulus, thoracic aorta, and coronary artery calcification (AVC, AVRC, MAC, TAC, and CAC, respectively) detected by computed tomography was assessed in 3,636 women within the Multi-Ethnic Study of Atherosclerosis (MESA) using regression modeling.
Analyses were age-stratified because of a significant interaction between age and NCBP use (interaction p-values: AVC p<0.0001; AVRC p<0.0001; MAC p=0.002; TAC p<0.0001; CAC p=0.046). After adjusting for age, body mass index, demographics, diabetes, smoking, blood pressure, cholesterol levels, and statin, hormone replacement, and renin-angiotensin inhibitor therapy, NCBP use was associated with a lower prevalence of cardiovascular calcification in women ≥65 years old (prevalence ratio [95% confidence interval]: AVC 0.68 [0.41, 1.13]; AVRC 0.65 [0.51, 0.84]; MAC 0.54 [0.33, 0.93]; TAC 0.69 [0.54, 0.88]; CAC 0.89 [0.78, 1.02]), whereas calcification was more prevalent in NCBP users among the 2,181 women <65 years old (AVC 4.00 [2.33, 6.89]; AVRC 1.92 [1.42, 2.61]; MAC 2.35 [1.12, 4.84]; TAC 2.17 [1.49, 3.15]; CAC 1.23 [0.97, 1.57]).
Among women in the diverse MESA cohort, NCBPs were associated with decreased prevalence of cardiovascular calcification in older subjects, but more prevalent cardiovascular calcification in younger ones. Further study is warranted to clarify these age-dependent NCBP effects.
PMCID: PMC3004769  PMID: 21070928
bisphosphonate; calcification; coronary artery; valve; vascular
22.  CREB Downregulation in vascular disease: a common response to cardiovascular risk 
To examine the impact of low density lipoprotein (LDL), an established mediator of atherosclerosis, on the transcription factor, cAMP Response Element Binding Protein (CREB), a regulator of vascular smooth muscle cell (VSMC) quiescence.
Methods and Results
VSMC CREB content is diminished in rodent models of diabetes and pulmonary hypertension. We examined aortic CREB content in rodent models of aging, hypertension and insulin resistance, and determined nuclear CREB protein in the medial VSMC of high fat-fed LDL receptor null mice. There was significant loss of CREB protein in all models. In vitro, primary culture rat aortic VSMC exposed to LDL and oxidized LDL (oxLDL) exhibited a rapid, transient increase in CREB phosphorylation and transient phosphorylation/activation of Akt and P38-, ERK- and JNK-MAPK. Exposure to oxLDL, but not LDL, for 24 – 48 h decreased CREB protein in a dose-dependent fashion and led to nuclear exclusion of CREB. Pharmacological reactive oxygen species (ROS) scavengers and inhibition of ERK activation blocked oxLDL-mediated CREB downregulation.
These data support a model wherein loss of VSMC CREB protein, which renders these cells more susceptible to activation and apoptosis, is a common pathological response to vascular injury and potentially contributes to plaque progression.
PMCID: PMC2841720  PMID: 20150559
23.  Incidence and Progression of Aortic Valve Calcium in the Multi-Ethnic Study of Atherosclerosis (MESA) 
The American journal of cardiology  2010;105(5):701-708.
Aortic valve calcium (AVC) is common among older adults and shares epidemiologic and histopathologic similarities to atherosclerosis. However, prospective studies have failed to identify meaningful risk-associations with incident (“new”) AVC or its progression. In this study, AVC was quantified from serial computed tomography (CT) images in 5,880 participants (aged 45–84 years) of the Multi-Ethnic Study of Atherosclerosis, using Agatston methodology. Multivariate backwards selection modeling was used to identify risk factors for incident AVC and AVC progression. During a mean follow up of 2.4±0.9 years, 210 subjects (4.0%) developed incident AVC. The incidence rate (mean 1.7 %/year) increased significantly with age (p<0.001). Risk factors for incident AVC included age, male gender, BMI, current smoking, and the use of lipid lowering and antihypertensive medications. Among those with AVC at baseline, the median rate of AVC progression was 2 Agatston units/year [IQR −21, 37]. Baseline Agatston score was a strong, independent predictor of progression, especially among those with high calcium scores at baseline. In conclusion, in this ethnically diverse, pre-clinical cohort, the rate of incident AVC a significantly with age. Incident AVC risk was associated with several traditional cardiovascular risk factors, specifically age, male gender, BMI, current smoking, and the use of both antihypertensive and lipid lowering medications. AVC progression risk was associated with male gender and the baseline Agatston score. Additional research is needed to determine if age- and stage-specific mechanisms underlie risk for AVC progression.
PMCID: PMC2829478  PMID: 20185020
valves; calcium; risk factors; epidemiology; imaging
24.  Relationship between Common Carotid Intima-Media Thickness and Thoracic Aortic Calcification: the Multi-Ethnic Study of Atherosclerosis 
Atherosclerosis  2009;209(1):142-146.
Mean maximum carotid intima-media thickness (CIMT) is associated with both coronary artery disease and cerebral thromboembolism. Thoracic aortic calcification (TAC) detected by computed tomography (CT) is also highly associated with vascular disease and cardiovascular risk. No previous study has examined the relationship between CIMT and TAC in a large patient cohort. We performed a cross-sectional study to determine whether, at baseline, there is a relationship between CIMT and CT-determined TAC score.
In the Multi-Ethnic Study of Atherosclerosis, the study cohort included a population based sample of four ethnic groups (Chinese, White, Hispanic and African-American) of 6814 women and men ages 45-84 years. After exclusion of 198 persons due to incomplete information, we compared results of 6616 participants with both CIMT and TAC. TAC was measured from the lower edge of the pulmonary artery bifurcation to the cardiac apex. CIMT at the common carotid artery site was represented as the mean maximal CIMT of the right and left near and far walls, respectively. Multivariable relative risk regression analysis was used to evaluate relationships between TAC and CIMT.
The prevalence of TAC was 28% (n=1846) and the mean maximum (±SD) CIMT was 0.87±0.19 mm. A higher prevalence of TAC was noted across increasing CIMT quartiles (1st: 12%, 2nd: 21%, 3rd: 30%, 4th: 49%, P<0.0001). One standard deviation increase in CIMT was associated with a 16% higher likelihood for presence of TAC after adjusting for demographics and cardiovascular disease (CVD) risk factors (95% CI: 1.12-1.26). In addition, individuals with CIMT in the highest quartile, as compared to those with CIMT in the first quartile, had a 76% higher likelihood for presence of TAC (prevalence ratio [PR]: 1.76, 95% CI: 1.37-2.26). In race-ethnic stratified analyses, similar associations were seen in all groups. Among those with TAC>0, a higher CIMT was significantly associated with continuous TAC scores (log transformed) in the overall population as well as among all ethnic-racial groups.
Our study demonstrates that TAC is associated with increasing severity of carotid atherosclerotic burden as measured by CIMT. The combined utility of these two noninvasive measures of subclinical atherosclerosis for CVD risk assessment needs to be determined in future studies.
PMCID: PMC2830343  PMID: 19782983
Atherosclerosis; carotid IMT; aortic calcification; ethnic; cardiac CT
25.  Age-Modification of Lipoprotein, Lipid, and Lipoprotein Ratio-Associated Risk for Coronary Artery Calcium (From the Multi-Ethnic Study of Atherosclerosis [MESA]) 
The American journal of cardiology  2009;105(3):352-358.
Though abnormal lipoproteins and lipoprotein ratios are powerful risk factors for clinical cardiovascular (CV) events, these associations are stronger in younger compared to older age. Whether age modifies the relationships of lipoproteins and lipoprotein ratios to the relative risk for subclinical CV disease (CVD), as assessed by coronary artery calcium (CAC) scores, has not been examined in a contemporary, multi-ethnic cohort. We performed multivariate relative risk regression to determine the relative risks (RRs) for associations of lipoproteins and lipoprotein ratios with prevalent CAC in participants in MESA. Participants were community-dwelling adults ages 45–84 years without baseline clinically apparent CVD. We excluded those on lipid lowering therapy (15%), and stratified results by decades of age. 5,092 participants met inclusion criteria. In fully adjusted models, per standard deviation (SD) of low-density lipoprotein (LDL), age-stratified, adjusted relative risks (RRs) for CAC were 1.17 (95% Confidence Interval (CI) 1.07–1.28) for those aged 45–54 but 1.05 (95% CI 1.01–1.10) for those aged 75–84 (p-interaction = 0.12). The RR per SD of Total/HDL cholesterol ratio was 1.20 (95% CI 1.12–1.29) for those aged 45–54 but only 1.04 (1.00–1.09) for those aged 75–84 (p-interaction <0.001). Lipoproteins and lipoprotein ratios were associated with increased RRs for CAC across all age categories. However, these associations were markedly attenuated by age. In conclusion, abnormal lipoproteins in middle age are a powerful risk factor for early atherosclerosis as manifested by prevalent CAC.
PMCID: PMC2855892  PMID: 20102947
lipoproteins; age; coronary artery calcium

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