Kevin D O'Brien

University of Washington Seattle, Seattle, Washington, United States

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Publications (118)792.92 Total impact

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    ABSTRACT: Piperidine-based peroxisome proliferator-activated receptor-α agonists are agents that are efficacious in improving lipid, glycemic, and inflammatory indicators in diabetes and obesity. This study sought to determine whether CP-900691 ((S)-3-[3-(1-carboxy-1-methyl-ethoxy)-phenyl]-piperidine-1-carboxylic acid 4-trifluoromethyl-benzyl ester; CP), a member of this novel class of agents, by decreasing plasma triglycerides, could prevent diabetic nephropathy in the Black and Tan, BRachyuric (BTBR) ob/ob mouse model of type 2 diabetes mellitus. Four-week old female BTBR WT and BTBR ob/ob mice received either regular chow or one containing CP (3 mg/kg per day) for 14 weeks. CP elevated plasma high-density lipoprotein, albuminuria, and urinary excretion of 8-epi PGF2α, a product of the nonenzymatic metabolism of arachidonic acid and whose production is elevated in oxidative stress, in BTBR WT mice. In BTBR ob/ob mice, CP reduced plasma triglycerides and non-esterified fatty acids, fasting blood glucose, body weight, and plasma interleukin-6, while concomitantly improving insulin resistance. Despite these beneficial metabolic effects, CP had no effect on elevated plasma insulin, 8-epi PGF2α excretion, and albuminuria, and surprisingly, did not ameliorate the development of diabetic nephropathy, having no effect on the accumulation of renal macrophages, glomerular hypertrophy, and increased mesangial matrix expansion. In addition, CP did not increase plasma high-density lipoprotein in BTBR ob/ob mice, while paradoxically increasing total cholesterol levels. These findings indicate that 8-epi PGF2α, possibly along with hyperinsulinemia and inflammatory and dysfunctional lipoproteins, is integral to the development of diabetic nephropathy and should be considered as a potential target of therapy in the treatment of diabetic nephropathy.Laboratory Investigation advance online publication, 23 June 2014; doi:10.1038/labinvest.2014.80.
    06/2014;
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    ABSTRACT: Inflammatory activation of myeloid cells is accompanied by increased glycolysis, which is required for the surge in cytokine production. Although in vitro studies suggest that increased macrophage glucose metabolism is sufficient for cytokine induction, the proinflammatory effects of increased myeloid cell glucose flux in vivo and the impact on atherosclerosis, a major complication of diabetes, are unknown. We therefore tested the hypothesis that increased glucose uptake in myeloid cells stimulates cytokine production and atherosclerosis. Overexpression of the glucose transporter GLUT1 in myeloid cells caused increased glycolysis and flux through the pentose phosphate pathway but did not induce cytokines. Moreover, myeloid-cell-specific overexpression of GLUT1 in LDL receptor-deficient mice was ineffective in promoting atherosclerosis. Thus, increased glucose flux is insufficient for inflammatory myeloid cell activation and atherogenesis. If glucose promotes atherosclerosis by increasing cellular glucose flux, myeloid cells do not appear to be the key targets.
    Cell reports. 04/2014;
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    ABSTRACT: Objectives This study sought to investigate associations of phosphate metabolism biomarkers with aortic valve calcification (AVC). Background Calcific aortic valve disease (CAVD) is a common progressive condition that involves inflammatory and calcification mediators. Currently there are no effective medical treatments, but mineral metabolism pathways may be important in the development and progression of disease. Methods We examined associations of phosphate metabolism biomarkers, including serum phosphate, urine phosphate, parathyroid hormone (PTH) and serum fibroblast growth factor (FGF)-23, with CT-assessed AVC at study baseline and in short-term follow-up in 6814 participants of the Multi-Ethnic Study of Atherosclerosis (MESA). Results At baseline, AVC prevalence was 13.2%. Higher serum phosphate levels were associated with significantly greater AVC prevalence (relative risk 1.3 per 1 mg/dL increment, 95% confidence incidence: 1.1 to 1.5, p < 0.001). Serum FGF-23, serum PTH, and urine phosphate were not associated with prevalent AVC. Average follow-up CT evaluation was 2.4 years (range 0.9–4.9 years) with an AVC incidence of 4.1%. Overall, phosphate metabolism biomarkers were not associated with incident AVC except in the top FGF-23 quartile. Conclusions Serum phosphate levels are significantly associated with AVC prevalence. Further study of phosphate metabolism as a modifiable risk factor for AVC is warranted.
    Atherosclerosis 01/2014; 233(2):331–337. · 3.71 Impact Factor
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    ABSTRACT: 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 MESA is a longitudinal cohort study of participants aged 45 to 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 (9%) of 5,895 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 years; 95% CI, 1.97-2.58; P < .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 to 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, 0.85-0.91; P < .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.
    American heart journal 11/2013; 166(5):904-12. · 4.65 Impact Factor
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    ABSTRACT: 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.
    Journal of the American College of Cardiology 08/2013; · 14.09 Impact Factor
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    ABSTRACT: 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 calcification (CAC). The relationship of NSAID use to AVC and CAC detected by computed tomography was assessed in 6814 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 4814 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.
    Atherosclerosis 08/2013; 229(2):310-6. · 3.71 Impact Factor
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    ABSTRACT: 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.
    Journal of the American College of Cardiology 07/2013; · 14.09 Impact Factor
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    ABSTRACT: The reversibility of diabetic nephropathy remains controversial. Here, we tested whether replacing leptin could reverse the advanced diabetic nephropathy modeled by the leptin-deficient BTBR ob/ob mouse. Leptin replacement, but not inhibition of the renin-angiotensin-aldosterone system (RAAS), resulted in near-complete reversal of both structural (mesangial matrix expansion, mesangiolysis, basement membrane thickening, podocyte loss) and functional (proteinuria, accumulation of reactive oxygen species) measures of advanced diabetic nephropathy. Immunohistochemical labeling with the podocyte markers Wilms tumor 1 and p57 identified parietal epithelial cells as a possible source of regenerating podocytes. Thus, the leptin-deficient BTBR ob/ob mouse provides a model of advanced but reversible diabetic nephropathy for further study. These results also suggest that restoration of lost podocytes is possible but is not induced by RAAS inhibition, possibly explaining the limited efficacy of RAAS inhibitors in promoting repair of diabetic nephropathy.
    Journal of the American Society of Nephrology 05/2013; · 8.99 Impact Factor
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    ABSTRACT: Rationale: 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. Objective: 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. Conclusions: 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.
    Circulation Research 03/2013; · 11.86 Impact Factor
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    ABSTRACT: 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 aortic-valve 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 aortic-valve 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 aortic-valve 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 aortic-valve calcification across multiple ethnic groups and with incident clinical aortic stenosis. (Funded by the National Heart, Lung, and Blood Institute and others.).
    New England Journal of Medicine 02/2013; 368(6):503-12. · 51.66 Impact Factor
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    ABSTRACT: 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.
    PLoS ONE 01/2013; 8(7):e67709. · 3.73 Impact Factor
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    ABSTRACT: Objective Calcific aortic valve disease is a progressive condition that shares some common pathogenic features with atherosclerosis. Transforming growth factor-β1 is a recognized mediator of atherosclerosis and is expressed in aortic valve lesions. Transforming growth factorβ1 stimulates glycosaminoglycan elongation of proteoglycans that is associated with increased lipid binding. We investigated the presence of transforming growth factor-β1 and downstream signaling intermediates in diseased human aortic valves and the effects of activated transforming growth factor-β1 receptor signaling on aortic valve interstitial cell proteoglycan synthesis and lipid binding as a possible mechanism for the initiation of the early lesion of calcific aortic valve disease.Methods and resultsDiseased human aortic valve leaflets demonstrated strong immunohistochemical staining for transforming growth factor-β1 and phosphorylated Smad2/3. In primary porcine aortic valve interstitial cells, Western blots showed that transforming growth factor-β1 stimulated phosphorylation in both the carboxy and linker regions of Smad2/3, which was inhibited by the transforming growth factor-β1 receptor inhibitor SB431542. Gel electrophoresis and size exclusion chromatography demonstrated that SB431542 decreased transforming growth factor-β1-mediated [35S]-sulfate incorporation into proteoglycans in a dose-dependent manner. Further, in proteoglycans derived from transforming growth factor-β1-treated valve interstitial cells, gel mobility shift assays demonstrated that inhibition of transforming growth factor-β1 receptor signaling resulted in decreased lipid binding.Conclusions Classic transforming growth factor-β1 signaling is present in human aortic valves in vivo and contributes to the modification of proteoglycans expressed by valve interstitial cells in vitro. These findings suggest that transforming growth factor-β1 may promote increased low-density lipoprotein binding in the early phases of calcific aortic valve disease.
    Cardiovascular pathology: the official journal of the Society for Cardiovascular Pathology 09/2012; 22(2):146–155. · 1.63 Impact Factor
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    ABSTRACT: Adipose tissue inflammation is associated with insulin resistance and increased cardiovascular disease risk in obesity. We previously showed that addition of cholesterol to a diet rich in saturated fat and refined carbohydrate significantly worsens dyslipidemia, insulin resistance, adipose tissue macrophage accumulation, systemic inflammation, and atherosclerosis in LDL receptor-deficient (Ldlr(-/-)) mice. To test whether inhibition of intestinal cholesterol absorption would improve metabolic abnormalities and adipose tissue inflammation in obesity, we administered ezetimibe, a dietary and endogenous cholesterol absorption inhibitor, to Ldlr(-/-) mice fed chow or high-fat, high-sucrose (HFHS) diets without or with 0.15% cholesterol (HFHS+C). Ezetimibe blunted weight gain and markedly reduced plasma lipids in the HFHS+C group. Ezetimibe had no effect on glucose homeostasis or visceral adipose tissue macrophage gene expression in the HFHS+C fed mice, although circulating inflammatory markers serum amyloid A (SSA) and serum amyloid P (SSP) levels decreased. Nevertheless, ezetimibe treatment led to a striking (>85%) reduction in atherosclerotic lesion area with reduced lesion lipid and macrophage content in the HFHS+C group. Thus, in the presence of dietary cholesterol, ezetimibe did not improve adipose tissue inflammation in obese Ldlr(-/-) mice, but it led to a major reduction in atherosclerotic lesions associated with improved plasma lipids and lipoproteins.
    The Journal of Lipid Research 09/2012; 53(11):2380-9. · 4.39 Impact Factor
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    ABSTRACT: The aim of this study was to evaluate the relationship between percentage of predicted left ventricular mass (%PredLVM) and valve calcification in the MESA (Multi-Ethnic Study of Atherosclerosis) study. Cardiac valve calcification has been associated with left ventricular hypertrophy (LVH), which portends cardiovascular events. However, this relationship and its mediators are poorly understood. The MESA study is a longitudinal cohort study of men and women 45 to 84 years of age 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 was observed in 442 of 5,042 subjects (median 55.9 and 71.1 Agatston units, respectively). After adjustment for age, sex, body mass index (BMI), 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 (odds ratio [OR]: 1.18/SD increase in %PredLVM [95% confidence interval (CI): 1.08 to 1.30]; p = 0.0004) and MAC (OR: 1.18 [95% CI: 1.06 to 1.32]; p = 0.002). Similarly, %PredLVM was associated with increased severity of prevalent AVC (risk difference = 0.26 [95% CI: 0.15 to 0.38]; p < 0.0001) and MAC (risk difference = 0.20 [95% CI: 0.03 to 0.37]; p = 0.02). During follow-up (mean 2.4 ± 0.9 years), 153 subjects (4%) developed AVC, and 198 (5%) developed MAC. The %PredLVM was associated with incident AVC (OR: 1.24 [95% CI: 1.04 to 1.47]; p = 0.02) and MAC (OR: 1.18 [95% CI: 1.01 to 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.
    JACC. Cardiovascular imaging 08/2012; 5(8):781-8. · 14.29 Impact Factor
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    ABSTRACT: This study sought 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. Also, it is unknown whether this association extends to younger individuals. We performed a prospective analysis of 6,685 participants in MESA (Multi-Ethnic Study of Atherosclerosis). All subjects, ages 45 to 84 years and free of clinical cardiovascular disease at baseline, underwent computed tomography for AVC and coronary artery calcium scoring. The primary, pre-specified combined endpoint of cardiovascular events included myocardial infarctions, fatal and nonfatal strokes, resuscitated cardiac arrest, and cardiovascular death, whereas 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 years (interquartile range: 5.6 to 5.9 years), adjusting for demographics and cardiovascular risk factors, subjects with AVC (n = 894, 13.4%) had higher risks of cardiovascular (hazard ratio [HR]: 1.50; 95% confidence interval [CI]: 1.10 to 2.03) and coronary (HR: 1.72; 95% CI: 1.19 to 2.49) events compared with those without AVC. Adjustments for inflammatory biomarkers did not alter these associations, but adjustment for coronary artery calcium substantially attenuated both cardiovascular (HR: 1.32; 95% CI: 0.98 to 1.78) and coronary (HR: 1.41; 95% CI: 0.98 to 2.02) event risk. AVC remained predictive of cardiovascular mortality even after full adjustment (HR: 2.51; 95% CI: 1.22 to 5.21). In this 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. (Multi-Ethnic Study of Atherosclerosis [MESA]; NCT00005487).
    JACC. Cardiovascular imaging 06/2012; 5(6):619-25. · 14.29 Impact Factor
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    Irl B Hirsch, Kevin D O'Brien
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    ABSTRACT: 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.
    Diabetes Technology &amp Therapeutics 06/2012; 14 Suppl 1:S22-32. · 2.21 Impact Factor
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    ABSTRACT: 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. The present study was undertaken to determine whether TLR4 deficiency has a protective role in inflammation, insulin resistance, and atherosclerosis induced by a diabetogenic diet. TLR4 and low-density lipoprotein (LDL) receptor double knockout mice and LDL receptor-deficient mice were fed either a normal chow or a diabetogenic diet for 24 weeks. TLR4 and LDL receptor double knockout mice fed a diabetogenic diet showed improved plasma cholesterol and triglyceride levels but developed obesity, hyperinsulinemia, and glucose intolerance equivalent to obese LDL receptor-deficient mice. Adipocyte hypertrophy, macrophage accumulation, and local inflammation were not attenuated in intraabdominal adipose tissue in TLR4 and LDL receptor double knockout mice. However, TLR4 deficiency led to markedly decreased atherosclerosis in obese TLR4 and LDL receptor double knockout mice. Compensatory upregulation 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.
    Arteriosclerosis Thrombosis and Vascular Biology 05/2012; 32(7):1596-604. · 6.34 Impact Factor
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    ABSTRACT: Although monocyte- and macrophage-derived molecules are known to promote extracellular matrix (ECM) disruption and destabilization, it is less appreciated that they also synthesize molecules contributing to ECM formation, stabilization, and function. We have identified and characterized the synthesis of proteoglycans and related proteins, some not previously known to be associated with macrophages. Proteoglycan extracts of [(35)S]sulfate- and (35)S-trans amino acid-radiolabeled culture media from THP-1 monocytes induced to differentiate by treatment with phorbol myristate acetate revealed three major proteins of ~25, 90, and 100 kDa following chondroitin ABC lyase digestion. The 25-kDa protein was predominant for monocytes, whereas the 90- and 100-kDa proteins were predominant for macrophages. Tandem mass spectrometry identified (i) the 25-kDa core protein as serglycin, (ii) the 90-kDa core protein as inter-α-inhibitor heavy chain 2 (IαIHC2), and (iii) the 100-kDa core as amyloid precursor-like protein 2 (APLP2). Differentiation was also associated with (i) a >500-fold increase in mRNA for TNF-stimulated gene-6, an essential cofactor for heavy chain-mediated matrix stabilization; (ii) a >800-fold increase in mRNA for HAS2, which is responsible for hyaluronan synthesis; and (iii) a 3-fold increase in mRNA for versican, which interacts with hyaluronan. Biochemical evidence is also presented for an IαIHC2-APLP2 complex, and immunohistochemical staining of human atherosclerotic lesions demonstrates similar staining patterns for APLP2 and IαIHC2 with macrophages, whereas serglycin localizes to the underlying glycosaminoglycan-rich region. These findings indicate that macrophages synthesize many of the molecules participating in ECM formation and function, suggesting a novel role for these molecules in the differentiation of macrophages in the development of atherosclerosis.
    Journal of Biological Chemistry 02/2012; 287(17):14122-35. · 4.65 Impact Factor
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    ABSTRACT: While monocyte- and macrophage-derived molecules are known to promote extracellular matrix (ECM) disruption and destabilization, it is less appreciated that they also synthesize molecules contributing to ECM formation, stabilization, and function. We have identified and characterized the synthesis of proteoglycans and related proteins, some not previously known to be associated with macrophages. Proteoglycan extracts of 35S-sulfate and 35S-trans amino acid radiolabelled culture media from THP-1 monocytes induced to differentiate by treatment with PMA revealed three major proteins of ~25, 90 and 100 kDa following chondroitin ABC lyase digestion. The 25 kDa protein was predominant for monocytes, whereas the 90 and 100 kDa proteins were predominant for macrophages. Tandem mass spectrometry identified: (i) the 25 kDa core protein as serglycin; (ii) the 90 kDa core protein as inter-α-inhibitor heavy chain 2 (IαIHC2); and (iii) the 100 kDa core as amyloid precursor-like protein 2 (APLP2). Differentiation was also associated with: (i) a >500-fold increase in mRNA for TNF-stimulated gene-6, an essential cofactor for heavy chain-mediated matrix stabilization; (ii) a >800-fold increase in mRNA for HAS-2, responsible for hyaluronan synthesis; and (iii) a 3-fold increase in mRNA for versican, which interacts with hyaluronan. Biochemical evidence is also presented for an IαIHC2-APLP2 complex, and immunohistochemical staining of human atherosclerotic lesions demonstrates similar staining patterns for APLP2 and IαIHC2 with macrophages, while serglycin localizes to the underlying glycosaminoglycan-rich region. These findings indicate macrophages synthesize many of the molecules participating in ECM formation and function, suggesting a novel role for these molecules in the differentiation of macrophages in the development of atherosclerosis.
    Journal of Biological Chemistry 02/2012; · 4.65 Impact Factor
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    ABSTRACT: 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. Here we found that netrin-1, a neuroimmune guidance cue, was secreted by macrophages in human and mouse atheroma, where it inactivated the migration of macrophages toward chemokines linked to their egress from plaques. Acting via its receptor, UNC5b, netrin-1 inhibited the migration of macrophages directed by the chemokines CCL2 and CCL19, activation of the actin-remodeling GTPase Rac1 and actin polymerization. Targeted deletion of netrin-1 in macrophages resulted in much less atherosclerosis in mice deficient in the receptor for low-density lipoprotein and promoted the emigration of macrophages from plaques. Thus, netrin-1 promoted atherosclerosis by retaining macrophages in the artery wall. Our results establish a causative role for negative regulators of leukocyte migration in chronic inflammation.
    Nature Immunology 02/2012; 13(2):136-43. · 26.20 Impact Factor

Publication Stats

5k Citations
792.92 Total Impact Points

Institutions

  • 1992–2014
    • University of Washington Seattle
      • • Division of Cardiology
      • • Division of Metabolism, Endocrinology and Nutrition
      • • Department of Medicine
      Seattle, Washington, United States
  • 2008–2013
    • Harvard Medical School
      Boston, Massachusetts, United States
    • Baker IDI Heart and Diabetes Institute
      Melbourne, Victoria, Australia
  • 2012
    • Massachusetts General Hospital
      • Department of Medicine
      Boston, MA, United States
  • 2010
    • Icahn School of Medicine at Mount Sinai
      Manhattan, New York, United States
    • Johns Hopkins University
      • Division of Cardiology
      Baltimore, MD, United States
  • 2009
    • Benaroya Research Institute
      Seattle, Washington, United States
  • 2006–2008
    • Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center
      • Department of Medicine
      Torrance, California, United States
  • 2007
    • University of California, San Francisco
      • Division of Hospital Medicine
      San Francisco, CA, United States
    • University of Melbourne
      • Bio21 Molecular Science and Biotechnology Institute
      Melbourne, Victoria, Australia
  • 1999
    • George Washington University
      • Division of Cardiology
      Washington, Washington, D.C., United States