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1.  INFLAMMATION AND HYPERTENSION IN RHEUMATOID ARTHRITIS 
The Journal of rheumatology  2013;40(11):10.3899/jrheum.130394.
Objective
Hypertension, a common modifiable cardiovascular risk factor, is more common in patients with rheumatoid arthritis (RA), but the underlying mechanisms are unclear. We examined the hypothesis that mediators of inflammation and markers of cardiovascular risk are associated with hypertension in RA.
Methods
We compared measures of inflammation (serum C-reactive protein (CRP), tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), homocysteine and leptin concentrations) and insulin resistance (homeostasis model assessment index (HOMA)) in RA patients with (n=90) and without hypertension (n=79). Hypertension was defined as blood pressure ≥140/90 mmHg or treatment with antihypertensive therapy. The independent association of markers of interest with hypertension was examined using multivariable logistic regression.
Results
Hypertensive patients were significantly older and had longer disease duration than those without hypertension (both P<0.001). Concentrations of homocysteine (11.1[8.5–13.5] μmol/L vs. 9.3[7.8–11.0] μmol/L were significantly higher in hypertensive patients (P<0.001). After adjustment for age, sex, race, smoking, body mass index, and corticosteroid and NSAID use, increased concentrations of homocysteine (OR 2.9, 95%CI: 1.5–5.5, P=0.001), and leptin (OR 2.0, 95%CI: 1.0–3.8, P=0.046) were significantly associated with hypertension, but the 28-joint Disease Activity Score, IL-6, CRP, TNF-α and HOMA index were not (all P values >0.05).
Conclusion
Hypertension in patients with RA is not associated with generalized systemic inflammation or insulin resistance, but is associated with increasing concentrations of homocysteine and leptin. The pathogenesis of hypertension in RA may involve pathways more likely usually associated with fat and vascular homeostasis.
doi:10.3899/jrheum.130394
PMCID: PMC3818311  PMID: 23996293
rheumatoid arthritis; inflammation; hypertension; blood pressure; homocysteine; leptin; insulin resistance
2.  Genetic variation in the β1-adrenergic receptor is associated with the risk of atrial fibrillation after cardiac surgery 
American heart journal  2013;167(1):10.1016/j.ahj.2013.09.016.
Background:
Postoperative atrial fibrillation (PoAF) after cardiac surgery is common and associated with increased morbidity and mortality. Increased sympathetic activation after surgery contributes to PoAF, and beta-blockers are the first-line recommendation for its prevention. We examined the hypothesis that common functional genetic variants in the β1-adrenoreceptor, the mediator of cardiac sympathetic activation and drug target of beta-blockers, are associated with the risk for PoAF and with the protective effect of beta-blockers.
Methods:
In a prospective cohort study, we studied 947 adult European Americans who underwent cardiac surgery at Vanderbilt University between 1999-2005. We genotyped two variants in the β1-adrenoreceptor, rs1801253 (Arg389Gly) and rs1801252 (Ser49Gly), and used logistic regression to examine the association between genotypes and PoAF occurring within 14 days after surgery, before and after adjustment for demographic and clinical covariates.
Results:
PoAF occurred in 239 patients (25.2%) and was associated with rs1801253 genotype (adjusted P=0.008), with Gly389Gly having an odds ratio of 2.63 (95% confidence interval, 1.42 to 4.89) for PoAF compared to the common Arg389Arg (P=0.002). In a predefined subgroup analysis, this association appeared to be stronger among patients without beta-blocker prophylaxis (adjusted OR=7.00; 95% CI, 1.82 to 26.96; P=0.005) compared to patients with beta-blocker prophylaxis, among whom the association between rs1801253 genotype and PoAF was not statistically significant (adjusted P=0.11).
Conclusion:
The Gly389 variant in the β1-adrenoreceptor is associated with PoAF, and this association appears to be modulated by beta-blocker therapy. Future studies of the association of other adrenergic pathway genes with PoAF will be of interest.
doi:10.1016/j.ahj.2013.09.016
PMCID: PMC3868008  PMID: 24332148
3.  Insulin Resistance is Associated with Increased Concentrations of NT-pro-BNP in Rheumatoid Arthritis: IL-6 as a Potential Mediator 
Inflammation  2014;37(3):801-808.
Objectives
To examine the hypothesis that insulin resistance (IR) decreases circulating concentrations of NT-pro brain natriuretic peptide (BNP).
Background
Obesity, despite being a risk factor for heart failure (HF), is paradoxically associated with lower concentrations of BNP, a marker of myocardial stress. Low BNP in obesity is postulated to be due to IR; however, it has been difficult to define the role of IR independent of obesity. IR in rheumatoid arthritis (RA) is increased, independent of obesity, thus allowing potential mechanistic insights into the relationship between IR and BNP.
Methods
We measured demographic factors, traditional cardiovascular risk factors, body mass index (BMI), markers of inflammation (interleukin-6 (IL-6), C-reactive protein (CRP), tumor necrosis factor α (TNFα)), NT-pro-BNP, and IR by the homeostatic model assessment (HOMA) in 140 patients with RA and 82 control subjects. Patients with heart failure and coronary artery disease were excluded. We used multiple linear regression models to examine the relationship between HOMA and NT-pro-BNP in RA and controls, and in RA alone, the additional effect of inflammation.
Results
As previously reported, NT-pro-BNP concentrations were higher in RA (median 80.49 pg/mL, IQR (23.67–167.08 pg/mL) than controls (17.84 pg/mL (3.28–36.28 pg/mL)) (P<0.001), and the prevalence of IR, defined by HOMA>2.114, was higher among RA than controls (53% vs. 15%, P>0.001). HOMA was positively correlated with NT-pro-BNP (rho=0.226, P=0.007) in RA, but not in controls (rho=−0.154, P=0.168). In a multivariable model adjusted for age, race and sex, we found that increasing HOMA was statistically associated with increasing NT-pro-BNP concentrations in RA (P=0.001), but not controls (P=0.543) (P for interaction = 0.036). In RA subjects, when IL-6 was further included in the model, IL-6 (P=0.0014), but not HOMA (P=0.43), remained significantly associated with NT-pro-BNP, suggesting that IL-6 may be mechanistically involved in the relationship between IR and NT-pro-BNP in RA.
Conclusions
We conclude that in patients with RA, insulin resistance is associated with higher, rather than the expected lower, concentrations of NT-pro-BNP and that this may be related to increased IL-6.
doi:10.1007/s10753-013-9799-4
PMCID: PMC4035432  PMID: 24402421
4.  Epicardial Adipose Tissue is Associated with Cardiometabolic Risk and the Metabolic Syndrome in Patients with Rheumatoid Arthritis 
Arthritis care & research  2013;65(9):1410-1415.
Objective
Patients with rheumatoid arthritis (RA) have increased coronary atherosclerosis possibly related to increased prevalence of visceral adiposity, insulin resistance, and metabolic syndrome. Epicardial adipose tissue (EAT), a type of visceral fat, may contribute to cardiometabolic risk. The aim of this study was to measure EAT volume in patients with RA and determine its relationship with cardiometabolic risk markers and coronary artery calcium.
Methods
EAT volume and coronary artery calcium score were measured by non-contrast cardiac computed tomography and compared in RA patients (n=162) and controls (N=89). The relationships between EAT volume and markers of cardiometabolic risk in RA were examined with adjustment for age, race and sex.
Results
Among RA patients, EAT volume was positively associated with IL-6 (P=0.03), triglycerides (P=0.004), hypertension (P=0.01), homeostatic model of insulin resistance (HOMA) (P<0.001), smoking history (P=0.04), and homocysteine (P=0.001) and negatively associated with HDL (P=0.005). With further adjustment for waist circumference (a measure of visceral obesity), EAT remained independently associated with triglycerides, HOMA, current smoking and homocysteine (all P<0.05). EAT volume was not associated with corticosteroid use or coronary artery calcium score. Patients with metabolic syndrome had significantly greater EAT volume (P<0.001) and each increase in metabolic syndrome criteria was associated, on average, with a 20% increase (95% CI, 14–26%) in EAT volume (P<0.001).
Conclusion
EAT volume is associated with metabolic syndrome and cardiometabolic risk factors including insulin resistance, triglycerides, current smoking, and homocysteine levels, but not with coronary artery calcium in RA patients.
doi:10.1002/acr.22027
PMCID: PMC3775927  PMID: 23592527
rheumatoid arthritis; epicardial adipose tissue; cardiometabolic risk; insulin resistance; atherosclerosis
5.  Warfarin Pharmacogenomics in Children 
Pediatric blood & cancer  2013;60(9):1402-1407.
Warfarin is the most commonly used oral anticoagulant worldwide. Warfarin has a narrow therapeutic index, requiring frequent monitoring of the INR to achieve therapeutic anticoagulation. The role of pharmacogenomics in warfarin disposition and response has been well-established in adults, but remains unclear for pediatric patients. In this review, we focus on the important CYP2C9 and VKORC1 variants involved in warfarin response, our current understanding of warfarin disposition and pharmacogenomics, and recent warfarin pharmacogenetic studies in pediatric patients. Finally, we discuss the need for future prospective pediatric studies and the clinical implications of developing pharmacogenetic-based dosing algorithms in children.
doi:10.1002/pbc.24592
PMCID: PMC3786327  PMID: 23682017
warfarin; pharmacogenomics; CYP2C9; VKORC1
6.  Variation in the α2A-adrenoceptor gene and the effect of dexmedetomidine on plasma insulin and glucose 
Pharmacogenetics and genomics  2013;23(9):479-486.
Objectives
Sympathetic activation inhibits insulin secretion through activation of pancreatic α2A-adrenoreceptors (α2AARs). A common genetic α2AAR variant (rs553668) is associated with impaired insulin secretion. α2AR-agonists would be expected to decrease insulin secretion, but their effects on glucose homeostasis in humans are poorly characterized. We examined the hypothesis that the selective α2AR-agonist dexmedetomidine (DEX) decreases plasma insulin and increases plasma glucose in humans, and that these effects are modified by genetic α2AAR variants.
Methods
Healthy, fasting white (n=31) and black (n=33) subjects aged 18-45 years received 3 sequential infusions of placebo (normal saline) at 30 minute intervals followed by 3 infusions of DEX (0.1, 0.15, and 0.15 mcg/kg). Plasma insulin and glucose concentrations were measured at baseline, after placebo, and after DEX. We genotyped ADRA2A rs553668 and rs2484516, which characterize haplotypes 4 and 4b, respectively.
Results
DEX decreased fasting insulin concentrations by 37%, from a median value after placebo of 7.9 (interquartile range, 6.0 to 12.6) μU/mL to 4.9 (3.5 to 7.9) μU/mL (P <0.001). Plasma glucose concentrations increased from 76±6 mg/dL to 79±7 mg/dL; P<0.001). The rs2484516 variant allele was associated with higher baseline insulin concentrations before (P=0.001) and after adjustment for potential confounders (P=0.014), and a greater decrease in insulin after DEX (P=0.016) that was no longer significant after adjustment for baseline concentrations and other confounders (P=0.58).
Conclusions
Low-dose DEX decreased plasma insulin and mildly increased plasma glucose concentrations in healthy fasting subjects. ADRA2A genetic variation may affect baseline insulin concentrations and thus the insulin decrease after DEX.
doi:10.1097/FPC.0b013e3283642f93
PMCID: PMC3787837  PMID: 23873118
7.  Initiation of Tumor Necrosis Factor Alpha (TNFα) antagonists and risk of fractures in patients with selected rheumatic and autoimmune diseases 
Arthritis care & research  2013;65(7):1085-1094.
Objectives
We tested the hypothesis that initiation of TNFα antagonists reduced the risk of fractures compared to nonbiologic comparator in patients with autoimmune diseases.
Methods
Using four large administrative databases, we assembled retrospective cohorts of patients with autoimmune diseases who initiated either a TNFα antagonist or a nonbiologic medication. We identified 3 mutually exclusive disease groups: rheumatoid arthritis (RA); inflammatory bowel disease (IBD); and psoriasis, psoriatic arthritis or ankylosing spondylitis (PsO-PsA-AS). We used baseline covariate data to calculate propensity scores (PS) for each disease group and used Cox regression to calculate hazard ratios (HR) and 95% confidence intervals (95%CI). We compared the risk of combined hip, radius/ulna, humerus, or pelvic fractures between PS-matched cohorts of new users of TNFα antagonists and nonbiologic comparator.
Results
We identified 9,020, 2,014 and 2,663 new PS matched episodes of TNFα antagonist and nonbiologic comparator use in RA, IBD and PsO-PsA-AS cohorts, respectively. The risk of combined fractures was similar between new users of TNFα antagonists and nonbiologic comparators for each disease (HR: 1.17, 95%CI [0.91, 1.51]; HR: 1.49, 95%CI [0.72, 3.11]; and HR: 0.92, 95%CI [0.47, 1.82] for RA, IBD and PsO-PsA-AS, respectively). In RA, the risk of combined fractures was associated with an average daily dose of prednisone equivalents >10 mg/day at baseline compared with no glucocorticoid (HR: 1.54, 95%CI [1.03, 2.30]).
Conclusions
The risk of fractures did not differ between initiators of a biologic and a nonbiologic comparator for any disease studied. Among RA patients, use of >10mg/day of prednisone equivalents at baseline increased the fracture risk.
doi:10.1002/acr.21937
PMCID: PMC3631448  PMID: 23281339
8.  Effect of drug transporter genotypes on pravastatin disposition in European- and African-American participants 
Pharmacogenetics and genomics  2007;17(8):647-656.
Objective
Our aims were to evaluate the effects of polymorphisms in the hepatic drug uptake transporter organic anion transporting polypeptide 1B1 (OATP1B1, SLCO1B1) and efflux transporters multidrug resistance-associated protein 2 (MRP2, ABCC2), bile salt export pump (BSEP, ABCB11), and breast cancer-related protein (BCRP, ABCG2) on single-dose pravastatin pharmacokinetics in healthy European- and African-American participants.
Methods
The pharmacokinetics of a single oral 40mg dose of pravastatin was determined in 107 participants (69 European-Americans and 38 African-Americans). Participants were genotyped for known OATP1B1, MRP2, BSEP, and BCRP polymorphisms. Baseline serum total and unconjugated plasma bilirubin concentrations were also determined.
Results
OATP1B1 genotypes were ethnicity-dependent with a 521C allele frequency of ~15% in European-Americans and ~1% in African-Americans. SLCO1B1 521TC genotype was associated with significantly higher pravastatin area under the curve [AUC(0–5)] (P =0.01) and Cmax values (P< 0.05). When analyzed by diplotype, SLCO1B1*1a/*15 (N =8) participants exhibited 45 and 80% higher AUC values than SLCO1B1*1a/*1a (N=29) (P=0.013) and SLCO1B1*1b/*1b (N=34) (P=0.001) carriers, respectively. SLCO1B1*15/*15 (N=2) participants exhibited 92 and 149% higher AUC values than SLCO1B1*1a/*1a (P=0.017) and SLCO1B1*1b/*1b (P= 0.011) carriers, respectively. European-Americans had significantly higher plasma pravastatin AUC(0–5) (P =0.01) and Cmax values (P=0.009) than African-Americans. Neither ABCC2, ABCB11, nor ABCG2 genotypes were associated with differences in pravastatin pharmacokinetics. We did not observe an effect of SLCO1B1 genotype on baseline total or unconjugated bilirubin levels.
Conclusion
SLCO1B1 genotype, in particular the 521C allele, had a significant effect on the pharmacokinetics of pravastatin. Even when adjusted for the presence of the SLCO1B1 521C or 388G variant allele, European-Americans demonstrated significantly higher pravastatin AUC and Cmax values than African-Americans.
doi:10.1097/FPC.0b013e3280ef698f
PMCID: PMC4063287  PMID: 17622941
ABCB11; ABCC2; ABCG2; BCRP; bilirubin; BSEP; MRP2; OATP1B1; pharmacokinetics; pravastatin; SLCO1B1; transporter
9.  Increased oxidative stress in patients with depression and its relationship to treatment 
Psychiatry research  2012;206(0):213-216.
Oxidative stress may play a role in the pathogenesis of depression. We tested the hypothesis that urinary F2 isoprostane, a robust marker of oxidative stress, was increased in patients with depression and associated with symptoms and response to treatment. Urinary F2 isoprostane was compared in 18 patients with depression and 36 age and sex matched control subjects. In patients, we tested the association between oxidative stress, depression questionnaires and antidepressant treatment. Urinary F2 isoprostane excretion was significantly higher in patients with depression than in control subjects. This association remained significant after adjustment for age, sex and BMI. Depression symptom severity scores were not correlated with F2 isoprostane excretion. Nine patients were treated with sertraline or bupropion for eight weeks. Depression severity rating scale scores decreased significantly and F2 isoprostane excretion increased. The increase in F2 isoprostane excretion was inversely correlated with the improvement in Hamilton Depression Rating 17 items. In conclusion, oxidative stress is increased in patients with depression. However, although treatment with either bupropion or sertraline reduces the symptoms of depression, it may increase F2 isoprostane excretion. These results suggest that alternative mechanisms, beyond oxidative stress, may be involved in the development of depression and subsequent responses to treatment.
doi:10.1016/j.psychres.2012.10.018
PMCID: PMC3615036  PMID: 23245537
depression; oxidative stress; F2 isoprostanes; antidepressants; sertraline; bupropion
10.  AFRICAN AMERICANS HAVE A GREATER SENSITIVITY TO ALPHA1-ADRENOCEPTOR-MEDIATED VENOCONSTRICTION COMPARED TO CAUCASIANS 
Hypertension  2013;61(4):915-920.
African Americans have increased hemodynamic responses to both physiologic and pharmacologic adrenergic stimulation compared to Caucasians, and this may contribute to the greater prevalence of hypertension in this ethnic group. A small study suggested enhanced α1-adrenoreceptor-mediated arterial vasoconstriction in the forearm vasculature of African Americans compared to Caucasians, but it is unknown whether this reflects a generalized vascular phenomenon. The objective of this study was to examine the hypothesis that there are ethnic differences in venous α1-adrenoreceptor responsiveness. Using a linear variable differential transformer, we measured local dorsal hand vein responses to increasing doses of the selective α1-adrenoreceptor agonist, phenylephrine, in 106 subjects (64 Caucasians and 42 African Americans). There was wide interindividual variability in responses to phenylephrine. The dose that produced 50% of maximal constriction (ED50) ranged from 11 to 5442 ng/min, and maximal venoconstriction (Emax) ranged from 13.5% to 100%. African Americans (geometric mean ED50=172 ng/min; 95% CI, 115 to 256 ng/min) were more sensitive to phenylephrine than Caucasians (310 ng/min; 95% CI, 222 to 434 ng/min; unadjusted P=0.026; adjusted P=0.003). Median Emax was slightly higher in African Americans (89%; IQR, 82% to 98%) compared to Caucasians (85%; IQR, 75% to 95%; P=0.07). Taken together with previous findings in arterial vessels, our results suggest a generalized increased sensitivity to α1-adrenoreceptor-mediated vasoconstriction in African Americans. Increased vascular α-adrenoreceptor sensitivity could predispose to hypertension, and future studies addressing this mechanism’s contribution to ethnic differences in the prevalence of hypertension will be of interest.
doi:10.1161/HYPERTENSIONAHA.111.00854
PMCID: PMC3627527  PMID: 23399717
Alpha-1 adrenergic receptor; vasoconstriction; phenylephrine; ethnicity; hypertension
11.  Propoxyphene and the Risk of Out-of-Hospital Death 
Purpose
The opioid analgesic propoxyphene was withdrawn from the U.S. market in 2010, motivated by concerns regarding fatality in overdose and adverse cardiac effects, including prolongation of the QT interval. These concerns were based on case reports, summary vital statistics, and surrogate endpoint studies.
Methods
Using the linked Tennessee Medicaid database (1992–2007), we conducted a retrospective cohort study that compared risk of sudden cardiac, medication toxicity, and total out-of-hospital death for propopxyphene users with that for comparable nonusers of any prescribed opioid analgesic and users of hydrocodone, an opioid with similar indications. Cohort members had 1,873,500 propoxyphene prescriptions, 1,873,500 matched nonuser control periods and 936,750 matched hydrocodone prescriptions.
Results
Current propoxyphene users had no increased risk for sudden cardiac death (versus nonusers: HR = 1.00 [0.81–1.23]; versus current hydrocodone users: HR = 0.91 [0.68–1.21]) but did have increased risk for medication toxicity deaths (versus nonusers: HR = 1.85 [1.07–3.19], p= 0.027; versus current hydrocodone users: HR = 2.10 [0.87–5.10], p = 0.100). Because toxicity deaths were a small proportion of study deaths, total out-of-hospital mortality differed by less than 10% between the study groups and was not significantly elevated for propoxyphene (versus nonusers: HR = 1.09[0.95–1.25]; versus current hydrocodone users: HR = 1.06 [0.87–1.29]).
Conclusions
Our findings support the concern that propoxyphene has greater toxicity in overdose but do not provide evidence that it increases the risk of sudden cardiac death.
doi:10.1002/pds.3411
PMCID: PMC3694329  PMID: 23408551
12.  Association of foot ulcer with tibial artery calcification is independent of peripheral occlusive disease in type 2 diabetes 
Aims
To determine the relationship between foot ulcers, arterial calcification, and peripheral occlusive disease in patients with type 2 diabetes.
Methods
We performed a cross-sectional study on 162 patients with type 2 diabetes who underwent assessment of tibial artery calcification (TAC) by non-contrasted CT scan. Peripheral artery occlusive disease was assessed by angiography. Foot status including the presence or absence of ulcers was documented at presentation. A multivariable logistic regression model was used to evaluate the association between foot ulcers, arterial calcification, and the extent of peripheral atherosclerotic occlusive disease.
Results
Patients with foot ulcers (n= 31) were more likely to be older and have a history of tobacco use. They were also more likely to have higher TAC scores (median [IQR]: 4324.6 [609.9, 11163.6] vs. 9.4 [0.0, 343.9], P < 0.001) and more advanced peripheral artery occlusive disease (occlusion index 5.5 [4.8, 6.4] vs. 2.2 [1.0, 3.6], P < 0.001. Foot ulcer was strongly associated with elevated TAC scores in a multivariable regression model (Odds ratio [95% CI] =2.76 [1.61, 4.75], P=0.0002).
Conclusions
There is a strong association between arterial calcification and diabetic foot ulcers that persists after adjusting for the extent of atherosclerosis in patients with type 2 diabetes.
doi:10.1016/j.diabres.2012.12.022
PMCID: PMC3628094  PMID: 23305901
diabetes; foot ulcer; artery calcification; atherosclerosis
13.  A polymorphism in the protein kinase C gene PRKCB is associated with α2-adrenoceptor-mediated vasoconstriction 
Pharmacogenetics and genomics  2013;23(3):127-134.
Objectives
α2-Adrenoceptors (α2-AR) mediate both constriction and dilatation of blood vessels. There is substantial inter-individual variability in dorsal hand vein (DHV) constriction responses to α2-AR agonist activation. Genetic factors appear to contribute significantly to this variation. The present study was designed to identify genetic factors contributing to the inter-individual variability in α2-AR-mediated vascular constriction induced by the selective α2-AR agonist dexmedetomidine.
Methods
DHV constriction responses to local infusion of dexmedetomidine were assessed by measuring changes in vein diameter with a linear variable differential transformer. The outcome variable was log-transformed dexmedetomidine ED50 for constriction. A genome-wide association study (GWAS) of 433,378 single nucleotide polymorphisms (SNPs) was performed for the sensitivity of DHV responses in 64 healthy Finnish subjects. 20 SNPs were selected based on the GWAS results and their associations with the ED50 of dexmedetomidine were tested in an independent North American study population of 68 healthy individuals.
Results
In both study populations (GWAS and replication samples), the SNP rs9922316 in the gene for protein kinase C type β was consistently associated with dexmedetomidine ED50 for dorsal hand vein constriction (unadjusted p = 0.00016 for the combined population).
Conclusions
Genetic variation in protein kinase C type β may contribute to the inter-individual variation in dorsal hand vein constriction responses to α2-AR activation by the agonist dexmedetomidine.
doi:10.1097/FPC.0b013e32835d247f
PMCID: PMC3912740  PMID: 23337848
receptors, adrenergic, alpha; dorsal hand vein; GWAS; candidate genes; dexmedetomidine
14.  Cystatin C is Associated with Inflammation but not Atherosclerosis in Systemic Lupus Erythematosus 
Lupus  2011;21(3):279-287.
Background
Even mild renal impairment is associated with increased atherosclerosis and cardiovascular mortality. Cystatin C, a novel measure of renal function, is more sensitive than conventional creatinine-based measures for the detection of subtle renal impairment. Increased cystatin concentrations are also associated with cardiovascular risk, independent of conventional measures of renal function. We examined the hypothesis that cystatin C is elevated in systemic lupus erythematosus (SLE) and is associated with coronary atherosclerosis.
Methods
We measured serum cystatin C, creatinine, TNF-α, IL-6, coronary artery calcium score (CACS), Framingham risk score (FRS), Modified Diet in Renal Disease estimated glomerular filtration rate (MDRD-eGFR) and other clinical parameters in 118 patients with SLE and 83 control subjects. The independent association between concentrations of cystatin C and SLE was evaluated using multivariable linear regression models, and the relationship between renal measures and coronary calcium was assessed with multivariable proportional odds logistic regression models.
Results
Cystatin C, but not other measures of renal function, was significantly higher in patients with SLE than controls (1.09[Interquartile range, IQR: 0.85–1.28]mg/L vs. 0.89 [IQR: 0.76–0.99]mg/L; P<0.001 after adjusting for age, race and sex and MDRD-eGFR). Cystatin C was significantly associated with SLICC (P=0.04), ESR (P<0.001), CRP (P=0.04), TNF-α (P=0.008) and IL-6 (P=0.01) after adjustment for age, race and sex. Cystatin C was not significantly correlated with coronary calcium score in SLE (rho=0.096, P= 0.31) and the association remained non-significant after adjustment for age, race, sex and Framingham risk score (P=0.99).
Conclusions
Cystatin C was higher in patients with SLE than control subjects even after adjustment for conventional measures of renal function. Cystatin C was significantly correlated with several markers of inflammation in SLE but was not associated with coronary atherosclerosis. Subtle renal dysfunction does not appear to be directly associated with accelerated atherosclerosis in SLE.
doi:10.1177/0961203311425527
PMCID: PMC3275887  PMID: 22072023
cystatin C; systemic lupus erythematosus; renal function; atherosclerosis; Inflammation
15.  Genetic Determinants of Response to Warfarin during Initial Anticoagulation 
The New England journal of medicine  2008;358(10):999-1008.
BACKGROUND
Genetic variants of the enzyme that metabolizes warfarin, cytochrome P-450 2C9 (CYP2C9), and of a key pharmacologic target of warfarin, vitamin K epoxide reductase (VKORC1), contribute to differences in patients’ responses to various warfarin doses, but the role of these variants during initial anticoagulation is not clear.
METHODS
In 297 patients starting warfarin therapy, we assessed CYP2C9 genotypes (CYP2C9 *1, *2, and *3), VKORC1 haplotypes (designated A and non-A), clinical characteristics, response to therapy (as determined by the international normalized ratio [INR]), and bleeding events. The study outcomes were the time to the first INR within the therapeutic range, the time to the first INR of more than 4, the time above the therapeutic INR range, the INR response over time, and the warfarin dose requirement.
RESULTS
As compared with patients with the non-A/non-A haplotype, patients with the A/A haplotype of VKORC1 had a decreased time to the first INR within the therapeutic range (P = 0.02) and to the first INR of more than 4 (P = 0.003). In contrast, the CYP2C9 genotype was not a significant predictor of the time to the first INR within the therapeutic range (P = 0.57) but was a significant predictor of the time to the first INR of more than 4 (P = 0.03). Both the CYP2C9 genotype and VKORC1 haplotype had a significant influence on the required warfarin dose after the first 2 weeks of therapy.
CONCLUSIONS
Initial variability in the INR response to warfarin was more strongly associated with genetic variability in the pharmacologic target of warfarin, VKORC1, than with CYP2C9.
doi:10.1056/NEJMoa0708078
PMCID: PMC3894627  PMID: 18322281
16.  Free Fatty Acids are Associated with Metabolic Syndrome and Insulin Resistance, but not Inflammation in SLE Patients 
Lupus  2012;22(1):26-33.
Free fatty acids (FFAs) are implicated in the pathogenesis of insulin resistance and atherosclerosis. Inflammatory cytokines promote lipolysis and increase FFAs, a cause of endothelial dysfunction and increased atherosclerosis risk. We hypothesized that increased inflammation is associated with increased FFAs, resulting in insulin resistance and atherosclerosis in patients with systemic lupus erythematosus (SLE). We measured clinical variables, serum FFAs, homeostasis model assessment for insulin resistance (HOMA), inflammatory cytokines, markers of endothelial activation, cholesterol concentrations, and coronary artery calcium in 156 patients with SLE and 90 controls. We compared FFAs in patients with SLE and controls using Wilcoxon rank sum tests and further tested for the independent association between FFAs and disease status with adjustment for age, race, and sex using multivariable regression models. We assessed the relationship between FFA and continuous variables of interest using Spearman correlation and multivariable regression analysis. FFAs levels were higher in patients with SLE than controls (0.55 mmol/l [0.37- 0.71] vs. 0.44 mmol/l [0.32- 0.60], P=0.02). FFAs remained significantly higher among patients with SLE after adjustment for age, race, and sex (P=0.03), but not after further adjustment for BMI (P=0.13). FFA levels did not differ according to current immunosuppressive medication use in univariate and adjusted analysis (all P>0.05). Among patients with SLE, concentrations of FFAs were higher among those with metabolic syndrome compared to those without (0.66 mmol/l [0.46-0.81] vs. 0.52 mmol/l [0.35- 0.66], P<0.001). FFAs were positively correlated with insulin resistance (HOMA) (rho=0.23, P=0.004, P adjusted=0.006) and triglyceride levels (rho=0.22, P=0.01, P adjusted=0.004). FFAs were not associated with inflammatory cytokines (IL-6, TNF-α) (all P>0.05), but were positively associated with levels of E-selectin (rho=0.33, P=<0.001, P adjusted=0.001) and ICAM-1 (rho=0.35, P<0.001, P adjusted=0.001). FFAs were correlated with coronary artery calcium score (rho=0.20, P=0.01), but this was attenuated after adjustment for age, race and sex (P=0.33). FFAs are elevated in patients with SLE, particularly those with metabolic syndrome. FFAs in SLE are not associated with markers of generalized inflammation but are associated with insulin resistance and markers of endothelial activation.
doi:10.1177/0961203312462756
PMCID: PMC3684362  PMID: 23060481
cardiovascular disease; systemic lupus erythematosus; free fatty acids; metabolic syndrome; endothelial activation; insulin resistance
17.  Novel cardiovascular risk prediction models in patients with systemic lupus erythematosus 
Lupus  2011;20(14):1526-1534.
Women with systemic lupus erythematosus (SLE) have increased risk for coronary heart disease (CHD) which is underestimated by the Framingham risk score (FRS). We hypothesized that new risk scores that include inflammation or vascular age in the risk calculation would better identify women with SLE at risk for CHD, particularly in those with subclinical coronary atherosclerosis. We calculated the FRS and Reynolds risk score (RRS) in 121 women with SLE and 65 age-matched female controls; coronary age-modified risk scores (camFRS, camRRS) were calculated using coronary age derived from the coronary artery calcium (CAC) score. Risk scores were compared in SLE and controls, and in SLE patients with and without CAC. Although CAC was present in 21 SLE patients (17%) and 4 controls (6%) (P=0.033); the FRS, camFRS, RRS, and camRRS, did not differ significantly among SLE and controls (P>0.05), but were all significantly higher in SLE patients with CAC compared to those without (P< 0.001 for all). The cam-FRS (8%, P=0.016) but not cam-RRS (5%, P=0.221) assigned significantly more SLE patients to a category of ≥10% risk than conventional FRS (1%) and RRS (2%). The RRS was of limited use but coronary age may improve CHD risk prediction in SLE.
doi:10.1177/0961203311420317
PMCID: PMC3227752  PMID: 21976402
SLE; cardiovascular risk; atherosclerosis
18.  Cystatin C, Renal Function and Atherosclerosis in Rheumatoid Arthritis 
The Journal of rheumatology  2011;38(11):2297-2300.
Objective
We examined the hypothesis that cystatin C, a novel marker of renal function, is elevated in rheumatoidarthritis (RA) and associated with inflammation and coronary atherosclerosis.
Methods
We measured serum cystatin C, creatinine, TNF-α and IL-6 concentrations, coronary artery calcium score (CACS), and Modified Diet in Renal Disease estimated GFR (MDRD-eGFR) in 167 patients with RA and 91 controls.
Results
Cystatin C was higher in RA (median [IQR]: 1.16 [0.99–1.35] mg/L) than controls (1.01 [0.90–1.19] mg/L), (P<0.001) and positively correlated with ESR (P<0.001), CRP (P=0.01), DAS28 (P=0.006), and Framingham risk score (FRS)(P=0.02). Cystatin C was correlated with CACS (P<0.001) in RA, but this was not significant after adjustment for age, race, sex and FRS (P =0.44).
Conclusions
Cystatin C concentrations are higher in RA than controls and may reflect inflammation and undetected subclinical renal dysfunction. Cystatin C provides information regarding the risk of atherosclerosis in RA, but this is linked to conventional cardiovascular risk factors.
doi:10.3899/jrheum.110168
PMCID: PMC3207028  PMID: 21844147
cystatin; rheumatoid arthritis; renal function; atherosclerosis
19.  High prevalence of the metabolic syndrome in patients with systemic lupus erythematosus: association with disease characteristics and cardiovascular risk factors 
Annals of the Rheumatic Diseases  2006;66(2):208-214.
Background
The metabolic syndrome is an independent risk factor for ischaemic heart disease. Patients with systemic lupus erythematosus (SLE) have accelerated atherosclerosis; however, there are no controlled studies of the metabolic syndrome in patients with SLE.
Objective
To compare the prevalence of the metabolic syndrome in patients with SLE and controls and to evaluate its relationship to other cardiovascular risk factors and inflammation.
Methods
102 patients with SLE and 101 controls were studied. The prevalence of the metabolic syndrome was compared in patients and controls using the National Cholesterol Education Program Adult Treatment Panel III (NCEP) and the World Health Organization (WHO) definitions, and associations with cardiovascular risk factors and lupus characteristics were examined.
Results
The metabolic syndrome was present in 32.4% of patients and in 10.9% of controls subjects (p<0.001) using the WHO definition that requires direct determination of insulin resistance, and in 29.4% of patients with SLE and in 19.8% of controls (p = 0.14) using the NCEP definition. Among patients with SLE, both definitions were significantly associated with higher concentrations of C reactive protein (p = 0.001) and the NCEP definition was significantly associated with higher concentrations of homocysteine (p<0.001), lipoprotein (a) (p = 0.02) and cholesterol (p = 0.04). Neither lupus disease activity nor damage scores were associated with the metabolic syndrome.
Conclusions
Patients with SLE have a higher prevalence of insulin resistance and consequently of the WHO‐defined metabolic syndrome than controls. In patients with SLE, the metabolic syndrome was associated with higher levels of inflammation and may provide a link between inflammation and increased cardiovascular risk.
doi:10.1136/ard.2006.054973
PMCID: PMC1798504  PMID: 16901956
20.  Inflammation-Associated Insulin Resistance: Differential Effects in Rheumatoid Arthritis and Systemic Lupus Erythematosus Define Potential Mechanisms 
Arthritis and rheumatism  2008;58(7):2105-2112.
Objective
Insulin resistance is increased by inflammation, but the mechanisms are unclear. The present study was undertaken to test the hypothesis that decreased insulin sensitivity is differentially associated with mediators of inflammation by studying 2 chronic inflammatory diseases of different pathogenesis, systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA).
Methods
We measured fasting insulin, glucose, and lipid levels, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), interleukin-6 (IL-6), tumor necrosis factor α (TNFα), and coronary artery calcification in 103 patients with SLE and in 124 patients with RA. Insulin sensitivity was measured using the homeostasis model assessment (HOMA) index.
Results
The HOMA value was higher in RA patients (median 2.05 [interquartile range (IQR) 1.05–3.54]) than in SLE patients (1.40 [0.78–2.59]) (P = 0.007). CRP and ESR did not differ significantly in RA and SLE patients. Body mass index (BMI) was significantly correlated with the HOMA index in both RA (ρ = 0.20) and SLE (ρ = 0.54), independently of age, sex, race, and current use of corticosteroids. In RA patients, the HOMA index was also significantly positively correlated with IL-6 (ρ = 0.63), TNFα (ρ = 0.50), CRP (ρ = 0.29), ESR (ρ = 0.26), coronary calcification (ρ = 0.26), and Disease Activity Score in 28 joints (ρ = 0.21); associations adjusted for age, sex, race, BMI, and current use of corticosteroids remained significant (P < 0.05). In SLE patients, the HOMA index was also significantly correlated with ESR (ρ = 0.35) and CRP (ρ = 0.25), but not with other variables. The association between the ESR and the HOMA value in patients with SLE remained significant after adjustment for confounding covariates (P = 0.008). In multivariable models, the major contributing factors to the HOMA index were the BMI in SLE patients, and IL-6 and TNFα levels in RA patients.
Conclusion
The pathogenesis of insulin resistance and its contribution to atherogenesis varies in different inflammatory settings.
doi:10.1002/art.23600
PMCID: PMC2755593  PMID: 18576352
21.  Peroxisome proliferator-activated receptor γ agonist effect on rheumatoid arthritis: a randomized controlled trial 
Arthritis Research & Therapy  2013;15(5):R110.
Introduction
Rheumatoid arthritis (RA), a chronic inflammatory disease, is associated with insulin resistance. Experimental evidence indicates that the relationship between insulin resistance and inflammation is bidirectional: Inflammation promotes insulin resistance, and insulin resistance promotes inflammation. Therefore, we examined the hypothesis that pioglitazone, a thiazolidinedione peroxisome proliferator-activated receptor γ agonist, would decrease inflammation and disease activity and improve insulin resistance in patients with RA.
Methods
In a single-center, randomized, double-blind, placebo-controlled crossover study patients with RA (N = 34) receiving stable therapy were randomized to also receive either pioglitazone 45 mg daily (n = 17) or matching placebo (n = 17) for eight weeks. This was followed by a four-week washout period and alternative treatment for eight weeks. Outcomes included change in Disease Activity Score in 28 joints (DAS28) score, individual components of the DAS28 score and homeostatic model assessment for insulin resistance (HOMA). Intention-to-treat analysis and linear mixed-effects models were used.
Results
Patients had a mean (±SD) age of 51 (±14.2) years, 82.4% were female and baseline DAS28 high-sensitivity C-reactive protein (DAS28-CRP) was 4.58 (±1.1) units. Addition of pioglitazone was associated with a 9.3% reduction (95% confidence interval (CI) = 0.17% to 17.6%) in DAS28-CRP (P = 0.046), but no significant change in DAS28 erythrocyte sedimentation rate (DAS28-ESR) (P = 0.92). There was a 10.7mm (95% CI = 0.4 to 20.9 mm) improvement in patient-reported global health (P = 0.042), a 48.6% decrease (95% CI = 27.6% to 63.5%) in CRP (P < 0.001) and a 26.4% decrease (95% CI = 3.7% to 43.8%) in insulin resistance as measured by HOMA (P = 0.025), but no significant reduction in swollen or tender joint count or in ESR (all P > 0.05). Lower-extremity edema was more common during pioglitazone treatment (16%) than placebo (0%).
Conclusion
Addition of pioglitazone to RA therapy improves insulin resistance and modestly reduces RA disease activity measured by DAS28-CRP and two of its components, including patient-reported global health and CRP, but not DAS28-ESR or ESR.
Trial registration
NCT00763139
doi:10.1186/ar4290
PMCID: PMC3978636  PMID: 24020899
22.  Macrophage Activation and Coronary Atherosclerosis in Systemic Lupus Erythematosus and Rheumatoid Arthritis 
Arthritis care & research  2011;63(4):535-541.
Objectives
Activation of macrophages may contribute to increased atherosclerosis and coronary artery disease in systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). Neopterin, a pteridine derivative, is a novel marker of monocyte and macrophage activation that is associated with atherosclerosis and cardiovascular risk in the general population. We examined the hypothesis that macrophage activation is associated with accelerated atherosclerosis in SLE and RA.
Methods
We compared serum neopterin concentrations, adjusted for age, race, sex and serum creatinine concentration, in patients with SLE (n=148), RA (n=166) and control subjects (n=177). In patients with SLE or RA, serum neopterin concentrations were then tested for association (adjusted for age, race, sex, serum creatinine and medication use) with measures of disease activity or damage, inflammatory markers and mediators, and coronary artery calcium measured by electron beam computed tomography.
Results
Neopterin concentrations were significantly higher in patients with SLE (median 8.0, IQR [6.5–9.8] nmol/l) and RA (6.7[5.3–8.9] nmol/l) than controls (5.7[4.8–7.1] nmol/l), and were higher in SLE than RA (all p<0.001). In SLE, neopterin was significantly correlated with higher ESR (p=0.001), TNF-α (p<0.001), MCP-1 (p=0.005) and homocysteine concentrations (p=0.01), but in RA only with ESR (p=0.01). Neopterin was not associated with coronary calcium in either SLE (p=0.65) or RA (p=0.21).
Conclusion
Macrophage activation, reflected by increased serum neopterin concentrations, was increased in both SLE and RA. Neopterin was more robustly associated with atherogenic mediators of inflammation and homocysteine in SLE than RA but was not associated with coronary atherosclerosis in either disease.
doi:10.1002/acr.20365
PMCID: PMC3020253  PMID: 20890983
Systemic Lupus Erythematosus; Rheumatoid Arthritis; Neopterin; Homocysteine; Atherosclerosis
23.  Genetic variations in the α2A-adrenoreceptor are associated with blood pressure response to the agonist dexmedetomidine 
Background
α2A-Adrenoceptors (α2A-ARs) have important roles in sympathetic cardiovascular regulation. Variants of ADRA2A affect gene transcription and expression and are associated with insulin release and risk for type 2 diabetes. We examined whether ADRA2A variants are also associated with cardiovascular responses to the selective α2-AR-agonist, dexmedetomidine.
Methods and Results
73 healthy subjects participated in a placebo-controlled single-blind study. After 3 infusions of placebo, subjects received 3 incremental infusions of dexmedetomidine (cumulative dose, 0.4 mcg/kg). Primary outcomes were changes in systolic blood pressure (SBP) and plasma norepinephrine concentrations, measured as difference of the area-under-the-curve during placebo and dexmedetomidine infusions (ΔAUC). We used multiple linear regression analysis to examine the associations between 9 ADRA2A tagging variants and 5 inferred haplotypes and ΔAUC after adjustment for covariates. Homozygous carriers of rs553668, and the corresponding haplotype 4, previously associated with increased α2A-AR expression, had a 2.2-fold greater decrease in AUCSBP after dexmedetomidine (adjusted P=0.006); similarly, the maximum decrease in SBP was 24.7±8.1 mmHg compared to 13.6±5.9 mmHg in carriers of the wildtype allele (P=0.007). Carriers of haplotype 3, previously associated with reduced α2A-AR expression, had a 44% smaller decrease in AUCSBP (P=0.013). Haplotype information significantly improved the model predicting the decrease in SBP (P<0.001). There were similar but non-significant trends for diastolic blood pressure and heart rate. Genotypes were not significantly associated with norepinephrine responses.
Conclusion
Common ADRA2A variants are associated with the hypotensive response to dexmedetomidine. Effects of specific variants/haplotypes in vivo are compatible with their known effects on gene expression in vitro.
doi:10.1161/CIRCGENETICS.110.957662
PMCID: PMC3080459  PMID: 21325151
receptors; adrenergic; alpha; genetic polymorphism; pharmacogenetics; receptor; variability in drug response
24.  Effects of Anti-Tumor Necrosis Factor α (anti-TNF) agents on Bone 
Current opinion in rheumatology  2012;24(5):576-585.
Purpose of the review
TNF inhibitors are effective for achieving disease control in several inflammatory diseases. Although anti-TNF agents can inhibit bone loss in vitro, their role in the prevention of clinically relevant outcomes such as osteoporosis and fractures has not been clearly established.
Recent findings
There are many studies of the effects of TNF inhibitors on markers of bone turnover; however few have measured bone mineral density (BMD) or fractures. Most of these studies have small sample sizes and a minority had a placebo control group. Overall these studies suggest that the anti-resorptive effects of anti-TNF therapy are related to control of disease activity.
Summary
The antiresorptive effects of TNF inhibitors are likely related to their anti-inflammatory properties. Studies to date have not demonstrated any advantages of TNF inhibitors over traditional non biologic therapies in the prevention of bone loss and fractures.
doi:10.1097/BOR.0b013e328356d212
PMCID: PMC3753172  PMID: 22810364
Anti-TNF; bone loss; rheumatoid arthritis; spondyloarthropaties
25.  Independent Regulation of Alpha1 and Alpha2 Adrenergic Receptor–Mediated Vasoconstriction in vivo 
Journal of hypertension  2011;29(2):251-256.
Background
Vascular α1- and α2-adrenergic receptors (ARs) mediate vasoconstriction and are major determinants of peripheral vascular tone. There is wide variability in vasoconstrictor sensitivity to α1- and α2AR-agonists among individuals. In previous studies this variability was not explained by identified α1- and α2-AR genetic variants. Thus, we hypothesized that adrenergic vasoconstrictor sensitivity is determined by shared constrictor mechanisms downstream of the individual receptors and that α1- and α2-AR-mediated vasoconstrictor sensitivity would therefore be correlated.
Methods
Dorsal hand vein responses to increasing doses of the α1-AR agonist phenylephrine (12 ng/min –12,000 ng/min) and the α2-AR agonist dexmedetomidine (0.01 ng/min – 100 ng/min) were measured in healthy subjects using a linear variable differential transformer. From individual dose-response curves we calculated the dose of phenylephrine and dexmedetomidine that produced 50% (ED50) of maximum venoconstriction (Emax) for each subject. We examined the correlation between phenylephrine and dexmedetomidine ED50 and Emax before and after adjustment for covariates (age, gender, ethnicity, BMI, blood pressure, heart rate, and baseline plasma norepinephrine concentrations).
Results
In 62 subjects (36 males, 34 African American, 28 Caucasians) the median ED50 for dexmedetomidine was 1.32 ng/min (IQR, 0.45–5.37 ng/min), and for phenylephrine 177.8 ng/min (IQR, 40.7– 436.5 ng/min). The Emax for phenylephrine was 90.8% (82.2–99.6%) and for dexmedetomidine 80.0% (64.7–95.2%). There was no correlation between individual sensitivities (ED50) to phenylephrine and dexmedetomidine, before and after adjustment for covariates (p>0.30).
Conclusions
Phenylephrine and dexmedetomidine both produce strong venoconstriction in the dorsal hand vein; however, there is no significant correlation between vascular sensitivity to an α1-AR and α2-AR agonist. These findings suggest independent regulation of vascular α1- and α2-AR-mediated responses.
doi:10.1097/HJH.0b013e3283407ffd
PMCID: PMC3012748  PMID: 21045729
α1 adrenoceptors; α2 adrenoceptors; vasoconstriction

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