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.
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.
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).
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.
rheumatoid arthritis; inflammation; hypertension; blood pressure; homocysteine; leptin; insulin resistance
Tacrolimus is the mainstay immunosuppressant drug used after solid organ and hematopoietic stem cell transplantation. Individuals who express CYP3A5 (extensive and intermediate metabolizers) generally have decreased dose-adjusted trough concentrations of tacrolimus as compared to those who are CYP3A5 non-expressers (poor metabolizers), possibly delaying achievement of target blood concentrations. We summarize evidence from the published literature supporting this association and provide dosing recommendations for tacrolimus based on CYP3A5 genotype when known (updates at www.pharmgkb.org).
Tacrolimus; CYP3A5; immunosuppressant; pharmacogenetics; pharmacogenomics; transplant
The influence of genetic variation on warfarin dose requirement is limited for paediatric patients. We performed a retrospective, cross-sectional study to examine the effect of variant CYP2C9 and VKORC1 genotypes on warfarin dose in 100 children. Those with VKORC1 genotype AA required 48% of the dose of homozygous wild-type (GG, p<0.0001). Patients with any variant CYP2C9 allele required 71% of the dose for wild-type (p=0.001). The effect of variant VKORC1 alleles tended to vary with age, suggesting developmental ontogeny may influence warfarin sensitivity. Age, CYP2C9 genotype, VKORC1 genotype and age:VKORC1 interaction accounted for 53% of warfarin dose variability.
warfarin; paediatrics; pharmacogenomics; CYP2C9; VKORC1
To examine the hypothesis that insulin resistance (IR) decreases circulating concentrations of NT-pro brain natriuretic peptide (BNP).
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.
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.
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.
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.
GlycA is a novel inflammatory biomarker measured using nuclear magnetic resonance (NMR). Its NMR signal primarily represents glycosylated acute phase proteins. GlycA was associated with inflammation and development of cardiovascular disease in initially healthy women. We hypothesized that GlycA is a biomarker of disease activity and is associated with coronary artery atherosclerosis in patients with rheumatoid arthritis (RA).
We conducted a cross-sectional study of 166 patients with RA and 90 control subjects. GlycA was measured from an NMR signal originating from N-acetylglucosamine residues on circulating glycoproteins. The relationship between GlycA and RA disease activity (Disease Activity Score based on 28 joints (DAS28)) and coronary artery calcium score was determined.
GlycA concentrations were higher in patients with RA (median (interquartile range): 398 μmol/L (348 to 473 μmol/L)) than control subjects (344 μmol/L (314 to 403 μmol/L) (P < 0.001). In RA, GlycA was strongly correlated with DAS28 based on erythrocyte sedimentation rate (DAS28-ESR) and DAS28 based on C-reactive protein (DAS28-CRP) and their components, including tender and swollen joint counts, global health score, ESR and CRP (all P < 0.001). The area under the receiver operating characteristic curve for GlycA’s ability to differentiate between patients with low versus moderate to high disease activity based on DAS28-CRP was 0.75 (95 % confidence interval (CI): 0.68, 0.83). For each quartile increase in GlycA, the odds of having coronary artery calcium increased by 48 % (95 % CI: 4 %, 111 %), independent of age, race and sex (P = 0.03).
GlycA is a novel inflammatory marker that may be useful for assessment of disease activity and is associated with coronary artery atherosclerosis in patients with RA.
Objective: Patients with rheumatoid arthritis (RA) have accelerated atherosclerosis, but there is limited information about the genetic contribution to atherosclerosis in this population. Therefore, we examined the association between selected genetic polymorphisms and coronary atherosclerosis in patients with RA. Methods: Genotypes for single-nucleotide polymorphisms (SNPs) in 152 candidate genes linked with autoimmune or cardiovascular risk were measured in 140 patients with RA. The association between the presence of coronary artery calcium (CAC) and SNP allele frequency was assessed by logistic regression with adjustment for age, sex, and race. To adjust for multiple comparisons, a false discovery rate (FDR) threshold was set at 20%. Results: Patients with RA were 54 ± 11 years old and predominantly Caucasian (89%) and female (69%). CAC was present in 70 patients (50%). A variant in rs2073618 that encodes an Asn3Lys missense substitution in the osteoprotegerin gene (OPG, TNFRSF11B) was significantly associated with the presence of CAC (OR = 4.09, p < 0.00026) and withstands FDR correction. Conclusion: Our results suggest that a polymorphism of the TNFRSF11B gene, which encodes osteoprotegerin, is associated with the presence of coronary atherosclerosis in patients with RA. Replication of this finding in independent validation cohorts will be of interest.
rheumatoid arthritis; genetic variation; SNP; atherosclerosis; rs2073618
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.
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.
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
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.
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.
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.
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.
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.
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.
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).
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.
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.
The pathogenesis of insulin resistance and its contribution to atherogenesis varies in different inflammatory settings.
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.
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.
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).
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.
cystatin C; systemic lupus erythematosus; renal function; atherosclerosis; Inflammation
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.
SLE; cardiovascular risk; atherosclerosis
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.
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.
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).
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.
cystatin; rheumatoid arthritis; renal function; atherosclerosis
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.
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.
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).
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.
rheumatoid arthritis; epicardial adipose tissue; cardiometabolic risk; insulin resistance; atherosclerosis
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.
warfarin; pharmacogenomics; CYP2C9; VKORC1
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.
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.
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).
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.
We tested the hypothesis that initiation of TNFα antagonists reduced the risk of fractures compared to nonbiologic comparator in patients with autoimmune diseases.
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.
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]).
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.
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.
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.
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).
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.
Systemic Lupus Erythematosus; Rheumatoid Arthritis; Neopterin; Homocysteine; Atherosclerosis
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.
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.
receptors; adrenergic; alpha; genetic polymorphism; pharmacogenetics; receptor; variability in drug response
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.
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.
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.
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.
ABCB11; ABCC2; ABCG2; BCRP; bilirubin; BSEP; MRP2; OATP1B1; pharmacokinetics; pravastatin; SLCO1B1; transporter
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.
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).
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).
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.
α1 adrenoceptors; α2 adrenoceptors; vasoconstriction
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.
depression; oxidative stress; F2 isoprostanes; antidepressants; sertraline; bupropion
We tested the hypothesis that oxidative stress is increased in patients with rheumatoid arthritis (RA) due to increased inflammation and contributes to the pathogenesis of atherosclerosis.
The independent association between urinary F2-isoprostane excretion, a measure of oxidative stress, and RA was tested using multiple linear regression models in 169 patients with RA and 92 control subjects frequency-matched for age, race and sex. The relationship between F2-isoprostane excretion and coronary calcium, a marker of atherosclerosis, was examined in multivariable proportional odds logistic regression models that also assessed the interactions between oxidative stress and LDL and HDL cholesterol.
F2-isoprostane excretion (median [IQR]) was significantly higher in patients with RA (median 2.75 [interquartile range: 1.60-4.06] ng/mg creatinine (Cr)) than control subjects (1.86 [1.25-2.62] ng/mg Cr, adjusted p=0.006). In patients with RA, F2-isoprostanes were positively correlated with BMI (p<0.001) but not with disease activity or mediators of inflammation, such as DAS28 or serum TNF-α, IL-6 and CRP concentrations in adjusted multivariable models (all P>0.05). In patients with RA, F2-isoprostanes significantly modified the effect of HDL cholesterol on coronary calcification (p-value for interaction=0.02) after adjustment for age, sex and race. As F2-isoprostane levels increased, HDL lost its protective effect against coronary calcification.
Oxidative stress measured as F2-isoprostane excretion was higher in patients with RA than control subjects. Among patients with RA, higher F2-isoprostane excretion and HDL cholesterol concentrations interacted significantly and were positively associated with the severity of coronary calcification.
Rheumatoid Arthritis; Oxidative Stress; F2-Isoprostanes; Atherosclerosis; HDL
Proton-pump inhibitors (PPIs) and clopidogrel are frequently co-prescribed though the benefits and harms of their concurrent use are unclear.
To examine the association between concurrent PPI and clopidogrel use and the risks for gastroduodenal bleeding hospitalizations and serious cardiovascular disease.
Retrospective cohort study that used automated data to identify patients who received clopidogrel between 1999 through 2005 following hospitalization for coronary heart disease.
Tennessee Medicaid Program
20,596 patients (including 7593 concurrent users of clopidogrel and PPIs) hospitalized for myocardial infarction, coronary artery revascularization, or unstable angina pectoris.
Baseline and followup drug use assessed from automated records of dispensed prescriptions. Primary outcomes were hospitalizations for gastroduodenal bleeding and serious cardiovascular disease (fatal or nonfatal myocardial infarction/sudden cardiac death, stroke, or other cardiovascular death).
Pantoprazole and omeprazole accounted for 62% and 9% of the concurrent PPI use. Adjusted gastroduodenal bleeding hospitalization incidence in concurrent PPI users was 50% lower than that in nonusers (HR, 0.50 [95% CI, 0.39 to 0.65]). For patients at highest risk of bleeding, PPI use was associated with an absolute reduction of 28 (12 to 37) gastroduodenal bleeding hospitalizations per 1000 person years. The hazard ratio associated with concurrent PPI use for risk of serious cardiovascular disease was 0.99 (CI, 0.82 to 1.19) and was 1.01 (CI, 0.77 to 1.30) among patients who had percutaneous coronary interventions with stenting.
There was possible unmeasured confounding and misclassification of exposure (no information on adherence or over-the-counter use of drugs) and endpoints (not confirmed by medical record review). Because many patients entered the cohort from hospitals with relatively few cohort members, the analysis relied on the assumption that after adjusting for observed covariates, PPI users from one such hospital could be compared with nonusers from a different hospital.
Among patients with serious coronary heart disease treated with clopidogrel, concurrent PPI use was associated with reduced incidence of gastroduodenal bleeding hospitalizations. The corresponding point estimate for serious cardiovascular disease was not increased; however, the 95% confidence interval included a clinically important increased risk.
Agency for Healthcare Quality and Research, National Heart Lung and Blood Institute.
Patients with rheumatoid arthritis (RA) are at increased risk of atherosclerosis, but routine lipid measurements differ little from those of people without RA. We examined the hypothesis that lipid subclasses determined by nuclear magnetic resonance spectroscopy (NMR) differed in patients with RA compared to controls and are associated with disease activity and the presence of coronary-artery atherosclerosis.
We measured lipoprotein subclasses by NMR in 139 patients with RA and 75 control subjects. Lipoproteins were classified as large LDL (diameter range: 21.2-27.0 nm), small LDL (18.0-21.2 nm), large HDL (8.2-13.0 nm), small HDL (7.3-8.2 nm), and total VLDL (≥27 nm). All subjects underwent an interview and physical examination; disease activity was quantified by the 28 joint disease activity score (DAS28) and coronary artery calcification (CAC) was measured with electron beam computed tomography.
Concentrations of small HDL particles were lower in patients with RA (18.2±5.4 nmol/L) than controls (20.0±4.4 nmol/L), P=0.003. In patients with RA, small HDL concentrations were inversely associated with DAS28 (rho=-0.18, P=0.04) and CRP (rho=-0.25, P=0.004). Concentrations of small HDL were lower in patients with coronary calcification (17.4±4.8 nmol/L) than in those without (19.0±5.8 nmol/L), P=0.03. This relationship remained significant after adjustment for the Framingham risk score and DAS28 (P=0.025). Concentrations of small LDL particles were lower in patients with RA (1390±722 nmol/L) than in control subjects (1518±654 nmol/L), P=0.05, but did not correlate with DAS28 or CAC.
Low concentrations of small HDL particles may contribute to increased coronary atherosclerosis in patients with RA.
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.
Alpha-1 adrenergic receptor; vasoconstriction; phenylephrine; ethnicity; hypertension