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.
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.
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.
Anti-TNF; bone loss; rheumatoid arthritis; spondyloarthropaties
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
Morbidity and mortality secondary to premature cardiovascular disease (CVD) in systemic lupus erythematosus (SLE) remain significant issues. The pathogenesis of CVD in SLE patients has not been fully explored. Epicardial adipose tissue (EAT) is believed to contribute to atherosclerosis development, through a paracrine and systemic inflammatory effect. We measured EAT volume in 162 SLE patients and 86 matched controls to assess the association of EAT with markers of atherosclerosis, cardiovascular risk and immunoactivation.
Clinical and laboratory characteristics collected included anthropomorphic measures, disease activity and damage indices, blood pressure measurement, lipid profile, inflammatory indices, adipokine levels and measures of adiposity. Coronary artery calcium (CAC) and EAT volume were measured using non-contrast cardiac computed tomography.
EAT volume was greater in patients with SLE [(mean± SD) 96.8±45.9cm3] than controls (78.2±40.7 cm3; P=0.001). The EAT volume was 31% larger (95% CI, 16.5% – 47.4%) in SLE patients than controls (P<0.001 adjusted for age, sex, and race; after additional adjustment for waist circumference P=0.007). Within SLE patients, after adjusting for age, race, sex, and waist circumference, EAT volume was associated with cumulative corticosteroid dose (P=0.007), current corticosteroid use (P<0.001), HDL cholesterol (P=0.033), and triglycerides (P=0.005). EAT was significantly correlated with CAC score (P<0.001), but the association was attenuated after adjustment for Framingham risk score (P=0.051).
The increased EAT volume seen in SLE patients is associated with corticosteroid use. Corticosteroids could have adverse cardiovascular effects in SLE via an increase in EAT volume, a marker of risk in the general population.
epicardial adipose tissue; systemic lupus erythematosus; atherosclerosis; coronary calcium score; corticosteroids
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
To examine the hypothesis that genetic variation in enzymes and transporters associated with synthesis, storage, release, and metabolism of catecholamines contributes to the interindividual variability in plasma catecholamine concentrations at rest and after exercise.
We measured plasma NE and epinephrine concentrations at rest and after a standardized exercise protocol in 165 healthy subjects (60% Caucasian, 40% African-American) and examined 29 functional or common variants in 14 genes involved in synthesis, transport, or metabolism of catecholamines. We examined the relationship among genotypes and NE concentrations at rest, and the increase after exercise (ΔNE), by multiple linear regression with adjustment for covariates (age, race, sex, BMI, fitness, and, for Δ NE, resting NE). As a secondary outcome, we performed similar analyses for epinephrine concentrations.
There was large interindividual variability in resting NE (mean, 204±102 pg/mL; range, 39 to 616 pg/mL) and ΔNE (mean, 256±206 pg/mL; range, −97 to 953 pg/mL). Resting NE was significantly associated with variants in 4 genes: CYB561 (P<0.001), VMAT2 (P=0.016), CHGA (P=0.039), and PNMT (P=0.038). ΔNE after exercise was associated with 3 variants in PNMT (P=0.041) and COMT (P=0.033 and 0.035), and resting and exercise epinephrine concentrations with 2 variants each.
The findings of this exploratory study suggest that variation in catecholamine pathway genes contributes to the interindividual variability in plasma NE and epinephrine concentrations at rest and after exercise.
Sympathetic Nervous System; Catecholamines; Exercise; Genetics; Polymorphism
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.
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
Tacrolimus, an immunosuppressive drug widely prescribed in kidney transplantation, requires therapeutic drug monitoring due to its marked interindividual pharmacokinetic variability and narrow therapeutic index. Previous studies have established that CYP3A5 rs776746 is associated with tacrolimus clearance, blood concentration, and dose requirement. The importance of other drug absorption, distribution, metabolism, and elimination (ADME) gene variants has not been well characterized.
We used novel DNA biobank and electronic medical record resources to identify ADME variants associated with tacrolimus dose requirement. Broad ADME genotyping was performed on 446 kidney transplant recipients who had been dosed to steady state with tacrolimus. The cohort was obtained from Vanderbilt's DNA biobank, BioVU, which contains linked, de-identified electronic medical record data. Genotyping included Affymetrix DMET Plus (1936 polymorphisms), custom Sequenom MassARRAY iPLEX Gold assay (95 polymorphisms), and ancestry-informative markers. The primary outcome was tacrolimus dose requirement defined as blood concentration-to-dose ratio.
In analyses that adjusted for race and other clinical factors, we replicated the association of tacrolimus blood concentration-to-dose ratio with CYP3A5 rs776746 (p = 7.15 × 10−29), and identified associations with nine variants in linkage disequilibrium with rs776746, including eight CYP3A4 variants. No NR1/2 variants were significantly associated. Age, weight, and hemoglobin were also significantly associated with the outcome. In final models, rs776746 explained 39% of variability in dose requirement, and 46% was explained by the model containing clinical covariates.
This study highlights the utility of DNA biobanks and electronic medical records for tacrolimus pharmacogenomic research.
pharmacogenomics; pharmacokinetics; calcineurin inhibitor; tacrolimus; electronic medical records; kidney transplant; cytochrome P4503A5; genetic polymorphism; dosing
Free fatty acids (FFAs) affect insulin signaling and are implicated in the pathogenesis of insulin resistance and atherosclerosis. Inflammatory cytokines such as interleukin-6 (IL-6) increase lipolysis and thus levels of FFAs. We hypothesized that increased IL-6 concentrations are associated with increased FFAs resulting in insulin resistance and atherosclerosis in rheumatoid arthritis (RA).
Clinical variables, serum FFAs and inflammatory cytokines, homeostasis model assessment for insulin resistance (HOMA-IR), and coronary artery calcium were measured in 166 patients with RA and 92 controls. We compared serum FFAs in RA and controls using Wilcoxon rank sum tests and further tested for multivariable association by adjusting for age, race, sex and BMI. Among patients with RA, we assessed the relationship between serum FFAs and inflammatory cytokines, HOMA-IR, and coronary artery calcium scores using Spearman correlation and multivariable regression analysis.
Serum FFAs did not differ significantly in patients with RA and controls (0.56 mmol/L [0.38-0.75] and 0.56 mmol/L [0.45-0.70] respectively, p=0.75). Presence of metabolic syndrome was associated with significantly increased serum FFAs in both RA and controls (p=0.035 and p=0.025). In multivariable regression analysis that adjusted for age, race, sex and BMI, serum FFAs were associated with HOMA-IR (p=0.011), CRP (p=0.01), triglycerides (p=0.005) and Framingham risk score (p=0.048) in RA, but not with IL-6 (p=0.48) or coronary artery calcium score (p=0.62).
Serum FFAs do not differ significantly in patients with RA and controls. FFAs may contribute to insulin resistance, but are not associated with IL-6 and coronary atherosclerosis in RA.
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
Although several macrolide antibiotics are proarrhythmic and associated with an increased risk of sudden cardiac death, azithromycin is thought to have minimal cardiotoxicity. However, published reports of arrhythmias suggest that azithromycin may increase the risk of cardiovascular death.
We studied a Tennessee Medicaid cohort designed to detect an increased risk of death related to short-term cardiac effects of medication, excluding patients with serious noncardiovascular illness and person-time during and shortly after hospitalization. The cohort included patients who took azithromycin (347,795 prescriptions), propensity-score–matched persons who took no antibiotics (1,391,180 control periods), and patients who took amoxicillin (1,348,672 prescriptions), ciprofloxacin (264,626 prescriptions), or levofloxacin (193,906 prescriptions).
During 5 days of therapy, patients taking azithromycin, as compared with those who took no antibiotics, had an increased risk of cardiovascular death (hazard ratio, 2.88; 95% confidence interval [CI], 1.79 to 4.63; P<0.001) and death from any cause (hazard ratio, 1.85; 95% CI, 1.25 to 2.75; P = 0.002). Patients who took amoxicillin had no increase in the risk of death during this period. Relative to amoxicillin, azithromycin was associated with an increased risk of cardiovascular death (hazard ratio, 2.49; 95% CI, 1.38 to 4.50; P = 0.002) and death from any cause (hazard ratio, 2.02; 95% CI, 1.24 to 3.30; P = 0.005), with an estimated 47 additional cardiovascular deaths per 1 million courses; patients in the highest decile of risk for cardiovascular disease had an estimated 245 additional cardiovascular deaths per 1 million courses. The risk of cardiovascular death was significantly greater with azithromycin than with ciprofloxacin but did not differ significantly from that with levofloxacin.
During 5 days of azithromycin therapy, there was a small absolute increase in cardiovascular deaths, which was most pronounced among patients with a high baseline risk of cardiovascular disease. (Funded by the National Heart, Lung, and Blood Institute and the Agency for Healthcare Quality and Research Centers for Education and Research on Therapeutics.)
The purpose of this study is to develop a statistical methodology to handle a large proportion of artifactual outliers in a population pharmacokinetic (PK) modeling. The motivating PK data were obtained from a population PK study to examine associations between PK parameters such as clearance of dexmedetomidine and cytochrome P450 2A6 phenotypes. The blood samples were sparsely sampled from patients in intensive care units (ICUs) while different doses of dexmedetomidine were continuously infused. Conventional population PK analysis of these data revealed several challenges and intricacies. Especially, there was strong evidence that some plasma drug concentrations were artifactually high and likely contaminated with the infused drug due to blood sampling processes that are sometimes unavoidable in an ICU setting. If not addressed, or if arbitrarily excluded, these outlying values could lead to biased estimates of PK parameters and miss important relationships between PK parameters and covariates due to increased variability. We propose a novel population PK model, a Bayesian hierarchical nonlinear mixture model, to accommodate the artifactual outliers using a finite mixture as the residual error model. Our results showed that the proposed model handles the outliers well. We also conducted simulation studies with a varying proportion of the outliers. These simulation results showed that the proposed model can accommodate the outliers well so that the estimated PK parameters are less biased.
finite mixture; outlier; nonlinear mixed effect model; pharmacogenetics; pharmacokinetics; NONMEM
To facilitate the use of automated databases for studies of sudden cardiac death, we previously developed a computerized case definition that had a positive predictive value between 86% and 88%. However, the definition has not been specifically validated for prescription opioid users, for whom out-of-hospital overdose deaths may be difficult to distinguish from sudden cardiac death.
We assembled a cohort of persons 30-74 years of age prescribed propoxyphene or hydrocodone who had no life-threatening non-cardiovascular illness, diagnosed drug abuse, residence in a nursing home in the past year, or hospital stay within the past 30 days. Medical records were sought for a sample of 140 cohort deaths within 30 days of a prescription fill meeting the computer case definition. Of the 140 sampled deaths, 81 were adjudicated; 73 (90%) were sudden cardiac deaths. Two deaths had possible opioid overdose; after removing these two the positive predictive value was 88%.
These findings are consistent with our previous validation studies and suggest the computer case definition of sudden cardiac death is a useful tool for pharmacoepidemiologic studies of opioid analgesics.
Case definition; Automated databases; Sudden cardiac death; Opioids; Propoxyphene
We developed and validated an automated database case definition for diabetes in children and youth to facilitate pharmacoepidemiologic investigations of medications and the risk of diabetes.
The present study was part of an in-progress retrospective cohort study of antipsychotics and diabetes in Tennessee Medicaid enrollees aged 6–24 years. Diabetes was identified from diabetes-related medical care encounters: hospitalizations, outpatient visits, and filled prescriptions. The definition required either a primary inpatient diagnosis or at least two other encounters of different types, most commonly an outpatient diagnosis with a prescription. Type 1 diabetes was defined by insulin prescriptions with at most one oral hypoglycemic prescription; other cases were considered type 2 diabetes. The definition was validated for cohort members in the 15 county region geographically proximate to the investigators. Medical records were reviewed and adjudicated for cases that met the automated database definition as well as for a sample of persons with other diabetes-related medical care encounters.
The study included 64 cases that met the automated database definition. Records were adjudicated for 46 (71.9%), of which 41 (89.1%) met clinical criteria for newly diagnosed diabetes. The positive predictive value for type 1 diabetes was 80.0%. For type 2 and unspecified diabetes combined, the positive predictive value was 83.9%. The estimated sensitivity of the definition, based on adjudication for a sample of 30 cases not meeting the automated database definition, was 64.8%.
These results suggest that the automated database case definition for diabetes may be useful for pharmacoepidemiologic studies of medications and diabetes.
Type 2 diabetes; Computer case definition; Health administrative data; Validity; Positive predictive value
Bleeding complications are a serious adverse effect of medications that prevent abnormal blood clotting. To facilitate epidemiologic investigations of bleeding complications, we developed and validated an automated database case definition for bleeding-related hospitalizations.
The case definition utilized information from an in-progress retrospective cohort study of warfarin-related bleeding in Tennessee Medicaid enrollees 30 years of age or older. It identified inpatient stays during the study period of January 1990 through December 2005 with diagnoses and/or procedures that indicated a current episode of bleeding. The definition was validated by medical record review for a sample of 236 hospitalizations.
We reviewed 186 hospitalizations that had medical records with sufficient information for adjudication. Of these, 165 (89% [95% CI, 83%-92%]) were clinically confirmed bleeding-related hospitalizations. An additional 19 hospitalizations (10% [7%-15%]) were adjudicated as possibly bleeding-related. Of the 165 clinically confirmed bleeding-related hospitalizations, the automated database and clinical definitions had concordant anatomical sites (gastrointestinal, cerebral, genitourinary, other) for 163 (99% [96%-100%]). For those hospitalizations with sufficient information to distinguish between upper/lower gastrointestinal bleeding, the concordance was 89%(76%-96%) for upper gastrointestinal sites and 91%(77%-97%) for lower gastrointestinal sites.
A case definition for bleeding-related hospitalizations suitable for automated databases had a positive predictive value of between 89% and 99% and could distinguish specific bleeding sites.
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.
Cardiovascular responses to stressors are regulated by sympathetic activity, increased in black Americans, and associated with future cardiovascular morbidity. Our aim was to determine whether two functional variants in genes regulating sympathetic activity, a deletion in the α2C-adrenergic receptor (ADRA2C del322-325) and a G-protein β3 subunit variant (GNB3 G825T), affect cardiovascular responses to physiologic stressors and contribute to their ethnic differences.
We measured heart rate and blood pressure responses to a cold pressor test (CPT) in 79 healthy subjects (40 blacks, 39 whites), aged 25.7 ± 5.3 years, and determined genotypes for the ADRA2C and GNB3 variants. We examined the response variables (increase in heart rate and blood pressure) in multiple linear regression analyses adjusting first for baseline measures, ethnicity, and other covariates, and then additionally for genotypes.
Black subjects had a greater heart rate response to CPT than whites (mean difference, 9.9 bpm; 95% confidence interval (CI), 4.1 to 15.6; P=0.001). Both the ADRA2C del/del (15.8 bpm; 95% CI, 8.0 to 23.7; P<0.001) and GNB3 T/T genotypes (6.8 bpm; 95% CI, 0.9 to 12.7; P=0.026) were associated with greater heart rate response. After adjusting for genotypes, the ethnic difference was abrogated (1.3 bpm; 95% CI, −5.4 to 8.0; P=0.70), suggesting that the genetic variants contributed substantially to ethnic differences.
Variation in genes that regulate sympathetic activity affects hemodynamic stress responses and contributes to their ethnic differences. This study elucidates how genetic factors may in part explain ethnic differences in cardiovascular regulation.
Cardiovascular physiology; Stress; Ethnic groups; Genetics; Receptors, Adrenergic, alpha-2; G-protein beta3 subunit
Several mediators of inflammation are associated with atherosclerotic cardiovascular disease in the general population, but their relationship to accelerated atherosclerosis associated with an inflammatory disease such as systemic lupus erythematosus (SLE) is not known.
We compared concentrations of cytokines (TNF-α, IL-1α, and VEGF), inflammatory enzymes (MPO and MMP-9), acute-phase reactants (ESR, CRP and SAA) and adhesion molecules (VCAM, ICAM and E-selectin), in 109 patients with SLE and 78 control subjects. The relationship between inflammatory markers and coronary atherosclerosis detected as calcified plaque by electron beam CT was determined in patients with SLE.
Concentrations of all markers of inflammation other than VCAM, MMP-9 and IL-1α were significantly higher in SLE. In multivariable analyses adjusting for Framingham risk score, cumulative corticosteroid dose and diabetes, E-selectin (OR 1.90, 95%CI (1.08–3.33)), VCAM (OR 1.99 (1.18–3.37)), ICAM (OR 2.30, (1.13–4.7)) and TNF-α (OR 2.36 (1.10–5.06)) were significantly associated with the severity of coronary calcium.
Concentrations of adhesion molecules and TNF-α are associated with coronary atherosclerosis in SLE independent of the Framingham risk score.
Systemic Lupus Erythematosus; Atherosclerosis; Cell Adhesion Molecule; TNF-α; Cytokine
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
The presynaptic norepinephrine (NE) transporter (NET) mediates synaptic clearance and recycling of NE. NET-deficient transgenic mice have elevated blood pressure, heart rate, and catecholamine concentrations. However, the in vivo effects of common NET variants on cardiovascular regulation at rest and during exercise are unknown.
We studied cardiovascular responses and plasma catecholamine concentrations at rest and during bicycle exercise at increasing workloads (25, 50 and 75 W) in 145 healthy subjects. We used multiple linear regressions to analyze the effect of common, purportedly functional polymorphisms in NET (rs2242446 and rs28386840) on cardiovascular measures.
44% and 58.9% of subjects carried at least one variant allele for NET T-182C and A-3081T, respectively. Systolic blood pressure (SBP) during exercise and SBP area-under-the-curve were higher in carriers of variant NET alleles (P=0.003 and 0.009 for T-182C and A-3081T, respectively) and NET haplotype -182C/-081T compared to -82T/-3081A (all P<0.01). Diastolic blood pressure (DBP) during exercise was also higher at lower, but not at higher exercise stages in carriers of NET -182C (P<0.01) and -081T (P< 0.05). NET genotypes were not associated with catecholamine concentrations or heart rate.
Common genetic NET variants (-182C and -081T) are associated with greater blood pressure response to exercise in humans.
orepinephrine transporter; Blood pressure; Exercise; Polymorphism
By guiding initial warfarin dose, pharmacogenetic (PGx) algorithms may improve the safety of warfarin initiation. However, once INR response is known, the contribution of PGx to dose refinements is uncertain. This study sought to develop and validate clinical and PGx dosing algorithms for warfarin dose refinement on days 6–11 after therapy initiation.
Materials and Methods
An international sample of 2,022 patients at 13 medical centers on 3 continents provided clinical, INR, and genetic data at treatment days 6–11 to predict therapeutic warfarin dose. Independent derivation and retrospective validation samples were composed by randomly dividing the population (80%/20%). Prior warfarin doses were weighted by their expected effect on S-warfarin concentrations using an exponential-decay pharmacokinetic model. The INR divided by that “effective” dose constituted a treatment response index.
Treatment response index, age, amiodarone, body surface area, warfarin indication, and target INR were associated with dose in the derivation sample. A clinical algorithm based on these factors was remarkably accurate: in the retrospective validation cohort its R2 was 61.2% and median absolute error (MAE) was 5.0 mg/week. Accuracy and safety was confirmed in a prospective cohort (N=43). CYP2C9 variants and VKORC1-1639 G→A were significant dose predictors in both the derivation and validation samples. In the retrospective validation cohort, the PGx algorithm had: R2= 69.1% (P<0.05 vs. clinical algorithm), MAE= 4.7 mg/week.
A pharmacogenetic warfarin dose-refinement algorithm based on clinical, INR, and genetic factors can explain at least 69.1% of therapeutic warfarin dose variability after about one week of therapy.
warfarin; VKORC1; CYP2C9; pharmacogenetic
Variable warfarin response during treatment initiation poses a significant challenge to providing optimal anticoagulation therapy. We investigated the determinants of initial warfarin response in a cohort of 167 patients. During the first nine days of treatment with pharmacogenetics-guided dosing, S-warfarin plasma levels and international normalized ratio were obtained to serve as inputs to a pharmacokinetic-pharmacodynamic (PK-PD) model. Individual PK (S-warfarin clearance) and PD (Imax) parameter values were estimated. Regression analysis demonstrated that CYP2C9 genotype, kidney function, and gender were independent determinants of S-warfarin clearance. The values for Imax were dependent on VKORC1 and CYP4F2 genotypes, vitamin K status (as measured by plasma concentrations of proteins induced by vitamin K absence, PIVKA-II) and weight. Importantly, indication for warfarin was a major independent determinant of Imax during initiation, where PD sensitivity was greater in atrial fibrillation than venous thromboembolism. To demonstrate the utility of the global PK-PD model, we compared the predicted initial anticoagulation responses with previously established warfarin dosing algorithms. These insights and modeling approaches have application to personalized warfarin therapy.
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