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Coronary Artery Disease: HELP
Articles by C. Michael Stein
Based on 18 articles published since 2010
(Why 18 articles?)
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Between 2010 and 2020, C. Stein wrote the following 18 articles about Coronary Artery Disease.
 
+ Citations + Abstracts
1 Article Predictive Utility of Polygenic Risk Scores for Coronary Heart Disease in Three Major Racial and Ethnic Groups. 2020

Dikilitas, Ozan / Schaid, Daniel J / Kosel, Matthew L / Carroll, Robert J / Chute, Christopher G / Denny, Joshua A / Fedotov, Alex / Feng, QiPing / Hakonarson, Hakon / Jarvik, Gail P / Lee, Ming Ta Michael / Pacheco, Jennifer A / Rowley, Robb / Sleiman, Patrick M / Stein, C Michael / Sturm, Amy C / Wei, Wei-Qi / Wiesner, Georgia L / Williams, Marc S / Zhang, Yanfei / Manolio, Teri A / Kullo, Iftikhar J. ·Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN 55905, USA. · Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA. · Department of Biomedical Informatics, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37212, USA. · Schools of Medicine, Public Health, and Nursing, Johns Hopkins University, Baltimore, MD 21205, USA. · Irving Institute for Clinical and Translational Research, Columbia University Medical Center, New York, NY 10032, USA. · Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37212, USA. · Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA. · Department of Medicine, University of Washington, Seattle, WA 98195, USA. · Geisinger, Danville, PA 17822, USA. · Center for Genetic Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA. · National Human Genome Research Institute, Bethesda, MD 20892, USA. · Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37212, USA. · Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN 55905, USA. Electronic address: kullo.iftikhar@mayo.edu. ·Am J Hum Genet · Pubmed #32386537.

ABSTRACT: Because polygenic risk scores (PRSs) for coronary heart disease (CHD) are derived from mainly European ancestry (EA) cohorts, their validity in African ancestry (AA) and Hispanic ethnicity (HE) individuals is unclear. We investigated associations of "restricted" and genome-wide PRSs with CHD in three major racial and ethnic groups in the U.S. The eMERGE cohort (mean age 48 ± 14 years, 58% female) included 45,645 EA, 7,597 AA, and 2,493 HE individuals. We assessed two restricted PRSs (PRS

2 Article Exploring the Lipid Paradox Theory in Rheumatoid Arthritis: Associations of Low Circulating Low-Density Lipoprotein Concentration With Subclinical Coronary Atherosclerosis. 2019

Giles, Jon T / Wasko, Mary Chester M / Chung, Cecilia P / Szklo, Moyses / Blumenthal, Roger S / Kao, Amy / Bokhari, Sabahat / Zartoshti, Afshin / Stein, C Michael / Bathon, Joan M. ·Columbia University, New York, New York. · Allegheny Health Network, Temple University School of Medicine, Pittsburgh, Pennsylvania. · Vanderbilt University, Nashville, Tennessee. · Johns Hopkins University, Baltimore, Maryland. · EMD Serono Research & Development Institute, Inc., Billerica, Maryland. ·Arthritis Rheumatol · Pubmed #30883031.

ABSTRACT: OBJECTIVE: Rheumatoid arthritis (RA) patients with the lowest circulating low-density lipoprotein (LDL) concentrations are at heightened risk of cardiovascular events. However, the atherosclerosis burden within this subgroup is unknown. METHODS: RA patients pooled from 4 cohort studies of cardiovascular disease (CVD; n = 546) were compared with non-RA controls from the Multi-Ethnic Study of Atherosclerosis (n = 5,279). Those taking lipid-lowering medications were excluded. Differences in cardiac computed tomography-derived Agatston coronary artery calcium (CAC) scores between the RA and control groups were compared across strata of LDL concentration. RESULTS: Among those with low LDL concentrations (<70 mg/dl), mean adjusted CAC scores were >4-fold higher for RA patients than for controls (18.6 versus 4.6 Agatston units, respectively; P < 0.001), a difference significantly greater than that in any other LDL concentration stratum except LDL concentration ≥160 mg/dl. Similarly, 32% of the RA patients with low LDL concentration had a CAC score of ≥100 Agatston units compared with only 7% of controls in the same LDL concentration stratum (odds ratio 5.97; P < 0.001), a difference significantly greater than that in all of the other LDL concentration strata. Low LDL concentration was most strongly associated with higher CAC score among RA patients who were white, had ever smoked, or were not obese. Other than a higher frequency of current smokers, RA patients with low LDL concentrations did not have more CVD risk factors or higher measures of RA disease activity or severity than RA patients with higher LDL concentrations. CONCLUSION: RA patients with low LDL concentration may represent a group for whom heightened screening and prevention of atherosclerotic CVD is appropriate.

3 Article Acute Effects of Low-Level Laser Therapy on Patients' Functional Capacity in the Postoperative Period of Coronary Artery Bypass Graft Surgery: A Randomized, Crossover, Placebo-Controlled Trial. 2018

Stein, Cinara / Fernandes, Rafael Oliveira / Miozzo, Aline Paula / Coronel, Christian Correa / Baroni, Bruno Manfredini / Belló-Klein, Adriane / Plentz, Rodrigo Della Méa. ·1 Physical Therapy Department, Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA) , Porto Alegre, RS, Brazil . · 2 Instituto de Cardiologia do Rio Grande do Sul (IC), Fundação Universidade de Cardiologia (FUC) , Porto Alegre, RS, Brazil . · 3 Laboratory of Cardiovascular Physiology, Institute of Basic Sciences of Health (ICBS), Universidade Federal do Rio Grande do Sul (UFRGS) , Porto Alegre, Rio Grande do Sul, Brazil . ·Photomed Laser Surg · Pubmed #29466116.

ABSTRACT: OBJECTIVE: The aim of this study was to evaluate the acute effects of low-level laser therapy (LLLT) on the functional capacity to exercise tested by incremental shuttle walking test (ISWT) after coronary artery bypass graft (CABG) surgery. METHODS: Fifteen male patients (60 ± 9 years) were crossed over during the experiment, to compare the outcomes after active LLLT and placebo LLLT treatments. LLLT (850 nm, 200 mW, 30 J to each point, resulting in a total of 240 J per quadriceps muscle), using a multidiode cluster (five spots; 6 J/spot) in eight points per leg was performed 3 min before the ISWT. We analyzed distance walked, Borg scale of perceived exertion, heart rate, and brachial arterial blood pressure. Markers of tissue damage [lactate dehydrogenase (LDH)] and oxidative stress [lipid peroxidation, total thiol levels, and antioxidant enzyme activity of superoxide dismutase (SOD) and catalase (CAT)] were also measured in peripheral blood. RESULTS: Comparison of the distances walked revealed no significant differences between the LLLT and placebo LLLT groups (p = 0.779). Regarding the Borg scale (p = 0.567), heart rate (p = 0.506) as well as systolic and diastolic blood pressure (p = 0.164 and p = 0.140, respectively), no differences were observed between LLLT and placebo LLLT groups. Application of LLLT was not able to change levels of LDH (p = 0.214), oxidative lipid damage (p = 0.733), total thiol levels (p = 0.925), SOD (p = 0.202), and CAT (p = 0.825) enzyme activities. CONCLUSIONS: Acute LLLT improved neither functional capacity to exercise nor the markers of oxidation after CABG. TRIAL REGISTRATION: Registered as a clinical trial (NCT02688426).

4 Article Coronary Artery Calcification and Rheumatoid Arthritis: Lack of Relationship to Risk Alleles for Coronary Artery Disease in the General Population. 2017

Ferraz-Amaro, Iván / Winchester, Robert / Gregersen, Peter K / Reynolds, Richard J / Wasko, Mary Chester / Oeser, Anette / Chung, Cecilia P / Stein, C Michael / Giles, Jon T / Bathon, Joan M. ·Hospital Universitario de Canarias, Tenerife, Spain. · Columbia University, New York, New York. · The Feinstein Institute for Medical Research, Manhasset, New York. · University of Alabama at, Birmingham. · West Penn Allegheny Health System, Pittsburgh, Pennsylvania, and Temple University School of Medicine, Philadelphia, Pennsylvania. · Vanderbilt University Medical Center, Nashville, Tennessee. ·Arthritis Rheumatol · Pubmed #27696788.

ABSTRACT: OBJECTIVE: Coronary artery disease (CAD) in the general population is characterized by an increased frequency of particular susceptibility single-nucleotide polymorphisms (SNPs). Because the frequency of CAD is increased among patients with rheumatoid arthritis (RA), we sought to determine whether the frequency of these SNPs is increased in RA patients with CAD, hypothesizing that RA could enhance CAD risk by acting through established genetic pathways predisposing to CAD. METHODS: Coronary artery calcification (CAC) as detected by computed tomography was used as a measure of CAD in 561 patients with RA. One hundred SNPs associated with CAD in the general population were genotyped or imputed, and their relationship to CAC was established through multiple regression analysis for individual SNPs and a genetic risk score representing their cumulative effect. RESULTS: Ninety-one CAD-related SNPs were genotyped successfully; of these, 81 exhibited no association with CAC (Agatston units) or different CAC categorizations, either individually or collectively, in the genetic risk score. Only rs579459 (ABO) and rs17676451 (HAL) had a consistent positive association between genotype and CAC, with a significant increase in the frequency of the effect allele in both homozygous and heterozygous genotype distributions. Five were variably negatively associated. Furthermore, a positive association between the Disease Activity Score in 28 joints and CAC was observed, and after adjustment for traditional cardiovascular risk factors, it was not modified by correcting for the CAD-related SNP genetic risk score. CONCLUSION: The increased risk of CAC in patients with RA does not appear to operate primarily through established genetically regulated atherogenic mechanisms that are preponderant in the general population.

5 Article Telomere Length and Coronary Atherosclerosis in Rheumatoid Arthritis. 2016

Ormseth, Michelle J / Solus, Joseph F / Oeser, Annette M / Bian, Aihua / Gebretsadik, Tebeb / Shintani, Ayumi / Raggi, Paolo / Stein, C Michael. ·From the departments of Medicine and Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee; the departments of Medicine and Radiology, Emory University, Atlanta, Georgia, USA; and the departments of Medicine and Radiology, University of Alberta, Edmonton, Alberta, Canada.M.J. Ormseth, MD, MSCI, Department of Medicine, Vanderbilt University Medical Center; J.F. Solus, PhD, Department of Medicine, Vanderbilt University Medical Center; A.M. Oeser, BS, MLAS, CCRP, Department of Medicine, Vanderbilt University Medical Center; A. Bian, MPH, Department of Biostatistics, Vanderbilt University Medical Center; T. Gebretsadik, MPH, Department of Biostatistics, Vanderbilt University Medical Center; A. Shintani, PhD, MPH, Department of Biostatistics, Vanderbilt University Medical Center; P. Raggi, MD, departments of Medicine and Radiology, University of Alberta; C.M. Stein, MD, Department of Medicine, Vanderbilt University Medical Center. ·J Rheumatol · Pubmed #27252422.

ABSTRACT: OBJECTIVE: Telomeres protect against chromosomal end damage and shorten with each cell division; their length may be a marker of cardiovascular and overall biological aging. We examined the hypothesis that reduced telomere length is associated with increased coronary atherosclerosis in rheumatoid arthritis (RA). METHODS: We performed a cross-sectional study in 145 patients with RA and 87 control subjects frequency-matched for age, race, and sex. Coronary artery calcium score was determined by noncontrast cardiac computed tomography. Telomere length was measured from whole blood DNA, using real-time quantitative polymerase chain reaction and expressed as telomeric product to a single-copy gene product ratio (T/S ratio). Associations between telomere length, coronary artery calcium score, and 28-joint Disease Activity Score (DAS28) were assessed with Spearman correlation, proportional odds logistic regression, and linear regression, adjusting for age, race, and sex. RESULTS: Telomere length was significantly inversely correlated with age in patients with RA (ρ = -0.37, p < 0.001) and control subjects (ρ = -0.39, p = 0.001). Among patients with RA, for every interquartile range (IQR) decrease in telomere length (T/S ratio), the odds of higher coronary artery calcium score increased by 38% (95% CI: 4-60) after adjusting for age, race, and sex (p adjusted = 0.03). Telomere length was not associated with DAS28 (p adjusted = 0.17). Telomere length was not significantly different in patients with RA [median (IQR): 1.02 units (0.9-1.11)] compared to control subjects [1.05 units (0.95-1.17); p = 0.10]. CONCLUSION: Telomere length is inversely associated with coronary artery calcium score, independent of age, race, and sex in patients with RA.

6 Article Utility of Select Plasma MicroRNA for Disease and Cardiovascular Risk Assessment in Patients with Rheumatoid Arthritis. 2015

Ormseth, Michelle J / Solus, Joseph F / Vickers, Kasey C / Oeser, Annette M / Raggi, Paolo / Stein, C Michael. ·Department of Medicine and Division of Rheumatology, Vanderbilt University Medical Center, Nashville, TN, USA. · Department of Medicine and Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN, USA. · Department of Medicine and Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, TN, USA. · Department of Medicine and Division of Cardiology, University of Alberta, Edmonton, Canada. ·J Rheumatol · Pubmed #26233505.

ABSTRACT: OBJECTIVE: MicroRNA (miRNA) are small noncoding RNA that posttranscriptionally regulate gene expression and serve as potential mediators and markers of disease. Recently, plasma miR-24-3p and miR-125a-5p concentrations were shown to be elevated in rheumatoid arthritis (RA) and useful for RA diagnosis. We assessed the utility of 7 candidate plasma miRNA, selected for biological relevance, for RA diagnosis and use as markers of disease activity and subclinical atherosclerosis in RA. METHODS: The cross-sectional study included 168 patients with RA and 91 control subjects of similar age, race, and sex. Plasma concentrations of miR-15a-5p, miR-24-3p, miR-26a-5p, miR-125a-5p, miR-146a-5p, miR-155-5p, and miR-223-3p were measured by quantitative PCR. Utility of plasma miRNA concentrations for RA diagnosis was assessed by area under the receiver-operating characteristic curve (AUROC). Associations between plasma miRNA concentrations and RA disease activity and coronary artery calcium score were assessed by Spearman correlations. RESULTS: Plasma concentrations of miR-15a-5p, miR-24-3p, miR-26a-5p, miR-125a-5p, miR-146a-5p, miR-155-5p, and miR-223-3p were significantly increased in patients with RA. The highest AUROC for diagnosis of RA (AUROC = 0.725) was found in miR-24-3p, including among rheumatoid factor-negative patients (AUROC = 0.772). Among all patients with RA, the combination of miR-24-3p, miR-26a-5p, and miR-125a-5p improved the model modestly (AUROC = 0.747). One miRNA, miR-155-5p, was weakly inversely associated with swollen joint count (p = 0.024), but no other miRNA were associated with disease activity or coronary artery calcium score. CONCLUSION: The combination of miR-24-3p, miR-26a-5p, and miR-125a-5p had the strongest diagnostic accuracy for RA. Candidate miRNA had little or no association with RA disease activity or subclinical atherosclerosis.

7 Article Utility of a novel inflammatory marker, GlycA, for assessment of rheumatoid arthritis disease activity and coronary atherosclerosis. 2015

Ormseth, Michelle J / Chung, Cecilia P / Oeser, Annette M / Connelly, Margery A / Sokka, Tuulikki / Raggi, Paolo / Solus, Joseph F / Otvos, James D / Stein, C Michael. ·Department of Medicine, Vanderbilt University Medical Center, 1161 21st Avenue South, T-3113 MCN, Nashville, TN, 37212, USA. michelle.ormseth@vanderbilt.edu. · Department of Medicine, Vanderbilt University Medical Center, 1161 21st Avenue South, T-3113 MCN, Nashville, TN, 37212, USA. c.chung@vanderbilt.edu. · Department of Medicine, Vanderbilt University Medical Center, 1161 21st Avenue South, T-3113 MCN, Nashville, TN, 37212, USA. annette.oeser@vanderbilt.edu. · LabCorp, 2500 Sumner Blvd, Raleigh, NC, 27616, USA. margery.commelly@liposcience.com. · Department of Rheumatology, University of Eastern Finland, Jyvaskyla Central Hospital, 40620, Jyvaskyla, Finland. tuulikki.sokka-isler@ksshp.fi. · Department of Medicine, University of Alberta, 4A7.050, 8440 - 112 Street, Edmonton, AB, T6G 2B7, Canada. raggip@gmail.com. · Department of Medicine, Vanderbilt University Medical Center, 1161 21st Avenue South, T-3113 MCN, Nashville, TN, 37212, USA. joseph.f.solus@vanderbilt.edu. · LabCorp, 2500 Sumner Blvd, Raleigh, NC, 27616, USA. jotvos@liposcience.com. · Department of Medicine, Vanderbilt University Medical Center, 1161 21st Avenue South, T-3113 MCN, Nashville, TN, 37212, USA. mike.stein@vanderbilt.edu. ·Arthritis Res Ther · Pubmed #25956924.

ABSTRACT: INTRODUCTION: 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). METHODS: 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. RESULTS: 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). CONCLUSION: 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.

8 Article A variant in the osteoprotegerin gene is associated with coronary atherosclerosis in patients with rheumatoid arthritis: results from a candidate gene study. 2015

Chung, Cecilia P / Solus, Joseph F / Oeser, Annette / Li, Chun / Raggi, Paolo / Smith, Jeffrey R / Stein, C Michael. ·Departments of Medicine and Biostatistics, Vanderbilt University, Nashville, TN 37232, USA. c.chung@vanderbilt.edu. · Departments of Medicine and Biostatistics, Vanderbilt University, Nashville, TN 37232, USA. joseph.f.solus@vanderbilt.edu. · Departments of Medicine and Biostatistics, Vanderbilt University, Nashville, TN 37232, USA. annette.oeser@vanderbilt.edu. · Biostatistics, Vanderbilt University, Nashville, TN 37232, USA. Chun.li3@case.edu. · Mazankowski Alberta Heart Institute, Department of Medicine, University of Alberta, Edmonton, AB T6G 2B7, Canada. raggi@ualberta.ca. · Departments of Medicine and Biostatistics, Vanderbilt University, Nashville, TN 37232, USA. jeffrey.smith@vanderbilt.edu. · Departments of Medicine and Biostatistics, Vanderbilt University, Nashville, TN 37232, USA. mike.stein@vanderbilt.edu. ·Int J Mol Sci · Pubmed #25679449.

ABSTRACT: 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.

9 Article Genetic variation and coronary atherosclerosis in patients with systemic lupus erythematosus. 2014

Chung, C P / Solus, J F / Oeser, A / Li, C / Raggi, P / Smith, J R / Stein, C M. ·Departments of Medicine, Vanderbilt University, Nashville, TN, USA c.chung@vanderbilt.edu. · Departments of Medicine, Vanderbilt University, Nashville, TN, USA. · Department of Biostatistics, Vanderbilt University, Nashville, TN, USA. · Department of Medicine, University of Alberta, Edmonton, AB, Canada. ·Lupus · Pubmed #24699314.

ABSTRACT: Coronary artery disease is the major cause of mortality in patients with systemic lupus erythematosus (SLE). Increased cardiovascular risk in SLE is not explained by traditional risk factors. We examined the hypothesis that genetic variation contributes to the presence of coronary atherosclerosis in patients with SLE. The genotypes of single-nucleotide polymorphisms (SNP) in 152 candidate genes linked with autoimmune or cardiovascular risk were determined in 125 patients with SLE. Coronary artery calcium (CAC), a measure of coronary atherosclerosis, was detected in 32 patients (26%) by electron-beam computed tomography. Polymorphism in 20 of the candidate genes (ADAM33, ADIPOQ, CCL5, CCR7, CDKN2B, CSF1, IL4, IL12A, IL23R, INS, IRF5, MIF, MS4A1, PTGS1, PTPN22, RETN, SELE, TNFSF4, TNFRSF11B, and VCAM1) were nominally associated with the presence of CAC (p-values = 0.001-0.047 after adjustment for age, sex and race). Some of these are known susceptibility genes for SLE and others have been implicated in cardiovascular disease in other populations. No association withstood false discovery rate adjustment. Replication studies in additional cohorts of patients with SLE may be informative.

10 Article Free fatty acids are associated with metabolic syndrome and insulin resistance but not inflammation in systemic lupus erythematosus. 2013

Ormseth, M J / Swift, L L / Fazio, S / Linton, M F / Raggi, P / Solus, J F / Oeser, A / Bian, A / Gebretsadik, T / Shintani, A / Stein, C M. ·Division of Rheumatology, Department of Medicine, Vanderbilt University, Nashville, TN 37232-2681, USA. michelle.ormseth@vanderbilt.edu ·Lupus · Pubmed #23060481.

ABSTRACT: 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 FFAs and continuous variables of interest using Spearman correlation and multivariable regression analysis. Levels of FFAs 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). Levels of FFAs remained significantly higher among patients with SLE after adjustment for age, race and sex (P = 0.03) but not after further adjustment for body mass index (P = 0.13). FFA levels did not differ according to the usage of current immunosuppressive medications 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). From our study we concluded that FFAs are elevated in patients with SLE, particularly those with metabolic syndrome. FFAs in patients with SLE are not associated with markers of generalized inflammation but are associated with insulin resistance and markers of endothelial activation.

11 Article High-sensitivity cardiac troponin-I is elevated in patients with rheumatoid arthritis, independent of cardiovascular risk factors and inflammation. 2012

Bradham, William S / Bian, Aihua / Oeser, Annette / Gebretsadik, Tebeb / Shintani, Ayumi / Solus, Joseph / Estis, Joel / Lu, Quynh Anh / Todd, John / Raggi, Paolo / Stein, C Michael. ·Division of Cardiology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America. william.bradham@vanderbilt.edu ·PLoS One · Pubmed #22761714.

ABSTRACT: OBJECTIVES: We examined the hypothesis that cardiac-specific troponin-I (cTn-I), a biomarker of myocardial injury, is elevated in patients with rheumatoid arthritis (RA). BACKGROUND: RA patients have an increased incidence of heart failure (HF). Chronic myocardial injury in RA may be a mechanism for the development of HF. METHODS: We compared cTn-I concentrations measured by high-sensitivity immunoassay in 164 patients with RA and 90 controls, excluding prior or active heart failure. We examined the relationship between cTn-I concentrations and cardiovascular risk factors, inflammation, and coronary artery calcium score (CACS), a measure of coronary atherosclerosis. RESULTS: cTn-I concentrations were 49% higher in patients with RA (median 1.15 pg/mL [IQR 0.73-1.92] than controls (0.77 pg/mL [0.49-1.28](P<0.001). The difference remained statistically significant after adjustment for demographic characteristics (P = 0.002), further adjustment for cardiovascular (CV) risk factors (P = 0.004), inflammatory markers (P = 0.008), and in a comprehensive model of CV risk factors and inflammatory markers (P = 0.03). In patients with RA, cTn-I concentrations were positively correlated with age (rho = 0.359), Framingham risk score (FRS) (rho = 0.366), and systolic blood pressure (rho = 0.248 (all P values ≤ 0.001)), but not with measures of inflammation or RA drug therapies. cTn-I was significantly correlated with CACS in RA in univariate analysis, but not after adjustment for age, race, sex and FRS (P = 0.79). Further model adjustments for renal function and coronary artery disease confirmed the significance of the findings. CONCLUSION: High-sensitivity cTn-I concentrations are elevated in patients with RA without heart failure, independent of cardiovascular risk profile and inflammatory markers. Elevated troponin concentrations in RA may indicate subclinical, indolent myocardial injury.

12 Article Cystatin C is associated with inflammation but not atherosclerosis in systemic lupus erythematosus. 2012

Lertnawapan, R / Bian, A / Rho, Y H / Raggi, P / Oeser, A / Solus, J F / Gebretsadik, T / Shintani, A / Stein, C M. ·Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University, Nashville, TN 37232-6602, USA. ·Lupus · Pubmed #22072023.

ABSTRACT: 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, independently of conventional measures of renal function. This study examined the hypothesis that cystatin C is elevated in systemic lupus erythematosus (SLE) and is associated with coronary atherosclerosis. METHODS: Serum cystatin C, creatinine, tumor necrosis factor (TNF)-α, interleukin (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 were measured 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 in 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 adjustment for age, race, sex and MDRD-eGFR). Cystatin C was significantly associated with SLICC (p = 0.04), erythrocyte sedimentation rate (ESR) (p = 0.02), 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 in 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.

13 Article Free fatty acids are associated with insulin resistance but not coronary artery atherosclerosis in rheumatoid arthritis. 2011

Ormseth, Michelle J / Swift, Larry L / Fazio, Sergio / Linton, Macrae F / Chung, Cecilia P / Raggi, Paolo / Rho, Young Hee / Solus, Joseph / Oeser, Annette / Bian, Aihua / Gebretsadik, Tebeb / Shintani, Ayumi / Stein, C Michael. ·Division of Rheumatology, Department of Medicine and Pharmacology, Vanderbilt University, Nashville, TN, USA. michelle.ormseth@vanderbilt.edu ·Atherosclerosis · Pubmed #21974844.

ABSTRACT: BACKGROUND: 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). METHODS: 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 analyses. RESULTS: Serum FFAs did not differ significantly in patients with RA and controls (0.56mmol/L [0.38-0.75] and 0.56mmol/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). CONCLUSIONS: 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.

14 Article Cystatin C, renal function, and atherosclerosis in rheumatoid arthritis. 2011

Lertnawapan, Ratchaya / Bian, Aihua / Rho, Young Hee / Kawai, Vivian K / Raggi, Paolo / Oeser, Annette / Solus, Joseph F / Gebretsadik, Tebeb / Shintani, Ayumi / Stein, C Michael. ·Divisions of Clinical Pharmacology and Rheumatology, School of Medicine, Vanderbilt University, Nashville, TN 37232-6602, USA. ·J Rheumatol · Pubmed #21844147.

ABSTRACT: OBJECTIVE: We examined the hypothesis that cystatin C, a novel marker of renal function, is elevated in rheumatoid arthritis (RA) and is associated with inflammation and coronary atherosclerosis. METHODS: We measured serum cystatin C, creatinine, tumor necrosis factor-α and interleukin 6 concentrations, coronary artery calcium score (CACS), and Modified Diet in Renal Disease estimated glomerular filtration rate in 167 patients with RA and 91 controls. RESULTS: Cystatin C was higher in RA patients [median (IQR) 1.16 (0.99-1.35) mg/l] than controls [1.01 (0.90-1.19) mg/l; p < 0.001] and correlated positively with erythrocyte sedimentation rate (p < 0.001), C-reactive protein (p = 0.01), 28-joint Disease Activity Score (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). CONCLUSION: 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 not independent of the information provided by conventional cardiovascular risk factors.

15 Article Macrophage activation and coronary atherosclerosis in systemic lupus erythematosus and rheumatoid arthritis. 2011

Rho, Young Hee / Solus, Joseph / Raggi, Paolo / Oeser, Annette / Gebretsadik, Tebeb / Shintani, Ayumi / Stein, C Michael. ·Department of Clinical Pharmacology, School of Medicine, Vanderbilt University, 23rd Avenue South at Pierce Avenue, Nashville, TN 37232-6602, USA. ·Arthritis Care Res (Hoboken) · Pubmed #20890983.

ABSTRACT: OBJECTIVE: 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) or 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, interquartile range [IQR] 6.5-9.8 nmoles/liter) and RA (median 6.7, IQR 5.3-8.9 nmoles/liter) than controls (median 5.7, IQR 4.8-7.1 nmoles/liter), and were higher in SLE patients than in RA patients (all P<0.001). In SLE, neopterin was significantly correlated with higher erythrocyte sedimentation rate (ESR; P=0.001), tumor necrosis factor α (P<0.001), monocyte chemoattractant protein 1 (P=0.005), and homocysteine concentrations (P=0.01), but in RA, it was only associated 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 in RA, but was not associated with coronary atherosclerosis in either disease.

16 Article Lipoprotein subclasses determined by nuclear magnetic resonance spectroscopy and coronary atherosclerosis in patients with rheumatoid arthritis. 2010

Chung, Cecilia P / Oeser, Annette / Raggi, Paolo / Sokka, Tuulikki / Pincus, Theodore / Solus, Joseph F / Linton, Macrae F / Fazio, Sergio / Stein, C Michael. ·Department of Medicine, Vanderbilt University, Nashville, Tennessee 37232-6602, USA. ·J Rheumatol · Pubmed #20516025.

ABSTRACT: OBJECTIVE: 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. METHODS: We measured lipoprotein subclasses by NMR in 139 patients with RA and 75 control subjects. Lipoproteins were classified as large low-density lipoprotein (LDL; diameter range 21.2-27.0 nm), small LDL (18.0-21.2 nm), large high-density lipoprotein (HDL; 8.2-13.0 nm), small HDL (7.3-8.2 nm), and total very low-density lipoprotein (VLDL; >or= 27 nm). All subjects underwent an interview and 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. RESULTS: 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 C-reactive protein (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 controls (1518 +/- 654 nmol/l; p = 0.05), but did not correlate with DAS28 or CAC. CONCLUSION: Low concentrations of small HDL particles may contribute to increased coronary atherosclerosis in patients with RA.

17 Article Interaction between oxidative stress and high-density lipoprotein cholesterol is associated with severity of coronary artery calcification in rheumatoid arthritis. 2010

Rho, Young Hee / Chung, Cecilia P / Oeser, Annette / Solus, Joseph F / Gebretsadik, Tebeb / Shintani, Ayumi / Raggi, Paolo / Milne, Ginger L / Stein, C Michael. ·Vanderbilt University, Nashville, Tennessee 37232-6602, USA. ·Arthritis Care Res (Hoboken) · Pubmed #20506360.

ABSTRACT: OBJECTIVE: To test the hypothesis that oxidative stress is increased in patients with rheumatoid arthritis (RA) due to increased inflammation and contributes to the pathogenesis of atherosclerosis. METHODS: 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 low-density lipoprotein and high-density lipoprotein (HDL) cholesterol. RESULTS: F₂-isoprostane excretion was significantly higher in patients with RA (median 2.75 [interquartile range (IQR) 1.60-4.06] ng/mg creatinine) than in control subjects (median 1.86 [IQR 1.25-2.62] ng/mg creatinine; adjusted P = 0.006). In patients with RA, F₂-isoprostanes were positively correlated with body mass index (P < 0.001), but not with disease activity or mediators of inflammation such as the Disease Activity Score in 28 joints or serum tumor necrosis factor α, interleukin-6, and C-reactive protein concentrations in adjusted multivariable models (P > 0.05 for all). In patients with RA, F₂-isoprostanes significantly modified the effect of HDL cholesterol on coronary calcification (P = 0.02 for interaction) after adjustment for age, sex, and race. As F₂-isoprostane levels increased, HDL lost its protective effect against coronary calcification. CONCLUSION: Oxidative stress measured as F₂-isoprostane excretion was higher in patients with RA than in 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.

18 Article Adipocytokines, insulin resistance, and coronary atherosclerosis in rheumatoid arthritis. 2010

Rho, Young Hee / Chung, Cecilia P / Solus, Joseph F / Raggi, Paolo / Oeser, Annette / Gebretsadik, Tebeb / Shintani, Ayumi / Stein, C Michael. ·Vanderbilt University, Nashville, Tennessee 37232-6602, USA. ·Arthritis Rheum · Pubmed #20213808.

ABSTRACT: OBJECTIVE: The prevalence of subclinical coronary atherosclerosis is increased in patients with rheumatoid arthritis (RA), and the increased risk is associated with insulin resistance. Adipocytokines have been linked to obesity, insulin resistance, inflammation, and coronary heart disease in the general population. This study was undertaken to examine the hypothesis that adipocytokines affect insulin resistance and coronary atherosclerosis among patients with RA. METHODS: The coronary calcium score, homeostatic model assessment for insulin resistance (HOMA-IR) index, and serum adipocytokine (leptin, adiponectin, resistin, and visfatin) concentrations were determined in 169 patients with RA. The independent effect of each adipocytokine on insulin resistance according to the HOMA-IR index and on coronary artery calcification determined by electron beam computed tomography was assessed in models adjusted for age, race, sex, body mass index (BMI), traditional cardiovascular risk factors, and inflammation mediators. In addition, an interaction analysis was performed to evaluate whether the effect of the HOMA-IR index on the coronary calcium score is moderated by adipocytokines. RESULTS: Increased concentrations of leptin were associated with a higher HOMA-IR index, even after adjustment for age, race, sex, BMI, traditional cardiovascular risk factors, and inflammation mediators (P < 0.001), but concentrations of visfatin (P = 0.06), adiponectin (P = 0.55), and resistin (P = 0.98) showed no association with the HOMA-IR index. None of the adipocytokines was independently associated with the coronary calcium score (all P > 0.05). Serum leptin concentrations showed a significant interaction with the HOMA-IR index (P for multivariate interaction = 0.02). Increasing leptin concentrations attenuated the increased risk of coronary calcification related to insulin resistance. Serum concentrations of the other adipocytokines showed no significant interactions with the HOMA-IR index (each P > 0.05). CONCLUSION: Leptin is associated with insulin resistance in patients with RA but, paradoxically, attenuates the effects of insulin resistance on coronary calcification.