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Objective. To examine the relationship between markers of systemic inflammation and carotid atherosclerosis in patients with rheumatoid arthritis (RA) and healthy controls.Methods. Carotid artery intima-media thickness (IMT) and carotid plaque were measured using highresolution B-mode ultrasound in 204 patients with RA, ages 40-85, and 102 age-and sex-matched healthy persons. No subject in either group had ever smoked cigarettes. Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) were used to measure systemic inflammation. The relationship of the carotid artery IMT and carotid plaque to inflammation markers was examined, adjusting for age, sex, RA versus control status, and the cardiovascular (CV) risk factors hypercholesterolemia, systolic blood pressure, diabetes mellitus, and body mass index (BMI).Results. A significant linear trend for increased carotid artery IMT was associated with increasing ESR and CRP categories (r ‫؍‬ 0.16, P ‫؍‬ 0.004 for ESR, and r ‫؍‬ 0.13, P ‫؍‬ 0.02 for CRP). These trends did not differ among RA cases and controls, and were independent of age, sex, and CV risk factors. The difference in carotid artery IMT between the lowest and highest categories of ESR was 0.221 mm (95% confidence interval [95% CI] 0.767-1.020, P ‫؍‬ 0.02). The difference between extreme CRP categories was 0.275 mm (95% CI 0.039-0.509, P ‫؍‬ 0.02). Both remained significant after CV risk factor adjustment. Carotid plaque displayed a similar relationship to markers of inflammation.Conclusion. Increased carotid artery IMT and the presence of carotid plaque are associated with markers of systemic inflammation in patients with RA and in healthy subjects. This observation is consistent with hypotheses that assign a role to systemic inflammation in atherosclerosis, and may have implications regarding RA and other chronic inflammatory diseases.

Background-Because of the prevalence and expense of congestive heart failure (CHF), significant efforts have been made to develop disease management (DM) programs that will improve clinical and financial outcomes. The effectiveness of such programs in a large, heterogeneous population of CHF patients remains unknown. Methods and Results-We randomized 1069 patients (aged 70.9Ϯ10.3 years) with systolic (ejection fraction 35Ϯ9%) or echocardiographically confirmed diastolic heart failure (HF) to assess telephonic DM over an 18-month period. Data were collected at baseline and at 6-month intervals. Survival analysis was performed by Kaplan-Meier and Cox regression methods. Healthcare utilization was defined after extensive record review, with an attempt to account for all inpatient and outpatient visits, medications, and diagnostic tests. We obtained data on 92% of the patients, from nearly 53 000 health-related encounters. Total cost per patient was defined by adding estimated costs for the observed encounters, excluding the cost of the DM. Kaplan-Meier analysis showed that DM patients had a reduced mortality rate (Pϭ0.037), with DM patients surviving an average of 76 days longer than controls. Subgroup analysis showed that DM had beneficial outcomes in patients with systolic HF (hazard ratio 0.62; Pϭ0.040), which was more pronounced in NYHA classes III and IV. Although improvements in NYHA class were more likely with DM (PϽ0.001), 6-minute walk data from 217 patients in whom data were available at each visit showed no significant benefit from DM (Pϭ0.08). Total and CHF-related healthcare utilization, including medications, office or emergency department visits, procedures, or hospitalizations, was not decreased by DM. Repeated-measures ANOVA for cost by group showed no significant differences, even in the higher NYHA class groups. Conclusions-Participation in DM resulted in a significant survival benefit, most notably in symptomatic systolic HF patients. Although DM was associated with improved NYHA class, 6-minute walk test results did not improve.

Objective. To estimate the contribution of cardiovascular (CV) risk factors and rheumatoid arthritis (RA) disease manifestations to atherosclerosis in RA.Methods. We used high-resolution carotid ultrasound to measure the carotid intima-media thickness (IMT) and plaque in 631 RA patients. Using R 2 measures from multivariable models, we estimated the contribution of demographic characteristics (age, sex, and ethnic group), CV risk factors (diabetes mellitus, hypercholesterolemia, cigarette smoking, hypertension, and body mass index, and RA manifestations (joint tenderness, swelling, and deformity, nodules, erythrocyte sedimentation rate [ESR], C-reactive protein, rheumatoid factor, the HLA-DRB1 shared epitope, and cumulative glucocorticoid dose) to each of the outcomes. Estimates were obtained in the full sample, and within strata defined by age, sex, and ethnic group. We tested for interaction between CV risk factors and RA manifestations.Results. The contribution of demographic factors, CV risk factors, and RA manifestations to IMT and plaque R 2 varied depending on the patients' age stratum. Demographic features explained 11-16% of IMT variance, CV risk factors explained 4%-12%, and RA manifestations explained 1-6%. The greatest contribution of RA manifestations occurred in the youngest age group, while that of CV risk factors occurred in the older age groups. Results for carotid plaque were similar. There was a significant interaction between the number of CV risk factors present and the ESR, suggesting that the ESR's effect on IMT varied according to the number of CV risk factors.Conclusion. Both established CV risk factors and manifestations of RA inflammation contribute significantly to carotid atherosclerosis in RA, and may modify one another's effects. These findings may have implications regarding the prevention of atherosclerosis in RA.The mechanism underlying the high frequency of cardiovascular (CV) morbidity that occurs in rheumatoid arthritis (RA) is not completely understood (1-16). Earlier studies have indicated that the excess CV event rate in RA is not explained by an excess of established CV risk factors (17,18). Those studies did not address whether these risk factors operate similarly in RA as they do in the general population.Diabetes mellitus, hypercholesterolemia, hypertension, cigarette smoking, and obesity are powerful classifiers of CV risk (19). One or more established CV risk factors are present in at least 80% of people with symptomatic coronary artery disease in the general population (20). The prevalence is even higher, approaching 100%, among persons with fatal myocardial infarction (21).People with and those without RA have similar CV risk factor profiles (17,18,22). The resemblance suggests that established CV risk factors may play an important role in the CV morbidity that occurs in RA, as they do in the general population. In earlier studies that

Background-Mechanisms by which neutrophils are attracted to the myocardium in ischemia/reperfusion are not fully defined. Lipopolysaccharide-induced CXC chemokine (LIX), cytokine-induced neutrophil chemoattractant (KC), and macrophage inflammatory protein-2 (MIP-2) are rodent chemokines with potent neutrophil-chemotactic activity. The goals of the present study were to evaluate the roles of these chemokines in a rat model of ischemia/reperfusion and to examine the mechanisms of chemokine induction by oxidative stress and cytokines in cultured cardiomyocytes. Methods and Results-Male Wistar-Kyoto rats underwent 45 minutes of ligation of the left anterior descending coronary artery, followed by reperfusion for various periods. Compared with sham-operated controls, myocardium from reperfused animals had higher levels of free radicals, increased neutrophil infiltration evidenced histologically and by elevated myeloperoxidase activity, and increased nuclear factor (NF)-B DNA binding activity. Ischemia-reperfusion also induced the expression of interleukin-1␤, tumor necrosis factor (TNF)-␣, LIX, KC, and MIP-2 mRNA and protein.LIX expression was localized to resident myocardial cells, whereas KC and MIP-2 were expressed only in infiltrating inflammatory cells. Neutralization of LIX inhibited 79% of neutrophil infiltration into previously ischemic myocardium.In contrast, neutralization of KC and MIP-2 reduced neutrophil infiltration by only 28% and 37%, respectively. In cultured cardiomyocytes, LIX expression was induced by oxidative stress or TNF-␣ and was blocked by the NF-B inhibitor pyrrolidinedithiocarbamate. Conclusions-LIX is expressed by resident myocardial cells during ischemia-reperfusion and is induced in cultured cardiomyocytes by oxidative stress or TNF-␣ via NF-B activation. Although KC and MIP-2 are expressed by inflammatory cells infiltrating the myocardium during reperfusion after ischemia, neutrophil recruitment to reperfused rat myocardium is mainly due to cardiomyocyte expression of LIX.

. Wnt-induced secreted protein-1 is a prohypertrophic and profibrotic growth factor. Am J Physiol Heart Circ Physiol 293: H1839-H1846, 2007. First published July 6, 2007; doi:10.1152/ajpheart.00428.2007.-Wnt1-induced secreted protein-1 (WISP-1) is a member of the cysteine-rich 61, connective tissue growth factor, and nephroblastoma overexpressed (CCN) family of growth factors and is expressed in the heart at low basal levels. The purpose of this study was to investigate whether WISP-1 is upregulated in postinfarct myocardium and whether WISP-1 exerts prohypertrophic and mitogenic effects stimulating myocyte hypertrophy, cardiac fibroblast (CF) proliferation, and collagen expression. Male C57Bl/6 (25 g) mice underwent permanent occlusion of the left anterior descending coronary artery. mRNA and protein levels were analyzed by Northern and Western blot analyses. Cardiomyocyte hypertrophy was quantified by protein and DNA synthesis. CF proliferation was quantified by CyQuant assay, and soluble collagen release by Sircol assay. A time-dependent increase in WISP-1 expression was detected in vivo in the noninfarct zone of the left ventricle, which peaked at 24 h (3.1-fold, P Ͻ 0.01). Similarly, biglycan expression was increased by 3.71-fold (P Ͻ 0.01). IL-1␤ and TNF-␣ expression preceded WISP-1 expression in vivo and stimulated WISP-1 expression in neonatal rat ventricular myocytes in vitro. WISP-1-induced cardiomyocyte hypertrophy was evidenced by increased protein (2.78-fold), but not DNA synthesis, and enhanced Akt phosphorylation and activity. Treatment of primary CF with WISP-1 significantly stimulated proliferation at 48 h (6,966 Ϯ 264 vs. 5,476 Ϯ 307 cells/well, P Ͻ 0.01) and enhanced collagen release by 72 h (18.4 Ϯ 3.1 vs. 8.4 Ϯ 1.0 ng/cell, P Ͻ 0.01). Our results demonstrate for the first time that WISP-1 and biglycan are upregulated in the noninfarcted myocardium in vivo, suggesting a positive amplification of WISP-1 signaling. WISP-1 stimulates cardiomyocyte hypertrophy, fibroblast proliferation, and ECM expression in vitro. These results suggest that WISP-1 may play a critical role in post-myocardial infarction remodeling.cysteine-rich 61, connective tissue growth factor, and nephroblastoma overexpressed family; myocardial infarction; myocardial remodeling; Akt; cardiomyocyte hypertrophy WNT1-INDUCED secreted protein-1 (WISP-1) is a member of the cysteine-rich 61, connective tissue growth factor (CTGF), and nephroblastoma overexpressed (CCN) family of growth factors shown to play a role in cellular growth, transformation, and survival (24,26,52,57). Because of the limited regenerative capacity of the heart, any structural adaptations of the myocardium occurring in response to chronic changes in hemodynamic loading conditions typically require alterations in the size of myocytes and composition of the interstitial components (46). When the stimulus is chronic pressure overload, as in hypertension or aortic stenosis, cardiac myocytes increase in diameter and there is increased deposition of interstitial col...

Objective. The role of atherosclerosis in the acute coronary syndromes (ACS) that occur in patients with rheumatoid arthritis (RA) has not been quantified in detail. We undertook this study to determine the extent to which ACS are associated with carotid atherosclerosis in RA.Methods. We prospectively ascertained ACS, defined as myocardial infarction, unstable angina, cardiac arrest, or death due to ischemic heart disease, in an RA cohort. We measured carotid atherosclerosis using high-resolution ultrasound. We used Cox proportional hazards models to estimate the association between ACS and atherosclerosis, adjusting for demographic features, cardiovascular (CV) risk factors, and RA manifestations.Results. We performed carotid ultrasound on 636 patients whom we followed up for 3,402 person-years. During this time, 84 patients experienced 121 new or recurrent ACS events, a rate of 3.5 ACS events per 100 patient-years (95% confidence interval [95% CI] 3.0-4.3). Among the 599 patients without a history of ACS, 66 incident ACS events occurred over 3,085 personyears, an incidence of 2.1 ACS events per 100 personyears (95% CI 1.7-2.7). The incidence of new ACS events per 100 patient-years was 1.1 (95% CI 0.6-1.7) among patients without plaque, 2.5 (95% CI 1.7-3.8) among patients with unilateral plaque, and 4.3 (95% CI 2.9-6.3) among patients with bilateral plaque. Covariates associated with incident ACS events independent of atherosclerosis included male sex, diabetes mellitus, and a cumulative glucocorticoid dose of >20 gm.Conclusion. Atherosclerosis is strongly associated with ACS in RA. RA patients with carotid plaque, multiple CV risk factors (particularly diabetes mellitus or hypertension), many swollen joints, and a high cumulative dose of glucocorticoids, as well as RA patients who are men, are at high risk of ACS.