Linda Tsang

Carotid artery plaque in women with rheumatoid arthritis and low estimated cardiovascular disease risk: a cross-sectional study

IntroductionWe previously reported that most patients with rheumatoid arthritis (RA) and moderate cardiovascular disease (CVD) risk according to the Systematic COronary Evaluation score (SCORE) experience carotid artery plaque. In this study, we aimed to identify patient characteristics that can potentially predict carotid plaque presence in women with RA and a concurrent low CVD risk according to the SCORE.MethodsA cohort of 144 women with an evaluated low risk of CVD (SCORE value of zero) was assembled amongst 550 consecutive patients with RA that underwent CVD risk factor recording and carotid artery ultrasound. Participants had no established CVD, moderate or severe chronic kidney disease, or diabetes. We assessed carotid plaque(s) presence and its associated patient characteristics.ResultsCarotid artery plaque was present in 35 (24.3%) of women with RA. Age, the number of synthetic disease-modifying agents (DMARDs) and total cholesterol concentrations were independently associated with plaque in multivariable stepwise backward regression analysis (odds ratio (95% confidence interval) = 1.15 (1.07 to 1.24), P <0.0001, 1.51 (1.05 to 2.17), P = 0.03 and 1.66 (1.00 to 2.73) P = 0.04), respectively). The area under the curve (AUC) of the receiver operating curve (ROC) for the association with plaque was 0.807 (P <0.0001), 0.679 (P = 0.001) and 0.599 (P = 0.08) for age, total cholesterol concentrations and number of synthetic DMARDs used, respectively. The optimal cutoff value in predicting plaque presence for age was 49.5 years with a sensitivity and specificity of 74% and 75%, respectively, and for total cholesterol concentration, it was 5.4 mmol/l with a sensitivity and specificity of 63% and 70%, respectively. The plaque prevalence was 37.5% in patients (n = 80; 55.6%) with age >49.5 years or/and total cholesterol concentration of >5.4 mmol/l, respectively, compared to only 7.8% in those (n = 64; 44.4%) with age ≤49.5 years or/and total cholesterol concentration of ≤5.4 mmol/l, respectively.ConclusionsApproximately one-third of women with RA who experience a low SCORE value and are aged >49.5 years or/and have a total cholesterol concentration of >5.4 mmol/l, experience high-risk atherosclerosis, which requires intensive CVD risk management.

Kidney Function, Endothelial Activation and Atherosclerosis in Black and White Africans with Rheumatoid Arthritis

Objective To determine whether kidney function independently relates to endothelial activation and ultrasound determined carotid atherosclerosis in black and white Africans with rheumatoid arthritis (RA). Methods We calculated the Jelliffe, 5 Cockcroft-Gault equations, Salazar-Corcoran, Modification of Diet in Renal Disease (MDRD) and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) estimated glomerular filtration rate (EGFR) equations in 233 (112 black) RA patients. Results The CKD-EPI eGFR was <90 ml/min/1.73m2 in 49.1% and 30.6% of black and white patients, respectively (odds ratio (95% confidence interval) = 2.19 (1.28–3.75), p = 0.004). EGFRs were overall consistently associated with monocyte chemoattractant protein-1 and angiopoietin 2 concentrations in white patients, and with carotid intima-media thickness and plaque in black participants. Amongst black patients, plaque prevalence was 36.7% and the area under the curve (AUC) of the receiver operating characteristic (ROC) curve was not associated with plaque presence for the MDRD equation (p = 0.3), whereas the respective relationship was significant or borderline significant (p = 0.003 to 0.08) and of similar extent (p>0.1 for comparisons of AUC (SE)) for the other 8 equations. Based on optimal eGFR cutoff values with sensitivities and specificities ranging from 42 to 60% and 70 to 91% respectively, as determined in ROC curve analysis, a low eGFR increased the odds ratio for plaque 2.2 to 4.0 fold. Conclusion Reduced kidney function is independently associated with atherosclerosis and endothelial activation in black and white Africans with RA, respectively. CKD is highly prevalent in black Africans with RA. Apart from the MDRD, eGFR equations are useful in predicting carotid plaque presence, a coronary heart disease equivalent, amongst black African RA patients.

Effect of Traditional Cardiovascular Risk Factors on the Independent Relationship of Leptin with Atherosclerosis in Rheumatoid Arthritis

To the Editor: Leptin is an adipokine that regulates appetite and energy expenditure1. Both high and low leptin production can further increase cardiovascular (CV) risk1. Leptin is also produced in inflamed joints and implicated in the pathophysiology of rheumatoid arthritis (RA)2. Whether leptin increases CV risk in RA is currently uncertain. Two studies reported a lack of association between leptin concentrations and carotid artery intima-media thickness (cIMT) in RA3,4. Leptin concentrations were also found to be unrelated to coronary artery classification scores in RA5. However, we recently reported an independent relationship between leptin concentrations and surrogate markers of early atherogenesis in young patients with RA2. Importantly, in the present context, carotid artery plaque is a more reliable indicator of atherosclerosis than cIMT6. In our present study, we examined the independent relationships of leptin concentrations with cIMT and plaque in 217 (112 black and 105 white) patients with RA. Because the production and effects of adipokines on CV risk depend on pathophysiological context1,2,7, we also determined whether the presence of conventional and nonconventional CV risk factors modified leptin concentrations and their associations with atherosclerosis. … Address correspondence to Prof. P.H. Dessein, P.O. Box 1012, Melville 2109, Johannesburg, South Africa. E-mail: dessein{at}telkomsa.net

Nesfatin-1 and visfatin expression is associated with reduced atherosclerotic disease risk in patients with rheumatoid arthritis

HIGHLIGHTSVisfatin levels were associated with cardio‐metabolic risk in RA.Nesfatin concentrations were related to reduced carotid IMT in RA.Nesfatin and visfatin associated with the plaque stability mediator MMP‐2 in RA.Nesfatin and visfatin concentrations were directly correlated in RA.MMP‐2 expression in relation to visfatin may represent a compensatory mechanism in RA. ABSTRACT Nesfatin is an anti‐inflammatory molecule that reduces atherosclerotic cardiovascular risk. By contrast, visfatin has pro‐inflammatory properties and is pro‐atherogenic. We examined the potential impact of nesfatin and visfatin on atherosclerotic disease in 232 (113 black and 119 white) consecutive rheumatoid arthritis (RA) patients from 2 centers. Independent relationships of nesfatin and visfatin concentrations with metabolic risk factors, endothelial activation, carotid atherosclerosis and altered plaque stability were determined in multivariable regression models. Rheumatoid factor (RF) positivity was associated with both nesfatin (&bgr;=0.650, p<0.0001) and visfatin levels (&bgr;=0.157, p=0.03). Visfatin concentrations were related to increased diastolic blood pressure (&bgr;=4.536, p=0.01) and diabetes prevalence (&bgr;=0.092, p=0.04). Nesfatin levels were associated with reduced carotid intima‐media thickness (&bgr;=−0.017, p=0.008). Nesfatin (&bgr;=0.116, p=0.001) and visfatin concentrations (&bgr;=0.234, p=0.001) were related to those of matrix metalloproteinase‐2 (MMP‐2), a plaque stability mediator. Nesfatin and visfatin concentrations were directly correlated (Spearmans rho=0.516). The nesfatin‐MMP‐2 and visfatin‐MMP‐2 relations were both stronger in RF negative compared to RF positive patients (interaction p=0.01 and p=0.04, respectively). Nesfatin is associated with reduced atherosclerosis and increased plaque stability mediator levels in RA. Visfatin is related to adverse cardio‐metabolic risk in RA. Increased MMP‐2 expression in relation to visfatin may represent a compensatory mechanism aimed at reducing cardiovascular risk in RA.

SAT0129 Kidney Function, Endothelial Activation and Atherosclerosis in Black and White Africans with Rheumatoid Arthritis

Background The role of impaired kidney function in enhanced atherogenesis associated with rheumatoid arthritis (RA) requires further elucidation. Objectives To determine whether kidney function independently relates to endothelial activation and ultrasound determined carotid atherosclerosis in black and white Africans with RA. Methods We calculated the Jelliffe, 5 Cockcroft-Gault equations, Salazar-Corcoran, Modification of Diet in Renal Disease (MDRD) and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) estimated glomerular filtration rate (EGFR) equations in 233 (112 black) RA patients. Results The CKD-EPI eGFR was <90 ml/min/1.73m2 in 49.1% and 30.6% of black and white patients, respectively (odds ratio (95% confidence interval)=2.19 (1.28-3.75), p=0.004). EGFRs were overall consistently associated with monocyte chemoattractant protein-1 and angiopoietin 2 concentrations in white patients, and with carotid intima-media thickness and plaque in black participants. Amongst black patients, plaque prevalence was 36.7% and the area under the curve (AUC) of the receiver operating characteristic (ROC) curve was not associated with plaque presence for the MDRD equation (p=0.3), whereas the respective relationship was significant or borderline significant (p=0.003 to 0.08) and of similar extent (p>0.1 for comparisons of AUC (SE)) for the other 8 equations. Based on optimal eGFR cutoff values with sensitivities and specificities ranging from 42 to 60% and 70 to 91% respectively, as determined in ROC curve analysis, a low eGFR increased the odds ratio for plaque 2.2 to 4.0 fold. Conclusions Reduced kidney function is independently associated with atherosclerosis and endothelial activation in black and white Africans with RA, respectively. CKD is highly prevalent in black Africans with RA. Apart from the MDRD, eGFR equations are useful in predicting carotid plaque presence, a coronary heart disease equivalent, amongst black African RA patients. Disclosure of Interest None declared

FRI0093 The Framingham Score is a Useful Surrogate Marker of High Risk Subclinical Atherosclerosis in Patients with Rheumatoid Arthritis

Background Carotid artery plaque as identified by ultrasound represents very high risk atherosclerosis. Objectives We determined the performance of cardiovascular disease (CVD) risk equations including the Systematic COronary Risk Evaluation (SCORE) and Framingham score in predicting plaque presence in patients with rheumatoid arthritis (RA). Methods A cohort of 330 cases was assembled amongst 451 Spanish patients that underwent CVD risk screening and carotid ultrasound. Applied exclusion criteria were established CVD, diabetes and moderate or severe chronic kidney disease. The findings were validated in 90 black and 97 white African RA patients. Results Carotid plaque was present in 162 (49.1%) of the Spanish patients. The SCORE and Framingham score were each strongly associated with plaque (P <0.0001). In predicting plaque presence, the area under the curve (AUC) (SE) of the receiver operator characteristic (ROC) curve for the Framingham score was larger than for the SCORE (0.799 (0.024) versus 0.747 (0.027), P =0.003). The optimal cut-off value and corresponding sensitivity and specificity for the Framingham score and SCORE were 11.0, 64% and 81% and 0.5, 86% and 58%, respectively. Based on optimal cut-off values, a high Framingham score but not SCORE was associated with carotid plaque independent of age, sex, erythrocyte sedimentation rate and C-reactive protein concentrations. Whereas a conventional Framingham score value of ≥20 correctly classified only 25% as being at high CVD risk, this proportion increased to 64% in those with a Framingham score of >11; the percentage of patients without plaque incorrectly classified as being at high CVD risk increased from 17% in those with a Framingham score or ≥20 to only 23% in those with a Framingham score of >11.0. External validation produced similar results in white but not black Africans with RA. Conclusions In this study, the Framingham score outperformed the SCORE in predicting plaque presence in RA. Upon CVD risk stratification, a Framingham score of >11.0 comprises a measure that can reclassify about 40% of white RA patients without established CVD, chronic kidney disease or/and diabetes more accurately. Delineation of effective population specific CVD risk assessment strategies is needed in black African RA patients. Disclosure of Interest None declared

SAT0124 Aortic stiffness and time to wave reflection are associated with left ventricular diastolic dysfunction measures in rheumatoid arthritis

Background Patients with rheumatoid arthritis (RA) experience an increased frequency of heart failure with a preserved ejection fraction (HFpEF) (1). The treatment of HFpEF is currently suboptimal. Elucidation of the underlying pathophysiological mechanisms of HFpEF may provide potential targets for its management. Diastolic dysfunction often precedes the progression to HFpEF (2). Abnormalities in aortic function contribute to diastolic dysfunction in non-RA populations (3,4). Objectives The aim of this study was to determine whether impaired aortic function is associated with left ventricular diastolic dysfunction in RA. Methods Arterial function was determined by applanation tonometry using SphygmoCor software and left ventricular diastolic function was assessed by echocardiography in 176 patients with RA. Markers of arterial function included carotid femoral pulse wave velocity (PWV), central systolic and pulse pressure, pulse pressure amplification and the magnitude and timing of the forward and reflected waves. Markers of diastolic function included the ratio of early-to-late transmitral blood flow velocity (E/A), the ratio of E to the mean of the lateral and septal wall myocardial tissue lengthening at the mitral annulus (e’)(E/e’) and the septal and lateral e’. Relationships of comprehensively evaluated arterial function with markers of LV diastolic function were determined in confounder adjusted multivariate regression models. Results The timing of the forward (Ft) and reflected (Rt) waves were each associated with E/A (Ft: partial r=0.20, p=0.02; Rt: partial r=0.30, p=0.001) and Rt was further associated with lateral e’ (partial r=0.36, p<0.0001) and septal e’ (partial r=0.36, p<0.0001); PWV was associated with E/e’ (partial r=0.18; p=0.03). Reflected wave timing was associated with two indices of impaired relaxation (E/A<0.8: OR (95% CI)=0.51 (0.29-0.91), p=0.01; lateral e’<10: OR (95% CI)=0.43 (0.26-0.71), p=0.001); PWV was associated with an increased left ventricular filling pressure (E/e’>12: OR (95% CI)=1.58 (1.04-2.38), p=0.03). Conclusions Aortic stiffness and time to wave reflection are associated with increased filling pressure and impaired relaxation of the left ventricle, respectively. The development of diastolic dysfunction in RA may be partly mediated by changes in large artery function. References: [1] Davis JM, Roger VL, Crowson CS, et al. The presentation and outcome of heart failure in patients with rheumatoid arthritis differs from that in the general population. Arthritis Rheumatol 2008;58:2603-11. [2] Aurigemma GP, Gottdiener JS, Shemanski L, et al. Predictive value of systolic and diastolic function for incident congestive heart failure in the elderly: the cardiovascular health study. J Am Coll Cardiol 2001;37:1042-8. [3] Peterson VR, Woodiwiss AJ, Libhaber CD, et al. Cardiac diastolic dysfunction is associated with aortic wave reflection, but not stiffness in a predominantly young-to-middle-aged community sample. Am J Hypertens 2016;29:1148-57. [4] Cauwenberghs N, Knez J, Tikhonoff V, et al. Doppler indexes of left ventricular systolic and diastolic function in relation to the arterial stiffness in a general population. J Hypertens 2016;34:762-71. Disclosure of Interest: None declared

FRI0170 Cardiovascular risk factors and disease characteristics are consistently associated with arterial stiffness in rheumatoid arthritis

Background In the non-rheumatoid arthritis (RA) population, arterial stiffness contributes to cardiovascular disease risk beyond brachial blood pressure and other established cardiovascular risk factors. The increased cardiovascular disease risk in RA is now well documented. In this regard, how RA impacts on arterial stiffness remains uncertain. Objectives The aim of the present study was to identify potential determinants of comprehensively assessed arterial stiffness in a relatively large group of ethnically diverse patients with RA. Methods Relationships of traditional cardiovascular risk factors and RA characteristics with 9 arterial stiffness markers including central systolic and pulse pressure, pulse wave velocity, augmentation index, forward and reflected wave pressure, reflection magnitude, brachial-to-aortic pulse pressure amplification (a marker of reduced wave reflection) and peripheral pulse pressure were identified in multivariable backward regression models among 177 (118 white, 32 Asian, 22 black, 5 mixed ancestry) patients without established cardiovascular disease. Results Recorded characteristics explained 37% (pulse wave velocity) to 71% (reflected wave pressure) of the variability in arterial stiffness. RA duration (partial r=0.17, p=0.04), rheumatoid factor status (partial r=-0.19 to 0.20, p=0.01 to 0.03), leukocyte counts (partial r=0.16 to 0.19, p=0.02 to 0.05) and total cholesterol (-0.18 to 0.26, p=0.00 to 0.03) were associated with enhanced central systolic blood pressure or/and wave reflection markers. C-reactive protein (partial r=-0.24, -0.17 and -0.20, respectively, p≤0.05) was paradoxically related to reduced central pulse pressure, pulse wave velocity and forward wave pressure, and body mass index (partial r=-0.39 to 0.42, p=0.00 to 0.02) and insulin resistance (partial r=-0.21 to -0.20, p=0.00 to 0.01) to reduced wave reflection and peripheral pulse pressure. Exercise (partial r=0.19, p=0.02) and alcohol (partial r=-0.27, p=0.00) consumption were associated with increased pulse pressure amplification and decreased peripheral pulse pressure, respectively. Tumour necrosis factor-α inhibition (partial r=-0.25, p=0.00) was related to reduced pulse wave velocity and tetracycline use (partial r=-0.20, p=0.02) to reduced peripheral pulse pressure. Conclusions Traditional cardiovascular risk factors and disease characteristics are consistently associated with vascular hemodynamic alterations in RA. The role of arterial stiffness in cardiovascular disease risk in RA needs further study. Disclosure of Interest None declared

THU0163 TNF-related Apoptosis-inducing Ligand and Cardiovascular Disease in Rheumatoid Arthritis

Background Whether TNF-related apoptosis-inducing ligand (TRAIL) impacts cardiovascular risk in rheumatoid arthritis (RA) is currently unknown. Objectives We examined the association of TRAIL concentrations with cardiovascular disease (CVD) in RA and, since osteoprotegerin (OPG) can act as a decoy receptor for TRAIL, whether TRAIL concentrations impact on the independent OPG level-atherosclerotic CVD relation that was recently documented in the present cohort (1). Methods TRAIL concentrations were assessed by ELISA in 151 RA patients of which 75 (49.7%) had CVD comprising ischemic heart disease (n=27), cerebrovascular accident (n=26), peripheral artery disease (n=9) or/and heart failure (HF) (n=27), and 62 controls. Results Mean RA duration was 12 years. In RA patients, C-reactive protein (CRP) levels and cholesterol-HDL cholesterol ratio related to TRAIL concentrations [partial R (p) = -0.222 (0.006) and 0.174 (p=0.04), respectively]. TRAIL concentrations were smaller in RA patients compared to controls (median (interquartile range) =80.2 (60.9-120.4) versus 130.4 (89.4-167.7) pg/ml, p<0.0001)). TRAIL levels were larger in RA patients with compared to those without HF (105.5 (66.5-143.4) versus 79.9 (57.8-110.6), p=0.02); this difference was independent of demographic characteristics and traditional cardiovascular risk factors (p=0.04) but not CRP concentrations (p=0.1). TRAIL levels were consistently unrelated to atherosclerotic CVD. Our previously reported OPG-atherosclerotic CVD relation in RA survived adjustment for TRAIL concentrations in a mixed regression model (p=0.04). Conclusions TRAIL concentrations are markedly reduced and associated with HF in established RA, this relationship being explained by CRP levels. OPG may directly enhance CVD risk in RA (1). References Lopez-Mejias, Ubilla B, Genre F, Corrales A, Hernandez JL, Ferraz-Amaro I, Tsang L, Llorca J, Blanco R, Gonzalez-Juanatey C, Gonzalez-Gay MA, Dessein PH. Osteoprotegerin concentrations relate independently to established cardiovascular disease in rheumatoid arthritis. J Rheumatol 2015;42:39-45. Disclosure of Interest None declared