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Smoking cessation in patients with RA is associated with reduced CVD event rates and improved lipid profiles and predicts lower RA disease activity

Background Aberrant hemostasis is implicated in the increased CVD risk experienced by patients with rheumatoid arthritis (RA) (1). Large circulating concentrations of plasminogen activator inhibitor-1 (PAI-1) predict cardiovascular event rates (2). PAI-1 levels are markedly smaller in American and African black populations than in those of European descent (3,4). Whether this protection persists in black persons who have RA is unknown. Objectives This study compared hemostasis factors among African black and white RA patients Methods PAI-1, tissue factor pathway inhibitor (TFPI) and tissue plasminogen activator (t-PA) levels were measured by ELISA in 236 (114 black; 122 white) African RA patients. Data were analysed in mixed regression models. Results In age and sex adjusted analysis, PAI-1 concentrations were larger in black compared to white patients with RA (median (interquartile range (IQR))=12.4 (3.1-28.7) versus 5.4 (1.5-25.0) ng/ml, p=0.006). In all patients, body mass index (BMI) (β (SE)=0.022 (0.007), p=0003), waist circumference (β (SE)=0.007 (0.003), p=0.04) and tetracycline use (β (SE)=0.291 (0.133), p=0.03) were associated with logarithmically transformed PAI-1 levels. Population grouping did not influence these relationships (interaction p>/=0.8) but impacted rheumatoid factor (RF) positivity- and azathioprine use-PAI-1 level associations (interaction p=0.03 and 0.004, respectively). In stratified analysis, RF positivity was associated with PAI-1 levels in white (β (SE)=0.344 (0.139), p=0.01) but not black patients (β (SE)=-0.102 (0.143), p=0.5), and azathioprine use was associated with PAI-1 levels in black (β=0.400 (0.155), p=0.01) but not white patients (β (SE)=0.305 (0.184), p=0.1). In age, sex, BMI, RF positivity and azathioprine and tetracycline use adjusted analysis, black population origin remained associated with PAI-1 levels (β (SE)=0.175 (0.091), p=0.05). In age and sex adjusted analysis, TFPI and t-PA levels did not differ in black compared to white RA patients (median (IQR)=221.0 (149.8-410.5) versus 225.0 (130.4-357.2) pg/ml, p=0.6, and 6.7 (4.9-9.1) versus 7.4 (4.4-10.0) pg/ml, p=0.3). Conclusion PAI-1 concentrations are substantially larger in African black compared to white patients with RA. References [1] Van den Hoever IAM, Sattar N, Nurmohamed MT. Thromboembolic and cardiovascular risk in rheumatoid arthritis: role of the haemostatic system. Ann Rheum Dis 2014;73:954-7. [2] Jung RG, Motazedian P, Ramirez FD, et al. Association between plasminogen activator-1 and cardiovascular events: a systematic review and meta-analysis. Thrombosis J (2018) 16:12. [3] Festa A, D’Agostino R, Rich SS, et al. Promoter (4G/5G) plasminogen activator inhibitor-1 genotype and plasminogen activator inhibitor-1 levels in blacks, Hispanics and non-Hispanic whites. The Insulin Resistance Atherosclerosis Study. Circulation 2003;107:2422-7. [4] De Lange Z, Rijken DC, Hoekstra T, et al. In black South Africans from rural and urban communities, the 4G/5G PAI-1 polymorphism influences PAI-1 activity, but not plasma clot lysis time. PLoS One 2013;8 (12): e83151. Disclosure of Interests None declared

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 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

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

Background Nesfatin-1 comprises a peptide that is involved in appetite suppression, energy homeostasis and fluid regulation, and was recently documented to participate in a range of cardiometabolic pathways (1,2). There is currently a need for the identification of novel biomarkers in the elucidation of CVD risk and its stratification in persons with rheumatoid arthritis (RA). The role of nesfatin-1 in cardiovascular disease risk among RA patients is uncertain. Objectives We investigated the potential impact of nesfatin-1 on subclinical cardiovascular disease manifestations in patients with RA by determining the associations of nesfatin-1 concentrations with atherosclerosis and circulating levels of matrix metalloproteinase (MMP)-2 that mediates plaque stability and those of MMP-3 and MMP-9 that cause plaque vulnerability. Methods Nesfatin-1 concentrations were measured in 236 (114 black; 122 white) RA patients. Relationships of nesfatin-1 concentrations with ultrasound determined carotid intima-media thickness (cIMT) and plaque and MMP levels were identified in confounder adjusted multivariate regression models. Results Nesfatin-1 concentrations were inversely associated with c-IMT (β (SE) = -0.022 (0.008), p=0.00) and directly with MMP-2 levels (β (SE) =0.117 (0.031), p=0.00). After adjustment for conventional risk factors and RA characteristics, these associations persisted (c-IMT: β (SE) = -0.017 (0.008), p=0.04; MMP-2: β (SE) =0.116 (0.033), p=0.00). Patient characteristics did not influence the nesfatin-1-to-cIMT relation (interaction p≥0.7). By contrast, the Disease Activity Score in 28 joints (DAS28) and Clinical Disease Activity Index impacted the nesfatin-1-to-cIMT association (interaction p=0.04 and 0.02, respectively). Nevertheless, in stratified analysis, nesfatin-1 concentrations were related to those of MMP-2 in patients with no or mild (β (SE) =0.148 (0.054), p=0.00) and moderate or high disease activity (β (SE) =0.086 (0.041), p=0.04) as determined by DAS28 (cut-off value 3.6) as well as by CDAI (cut-off value =10) (β (SE) =0.130 (0.048), p=0.00 and 0.107 (0.046), p=0.02), respectively). Conclusions Nesfatin-1 concentrations are consistently associated with a reduced atherosclerosis burden and increased MMP-2 levels in patients with RA. References Oh-I S, Shimizu H. Identification of nesfatin-1 as a satiety molecule in the hypothalamus. Nature. 2006;443:709–712. Dore R, Levata L, Lehnert H, Schulz C. Nesfatin-1: functions and physiology of a novel regulatory peptide. Journal of Endocrinology. 2016; e-pub ahead of print: doi: 10.1530/JOE-16–0361. Disclosure of Interest None declared

Background Heart failure contributes to the excess mortality experienced by patients with rheumatoid arthritis (RA) (1). Impaired diastolic function represents a pre-clinical cardiac alteration which is highly predictive of cardiac events and often progresses to heart failure. Diastolic dysfunction is the most common cause of heart failure in patients with a preserved ejection fraction. Whereas RA is associated with an increased prevalence of impaired diastolic function (2,3), the pathophysiological mechanisms that mediate this comorbidity await further elucidation. Objectives This study aimed to identify potential determinants of ventricular (LV) diastolic function in patients with RA. Methods LV diastolic function was determined in 176 patients with RA; 9 patients had established cardiovascular disease. LV diastolic function was determined by echocardiography from 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 (e9) (E/e9), and the lateral e9. Relationships of comprehensively evaluated traditional cardiovascular risk factors and RA characteristics with markers of LV diastolic function were determined in confounder adjusted multivariate regression models. Results Disease duration (partial r=-0.23, p=0.00), rheumatoid factor status (partial r=-0.16, p=0.04) and erythrocyte sedimentation rate (partial r=-0.16, p=0.04) were associated with lower logarithmically transformed (log) E/A. Upon further adjustment for left ventricular mass index or relative wall thickness, these relationships remained significant (p≤0.05). Diastolic blood pressure was related to log E/e9 (partial r=-0.16, p=0.04); this association was no longer significant after additional adjustment for left ventricular mass index (p=0.06) or relative wall thickness (p=0.06). Disease duration (partial r=-0.32, p=0.00), waist-to-hip ratio (partial r=-0.29, p=0.00) and triglycerides (partial r=-0.17, p=0.03) were related to log lateral e9. These relationships remained significant upon further adjustment for left ventricular mass index (for all p=0.00) or relative wall thickness (for all p=0.00). In sensitivity analysis among RA patients without established cardiovascular disease (n=167), the results were not materially altered. Conclusions Modifiable traditional cardiovascular disease risk factor and disease characteristics are consistently associated left ventricular diastolic function in RA. References Nicola PJ, Crowson CS, Maradit-Kremers H et al. Contribution of congestive heart failure and ischemic heart disease to excess mortality in rheumatoid arthritis. Arthritis Rheum 2006;54:60–7. Gonzalez-Juanatey C, Testa A, Garcia-Castelo A et al. Echocardiographic findings in long-term treated rheumatoid arthritis patients without clinically evident cardiovascular disease. Semin Arthritis Rheum 2004;33:231–8. Liang KP, Myasoedova E, Crowson CS et al. Increased prevalence of diastolic dysfunction in rheumatoid arthritis. Ann Rheum Dis 2010;69:1665–70. Disclosure of Interest None declared