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Hon-Chun Hsu,1,2,&ast; Grace Tade,1,&ast; Gavin R Norton,1 Ferande Peters,1 Chanel Robinson,1 Noluntu Dlongolo,3 Gloria Teckie,4 Angela J Woodiwiss,1 Patrick H Dessein1,5 1Cardiovascular Pathophysiology and Genomics Research Unit, School of Physiology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa; 2Nephrology Unit, Milpark Hospital, Johannesburg, South Africa; 3Rheumatology Unit, Rosebank Hospital, Johannesburg, South Africa; 4Division of Nephrology, Department of Medicine, Chris Hani Baragwanath Hospital and Faculty of Health Sciences, University of Witwatersrand, Johannesburg, South Africa; 5Internal Medicine Department, University of the Witwatersrand, Johannesburg, South Africa&ast;These authors contributed equally to this workCorrespondence: Patrick H Dessein, Tel +27 662491468, Email patrick.dessein22@gmail.comPurpose: We assessed whether aortic stiffness and pulsatile pressures can mediate chronic kidney disease (CKD)-associated impaired diastolic function.Participants and Methods: In 276 black Africans including 46 CKD (19 non-dialysis; 27 dialysis) and 230 control subjects, pulse wave velocity (PWV) estimated aortic stiffness and pulsatile pressures (forward and backward wave pressure, central systolic blood pressure (CSBP) and pulse pressure (CPP)) were determined by applanation tonometry; e’ as an index of left ventricular active relaxation and E/e’ as a measure of left ventricular filling pressure or passive relaxation were evaluated by echocardiography.Results: In age, sex, traditional cardiovascular risk factor and mean arterial pressure (MAP) adjusted regression models, CKD was inversely associated with e’ (p = 0.03) and directly with E/e’ (p < 0.01). The CKD-e’ relationship was attenuated and no longer significant (p = 0.31) upon additional adjustment for aortic PWV but not pulsatile pressures (p = 0.03– 0.05). In product of coefficient mediation analysis, PWV accounted for 47.6% of the CKD-e’ association. CSBP (22.9%) and CPP (18.6%) but not PWV (11.3%) accounted for a significant and relevant proportion of the CKD-E/e’ relationship. However, CKD remained strongly associated with E/e’ independent of aortic function measures (p < 0.01). Treatable covariates that were or tended to be consistently associated with diastolic function included MAP (p < 0.01) and diabetes (p = 0.02– 0.07) for the CKD-e’ and CKD-E/e’ relations, respectively.Conclusion: Aortic stiffness rather than pulsatile pressures mediates CKD-related impaired left ventricular active relaxation. By contrast, aortic pulsatile pressures (and not stiffness) contribute to CKD-related left ventricular filling pressures but do not fully account for the respective association.Keywords: chronic kidney disease, diastolic function, arteriosclerosis, aortic stiffness, pulsatile pressures

Grace Tade,1,&ast; Hon-Chun Hsu,1,2,&ast; Angela J Woodiwiss,1 Ferande Peters,1 Chanel Robinson,1 Noluntu Dlongolo,3 Gloria Teckie,4 Ahmed Solomon,5 Gavin R Norton,1 Patrick H Dessein1,5,6 1Cardiovascular Pathophysiology and Genomics Research Unit, School of Physiology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa; 2Nephrology Unit, Milpark Hospital, Johannesburg, South Africa; 3Rheumatology Unit, Rosebank Hospital, Johannesburg, South Africa; 4Division of Nephrology, Department of Medicine, Chris Hani Baragwanath Hospital and Faculty of Health Sciences, University of Witwatersrand, Johannesburg, South Africa; 5Rheumatology Department, University of the Witwatersrand, Johannesburg, South Africa; 6Internal Medicine Department, University of the Witwatersrand, Johannesburg, South Africa&ast;These authors contributed equally to this workCorrespondence: Patrick H Dessein, Departments of Medicine, Rheumatology and Physiology, Charlotte Maxeke Johannesburg Academic Hospital, University of the Witwatersrand Medical School, 7 York Road, Parktown, Johannnesburg, 2193, South Africa, Tel +27 662491468, Email patrick.dessein22@gmail.comIntroduction: Circulating uric acid, ferritin, albumin, intact parathyroid hormone and gamma-glutamyl transferase each participate in biochemical reactions that reduce or/and enhance oxidative stress, which is considered the final common pathway through which pathophysiological mechanisms cause uremic cardiomyopathy. We hypothesized that the respective biomarkers may be involved in the development of uremic cardiomyopathy characteristics and can be useful in their identification among chronic kidney disease patients.Methods: We assessed traditional and non-traditional cardiovascular risk factors including biomarker concentrations and determined central systolic blood pressure using SphygmoCor software and cardiac structure and function by echocardiography in 109 (64 non-dialysis and 45 dialysis) patients. Associations were evaluated in multivariate regression models and receiver operator characteristic (ROC) curve analysis.Results: Each biomarker concentration was associated with left ventricular mass beyond stroke work and/or inappropriate left ventricular mass in all, non-dialysis and/or dialysis patients. Ferritin, albumin and gamma-glutamyl transferase levels were additionally associated with E/e’ in all, non-dialysis and/or dialysis patients. Dialysis status influenced the relationship of uric acid concentrations with inappropriate left ventricular mass and those of gamma-glutamyl transferase levels with left ventricular mass and inappropriate left ventricular mass. In stratified analysis, low uric acid levels were related to inappropriate left ventricular mass in dialysis but not non-dialysis patients (interaction p=0.001) whereas gamma-glutamyl transferase concentrations were associated with left ventricular mass and inappropriate left ventricular mass in non-dialysis but not dialysis patients (interaction p=0.020 to 0.036). In ROC curve analysis, uric acid (area under the curve (AUC)=0.877), ferritin (AUC=0.703) and albumin (AUC=0.728) concentrations effectively discriminated between dialysis patients with and without inappropriate left ventricular hypertrophy, left ventricular hypertrophy, and increased E/e,’ respectively.Conclusion: Uric acid, ferritin, albumin, parathyroid hormone and gamma-glutamyl transferase were associated with uremic cardiomyopathy characteristics and could be useful in their identification. Our findings merit validation in future longitudinal studies.Keywords: uremic cardiomyopathy, uric acid, ferritin, albumin, parathyroid hormone and gamma-glutamyl transferase

Background: Whether systolic blood pressure (SBP) control in sustained volume-dependent primary hypertension is associated with blunted ANP (atrial natriuretic peptide) relationships with indexes of volume load is unknown. Methods: Systemic hemodynamics (central pressure, echocardiographic aortic velocity and diameter measurements in the outflow tract), circulating ANP concentrations (ELISA assays) and glomerular and tubular function (24-hour urine collections [n=519]) were determined in a community of African ancestry (n=772). Results: As compared with those with a controlled SBP, those with an uncontrolled SBP (n=198) showed lower ANP concentrations ( P P + excretion (FeNa + ; P P P P P P >0.25), cardiac output ( P >0.29), FeNa + ( P >0.77), or glomerular filtration rate ( P >0.47) and ANP concentrations were noted. Furthermore, in those with an uncontrolled SBP, no relationships between ANP concentrations and SVR or Zc were observed ( P >0.34). Conclusions: In a population where primary hypertension is strongly volume-dependent, those with an uncontrolled SBP have an attenuated relationship between ANP and both renal and hemodynamic indexes of volume overload and the vascular effects of ANP.

AIMS Whether renal mechanisms of hypertension primarily translate into increases in systemic vascular resistance (SVR) in all populations is uncertain. We determined whether renal mechanisms associate with either increases in SVR (and impedance to flow) or systemic flow in a community of African ancestry. METHOD In a South African community sampled across the full adult age range (n = 546), we assessed stroke volume (SV), peak aortic flow (Q), SVR, characteristic impedance (Zc) and total arterial compliance (TAC) from velocity and diameter measurements in the outflow tract (echocardiography) and central arterial pressures. Renal changes were determined from creatinine clearance (glomerular filtration rate, GFR) and fractional Na+ excretion (FeNa+) (derived from 24-h urine collections). RESULTS Independent of confounders (including MAP and pressures generated by the product of Q and Zc), SV (and hence cardiac output) (P

Hon-Chun Hsu,1,2 Gavin R Norton,1 Ferande Peters,1 Chanel Robinson,1 Noluntu Dlongolo,3 Ahmed Solomon,4 Gloria Teckie,5 Angela J Woodiwiss,1 Patrick H Dessein1,6,7 1Cardiovascular Pathophysiology and Genomics Research Unit, School of Physiology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa; 2Nephrology Unit, Milpark Hospital, Johannesburg, South Africa; 3Rheumatology Unit, Rosebank Hospital, Johannesburg, South Africa; 4Division of Rheumatology, Charlotte Maxeke Johannesburg Academic Hospital and Faculty of Health Sciences, University of Witwatersrand, Johannesburg, South Africa; 5Division of Nephrology, Department of Medicine, Chris Hani Baragwanath Hospital and Faculty of Health Sciences, University of Witwatersrand, Johannesburg, South Africa; 6Internal Medicine Department, University of the Witwatersrand, Johannesburg, South Africa; 7Internal Medicine Department, Free University and University Hospital, Brussels, BelgiumCorrespondence: Patrick H DesseinCardiovascular Pathophysiology and Genomics Research Unit, School of Physiology, Faculty of Health Sciences, University of the Witwatersrand, 80 Scholtz Road, Norwood, 2117, Johannesburg, South AfricaTel +27662491468Email patrick.dessein22@gmail.comIntroduction: We hypothesized that post transplantation anaemia and persistent secondary hyperparathyroidism are potential determinants of diastolic function in stable kidney transplant recipients.Methods: We assessed traditional and non-traditional cardiovascular risk factors and determined carotid artery intima-media thickness and plaque by ultrasound, arterial function by applanation tonometry using SphygmoCor software and diastolic function by echocardiography in 43 kidney transplant recipients with a transplant duration of ≥ 6 months, no acute rejection and a glomerular filtration rate of ≥ 15 mL/min/1.73m2.Results: Mean (SD; range) transplant duration was 12.3 (8.0; 0.5– 33.8) years. Post transplantation anaemia and persistent secondary hyperparathyroidism were identified in 27.9% and 30.8% of the patients, respectively; 67.5% of the participants were overweight or obese. In established confounder adjusted analysis, haemoglobin (partial R=− 0.394, p=0.01) and parathyroid hormone concentrations (partial R=0.382, p=0.02) were associated with E/e’. In multivariable analysis, haemoglobin (partial R=− 0.278, p=0.01) and parathyroid levels (partial R=0.324, p=0.04) were independently associated with E/e’. Waist–height ratio (partial R=− 0.526, p=0.001 and partial R=− 0.355, p=0.03), waist circumference (partial R=− 0.433, p=0.008 and partial R=− 0.393, p=0.02) and body mass index (partial R=− 0.332, p=0.04 and partial R=− 0.489, p=0.002) were associated with both e’ and E/A, respectively, in established confounder adjusted analysis. The haemoglobin-E/e’ (partial R=− 0.422, p=0.02), parathyroid hormone-E/e’ (partial R=0.434, p=0.03), waist–height ratio-e’ (partial R=− 0.497, p=0.007) and body mass index-E/A (partial R=− 0.386, p=0.04) relationships remained consistent after additional adjustment for left ventricular mass index and cardiac preload and afterload measures.Conclusion: Haemoglobin and parathyroid hormone concentrations as well as adiposity measures are independently associated with diastolic function in kidney transplant recipients. Whether adequate management of post transplantation anaemia, persistent secondary hyperparathyroidism and excess adiposity can prevent the development of heart failure with preserved ejection fraction in kidney transplant recipients merits further investigation.Keywords: haemoglobin, parathyroid hormone, obesity, diastolic function, kidney transplantation

Through both backward (Pb) and forward (Pf) wave effects, a lower heart rate (HR) associates with increased central (PPc), beyond brachial pulse pressure (PP). However, the relative contribution to Pf of aortic flow (Q) versus re-reflection of Pb, has not been determined. Using central pressure, aortic velocity and diameter measurements in the outflow tract (echocardiography), we constructed central pressure waveforms that account for the relative contribution of Q versus re-reflection to Pf. We thus evaluated the mechanisms of HR-PPc relations in a community sample (n=824) and the impact of age thereon. Inverse HR-PPc ( P P =0.064) relations were noted. The slope of HR-PPc relation was increased in older adults ( P P P P P P

AIM We hypothesized that arterial function and N-terminal natriuretic peptide (NT-proBNP) levels as a marker of volume overload, relate differently to E/e' as an index of diastolic function in dialysis compared with non-dialysis patients with chronic kidney disease. We further examined whether cardiovascular risk factors attenuated these relationships. METHODS We assessed cardiovascular risk factors and determined arterial function indices by applanation tonometry using SphygmoCor software and E/e' by echocardiography in 103 (62 non-dialysis and 41 dialysis) patients. RESULTS In established confounder adjusted analysis, dialysis status impacted the pulse wave velocity-E/e' relationship (interaction p = .01) but not the NT-proBNP level-E/e' association (interaction p = .1). Upon entering arterial function measures and NT-proBNP levels simultaneously in regression models, arterial function measures were associated with E/e' (p = .008 to .04) in non-dialysis patients whereas NT-proBNP levels were related to E/e' in dialysis patients (p = .009 to .04). Bivariate associations were found between diabetes (p

Patients with rheumatoid arthritis (RA) experience a markedly increased risk of cardiovascular disease (CVD)1,2,3. Atherogenesis in RA remains poorly elucidated but traditional cardiovascular (CV) risk factors, systemic inflammation and their interactions, as well as genetic components certainly contribute1,2,3. In a recent 13-center study, the population-attributable CV event risk for disease activity as estimated by the Disease Activity Score in 28 joints (DAS28) and positive rheumatoid factor and/or anti cyclic citrullinated peptide antibodies, were both as large as that for lipids in RA4. It is therefore not unexpected that current CVD risk stratification tools calculated based on major traditional CV risk factors, such as the Framingham score and Systematic Coronary Risk Evaluation (SCORE), perform suboptimally in RA1,2,3. Recently developed disease-specific CVD risk calculators may also not perform better than those developed for the general population in predicting CV events in RA5. In this regard, during the past 2 decades, many population studies revealed that circulating gamma-glutamyl transferase (GGT) concentrations within normal ranges relate to major traditional CV risk factors, systemic inflammation, and incident CV events6,7,8,9,10,11,12. In RA, GGT levels were also found to be associated with disease activity markers13. These reported observations suggest that serum GGT concentrations may be useful in the identification of patients with RA who are at increased CVD risk. In this issue of The Journal , Vergneault and colleagues14 explored the associations of circulating GGT levels with CV risk factors in 129 patients with RA. Only patients with unstable hepatic disease and manifestations of liver dysfunction or failure were excluded. GGT concentrations were weakly associated with C-reactive protein … Address correspondence to Dr. P.H. Dessein, Departments of Medicine and Physiology, University of the Witwatersrand Medical School, 7 York Road, Parktown, 2193, Johannesburg, South Africa. Email: patrick.dessein22{at}gmail.com.

Hon-Chun Hsu,1,2 Chanel Robinson,1 Gavin R Norton,1 Angela J Woodiwiss,1 Patrick H Dessein1,3,4 1Cardiovascular Pathophysiology and Genomics Research Unit, School of Physiology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa; 2Nephrology Unit, Milpark Hospital, Johannesburg, South Africa; 3Internal Medicine Department, University of the Witwatersrand, Johannesburg, South Africa; 4Free University and University Hospital, Brussels, BelgiumCorrespondence: Patrick H Dessein 80 Scholtz Road, Norwood, Johannesburg 2117, South AfricaEmail patrick.dessein22@gmail.comIntroduction: It remains unclear why the optimal haemoglobin target is lower in patients with chronic kidney disease (CKD) than in non-CKD persons. Arteriosclerosis and consequent impaired arterial function comprise a central cardiovascular risk mechanism in CKD. We hypothesized that the optimal haemoglobin target depends on its opposing effects on arterial stiffness and pressure pulsatility in CKD.Methods: Arterial stiffness (aortic pulse wave velocity), wave reflection (augmentation index, reflected wave pressure and reflection magnitude), and pressure pulsatility (central systolic and pulse pressure, peripheral pulse pressure, pressure amplification and forward wave pressure) were assessed in 48 dialysis patients.Results: In established confounder and diabetes adjusted linear regression models, haemoglobin levels were directly associated with arterial stiffness (partial R=0.366, p=0.03) and inversely with central systolic pressure (partial R=− 0.344, p=0.04), central pulse pressure (partial R=− 0.403, p=0.01), peripheral pulse pressure (partial R=− 0.521, p=0.001) and forward wave pressure (partial R=− 0.544, p=0.001). The presence of heart failure and use of angiotensin converting enzyme inhibitors or angiotensin receptor blockers and erythropoietin stimulating agents did not materially alter these relationships upon further adjustment for the respective characteristics in the models, and in sensitivity analyses. In receiver operator characteristic curve analysis, the optimal haemoglobin concentration cut-off values in predicting arterial stiffness and increased central pulse pressure were remarkably similar at 10.95 g/dl and 10.85 g/dl, respectively, and with clinically useful sensitivities, specificities and positive and negative predictive values. In logistic regression models, a haemoglobin value of > 10.9 mg/dl was associated with both arterial stiffness (> 10 m/sec; OR (95% CI) = 10.48 (1.57– 70.08), p=0.02) and normal central pulse pressure (> 50 mmHg; OR (95% CI) = 7.55 (1.58– 36.03), p=0.01).Conclusion: This study suggests that the optimal haemoglobin target in dialysis patients is ∼ 11g/dl and determined by its differential and contrasting effects on arterial stiffness and pressure pulsatility.Keywords: haemoglobin target, dialysis, arterial stiffness, pressure pulsatility

Background: It is plausible that optimal cardiovascular disease (CVD) risk management differs in patients with rheumatoid arthritis (RA) from low or middle income compared to high income populations. This study aimed at producing evidence-based points to consider for CVD prevention in South African RA patients. Methods: Five rheumatologists, one cardiologist and one epidemiologist with experience in CVD risk management in RA patients, as well as two patient representatives, two health professionals and one radiologist, one rheumatology fellow and 11 rheumatologists that treat RA patients regularly contributed. Systematic literature searches were performed and the level of evidence was determined according to standard guidelines. Results: Eighteen points to consider were formulated. These were grouped into 6 categories that comprised overall CVD risk assessment and management (n = 4), and specific interventions aimed at reducing CVD risk including RA control with disease modifying anti-rheumatic drugs, glucocorticoids and non-steroidal anti-inflammatory drugs (n = 3), lipid lowering agents (n = 8), antihypertensive drugs (n = 1), low dose aspirin (n = 1) and lifestyle modification (n = 1). Each point to consider differs partially or completely from recommendations previously reported for CVD risk management in RA patients from high income populations. Currently recommended CVD risk calculators do not reliably identify South African black RA patients with very high-risk atherosclerosis as represented by carotid artery plaque presence on ultrasound. Conclusions: Our findings indicate that optimal cardiovascular risk management likely differs substantially in RA patients from low or middle income compared to high income populations. There is an urgent need for future multicentre longitudinal studies on CVD risk in black African patients with RA., The first meeting held amongst local Rheumatologists was funded by the South African Arthritis and Rheumatology Association. The studies by Professor González-Gay have been supported by grants from “Fondo de Investigaciones Sanitarias” PI06/0024, PS09/00748, PI12/00060, PI15/00525, PI18/00043, and RD12/0009/0013 and RD16/0012 (RIER) from “Instituto de Salud Carlos III” (ISCIII) (Spain), co-funded by FEDER funds

Background In younger individuals, low absolute risk of cardiovascular disease (CVD) may conceal an increased risk age and relative risk of CVD. Calculation of risk age is proposed as an adjuvant to absolute CVD risk estimation in European guidelines. We aimed to compare the discriminative ability of available risk age models in prediction of CVD in rheumatoid arthritis (RA). Secondly, we also evaluated the performance of risk age models in subgroups based on RA disease characteristics. Methods RA patients aged 30–70 years were included from an international consortium named A Trans-Atlantic Cardiovascular Consortium for Rheumatoid Arthritis (ATACC-RA). Prior CVD and diabetes mellitus were exclusion criteria. The discriminatory ability of specific risk age models was evaluated using c-statistics and their standard errors after calculating time until fatal or non-fatal CVD or last follow-up. Results A total of 1974 patients were included in the main analyses, and 144 events were observed during follow-up, the median follow-up being 5.0 years. The risk age models gave highly correlated results, demonstrating R2 values ranging from 0.87 to 0.97. However, risk age estimations differed > 5 years in 15–32% of patients. C-statistics ranged 0.68–0.72 with standard errors of approximately 0.03. Despite certain RA characteristics being associated with low c-indices, standard errors were high. Restricting analysis to European RA patients yielded similar results. Conclusions The cardiovascular risk age and vascular age models have comparable performance in predicting CVD in RA patients. The influence of RA disease characteristics on the predictive ability of these prediction models remains inconclusive.

Rheumatoid arthritis (RA) is associated with increased cardiovascular morbidity, partly due to alterations in lipoprotein quantity, quality and cell cholesterol trafficking. Although cardiovascular disease significantly contributes to mortality excess in RA, cardiovascular prevention has been largely insufficient. Because of limited evidence, optimal strategies for lipid management (LM) in RA have not been determined yet, and recommendations are largely based on expert opinions. In this position paper, we describe abnormalities in lipid metabolism in RA and introduce a new algorithm for estimation of cardiovascular risk (CVR) and LM in RA. The algorithm stratifies patients according to RA-related factors impacting CVR (such as RA activity and severity and medication) and therefore enables a more nuanced approach than other current methods. We propose strategies for monitoring of lipid parameters and treatment of dyslipidemia in RA (including lifestyle, statins and other lipid-modifying therapies, and disease modifying anti-rheumatic drugs). These opinion-based recommendations are meant to facilitate LM in RA until more evidence is available.

Objectives Smoking is a major risk factor for the development of both cardiovascular disease (CVD) and RA and may cause attenuated responses to anti-rheumatic treatments. Our aim was to compare disease activity, CVD risk factors and CVD event rates across smoking status in RA patients. Methods Disease characteristics, CVD risk factors and relevant medications were recorded in RA patients without prior CVD from 10 countries (Norway, UK, Netherlands, USA, Sweden, Greece, South Africa, Spain, Canada and Mexico). Information on CVD events was collected. Adjusted analysis of variance, logistic regression and Cox models were applied to compare RA disease activity (DAS28), CVD risk factors and event rates across categories of smoking status. Results Of the 3311 RA patients (1012 former, 887 current and 1412 never smokers), 235 experienced CVD events during a median follow-up of 3.5 years (interquartile range 2.5–6.1). At enrolment, current smokers were more likely to have moderate or high disease activity compared with former and never smokers (P Conclusion Smoking cessation in patients with RA was associated with lower disease activity and improved lipid profiles and was a predictor of reduced rates of CVD events.

Introduction: Increased cardiovascular (CV) morbidity and mortality is observed in inflammatory joint diseases (IJDs) such as rheumatoid arthritis, ankylosing spondylitis, and psoriatic arthritis. However, the management of CV disease in these conditions is far from being well established.Areas covered: This review summarizes the main epidemiologic, pathophysiological, and clinical risk factors of CV disease associated with IJDs. Less common aspects on early diagnosis and risk stratification of the CV disease in these conditions are also discussed. In Europe, the most commonly used risk algorithm in patients with IJDs is the modified SCORE index based on the revised recommendations proposed by the EULAR task force in 2017.Expert opinion: Early identification of IJD patients at high risk of CV disease is essential. It should include the use of complementary noninvasive imaging techniques. A multidisciplinary approach aimed to improve heart-healthy habits, including strict control of classic CV risk factors is crucial. Adequate management of the underlying IJD is also of main importance since the reduction of disease activity decreases the risk of CV events. Non-steroidal anti-inflammatory drugs may have a lesser harmful effect in IJD than in the general population, due to their anti-inflammatory effects along with other potential beneficial effects. MA González-Gay’s research has been supported by grants from “Fondo de Investigaciones Sanitarias” PI06/0024, PS09/00748, PI12/00060, PI15/00525,PI18/00043, and RD12/0009/0013 and RD16/0012 (RIER) from “Instituto de Salud Carlos III” (ISCIII) (Spain), co-funded by FEDER funds.

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

Rheumatoid arthritis (RA) impacts arterial and diastolic function. This study examined whether arterial properties can determine diastolic function in RA. In 173 RA patients, arterial function measures including 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 were measured using applanation tonometry. Diastolic function parameters including the ratio of early-to-late transmitral velocity (E/A) and ratio of E to the mean of the lateral and septal wall myocardial tissue lengthening (e') were measured using echocardiography. The timing of the reflected wave was associated with E/A; PWV was related to E/e'. The timing of the reflected wave, forward wave magnitude, and pulse pressure amplification were associated with impaired relaxation; PWV was related to increased left ventricular (LV) filling pressure. Early wave reflection and PWV are associated with LV-impaired relaxation and increased filling pressure, respectively, in RA.

AIM: To identify whether the more recently developed equation for estimated glomerular filtration rate (eGFR) [Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI)] is more closely associated with end-organ changes than previous equations in a group of black African descent. METHODS: In 1221 randomly recruited participants of black African ancestry in South Africa, we evaluated serum creatinine concentrations, echocardiographic left ventricular mass index (n = 833), carotid-femoral (aortic) pulse wave velocity (PWV) (n = 1053) and carotid intima-media thickness (n = 633). We calculated eGFR from the Jelliffe, five Cockcroft-Gault, Salazar-Corcoran, Modification of Diet in Renal Disease (MDRD) and CKD-EPI equations. RESULTS: After multivariate adjustments, eGFR calculated from all formulae was inversely associated with left ventricular mass index (P 0.08). However, although eGFR determined from all equations except Cockcroft-Gault lean body weight or adjusted body weight was independently associated with left ventricular hypertrophy (n = 390 of 833), CKD-EPI-derived eGFR, but not eGFR determined from alternative equations, was independently associated with an increased PWV (n = 88 of 1053). eGFR derived from the CKD-EPI and MDRD equations showed a better performance (area under the receiver operator characteristic curve) for the detection of left ventricular hypertrophy (P

Objective.We determined the performance of the Framingham score and the Systematic COronary Risk Evaluation (SCORE) in assessing high-risk atherosclerosis in patients with rheumatoid arthritis (RA).Methods.We assembled 330 cases without established cardiovascular disease (CVD), diabetes, and moderate or severe chronic kidney disease among 451 consecutive Spanish patients who underwent CVD risk screening and carotid ultrasound-determined plaque assessment. The findings were validated in 90 black and 97 white African patients.Results.When sensitivity for the Framingham score was set at 80% in receiver-operator curve analysis [area under the curve (AUC) = 0.799], the corresponding cutoff value and specificity were 7.3% and 63%, respectively. At a specificity of 80%, the cutoff value and sensitivity were 10.8% and 65%, respectively. When sensitivity for SCORE (AUC = 0.747) was set at 80%, the cutoff value and specificity were 0.5% and 58%, respectively. At a specificity of 80%, the cutoff value and sensitivity were 1.5% and 50%, respectively. Upon applying a cutoff value of 7.3% for the Framingham and 0.5% for SCORE in African white patients with RA, the corresponding sensitivities and specificities were 67% and 72%, and 67% and 55%, respectively. CVD risk equations did not discriminate between black African patients with and without plaque (AUC = 0.544 and 0.549 for Framingham score and SCORE, respectively).Conclusion.The Framingham score and SCORE at markedly low cutoff values of 7.3% to 10.8% and 0.5% to 1.5%, respectively, can usefully estimate plaque presence in RA. Effective population-specific CVD risk assessment strategies are needed in black African patients with RA.

Background Patients with rheumatic and musculoskeletal diseases (RMDs) from developed populations often experience increased atherosclerotic cardiovascular disease (ACVD) risk. In European countries, increasing proportions of inhabitants originate in developing countries and are therefore reportedly at an earlier epidemiological transition stage, which is associated with reduced ACVD.1 Objectives This study aimed to determine whether population origin specific cardiovascular risk management is indicated in Belgian patients with RMDs. Methods We recorded major conventional cardiovascular risk factors included in the Systematic Coronary Risk Evaluation (SCORE) or/and Framingham score equation, other conventional and non-conventional cardiovascular risk factor profiles and the prevalence of subclinical ACVD comprising arterial stiffness (pulse pressure >60 mmHg) and established ACVD (coronary artery disease, ischaemic cerebrovascular disease or/and peripheral artery disease) in 673 consecutive patients with RMDs; 126 and 547 were of North-African and European ancestry, respectively. Cardiovascular risk factors and disease were compared between patients of North African and European descent in multivariable logistic and linear regression models. Results Patients of North African descent tended to have less frequently inflammatory RMDs (OR (95% CI)=0.69 (0.45–1.04)) including rheumatoid arthritis (RA) (OR (95% CI)=0.46 (0.19–1.09)), and had more often fibromyalgia (OR (95% CI)=2.93 (1.84–4.65)). Patients of North African descent were younger than their European descent counterparts (mean (SD)=47.5 (14.7) vs 55.7 (16.5) years, p Conclusions Consistent disparities exist in ACVD risk factor profiles between RMD patients of North-African and European descent. However, the overall cardiovascular risk factor and disease burden is currently as large in RMD patients of North African compared to European ancestry. Adequate ACVD risk management in RMD patients should be performed irrespective of population origin. References [1] Solomon A, et al. J Rheumatol2010;37:953–60. [2]. Agca R, et al. Ann Rheum Dis 2016;0:1–12. Disclosure of Interest None declared

Background: Preventive pharmacotherapy for atherosclerotic cardiovascular disease (ACVD) is reportedly underused in patients with rheumatoid arthritis (RA). Whether this shortcoming is RA specific amongst patients with prevalent rheumatic and musculoskeletal diseases (RMD) is currently unknown. Objectives: This study aimed to compare high ACVD risk profiles and statin use by indication between RA and non-RA patients with RMD. Methods: We investigated 470 consecutive RMD patients of which 80 had RA, 92 undifferentiated inflammatory/early arthritis (UIA), 127 fibromyalgia and 171 osteoarthritis. High risk profiles comprised established ACVD (coronary artery disease, ischemic cerebrovascular disease or/and peripheral artery disease), diabetes (type 2 or type 1 aged >40 years), high LDL cholesterol concentration (≥190 mg/dl), chronic kidney disease (CKD) (Chronic Kidney Disease Epidemiology Collaboration equation value Results: RA patients were older (mean (SD) age=62.1 (15.8) versus 54.0 (15.4) years, p Conclusions: In this single center study, having one or more high ACVD risk profiles was equally prevalent in non-RA and RA patients. Circa 60% of patients with RMD and any high risk ACVD profile did not use statins and this finding did not differ in non-RA compared to RA patients. There is a vast and urgent need for improved ACVD risk management among patients with RMD irrespective of RA status. Reference [1]Agca R, et al. EULAR recommendations for cardiovascular disease risk management in patients with rheumatoid arthritis and other forms of inflammatory joint disorders: 2015/2016 update. Ann Rheum Dis2016;0:1–12. Disclosure of Interest: None declared

Background Patients with rheumatoid arthritis (RA) experience an increased risk of developing heart failure with a preserved ejection fraction. Although there is some evidence to support a role of chronic inflammation in the pathogenesis of impaired left ventricular (LV) function in RA,1 the direct effects of inflammatory cytokines on the LV function in collagen-induced arthritis (CIA) (an experimental model most similar to RA) require further elucidation. Objectives The aim of this study was to determine LV systolic and diastolic function and their association with circulating inflammatory markers in CIA. Methods Male Sprague Dawley rats were randomly divided into two groups: a control group (n=12) and a collagen-induced arthritis group (CIA, n=21). Rats in the CIA group were immunised with 0.2 ml type-II bovine collagen emulsified in incomplete Freund’s adjuvant at the base of the tail followed by a 0.1 ml booster injection 7 days later. Eight weeks post-immunisation, markers of LV systolic function and geometry including ejection fraction (EF), fractional shortening (FS), stroke volume (SV) and LV end systolic diameter (ESD) were assessed echocardiographically using two-dimensional directed M-mode imaging. Markers of LV diastolic function including the early-to-late diastolic filling velocity ratio (E/A), the lateral (Lat e’) and septal (Sep e’) wall myocardial tissue lengthening at the mitral annulus and the ratio between early mitral inflow velocity and mitral annular early diastolic velocity (E/e’) were assessed using pulsed Doppler and tissue Doppler echocardiography. Serum concentrations of interleukin 6 (IL-6), interleukin 1β (IL-1β), tumour necrosis factor alpha (TNF-α) and C-reactive protein (CRP) were determined by an enzyme-linked immunosorbent assay. Results No significant differences in markers of systolic function or geometry (EF, FS, SV and ESD) were observed between the groups (p>0.05). Compared to the control group, E/A (control=2.17±0.39; CIA=1.46±0.46; p=0.0001) and Sep e’ (control=3.75±0.69; CIA=3.23±0.47; p=0.04) were lower in the CIA group. By contrast, E/e’ (control=29.94±6.99; CIA=24.17±8.49; p=0.13) and Lat e’ (control=3.99±0.43; CIA=3.79±0.78; p=0.31) did not differ amongst the two groups. IL-6 (115±70.09 versus 365.3±88.96 pg/mL; p Conclusions Diastolic function is impaired in male Sprague Dawley rats with CIA. Our results indicate that exposure to high grade inflammation can reduce LV relaxation without impairing systolic function in CIA. Markers of inflammation were also associated with increased filling pressures in this animal model. Systemic inflammation may directly impact myocardial diastolic function in CIA. Reference [1] Liang KP, Myasoedova E, Crowson CS, et al. Increased prevalence of diastolic dysfunction in rheumatoid arthritis. Ann Rheum Dis. 2010;69:1665–1670. Disclosure of Interest 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

Cardiovascular risk age and vascular age estimations in predicting cardiovascular events in rheumatoid arthritis patients

Apelin can improve arterial function by enhancing the expression of endothelial nitric oxide synthase but this effect depends markedly on endothelial integrity. We hypothesized that inflammation influences the potential impact of apelin on arterial function in rheumatoid arthritis (RA). We assessed the associations of apelin concentrations with arterial stiffness (pulse wave velocity), wave reflection (augmentation index, reflected wave pressure, and reflection magnitude), and pressure pulsatility (central systolic pressure (CSP), central pulse pressure (CPP), peripheral pulse pressure (PPP), pulse pressure amplification (PPamp), and forward wave pressure (Pf)) among 170 RA patients without cardiovascular disease. In multivariable regression models, apelin concentrations were not independently associated with arterial function measures (p ≥ 0.15) in all patients. Inflammation markers were not consistently associated with apelin levels but joint deformity counts, Disease Activity Score in 28 joints (DAS28), and erythrocyte sedimentation rate (ESR) impacted apelin-pressure pulsatility relations (interaction p ≤ 0.05). In stratified analysis, apelin was associated with CSP (partial r = − 0.33, p = 0.01), CPP (partial r = − 0.26, p = 0.04), PPamp (partial r = 0.27, p = 0.03), and Pf (partial r = − 0.33, p = 0.01) in patients without but not with joint deformities; apelin was related to CSP (partial r = − 0.24, p = 0.05) in those with a DAS28 joint

ObjectivesPatients with rheumatoid arthritis (RA) have an excess risk of cardiovascular disease (CVD). We aimed to assess the impact of CVD risk factors, including potential sex differences, and RA-specific variables on CVD outcome in a large, international cohort of patients with RA.MethodsIn 13 rheumatology centres, data on CVD risk factors and RA characteristics were collected at baseline. CVD outcomes (myocardial infarction, angina, revascularisation, stroke, peripheral vascular disease and CVD death) were collected using standardised definitions.Results5638 patients with RA and no prior CVD were included (mean age: 55.3 (SD: 14.0) years, 76% women). During mean follow-up of 5.8 (SD: 4.4) years, 148 men and 241 women developed a CVD event (10-year cumulative incidence 20.9% and 11.1%, respectively). Men had a higher burden of CVD risk factors, including increased blood pressure, higher total cholesterol and smoking prevalence than women (all pConclusionsIn a large, international cohort of patients with RA, 30% of CVD events were attributable to RA characteristics. This finding indicates that RA characteristics play an important role in efforts to reduce CVD risk among patients with RA.

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 (β = 0.650, p

Objective.Arterial properties influence cardiovascular disease (CVD) risk. We identified potential determinants of arterial function in patients with rheumatoid arthritis (RA).Methods.Relationships of traditional cardiovascular risk factors and RA characteristics with arterial stiffness (pulse wave velocity), wave reflection (augmentation index, reflected wave pressure, and reflection magnitude), and pressure pulsatility (central systolic and pulse pressure, peripheral pulse pressure, pulse pressure amplification, and forward wave pressure) were identified in multivariable backward regression models among 177 patients without established CVD (118 white, 32 Asian, 22 black, 5 mixed ancestry).Results.Recorded characteristics explained 37% (pulse wave velocity) to 71% (reflected wave pressure) of the variability in arterial function. These factors were particularly associated with wave reflection and pressure pulsatility: RA duration (p = 0.04), rheumatoid factor status (p = 0.01 to 0.03), leukocyte counts (p = 0.02 to 0.05), and total cholesterol (p < 0.01 to 0.03). Body mass index (p < 0.01 to 0.02) and insulin resistance (p < 0.01 to 0.01) were related to reduced wave reflection and peripheral pulse pressure. Exercise (p = 0.02) and alcohol consumption (p < 0.01) were associated with increased pulse pressure amplification and decreased peripheral pulse pressure, respectively. Tumor necrosis factor-α inhibition (p < 0.01) was related to reduced pulse wave velocity, and tetracycline use (p = 0.02) to decreased peripheral pulse pressure.Conclusion.Traditional cardiovascular risk factors and disease characteristics are consistently associated with vascular hemodynamic alterations in RA. The relative effect of arterial stiffness, wave reflection, and pressure pulsatility on CVD risk in RA needs further study.

Atherosclerotic cardiovascular disease risk is increased in rheumatoid arthritis (RA). Wave reflection occurs at arterial branching points, which are particularly prone to atherosclerosis. We explored the relationship of wave reflection with atherosclerosis in RA.One hundred and sixty three RA patients (110 white, 31 Asian, 17 black and 5 of mixed ancestry) without cardiovascular disease participated. Arterial stiffness, wave reflection, pressure pulsatility, plaque in the extracranial carotid artery tree and the mean of the left and right common carotid arteries intima-thickness were determined. Associations were identified in multivariable regression models.One SD increase in reflected wave pressure (OR (95% CI) = 2.54 (1.41-4.44), p=0.001), reflection magnitude (OR (95% CI) = 1.84 (1.17-2.89), p=0.008), central pulse pressure (OR (95% CI) = 1.89 (1.12-3.22), p=0.02) and peripheral pulse pressure (OR (95% CI) = 2.09 (1.23-3.57), p=0.007) were associated with plaque. The association of wave reflection with plaque was independent of arterial stiffness and pressure pulsatility, and was present in both hypertensive and normotensive RA patients. In receiver operator characteristic curve analysis, the optimal cutoff value for reflected wave pressure in predicting plaque presence was 25 mmHg with a sensitivity, specificity, positive predictive value and negative predictive value of 45.2%, 89.3%, 78.6% and 66.2%, respectively; a reflected wave pressure of25 mmHg was associated with plaque in univariate and adjusted analysis (p0.0001 for both). Arterial function was not independently related to carotid intima-media thickness.Consideration and therapeutic targeting of wave reflection may improve cardiovascular disease prevention in RA.

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

Arterial stiffness can enhance cardiovascular risk by increasing atherogenesis or adverse hemodynamic effects. We examined whether the arterial stiffness markers of aortic pulse wave velocity (PWV) and the augmentation index (AIx) are independently associated with carotid artery intima-media thickness (IMT) and plaque in patients with rheumatoid arthritis (RA). PWV and AIx were determined by brachial oscillometry using the Mobil-O-GraphA (R) system and carotid IMT and plaque by ultrasound in 194 consecutive RA patients without established cardiovascular disease, chronic kidney disease, and diabetes at disease onset. In crude analysis, PWV was associated with IMT (beta (95% CI) = 0.04 (0.03 to 0.05), p value < 0.0001) and plaque (OR (95% CI) = 1.69 (1.40 to 2.04), p value < 0.0001). Upon adjustment for the confounders of age, sex, mean blood pressure, body height, and cardiovascular risk factors comprising smoking, the atherogenic index, and diabetes, PWV was not related to IMT (beta (95% CI) = 0.01 (-0.02 to 0.04), p value = 0.5) or plaque (OR (95% CI) = 0.99 (0.96 to 1.01), p value = 0.3). AIx was not associated with IMT in crude (beta (95% CI) = -0.002 (-0.004 to 0.007), p value = 0.2) and adjusted analyses (beta (95% CI) = -0.002 (-0.004 to 0.000), p value = 0.06). AIx was also unrelated to carotid plaque in crude (OR (95% CI) = 1.04 (0.60 to 1.82), p value = 0.9) and adjusted analyses (OR (95% CI) = 0.97 (0.94 to 1.01), p value = 0.1). PWV and AIx are not independently associated with subclinical carotid atherosclerosis in RA.

This study compared the estimated prevalence and potential determinants of left ventricular (LV) diastolic dysfunction upon applying different classification criteria in rheumatoid arthritis (RA). LV diastolic function was assessed echocardiographically by pulsed Doppler (E/A), tissue Doppler (E/e′, lateral and septal e′), and left atrial volume index in 176 RA patients. Relationships of traditional cardiovascular risk factors and RA characteristics with LV diastolic function and dysfunction according to previous and current criteria were determined in multivariate regression models. Waist-hip ratio was associated with E/A (standardised β (SE) = -0.28±0.09, p=0.0002) and lateral e′ (standardised β (SE) = 0.26±0.09, p=0.01); low diastolic blood pressure was related to E/e′ (standardised β (SE) = -0.16±0.08, p=0.04). Diastolic dysfunction prevalence differed upon applying previous (59%) compared to current (22%) criteria (p<0.0001). One SD increase in waist-hip ratio was associated with diastolic dysfunction when applying current criteria (OR = 2.61 (95% CI = 1.51–4.52), p=0.0006), whereas one SD increase in diastolic blood pressure was inversely related to diastolic dysfunction upon using previous criteria (OR = 0.57 (95% CI = 0.40–0.81), p=0.002). In conclusion, application of current and previous diastolic dysfunction criteria markedly alters the prevalence and risk factors associated with diastolic dysfunction in RA.

Item does not contain fulltext Targeted therapies in connective tissue diseases (CTDs) have led to improvements of disease-associated outcomes, but life expectancy remains lower compared to general population due to emerging co-morbidities, particularly due to excess cardiovascular risk. Cardiovascular magnetic resonance (CMR) is a noninvasive imaging technique which can provide detailed information about multiple cardiovascular pathologies without using ionizing radiation. CMR is considered the reference standard for quantitative evaluation of left and right ventricular volumes, mass and function, cardiac tissue characterization and assessment of thoracic vessels; it may also be used for the quantitative assessment of myocardial blood flow with high spatial resolution and for the evaluation of the proximal coronary arteries. These applications are of particular interest in CTDs, because of the potential of serious and variable involvement of the cardiovascular system during their course. The International Consensus Group on CMR in Rheumatology was formed in January 2012 aiming to achieve consensus among CMR and rheumatology experts in developing initial recommendations on the current state-of-the-art use of CMR in CTDs. The present report outlines the recommendations of the participating CMR and rheumatology experts with regards to: (a) indications for use of CMR in rheumatoid arthritis, the spondyloarthropathies, systemic lupus erythematosus, vasculitis of small, medium and large vessels, myositis, sarcoidosis (SRC), and scleroderma (SSc); (b) CMR protocols, terminology for reporting CMR and diagnostic CMR criteria for assessment and quantification of cardiovascular involvement in CTDs; and (c) a research agenda for the further development of this evolving field.

Background and aims Apelin-APJ signaling reduces cardiovascular disease (CVD) risk. In rheumatoid arthritis (RA), the atherosclerosis burden and plaque vulnerability to rupture are increased. We explored relationships between apelin concentrations and subclinical CVD in RA. Methods Apelin levels were measured in 235 (114 black, 121 white) RA patients. Associations between apelin concentrations and ultrasound determined carotid artery intima-media thickness (cIMT) and plaque, and levels of matrix metalloproteinase (MMP)-2 and -9 that mediate plaque stability and vulnerability respectively, were identified in confounder adjusted multivariate regression analysis. Results In all patients, apelin concentrations were directly associated with those of MMP-2 (β (SE) = 0.324 (0.112), p = 0.004) and inversely with those of MMP-9 (β (SE) = -0.239 (0.060), p = 0.000). Apelin concentration-subclinical CVD relations were influenced by population origin, RA disease activity, erythrocyte sedimentation rate (ESR) and interleukin (IL)-6 concentrations (interaction p = 0.001 to 0.04). Accordingly, the apelin-MMP-2 concentration relationship was reproduced in white (β (SE) = 0.367 (0.146), p = 0.01) but not black RA patients (β (SE) = 0.197 (0.220), p = 0.4), and only in those without (but not with) large erythrocyte sedimentation rates (β (SE) = 0.428 (0.143), p = 0.003) or interleukin-6 levels (β (SE) = 0.485 (0.288), p = 0.04). By contrast, the apelin-MMP-9 concentration relation was reproduced more consistently. Apelin levels were inversely related to cIMT in patients with RA remission or mild (β (SE) = -0.068 (0.033), p = 0.04) but not moderate or high disease activity (β (SE) = 0.015 (0.112), p = 0.7). Conclusions Apelin concentrations are associated with altered plaque stability mediator levels and atherosclerosis in patients with RA. These relations are partially dependent on population origin and systemic inflammatory status.

Omentin is an adipokine that reportedly protects against cardiometabolic risk. We investigated the relationships between omentin concentrations and subclinical cardiovascular disease in rheumatoid arthritis (RA). Omentin concentrations were measured in 213 (104 black; 109 white) RA patients. Relationships of omentin levels with those of endothelial activation markers, ultrasound determined carotid intima-media thickness and plaque, and matrix metalloproteinase (MMP)-2, -3 and -9 that mediate altered plaque stability, were identified in confounder adjusted multivariate regression models. Omentin concentrations were inversely associated with MMP-3 levels [β = -364 (0.113), p = 0.002]. This relationship was influenced by population origin, RA activity and the erythrocyte sedimentation rate and joint deformity count (interaction p value = 0.009, 0.04, 0.04 and 0.007, respectively). Accordingly, the omentin-MMP-3 concentration relationship was reproduced in white [β (SE) = -0.450 (0.153), p = 0.0004)] but not black patients [β (SE) = -0.099 (0.195), p = 0.6)], in participants with disease remission or mild disease activity [β (SE) = -0.411 (0.139), p = 0.004] but not with moderate or severe RA activity [β (SE) = -0.286 (0.202), p = 0.2], and in those with a small [β (SE) = -0.534 (0.161), p = 0.001] but not large erythrocyte sedimentation rate [-0.212 (0.168), p = 0.2] and without [β (SE) = -0.554 (0.165), p = 0.0001] but not with large joint deformity counts [-0.110 (0.173), p = 0.5]. Omentin levels were unrelated to endothelial activation and atherosclerosis. Among patients with RA, a lack of plaque stabilizing effects by omentin may contribute to the reported link between severe disease and increased cardiovascular risk. The association between concentrations of omentin and MMP-3 is population specific in RA.

Atherosclerotic cardiovascular disease (CVD) is the leading cause of death worldwide1. Although many genetic and environmental factors contribute to CVD, lipoproteins remain the pivotal agents in atherosclerosis1. Patients with rheumatoid arthritis (RA) experience a 2- to 3-fold increased risk for atherosclerotic CVD, a phenomenon that is likely attributable to unfavorable effects of cytokine-mediated high-grade inflammation on traditional risk factors such as insulin sensitivity and its direct adverse effects on the vasculature2. The ameliorations in traditional CV risk factor profiles3–5 and interleukin 6-related endothelial dysfunction6 upon disease activity suppression in RA support this paradigm. Considering the fundamental role of dyslipidemia in atherosclerosis in non-RA subjects prompts the question whether RA characteristics alter lipoprotein profiles. Such potential interactions have been the topic of numerous studies performed over the past 3 to 4 decades. As applies to other inflammatory conditions7, high-grade inflammation or disease activity in the context of RA results in a reduction in total and low-density lipoprotein (LDL) cholesterol and a more consistent and marked decrease in high-density lipoprotein (HDL) cholesterol, thereby increasing the atherogenic index, i.e., the total cholesterol/HDL cholesterol ratio3,4. Treatment with traditional disease modifying agents for rheumatic disease (DMARD) and glucocorticoids reverses these changes3,4, an effect that may be less consistent with tumor necrosis factor-α blockade8. The increase in total and LDL cholesterol with traditional DMARD therapy can be prevented by insulin sensitivity-enhancing dietary intervention3. Currently recommended treatment strategies generally comprise aggressive use of DMARD as soon as the disease is diagnosed. As a consequence, the typical RA patients may now no longer experience high-grade inflammation-induced dyslipidemia except during the time prior to seeking medical care. In this new era, then, do lipoprotein profiles … Address correspondence to Dr. P. Dessein, PO Box 1012, Melville 2109, Johannesburg, South Africa. E-mail: dessein{at}telkomsa.net

AIM To determine whether high-quality nurse-recorded auscultatory blood pressure (BP) values obtained at a single visit predict cardiovascular target organ changes as closely as ambulatory BP measurements. METHODS In a randomly selected population sample (n = 458, 21% receiving antihypertensive treatment; approximately 40% hypertensive), we compared high-quality single visit nurse-recorded auscultatory BP values to same-day 24-h ambulatory BP in their ability to predict multiple target organ changes [left ventricular mass index (LVMI), left ventricle (LV) mean wall thickness (MWT), early-to-late transmitral velocity ratios (E/A), (echocardiography); log of urinary albumin-to-creatinine ratios (log ACR) (24-h urine samples); large artery dysfunction [carotid-femoral pulse wave velocity (PWV) and central augmentation index (Alc) (applanation tonometry)]. RESULTS Nurse-recorded systolic BP (SBP) measurements obtained at a single visit were as closely associated with LVMI (r = 0.44), LV MWT (r = 0.44), E/A (r = -0.55), log ACR (r = 0.20), PWV (r = 0.62) and AIc (r = 0.41) (P < 0.0001 for all relations) as was 24-h SBP (LVMI; r = 0.33, LV MWT; r = 0.37, E/A; r = -0.35, log ACR; r = 0.24, PWV; r = 0.41, and AIc; r = 0.18, P < 0.001 for all relations) and either day or night SBP. On multivariate regression analysis with both nurse-recorded SBP and 24-h SBP in the same model, nurse-recorded SBP was independently associated with LVMI (P = 0.006), LV MWT (P = 0.03), E/A (P < 0.02), PWV (P < 0.0001) and AIc (P = 0.0002), and 24-h SBP was independently and positively associated with log ACR (P < 0.005), and PWV (P = 0.01). CONCLUSION One or more, high-quality single visit nurse-recorded auscultatory BP measurements may be equally as effective as ambulatory BP in predicting target organ damage in a population sample of African ancestry.

The metabolic syndrome is a cluster of cardiovascular risk factors that are of metabolic origin and include atherogenic dyslipidemia, hypertension and hyperglycemia. This syndrome is generally considered to develop as a consequence of excess adiposity- mediated insulin resistance. In rheumatoid arthritis (RA), apart from excess adiposity, high-grade inflammation, routine glucocorticoid use and subclinical hypothyroidism are further implicated in insulin resistance. Several more recently uncovered metabolic risk factors including microalbuminuria, hypercoagulability, autonomic dysfunction, hyperuricemia, renin–angiotensin activation and raised aminotransferase concentrations prior to methotrexate use are also more prevalent in RA subjects as compared with non-RA subjects, linked to other metabolic syndrome components and/or related to RA characteristics. Suppression of RA disease activity improves metabolic cardiovascular risk. Systemic inflammation, glucocorticoid therapy, hypothyroidism, insulin resistan...

BACKGROUND We aimed to clarify whether age influences the independent relationship between adiposity and pulse-wave velocity (PWV). METHODS We explored the effect of age on the independent relationships between indexes of central adiposity (waist circumference (WC) and waist-to-hip ratio (WHR)) and carotid-femoral PWV, central augmentation index (AIc), or pressure wave amplification assessed from applanation tonometry measurements obtained at the radial, carotid, and femoral arteries in 508 randomly selected subjects >16 years of age in a population sample of African ancestry with a high prevalence of excess adiposity ( approximately 63% overweight or obese). RESULTS In women a strong interaction between age and either WC or WHR was associated with logPWV independent of confounders and the individual terms (r = 0.68, P < 0.0001). This translated into a markedly greater increase in logPWV with increases in either WC or WHR in women older than the median age as compared to women younger (slopes of WC-logPWV relationships = 0.0031 +/- 0.0009 vs. -0.0007 +/- 0.0007, P < 0.002). In women older than the median age for the group, a one s.d. increase in WC (12.8 cm) translated into a 0.70 m/s increase in PWV as compared to a 0.14 m/s decrease in PWV for each one s.d. increase in WC (13.0 cm) in women younger than the median age (P < 0.001). No index of adiposity was independently associated with the log of AIc or aortic-brachial wave amplification. CONCLUSION In women of African ancestry, a greater independent effect of adiposity on PWV is noted in older as compared to younger women.

Our objective was to examine associations of traditional and non-traditional cardiovascular risk factors with relative leukocyte telomere length and confounder adjusted relationships of relative telomere length with endothelial activation and carotid atherosclerosis in black and white African patients with rheumatoid arthritis (RA).Relative telomere length of leukocyte DNA in whole blood was determined using quantitative RT-PCR in 205 (101 black) African patients with RA.In demographic characteristic adjusted analysis, relative telomere length tended to be larger in black compared to white patients (median (IQR)=0.54 (0.42-0.54) and 0.48 (0.37-0.60) (p=0.07), respectively). In black patients, waist circumference, systolic, diastolic and mean blood pressure were associated with relative telomere length (β (SE)=-0.00270 (0.00114) (p=0.02), -0.00185 (0.00060) (p=0.003), -0.00243 (0.00112) (p=0.03) and -0.00225 (0.00075) (p=0.003), respectively); in white patients, age, anti-cyclic citrullinated antibody positivity, biologic agent use, a cholesterol-HDL cholesterol ratio of4 and the number of major traditional risk factors were related to relative telomere length (β (SE) =-0.00242 (0.00113) (p=0.03), 0.06629 (0.03374) (p=0.05), -0.09321 (0.04310) (p=0.03), 0.08225 (0.03420) (p=0.02) and 0.04046 (0.01719) (p=0.02), respectively). One SD increase in relative telomere length was associated with carotid plaque (OR (95% CI)=1.65 (0.99-2.75) (p=0.05)) and vascular cell adhesion molecule-1 concentrations (β (SE)=-0.05031 (0.02480) (p=0.04)) in black and white patients, respectively.This study disclosed paradoxically direct relationships between relative telomere length and cardiovascular risk factors in white and atherosclerosis in black African RA patients. The role of relative telomere length in cardiovascular risk and its stratification in RA requires longitudinal investigation.

The increased risk of cardiovascular disease (CVD) in rheumatoid arthritis (RA) has been recognized for many years. However, although the characteristics of CVD and its burden resemble those in diabetes, the focus on cardiovascular (CV) prevention in RA has lagged behind, both in the clinical and research settings. Similar to diabetes, the clinical picture of CVD in RA may be atypical, even asymptomatic. Therefore, a proactive screening for subclinical CVD in RA is warranted. Because of the lack of clinical trials, the ideal CVD prevention (CVP) in RA has not yet been defined. In this article, we focus on challenges and controversies in the CVP in RA (such as thresholds for statin therapy), and propose recommendations based on the current evidence. Due to the significant contribution of non-traditional, RA-related CV risk factors, the CV risk calculators developed for the general population underestimate the true risk in RA. Thus, there is an enormous need to develop adequate CV risk stratification tools and to identify the optimal CVP strategies in RA. While awaiting results from randomized controlled trials in RA, clinicians are largely dependent on the use of common sense, and extrapolation of data from studies on other patient populations. The CVP in RA should be based on an individualized evaluation of a broad spectrum of risk factors, and include: 1) reduction of inflammation, preferably with drugs decreasing CV risk, 2) management of factors associated with increased CV risk (e.g., smoking, hypertension, hyperglycemia, dyslipidemia, kidney disease, depression, periodontitis, hypothyroidism, vitamin D deficiency and sleep apnea), and promotion of healthy life style (smoking cessation, healthy diet, adjusted physical activity, stress management, weight control), 3) aspirin and influenza and pneumococcus vaccines according to current guidelines, and 4) limiting use of drugs that increase CV risk. Rheumatologists should take responsibility for the education of health care providers and RA patients regarding CVP in RA. It is immensely important to incorporate CV outcomes in testing of anti-rheumatic drugs.