International Journal of Cardiology 172 (2014) e116–e118

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Letter to the Editor

High BNP levels in rheumatoid arthritis are related to inflammation but not to left ventricular abnormalities: A prospective case–control study Jacob George a, G. Mackle a, A. Manoharan a, F. Khan b, A.D. Struthers a,⁎ a b

Centre for Cardiovascular & Lung Biology, Division of Medical Sciences, Mailbox 2, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK Institute of Cardiovascular Research, Vascular & Inflammatory Diseases Research Unit, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK

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Article history: Received 7 October 2013 Accepted 22 December 2013 Available online 5 January 2014 Keywords: Rheumatoid arthritis Brain natriuretic peptide Inflammation Left ventricular hypertrophy

Rheumatoid arthritis (RA) is the most common autoimmune condition in the developed world with a prevalence of between 0.5 and 1% [1]. It is becoming increasingly apparent that patients with RA have a significantly higher risk of cardiovascular (CV) disease than the general population [2]. However, despite advances in the treatment of RA, CV risk remains high even in treated patients and the increased mortality seen in RA patients compared with the normal population is primarily driven by excess CV deaths [3]. B-type natriuretic peptide (BNP) is now established in the diagnosis of heart failure but newer evidence also points to a role for BNP in diagnosing myocardial ischemia in asymptomatic primary prevention patients [4]. BNP has been previously shown to be raised in RA but the cause of this has hitherto remained unknown. Possible causes for a raised BNP include LV abnormalities such as LV Hypertrophy (LVH) and vascular inflammation resulting in coronary ischemia. The three prior studies which have examined the relationship between LV mass and RA have produced differing results [5–7]. Patients with a clinical diagnosis of seropositive RA attending specialist rheumatology clinics at a tertiary referral centre were studied. Age and sex matched healthy controls were also recruited. Ethical approval was obtained from the Tayside Committee of Medical Research Ethics. All subjects gave written informed consent to participate in the study, which was conducted in accordance with the Declaration of

⁎ Corresponding author at: Division of Medicine and Therapeutics, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK. Tel.: +44 1382 632180; fax: +44 1382 644972. E-mail address: [email protected] (A.D. Struthers). 0167-5273/$ – see front matter © 2014 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ijcard.2013.12.119

Helsinki. Exclusion criteria included previous history of CVD, diabetes mellitus, uncontrolled hypertension or hypercholesterolemia and any other inflammatory conditions. Clinical evaluation including clinical history, examination, 12-lead ECG, office blood pressure, 24-hour ambulatory blood pressure monitoring (ABPM), transthoracic echocardiography, Disease Activity Score (DAS-28) [8] and the Stanford Global Health Assessment Questionnaire (HAQ) scores were performed. Blood samples for BNP and high-sensitivity CRP (hs-CRP) were also taken. 59 patients with RA were included in the data analysis. 78% (n = 46) were females and the mean age of the cohort was 60.9 (±8.7) years. 28.8% and 30.5% had a past history of hypertension and hypercholesterolemia respectively. The average duration of RA was 15.1 ± 10.7 years. We also recruited 34 healthy age-matched individuals (17 males, 17 females) as a reference cohort. Treatment and demographic characteristics for RA patients and for the healthy volunteer cohort are shown in Table 1. Mean B-type natriuretic peptide (BNP) was significantly higher in patients with RA than HV (mean log BNP 1.72 ± 0.42 vs 1.41 ± 0.29, p b 0.001) but we found no difference in BNP levels between RA patients with LVH and those without LVH. BNP was significantly correlated with hs-CRP in the RA cohort (r = 0.317, p = 0.015). LV ejection fraction was preserved in RA and HV cohorts with no significant difference between them (p = 0.88). Despite more history of hypertension in the RA cohort, there was no difference in left ventricular mass index (LVMI), a measure of LVH corrected for body surface area, between the RA cohort and healthy volunteers (Fig. 1). There was no difference in ABPM measurements between RA and HV patients. Within the RA cohort in a multiple regression analysis, only hs-CRP (p b 0.01) showed a significant beta coefficient (0.33, p = 0.005) when corrected for office blood pressure. LVMI was lower in patients taking anti-TNFα therapy (81.9 ± 30.6 versus 91.4 ± 23.5 in those not on biologic therapy), this difference did not achieve statistical significance (p = 0.197). This present study has confirmed that BNP is significantly raised in patients with RA, which is consistent with previously published studies. In addition to this, we have now shown for the first time that this significant rise in BNP occurs despite similar LV mass and function to age- and blood pressure-matched healthy volunteers. Furthermore, RA patients with LVH had similar BNP levels to those without LVH suggesting that LVH is not a driver of the raised BNP seen in these patients. One possible explanation for the rise in BNP from our

J. George et al. / International Journal of Cardiology 172 (2014) e116–e118 Table 1 Baseline characteristics for RA patients and reference healthy volunteer group. Variable

RA

HV

Sex (M/F) Age (y) BMI (kg/m2) Biologic agents (%) Methotrexate (%) % NSAIDs Mean hs-CRP (mg/L) Smokers (current/ex/non) Past history hypertension (%) Mean 24-hour systolic bp (mm Hg)a Mean 24-hour diastolic bp (mm Hg)a Mean office systolic bp (mm Hg) Mean office diastolic bp (mm Hg) Log B-type natriuretic peptide LV ejection fraction (%) HAQ score DAS-28 (hs-CRP) score

13/46 60.9 (8.7) 28.3 (8.8) 15 (25.4) 49 (83.1) 24 (40.7) 12.2 (18.6) 8/28/24 17 (28) 121 (17) 71 (8) 140 (17) 80 (9) 1.72 (0.42) 67.6 (9.2) 1.45 (0.74) 3.91 (1.25)

17/17 59.3 (11.0) 27.11 – – – – 2/12/17 3 (9.1) 118 (9) 73 (7) 129 (12) 76 (8) 1.41 (0.29) 68.0 (12.6) – –

p 0.24 0.32 – – – – b0.001 0.67 0.28 0.01 0.03 b0.0001 0.88 – –

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activation of a broad variety of hypertrophy signalling kinases and transcription factors [9]. Reactive oxygen species appear to mediate the hypertrophic response to other known hypertrophic stimuli such as the anti-apoptotic Mitogen Activated Protein (MAP) Kinase pathway [10]. Despite the limitation of a small cohort size, this is a signal for the need for a much larger trial to study the relationship between vascular inflammation and possible triggers for BNP release in these patients such as myocardial ischemia. The major strength of this study is that age and 24-hour ambulatory blood pressure were identical between RA patients and controls. This is seldom achievable but important since LV mass is mainly related to age and BP in populations. In conclusion, high BNP in patients with RA patients may be related to vascular inflammation rather than LVH. There is a significant and clinically relevant relationship between inflammation as measured by hs-CRP and BNP. Future studies should assess whether identifying raised BNP in patients with RA and aggressively managing their CV risk factors or their inflammation will reduce CV mortality in these patients.

All values are Mean (SD) unless stated otherwise. a All blood pressures are 24-hour mean.

Fig. 1. Left Ventricular mass Index comparisons between Rheumatoid Arthritis patients (RA) and healthy Volunteers (HV).

data could be the significant correlation between inflammation as measured by hs-CRP and BNP levels which would indicate the possibility that vascular inflammation increases either macrovascular or microvascular ischemia in the heart which therefore results in a rise in BNP. A previous study reporting higher LV mass in RA was conducted in younger patients [7] whereas both the studies showing reduced LV mass [5,6] were in patients with a comparable age to our cohort. As reported in these latter studies, there remains the possibility of sequential change in LV mass in longstanding RA from myocardial hypertrophy to myocardial wasting [5,6]. Finally, another finding of this study is that although LV mass in RA patients was not significantly different to that seen in healthy volunteers, there remains a significant relationship between hs-CRP levels and LVMI in patients with RA. There are plausible pathophysiological reasons as to why this relationship between inflammation and LV mass may be true. Recent evidence have shown that LV mass is directly related to levels of inflammation and oxidative stress (OS) due to

Acknowledgements This study was funded by a grant from the Anonymous Trust. References [1] Helmick CG, Felson DT, Lawrence RC, et al. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part I. Arthritis Rheum 2008;58(1):15–25. [2] Kitas GD, Gabriel SE. Cardiovascular disease in rheumatoid arthritis: state of the art and future perspectives. Ann Rheum Dis 2011;70(1):8–14. [3] Avina-Zubieta JA, Choi HK, Sadatsafavi M, Etminan M, Esdaile JM, Lacaille D. Risk of cardiovascular mortality in patients with rheumatoid arthritis: a meta-analysis of observational studies. Arthritis Rheum 2008;59(12):1690–7. [4] Nadir MA, Rekhraj S, Wei L, et al. Improving the primary prevention of cardiovascular events by using biomarkers to identify individuals with silent heart disease. J Am Coll Cardiol 2012;60(11):960–8. [5] Giles JT, Malayeri AA, Fernandes V, et al. Left ventricular structure and function in patients with rheumatoid arthritis, as assessed by cardiac magnetic resonance imaging. Arthritis Rheum 2010;62(4):940–51.

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[6] Liang KP, Myasoedova E, Crowson CS, et al. Increased prevalence of diastolic dysfunction in rheumatoid arthritis. Ann Rheum Dis 2010;69(9):1665–70. [7] Rudominer RL, Roman MJ, Devereux RB, et al. Independent association of rheumatoid arthritis with increased left ventricular mass but not with reduced ejection fraction. Arthritis Rheum 2009;60(1):22–9. [8] Wells G, Becker JC, Teng J, et al. Validation of the 28-joint Disease Activity Score (DAS28) and European League Against Rheumatism response criteria based on

C-reactive protein against disease progression in patients with rheumatoid arthritis, and comparison with the DAS28 based on erythrocyte sedimentation rate. Ann Rheum Dis 2009;68(6):954–60. [9] Takimoto E, Kass DA. Role of oxidative stress in cardiac hypertrophy and remodeling. Hypertension 2007;49(2):241–8. [10] Tanaka K, Honda M, Takabatake T. Redox regulation of MAPK pathways and cardiac hypertrophy in adult rat cardiac myocyte. J Am Coll Cardiol 2001;37(2):676–85.

High BNP levels in rheumatoid arthritis are related to inflammation but not to left ventricular abnormalities: a prospective case-control study.

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