Rheumatology Advance Access published July 4, 2014

RHEUMATOLOGY

Original article

284

doi:10.1093/rheumatology/keu256

In active juvenile dermatomyositis, elevated eotaxin and MCP-1 and cholesterol levels in the upper normal range are associated with cardiac dysfunction Thomas Schwartz1,2,3, Ivar Sjaastad1,2,3,4, Berit Flatø3,5, Maria Vistnes1,2, Geir Christensen1,2,3 and Helga Sanner5 Abstract

Results. In patients, but not in controls, eotaxin and monocyte chemoattractant protein 1 (MCP-1) correlated with systolic (r = 0.65 and r = 0.45) and diastolic (r = 0.59 and r = 0.65) function, particularly in those with active disease (systolic function, r = 0.74 and r = 0.60; diastolic function, r = 0.69 and r = 0.80). Total cholesterol level was lower in patients than controls [mean 4.19 mmol/l (S.D. 0.82) vs 4.60 (0.87), P 4 0.01]. However, total cholesterol levels in the upper normal range were associated with systolic (r = 0.56, P < 0.01) and diastolic (r = 0.64, P < 0.001) dysfunction and with high eotaxin and MCP-1 (r = 0.56 and r = 0.50, P < 0.01) in patients with active disease, but not in those with inactive disease or in controls (all r < ±0.2). Conclusion. In the active disease state of JDM, eotaxin and MCP-1 were associated with cardiac dysfunction, possibly through sustained inflammation. In those with active disease and cholesterol levels in the upper normal range, eotaxin and MCP-1 might enhance susceptibility to cardiac dysfunction. Key words: paediatric/juvenile rheumatology, myositis and muscle disease, cytokines and inflammatory mediators, cardiovascular, vasculitis.

Introduction JDM is a rare systemic CTD in childhood. It is characterized by inflammation and vasculopathy of small vessels in skeletal muscles, skin and internal organs [1, 2]. The use

1 Institute for Experimental Medical Research, Oslo University Hospital–Ulleva˚l, 2KG Jebsen Cardiac Research Center and Center for Heart Failure Research, 3Institute for Clinical Medicine, University of Oslo, 4Department of Cardiology, Oslo University Hospital–Ulleva˚l and 5 Section of Rheumatology, Oslo University Hospital–Rikshospitalet, Oslo, Norway

Submitted 9 September 2013; revised version accepted 1 May 2014. Correspondence to: Thomas Schwartz, Institute for Experimental Medical Research, Oslo University Hospital, 0407 Oslo, Norway. E-mail: [email protected]

of corticosteroids has substantially decreased the mortality of JDM, from >30% to 48 pg/ml, respectively). Total cholesterol (TC), high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, triglycerides and lipoprotein A were analysed and HDL:LDL and TC:HDL ratios [28] were calculated. The serum samples were collected from non-fasting patients and controls.

Echocardiography Two-dimensional M-mode and Doppler echocardiography was performed by an experienced investigator (I.S.) with a Vivid 7 ultrasound scanner (GE Vingmed Ultrasound, Horten, Norway) [29, 30]. A minimum of three cardiac cycles were recorded, analysed and averaged. The echocardiographic data were analysed blinded to clinical information and to patient/control identity (T.S.). Mitral annulus (MA) displacement was assessed by anatomical M-mode in the lateral and septal position using the four-chamber apical view. LV length was assessed as the distance from the endocardial border of the apex to the midportion of the MA plane. Long-axis strain was calculated as MA displacement as a percentage of LV end-diastolic length, as previously described in detail [21]. Low long-axis strain is associated with systolic dysfunction. Colour-coded tissue Doppler was performed in 53 patients and 53 controls, with a frame rate of 180. We used sample volumes from MA in the lateral and septal position in four-chamber view and two corresponding positions in two-chamber view. Early diastolic transmitral flow (E) and early diastolic tissue velocity (e0 ). Both high E/e0 [31] and

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cholesterol levels in RA were observed in a controlled study of 93 patients in 1991 [14]. Indeed, increased atherosclerotic burden in rheumatic diseases has been well documented [15], which may seem like a paradox [16]. Patients with rheumatic diseases have increased susceptibility to atherosclerotic disease despite cholesterol levels in the normal range. Impaired lipid metabolism in JDM has also been reported [17, 18]. Lipodystrophy is associated with impaired lipid metabolism and is a known complication of the disease, reported in 17–40% of cases [19, 20]. An uncontrolled study showed elevated triglycerides and insulin resistance in 50% of 20 JDM patients with a median disease duration of 2.5 years (range 0–13) [17]. We have recently shown systolic and diastolic cardiac dysfunction [21, 22] and higher serum levels of eotaxin and MCP-1 [23] in JDM after long-term follow-up. However, no studies have previously addressed the impact of circulating lipid and cytokine levels on cardiac function in patients with myositis. In this study we assessed lipid levels in patients compared with sex- and age-matched controls and in patients with active vs inactive disease. Since the mechanism of cardiac affection in JDM remains unknown, we wanted to study the significance of interactions between cytokines, lipid parameters and inflammation in the development of cardiac dysfunction.

Eotaxin, MCP-1, cholesterol and cardiac dysfunction in JDM

low e0 are commonly used parameters reflecting LV diastolic dysfunction [32]. In our calculations we used e0 alone, thus when using the term diastolic function we are referring to this.

Statistical analysis

Results Characteristics, cardiovascular parameters and chemokine levels in patients and controls As previously shown [23], MCP-1, IP-10 and eotaxin were elevated in patients compared with controls (P = 0.006, P = 0.026 and P = 0.039, respectively), but no differences in cytokine level were seen between JDM active and inactive patients. Patients with JDM had lower long-axis strain and e0 than matched controls, whereas no differences were seen in blood pressure or ejection fraction (Table 1). HDL, LDL and TC were all lower, while the TC:HDL ratio and triglycerides were higher in patients than in controls. Lipoprotein A and the HDL:LDL ratio as well as BMI were comparable in patients and controls. Between JDM active and JDM inactive patients, none of these parameters differed. Lipodystrophy was clinically present in 10 patients (18%), 7 JDM active and 3 JDM inactive

TABLE 1 Age, cardiovascular parameters and chemokines in JDM patients with active and inactive disease and in controls JDM patients Controls (n = 54) Characteristics

Active (n = 28)

Inactive (n = 26)

Total (n = 54)

Age, median (range), years BMI, kg/m2 Long-axis strain, % e0 , cm/s BP systolic, mmHg BP diastolic, mmHg LVEFa, %) TC, mmol/l HDL, mmol/l LDL, mmol/l HDL:LDL ratio TC:HDL ratio Lipoprotein A, mg/l Glucose TG, mmol/l MCP-1, pg/ml Eotaxin, pg/ml IP-10, pg/ml

21.5 (6.7–55.4) 21.7 (5.1) 16.6 (2.7) 10.9 (2.9) 123 (25.7) 72 (15.3) 64.2 (5.0) 4.37 (0.77) 1.20 (0.30) 2.34 (0.65) 0.48 (0.19) 4.04 (2.01) 311 (242) 5.14 (0.81) 1.32 (1.00) 35.5 (19.9) 150 (118) 1597 (1631)

23.5 (7.8–43.3) 22.4 (4.4) 16.3 (2.5) 11.5 (2.6) 112 (18.8) 67 (11.5) 63.3 (5.2) 4.00 (0.85) 1.14 (0.35) 2.23 (0.78) 0.57 (0.27) 3.80 (1.90) 343 (220) 5.10 (0.92) 1.57 (1.72) 33.8 (24.2) 133 (90.1) 1361 (877)

25.0 (6.7–55.4) 22.0 (4.7) 16.5 (2.6) 11.2 (2.7) 118 (23.1) 70 (13.7) 63.8 (5.1) 4.19 (0.82) 1.17 (0.32) 2.29 (0.70) 0.52 (0.23) 3.92 (1.94) 327 (230) 5.12 (0.86) 1.45 (1.41) 34.7 (21.9) 141 (105) 1484 (1316)

25.0 (6.2–55.4) 22.4 (4.4) 17.7 (2.0)** 12.6 (2.1)** 112 (13.5) 67 (8.9) 62.2 (5.6) 4.60 (0.87)* 1.46 (0.38)** 2.68 (0.77) 0.59 (0.27) 3.32 (1.24)* 391 (376) 4.9 (0.66) 0.97 (0.57)* 25.3 (11.4)** 109 (63.6)* 1036 (475)*

Values are mean (S.D.) unless stated otherwise; n = 54 patients and 54 controls except footnote a. an = 48 pairs due to difficulties with data acquisition when measuring left ventricular ejection fraction (LVEF). Long-axis strain (parameter of systolic function): mitral annulus displacement as a percentage of end-diastolic left ventricular length; e0 (parameter of diastolic function): early diastolic tissue velocity; BP: blood pressure; TC: total cholesterol; HDL: high-density lipoprotein cholesterol; LDL: low-density lipoprotein cholesterol; TG: triglycerides; MCP: monocyte chemoattractant protein; IP: interferon-inducible protein. No parameters were significantly different between patients with active and inactive disease. *P < 0.05, and **P < 0.01 when comparing patients and controls.

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Paired and unpaired sample t-tests were used in comparisons between patients and matched controls and between patient groups, respectively, for normally distributed continuous variables. Two-tailed tests were used for all calculations except for comparisons where a priori patients based on the literature were likely not to have lower values than controls. P-values