Systemic sclerosis is an independent risk factor for increased coronary artery calcium deposition.код для вставкиСкачать
ARTHRITIS & RHEUMATISM Vol. 63, No. 5, May 2011, pp 1387–1395 DOI 10.1002/art.30283 © 2011, American College of Rheumatology Systemic Sclerosis Is an Independent Risk Factor for Increased Coronary Artery Calcium Deposition Mo Yin Mok, Chak Sing Lau, Sonny Sau Hin Chiu, Annette Wai Kwan Tso, Yi Lo, Lawrence Siu Chun Law, Ka Fung Mak, Woon Sing Wong, Peh Lan Khong, and Karen Siu Ling Lam protein cholesterol levels (P ⴝ 0.01), diastolic blood pressure, waist circumference, and body mass index and were more likely to be receiving vasodilators (all P < 0.001). There was a significantly higher proportion of SSc patients among subjects with more severe coronary calcification (CACS >101) compared to those with lesser severity (CACS <100) (56.5% versus 29.4%; P ⴝ 0.01). Multiple logistic regression analysis revealed SSc to be an independent determinant for a CACS >101 (OR 10.89 [95% CI 2.21–53.75], P ⴝ 0.003) together with age and LDL cholesterol level after adjustment for other cardiovascular risk factors. Among diseasespecific factors, only disease duration (OR 1.14 [95% CI 1.02–1.27], P ⴝ 0.02) was independently associated with more severe coronary calcification (CACS >101). Conclusion. Our findings indicate that SSc is an independent risk factor for coronary calcification, in addition to the conventional risk factors for coronary atherosclerosis, such as age and hypertension. Objective. Endothelial dysfunction and inflammation are pathogenic mechanisms common to systemic sclerosis (SSc) and atherosclerosis. This study was undertaken to examine the relationship between coronary atherosclerosis, as assessed by the coronary artery calcium score (CACS), and conventional cardiovascular and disease-specific risk factors in SSc patients. Methods. The CACS was measured by computed tomography, and cardiovascular risk factors were examined in SSc patients and compared with controls matched for age, sex, and glycemic status. Disease activity score, antiphospholipid antibodies, highsensitivity C-reactive protein level, and erythrocyte sedimentation rate were measured in SSc patients. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were determined. Results. We recruited 53 SSc patients (50 women and 3 men) and 106 controls. The patients had a mean ⴞ SD age of 53.1 ⴞ 12.9 years and a median disease duration of 9 years. Compared to controls, SSc patients had significantly lower low-density lipoprotein (LDL) cholesterol levels (P ⴝ 0.001), high-density lipo- Systemic sclerosis (SSc) is a connective tissue disease that is characterized by Raynaud’s phenomenon (RP), sclerodermatous skin changes, and internal organ fibrosis. In addition to inflammatory cell activation and fibroblast hypertrophy (1), endothelial dysfunction has been suggested to be a pivotal pathogenic mechanism in this condition (2). Endothelial dysfunction is also recognized as an early marker of atherosclerosis (3). Increased cardiovascular risks have been described in patients with rheumatic diseases, including rheumatoid arthritis and systemic lupus erythematosus, secondary to both conventional cardiovascular risk factors and the underlying inflammatory processes (4). Since inflammation and endothelial dysfunction are implicated in the initiation and progression of atherosclerosis (3), it is likely that SSc patients are predisposed to the development of macrovascular disease. Unlike microvascular Supported by the Hong Kong Arthritis and Rheumatism Foundation Research Fund. Mo Yin Mok, MD, FRCP, FRCPA, Chak Sing Lau, MB, MD, FRCP, Sonny Sau Hin Chiu, FRCR, Annette Wai Kwan Tso, MBBChir, MRCP, FRCP, FHKCP, FHKAM, Yi Lo, MBChB, Lawrence Siu Chun Law, BSc, Ka Fung Mak, FRCR, Woon Sing Wong, FRCP, Peh Lan Khong, MD, FRCR, Karen Siu Ling Lam, MD, FRCP, FRACP: Queen Mary Hospital and University of Hong Kong, Hong Kong. Dr. Lau has received consulting fees, speaking fees, and/or honoraria from Merck Sharpe & Dohme, Roche, Pfizer, Novartis, Johnson & Johnson, and Aspreva (less than $10,000 each). Address correspondence to Mo Yin Mok, MD, FRCP, FRCPA, Division of Rheumatology and Clinical Immunology, Queen Mary Hospital, The University of Hong Kong, Pokfulam Road, Hong Kong. E-mail: firstname.lastname@example.org. Submitted for publication October 2, 2010; accepted in revised form January 27, 2011. 1387 1388 MOK ET AL disease, this has not been studied extensively. Impaired coronary artery reserve has previously been demonstrated in SSc patients by noninvasive imaging techniques (5–7). Studies published a few decades ago suggested an underlying microvascular disease of the myocardium, based on normal findings on coronary angiogram (8) and the absence of coronary atherosclerosis upon histologic examination at autopsy (9–12). However, clinical and subclinical coronary artery disease (CAD) is increasingly reported in SSc patients (13–15), although the prevalence of coronary atherosclerosis and the predisposing factors in SSc patients remain unknown. In this study, we sought to examine our hypothesis that SSc patients are more predisposed to coronary atherosclerosis than controls and to determine the conventional and disease-specific risk factors in these patients. We studied the coronary artery calcium score (CACS), measured by computed tomography (CT) scan in our SSc patients, as compared with age- and sexmatched controls. Patients and controls were also stringently matched for their glycemic status, since diabetes mellitus (DM) is known to be a strong risk factor for CAD and is regarded as a CAD equivalent in the updated guidelines of the National Cholesterol Education Program, with increased 10-year risk of CAD (16). PATIENTS AND METHODS Patients and controls. This study was approved by the Institutional Review Board of The University of Hong Kong/ Hospital Authority Hong Kong West Cluster. Written consent was obtained from all participating subjects according to the Declaration of Helsinki. Consecutive SSc patients were recruited from the university-affiliated rheumatology clinic. Controls matched for age, sex, and glycemic status were recruited from among subjects in a community-based 10-year prospective study of the development of type 2 DM (17) and were enrolled in the present study at a 2:1 ratio to SSc patients. SSc was designated as limited cutaneous SSc (lcSSc) or diffuse cutaneous SSc (dcSSc) based on the extent of skin involvement according to the method described by LeRoy et al (1). Limited cutaneous disease was defined as skin thickness confined to areas of the extremities below the elbows and knees. Diffuse cutaneous disease was defined as skin thickness involving the proximal extremities or the trunk below the clavicles. Disease duration was measured from the onset of the first non-RP manifestations. Baseline demographic features, clinical features, and medications were documented. Pulmonary involvement was defined as ⬍80% predicted of one or more of the parameters on lung function, including total lung capacity, forced vital capacity, and diffusing capacity for carbon monoxide. Elevated pulmonary artery pressure (PAP) was defined as a reading of ⬎35 mm Hg on at least 2 occasions, as measured by Doppler echocardiography. Gastrointestinal in- volvement included clinical dysphagia, reflux esophagitis requiring the use of proton-pump inhibitors, or small bowel bacterial overgrowth. Evaluation of conventional cardiovascular risk factors. History of peripheral vascular disease, CAD, cerebrovascular disease, and angina symptoms was recorded. Smoking status included current and former smoking. Venous blood was obtained after an overnight fast, and the fasting blood glucose and lipid profile were determined. Anthropometric parameters (weight, height, body mass index [BMI], and waist circumference) were measured as described previously (17). After subjects rested for at least 10 minutes, 2 blood pressure readings were obtained, and the mean was used. Subjects were considered to have hypertension if their blood pressure was ⱖ140/90 mm Hg or they were regularly taking antihypertensive drugs. Glycemic status was defined according to the 2003 American Diabetes Association criteria (18). Patients who fulfilled the criteria for impaired fasting glucose or DM were classified as having dysglycemia. Subjects were considered to have hypercholesterolemia if they had a low-density lipoprotein (LDL) cholesterol level of ⱖ3.4 mmoles/liter or were regularly taking cholesterol-lowering drugs. Measurement of disease-specific factors. Erythrocyte sedimentation rate (ESR) was measured immediately after venous blood samples were collected. High-sensitivity Creactive protein (hsCRP) level was measured in plasma samples with a commercial enzyme-linked immunosorbent assay (ELISA) kit (ImuClone; American Diagnostica). Positive antiphospholipid antibody (aPL) status was defined by the presence of one or more aPL subsets, including lupus anticoagulant and IgG anticardiolipin antibodies (aCL), measured as described previously (19). Briefly, serum IgG aCL antibodies were identified by ELISA, using cardiolipin (Sigma) as a substrate, according to standard methods (20). IgG aCL antibodies with a titer of ⬎15 IgG phospholipid units were regarded as positive. The presence of lupus anticoagulant was screened for by a dilute Russell’s viper venom time assay (21) and confirmed by platelet neutralization assay (22). An underlying inhibitor was suspected following failure to normalize the coagulation time in a 1:1 patient:control plasma mixing assay. Total disease activity was scored according to the European Scleroderma Activity criteria, which includes the total skin score, scleredema, digital necrosis, arthritis, reduced total lung carbon monoxide transfer factor, ESR ⬎30 mm/ hour, hypocomplementemia, and deterioration in skin, vascular, and muscular/articular conditions in the month preceding the assessment (23,24). CT coronary calcium score assessment. CT scan, lung function test, and blood sampling in the SSc patients were carried out on the same day. All subjects underwent CT scanning by a 64-slice multidimensional CT (Discovery 64, VCT; General Electric Medical Systems) incorporating electrocardiogram gating. The multidimensional CT imaging parameters were as follows: 120 kVp, 500 mA with dose modulation, and a 350-msec gantry rotation. Images were reconstructed at 2.5-mm thickness and transferred to a freestanding 3-dimensional workstation for processing (Advantage Workstation 4.3; General Electric Medical Systems). CACS in the left main coronary artery, left anterior descending artery, left circumflex coronary artery, right coronary artery, and posterior descending artery were analyzed. CACS was CALCIUM SCORE IN SSc Table 1. 1389 Clinical characteristics of the SSc patients and controls* Matched variables Age, years No. of women/no. of men Glycemic status, no. (%)† Normal fasting glucose Impaired fasting glucose Diabetes mellitus Cardiovascular risk factors History of smoking, no. (%) Fasting blood glucose, median (IQR) mg/dl‡ Hypertension, no. (%) Hypercholesterolemia, no. (%) HDL cholesterol, mmoles/dl LDL cholesterol, mmoles/dl Triglycerides, median (IQR) mmoles/dl‡ Systolic blood pressure, mm Hg Diastolic blood pressure, mm Hg Waist circumference, cm Body mass index, kg/m2 hsCRP, median (IQR) mg/liter‡ Medications Vasodilators, no. (%)§ Lipid-lowering drugs, no. (%) SSc patients (n ⫽ 53) Controls (n ⫽ 106) P 53.1 ⫾ 12.9 50/3 53.6 ⫾ 11.2 100/6 0.80 1.00 0.76 45 (84.9) 4 (7.5) 4 (7.5) 86 (81.1) 8 (7.5) 12 (11.3) 6 (11.3) 4.5 (4.0–5.0) 11 (20.8) 1 (1.9) 1.4 ⫾ 0.4 2.4 ⫾ 0.6 1.0 (0.7–1.5) 117.9 ⫾ 18.1 66.4 ⫾ 9.5 71.9 ⫾ 9.4 21.1 ⫾ 3.8 1.19 (0.50–4.27) 37 (69.8) 1 (1.9) 4 (3.8) 4.8 (4.5–5.1) 33 (31.1) 23 (21.7) 1.6 ⫾ 0.4 2.8 ⫾ 0.7 0.9 (0.7–1.4) 124.0 ⫾ 19.8 73.9 ⫾ 10.1 78.3 ⫾ 10.0 23.9 ⫾ 3.9 1.39 (0.78–2.90) 24 (22.6) 7 (6.6) 0.09 0.15 0.19 0.01 0.01 0.001 0.58 0.07 ⬍0.001 ⬍0.001 ⬍0.001 0.35 ⬍0.001 0.27 * Except where indicated otherwise, values are the mean ⫾ SD. Controls were matched with systemic sclerosis (SSc) patients for age, sex, and glycemic status. IQR ⫽ interquartile range; HDL ⫽ high-density lipoprotein; LDL ⫽ low-density lipoprotein; hsCRP ⫽ high-sensitivity C-reactive protein. † Determined according to the criteria of the American Diabetes Association. ‡ Natural log–transformed before analysis. § Includes both patients taking vasodilators for hypertension and patients taking vasodilators for Raynaud’s phenomenon. determined using dedicated software (SmartScore 3.5). Calcification was classified as absent (CACS ⫽ 0), minimal to mild (CACS ⫽ 1–100), moderate (CACS ⫽ 101–400), or severe (CACS ⱖ401) (25). All CT scans were performed on the same machine and were scored by a single reader (SSHC) who was blinded with regard to subject status. Statistical analysis. Data were analyzed using SPSS software, version 16.0. Results are presented as the mean ⫾ SD or the median (interquartile range [IQR]) as appropriate. Data with skewed distributions, as determined using the Kolmogorov-Smirnov test, were logarithmically transformed before analysis. Chi-square test or Fisher’s exact test, where appropriate, was used to compare categorical variables, and one-way analysis of variance was used for continuous variables. Multiple logistic regression analysis was performed using CACS ⱖ101 as the dependent variable and variables identified in univariate analysis with P ⬍ 0.1 as independent factors, using an enter regression model. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were determined. P values less than 0.05 were considered significant. RESULTS Characteristics of the patients and controls. Fifty-three SSc patients (50 women and 3 men) and 106 controls (100 women and 6 men) who were matched for age, sex, and glycemic status were recruited. All recruited subjects were Southern Chinese in ethnicity. Of the patients, 41 had lcSSc and 12 had dcSSc. The mean ⫾ SD age was 53.1 ⫾ 12.9 years in the SSc patients and 53.6 ⫾ 11.2 years in the controls (P ⫽ 0.80). The patients had a median disease duration of 9 years (IQR 5.5–19.5 years) and a median disease activity score of 2.5 (IQR 1.0–4.0). Fifteen patients (28.3%) were receiving prednisolone (median dosage 5 mg/day) for underlying interstitial lung disease. Thirty-seven patients (69.8%) were taking vasodilators; 11 (20.8%) had a history of hypertension. One patient (1.9%) was receiving a lipidlowering drug. Conventional cardiovascular risk factors in SSc patients. All SSc patients were asymptomatic, but 2 controls had angina symptoms. As shown in Table 1, significantly more SSc patients were receiving vasodilators (P ⬍ 0.001) but fewer had hypercholesterolemia (P ⫽ 0.01) compared to controls. SSc patients also had lower high-density lipoprotein (HDL) cholesterol levels (P ⫽ 0.01), LDL cholesterol levels (P ⫽ 0.001), diastolic blood pressure (P ⬍ 0.001), waist circumference (P ⬍ 1390 MOK ET AL Figure 1. Proportion of subjects in each coronary artery calcium score group who had systemic sclerosis. P for trend ⫽ 0.02, by Spearman’s correlation. 0.001), and BMI (P ⬍ 0.001) than the age-, sex-, and glycemic status–matched controls. Levels of hsCRP were comparable between SSc patients and controls. Association of SSc with a higher CACS. Among the SSc patients (n ⫽ 53), 32 (60.4%) had a CACS of 0 and 8 (15.1%), 9 (17.0%), and 4 (7.5%) had a CACS of 1–100, 101–400, and ⱖ401, respectively. Figure 1 shows an increasing proportion of SSc patients among subjects with coronary calcification of increasing severity. There were significantly more SSc patients among subjects who had a CACS of ⱖ101 (n ⫽ 23) compared to those with a CACS of ⱕ100 (n ⫽ 136) (56.5% versus 29.4%; P ⫽ 0.01). As illustrated in Table 2, subjects who had higher CACS were older (P ⬍ 0.001), more likely to be men (P ⫽ 0.03), have SSc (P ⫽ 0.01), and receive vasodilators (P ⫽ 0.001). They also had higher fasting blood glucose (P ⫽ 0.004), LDL cholesterol levels (P ⫽ 0.047), and systolic blood pressure (P ⬍ 0.001). SSc is an independent risk factor for coronary artery calcification. To examine the role of SSc in the predisposition to moderate to severe coronary calcification, as defined by a CACS ⱖ101, multiple logistic regression analysis was performed. The model included age, sex, dysglycemia, hypertension, LDL cholesterol level, HDL cholesterol level, and SSc. Treatment with lipid-lowering drugs was included in the model to correct LDL and HDL cholesterol levels in subjects who were receiving these medications. As illustrated in Table 3, a significant independent association was found between SSc and a CACS of ⱖ101. A CACS ⱖ101 was also associated with age and LDL cholesterol level. SSc patients had an 11-fold increased risk of having more severe coronary calcification compared to controls (OR 10.89 [95% CI 2.21–53.75], P ⫽ 0.003). If fasting blood glucose replaced dysglycemia in the model, SSc patients also had an 11-fold risk of having more severe coronary Table 2. Clinical characteristics and conventional cardiovascular risk factors in subjects with different extents of coronary calcification, as indicated by the coronary artery calcium score* Age, years Women, no. (%) Dysglycemia, no. (%) History of smoking, no. (%) Hypertension, no. (%) Hypercholesterolemia, no. (%) Fasting blood glucose, median (IQR) mg/dl† HDL cholesterol, mmoles/dl LDL cholesterol, mmoles/dl Triglycerides, median (IQR) mmoles/dl† Systolic blood pressure, mm Hg Diastolic blood pressure, mm Hg Waist circumference Body mass index, kg/m2 hsCRP, median (IQR) mg/liter† Vasodilators, no. (%)‡ Lipid-lowering drugs, no. (%) SSc, no. (%) Calcium score ⬍100 (n ⫽ 136) Calcium score ⱖ101 (n ⫽ 23) P 51.0 ⫾ 10.3 131 (96.3) 21 (15.4) 7 (5.1) 30 (22.1) 24 (17.6) 4.6 (4.3–5.0) 1.6 ⫾ 0.4 2.6 ⫾ 0.7 0.9 (0.7–1.4) 119.9 ⫾ 18.9 71.2 ⫾ 10.8 76.0 ⫾ 10.1 23.0 ⫾ 4.0 1.27 (0.69–2.91) 45 (33.1) 6 (4.4) 40 (29.4) 67.3 ⫾ 9.1 19 (82.6) 7 (30.4) 3 (13.0) 14 (60.9) 6 (26.1) 5.0 (4.3–5.7) 1.4 ⫾ 0.4 2.9 ⫾ 0.8 1.1 (0.8–1.8) 136.5 ⫾ 17.0 72.6 ⫾ 8.3 77.6 ⫾ 11.1 22.8 ⫾ 4.5 2.54 (0.57–5.95) 16 (69.6) 2 (8.7) 13 (56.5) ⬍0.001 0.03 0.08 0.16 ⬍0.001 0.34 0.004 0.09 0.047 0.17 ⬍0.001 0.55 0.49 0.84 0.96 0.001 0.33 0.01 * Except where indicated otherwise, values are the mean ⫾ SD. See Table 1 for definitions. † Natural log–transformed before analysis. ‡ Includes both patients taking vasodilators for hypertension and patients taking vasodilators for Raynaud’s phenomenon. CALCIUM SCORE IN SSc 1391 Table 3. Logistic regression analysis of the role of clinical features and cardiovascular risk factors in predisposing to different extents of coronary artery calcification* Age Female sex Dysglycemia LDL cholesterol HDL cholesterol Lipid-lowering drugs† Hypertension SSc OR (95% CI) P 1.17 (1.08–1.26) 1.64 (0.18–15.24) 0.26 (0.05–1.40) 3.02 (1.06–8.57) 0.27 (0.05–1.55) 1.10 (0.11–10.89) 3.11 (0.72–13.50) 10.89 (2.21–53.75) ⬍0.001 0.66 0.12 0.04 0.14 0.94 0.13 0.003 * Values are the odds ratio (OR) (95% confidence interval [95% CI]) for a calcium score ⱖ101 versus a calcium score ⬍101. See Table 1 for other definitions. † Treatment with lipid-lowering drugs was included in the model to correct LDL and HDL cholesterol levels in subjects who were receiving these medications. calcification compared to controls (OR 10.67 [95% CI 2.28–49.87], P ⫽ 0.003) after adjustment for conventional risk factors. If systolic blood pressure (⫹10 mm Hg for those receiving vasodilators ) or diastolic blood pressure (⫹5 mm Hg for those receiving vasodilators ) replaced hypertension in the model, SSc patients had a 10-fold and 11-fold increase in risk of coronary calcification (OR 10.26 [95% CI 2.15–49.12], P ⫽ 0.004 and OR 11.24 [95% CI 2.29–55.18], P ⫽ 0.003, respectively). There were no significant changes in the ORs of the various independent variables when smoking history was also included in the model; SSc remained an independent risk factor for moderate to severe coronary calcification (OR 10.89 [95% CI 2.21–53.75], P ⫽ 0.003). Conventional and disease-specific factors in SSc patients with coronary artery calcification. Conventional and disease-specific factors in relation to the CACS were examined in SSc patients. As illustrated in Table 4, SSc patients who had moderate to severe coronary calcification (CACS ⱖ101) were likely to be older (P ⬍ 0.001) and have higher systolic blood pressure (P ⬍ 0.001) and diastolic blood pressure (P ⫽ 0.02). With regard to disease-specific factors, patients who had more severe coronary calcification were more likely to have longer disease duration (P ⫽ 0.02). SSc subset, Table 4. Conventional and disease-specific risk factors in relation to different extents of coronary artery calcification in the 53 SSc patients* Conventional risk factors Age, years Female sex, no. (%) Dysglycemia, no. (%) Hypercholesterolemia, no. (%) Hypertension, no. (%) History of smoking, no. (%) Fasting blood glucose, median (IQR) mg/dl† HDL cholesterol, mmoles/dl LDL cholesterol, mmoles/dl Triglycerides, median (IQR) mmoles/dl† Systolic blood pressure, mm Hg Diastolic blood pressure, mm Hg Waist circumference, cm Body mass index, median (IQR) kg/m2 Medications Vasodilators, no. (%)‡ Lipid-lowering drugs, no. (%) Disease-specific factors Disease duration, years No. with diffuse SSc/no. with limited SSc SSc disease activity score Prednisolone use, no. (%) Antiphospholipid antibodies, no. (%) hsCRP, median (IQR) mg/dl† ESR, median (IQR) mm/hour† Calcium score ⬍100 (n ⫽ 40) Calcium score ⱖ101 (n ⫽ 13) P 48.8 ⫾ 10.6 39 (97.5) 5 (12.5) 0 (0) 4 (10.0) 5 (12.5) 4.4 (3.9–4.9) 1.4 ⫾ 0.4 2.3 ⫾ 0.6 1.0 (0.7–1.4) 113.5 ⫾ 14.7 64.7 ⫾ 8.8 71.5 ⫾ 9.4 20.6 (18.7–22.4) 66.5 ⫾ 10.0 11 (84.6) 3 (23.1) 1 (7.7) 7 (53.8) 1 (7.7) 5.0 (4.2–6.2) 1.4 ⫾ 0.4 2.6 ⫾ 0.5 1.1 (0.8–2.0) 135.5 ⫾ 20.2 71.9 ⫾ 9.8 73.0 ⫾ 9.9 20.6 (18.1–23.7) ⬍0.001 0.15 0.39 0.25 0.002 1.00 0.11 0.95 0.25 0.25 ⬍0.001 0.02 0.64 0.60 26 (65.0) 0 (0) 9.7 ⫾ 7.2 11/29 2.5 ⫾ 1.6 14 (35.0) 6 (15.0) 0.11 (0.05–0.34) 28.5 (14.3–42.5) 11 (84.6) 1 (7.7) 19.5 ⫾ 12.4 1/12 3.3 ⫾ 2.0 5 (38.5) 1 (7.7) 0.27 (0.08–0.62) 31.0 (17.0–64.5) 0.30 0.25 0.02 0.25 0.25 1.00 0.67 0.23 0.41 * Except where indicated otherwise, values are the mean ⫾ SD. ESR ⫽ erythrocyte sedimentation rate (see Table 1 for other definitions). † Natural log–transformed before analysis. ‡ Includes both patients taking vasodilators for hypertension and patients taking vasodilators for Raynaud’s phenomenon. 1392 MOK ET AL Table 5. Logistic regression analysis of the role of clinical features and cardiovascular risk factors in predisposing to different extents of coronary artery calcification in systemic sclerosis patients* Age Hypertension Disease duration OR (95% CI) P 1.16 (1.05–1.28) 2.62 (0.34–20.22) 1.14 (1.02–1.27) 0.004 0.36 0.02 * Values are the odds ratio (OR) (95% confidence interval [95% CI]) for calcium score ⱖ101 versus calcium score ⬍101. disease activity score, prednisolone use, presence of aPL antibodies, and levels of ESR and hsCRP were not found to be related to coronary atherosclerosis. There was a trend toward more subjects with a CACS of ⱖ101 having an elevated PAP than those with a CACS of ⱕ100 (42.9% versus 17.9%; P ⫽ 0.08), but there was no correlation between the CACS and a history of RP (P ⫽ 0.31) or digital ulceration (P ⫽ 0.50). Logistic regression analysis revealed that disease duration was significantly associated with more severe coronary calcification (CACS ⱖ101) (OR 1.14 [95% CI 1.02–1.27], P ⫽ 0.02), after adjustment for age and hypertension (Table 5), suggesting a 14% increased risk of moderate to severe coronary calcification with each additional year of SSc disease duration. A 13% increased risk was obtained if hypertension was replaced by systolic blood pressure in the model. DISCUSSION Our findings indicate that SSc is an independent determinant of moderate to severe coronary calcification, in addition to age and LDL cholesterol level, and that SSc patients have an 11-fold increased risk of moderate to severe coronary calcification after adjustment for conventional cardiovascular risk factors. Increased frequency of coronary artery calcification in SSc patients compared to controls has also recently been reported in a pilot study of smaller sample size (27), despite the similar or lower rate of CAD in SSc patients compared with controls demonstrated by some studies (13,15). Although myocardial insufficiency in SSc has been attributed to microvascular disease (28) and imbalanced hemostasis (29) in earlier studies, coronary atherosclerosis has been increasingly revealed by conventional coronary angiography in SSc patients (13,14), concomitant with the significantly improved survival of these patients over the past decades (30). Other macrovascular diseases, such as peripheral vascular disease, have also been frequently reported in SSc patients (31,32). Among conventional cardiovascular factors, our study confirmed a strong influence of age on coronary atherosclerosis, consistent with the results of previous studies (33). Male sex was not found to be an important contributing factor, due to the overwhelming female predominance in this study cohort. The frequency of hypertension did not differ significantly between SSc patients and controls. Glycemic status was a matching factor in this study and so could not be evaluated further. SSc patients had significantly lower HDL and LDL cholesterol levels compared to controls, whereas both atherogenic and normal lipid profiles have previously been found in SSc patients (34,35). In this study, SSc patients were also shown to have a lower frequency of certain cardiovascular risk factors, including hypercholesterolemia, waist circumference, and BMI, compared with age- and sex-matched controls. Indeed, over onethird of the SSc patients were defined as underweight according to the BMI cutoffs for Asian populations recommended by the World Health Organization (36). The significantly lower diastolic blood pressure observed in SSc patients was likely related to the use of vasodilators (indicated for RP or blood pressure control), which were taken by the majority of the patients (69.8%). Normotensive patients receiving vasodilators for RP may have falsely lower blood pressure readings. To capture the full effects of blood pressure on the CACS, we replaced hypertension with adjusted systolic or diastolic blood pressure in the logistic regression model and adjusted for the blood pressure–lowering effects of vasodilator therapy by adding 10 mm Hg and 5 mm Hg to the systolic and diastolic blood pressure readings, respectively, according to the method of Cui et al (26) for patients receiving vasodilators, regardless of the indication. SSc remained a highly significant independent risk factor for increased coronary calcification. Thus, the observed increased risk of coronary calcification in the context of a lower prevalence of some conventional cardiovascular factors suggested a contributory role of disease-specific factors to coronary atherosclerosis in SSc. The level of hsCRP, a recently identified independent predictor of future cardiovascular events (37), did not differ between SSc patients and controls and was not associated with coronary calcification. Likewise, the ESR, disease activity score, and SSc subset were not found to predict coronary calcification. Antiphospholipid antibodies were present in 13.2% of the SSc patients in this study and were not particularly CALCIUM SCORE IN SSc associated with coronary atherosclerosis, consistent with the results of a previous study (38). Other previously identified predisposing factors to atherosclerosis, including lipoprotein(a) and anti–oxidized LDL antibodies (34,39), are worth examining in future studies. Disease duration, age, and hypertension were the only factors associated with moderate to severe coronary calcification in SSc patients. Only age and disease duration remained as independent determinants on multivariate analysis. Our study showed a 14% increased risk of moderate to severe coronary calcification for each additional year of disease duration. As postulated for other rheumatic diseases, coronary atherosclerosis may be related to the long-term effect of the underlying inflammation (4), which may not be adequately reflected by cross-sectional measurements of markers of inflammation or disease activity score. We postulated that endothelial dysfunction and inflammation were the key pathogenic mechanisms shared by atherosclerosis and SSc (31). Endothelial dysfunction has been well described in SSc patients, as evidenced by impaired flow-mediated dilation of the brachial artery on Doppler ultrasound scan (40,41) and elevated serum levels of markers of endothelial injury (42). Repetitive ischemia-reperfusion injury with associated oxidative stress and inflammation, hemostasis imbalance, and impaired number and function of endothelial progenitor cells have also been shown to contribute to endothelial dysfunction in SSc (41,43,44). The CACS, as measured by multidimensional CT scan, is a well-established surrogate for coronary atherosclerosis since it has been shown to correlate closely with the total coronary atherosclerosis burden (45,46) and predict the development of cardiovascular morbidity and mortality (47,48). Although the high predictive value of the CACS for coronary atherosclerosis has been demonstrated to be due to its greater sensitivity among patients with typical angina symptoms (49), SSc patients in our study were rather asymptomatic for the level of coronary calcification observed, which may be related to restricted exercise tolerance due to musculoskeletal and cardiopulmonary involvement. Since SSc patients are predisposed to ectopic calcification, increased coronary calcification may also occur as a result of increased calcium deposition in atherosclerotic plaques. This may explain the discrepancies between the frequency of some conventional cardiovascular risk factors and the severity of coronary calcification in the SSc patients in this study. Indeed, coronary calcification has also been reported to involve the muscular media instead of the subintimal 1393 space in some patients with DM, end-stage renal failure (50), and human immunodeficiency virus infection (51). The independent association of SSc disease duration with the CACS was consistent with a predisposition of the disease per se to enhanced coronary calcification. In a pilot study of 19 patients, we previously found that coronary atherosclerotic plaques, as demonstrated on CT coronary angiogram, are not uncommon in asymptomatic SSc patients (52). Future studies are warranted to supplement the coronary calcium score measurement with other imaging techniques for further evaluation of coronary atherosclerosis in SSc patients. These can include intravascular ultrasound imaging, which allows for the measurement of arterial stenosis, extent of eccentricity, and plaque volume, as well as percentages of fatty, fibrous, or calcified components (53). It will also be of interest to investigate in prospective studies whether the CACS in SSc patients is predictive of future coronary events as it is in the general population. In conclusion, our findings suggest that SSc is an independent determinant of moderate to severe coronary calcification. Conventional cardiovascular risk factors, such as age, also predispose SSc patients to coronary calcification as in the general population. Since CAD remains a global health issue that has also been recognized as a major cause of death in the Chinese population in recent years (54), future studies are needed to examine SSc-specific factors that may be amenable to correction and hence the prevention of CAD in these patients. AUTHOR CONTRIBUTIONS All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. Dr. Mok had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study conception and design. Mok, Lam. Acquisition of data. Mok, Chiu, Lo, Mak, Wong, Khong. Analysis and interpretation of data. Mok, Lau, Tso, Law, Lam. REFERENCES 1. LeRoy EC, Black C, Fleischmajer R, Jablonska S, Krieg T, Medsger TA Jr, et al. Scleroderma (systemic sclerosis): classification, subsets and pathogenesis. J Rheumatol 1988;15:202–5. 2. Freedman RR, Girgis R, Mayes MD. Endothelial and adrenergic dysfunction in Raynaud’s phenomenon and scleroderma. J Rheumatol 1999;26:2386–8. 3. Le Brocq M, Leslie SJ, Milliken P, Megson IL. Endothelial dysfunction: from molecular mechanisms to measurement, clinical implications, and therapeutic opportunities. Antioxid Redox Signal 2008;10:1631–74. 4. Tyrrell PN, Beyene J, Feldman BM, McCrindle BW, Silverman 1394 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. ED, Bradley TJ. Rheumatic disease and carotid intima-media thickness: a systematic review and meta-analysis. Arterioscler Thromb Vasc Biol 2010:1014–26. Sulli A, Ghio M, Bezante GP, Deferrari L, Craviotto C, Sebastiani V, et al. Blunted coronary flow reserve in systemic sclerosis. Rheumatology (Oxford) 2004;43:505–9. Montisci R, Vacca A, Garau P, Colonna P, Ruscazio M, Passiu G, et al. Detection of early impairment of coronary flow reserve in patients with systemic sclerosis. Ann Rheum Dis 2003;62:890–3. Nitenberg A, Foult JM, Kahan A, Perennec J, Devaux JY, Menkes CJ, et al. Reduced coronary flow and resistance reserve in primary scleroderma myocardial disease. Am Heart J 1986;112:309–15. Follansbee WP, Curtiss EI, Medsger TA Jr, Steen VD, Uretsky BF, Owens GR, et al. Physiologic abnormalities of cardiac function in progressive systemic sclerosis with diffuse scleroderma. N Engl J Med 1984;310:142–8. Bulkley BH, Ridolfi RL, Salyer WR, Hutchins GM. Myocardial lesions of progressive systemic sclerosis: a cause of cardiac dysfunction. Circulation 1976;53:483–90. Bulkley BH, Klacsmann PG, Hutchins GM. Angina pectoris, myocardial infarction and sudden cardiac death with normal coronary arteries: a clinicopathologic study of 9 patients with progressive systemic sclerosis. Am Heart J 1978;95:563–9. D’Angelo WA, Fries JF, Masi AT, Shulman LE. Pathologic observations in systemic sclerosis (scleroderma): a study of fiftyeight autopsy cases and fifty-eight matched controls. Am J Med 1969;46:428–40. Leinwand I, Duryee AW, Richter MN. Scleroderma; based on a study of over 150 cases. Ann Intern Med 1954;41:1003–41. Akram MR, Handler CE, Williams M, Carulli MT, Andron M, Black CM, et al. Angiographically proven coronary artery disease in scleroderma. Rheumatology (Oxford) 2006;45:1395–8. Tarek EG, Yasser AE, Gheita T. Coronary angiographic findings in asymptomatic systemic sclerosis. Clin Rheumatol 2006;25: 487–90. Derk CT, Jimenez SA. Acute myocardial infarction in systemic sclerosis patients: a case series. Clin Rheumatol 2007;26:965–8. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive summary of the third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001;285:2486–97. Tso AW, Xu A, Sham PC, Wat NM, Wang Y, Fong CH, et al. Serum adipocyte fatty acid binding protein as a new biomarker predicting the development of type 2 diabetes: a 10-year prospective study in a Chinese cohort. Diabetes Care 2007;30:2667–72. Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 2003;26 Suppl 1:S5–20. Mok MY, Chan EY, Fong DY, Leung KF, Wong WS, Lau CS. Antiphospholipid antibody profiles and their clinical associations in Chinese patients with systemic lupus erythematosus. J Rheumatol 2005;32:622–8. Gharavi AE, Harris EN, Asherson RA, Hughes GR. Anticardiolipin antibodies: isotype distribution and phospholipid specificity. Ann Rheum Dis 1987;46:1–6. Thiagarajan P, Pengo V, Shapiro SS. The use of the dilute Russell viper venom time for the diagnosis of lupus anticoagulants. Blood 1986;68:869–74. Triplett DA, Brandt JT, Kaczor D, Schaeffer J. Laboratory diagnosis of lupus inhibitors: a comparison of the tissue thromboplastin inhibition procedure with a new platelet neutralization procedure. Am J Clin Pathol 1983;79:678–82. Valentini G, Della Rossa A, Bombardieri S, Bencivelli W, Silman AJ, D’Angelo S, et al. European multicentre study to define MOK ET AL 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. disease activity criteria for systemic sclerosis. II. Identification of disease activity variables and development of preliminary activity indexes. Ann Rheum Dis 2001;60:592–8. Valentini G, Bencivelli W, Bombardieri S, D’Angelo S, Della Rossa A, Silman AJ, et al. European Scleroderma Study Group to define disease activity criteria for systemic sclerosis. III. Assessment of the construct validity of the preliminary activity criteria. Ann Rheum Dis 2003;62:901–3. Agatston AS, Janowitz WR, Hildner FJ, Zusmer NR, Viamonte M Jr, Detrano R. Quantification of coronary artery calcium using ultrafast computed tomography. J Am Coll Cardiol 1990;15: 827–32. Cui JS, Hopper JL, Harrap SB. Antihypertensive treatments obscure familial contributions to blood pressure variation. Hypertension 2003;41:207–10. Khurma V, Meyer C, Park GS, McMahon M, Lin J, Singh RR, et al. A pilot study of subclinical coronary atherosclerosis in systemic sclerosis: coronary artery calcification in cases and controls. Arthritis Rheum 2008;59:591–7. Allanore Y, Meune C, Kahan A. Systemic sclerosis and cardiac dysfunction: evolving concepts and diagnostic methodologies. Curr Opin Rheumatol 2008;20:697–702. Lau CS, McLaren M, Saniabadi A, Belch JJ. Increased whole blood platelet aggregation in patients with Raynaud’s phenomenon with or without systemic sclerosis. Scand J Rheumatol 1993; 22:97–101. Nihtyanova SI, Tang EC, Coghlan JG, Wells AU, Black CM, Denton CP. Improved survival in systemic sclerosis is associated with better ascertainment of internal organ disease: a retrospective cohort study. QJM 2010;103:109–15. Hettema ME, Zhang D, de Leeuw K, Stienstra Y, Smit AJ, Kallenberg CG, et al. Early atherosclerosis in systemic sclerosis and its relation to disease or traditional risk factors. Arthritis Res Ther 2008;10:R49. Veale DJ, Collidge TA, Belch JJ. Increased prevalence of symptomatic macrovascular disease in systemic sclerosis. Ann Rheum Dis 1995;54:853–5. Allison MA, Wright CM. Age and gender are the strongest clinical correlates of prevalent coronary calcification (R1). Int J Cardiol 2005;98:325–30. Lippi G, Caramaschi P, Montagnana M, Salvagno GL, Volpe A, Guidi G. Lipoprotein[a] and the lipid profile in patients with systemic sclerosis. Clin Chim Acta 2006;364:345–8. Tsifetaki N, Georgiadis A, Alamanos Y, Fanis S, Argyropoulou M, Drosos A. Subclinical atherosclerosis in scleroderma patients. Scand J Rheumatol 2010;39:326–9. Appropriate body-mass index for Asian populations and its implications for policy and intervention strategies. Lancet 2004;363: 157–63. Ballantyne CM, Hoogeveen RC, Bang H, Coresh J, Folsom AR, Heiss G, et al. Lipoprotein-associated phospholipase A2, highsensitivity C-reactive protein, and risk for incident coronary heart disease in middle-aged men and women in the Atherosclerosis Risk in Communities (ARIC) study. Circulation 2004;109:837–42. Ostrowski RA, Robinson JA. Antiphospholipid antibody syndrome and autoimmune diseases. Hematol Oncol Clin North Am 2008;22:53–65, vi. Sherer Y, Cerinic MM, Bartoli F, Blagojevic J, Conforti ML, Gilburd B, et al. Early atherosclerosis and autoantibodies to heat-shock proteins and oxidized LDL in systemic sclerosis. Ann N Y Acad Sci 2007;1108:259–67. Celermajer DS, Sorensen KE, Gooch VM, Spiegelhalter DJ, Miller OI, Sullivan ID, et al. Non-invasive detection of endothelial dysfunction in children and adults at risk of atherosclerosis. Lancet 1992;340:1111–5. Mok MY, Yiu KH, Wong CY, Qiuwaxi J, Lai WH, Wong WS, CALCIUM SCORE IN SSc 42. 43. 44. 45. 46. 47. 48. et al. Low circulating level of CD133⫹KDR⫹cells in patients with systemic sclerosis. Clin Exp Rheumatol 2010;28:S19–25. Allanore Y, Batteux F, Avouac J, Assous N, Weill B, Kahan A. Levels of circulating endothelial progenitor cells in systemic sclerosis. Clin Exp Rheumatol 2007;25:60–6. Mok MY, Lau CS. The burden and measurement of cardiovascular disease in SSc. Nat Rev Rheumatol 2010;6:430–4. LeRoy EC. Systemic sclerosis: a vascular perspective. Rheum Dis Clin North Am 1996;22:675–94. Rumberger JA, Sheedy PF III, Breen JF, Schwartz RS. Coronary calcium, as determined by electron beam computed tomography, and coronary disease on arteriogram: effect of patient’s sex on diagnosis. Circulation 1995;91:1363–7. Schmermund A, Denktas AE, Rumberger JA, Christian TF, Sheedy PF II, Bailey KR, et al. Independent and incremental value of coronary artery calcium for predicting the extent of angiographic coronary artery disease: comparison with cardiac risk factors and radionuclide perfusion imaging. J Am Coll Cardiol 1999;34:777–86. Greenland P, LaBree L, Azen SP, Doherty TM, Detrano RC. Coronary artery calcium score combined with Framingham score for risk prediction in asymptomatic individuals. JAMA 2004;291: 210–5. Kondos GT, Hoff JA, Sevrukov A, Daviglus ML, Garside DB, Devries SS, et al. Electron-beam tomography coronary artery 1395 49. 50. 51. 52. 53. 54. calcium and cardiac events: a 37-month follow-up of 5635 initially asymptomatic low- to intermediate-risk adults. Circulation 2003; 107:2571–6. Van Werkhoven JM, Heijenbrok MW, Schuijf JD, Jukema JW, Boogers MM, van der Wall EE, et al. Diagnostic accuracy of 64-slice multislice computed tomographic coronary angiography in patients with an intermediate pretest likelihood for coronary artery disease. Am J Cardiol 2010;105:302–5. Tong LL, Mehrotra R, Shavelle DM, Budoff M, Adler S. Poor correlation between coronary artery calcification and obstructive coronary artery disease in an end-stage renal disease patient. Hemodial Int 2008;12:16–22. Micheletti RG, Fishbein GA, Currier JS, Singer EJ, Fishbein MC. Calcification of the internal elastic lamina of coronary arteries. Mod Pathol 2008;21:1019–28. Mok MY, Chiu SS, Lo Y, Mak HK, Wong WS, Khong PL, et al. Coronary atherosclerosis using computed tomography coronary angiography in patients with systemic sclerosis. Scand J Rheumatol 2009;38:381–5. DeMaria AN, Narula J, Mahmud E, Tsimikas S. Imaging vulnerable plaque by ultrasound. J Am Coll Cardiol 2006;47:C32–9. He J, Gu D, Wu X, Reynolds K, Duan X, Yao C, et al. Major causes of death among men and women in China. N Engl J Med 2005;353:1124–34.