close

Вход

Забыли?

вход по аккаунту

?

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: temy@hkucc.hku.hk.
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 [26]) or diastolic
blood pressure (⫹5 mm Hg for those receiving vasodilators [26]) 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.
Документ
Категория
Без категории
Просмотров
7
Размер файла
117 Кб
Теги
factors, artery, increase, deposition, systemic, coronary, calcium, sclerosis, independence, risk
1/--страниц
Пожаловаться на содержимое документа