O R I G I N A L A R T I C L E
High prevalence of asymptomatically poor muscle perfusion of lower
extremities measured in systemic lupus erythematosus patients
with abnormal myocardial perfusion
Received: 20 January 2003 / Accepted: 18 May 2003 / Published online: 15 July 2003 Springer-Verlag 2003
Abstract Patients with systemic lupus erythematosus
(SLE) may develop premature atherosclerosis, notably
peripheral vascular disease (PVD) presenting with
intermittent claudication or gangrene. Therefore, it is
important to investigate if high prevalence of poor
muscle perfusion of lower extremities in SLE patients
with abnormal myocardial perfusion is related to more
cardiovascular risk factors. We used a well-established
and noninvasive radionuclide method (xenon 133 muscle
washout) to evaluate objectively the anterior tibial
muscle perfusion of 34 SLE female patients without
symptoms/signs of PVD in the lower extremities. The
patients were separated into two groups according to
myocardial perfusion imaging results. Meanwhile, 30
normal female controls with matched age distribution
were
also
included
for
comparison.
The
muscle
perfusion differed significantly (P <0.05) between
patients (1.90±0.41 ml/100 g per min) and controls
(2.91±0.50 ml/100 g per min), as well as between 18
SLE patients with abnormal myocardial perfusion
(1.33±0.43 ml/100 g per min) and 16 with normal
myocardial perfusion (2.26±0.45 ml/100 g per min).
Based on the xenon 133 muscle washout method, we
conclude that muscle perfusion in the lower extremities
of SLE patients without symptoms/signs of PVD
is significantly decreased and related to abnormal
myocardial perfusion.
Keywords Muscle perfusion Æ Myocardial perfusion Æ
Systemic lupus erythematosus
Introduction
Arterial vascular disease in systemic lupus
erythemato-sus (SLE) has a number of pathogenic mechanisms
including arteritis, intravascular coagulation frequently
associated with a lupus anticoagulant [1] and, in chronic
lupus, atherosclerosis [2]. The last mechanism is
cur-rently recognised as a major cause of death and
mor-bidity in patients with SLE [3].
Arteriography is the gold but invasive standard for
diagnosing occlusive arterial disease of the legs. It
pro-vides morphological data but no information about
muscle perfusion, which depends on collateral circulation
and the presence of small-vessel disease. When xenon
(Xe)-133 (an inert gas can not react with tissues) diffuses
from muscle of the lower extremities into the peripheral
capillaries and reaches the lungs, it can be rapidly cleared
without recirculation. Therefore, this clearance rate
correlates with the blood perfusion that really reaches the
muscle [4, 5]. In addition, poor muscle perfusion of lower
extremities may result not only from macrovascular
disease but also from microvascular disorders.
Therefore, in this study, we used an objective and
noninvasive
radionuclide
method
(Xe-133
muscle
washout) to evaluate anterior tibial muscle perfusion of
SLE patients without symptoms/signs of peripheral
Rheumatol Int (2004) 24: 227–229 DOI 10.1007/s00296-003-0353-9
C. C. Lin Æ H. J. Ding Æ Y. W. Chen Æ J. J. Wang
S. T. Ho Æ A. Kao
C. C. Lin
Cardiovascular Division, Department of Internal Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan H. J. Ding
Department of Medical Research,
School of Technology for Medical Sciences, Kaohsiung Medical University, Kaohsiung, Taiwan Y. W. Chen
Department of Nuclear Medicine,
Kaohsiung Medical University, Kaohsiung, Taiwan J. J. Wang
Department of Medical Research, Chi-Mei Medical Center, Tainan, Taiwan S. T. Ho
Department of Anesthesiology,
Tri-Service General Hospital, Taipei, Taiwan A. Kao (&)
Department of Medical Research, China Medical University Hospital,
No. 2 Yuh-Der Road, Taichung 404, Taiwan E-mail: [email protected]
Tel.: +886-4-22052121 ext 3475 Fax: +886-4-22023442
vascular disease (PVD). In addition, we investigated
whether there is a high prevalence of poor muscle
per-fusion of lower extremities in SLE patient subgroups
with or without abnormal myocardial perfusion.
Patients and materials
Thirty-four female patients (age 45.0±12.8 years) with SLE satis-fying the American College of Rheumatology criteria [6] were in-cluded in this study. They were separated into subgroups according to myocardial perfusion imaging results: 18 with abnormal and 16 with normal myocardial perfusion. However, the two groups did not differ significantly in age, duration of SLE, partial thrombo-plastin time, antibodies to cardiolipin, lupus activity criteria count, mean steroid dose, mean duration of steroid use, or risk factors for developing PVD (such as smoking, hypertension, hyperlipidemia, and use of oral contraceptives) (Table 1). For comparison, 30 normal female controls (age 46.1±12.1 years) with the same age distribution were also included. The inclusion criteria for all sub-jects were: absence of myocardial infarction and angina pectoris, normal results on 12-lead resting electrocardiography (ECG), and absence of PVD which was defined as one of intermittent claudi-cation, absent peripheral pulses, gangrene, and angiographic or Doppler evidence of large vessel disease. None of the patients or controls had histories of stroke, congenital heart disease, cardiomyopathy, or vasculitis.
A one-day protocol of Tc-99m-sestamibi myocardial perfusion imaging during rest and stress after dipyridamole infusion (0.56 mg/kg over 4 min during ECG monitoring) was performed in all patients. Ten mCi and 25 mCi of Tc-99m-sestamibi were in-jected during rest and dipyridamole stress imaging, respectively. During the latter, Tc-99m-sestamibi was injected 2 min after the end of the infusion. All patients were instructed not to consume drugs or substances containing xanthine for 2 days before the study. Intravenous aminophylline was given 4 min after the Tc-99m-sestamibi, if patients had discomfort during dipyridamole infusion. Single photon emission computed tomography (SPECT) images were acquired 1 h after the Tc-99m-sestamibi injection using a large field of view, dual-headed, gamma camera equipped with a low-energy, all-purpose, parallel-hole collimator. Data were obtained from 64 projections of 25 s each in the 140 keV photo-peak over a 180 arc in a 64·64 matrix. Short-axis, vertical long-axis, and horizontal long-axis images were reconstructed from the raw data by filtered back projection using a Butterworth filter with a cutoff frequency of 0.5 and order of 10 in the rest studies and cutoff frequency of 0.66 and order of 5 in the stress studies.
All images were interpreted blindly and separately by the agreement of at least two of three experienced nuclear medicine physicians. The imaging results were classified as normal or abnormal including persistent perfusion defect (present on both rest and dipyridamole stress images), reversible perfusion defect (present only on dipyridamole stress image), and reverse
redistribution defect (demonstrated in the redistribution image and not in the stress image) [7, 8].
Each subject was allowed to rest for at least 30 min and accli-mate to room temperature in the supine position under a digital gamma camera linked to a minicomputer. Approximately 0.1 ml (0.3–0.5 mCi) of Xe-133 dissolved in isotonic saline was slowly injected with a 27-gauge needle into the anterior tibial muscle (approximately 10 cm below the tibial tuberosity and 2 cm lateral to the tibia) of the right leg. The needle was held in place for at least 10 s to avoid Xe-133 leakage. The data were acquired simulta-neously in a frame mode with 64·64 matrix at one frame/min for 20 min with a low-energy, parallel-hole collimator. A time-activity curve was generated from the region of interest at the site of injection. The power exponential fitting technique was used for curve fitting. The Xe-133 clearance half-time (T1/2) was measured from the power exponential fitted curve. Then the muscle perfusion was calculated (Q = 0.7 ln2 100 g muscle‚ T1/2) [4, 5].
Statistical analyses were performed using SPSS software (SPSS, Chicago, Ill., USA). Anterior tibial muscle perfusion (ml/100 g per min) of the study groups and subgroups was expressed as mean ± standard deviation. Two-tailed independent Student’s t-tests were used to evaluate the differences between study subgroups. P values of <0.05 were considered significant.
Results
Based on the myocardial perfusion imaging results, the
34 female SLE patients were separated into (A) 18
pa-tients with abnormal myocardial perfusion and (B) 16
with normal myocardial perfusion. The subgroup
char-acteristics are listed in Table 1. Anterior tibial muscle
perfusion in the normal female controls (2.91±0.50 ml/
100 g per min) was significantly higher than in the
fe-male SLE patients (1.90±0.41 ml/100 g per min).
Among the SLE patients, subgroup A patients with
abnormal
myocardial
perfusion
imaging
results
(1.33±0.43 ml/100 g per min) had significantly poorer
muscle perfusion than subgroup B patients with normal
myocardial perfusion imaging results (2.26±0.45 ml/
100 g per min) (Table 2).
Discussion
As SLE patients survive longer, the morbidity patterns
are changing [9]. Specifically, atherosclerotic
complica-tions involving coronary arteries have been reported.
However, PVD due to atherosclerosis has only been
Table 1 Patient subgroup characteristics. SLE systemic lupus erythematosus, PTT partial thromboplastin time, LACClupus activity criteria count
Parameters Subgroup A Subgroup B
Ncases 18 16
Age (years) 45.6±12.3 44.9±11.7
Duration of SLE (years) 8.6±1.3 9.0±1.9
PTT (seconds) 31.5±4.2 32.1±5.6
LACC 0.74±0.12 0.70±0.11
Antibodies to cardiolipin 6 (33.3%) 5 (31.3%) Mean steroid dose (mg prednisone/day) 13.5±1.5 14.0±1.2 Mean duration of steroid use (years) 8.3±1.5 8.7±1.6
Smoking 2/18 (11.1%) 2/16 (12.5%)
Hypertension 7/18 (38.9%) 6/16 (37.5%) Hyperlipidemia 5/18 (27.8%) 5/16 (31.3%) Use of oral contraceptives 6/18 (33.3%) 5/16 (31.3%) 228
rarely reported. After reviewing the literature, DePalma
[10] described three patients with well-controlled SLE
who developed symptomatic PVD of the feet. The
pa-tients had been treated with prednisone (5–12 mg daily)
for 1–10 years. Other authors demonstrated that
vas-culitis of the foot usually was sudden, catastrophic,
gangrenous, and accompanied by very active systemic
disease [11, 12]. In addition, the general nature of
ath-erosclerosis in SLE patients includes a combination of
coronary artery disease and PVD [13]. Therefore, it
could be expected that microvascular disease in SLE
patients is likely to be systemic and associated with poor
muscle perfusion of lower extremities and abnormal
myocardial perfusion, as in our findings.
Histories of hypertension and smoking showed a
trend towards increased frequency in those patients with
PVD. Factors significantly related to the development of
PVD included duration of SLE and corticosteroid use
[13]. However, the two SLE subgroups in our study did
not differ significantly in duration of SLE, classic
ther-apy (mean steroid dose and duration of steroid use), or
risk factors for developing PVD. Although at least six
common indices (such as BILAG, ECLAM, LAI, SIS,
SLAM, and SLEDAI) were routinely used to calculate
the SLE activity, none of them focusses on
cardiovas-cular involvement in SLE [14]. Thus, we did not
calcu-late the SLE disease activity index to correcalcu-late the
anterior tibial muscle perfusion by the Xe-133 washout
technique in this study.
All of the 34 female SLE patients in our study had
palpable pedal pulses, no resting pain, and intermittent
claudication from large vessel occlusion in the lower
extremities. Previously reported cases of atherosclerosis
in SLE have described vasculitis, representing a vascular
response to intimal proliferative lesions [13]. In addition,
such lesions may be initiated by endothelial injury.
However, subtle endothelial injury may be without
morphological alteration. The Xe-133 washout
tech-nique can calculate individual muscle perfusion supplied
by smaller vessels and differs from other modalities [4, 5]
such as histological examinations, angiography,
pleth-ysmography, vital capillaroscopy, and Doppler
echog-raphy,
which
can
only
detect
either
anatomic
abnormalities of large vessels or the total blood flow in
the capillary. Therefore, we can suppose that such small
vessel disease might be involved in SLE patients with
poor muscle perfusion of lower extremities as detected
by Xe-133 washout but without significant PVD,
dem-onstrated as a larger vessel disease detected by
angiog-raphy or other modalities. In addition, we considered
that the abnormal myocardial perfusion in SLE
subgroup A was due to small vessel disease.
The objective and noninvasive Xe-133 washout
technique may represent the actual muscle perfusion. It
was proven to be useful for both early detection and
research on the pathophysiology of microangiopathy in
a subgroup of SLE patients with small vessel diseases.
We conclude that muscle perfusion in the lower
extremities of female SLE patients is lower, particularly
in those with abnormal myocardial perfusion. However,
in the present study, the Xe-133 injections were given in
the right legs only. Therefore, we did not compare the
difference in muscle perfusion between both legs of
individual patients, and further investigation of this is
necessary in a larger series.
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patients
Normal female controls 2.91±0.50 ml/100 g per min Female SLE patients 1.90±0.41 ml/100 g per min) Subgroup B SLE patients 1.33±0.43 ml/100 g per min Subgroup A SLE patients 2.26±0.45 ml/100 g per min
