S.-S.Sun,Y.-C.Shiau 1,S.-C.Tsai 2,C.-C.Lin 3,A.Kao 4 and C.-C. Lee 4

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1 Rheumatology 2001;40: The role of technetium-99m sestamibi myocardial perfusion single-photon emission computed tomography (SPECT) in the detection of cardiovascular involvement in systemic lupus erythematosus patients with non-specific chest complaints S.-S.Sun,Y.-C.Shiau 1,S.-C.Tsai 2,C.-C.Lin 3,A.Kao 4 and C.-C. Lee 4 Departments of Nuclear Medicine, 3 Family Medicine and 4 Medical Research, China Medicine College Hospital, Taichung, 1 Department of Nuclear Medicine, Far Eastern Memorial Hospital and Institute of Biomedical Engineering, College of Electrical Engineering, National Taiwan University, Taipei and 2 Department of Nuclear Medicine, Show-Chwan Memorial Hospital, Chunghua, Taiwan Abstract Objectives. Systemic lupus erythematosus (SLE) can affect multiple organs. Coronary artery disease has received increasing recognition as a major cause of morbidity and mortality in SLE in recent years. The purpose of this study was to evaluate the utility of technetium-99m sestamibi single-photon emission computed tomography ( 99m Tc-sestamibi SPECT) in the detection of cardiovascular involvement in SLE patients with non-specific clinical chest symptoms such as chest discomfort anduor dyspnoea anduor occasional palpitation. Methods. Thirty-three SLE female patients (age range: yr) with non-specific complaints such as chest discomfort anduor dyspnoea anduor occasional palpitation were investigated using a 99m Tc-sestamibi myocardial perfusion SPECT scan at rest and after dipyridamole infusion in a stress study. The age- and sex-matched healthy group (24 cases) and SLE patients without any cardiovascular symptomsusigns (28 cases) were also included as controls in this study. The results of the uptake pattern of 99m Tc-sestamibi were classified into four types including normal, persistent perfusion defect, reversible perfusion defect and reverse redistribution. Results. Perfusion abnormalities were detected in 27 cases (seven patients had persistent perfusion defects, 15 patients had reversible perfusion defects, one patient had both persistent and reversible perfusion defects, two patients showed a reverse redistribution pattern and two patients had both reversible perfusion defects and a reverse redistribution pattern). The results of the SPECT in the healthy group were all normal. However, perfusion abnormalities were detected in 12 cases in the group of asymptomatic SLE patients. Conclusions. 99m Tc-sestamibi myocardial perfusion SPECT is a useful non-invasive imaging modality to detect cardiovascular involvement in SLE patients with non-specific clinical complaints of heart disease. KEY WORDS: 99m Tc-sestamibi SPECT, Systemic lupus erythematosus, Coronary artery disease. Submitted 24 November 2000; revised version accepted 2 April Correspondence to: A. Kao, Departments of Nuclear Medicine and Medical Research, China Medical College Hospital, No. 2, Yuh-Der Road, Taichung 404, Taiwan. Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by remission and exacerbation with multisystemic manifestations. SLE can affect every organ directly or indirectly. Coronary artery disease (CAD) has received increasing recognition as a major cause of morbidity and mortality in SLE in recent years and involvement of the cardiovascular system is now considered the third leading cause of death in patients with SLE w1 4x. The reported 1106 ß 2001 British Society for Rheumatology

2 Detection of cardiovascular involvement in SLE 1107 frequency of clinically recognizable CAD in adults with SLE is between 6.1 and 8.9% w5, 6x. However, previous studies had reported that the frequency of subclinical myocardial perfusion abnormalities in patients with SLE is higher w7, 8x. Thus, we need a useful non-invasive method to detect early cardiovascular involvement in SLE patients with non-specific clinical complaints and to prevent later cardiac events. To our knowledge, the evaluation of myocardial perfusion using technetium-99m sestamibi single-photon emission computed tomography ( 99m Tc-sestamibi SPECT) has not been investigated in SLE patients with non-specific clinical symptoms of heart disease, although few data have been reported w7, 8x on the evaluation of myocardial perfusion in asymptomatic lupus patients. The present study aimed to evaluate the utility of 99m Tc-sestamibi SPECT in the detection of cardiovascular involvement in SLE patients with non-specific clinical symptoms of heart disease. Materials and methods Patients Thirty-three SLE female patients (age range: yr) with a definite diagnosis of SLE according to the revised criteria of the American College of Rheumatology w9x were enrolled in this study. All patients were undergoing various treatments and had low to moderate disease activity. We were concerned that some drugs used in SLE treatment may influence the results of the scan. Therefore, all treatment was withheld for 24 h before 99m Tc-sestamibi myocardial perfusion SPECT. All patients had non-specific clinical complaints such as chest discomfort anduor dyspnoea anduor occasional palpitation and none had a previous operative history of heart disease. In addition, an age- and sex-matched healthy group (24 females; age range: yr) and SLE patients without any cardiovascular symptomsu signs (28 females; age range: yr) were also included as controls in this study. These 28 asymptomatic SLE female patients followed the same procedures as the above symptomatic SLE female patients. Data on anticardiolipin antibodies (acl), chest X-ray, resting ECG and cardiovascular risk factors were also obtained in all SLE patients in this study. 99m Tc-sestamibi myocardial perfusion SPECT A 1-day protocol of 99m Tc-sestamibi myocardial perfusion SPECT at rest and after dipyridamole infusion (0.56 mgukg over 4 min during ECG monitoring) in a stress study was performed in all patients. 99m Tcsestamibi, 10 and 25 mci, was injected in the rest and dipyridamole stress studies, respectively. In the dipyridamole stress imaging, 99m Tc-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 this study. Intravenous aminophylline was given 4 min after the administration of the 99m Tc-sestamibi if patients had discomfort during dipyridamole infusion. SPECT images were acquired 1 h after 99m Tc-sestamibi injection using a large field of view dual-headed gamma camera (ADAC, Vertex plus) equipped with a low-energy, all-purpose, parallel-hole collimator. Data were obtained from 64 projections of 25 s each in the 140 kev photopeak over a 1808 arc in a matrix. A short axis, vertical long axis and horizontal long axis were reconstructed from the raw data by filtered backprojection with a Butterworth filter, with a cut-off frequency of 0.5 and order of 10 in the rest study and a cut-off frequency of 0.66 and order of 5 in the stress study. All images were interpreted blind and separately by at least two experienced nuclear medicine physicians. The classification of the 99m Tc-sestamibi myocardial perfusion SPECT results is shown in Table 1. The results of the 99m Tc-sestamibi uptake pattern were classified into four types including normal, persistent perfusion defect (defects present on both rest and dipyridamole stress images), reversible perfusion defect (defects present only on dipyridamole stress image) and reverse redistribution pattern (defect demonstrated in the redistribution image which is not present in the stress image). The final diagnosis was obtained by consensus where the conclusions of the physicians differed. Results No definite perfusion abnormalities were found in the 24 healthy controls. Detailed results and the data on symptomatic and asymptomatic SLE patients are shown in Tables 2 and 3. Perfusion abnormalities were noted in 27 symptomatic SLE patients (82%) in this study. Seven patients had persistent perfusion defects (Fig. 1), 15 patients had reversible perfusion defects (Fig. 2), one patient had both persistent and reversible perfusion defects, two patients showed the reverse distribution pattern (Fig. 3) and two patients had both reversible perfusion defects and the reverse distribution pattern. The remaining six cases had normal perfusion during rest and after dipyridamole infusion (Fig. 4). However, perfusion abnormalities were detected in 12 cases (43%) in the group of asymptomatic SLE patients (four patients had persistent perfusion defects, five patients had reversible perfusion defects, one patient had both persistent and reversible perfusion defects TABLE 1. Classification SPECT results of 99m Tc-sestamibi myocardial perfusion Myocardial uptake Type Rest Stress Normal Normal Normal Reversible defect Normal Reduced Reverse distribution Reduced Normal Persistent defect Reduced Reduced

3 TABLE 2. Characteristics and findings of 99m Tc-sestamibi myocardial perfusion SPECT in symptomatic SLE patients Case no. Age (yr) SPECT results PD RD RR Clinical symptomsusigns acl Risk factors for CAD Chest X-ray Resting ECG 1 22 Ant, Sep Chest discomfort 2 22 Inf Chest discomfort 3 24 Ant Chest discomfort + Non-specific ST-T change 4 24 Inf Ant Chest discomfort, dyspnoea 5 24 Inf Palpitation + Family history 6 25 Ant Chest discomfort 7 26 Ant Chest discomfort + Non-specific ST-T change 8 27 Ant, Sep, Inf Chest discomfort, palpitation 9 27 Ant, Inf Chest discomfort Ant Chest discomfort Ant, Inf Dyspnoea, palpitation Palpitation Palpitation + Non-specific ST-T change Dyspnoea + Family history Ant, Inf Chest discomfort Ant, Inf Chest discomfort Inf Chest discomfort Ant Inf Chest discomfort, dyspnoea Chest discomfort + Non-specific ST-T change Chest discomfort Ant, Inf, Apex Chest discomfort, palpitation Inf Chest discomfort Non-specific ST-T change Ant Chest discomfort Ant Dyspnoea + Diabetes mellitus Ant Chest discomfort Ant Chest discomfort Inf Chest discomfort Hypertension Ant, Inf Chest discomfort Inf Chest discomfort, palpitation Inf Ant Chest discomfort Ant, Inf Chest discomfort Non-specific ST-T change Ant, Inf, Apex Chest discomfort Palpitation + Hypertension 1108 S.-S. Sun et al. PD, persistent defect; RD, reversible defect; RR, reverse distribution; Ant, anterior segment; Inf, inferior segment; Sep, septal segment;, negative finding.

4 Detection of cardiovascular involvement in SLE 1109 TABLE 3. Characteristics and findings of 99m Tc-sestamibi myocardial perfusion SPECT in asymptomatic SLE patients Case no. Age (yr) SPECT results PD RD RR acl Risk factors for CAD Chest X-ray Resting EKG Ant Inf Inf Ant, Sep 9 25 Ant, Sep + Non-specific ST-T change Family history Inf Ant + Family history Non-specific ST-T change Inf Ant Non-specific ST-T change Family history Ant Ant Sep Hypertension Hypertension Ant, Inf PD, persistent defect; RD, reversible defect; RR, reverse distribution; Ant, anterior segment; Inf, inferior segment; Sep, septal segment;, negative finding. FIG m Tc-sestamibi myocardial perfusion SPECT of case no. 4 with a persistent defect in the inferior wall (arrows) during rest and after dipyridamole infusion. FIG m Tc-sestamibi myocardial perfusion SPECT of case no. 2 with a reversible defect in the inferior wall (arrows) after dipyridamole infusion.

5 1110 S.-S. Sun et al. FIG m Tc-sestamibi myocardial perfusion SPECT of case no. 5 with a reverse distribution in the inferior wall (arrows) during rest. FIG. 4. Normal perfusion during rest and after dipyridamole infusion in 99m Tc-sestamibi myocardial perfusion SPECT of case no. 33. and two patients showed the reverse redistribution pattern). ECG had a minor positive change with slight ST-depression (<1 mm) in three patients of the symptomatic SLE patient group and one patient of the asymptomatic SLE patient group. Ten patients of the symptomatic SLE patient group and three patients of the asymptomatic SLE patient group experienced some discomfort during the dipyridamole stress test (dizziness anduor headache anduor flushing anduor chest pain). However, all discomfort symptomsu signs were mild, well-tolerated and promptly reversed by aminophylline. No ECG change and no chest discomfort symptomsusigns were found after dipyridamole infusion in the healthy group. No significant adverse reaction occurred in any patient after dipyridamole infusion in this study. No definite correlation was found between clinical features and acl data and the results of SPECT in our study. Discussion Cardiovascular involvement is one of the most important complications of SLE and may contribute significantly to the morbidity and mortality w10, 11x. However, the diagnosis of cardiovascular involvement in SLE is difficult because clinical manifestations have been reported in only a small percentage of SLE patients and because of the lack of effective non-invasive imaging methods for the detection of cardiovascular involvement when SLE patients have non-specific clinical complaints. Autopsy studies w12, 13x have also documented that the heart is affected in most patients, but clinical manifestations occur in less than 10%. A previous study w7x described that the restudipyridamole 99m Tc-sestamibi myocardial SPECT can be a useful noninvasive method to identify subclinical myocardial involvement in SLE patients without definite clinical symptoms. In this study, 33 lupus patients with nonspecific clinical complaints such as chest discomfort anduor dyspnoea anduor occasional palpitation were investigated and abnormal myocardial perfusion defects were detected in 27 patients using restudipyridamole 99m Tc-sestamibi myocardial SPECT. It is not surprising that a high prevalence (27 of 33 symptomatic SLE patients; 82%) was revealed in this study because a high prevalence (43%) was also noted in the asymptomatic SLE patient group, which was similar to the results of a previous study w8x. The clinical features of SLE patients related to cardiovascular diseases (pericarditis, myocarditis, valvular disease, CAD, etc.) such as chest discomfort, dyspnoea and occasional palpitation are non-specific clinical symptoms because all cardiac abnormalities may have these symptoms w1x. Thus, the complaints of the SLE patients in this study were non-specific. The pathogenesis of CAD in SLE patients is thought to be multifactorial with disease- and treatment-related factors, as well as independent cardiovascular risk factors contributing to the overall risk w5x. The pathological findings of the myocardium include interstitial infiltration with lymphocytes and neutrophils, coronary vasculitis, anterior intimal proliferation, myocardial degeneration, fibrosis and scarring; all these abnormalities are mainly attributed to the primary immunological damage caused by the lupus process w1x. In our series, none of these patients was submitted to coronary angiography. Schillaci et al. w7x reported that normal results of

6 Detection of cardiovascular involvement in SLE 1111 coronary angiography were noted in all SLE patients with positive 99m Tc-sestamibi myocardial SPECT scan. These findings suggest intramyocardial small vessel disease due to the primary immunological damage of SLE. We also found that four of the six patients with normal results on 99m Tc-sestamibi myocardial SPECT scan received high-dose corticosteroid therapy over a long period of time. However, we did not have a complete record of corticosteroid doses from the time of initial therapy in most patients and thus we could not obtain statistical differences in this study. Whether there is a relationship between corticosteroid therapy and myocardial perfusion defects in SLE patients needs further investigation. The possible causes of myocardial perfusion abnormalities in SPECT studies in SLE patients include atherosclerosis anduor vasculitis. Therefore, the possible treatments of SLE patients with altered SPECT include high-dose steroids, percutaneous transluminal coronary angioplasty and bypass surgery. After reviewing the previous literature, we found only one possibly related autoantibody (acl) to cardiovascular involvement in SLE patients w14x. However, we found no significant correlation between the data on acl and the results of SPECT in our study. Although at least six common indices (such as BILAG, ECLAM, LAI, SIS, SLAM and SLEDAI) are routinely used to calculate SLE activity index, none of these indices focuses on cardiovascular involvement in SLE w15x. According to a previous study w16x, there was no difference in SLE activity (SLEDAI) score between patients with positive SPECT results and those with negative SPECT results. Thus, we did not calculate SLEDAI to correlate the SPECT results in this study. In conclusion, our results show that 99m Tc-sestamibi myocardial perfusion SPECT is a useful non-invasive imaging method to detect early cardiovascular involvement in SLE patients with non-specific clinical complaints. Further follow-up studies are needed to evaluate whether patients with these perfusion defects are at risk of later cardiac events. References 1. Doherty NE, Siegel RJ. Cardiovascular manifestations of systemic lupus erythematosus. Am Heart J 1985; 110: Rubin LA, Urowitz MB, Gladman DD. Mortality in systemic lupus erythematosus: the bimodal pattern revisited. Q J Med 1985;55: Wallace DJ, Podell T, Weiner J, Klinenberg JR, Forouzesh S, Dubois EL. Systemic lupus erythematosus survival patterns. Experience with 609 patients. J Am Med Assoc 1981;245: Gladman DD, Urowitz MB. Morbidity in systemic lupus erythematosus. J Rheumatol 1987;14: Petri M, Perez-Gutthann S, Spence D, Hochberg MC. Risk factors for coronary artery disease in patients with systemic lupus erythematosus. Am J Med 1992;93: Shome GP, Sakauchi M, Yamane K, Takemura H, Kashiwagi H. Ischemic heart disease in systemic lupus erythematosus. A retrospective study of 65 patients treated with prednisolone. Jpn J Med 1989;28: Schillaci O, Lagana B, Danieli R et al. Technetium-99m sestamibi single-photon emission tomography detects subclinical myocardial perfusion abnormalities in patients with systemic lupus erythematosus. Eur J Nucl Med 1999;26: Hosenpud JD, Montanaro A, Hart MV et al. Myocardial perfusion abnormalities in asymptomatic patients with systemic lupus erythematosus. Am J Med 1984;77: Tan EM, Cohen AS, Fries JF et al. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1982;25: Crozier IG, Li E, Milne MJ, Nicholls MG. Cardiac involvement in systemic lupus erythematosus detected by echocardiography. Am J Cardiol 1990;65: Ansari A, Larson PH, Bates HD. Cardiovascular manifestations of systemic lupus erythematosus: current perspective. Prog Cardiovasc Dis 1985;27: Mandell BF. Cardiovascular involvement in systemic lupus erythematosus. Semin Arthritis Rheum 1987;17: Estes D, Christian CL. The natural history of systemic lupus erythematosus by prospective analysis. Medicine 1971;50: Sturfelt G, Eskilsson J, Nived O, Truedsson L, Valind S. Cardiovascular disease in systemic lupus erythematosus a study of 75 patients from a defined population. Medicine 1992;71: Strand V, Gladman D, Isenberg D, Petri M, Smolen J, Tugwell P. Outcome measures to be used in clinical trials in systemic lupus erythematosus. J Rheumatol 1999; 26: Gazarian M, Feldman BM, Benson LN, Gilday DL, Laxer RM, Silverman ED. Assessment of myocardial perfusion and function in childhood systemic lupus erythematosus. J Pediatr 1998;132: