Premature Coronary Artery Disease in Systemic Lupus Erythematosus with Extensive Reocclusion Following Coronary Artery Bypass Su

Advances in medical therapy and a better understanding of systemic lupus erythematosus (SLE) have contributed to a dramatic improvement in the long-term survival of patients. However, despite the overall long-term improvement, coronary artery disease remains a major cause of morbidity and mortality1 (Table 1) with an incidence that is approximately nine-fold greater than would be expected for this population.2 Following active lupus, coronary artery disease is the second most common cause of hospitalization for SLE patients.3 Manzi et al. found that, when controlled for age and gender, women with SLE who are 35–44 years old have a 50-times higher risk of myocardial infarction (MI).4 Previous autopsy studies have observed that severe coronary artery disease is present in as many as 40% of patients with SLE compared with only 2% of age-matched controls at the time of death.5,6 Etiologies of myocardial damage in SLE patients include premature atherosclerotic disease,7 antiphospholipid antibody syndrome,8 coronary artery spasm,9 coronary artery vasculitis10 and restenosis after percutaneous revascularization procedures. The present case illustrates the importance and challenge of differentiating among these etiologies, especially since the therapies used are different in each situation. The following discussion will focus on the diagnosis and pathogenesis of coronary artery disease with an emphasis on premature atherosclerosis and coronary vasculitis in patients with SLE. Case Report. A 21-year-old woman presented to the emergency room with a chief complaint of substernal chest pain. The pain was scaled a 9/10, was non-radiating and not associated with diaphoresis, dizziness, nausea or vomiting. The patient had a history of SLE, with a positive ANA and double-stranded DNA antibodies seven years ago. Clinical manifestations included a malar rash and joint swelling. Subsequently, the patient was only treated with hydroxychloroquine. As a child she had several hospitalizations for lupus flares for which she was treated with short courses of steroids. She had no history of pregnancy, deep venous thrombosis, pulmonary embolus or migraine headaches. She had undergone a four-vessel coronary artery bypass graft operation in June of 2000 with separate saphenous vein grafts to the left anterior descending (LAD), obtuse marginal (OM) 1 and 2, and distal right coronary arteries (RCA) 4 months prior to admission. At that time, a biopsy was taken of the internal mammary artery that reported a chronic mural inflammatory infiltrate composed of lymphocytes and occasional eosinophils (Figure 1). Her medications included enteric-coated aspirin 325 mg QD, metoprolol 25 mg BID, omeprazole 30 mg QD and hydroxychloroquine 200 mg QD. She reported allergies to sulfonamides, clarithromycin, metronidazole, nifedipine and ranitidine. The patient denied any family history of hypercholesterolemia or coronary artery disease. She reported a history of tobacco use of one pack per day for 2 years, but this was discontinued one month prior to admission. There was no history of drug or alcohol use. Physical exam revealed a well-developed young female who was alert and in no acute distress. Vital signs showed arterial pressure of 117/66 mmHg, pulse rate of 85 bpm, respiratory rate of 16/minute, and temperature of 99 °F. The patient had no rash, oral ulcers, alopecia or adenopathy. Her chest had a sternotomy scar and her lungs were clear bilaterally. Auscultation of the heart revealed a regular rate and rhythm with normal heart sounds without murmur, gallop or rub. Her abdominal exam was benign. Extremity examination did not show clubbing, cyanosis or edema. Joint examination revealed mild erythema of the metacarpophalangeal joints bilaterally without associated swelling. Laboratory evaluation: white blood count, 7,700/mm3 with a mild lymphopenia; hematocrit, 36%; mean corpuscular volume, 76 µm3; and platelets, 188,000/mm3. Erythrocyte sedimentation rate (ESR) was 55 mm/hour and C-reactive protein (CRP) was 0.2 mg/dl. A chemistry panel was normal including a BUN/Cr of 17/0.9 mg/dl, respectively. Creatine phosphokinase (CPK) was 740 IU/L; MB was 112.6 IU/L; troponin I was 10.9 ng/ml (all positive for myocardial infarction). A lipid profile showed total cholesterol of 157 mg/dl, high-density lipoprotein of 58 mg/dl and low-density lipoprotein of 86 mg/dl. Lipoprotein (a) was 15 mg/dl (0–30 mg/dl) and homocysteine level was 10 µmol/L (5–15 µmol/L). Immunologic studies revealed the following: ANA titer of 1:320; anti-DS DNA titer Discussion Premature atherosclerotic disease. Premature atherosclerotic disease remains the leading cause of myocardial infarction in patients with SLE. It has been observed that patients with SLE have an elevated number of conventional risk factors — especially obesity, hypertension and hyperlipidemia.14 The incidence of MI and angina in women with SLE has been compared to patients in the Framingham Offspring study.15 It was observed that of 498 women with SLE, thirty (6.6%) developed CAD compared with 36 of 2,208 women (1.6%) in the Framingham Offspring Study. In addition, MI was not recorded in any woman in the Framingham cohort below the age of 34 years, but was reported in all age groups in the SLE cohort. The above study and others16 have helped confirm that the onset of CAD in SLE patients is premature, often occurring in premenopausal women. The occurrence of MI and stroke in SLE was compared with expected outcomes, using the risk factor profile according to the Framingham regression model. After removing the effect of Framingham risk factors, the risk for MI was still increased (relative risk, 8.3; 95% CI, 4.9–12.4).17 These data suggest that the “classic” CAD risk factors do not account for the whole risk of CAD in patients with SLE. Duration of SLE has been shown to influence the risk of dying from atherosclerosis, with patients having duration of disease >= 5 years at the highest risk.18 Several studies have shown that lipid abnormalities occur in untreated SLE. This dysbetalipidemia is characterized by elevated triglycerides (TG) and very low-density lipoprotein cholesterol (VLDL-C); while levels of high-density lipoprotein cholesterol (HDL-C), and apolipoprotein (Apo) A-1 are reduced.19 The occurrence of these lipid abnormalities in untreated SLE suggests that the disease itself may promote atherosclerosis, possibly due to the effect of inflammatory cytokines.20 Anticardiolipin antibodies may also influence lipid levels. In one study, patients with IgG anticardiolipin antibodies who were not on steroids had significantly lower HDL-C levels compared to patients without anticardiolipin antibodies.21 Prior to the use of corticosteroids, coronary atherosclerosis was rarely described in patients with SLE.5 Thus, treatment of SLE, particularly with corticosteroids, has been found to be pro-atherogenic in addition to the disease itself. Steroid therapy is associated with increased total cholesterol (TC), VLDL-C, LDL-C, and TG levels.14,22 Petri et al. noted that a prednisone dose of greater than 10 mg daily was a significant predictor of hypercholesterolemia.10 In addition, it was noted that a 10 mg increase in prednisone dose was associated with a 7.5% change in serum cholesterol level after adjustment for all other variables.10 Another study reported that the lumen of at least one of the three major coronary arteries was narrowed more than 50% by atherosclerotic plaque in 42% of patients who received corticosteroids for more than 1 year, but in none of the patients who received corticosteroids for less than 1 year.23 Another study demonstrated that patients who received corticosteroids for long periods of time for rheumatoid arthritis had calcified deposits in peripheral vessels three times more frequently and far more extensively than patients with or without rheumatoid arthritis who did not receive corticosteroid therapy.24 Prednisone may also promote hypertension due to water and sodium retention,25 increase left ventricular hypertrophy,24 promote hyperglycemia26 and increase homocysteine levels.15 It has been suggested that by increasing life expectancy prednisone may allow more time for atherosclerosis to develop.27 However, autopsy studies by Fukumoto et al. concluded that disease activity and duration play a greater role in the development of coronary artery disease in SLE patients than intensity or length of corticosteroid treatment.28 Although contrasting study conclusions also exist, the evidence for corticosteroids as a risk factor for premature atherogenesis in SLE patients is becoming more convincing. Lipoprotein (a) is considered an independent risk factor for CAD and has been detected in large amounts in human coronary atheroma and predominately in acute coronary syndromes. According to Dangas et al., lipoprotein (a) is detected in larger amounts in tissue from culprit lesions in patients with unstable compared to stable syndromes, and remains ubiquitous in human coronary atheroma.29,30 Lipoprotein (a) was found to be significantly higher in white SLE patients compared to age-matched patients without SLE, and was independently associated with MI in this SLE population.31 Homocysteine is also considered a risk factor for CAD and other thrombotic disorders,32 and is also implicated in accelerated atherogenesis in SLE patients. A study measured plasma homocysteine in 337 patients with SLE and found elevated levels in 15% of patients; levels were higher in males, in patients with renal impairment, in those receiving steroid therapy, and in those with abnormal Russel Viper venom.33 Another study recorded clinical parameters in 22 autopsy patients with SLE and found that ten patients with > 75% narrowing of the coronary arteries had a significantly higher frequency of pericardial adhesions and mitral valve abnormalities as compared to 12 patients with SLE who had less than 75% narrowing. This suggests that local immunologic factors or SLE activity may play a role in accelerating atherogenesis.6 Coronary vasculitis. Coronary artery vasculitis remains an infrequent complication of SLE. Prior to the widespread use of coronary angiography, coronary vasculitis was a post mortem diagnosis. Coronary angiography has helped in evaluating patients with suspected coronary vasculitis.34 It has been suggested that a rapid rate of progression of coronary lesions is more suggestive of a vasculitic process and, therefore, single angiographic studies may be inadequate.35 One case report documented a tertiary referral center experience where only two patients younger than 35 years of age with coronary vasculitis were identified over a period of 40 years.34 A possible mechanism of arterial injury in SLE might be the development of auto-antibodies that may target the heart or the blood vessels. According to Dangas et al., there are increased auto-antibodies against actin and myosin during and after an acute coronary syndrome.36 The present case represents only the fourth case reported in detail with SLE and coronary artery disease in a patient younger than 21 years old. The diagnosis of coronary vasculitis secondary to SLE in this case is suggested by the documentation of the diagnosis of SLE, the absence of classic risk factors for atherosclerotic heart disease (no evidence of diabetes, hypertension, family history of CAD or smoking) and the occurrence of angina pectoris or myocardial infarction at a young age. In addition to premature coronary artery disease, there was clearly a rapid change in the patient’s anatomy after coronary artery bypass graft surgery with total occlusion of 3 out of 4 grafts over only a 4-month period. The fourth graft displayed segmental narrowing. This is higher than early occlusion rates reported in multiple trials.37,38 Also, the internal mammary artery of our patient displayed areas of fibrosis and intimal thickening per the operative report, precluding its use as a graft. These events suggest vasculitis as a possible etiology for her deterioration, as is suggested from the pathology slide. Immune complex deposition in the coronary artery walls in patients with SLE have been documented via immunofluorescence studies,22 and the relationship between inflammatory immunologic injury and atherosclerosis has been demonstrated experimentally.39 Similar immune complex deposition in coronary vessels of SLE patients may predispose to intimal thickening and atherosclerosis, thus increasing the frequency of myocardial infarction. Histologic findings at autopsy have displayed both neutrophilic and lymphocytic infiltration, fibrinoid necrosis and immune complex deposition. Hypercoagulability. Hypercoagulability in SLE patients is well recognized. Patients with SLE may have arterial and/or venous thromboses.40,41 Thrombosis has been associated with the presence of a lupus anticoagulant (LAC) or antiphospholipid antibodies (APA) as part of a secondary antiphospholipid syndrome (APS). It has been noted that APA may promote cross-reactivity with anticardiolipin (aCL) binding to both the cardiolipin-protein complex and to oxidized low-density lipoprotein (LDL) cholesterol42–45 linking oxidation, inflammation, autoimmunity, atherosclerosis and thrombosis.46 However, it has also been suggested that the development of the antibody is an epiphenomenon as part of an immune reaction to vascular injury. The precise role of APA in coronary artery disease in SLE patients remains unclear.27 In addition, most studies have been retrospective and screened patients for APA after a thrombotic event had occurred.47 Thus, it has been debated whether the observed associations are causative or whether they are only markers for an inflammatory or immune response causing vascular injury.27 Interestingly, Vaarala et al. designed a prospective 5-year study in which it was found that the APA levels were significantly higher in patients with MI than in age- and gender-matched controls, even after adjusting for conventional risk factors.48 Young patients with SLE may be predisposed to microvascular thrombosis. Microvascular thrombosis in mildly atherosclerotic coronary arteries has been described in a 22-year-old woman with SLE and extensive myocardial necrosis.49 Another case report described a 29-year-old non-lupus patient with primary APS.50 Conclusion. The pathogenesis of coronary artery disease in young patients with SLE appears to be multifactorial and includes accelerated atherosclerosis, vasculitis and hypercoagulable states, and thus may require multidisciplinary treatment modalities.

1. Urowitz MB, Bookman AA, Koehler B, et al. The bimodal mortality pattern of systemic lupus erythematosus. Am J Med 1976;60:221–225. 2. Jonsson H, Nived O, Sturfelt G. Outcome in systemic lupus erythematosus: A prospective study of patients from a defined population. Medicine 1989;68:141–150. 3. Petri M, Genovese M. Incidence of and risk factors for hospitalizations in systemic lupus erythematosus: A prospective study of the Hopkins Lupus Cohort. J Rheumatol 1992;19:1559–1565. 4. Manzi S, Meilahn EN, Rairie JE, et al. Age-specific incidence rates of myocardial infarction and angina in women with systemic lupus erythematosus: Comparison with the Framingham study. Am J Epidemiol 1997;145:408–415. 5. Heibel RH, O’Toole JD, Curtiss EI, et al. Coronary arteritis in systemic lupus erythematosus. Chest 1976;69:700–703. 6. Haider YS, Roberts WC. Coronary artery disease in systemic lupus erythematosus quantification of degrees of narrowing in 22 necropsy patients aged 16 to 36 years. Am J Med 1981;70:775–781. 7. Tsakraklides VG, Blieden LC, Edwards JE. Coronary atherosclerosis and myocardial infarction due to lupus erythematosus. Am Heart J 1974;87:637–641. 8. Kaplan SD, Chartash EK, Pizzarello RA, Furie RA. Cardiac manifestations of the antiphospholipid syndrome. Am Heart J 1992;124:1331–1338. 9. Takatsu Y, Hattori R, Sakaguchi K, et al. Acute myocardial infarction associated with systemic lupus erythematosus documented by coronary angiograms. Chest 1985;88:147–149. 10. Bonfiglio TA, Botti RE, Hagstrom JWC. Coronary arteritis, occlusion and myocardial infarction due to lupus erythematosus. Am Heart J 1972;83:153–158. 11. Petri M, Lakatta C, Magder L, et al. Effect of predinisone and hydroxychloroquine on coronary artery disease risk factors in systemic lupus erythematosus: A longitudinal data analysis. Am J Med 1994;96:254–259. 12. Fauci AS, Katz P, Haynes BF, Wolff SM. Cyclophosphamide therapy of severe necrotizing vasculitis. N Engl J Med 1979;301:235–238. 13. Haynes BF, Allen NB, Fauci AS. Diagnosis and therapeutic approach to the patient with vasculitis. Med Clin North Am 1986;70:355. 14. Petri M, Spence D, Bone LR, et al. Coronary artery disease risk factors in the Johns Hopkins Lupus Cohort: Prevalence, recognition by patients, and preventative practices. Medicine 1992;71:291–302. 15. Manzi S, Selzer F, Sutton-Tyrrell K, et al. Prevalence and risk factors of carotid plaque in women with systemic lupus erythematosus. Arthritis Rheum 1999;42:51–60. 16. Ward MM. Premature morbidity from cardiovascular and cerebrovascular disease in women with systemic lupus erythematosus. Arthritis Rheum 1999;42:338–346. 17. Esdaile JM, Abrahamowicz M, Grodzicky T, et al. Myocardial infarction (MI) and stroke in SLE: Marked increased incidence after controlling for risk factors. Arthritis Rheum 1998;41(Suppl):S139. 18. Abu-Sharka M, Urowitz MB, Gladman DD, Gough J. Mortality studies in systemic lupus erythematosus. Results from a single center. I. Causes of death. J Rheumatol 1995;22:1259–1264. 19. Ilowite NT, Samuel P, Ginzler E, et al. Dysbetalipoproteinemia in pediatric systemic lupus erythematosus. Arthritis Rheum 1988;31:859–863. 20. Lahita RG, Rivkin E, Cavanagh I, et al. Low levels of total cholesterol, high-density lipoprotein, and apolipoprotein A1 in association with anticardiolipin antibodies in patients with systemic lupus erythematosus. Arthritis Rheum 1993;36:1566–1574. 21. Ettinger WH, Goldberg AP, Appelbaum-Bowden D, et al. Dysbetalipoproteinemia in systemic lupus erythematosus. Effect of steroids. Am J Med 1987;83:503–508. 22. Minick CR, Alonso DR, Rankin L. Role of immunologic arterial injury in atherogenesis. Thromb Haemost 1978;39:304–311. 23. Buckley BH, Roberts WC. The heart in systemic lupus erythematosus and the changes induced in it by corticosteroid therapy: A study of 36 necropsy patients. Am J Med 1975;58:243–264. 24. Kalbak K. Incidence of arteriosclerosis in patients with rheumatoid arthritis receiving long-term corticosteroid therapy. Ann Rheum Dis 1972;31:196. 25. 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;93:513–519. 26. Axelrod L. Glucocorticoid therapy. Medicine 1976;55:39–65. 27. Moder KG, Miller TD, Tazelaar HD. Cardiac involvement in systemic lupus erythematosus (Review). Mayo Clinic Proc 1999;74:275–284. 28. Fukomoto S, Tsumagari T, Kinso M, et al. Coronary atherosclerosis in patients with systemic lupus erythematosus at autopsy. Acta Pathol Jpn 1987;37:1–9. 29. Dangas G, Mehran R, Harpel PC, et al. Lipoprotein (a) and inflammation in human coronary atheroma: Association with the severity of clinical presentation. J Am Coll Cardiol 1998;32:2035–2042. 30. Dangas G, Ambrose JA, D’Agate DJ, et al. Correlation of serum lipoprotein (a) with the angiographic and clinical presentation of coronary artery disease. Am J Cardiol 1999;83:583–585. 31. Petri M, Miller J, Ebert RF, et al. Lipoprotein (a) [Lp(a)] is predictive of myocardial infarction in SLE. Arthritis Rheum 1995;38(Suppl):S220. 32. Clarke R, Daly L, Robinson K, et al. Hyperhomocysteinemia: An independent risk factor for vascular disease. N Engl J Med 1991;324:1149–1155. 33. Petri M, Roubernoff R, Dallal GE, et al. Plasma homocysteine as a risk factor for atherothrombotic events in systemic lupus erythematosus. Lancet 1996;348:1120–1124. 34. Homcy CJ, Liberthson RR, Fallon JT, et al. Ischemic heart disease in systemic lupus erythematosus in the young patient: Report of six cases. Am J Cardiol 1982;49:478–484. 35. Gould SE. Pathology of the Heart and Blood Vessels. Springfield Illinois, Charles C. Thomas, 1968: pp. 582–584. 36. Dangas G, Konstadoulakis MM, Epstein SE, et al. Prevalence of autoantibodies against contractile proteins in coronary artery disease and their clinical implications. Am J Cardiol 2000;85:870–872. 37. Gavaghan TP, Bebski V, Baron DW. Immediate postoperative aspirin improves vein graft patency early and late after coronary artery bypass graft surgery: A placebo controlled randomized trial. Circulation 1991;8:1526–1533. 38. Goldman S, Copeland J, Moritz T, et al. Starting aspirin therapy after operation: Effects on early graft patency. Circulation 1991;84:520–526. 39. Kabakov AE, Tertov VV, Saenko VA, et al. The atherogenic effect of lupus sera: Systemic lupus erythematosus-derived immune complexes stimulate the accumulation of cholesterol in cultured smooth muscle cells from human aorta. Clin Immunol Immunopathol 1992;63:214–220. 40. Wahl DG, Guillemin F, de Maistre E, et al. Risk of venous thrombosis related to antiphospholipid antibodies in systemic lupus erythematosus. Lupus 1997;6:467–473. 41. Wu R, Nityanand S, Berglund L, et al. Antibodies to cardiolipin and oxidatively modified LDL in 50-year-old men predict myocardial infarction. Atheroscler Thromb Vasc Biol 1997;17:3159–3163. 42. Mitzutani H, Kurata Y, Kosugi S. Monoclonal anticardiolipin autoantibodies established from (New Zealand white x BXSF)F1 mouse model of antiphospholipid syndrome cross-react with oxidized low-density lipoprotein. Arthitis Rheum 1995;38:1382–1388. 43. Vaarala O, Puurunen M, Lukka M. Affinity-purified cardiolipin-binding antibodies show heterogeneity in their binding to oxidized low-density lipoprotein. Clin Exp Immunol 1996;104:269–274. 44. Horkko S, Miller E, Dudi E. Antiphospholipid antibodies are directed against epitopes of oxidized phospholipids. J Clin Invest 1996;98:815–825. 45. Palinski W, Horkko Miller E. Cloning of monoclonal antibodies to epitopes of oxidized lipoproteins from apolipoprotein E-deficient mice. J Clin Invest 1996;98:800–814. 46. Ames PRJ. Medical perspective on antiphospholipid antibodies, thrombosis and atherosclerosis in systemic lupus erythematosus: A unifying “membrane stress syndrome” hypothesis. Lupus 1994;3:371–377. 47. Love PE, Santoro SA. Antiphospholipid antibodies: Anticardiolipin and the lupus anticoagulant in systemic lupus erythematosus (SLE) and in non-SLE disorders. Prevalence and clinical significance. Ann Intern Med 1990;112:682–698. 48. Vaarala O, Manttari M, Manninen V, et al. Anticardiolipin antibodies and the risk of myocardial infarction in a prospective cohort of middle-aged men. Circulation 1995;1:23–27. 49. Brown JH, Doherty CC, Allen DC, Morton P. Fatal cardiac failure due to cardiac microthrombi in systemic lupus erythematosus. Br Med J 1988;296:1505. 50. Kattwinkel N, Villanueva AG, Labib SB, et al. Myocardial infarction caused by cardiac microvasculopathy in a patient with the primary antiphospholipid syndrome. Ann Intern Med 1992;116:974–976.