Premature atherosclerosis and acute coronary syndrome in systemic lupus erythematosus

Amal Mattu MD^a,1, Joyce Petrini MD^b, Sharon Swencki MD^c,

Chirag Chaudhari MD^d, William J. Brady MD^e,*

^aUniversity of Maryland School of Medicine, Baltimore, MD 21201, USA

^bJeanes Hospital-Temple University Health System, Philadelphia, PA 19111, USA

^cUniversity of Maryland Medical Center, Baltimore, MD 21201, USA ^dBaltimore Washington Medical Center, Glen Burnie, MD 21061, USA ^eUniversity of Virginia School of Medicine, Charlottesville, VA 22908, USA

Received 21 December 2004; accepted 22 December 2004

Abstract systemic lupus erythematosus is a vasculitic disorder with potential for multisystem organ dysfunction. Among the organ systems affected is the cardiovascular system. Patients with SLE are prone to premature atherosclerosis; this premature atherosclerosis places the patient at risk for myocardial infarction with onset at a relatively young age. We present 4 patients with SLE who experienced myocardial infarction; these patients also experienced diagnostic and treatment delays because of their relatively young age at presentation. Relevant pathophysiology and Diagnostic strategies are discussed.

D 2005

Introduction

systemic lupus erythematosus is a multisystem autoimmune disorder that is common in the general popu- lation. Its prevalence is estimated to be 1 in 2000, with a 10:1 female predominance [1,2]. Emergency physicians treat many of these patients for a number of different complica- tions of SLE, as the disorder can affect any tissue or organ.

T Corresponding author. Tel.: +1 434 924 8485; fax: +1 434 982 2877,

4118.

E-mail addresses: [email protected] (A. Mattu)8 [email protected] (W.J. Brady).

¹ Address for Reader Correspondence: Amal Mattu, MD, Department of Emergency Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.

Among the organ systems affected is the cardiovascular system. It is well known that patients with SLE are prone to the development of myocarditis, pericarditis, nonInfectious endocarditis, and vasculitis [3]. Perhaps of even greater concern, however, is that patients with SLE are prone to premature atherosclerosis, with incidence of atherosclerosis- related myocardial infarction (MI) in young patients as much as 50-fold greater than age-matched controls [4]. The fact that SLE is an independent risk factor for premature atherosclerosis and early MI is well reported in the cardiology and rheumatology literature, but to date, this important concept has not yet been reported in the emergency medicine literature or in the major emergency medicine textbooks [2,3,5].

We present 4 cases of young patients with acute MI in whom SLE was the major cardiac risk factor. In each of the

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case presentations”>first 3 cases, delays in management were caused by a lack of knowledge of the association of SLE with premature atherosclerosis by multiple physicians in different special- ties. A brief review of the literature on this topic follows. This case series represents the first report in the emergency medicine literature pertaining to premature atherosclerosis and early MI in patients with SLE. Emergency physicians should maintain a low threshold for performing a workup for acute coronary syndrome (ACS) in patients with SLE, regardless of age, when those patients present to the ED with Cardiopulmonary symptoms.

Case presentations

Case 1

A 24-year-old African-American man presented to a community hospital ED complaining of sharp midsternal chest pain and mild dyspnea. The chest pain was not posi- tional or pleuritic, and it did not radiate. The pain had been intermittent for the prior 12 hours. The patient was asymptomatic upon arrival to the ED. The patient reported chronic joint aches which were unchanged from their baseline. He had no diaphoresis, nausea, or cough. His medical history was notable for SLE, which had been diagnosed approximately 4 years earlier. He reported that he smoked less than a half pack of cigarettes on a daily basis

for the prior 3 years, but he denied any history of illicit drug use. He had no history of hyperlipidemia or other cardiac risk factors. His vital signs (VS) were all normal. His physical examination was notable for a nontender chest wall and normal cardiac and lung examinations.

An electrocardiogram (ECG) was obtained (Fig. 1) and demonstrated Sinus bradycardia (rate 50 beats per minute), high left ventricular voltage, and slight terminal inversions of the T waves in the midprecordial leads. No abnormalities were seen in laboratory studies, including cardiac markers, and chest radiography.

The patient was admitted to the hospital and remained asymptomatic; he ruled out for MI based on cardiac marker testing. No further ECG or ACS provocative testing was performed in the hospital. After ruling out for MI, the patient was discharged home.

During the next 24 hours, the patient developed Recurrent episodes of chest pain and dyspnea, prompting a repeat visit to the ED. His history and physical examination demon- strated no new findings except for bradycardia. A repeat ECG was performed (Fig. 2) and demonstrated further progression of the T-wave abnormality in the midprecordial leads. No abnormalities were seen in laboratory studies, including cardiac markers. The intensive care physician and cardiologist on call were consulted to see the patient. Because of the patient’s history of lupus, pericarditis or myocarditis was the primary suspected diagnosis. ACS was discounted, once again because of the patient’s apparent

Fig. 1 ECG from Case One with sinus bradycardia, left ventricular hypertrophy by voltage criteria, and terminal inversions of the T-waves in the mid-precordial leads.

Fig. 2 Repeat ECG the following day from Case One with further progression of the T-wave abnormality in the mid-precordial leads.

lack of cardiac risk factors. Nevertheless, because of the ECG abnormality, the patient transferred to a university hospital for urgent cardiac catheterization, which demon- strated a bnear-completeQ thrombotic occlusion of the left anterior descending artery. The patient received a coronary stent and did well.

Case 2

A 31-year-old African-American woman presented to a community hospital ED complaining of onset of left chest pain while at rest approximately 90 minutes before arrival. The pain was pleuritic in nature and worsened when she laid flat. She reported mild dyspnea but no diaphoresis, nausea, or any other complaints. Her medical history was notable for SLE, diagnosed 10 years earlier, and she had developed pericarditis 5 years earlier. Her only medication was hydroxychloroquine. She denied any history of tobacco or illicit drug use, and she had no cardiac risk factors. Her VS were notable only for a heart rate of 105 beats per minute and respiratory rate 22 breaths per minute. No abnormalities were seen in her examinations, including cardiac, lung, and chest wall examinations. No murmurs or rubs were present.

An ECG was performed and demonstrated (Fig. 3) ST- segment elevations in leads I, aVL, and V₂ to V₄ with ST- segment depressions in leads II, III, and aVF consistent with an acute anterolateral MI with reciprocal change. No

abnormalities were seen in an initial set of laboratory studies including cardiac markers, as well as in a chest radiograph. Despite the presence of Reciprocal changes on the ECG, the emergency physician caring for the patient suspected a diagnosis of acute pericarditis, primarily because of the patient’s history of SLE. The treating cardiologist agreed with a probable diagnosis of pericarditis and recommended treating the patient with aspirin, b-blockers, and nitroglyc- erin and repeating cardiac marker testing after only 2 hours. The second set of cardiac markers confirmed an acute MI: creatine kinase (CK) 436 U/L, CK-MB 46.5 ng/mL, and troponin I 6.9 ng/mL. The patient was then emergently transferred to a tertiary care center for percutaneous coronary intervention, where she was discovered to have a 100% thrombotic occlusion of the LAD. A coronary stent

was placed, and the patient did well.

Case 3

A 25-year-old white woman presented to a community hospital ED complaining of onset of midsternal tightness associated with dyspnea, nausea, and 1 episode of vomiting. The pain had been waxing and waning for the previous

18 hours. The pain was worse with exertion and deep inspiration. She had no prior history of similar pain. Her medical history was notable for SLE, diagnosed 7 years earlier, and she had been on prednisone for more than a year. She also reported a history of hypertension for which she took

Fig. 3 ECG from Case Two with ST segment elevation in leads I, aVL, and V2 to V4 with ST segment depression in leads II, III, and aVF consistent with an acute anterolateral MI with reciprocal change.

diltiazem and enalapril daily. She did smoke boccasionalQ cigarettes but denied use of any illicit drugs. Her VS were normal, and her physical examination revealed no abnor- malities as well, including the cardiac examination.

An ECG was performed and (Fig. 4) demonstrated ST- segment elevations in leads II, III, and aVF with ST-segment depressions in leads I, aVL, V₁, and V₂ consistent with an acute inferior wall MI with reciprocal change. Laboratory

Fig. 4 ECG from Case Three with ST segment elevations in leads II, III, and aVF as well as ST segment depressions in leads I, aVL, V1, and V2 consistent with an acute inferior wall MI with reciprocal change.

studies that were initially ordered were notable for a normal CK of 73 U/L and an intermediate troponin I elevation of

0.12 ng/mL. The remainder of the laboratory studies and the chest radiograph revealed no abnormalities.

The patient was treated in the ED with ketorolac and aspirin. Sublingual nitroglycerin was administered as well without much change in the patient’s level of chest discom- fort. The patient was also treated with a proton pump inhibitor, b-blocker, low-molecular-weight heparin, and clopidogrel. The admitting diagnosis was bAtypical chest pain, R/O pericarditis, R/O acute MI.Q

The admitting physician‘s primary suspicion was acute pericarditis based on the patient’s age and absence of signi- ficant risk factors. A cardiologist was also consulted. When the cardiologist saw the patient, a repeat troponin I had become positive, 7.44 ng/mL. The ECG demonstrated improvements in the ST-segment deflections but new T-wave inversions in the inferior leads (Fig. 5). A diagnosis of acute MI was made. The patient was transferred to a university hospital for urgent cardiac catheterization, which demonstrated a 99% distal Right coronary artery stenosis caused by thrombus formation. There was no evidence of vasculitis or Coronary spasm. A Balloon angioplasty with stent was performed successfully, and the patient recovered.

Case 4

A 31-year-old African-American woman presented to the ED complaining of substernal chest pain radiating to the left

shoulder and arm which began several hours before arrival. The pain was persistent and not associated with any identifiable precipitating factors. The pain was neither positional nor pleuritic. Her medical history was notable for hypertension, mild renal insufficiency, and SLE. Her medications included lisinopril, amlodipine, prednisone, and hydroxychloroquine. She denied Tobacco use and had no other cardiac risk factors. The initial VS showed a blood pressure of 200/100 mm Hg and heart rate 100 beats per minute, but the remainder of the VS revealed no abnormal- ities. The physical examination revealed a slightly cush- ingoid appearance; the cardiac examination revealed no abnormalities, and the remainder of the examination was within normal limits.

An ECG was obtained (Fig. 6) and demonstrated sinus tachycardia (rate 102 beats per minute) with ST-segment elevations in leads V₂ to V₄, and minor ST elevations in leads II, III, and aVF as well. PR-segment depressions were also noted in leads II, III, and aVF suggestive of pericarditis. However, the horizontal ST-segment morphology in leads V₃ and V₄ and the absence of any positional changes in the chest pain (eg, supine vs sitting upright) aroused greater suspicion of acute MI. The initial chest radiograph demonstrated mild cardiomegaly but clear lung fields. Initial laboratory studies revealed normal cardiac markers.

ED treatment included aspirin, unfractionated heparin, and sublingual followed by Intravenous nitroglycerin. The emergency physician caring for the patient consulted an interventional cardiologist immediately, and the patient was

Fig. 5 ECG later that day from Case Three with improvements in the ST segment deflections yet new T wave inversions in the inferior leads.

Fig. 6 ECG from case Four with sinus tachycardia and ST segment elevations (obliquely straight morphology) in leads V2 to V4, as well as minor ST segment elevation in leads II, III, and aVF1. PR segment depression were also noted in leads II, III, and aVF suggestive of percarditis.

taken for cardiac catheterization at the same hospital soon thereafter. The catheterization revealed a thrombotic 100% occlusion in the distal LAD. The cardiologist was able to successfully perform balloon angioplasty.

Discussion

SLE is a chronic inflammatory disorder, thought to be of autoimmune origin, which affects many organ systems in the body. Among the organ systems known to be at risk is the cardiovascular system. Well-recognized cardiac manifesta- tions of SLE include pericarditis, myocarditis, noninfectious endocarditis (Libman-Sachs endocarditis), hypertension (pri- marily attributed to lupus nephritis and steroid use), and vasculitis [3]. Premature atherosclerosis as a primary manifestation or complication of SLE is not as well known. Although a Medline review of the literature reveals dozens of articles primarily in cardiology and rheumatology journals documenting this association, the emergency medicine literature in this regard is lacking.

Epidemiology

Early case reports of the association of SLE with premature atherosclerosis date back to the 1960s and early 1970s [6,7]. Several years later, a case series from Toronto described a bimodal mortality pattern in patients with SLE in which 1 group of patients all died of MI [8]. In this

same Toronto clinic, 665 patients were followed up until 1993. In that cohort of patients, the average age of MI was 49 years old, approximately 20 years earlier than in the general population [9,10]. The observations of this and other cohorts of SLE patients [11,12] suggest that athero- sclerosis is increased in prevalence and accelerated in development in patients with SLE [10]. The increased risk of clinically significant coronary artery disease (CAD) in young patients with SLE is estimated to be 9-fold [13] higher than age-matched controls. This increased risk appears to be greatest in young women. Manzi et al [4] reported a 50-fold increased risk of MI among women aged 35 to 44 years old. The increased risk is independent of other Traditional cardiac risk factors [14,15]. Like diabetes, SLE is a condition that seems to negate a woman’s expected premenopausal protection against CAD [10]. Because premenopausal women are usually considered a low-risk group for ACS, the diagnosis can easily be overlooked even in the presence of Typical symptoms [4,16] and diagnostic ECG findings, as occurred in cases 2 and 3 above.

Among SLE patients younger than 35 years with atherosclerotic disease, acute MI is the most common presenting manifestation of CAD, followed by congestive heart failure, sudden death, and angina [16,17]. However, subclinical atherosclerotic disease is common as well. Autopsy studies of patients with SLE who died of undiffer- entiated causes have identified evidence of significant atherosclerosis in up to 54% of patients [9,18]. Using

exercise thallium-201 scintigraphy, Hosenpud et al [19] found segmental perfusion abnormalities in 38.5% of a group of asymptomatic patients with SLE who were selected irrespective of previous cardiac history. Similarly, Bruce et al [20] found a 35% to 40% prevalence of subclinical atherosclerotic disease using SPECT dual isotope myocardial perfusion imaging in asymptomatic women. Studies in asymptomatic patients have also found significant Common carotid artery plaques in young patients with SLE [15,21]. The presence of atherosclerotic disease in the common carotid artery has been found to be highly associated with CAD [22] and an independent predictor of future MI [23], as well as stroke.

Pathophysiology

Several mechanisms have been suggested to explain the premature atherosclerosis in patients with SLE, although none of these have been definitively proven. There has been increasing support for the concept that atherosclerosis is an inflammatory disease [24]. Based on this concept, it has been hypothesized that SLE promotes atherogenesis because of its chronic inflammatory effect on blood vessels. Inflammatory alterations of vessel walls favor lipid deposition and atherogenesis [10]. Other evidence that inflammation may increase the susceptibility to atheroscle- rosis includes the observation that patients with SLE who have had previous episodes of pericarditis or myocarditis more frequently also developed MI [10,25]. In addition, premature atherosclerosis and early MI have also been noted in patients with rheumatoid arthritis and attributed to rheumatoid arthritis’ chronic inflammatory effects [26-28]. Another common theory is that premature atheroscle- rosis occurs in patients with SLE because of the presence of dyslipidemias. A pattern of elevated levels of very low- density lipoproteins and triglycerides and low levels of high-density lipoproteins has been described in patients with SLE [29]. Dyslipidemias in patients with SLE have also been noted to increase in patients with increased disease activity [30]. Other lipid alterations in patients with SLE have been described as well, including elevations of serum lipoprotein(a) [29], alterations in chylomicron metabolism, and modifications of lipoprotein lipase activity resulting in an bimmune lipidemiaQ [16,30]. The exact cause of the dyslipidemias is uncertain but may be attributable in part to the increased prevalence of nephrosis and hypertension in this population [16]. Some authors have proposed that the use of glucocorticoids in patients with SLE contributes to higher levels of serum triglycerides, choles- terol, and low-density lipoproteins [31-34], whereas others have argued against this association [15,19,35,36]. Lipid levels were obtained during hospitalization in the patients presented in cases 3 and 4 above. Both patients had been treated chronically with prednisone. The lipid profiles for both patients were within normal limits, suggesting a mechanism other than dyslipidemia as a cause for the

atherosclerotic disease in these patients. Information pertain- ing to lipid testing in the patients described in the first 2 cases could not be obtained.

Another possible explanation for the premature athero- sclerosis in patients with SLE is that it is immune-mediated. Immune deposits reported in the vessels of the myocardium of patients with SLE [37] may be responsible for immuno- logic injury that initiates atherogenesis [38] or may initiate an inflammatory response that leads to atherosclerosis [39]. Premature atherosclerosis and early MI in patients with SLE have also been attributed, at least in part, to the presence of autoantibodies to high-density lipoprotein and phospholipids [36].

There are several other suggested etiologies for prema- ture atherosclerosis in patients with SLE. Broadly, these include metabolic factors, hematologic factors, and other immunologic factors, the details of which are beyond the scope of this review. In all likelihood, the exact cause is multifactorial. There also appears to be a synergistic effect on atherogenesis when the traditional cardiac risk factors are present as well.

Diagnosis and management of ACS

Patients with SLE should undergo the same diagnostic workup for ACS as their non-SLE counterparts. The standard treatment modalities should be used as well, including oxygen, aspirin, b-blockers, heparin, glycoprotein receptor antagonists, and thrombolytic agents or percutane- ous coronary intervention when indicated. We were unable to find any literature indicating that patients with SLE should be managed differently when they present with a suspected ACS. On a chronic outpatient basis, however, patients with SLE must be managed for both disease activity and traditional cardiac risk factors very aggressively. Particular emphasis should be placed on correcting dyslipi- demias in these patients, because the risk of MI in patients with SLE and dyslipidemias is particularly increased [10].

Conclusion

SLE is a significant risk factor for atherosclerosis independent of the traditional cardiac risk factors. The risk of clinically significant CAD and MI is 9-fold higher in patients with SLE than age-matched controls, and the risk is as much as 50-fold higher in young women with SLE. The prevalence of CAD in this patient population appears to be not widely known, and this may lead to a high rate of misdiagnosis or delayed diagnosis of ACS. Several theories pertaining to the cause of premature atherosclerosis have been proposed; none have proven to be definitive, and the actual cause is likely multifactorial. Emergency physicians should maintain a low threshold for performing ACS evaluations on patients with SLE who present with cardiopulmonary symptoms regardless of age or presence of other cardiac risk factors.

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