Cardiac Involvement in Systemic Lupus Erythematosus

Cardiac Involvement in Systemic Lupus Erythematosus KEVIN

G. MODER, M.D., TODD D. MILLER, M.D., AND HENRY D.

involvement. Moreover, antiphospholipid antibodies have been linked to several cardiac manifestations in patients with SLE, including valvular abnormalities and possibly coronary artery disease. This updated, comprehensive review summarizes the new literature on SLE and the heart.

Systemic lupus erythematosus (SLE), a connective tissue diseasecharacterized by the production of autoantibodies, can affect all organ systems. Cardiac involvement in patients with SLE has been describedsince the early 20th century. The manifestations are numerous and can involve all components of the heart, including the pericardium, conduction system, myocardium, valves, and coronary arteries. In recent years, echocardiography has yielded additional information about the heart in patients who have SLE with and without clinical cardiac

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SLE

S

ystemic lupus erythematosus (SLE) is a connective tissue disease characterized by the formation of autoantibodies and immune complexes. It can affect all organs, including the heart. SLE may affect all parts of the heart, including the pericardium, conduction system, myocardium, valves, and coronary arteries. The prevalence of cardiovascular involvement in patients with SLE has been estimated to be more than 50%.1,2 This prevalence, however, varies greatly from study to study, depending on what manifestations are included (for example, arterial hypertension in some studies) and whether clinical or subclinical (asymptomatic) disease is considered.

=systemic lupus erythematosus

With the advent of echocardiography, several early Mmode echocardiographic studies in patients with SLE yielded results consistent with previously reported prevalence rates for pericardial effusions (21 to 49% in unselected patients with SLE).25.26 Using M-mode and twodimensional echocardiography, Doherty and associates" found that 42% of patients with SLE had pericardial effusion (Fig. 1). In a controlled, prospective study in which echocardiography was used, pericardial involvement (pericardial effusion or thickening) was detected in 37% of patients with SLE. 30 Two other controlled studies found significantly more echocardiographic evidence of pericardial involvement in patients with SLE (22 to 54%) than in control subjects (0 to 10%).27,29 On the basis of available data, reasonable estimates are that symptomatic pericarditis occurs in about one-fourth of patients with SLE at some point during the course of the disease and that asymptomatic involvement is more common, most likely occurring in more than half of all patients with SLE. Intuitively, one would expect clinical and asymptomatic pericarditis to be more common in patients with active SLE. Currently, only inferential data support this concept. Estes and Christian" found that, in most cases (76%), pericarditis occurs together with pleural effusion as part of a generalized serositis. Pericarditis occurred as the initial manifestation of SLE in 1% of patients in a large study. Signs and symptoms of pericarditis in patients with SLE are typical of those of pericarditis in general. Symptoms include precordial or substernal chest discomfort, which may be positional. The degree of pain varies from mild to severe. Signs include fever, tachycardia, and decreased heart sounds (especially with large effusions). In patients with tamponade or constrictive pericarditis, the jugular

PERICARDIUM

Pericardial involvement was the first recognized cardiac manifestation of SLE. It is also the most common cardiovascular manifestation.' The reported prevalence of pericarditis in patients with SLE varies from 12 to 48%1-19 (Table 1). Some of this variability is attributable to the methods used to document involvement and whether symptomatic or asymptomatic cases are included, Clearly, asymptomatic pericardial involvement with SLE occurs more frequently than does clinical pericarditis. A combined series reported clinically evident pericarditis in approximately 25% of patients with SLE, whereas a combined autopsy series revealed pericardial involvement in 62% of patients with SLE.3 From the Division of Rheumatology and Internal Medicine (K.G.M.), Division of Cardiovascular Diseases and Internal Medicine (T.D.M.), and Department of Laboratory Medicine and Pathology (H.D.T.), Mayo Clinic Rochester, Rochester, Minnesota. Address reprint requests and correspondence to Dr. K. G. Moder, Division of Rheumatology, Mayo Clinic Rochester, 200 First Street SW, Rochester, MN 55905. Mayo Clin Proc 1999;74:275-284

T AZELAAR, M.D.

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Car diac Disease in Systemic Lupus Erythematosus

Table i.-Prevalence of Pericarditis in Patients With Systemic Lupus Erythematosus* Reference Libman & Sacks; 1924 Gross," 1940 Humphreys," 1948 Griffith & Vural,? 1951 Jessar et al," 1953 Harvey et a1 ,9 1954 Copeland et a1,20 1958 Armas -Cruz et al,' ? 1958 Shearn," 1959 Brigden et a1,12 1960 Kong et al," 1962 Hejtmancik et al,14 1964 Jame s et al," 1965 Estes & Christian," 1971 Bulkley & Roberts," 1975 Dubois," 1976 Rope s,'? 1976 E1kayam et a1,2J 1977 Collins et aI,24 1978 Ito et a1,25 1979 Chia et al,26 1981 Klinkhoff et aI,27 1985 Badui et a1,18 1985 Dohert y et al," 1988 Crozier et al,29 1990 Kahl,' 9 1992 Total

Clinical or echo prevalence

Autop sy prevalence

4/4

4/4 14/23 9/21 11/18 7/15

10/44 63/138 11/47 13/ 108 26/83 24/142 8/8 29/ 15 1

Cardiac tampon ade

Comment

15/18 7/16 20/27 14/30 11/16 8/8

4 2

2

19/36 159/520 41/142 2/32 6/17 22/48 5/21 10/47 39/100 2 1/50 27/50 75/395 595/2 ,147 (28%)

48/58 1/1

188/291 (65%)

10 20

Echo Echo Echo Echo Echo Echo Echo Echo 11 episodes

*Echo = echocardiography .

veno us pressure is increased, and the jugular pulse is prominent. In tamponade, the x descent is pro minent, and the y is absent. In constrictive pericarditis, the y is prominent, and the venous pressure does not decrease or increase with inspiration (Kussmaul's sign).':' A pericardial friction rub may be heard in a minority of patients . 17 An electrocardiogram may reveal changes suggestive of pericarditis: PR depression and ST-segment elevation. A chest radiogram may show an enlarged cardiac silhouette.'? Analy sis of pericardial fluid from patients with SLE typically reveals an exudate with an increased leukocyte count and predominantly po lymorphonuclear cell s. P Rarel y, the fluid is hemorrhagic. A markedly acidic fluid (pH, less than 7) may occur in SLE and may be useful in distinguishing it from other type s of effu sion s." Protein concentration in the fluid is increased , and the glucose level is usually normal but can be IOW . I •3.31 Complement levels are usually low. Autoantibodies, including antinuclear antibody, anti-double-stranded DNA, and positive lupus erythematosus cell preparations, can be seen.I.3.32.33 The sensitivity, specificity, and prevalence of these markers in pericardial fluid are unknown becau se the number of reported patients with SLE is small and many reports do not

compare results among patients with other connective tissue diseases. In both adult-onset Still's disease and rheumatoid arthritis, the pericardial fluid may be an exudate with increased leukocyte counts. In rheumatoid arthriti s, the complement and glucose levels may be reduced as in SLE, but these levels are not decreased in adult-onset Still 's disease. Although cardiac tamponade may occur in SLE, it is rare. In combined series of more than 1,300 patients with SLE , tamponade was found in fewer than 1%.3 Another retrospective study found that the prevalence of tamponade was 2.5% in 395 patients and that 10 of 75 patients (13 %) with clinical evidence of pericarditis had tamponade.'? Several case reports have included episodes occurring in patients with drug-induced lupu s erythematosus and rarely as the initial manifestation of lupus.P-" Symptoms of cardiac tamponade may include progressive dyspnea with findings of arterial hypotension, increased venous pressures , pulsus paradoxus, and a small, quiet heart. If tamponade is acute, as it occasionally is, the effusion may be small. Echocardiographic findings in tamponade include large pericardial effusions, decreased total transverse dimensions, dec reased right ventricular diame ter, early col-

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Fig. 1. Pericardial effusion in patient with systemic lupus erythematosus, A, Transthoracic echocardiogram (four-chamber view), showing moderate-sized pericardial effusion (PE). B, Three weeks after initiation of corticosteroid treatment, effusion has resolved. LA = left atrium; LV =left ventricle; RA =right atrium; RV =right ventricle.

lapse of the right ventricular outflow tract, and indentation of the left atrial free wall. Pericardial thickening may occur in 29% of patients with SLE. 26 Constrictive pericarditis in SLE, however, is extremely rare. Four cases have been reported in men with idiopathic lupus erythematosus, all of whom had received corticosteroid therapy.14,34,35 Two cases have also been reported in men with procainamide-induced lupus erythematosus." The only reported case in a woman occurred in conjunction with anti-myosin antibodies.l" The exact prevalence of these antibodies, the significance of gender differences, and the role of corticosteroids in the development of constrictive pericarditis in SLE are currently unclear. Treatment of pericarditis depends on its severity and acuity. Many cases can be treated with nonsteroidal antiinflammatory drugs, but corticosteroids may be necessary in refractory cases. Rarely, pericardiocentesis is necessary. Obviously, optimization of therapy for the underlying lupus disease is indicated, especially in patients with chronic or recurrent episodes. Rarely, pericarditis in patients with SLE can be caused by infectious agents, but this should be considered the exception rather than the rule. CONDUCTION SYSTEM

Abnormalities of heart rhythm and conduction occur in a minority of patients with SLE. One study suggested a prevalence of more than 10%.21 Types of rhythm and conduction disturbances reported in patients with SLE include atrioventricular block (first, second, or third degree), bundle branch block, sinus tachycardia, atrial premature contractions, and atrial fibrillation. 1.2,8,11,14,37 That these

arrhythmias are directly related to SLE in all cases is unlikely. At times, they reflect coexisting coronary artery disease or idiopathic conduction system disease. The clinical implications of this association are currently unclear. Several studies, however, have shown that structural damage to the conduction system can be documented in patients with SLE who have cardiac conduction defects.v-" Recently, two studies suggested that a significant number of patients with SLE have a dysautonomia reflected by abnormalities in heart rate variability.38,39 Congenital heart block can occur in children born to mothers with anti-SS-A antibodies with or without evidence of clinical SLE.40.46 One study estimated that onethird of infants born with complete heart block have a mother who has or will have connective tissue disease. Another study suggested that 3% of infants born to mothers who have the SS-A antibody will have complete heart block." Genetic associations of this antibody have been noted in patients with SLE who have human leukocyte antigens DR2, DR3, DQw2, and B8. 40.42 In contrast to other features of neonatal lupus, heart block is usually irreversible, and often pacemaker placement is necessary. Several pathologic studies have suggested that immune complexes or antibodies that cross the placenta are directed against the child's conduction system tissue. 41,48,49 These findings suggest that the antibodies themselves are pathogenic. In some cases, partial or complete absence of conduction tissue fibers was noted in patients with congenital complete heart block, including infants whose mothers had anti-SS-A antibodies regardless of whether they had clinically apparent lupus erythematosus. Therefore, congenital heart block in children born to mothers with SLE seems to

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be related to structural damage or maldevelopment of the conduction system. No studies have documented a relationship between HLA haplotype and particular autoantibodies in adult patients with SLE and cardiac conduction defects . Signs and symptoms of conduction abnormalities depend on the type of rhythm and its severity . Likewise, these features dictate the treatment. Most infants with complete heart block have bradycardia, which is well tolerated in some infants but compromises circulation in others.'

MYOCARDIUM Clinically apparent cardiomyopathy or myocarditis associated with SLE is uncommon; most studies have noted a prevalence of about 10%.9.15.17.18 As with other SLE manifestations, subclinical involvement is substantially more common. A combined series of autopsy studies found involvement in 40 to 50% of patients.' As with other cardiac manifestations, the frequency in which cardiomyopathy is directly related to SLE is unclear. Mo st case s of myocardial dysfunction are indirectly related to contributing factors , including hypertension, coronary artery disease, and even medications used to treat SLE , such as antimalarials. An immune-mediated myocarditis also seem s to occur in a minority of patients. The only scenario in which lupu s can be suspected as the cause is when a biopsy specimen shows an immune-mediated process. The reported prevalence of congestive heart failure in patients with SLE varies from 7 to 36%.12,14.15,1 8 Hypertrophic cardiomyopathy has been reported in one patient with SLE and in another with a "Iupuslike" illness." Whether this occurrence is truly related to the underlying connective tissue disease or merely happened in the same patient is debatable. In recent years, several echocardiographic studies have demonstrated abnormal cardiac function in patients with SLE. These abnormalities include a shorter left ventricular ejection time and a longer preejection period consistent with impaired left ventricular systolic function. Other studies have demonstrated dia stolic dysfunction and abnormal responses to exercise. A recent 5-year prospective study of patients with SLE concluded that abnormalities of systolic and diastolic left ventricular function were common , progressive , and often related to coexistent hypertension and coronary arter y disease. " Echocardiography is an excellent method to assess function but cannot determine the underlying cause of cardiac dysfunction. Autopsy study of the heart in patients with SLE has demonstrated immune complex deposition. Biopsy specimens of the endomyocardium have demonstrated an immune-mediated myocarditis in some patients with SLE.52 A biopsy specimen may show fibrous thickening of arterial walls, luminal narrowing, immunoglobulin

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deposition in perivascular areas, and fibrinoid necrosis. Hematoxylin bodies and interstitial mononuclear cell infiltrate s with myocyte necrosis are characteristic of myocarditis. Patchy foci of myocardial fibrosis and scarring can also be seen , especially in patients treated with corticosteroids. 1.12.16 Several theories exist regarding the cause of myocarditis in patients with SLE. As mentioned earlier, some patients have evidence of immune complex deposition. Additionally, antimyocardial antibodies have been found in some patients with SLE.53 Myocarditis can also occur in patients with SLE who have an inflammatory myositis. Borenstein and associates" described a subset of patients with SLE who were positive for ribonucleoprotein antibody and had both skeletal myositis and myocarditis; other investigators made a similar observation in patients with both SLE and overlap types of connective tissue diseases. Symptoms of lupu s myocarditis are similar to those of myocarditis due to other cau ses and include dyspnea, tachycardia, and, if the disea se is severe, other features of congestive heart failure. Treatment depends on the severity and type of symptoms together with the activity of the associated lupu s. Immunosuppressive treatment has been shown to be beneficial in patients in whom active inflam mation is detected on endomyocardial biopsy. " Treatment of congestive heart failure with afterload-reducing agent s, diuretics, and inotropic agents is also appropriate. Moreover, correction of further contributing factors , such as control of hypertension, is indicated. Of course, optimization of the treatment of the underlying SLE activity is indicated.

VALVULAR DISEASE The most classic and characteristic cardiac valvular abnormality in patients with SLE consists of noninfecti ve, verrucous vegetations (marantic endocarditis), the socalled Libman-Sacks endocarditis first described in 1924.4 The reported frequency of Libman-Sacks endocarditis varie s widely. In autop sy studies, the prevalence range s from 13 to 74%.5.6.8,9,1 1-15.17 Some investigators have suggested that the introduction of corticosteroids as treatment of SLE may have decreased the frequency. Prevalence rate s reported in a large combined autopsy series were 59% before corticosteroids were commonly used and 35% after their introduction.' Becau se of differences, however, in patient populations, methods, and other factors among studies, comparing prevalence rates or making firm conclusions on trends is extremely difficult. Clinical examination is only minimally helpful in identifying affected patients. Systolic murmurs were noted in only two of six patients who later had autopsy-proven lesions." Conversely, only 4 of 13 patients with SLE who

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had systolic murmurs before death had Libman-Sacks endocarditis at autopsy." Echocardiographic abnonnalities of valves can be suggestive, but a definitive diagnosis can be made only on pathologic examination of affected tissue. Therefore, prevalence studies must be done at either operation or autopsy, and this population of patients with SLE may be inherently biased. Libman-Sacks lesions occur most frequently on the mitral valve, although the original investigators reported that the tricuspid valve was the most frequently affected. 3-5,9,16 Any valve may be affected, and multi valvular involvement often occurs. On the mitral valve, the most common site of the vegetations is in the recess between the ventricular wall and the posterior valve leaflet. P The lesions can occur near the edge of the valve and may affect both surfaces of the valve as well as the rings and commissures (Fig, 2). Chordae tendineae, papillary muscles, and atrial and ventricular endocardium are infrequently involved.' :' The verrucae are generally small (1 to 4 mm in diameter) and consist of fine granular material that may contain hematoxylin bodies. ':" Immunoglobulin deposits have been identified in the core of the vegetations, a suggestion that immune complexes contribute pathogenically. This process is usually accompanied by an intense valvulitis, which may in part be associated with fibrinoid necrosis of the valve . During the past decade, investigators have suggested that antiphospholipid antibodies contribute to the pathogenesis of the valvular disease. Ford and associates" described two patients with clinically significant mitral valve disease and circulating lupus anticoagulant. At operation, thrombi were found on the valves of these patients. In another series, 11 patients with cardiac valve disease and antiphospholipid antibodies were described. Several studies have demonstrated an increased prevalence of cardiac valve dysfunction with the antiphospholipid antibody syndrome,":" and recently, anticardiolipin antibody deposition was identified in affected valves of patients with this syndrome.v Other investigators, however, have found that valvular lesions were common in patients with SLE without anticardiolipin antibodies." Therefore, antiphospholipid antibodies most likely have a role in the development of pathogenic immune complexes in some patients, but their exact function in the pathogenesis of valvular disease in SLE remains to be fully elucidated. The prevalence of significant valve dysfunction was 3 to 4% in one large retrospective study of patients with SLE , with I to 2% of patients requiring a valve operation. A smaller but prospective and controlled study found that 18% of patients with SLE had clinically significant cardiac valve dysfunction, and 8% required surgical treatment.f Aortic insufficiency is the most common abnormality re-

279

Fig. 2. Noninfective thrombotic endocarditis involving mitral valve in systemic lupus erythematosus. Note nodular vegetations along line of closure and extending onto chordae tendineae. (Photograph courtesy of Dr. William D, Edwards, Division of Anatomic Pathology, Mayo Clinic Rochester .)

ported, but mitral insufficiency, multivalve insufficiency, and stenosis of the aortic and mitral valves have also been reported. 1,3,7,9,12.14,17,23.55.63-65 Doherty and Siegel' suggested that insufficiency of the valves may be due to a combination of Libman-Sacks endocarditis, fibrinoid degeneration, fibrosis, valvulitis, bacterial endocarditis (less commonly), and aortic dissection. Other contributing factors could be hypertension, prior rheumatic fever, an underlying bicuspid aortic valve, and corticosteroid therapy. Bulkley and Roberts" stated that corticosteroid therapy may lead to healing of the verrucous lesions, with subsequent scarring and shortening of the posterior mitral valve leaflet and chordae tendineae, increased adherence to the endocardium, and valvular insufficiency. In addition to valvular insufficiency and stenosis, rupture of chordae, thromboembolic events, cerebral emboli, intracardiac thrombus, and infective endocarditis have all been reported in patients with SLE.I,3.64.66-69 Several investigators have suggested that the risk of bacterial endocarditis is increased in patients with SLE, but whether the increase is due to SLE itself, medications used in treatment, or underlying valvular damage is unclear.v" Other investigators have also reported an increased prevalence of mitral valve prolapse in patients with SLE , and this may be an additional predisposing factor to endocarditis.V' :" Treatment of valvular manifestations of SLE depends on the type and severity of involvement. Numerous patients with hemodynamically significant valvular dysfunction have undergone surgical valve replacement. In one series of 12 patients with SLE who had 15 total valve replacements, mortality was higher than expected

(25%).65

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CORONARY ARTERY DISEASE Coronary artery involvement in SLE was initially described much later than the other cardiovascular manifestations. Early reviews either did not mention coronary artery disease or noted only that the smaller intramural coronary arteries were obstructed with fibrinoid materia1.6,9,1l,l2 Involvement of the larger epicardial coronary arteries has been recognized only during the last half of this century. Clinical manifestations of coronary artery disease in SLE can result from several pathophysiologic mechanisms, including atherosclerosis, arteritis, thrombosis, embolization, spasm, and abnormal coronary flow reserve. The most common clinical manifestation of coronary artery disease is myocardial infarction.' Numerous case reports and small series have documented the development of myocardial infarction in patients with SLE.7l-79 In contrast to myocardial infarction in patients without SLE, the striking clinical characteristic of most patients with SLE who have a myocardial infarction is their young age. Many of these patients are premenopausal women, and several reports have described involvement in children." These demographic characteristics suggest that patients with SLE are at increased risk of myocardial infarction and that reports of myocardial infarction in patients with SLE do not simply represent chance occurrences. Fatal myocardial infarction has been reported to be 3 times higher in patients with SLE than in age- and sex-matched control subjects." Recent case-control series have confirmed that the risk of myocardial infarction in patients with SLE is increased between 9- and 50-fold over that in the general population.P:" Although the risk of the development of coronary artery disease is increased in patients with SLE, only a minority of patients have clinical manifestations. The incidence of events varies depending on the study. Angina or myocardial infarction (or both) occurs in 2 to 16% of patients. 14,18,82-84 The prevalence of subclinical disease is higher. One study reported that 38% of patients with SLE who underwent thallium exercise treadmill testing had perfusion defects. Autopsy series have reported significant narrowing of the coronary arteries in 25 to 45% of patients. 16,85 Many of these patients had no clinical manifestations of coronary artery disease. Most clinical and autopsy studies have reported that fatal myocardial infarction is uncommon, occurring in 3 to 20% of patients with SLE.I3-l5,8l,85 The risk of fatal coronary artery disease seems to increase with the duration of SLE. A bimodal mortality pattern has been noted in patients with SLE, with the most common cause of late death being myocardial infarction. 15,86 Additionally, the most common cause of death in patients with late onset (at 50 years or older) of SLE is cardiovascular disease.

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Atherosclerosis Atherosclerosis is the most common type of coronary artery involvement in patients with SLE. In an autopsy series of 36 patients with SLE, Bulkley and Roberts" described 8 patients in whom the lumens of at least one of the major epicardial arteries were narrowed more than 50% by atherosclerotic plaque. In a subsequent study, Haider and Roberts" examined 5-mm segments of each of the four major epicardial coronary arteries at autopsy in 22 patients with SLE and compared the results with those in 13 control subjects. Ten of the patients with SLE but none of the control subjects had at least one of their major coronary arteries narrowed more than 75% in a cross-sectional area by atherosclerotic plaque. The reason that premature coronary atherosclerosis develops in patients with SLE is unknown. By light microscopy, coronary atherosclerosis that occurs in patients with SLE appears the same as atherosclerosis that occurs in patients without SLE. The leading theory is that immune complex deposition causes the initial intimal damage, which is followed by accelerated development of atherosclerosis in patients with traditional coronary risk factors. In mice with lupuslike disease, vascular lesions are caused by antigen-antibody complexes. Humans with SLE have also been shown to have immune deposits in the walls of blood vessels. Haider and Roberts'" found that patients with severe coronary atherosclerosis also had a higher prevalence of pericarditis and valvular disease, which suggests that an immune factor is the cause of the coronary arterial narrowing. Patients with SLE in whom coronary atherosclerosis develops generally are older and have a longer duration of disease, usually of many years. 81-83,86 Exceptions to this observation include fatal myocardial infarction due to coronary atherosclerosis in a 5-year-old child. Several investigators have suggested that the development of coronary atherosclerosis may be related to corticosteroid use. 3,16.83 The mechanism by which corticosteroids act in this situation is unclear. They may simply prolong life, an outcome that allows more time for atherosclerosis to develop in patients with SLE, or they may be more causative by exacerbating the risk factors of hypertension and hyperlipidemia.P" The prevalence of traditional coronary risk factors is high in patients with SLE in whom coronary artery disease develops.' A few published reports have discussed lipid levels in patients with SLE who did not receive corticosteroid treatment. One study reported that 10 pediatric patients with a new diagnosis of SLE had decreased high-density lipoprotein and apolipoprotein A-I levels and increased very-low-density lipoprotein and triglyceride levels before treatment. MacGregor and coworkers," however, reported that untreated patients with SLE

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Fig. 3. Coronary angiograms in patient with systemic lupus erythematosus. A, Aneurysmal dilatation of right coronary artery in left anterior oblique projection. Arrowheads outline peripherally calcified filling defect consistent with thrombosis. B, Aneurysmal dilatation of left anterior descending coronary artery in right anterior oblique projection. (From Nobrega and associates." By permission.)

did not have decreased high-density lipoprotein levels. Most studies of corticosteroid-treated patients have reported increased total cholesterol or triglyceride levels. One group found that, after initiation of corticosteroid therapy, total cholesterol, low-density lipoprotein, and very-low-density lipoprotein levels increased. Petri and associates" noted that an increase in the dose of prednisone of 10 mg/dL was associated with increases of 2.5 kg in weight, 7.5 mg/dL in total cholesterol, and 1.1 mm Hg in blood pressure. In addition, lipoprotein Lp(a) levels are also increased in patients with SLE.90 The treatment of coronary atherosclerosis in patients with SLE is the same as that in patients without SLE. Ischemic symptoms generally respond to antianginal medications." Percutaneous transluminal coronary angioplasty and coronary artery bypass grafting have been performed in a few patients. v' v" Because of the potential increased risk of thrombosis, some investigators have advocated that all arterial grafts, rather than venous grafts, should be used.

Coronary Arteritis After atherosclerosis, arteritis is the next most common type of coronary artery involvement in patients with SLE.3. Several case reports and small series of patients with SLE have described coronary arteritis at autopsy. 13,14,71,73.74 The only definitive method of distinguishing arteritis from atherosclerosis is by pathologic examination. Even then, the distinction may be difficult. The prevalence of arteritis in autopsy studies has varied. In one study, 6 of 16 patients at

autopsy had evidence of arteritis," whereas in another study, none of 22 patients had evidence of arteritis." The premortem distinction between coronary atherosclerosis and coronary arteritis is difficult. Evidence of vasculitis involving other organ systems favors a diagnosis of coronary arteritis.v-" The absence of active noncardiac disease, however, does not exclude coronary arteritis." In several reports, coronary arteritis has been detected on coronary angiography72,73,75.91 (Fig. 3). Coronary artery aneurysms or rapidly developing stenoses or occlusions on serial angiograms are not pathognomonic but support a diagnosis of arteritis.72,73,75.79.91 Clinically, the distinction is important because the treatment of arteritis is to increase the corticosteroid dose, whereas a higher corticosteroid dose can worsen risk factors and potentially prove to be detrimental to a patient with atherosclerotic disease." Warfarin and antiplatelet agent s have been used in patients with arteritis in an attempt to reduce the risk of thrombotic occlusion. Ticlopidine has been shown to be helpful for preventing myocardial infarction associated with coronary arteriti s in a mouse model and has been recommended by some investigators" for clinical use in patients with aneurysms.

Other Types of Coronary Artery Involvement A few reports of patients with SLE have described embolization of valvular material down a coronary artery.16,69,91,92 One report described a patient with SLE and coronary artery spasm. Involvement of the microcircula-

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tion has long been recognized. Microscopically, thrombosis and hyalinization of the small coronary arteries are found." These findings have been associated with necrosis and intramural perivascular fibrosis." Smallvessel disease has also been implicated as the cause of "lupus cardiomyopathy.t'v" Patients with this entity have been shown to have decreased coronary flow reserve. Antiphospholipid Antibodies The relationship between antiphospholipid antibodies and coronary artery disease is controversial. In patients with established SLE, some studies 58•89 have found that antiphospholipid antibodies increase the risk of the development of cardiovascular disease. Suggestive evidence implies that patients without clinical documentation of SLE but with antiphospholipid antibodies are at increased risk of cardiovascular disease. Reports have described individual cases and small series of patients with increased anticardiolipin antibodies who have had clinical evidence of coronary artery disease.v" As in case reports of patients with SLE and myocardial infarction, many of these patients have been young. Obstruction of both the large epicardial coronary arteries and the coronary microcirculation has been described." Hamsten and associates" measured anticardiolipin antibodies serially during a 3year period in 62 survivors of myocardial infarction who were younger than 45 years. Thirteen patients (21%) had increased levels, 8 of whom had recurrent cardiovascular events. Some investigators have also found that a high percentage of patients with coronary artery disease have increased levels of anticardiolipin antibodies. Other investigators, however, have been unable to demonstrate any difference in antibody levels between patients with coronary artery disease and control subjects.v-" In the Warfarin Reinfarction Study, an increased percentage of patients with myocardial infarction had increased anticephalin antibodies in comparison with control subjects, but no difference in anticardiolipin antibodies was noted between groups, Even if an association does exist between antiphospholipid antibodies and coronary artery disease, whether the antiphospholipid antibodies are causative or form as an immune response to myocardial ischemia or necrosis is unclear." To address this issue, Vaarala and associates'P' used a nested case-control design in the Helsinki Heart Study to compare findings in 129 control subjects with those in 129 patients who had no evidence of coronary artery disease at enrollment in the study but in whom myocardial infarction or cardiac death occurred during follow-up. Anticardiolipin antibody levels were an independent predictor of coronary artery disease. Men in the highest quartile had twice the risk of development of this disease. These investigators con-

Table 2.-Cardiac Involvement in Systemic Lupus Erythematosus Type of involvement

Reported incidence (%)

Pericarditis Cardiac tamponade Myocarditis Congestive heart failure Libman-Sacks endocarditis Coronary artery disease

12-48 <3 10-40 7-36 13-74 25-45

eluded that a high anticardiolipin antibody level is a risk factor predictive of future cardiac events. SUMMARY

Cardiac involvement in patients with SLE is common and is a significant source of morbidity and mortality. All parts of the heart can be affected, including the pericardium, endocardium, myocardium, valves, conduction system, and coronary arteries (Table 2). Improved technology, especially echocardiography, has made the diagnosis of many of these conditions easier. Associations between antiphospho1ipid antibodies and valvular disease have been identified. Other factors including hypertension, hyperlipidemia, and corticosteroid use also contribute to the development of cardiac abnormalities in patients with SLE. As we enter the 21st century, our understanding of the pathogenesis and extent of cardiac disease in SLE is still incomplete.

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Qulsmorlo FP Jr. Cardiac abnormalities in systemic lupus erythematosus. In: Wallace DJ, Hahn BH, editors. Dubois' Lupus Erythematosus. 4th ed. Philadelphia: Lea & Febiger; 1993. pp 332-342 Stevens MB. Systemic lupus erythematosus and the cardiovascular system: the heart. In: Lahita RG, editor. Systemic Lupus Erythematosus. 2nd ed. New York: Churchill Livingstone; 1992. pp 707-717 Doherty NE, Siegel RJ. Cardiovascular manifestations of systemic lupus erythematosus. Am Heart J 1985;110:1257-1265 Libman E, Sacks B. A hitherto undescribed form of valvular and mural endocarditis. Arch Intern Med 1924;33:701-737 Gross L. Cardiac lesions in Libman-Sacks disease, with consideration of its reiationship to acute diffuse lupus erythematosus. Am J Pathol 1940;16:375-408 Humphreys EM. The cardiac lesions of acute disseminated lupus erythematosus. Ann Intern Med 1948;28:12-14 Griffith GC, Vural IL. Acute and subacute disseminated lupus erythematosus: a correlation of clinical and postmortem findings in eighteen cases. Circulation 1951;3:492-500 Jessar RA, Lamont-Havers RW, Ragan C. Natural history of lupus erythematosus disseminatus, Ann Intern Med 1953;38:717731 Harvey AM, Shulman LE, Tumulty PA, Conley CL, Schoenrlch EH. Systemic lupus erythematosus: review of the literature and clinical analysis of 138 cases. Medicine 1954;33:291-437 Armas-Cruz R, Harnecker J, Ducach G, Jalll J, GonzalezF. Clinicai diagnosis of systemic lupus erythematosus. Am J Med 1958; 25:409-419

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