Cardiac manifestations of systemic lupus erythematosus

Feb 17, 2000

Cardiac disease is common among patients with systemic lupus erythematosus (SLE) as pericardial, myocardial, valvular, and coronary artery involvement can occur. Several studies have also described associations of valvular disease with antiphospholipid antibodies. The incidence of these problems can be summarized as follows.

  •  Cardiac abnormalities — over 50 percent [1,2]
  •  Valvular disease, most often mitral regurgitation and usually hemodynamically insignificant — approximately 75 percent [2,3]
  •  Pericardial disease, usually a clinically silent effusion — up to 55 percent [2]
  •  Myocardial dysfunction — up to 78 percent [1]
  •  Coronary artery disease [1]

VALVULAR DISEASE — Systolic murmurs have been noted in 16 to 44 percent of patients [1]. Structural valvular disease is most common [3,4,5,6,7], but anemia, fever, tachycardia, and cardiomegaly can induce functional murmurs. Diastolic murmurs have been noted in one to three percent of patients [1]. They often reflect aortic insufficiency, which occasionally requires valve replacement. (See "Auscultation of cardiac murmurs-I").

Some studies have suggested an association between the valvular disease and antiphospholipid antibodies [3,8,9,10]. In one report, for example, 78 percent with high levels of antiphospholipid antibodies had at least one cardiac abnormality [10]. Patients with mild pulmonary hypertension, a less common complication of lupus, are also more likely to have antiphospholipid antibodies [10]. (See "Pulmonary manifestations of systemic lupus erythematosus"). However, other reports have not confirmed the relationship between antiphospholipid antibodies and cardiac disease [3,11,12]. (See "Clinical manifestations and diagnosis of the antiphospholipid antibody syndrome").

Mitral valve involvement is most common; a mild to moderate regurgitant murmur may be heard but most patients remain asymptomatic [4,9,11]. Mitral valve prolapse appears to occur with increased frequency in lupus, occurring in 25 percent of cases in another study versus nine percent of controls [11]. (See "Definition and diagnosis of mitral valve prolapse").

A recent report used transesophageal echocardiography, which is more sensitive than transthoracic echocardiography, to determine the frequency, clinical course, and complications of valvular disease in 69 patients with SLE, most of whom underwent a second study at a mean of 29 months later [5]. The following findings were noted:

  •  Thickening of the leaflets was the most common, occurring in 51 and 52 percent of patients at the two study times. This lesion is due to initial valvulitis followed by healing with fibrosis and thickening.

  •  Valvular vegetations were present in 43 and 34 percent of patients.

  •  Valvular regurgitation was noted in 28 percent at both time periods.

  •  Valvular stenosis, which was not progressive, was found in 4 and 3 percent.

  •  The manifestations of the valvular disease frequently changed: some resolved, others appeared for the first time, and some changed their appearance.

  •  Neither the presence of nor changes in valvular disease were temporally related to disease activity, therapy, or the duration of SLE.

  •  Perhaps most importantly, there was an appreciable incidence of serious complications in the patients with valvular disease. After a mean follow-up of almost five years, the combined incidence of stroke, peripheral embolism, heart failure, infective endocarditis, and death was 22 percent versus 15 percent in the 13 patients without valvular disease. The incidence of stroke in patients with valvular disease was 13 percent.

If these data were broadly applicable, then all patients with lupus would require serial echocardiographic monitoring on a continuing basis to detect and treat the development of new, potentially serious valvular lesions. However, the high incidence of complications from valvular disease in this study has not been observed by myself or others. The reason for this discrepancy is not known. Our routine practice is to perform cardiac auscultation at most visits, followed by echocardiography for the evaluation of significant or changing murmurs or changing cardiac function. (See "Transesophageal echocardiography: Technology; complications; indications; and normal views").

In addition to valvular disease, plasma homocysteine levels appear to be another risk factor for stroke in SLE (and in the general population). A prospective study from the Hopkins Lupus Cohort study evaluated 337 patients with SLE for a mean duration of 4.8 years [13]. The endpoints were stroke or arterial or venous thrombotic events. After adjustment for established risk factors, an increase of one log unit of plasma homocysteine concentration was an independent risk factor for both stroke and arterial thromboses (relative risk 2.44 and 3.49, respectively). (See "Hyperhomocyst(e)inemia; atherosclerosis; and venous thromboembolism").

Verrucous endocarditis — Libman-Sacks (verrucous) endocarditis is a not uncommon complication of SLE. In one report of 74 patients, for example, seven had verrucous lesions detected by transthoracic echocardiography [4]. As noted above, however, a higher frequency (43 percent) has been noted when more sensitive transesophageal echocardiography is performed [5]. In addition, Libman-Sacks endocarditis has been associated with antiphospholipid antibodies in some [8], but not all [14], studies.

The verrucae are usually near the edge of the valve and consist of accumulations of immune complexes, mononuclear cells, hematoxylin bodies, and fibrin and platelet thrombi (show picture 1).

The mitral, aortic, and tricuspid valves are more often involved [1,2]. Healing usually leads to fibrosis, scarring, and, in some cases, calcification. If the verrucal lesions are extensive, the healing process can produce deformity of the valve, possibly leading to mitral or aortic regurgitation.

Verrucous endocarditis is typically asymptomatic. However, the verrucae can fragment and produce systemic emboli, and infective endocarditis can develop on already damaged valves [1,5,14]. As a result, blood cultures and echocardiography should be performed whenever fever and a new murmur are noted in a patient with SLE [3]. In addition, one can consider antibiotic prophylaxis for patients with SLE undergoing procedures associated with a risk of developing bacteremia (such as dental care) in view of the high frequency of valvular disease [15]. My routine practice is to use antibiotics only with procedures at high-risk for transient bacteremia, such as gum surgery. (See "Antimicrobial prophylaxis for bacterial endocarditis").

Therapy — Corticosteroid and/or cytotoxic therapy have no effect upon valvular lesions [14]. Anticoagulation treatment should be considered among those vegetations.

PERICARDIAL DISEASE — Pericardial involvement is the second most common echocardiographic lesion in SLE, and is the most frequent cause of symptomatic cardiac disease. Pericardial effusion occurs at some point in over one-half of patients, and a benign pericarditis may precede the clinical signs of lupus [2].

Characteristics — Pericardial disease is usually asymptomatic, and is generally diagnosed by echocardiography performed for some other reason, such as suggestive electrocardiographic abnormalities [16]. Symptomatic pericarditis typically presents with positional substernal chest pain with an audible rub on auscultation. There may also be signs of serositis at other sites (such as pleural effusion and ascites). (See "Auscultation of heart sounds-I").

The pericardial fluid is a fibrinous exudate or transudate that may contain antinuclear antibodies, LE cells, low complement levels, and immune complexes similar to those seen in lupus pleural effusions [17]. The glucose concentration is normal and the protein concentration is variable, being low with a transudate and elevated with an exudate. The pericardium may reveal foci of inflammatory lesions with immune complexes. There is usually a predominance of mononuclear cells, but scarring may be the primary finding in healed disease.

Course and treatment — The course is benign in the large majority of patients with pericardial disease. Symptomatic pericarditis often responds to a nonsteroidal antiinflammatory drug, especially indomethacin [1]. Patients who do not tolerate or respond to an NSAID can be treated with prednisone (0.5 to 1 mg/kg per day in divided doses). The most serious consequence is the development of purulent pericarditis in the immunosuppressed, debilitated patient [18]. Large effusions, suggestive of tamponade, and constrictive pericarditis are rare in SLE [19].

MYOCARDITIS — Myocarditis is an uncommon, often asymptomatic manifestation of SLE with a prevalence of eight to 25 percent in different studies [1].

Characteristics — Myocarditis should be suspected if there is resting tachycardia disproportionate to body temperature, electrocardiographic abnormalities (such as ST and T wave abnormalities), and unexplained cardiomegaly. The cardiomegaly may be associated with symptoms and signs of congestive heart failure, conduction abnormalities, and/or arrhythmias. Echocardiography may reveal abnormalities in both systolic and diastolic function of the left ventricle. Myocarditis has been associated in some cases with antibodies to ribonucleoprotein and extractable nuclear antigen [20].

Acute myocarditis may accompany other manifestations of acute SLE, particularly pericarditis. Histologic examination reveals infiltration of the myocardium with mononuclear cells. Resolution of the inflammation leads to fibrosis that may be manifested clinically as dilated cardiomyopathy. Myocardial biopsy may be needed to distinguish active myocarditis from fibrosis and other causes of cardiomyopathy [2,21].

Treatment — Myocarditis should be treated with prednisone (1 mg/kg per day in divided doses) plus usual therapy for congestive heart failure if present. A few patients have been treated with cyclophosphamide or azathioprine [21,22]. Cardiomyopathy with fibrosis is usually resistant to steroids and/or immunosuppressive drugs.

CONDUCTION ABNORMALITIES — Conduction defects, which may represent a sequel of active or past pericarditis and/or myocarditis have been noted in 34 to 70 percent of patients with SLE [1]. First-degree heart block may be seen and is often transient; in comparison, higher degrees of heart block and arrhythmias (such as atrial fibrillation) are unusual in adults. Autopsy studies have revealed focal inflammatory cell infiltrates or, more often, fibrous scarring of the conduction system.

Congenital heart block — Congenital heart block may be part of the neonatal lupus syndrome. Many mothers of these infants have either SLE or Sjögren's syndrome, have antibodies to Ro (SS-A) or La (SS-B), and are HLA A1, Cw7, B8, or DR3 positive [23]; the children have an increased frequency of DQA1*03 and DQB1*03 relative to their mothers [24]. The anti-Ro and anti-La antibodies may induce autoimmune injury that prevents normal development of the conduction fibers [25]. It is therefore recommended that anti-Ro antibody titers be measured early in pregnancy in women with SLE. (See "Pregnancy in women with systemic lupus erythematosus", section on Neonatal lupus).

Resting heart rate — The resting heart rate may correlate with disease activity. In one report, for example, 14 of 15 patients with a resting heart rate above 90 beats/min had active disease [26].

CORONARY ARTERY DISEASE — Coronary artery disease has been recognized in two to sixteen percent of patients with SLE [27,28,29,30,31], and can lead to acute myocardial infarction in young women [28,30,31]. In some cases, however, thrombi rather than coronary disease is responsible for the ischemia [32]. Coronary artery vasculitis is rare.

In our experience and that of others, coronary disease, leading to angina, myocardial infarction, congestive heart failure, and death, is becoming an increasing problem, particularly in the young patient with long-standing SLE maintained on corticosteroids [28,29,33,34]. One author has noted the bimodal character of mortality in SLE: infection due in part to immunosuppression is most common early in the course, while coronary disease is more prominent after two years [33]. In another report, coronary disease (defined as angina, myocardial infarction, or sudden death) occurred in 8.3 percent of 229 patients and was responsible for 3 of 10 deaths [30].

It has been proposed that autoimmune vascular injury in SLE may predispose to atherosclerotic plaque formation via a number of possible mechanisms [35,36]:

  •  The deposition of immune complexes stimulates the accumulation of cholesterol in the plaque.

  •  Antibodies to oxidized low density lipoprotein help concentrate these atherogenic particles in the vessel wall macrophages.

  •  Vascular endothelium dysfunction

  •  Platelet hyperactivity

  •  Impaired fibrinolysis

Risk factors — The factors responsible for premature coronary disease are incompletely understood. An increased incidence of risk factors (some nontraditional) for atherosclerosis has been noted. In one study, for example, three or more risk factors were found in 53 percent of a cohort of 229 patients with a mean age of only 38.3 years [28]. These include hypertension, smoking, menopause, obesity, lipid abnormalities [37,38,39,40], corticosteroids (which can cause or exacerbate hyperlipidemia, diabetes, and obesity) [38], previous coronary disease [41], increased plasma homocysteine concentrations [13], chronic nephritis [42], low serum levels of C3 [43], elevated levels of antibodies to dsDNA [43], and antiphospholipid antibodies [44,45] (which promote thrombosis). The presence of such risk factors may also enhance the risk of cerebrovascular disease [46]. (See "Overview of the risk factors for cardiovascular disease-I").

The importance of these factors can be illustrated by the clinical differences that have been noted in patients with coronary disease when compared to those without coronary disease [30]:

  •  Increased age at diagnosis of SLE (37.1 versus 28.9 years) and at entry into the study (47.1 years versus 34.7 years).

  •  Longer mean duration of SLE (12.3 versus 8.1 years).

  •  Longer mean duration of prednisone use (14.3 versus 7.2 years).

  •  Higher mean plasma cholesterol concentration (271 versus 215 mg/dL [7.0 versus 5.6 mmol/L]) and more frequent occurrence of a cholesterol level above 200 mg/dL (5.2 mmol/L).

  •  Greater prevalence of hypertension and a history of use of antihypertensive medication.

The specific effect of prednisone and hydroxychloroquine on coronary risk factors was studied in a cohort of 264 patients [47]. The administration of hydroxychloroquine produced a decrease in plasma cholesterol of 8.9 mg/dL (0.23 mmol/L). In contrast, in a regression model corrected for age, weight and antihypertensive dose, a 10 mg/day increase in prednisone dose led to definable worsening of the following risk factors:

  •  An increase in serum cholesterol of 7.5 mg/dL (0.19 mmol/L).
  •  An increase in mean arterial blood pressure of 1.1 mmHg.
  •  An increase in body weight of 2.5 kg.

Evaluation — The evaluation of the individual suspected of having coronary artery disease is performed similarly in patients with and without SLE. (See "Diagnostic approach to the patient with chest pain-I").

Prevention and treatment — Patients with SLE should be made aware of the importance of risk factor reduction. In one study, for example, only 17 percent of the patients believed that they were at high risk for developing coronary disease within five years, when in fact three or more risk factors were present in 53 percent of patients [28].

Patients with lupus should be advised to stop smoking, exercise, consider the use of hormone replacement therapy, and follow measures designed to improve lipid profiles. (See "Treatment guidelines for hypercholesterolemia"). Hydroxychloroquine should be used in preference to prednisone whenever possible and aspirin should be prescribed for its antiplatelet properties. (See "Benefits of aspirin in cardiovascular disease").

Hypertension is an important risk factor in SLE [47]. We favor aggressive therapy, aiming for a diastolic pressure below 85 mmHg, especially in younger patients. The choice of antihypertensive agent depends in part upon coexisting disorders. As examples, we use nifedipine in patients with Raynaud's phenomenon and an angiotensin converting enzyme inhibitor in patients with renal disease. Steroids may contribute to hypertension and diabetes, so the steroid dosage should be reduced, if possible. (See "Antihypertensive therapy and progression of renal failure-I").

Symptomatic coronary artery disease should be treated as in patients without lupus. (See "Management of stable angina pectoris").

VENOUS THROMBOSIS — Thrombophlebitis has been reported in approximately 10 percent of patients with SLE [48]. It generally involves the lower extremity, but can also affect the renal veins and inferior vena cava; pulmonary embolism is rare. Risk factors for venous thrombosis include antiphospholipid antibodies and the use of oral contraceptives, particularly in association with smoking cigarettes.