Cardiac manifestations of systemic lupus
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
• Pericardial disease, usually a clinically
silent effusion ！ up to 55 percent [2
• Myocardial dysfunction ！ up to 78 percent [1
• Coronary artery disease [1
！ 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
They often reflect aortic insufficiency, which occasionally requires valve
"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
"Pulmonary manifestations of systemic lupus erythematosus"
However, other reports have not confirmed the relationship between
antiphospholipid antibodies and cardiac disease [3,11,12
"Clinical manifestations and diagnosis of the antiphospholipid antibody
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
"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
• 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
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"
！ 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
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
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
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
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"
！ Corticosteroid and/or cytotoxic
therapy have no effect upon valvular lesions [14
Anticoagulation treatment should be considered among those vegetations.
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
！ 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
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,
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
Large effusions, suggestive of tamponade, and constrictive pericarditis are
rare in SLE [19
！ Myocarditis is an uncommon,
often asymptomatic manifestation of SLE with a prevalence of eight to 25
percent in different studies [1
！ 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
！ Myocarditis should be treated
(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
Cardiomyopathy with fibrosis is usually resistant to steroids and/or
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"
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
！ 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
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
"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
• 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
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
• An increase in mean arterial blood pressure of
• An increase in body weight of 2.5 kg.
！ 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"
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
"Antihypertensive therapy and progression of renal failure-I"
Symptomatic coronary artery disease should be treated as in patients without
"Management of stable angina pectoris"
！ 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.