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Is Your
Child at Risk?
Atherosclerotic Heart Disease in Young
People with Lupus
Susan Manzi, M.D., M.P.H., Janice M. Sabatine, Ph.D.,
and Laura E. Schanberg, M.D.
From Lupus News Fall 2002, Vol. 22, N. 3
Introduction
Evidence of heart problems in
children with lupus
What causes heart disease in lupus
Is there a link between corticosteroids
and atherosclerosis?
How can atherosclerosis be managed
in young people?
Strategies for Managing Cardiovascular
Disease Risk in Children with Lupus
Bottom line
About the authors
References
Introduction
It has been well established that accelerated atherosclerosis,
or hardening of the arteries, occurs in adults with
lupus, along with its eventual clinical outcomes-myocardial
infarction (heart attack) and stroke.
However, atherosclerotic heart disease
is emerging as one of the most serious concerns in
children and adolescents with lupus. Young, premenopausal
women with lupus are up to 50 times more likely to
have a heart attack than women of the same age who
do not have lupus (1). Our research and that of other
investigators indicate that these clinical outcomes
are generally related to accelerated atherosclerosis
(2,3).
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Evidence of
heart problems in children with lupus
Children with lupus are known to experience myocardial
infarction and stroke. Although the frequency of atherosclerosis
in these young patients is not fully known, emerging
evidence suggests the incidence may be similar to
that in premenopausal women with lupus.
It is not unreasonable to suspect atherosclerotic
development at young ages, as evidence of fatty streak
formation-an early step in plaque formation-has been
noted in healthy children as young as two to three
years of age.
Atherosclerosis-promoting patterns of
cholesterol, triglycerides, and other lipoproteins
in children and adolescents with lupus have been documented
(4). Coronary blood flow abnormalities were found
in 16 percent of children and adolescents with lupus
who had no cardiac symptoms. This suggests that there
may be a significant percentage of young lupus patients
with undiagnosed heart disease.
In addition, evidence of carotid atherosclerotic
plaque and abnormal coronary blood flow have been
detected two to five years after the onset of lupus,
indicating that atherosclerosis may develop very early
in the course of disease (5,6).
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What causes
heart disease in lupus?
We do not completely understand the underlying biological
cause for accelerated atherosclerosis in young patients
with lupus, probably because we do not yet completely
understand the underlying biological cause of lupus.
One thing we do know is that two key factors are the
disease of lupus, itself, and its treatment.
It was initially thought that the increased risk
of heart disease in patients with lupus might be due
to traditional risk factors, such as:
But recent evidence indicates that the
presence of lupus itself, or the treatment for lupus,
contribute more than those risk factors alone (2,7).
The task now is to identify the biological processes
occurring in lupus or resulting from its treatment
that promote atherosclerosis.
It was once believed that excess cholesterol
built up as plaque inside the blood vessels and obstructed
blood flow. Investigators now know that fewer than
20 percent of heart attacks are due to restricted
blood flow in progressively narrowed coronary vessels.
More commonly, heart attacks occur when an atherosclerotic
plaque ruptures and a blood clot forms around the
plaque (8).
There are several potential parallels
between lupus and the formation and rupture of atherosclerotic
plaques (9).
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A. For instance, damage to the lining of the blood
vessels provokes an inflammatory response, which
leads to deposits of immune cells containing fat
droplets into the arterial wall. This in turn leads
to plaque formation.
B. Inflammation is also responsible for thinning
the fibrous cap that covers a plaque, making it
more vulnerable to rupture. The inflammatory substances
known as cytokines that drive the formation of atherosclerotic
plaques and increase the vulnerability of the plaques
to rupture are the same substances that play a major
role in the inflammatory processes seen in lupus.
This may explain why cardiovascular disease is accelerated
in lupus.
C. Another factor related to lupus as a prime suspect
as sources of damage to the lining of the arterial
wall is high levels of circulating immune complexes.
Although immune responses are important in the body's
normal response to damage and microbial infections,
in systemic lupus-and perhaps in atherosclerosis
in general-these normally protective immune responses
become dysregulated, leading to a high degree of
inflammation and tissue damage.
D. A wide variety of autoantibodies may also hold
responsibility. Elevated levels of antiphospholipid
antibodies, which are often found in people with
lupus, have traditionally been linked to an increased
risk of blood clotting and may increase the risk
of clot formation at the plaque site. More recent
evidence suggests that these antibodies may also
facilitate the uptake of oxidized low density lipoprotein,
the "bad cholesterol," into inflammatory
cells in the vessel wall. This is a key step in
the formation of atherosclerotic plaque (10).
E. The amino acid homocysteine is another agent
that is often elevated in lupus patients and is
a likely source of arterial injury. Elevated levels
of homocysteine have been linked to thrombosis in
lupus patients (11) and to coronary heart disease
and stroke in non-lupus patients. The reasons for
elevated homocysteine in lupus are not entirely
known, but may be related to kidney disease, diet,
or treatment.
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Is there a link
between corticosteroids and atherosclerosis?
With the advent of glucocorticoids (prednisone) in
the 1950s, there has been a significant improvement
in the lifespan of young people with lupus. Yet there
is concern that these agents may actually contribute
to the development of atherosclerosis, either directly
by promoting plaque formation or indirectly by intensifying
risk factors such as:
In contrast, some evidence indicates
that the anti-inflammatory effects of glucocorticoids
may actually provide protection against atherosclerosis,
suggesting that poorly controlled lupus activity may
contribute to cardiac disease, with corticosteroid
treatment providing a degree of protection.
Perhaps with the use of newer biologic
therapies with similar anti-inflammatory and immunomodulatory
effects as corticosteroids, but fewer adverse side
effects, we will begin to see a reduction in heart
disease.
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How can
atherosclerosis be managed in young people?
It is of critical importance that physicians and patients
be aware of the increased risk of cardiovascular complications
in lupus. Young people generally view their risk of
heart disease as negligible, yet cardiovascular disease
intervention and prevention has the potential to significantly
lengthen and improve the quality of their lives over
many years.
Chest pain. Any physician treating
a young person with lupus, regardless of the patient's
age or sex, should be suspicious of chest pain. Because
the patients are young and because chest pain in lupus
may be attributable to other causes, physicians may
overlook conditions, such as angina (chest pain due
to myocardial ischemia). Yet often there are no warning
signs for an impending heart attack. For these reasons,
a major focus on management strategies should rest
on preventing the development of atherosclerosis.
Diet. There have been reports on the
potential benefits of diet modification in controlling
abnormal lipid levels in children with lupus, but
diet alone is not always sufficient, and pharmacologic
therapy may be necessary. However, the type, timing,
and dosage of such therapy in children have not been
well established by large studies.
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Blood clots. Measures to reduce
potential blood clots, such as anticoagulation or
antiplatelet therapy, should be considered in patients
at increased risk, such as those with kidney disease,
antiphospholipid antibodies, and other coronary disorders.
There are few clinical data on the effects
of non-steroidal anti-inflammatory drugs (NSAIDs)
on atherosclerosis. However, some evidence suggests
that the selective inhibitors of the prostaglandin-producing
enzyme COX-2 might actually enhance blood clot formation
in some non-lupus populations. Further investigation
in this area is currently underway.
Aspirin. There is strong evidence
from clinical trials to support the use of low-dose
aspirin therapy in preventing heart attacks in the
general population. At low doses, aspirin is probably
reducing the clotting risk but not reducing inflammation.
Dietary supplements. There is
some evidence that the antioxidant vitamins E and
C may improve arterial dilatation in children with
familial hypercholesterolemia or combined hyperlipoproteinemia.
However, the long-term benefit of antioxidant therapies
in reducing cardiovascular risks in lupus is unknown.
Measures to reduce homocysteine levels with folate
supplementation may be beneficial; again, however,
the effects on prevention of coronary events are unproven.
Steroids. Based on the possible
opposing effects of corticosteroids-increasing traditional
risk factors and controlling inflammation-there are
no established recommendations about the use of corticosteroids
concerning cardiovascular risk in lupus. In general,
judicious use of these agents to control the underlying
disease and to minimize the proven long-term side
effects is recommended.
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Table 1 (below)
illustrates suggested strategies to manage and/or
prevent atherosclerosis in young patients with lupus.
These strategies are targeted at both traditional
cardiovascular risk factors and at potential lupus-specific
factors. Physicians should communicate these potential
risks to patients and their parents, and provide relevant
information and resources for patient education.
Table 1. Strategies For Managing
Cardiovascular Disease Risk In Children With
Lupus
Step 1: Physician awareness
Step 2: Patient education
Step 3: Minimize traditional
cardiovascular risk factors
-
Encourage a regular aerobic
exercise program.
-
Establish guidelines for
a heart-healthy diet.
-
Assist with weight loss
program, if necessary.
-
Start a smoking cessation
program.
-
Control hypertension and
diabetes, if present.
-
Treat hyperlipidemia.
Step 4: Address potential
lupus-specific risk factors
-
Use corticosteroids judiciously.
-
Reduce homocysteine levels
(folate supplementation).
-
Consider aspirin or anticoagulant
therapy for patients at high risk for blood
clotting.
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Physicians also should work together with the patients and parents
to encourage a heart-healthy diet, a regular exercise
program that involves aerobic activity, and weight
loss, if necessary. Patients should be advised not
to start smoking and to quit if they have already
started. Hypertension and diabetes should be managed
aggressively.
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Bottom line
It is clear that premature atherosclerosis in children,
adolescents, and young, premenopausal women with lupus
is a substantial medical concern. The reasons that
atherosclerosis is accelerated in lupus patients likely
involve the inflammatory and immune-mediated mechanisms
shared by these two disease processes.
Until new biologic therapies are available
that can halt the immune dysregulation and resulting
inflammation and vascular damage in lupus, we must
promote aggressive approaches to reducing traditional
cardiovascular risk factors.
Noninvasive methods for specifically
identifying vulnerable plaques might also pinpoint
those lupus patients at greatest risk for heart attack
and those most likely to benefit from intervention.
Investigations into the pathways that lead to premature
heart disease in lupus may provide an ideal model
for examining the role of inflammation in all populations
with cardiovascular disease.
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About the Authors
Susan Manzi, MD, M.P.H., is an Associate Professor
of Medicine and Epidemiology at the University of
Pittsburgh School of Medicine in Pennsylvania.
Janice M. Sabatine, Ph.D. is a medical
writer and editor.
Laura E. Schanberg, MD is an Assistant
Professor of Pediatric Rheumatology at Duke University
Medical Center in Durham, NC.
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References
1. Manzi S, Meilahn EN, Rairie JE,
Conte CG, Medsger TA, Jr., Jansen-McWilliams L et
al. Age-specific incidence rates of myocardial infarction
and angina in women with systemic lupus erythematosus:
comparison with the Framingham Study. Am J Epidemiol
1997;145:408-415.
2. Manzi S, Selzer F, Sutton-Tyrrell K, Fitzgerald
SG, Rairie JE, Tracy RP et al. Prevalence and risk
factors of carotid plaque in women with systemic lupus
erythematosus. Arthritis Rheum 1999;42:51-60.
3. Selzer F, Sutton-Tyrrell K, Fitzgerald S, Tracy
R, Kuller L, Manzi S. Vascular stiffness in women
with systemic lupus erythematosus. Hypertension 2001;37:1075-1082.
4. Ilowite NT. Premature atherosclerosis in systemic
lupus erythematosus. J Rheumatol 2000;27 Suppl 58:15-19.
5. Gazarian M, Feldman BM, Benson LN, Gilday DL, Laxer
RM, Silverman ED. Assessment of myocardial perfusion
and function in childhood systemic lupus erythematosus.
J Pediatr 1998;132:109-116.
6. Falaschi F, Ravelli A, Martignoni A, Migliavacca
D, Sartori M, Pistorio A et al. Nephrotic-range proteinuria,
the major risk factor for early atherosclerosis in
juvenile-onset systemic lupus erythematosus. Arthritis
Rheum 2000;43:1405-1409.
7. Esdaile JM, Abrahamowicz M, Grodzicky T, Li Y,
Panaritis C, du BR et al. Traditional Framingham risk
factors fail to fully account for accelerated atherosclerosis
in systemic lupus erythematosus. Arthritis Rheum 2001;44:2331-2337.
8. Libby P. What have we learned about the biology
of atherosclerosis? The role of inflammation. Am J
Cardiol 2001;88:3J-6J.
9. Manzi S. Systemic lupus erythematosus: a model
for atherogenesis? Rheumatology (Oxford) 2000;39:353-359.
10. Vaarala O. Autoantibodies to modified LDLs and
other phospholipid-protein complexes as markers of
cardiovascular diseases. J Intern Med 2000;247:381-384.
11. Petri M, Roubenoff R, Dallal GE, Nadeau MR, Selhub
J, Rosenberg IH. Plasma homocysteine as a risk factor
for atherothrombotic events in systemic lupus erythematosus.
Lancet 1996;348:1120-1124.
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July 30, 2003
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