Thursday, October 19, 2006

Is Your Child at Risk?Atherosclerotic Heart Disease in Young People with Lupus

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


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).

Evidence of heart problems in children with lupusChildren 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).

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:
hypertension
diabetes
obesity
elevated cholesterol levels.

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).

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.

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:

weight gain
hypertension
elevated serum glucose and lipid levels.

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.

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.

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.

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
Recognize increased risk in young population.
Conduct a thorough cardiac evaluation if there is any suspicion of heart disease.

Step 2: Patient education
Make patients and parents aware of increased risk.

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.

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.

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.

About the AuthorsSusan 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.

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.

July 30, 2003

=========================================================== This information is for"informational purposes" and is not meant to be used for medical diagnosis. Alwaysconsult your physician on matters such as this.