What alarmingly few women realize, however, is that if they have the chronic autoimmune disease, systemic lupus (lupus)—and approximately 1.3 million do—they are even more vulnerable than others to heart disease. In fact, they are 7 to 10 times more likely than their peers to have a heart attack or stroke. In lupus, the body attacks its own healthy tissues and organs in a repetitive cycle of flare-ups and remissions.

“It’s high time that the national spotlight turn on this twin threat—lupus and heart disease—that cripples the lives of so many women,” said Margaret G. Dowd, president of the Lupus Research Institute. (Men are affected by lupus as well, though at a much lower rate of 1 in 10.)

The Lupus Research Institute is the nation’s leading nonprofit organization funding novel lupus research. It focuses on fresh, innovative ideas for demystifying lupus, and has made cardiovascular investigation a major priority, earmarking more than $2 million of its $14.5 million in grants for this area.

Defining the Risk

The prevalence and dangers of lupus-related heart disease in women is rapidly accumulating, thanks to research funded by the Lupus Research Institute and others. Investigators have found that heart disease and stroke threaten the lives of more than a third of women with lupus, with certain groups at particular risk. African American women, for example, run the double hazard of being three times more likely than Caucasian women to have lupus, and, for various reasons, being more likely to die from heart disease or a stroke if either develops.

Young women are also, in many cases, unwitting targets. According to key research reported in the December 2003 issue of The New England Journal of Medicine, women with lupus under age 40 are nearly five times more likely to have atherosclerosis (dangerous clogging and hardening of the coronary arteries) than their healthy, same-age peers. And that’s regardless of the conventional risk factors—smoking, high cholesterol, advanced age, high blood pressure, obesity, diabetes.

Solutions in Sight

Lupus Research Institute (LRI)-funded investigators are looking at why heart disease develops in people with lupus, and how to detect and treat it most effectively. Notes William Paul, MD, chief of the Laboratory of Immunology at the National Institutes of Health and chairman of LRI’s Scientific Board, “LRI researchers are taking the bold and unconventional approaches needed to finally get some answers not just about lupus, but about the interconnections of heart disease, inflammation, and autoimmunity.”

As for why women with lupus are at such dramatically increased risk for heart disease, it appears that inflammation and other immune system abnormalities cause atherosclerosis. In time, clots can form or bits of plaque can break off from artery linings, interfering with blood flow to the heart and brain.

The groundbreaking work of Mariana J. Kaplan MD, at the University of Michigan in Ann Arbor, initially funded by the LRI, has found that some people with lupus appear to get premature atherosclerotic changes due to the rapid death and much-too slow replacement of endothelial cells. These cells, which line the blood vessels and cavities of the heart, normally keep plaques and clots from forming.

“We found that the lupus patients had abnormal vascular function that was impaired to the same extent seen in the heart disease patients – despite the fact that the lupus patients were approximately half the age,” she explains. Dr. Kaplan envisions designing therapies to prevent endothelial cell damage and thereby slash the risk for premature atherosclerosis.

Amy Major, PhD, at the Vanderbilt University School of Medicine has an LRI grant that she will use to for feeding a normal, non-high fat diet to lupus-prone, atherosclerosis-susceptible mice (a model she aims to develop) to observe whether the animals quickly develop hardened arteries, all the while examining the effect of slight changes in cholesterol and the immune system.

And a grant to Robert A. Eisenberg, MD, at the University of Pennsylvania School of Medicine in Philadelphia, is designed to compensate for some of the limitations of researching atherosclerosis in people with lupus. One limitation is that coronary artery plaques accumulate gradually (stretching studies out over years). Another is that the disease tends to be clinically silent until a heart attack or other serious problem occurs.

Dr. Eisenberg’s solution is to develop a new breed of mice with an inherited susceptibility to both conditions: lupus and atherosclerosis. This mouse model will give researchers a powerful tool for dissecting the mechanisms by which lupus causes such a rapid acceleration of atherosclerosis. The anticipated result: novel methods to prevent and treat premature heart disease in young people with lupus.

Headway in Biomarkers

Researchers are hunting for markers in the blood (biomarkers) that signal the likely development of heart disease in people with lupus, so that a simple blood test or noninvasive imaging study can tell who is at risk, and who might benefit from powerful yet costly and often problematic cholesterol-lowering drugs or blood thinners.

“Since not everybody with lupus develops accelerated atherosclerosis, it’s crucial to identify people who can then be started on preventive treatment like statins,” explains Bevra H. Hahn, MD, at the UCLA Medical School in Los Angeles. Many people with lupus actually have normal levels of total cholesterol, LDL cholesterol, and HDL cholesterol. Yet images of the coronary arteries show calcification.

Groundbreaking research recently reported by Dr. Hahn, Maureen McMahon, MD, and colleagues at the annual meeting of the American College of Rheumatology in November 2005 indicates that a subtype of the normally “good” high density lipoprotein (HDL) cholesterol appears to play a destructive role in people with lupus and rheumatoid arthritis, promoting atherosclerosis and heart disease in many of these individuals.

One day soon doctors may be able to test people with lupus for this menacing HDL form—pro-inflammatory HDL (piHDL) and be able to take measures to aggressively treat (prevent or reverse) the damage it can do.

In another study funded by the LRI, Robert M. Clancy, PhD, and his team at the New York University School of Medicine will to assess a separate biomarker for predicting subclinical atherosclerosis: Circulating Endothelial Cells (specifically, endothelial cell protector C receptor, or ECPR), a protein found only on endothelial cells. Endothelial cells are likely participants in the inflammation that leads to tissue damage and later atherosclerotic changes. They’re activated by immune stimuli likely present during a lupus flare.

Endothelial disorders are “an underdeveloped area for drug development and our work will put a spotlight on it,” Dr. Clancy says. Measurement of circulating endothelial cell levels also may help to monitor the effectiveness of atherosclerosis-prevention therapies.

In addition to premature atherosclerosis, people with lupus patients have an increased risk of blood clotting complications, such as strokes and heart attacks. A new line of research taken by Robert Roubey, MD (University of North Carolina at Chapel Hill) could help pinpoint the subgroup of patients at risk of these potentially fatal problems.

Dr. Roubey will develop new tests to measure tissue factor activity in the blood to see if this biomarker accurately predicts which of the 33% of lupus patients with phospholipid-binding antibodies are at increased risk of developing clots and should be prescribed blood thinners.

Self-Care is Crucial

As these and other new discoveries generated by LRI researchers progress to expanded clinical studies and new treatments, people with lupus can be increasingly confident that they will know freedom from a life of sickness and early death from heart disease. Moreover, given that lupus is the prototypical inflammatory disease, millions of others imperiled by heart disease—now considered to result from an inflammatory process—could likely benefit as well.

“It’s a promising time in cardiac research,” notes Dr. Paul, “but especially so for those with lupus.”

In the meantime, while researchers continue their hunt for clues and tools to fight lupus-related heart disease, women with lupus can take steps to protect themselves right away. They can lessen their chances of developing heart problems by not smoking, aggressively lowering blood pressure with medicines if it’s high, taking off excess weight, and doing other heart-healthy activities such as exercising regularly. Even 30 minutes of daily brisk walking can make a difference.

Women with lupus should not only bring up the subject of heart disease with their rheumatologist, but also ask about visiting a cardiologist (heart doctor). Familiarity with the warning signs of a heart attack and stroke is key—they are often different in women than in men—as is making sure that conventional indicators of heart disease, such as high cholesterol and high homocysteine levels (an amino acid in the blood), are taken care of.