ORLANDO, Fla. – Mass suicide by protective cells that line every blood vessel in the body may be to blame for the increased risk of heart and vascular disease faced by patients with the autoimmune disease known as lupus, new research suggests.
And the test used to see those dying cells in the bloodstream may one day help lupus patients – and people with other diseases – understand, predict and do something about their personal risk of heart disease.
At American Heart Association's Scientific Sessions 2003, researchers from the University of Michigan Cardiovascular Center will present their findings that levels of apoptotic endothelial cells detected in the blood of 43 young female lupus patients correlated well with the patients’ blood vessel function and lupus symptoms. The lupus patients had no other major risk factors for heart or vascular disease.
The study compared lupus patients with 43 older patients with clogged heart arteries, and 43 healthy controls. 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 of the heart disease control patients. Impaired blood vessel or vascular function — also known as endothelial function — is an accurate predictor of heart disease risk.
But even the heart patients had fewer dying endothelial cells in their blood than the lupus patients, suggesting a rapid death rate of these protective vessel-lining cells. It’s the first time apoptotic endothelial cells have been detected in the blood of lupus patients.
“Because of lupus, these women in their 30s had the vascular health of 65-year-olds with coronary artery disease, and therefore presumably a much higher risk of heart attack and stroke,” says lead author Sanjay Rajagopalan, M.D., the U-M vascular medicine specialist and associate professor of internal medicine who will present the study. “The rapid apoptosis of endothelial cells is apparently outpacing the body’s ability to repair the affected vessels, so the protection usually offered by the cells suffers.”
Says senior author and U-M rheumatologist Mariana Kaplan, M.D., “Even in the absence of other risk factors, these women have a tremendously high risk of dying young from cardiovascular events. Heart disease is the No. 3 cause of death among lupus patients, and we’re only just beginning to understand why.” She adds, “We need to characterize the mechanisms of endothelial cell damage, and understand its contribution to atherosclerosis and clot formation, to help patients and develop therapies for the future.” Kaplan is an assistant professor of internal medicine at the U-M Medical School.
More than 1.4 million Americans, nearly all of them women in their 20s, 30s and 40s, have lupus. The disease causes the body’s immune system to become hyperactive and form antibodies and immune complexes that attack normal tissues and organs. The disease can cause sporadic periods of fatigue, pain, organ damage and disability that persist for years. Many patients die prematurely of kidney failure, infection or cardiovascular diseases, such as heart attack or stroke.
Even at a young age, many people with lupus have narrowed or partially blocked coronary arteries, mainly caused by cholesterol deposits on the blood vessel walls (atherosclerosis). And in addition to damage done by the disease itself, they also face an increased risk of blood vessel blockage if they take corticosteroids like prednisone to reduce the severity of their autoimmune attacks.
The new study suggests that lupus patients’ heightened heart risk may be due to the rapid death and much-too-slow replacement of endothelial cells, which normally keep plaques and clots from forming in blood vessels. Loss of these cells through accelerated apoptosis may affect vascular and heart health in many ways, says Rajagopalan, since endothelial cells serve an important barrier function, and make nitric oxide that regulates blood vessel dilation and contraction and blood flow.
Rajagopalan and Kaplan, along with a team of U-M colleagues, suspected something must be damaging the endothelial cell layer in order to cause cardiovascular disease in women with no other risk factors besides lupus. They set out to determine if they could see these apoptotic endothelial cells in the blood, and correlate them to both vascular function and the flaring up of lupus symptoms.
“ We hypothesized that rapid apoptosis could exist at the level of the endothelial cells, that they might commit suicide and thereby affect vascular function,” says Rajagopalan.
Apoptosis is a normal process by which cells self-destruct at the end of their useful lives. Endothelial cells routinely die, and are taken away by the body’s “garbage truck” cells. But previous research has shown that in lupus, there’s an increased pace of cell suicide in major organs and a decreased clearance of those dead cells by the immune system.
For the new study, the U-M researchers tested blood for the presence of a type of endothelial cell called CD146, combined with a test for the apoptosis-related protein annexin V. They found that lupus patients had about seven times the levels of endothelial cells and annexin V seen in the normal and heart-diseased patients. “It’s as if more garbage was being generated than could be cleaned up by the body’s normal means, so it piled up in the blood,” says Rajagopalan.
The researchers also measured all the study participants’ vascular health by monitoring blood flow in the arm using techniques often used for people with vascular disease: brachial-artery-flow-mediated dilation and nitroglycerin-mediated dilation. Both the lupus patients and coronary artery disease patients had abnormal flow-mediated dilation, while normal control subjects did not.
In most patients tested for vascular function, abnormal results are caused by diabetes, smoking, high LDL cholesterol in the blood, or high blood pressure. But the lupus patients in the study had none of these. What’s more, their abnormal vascular function readings correlated directly with their blood levels of apoptotic endothelial cells, and the severity of their lupus symptoms at the time.
Kaplan and Rajagopalan plan to evaluate how well the apoptotic endothelial cell test predicts actual incidence of atherosclerosis and other heart and vascular diseases in lupus patients and others, and whether it could be combined with measures of vascular function to predict an individual patient’s risk. This could eventually lead to individual preventive therapy for lupus patients, with drugs now used in people who have a high risk of heart disease due to other factors.
Besides Kaplan and Rajagopalan, the U-M research team included Emily Somers; Robert Brook, M.D.; Christine Kehrer; Dana Pfenninger; Robert Pavlic; Emily Lewis; Anjan Chakrabarti; Bruce Richardson, M.D., Ph.D.; Eric Shelden, Ph.D.; and William J. McCune, M.D. The study was funded by the Lupus Research Institute, the Arthritis Foundation and the Herbert and Carol Amster Lupus Fund.
Reference: “Circulating Apoptotic Endothelial Cells in Systemic Lupus Erythematosus: An Independent Predictor of Vascular Risk?” Abstract 2389, Oral Session 42.1, Tues., Nov. 11, 8:45 a.m., Room 330D.
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