Dec. 26, 2002 DALLAS, Dec. 24 – Nitric oxide, a substance that helps blood vessels dilate, is up to two times more available in women than men with the genetic condition, sickle cell anemia. This may help explain gender differences in survival, researchers report in today's rapid access issue of Circulation: Journal of the American Heart Association.
Sickle cell anemia is an inherited blood disorder, in which normally round red blood cells become misshaped like sickles and clog vessels. These blockages cause painful episodes known as sickle cell crises. An estimated 1 in 500 African Americans have the genetic condition that occurs when someone inherits two copies of a mutated gene for hemoglobin, the oxygen carrier in red blood cells.
"Like coronary artery disease, sickle cell disease seems linked to inflammation in the arteries," says Mark Gladwin, M.D., a clinician-researcher, critical care medicine, National Institutes of Health Clinical Center. He collaborated on this study with Richard O. Cannon III, M.D., clinical director, National Heart, Lung, and Blood Institute.
Inflammation in sickle cell disease is probably due to the blocking of the blood vessel by the misshapen red blood cells. "Sickle cell disease's connection to inflammation made us want to investigate the molecule nitric oxide (NO), which is 'the WD-40' of the blood vessels," Gladwin says.
The body makes NO and uses it to dilate blood vessels, so blood can flow through them easily. When the body attempts to repair injured areas of the blood vessels – such as after blood flow is cut off in a heart attack or sickle cell crisis – NO prevents the inflammatory white cells of that repair process from sticking to the cells that line the arteries. NO also reduces clotting by keeping the platelets in the blood from sticking together. Finally, NO protects vessels by knocking out a substance called superoxide that generates highly destructive particles, "free radicals," that can damage vessels, he says.
The researchers studied 21 African-American patients (11 men and 10 women, ages 18 to 55) with sickle cell disease and 18 African Americans without sickle cell disease (controls). They measured forearm blood flow before and after administering a series of drugs known to affect vessel dilation and blood flow.
"These studies had a surprising result," Gladwin says. "The men appear to have problems both in making nitric oxide and with increased destruction of nitric oxide."
When the men were given a substance containing NO, their blood flow increased by 86 percent, while women's blood flow increased 171 percent, he says.
That may help explain results from previous studies that found that men with sickle cell disease experience more sickle cell crises after puberty than do women; and that the median age of death was 42 for men compared to 48 for women. But few studies have been done in adults with sickle cell disease, Gladwin says. Sickle cell was considered a usually fatal disease of childhood, until the use of childhood vaccinations and routine penicillin starting in infancy helped sickle cell disease patients live to adulthood.
"One of the great mysteries of sickle cell disease is that everyone has the same mutation for the most part, yet others have extremely severe disease and early death and some patients have hardly any complications or pain," he says.
During the last 20 years cardiologists have shown that the hormone estrogen, which rises in women beginning at puberty, increases the production of NO. There are also factors that can destroy NO, such as the cell-free hemoglobin released when red blood cells rupture. A lower level of estrogen could lead to more severe disease, more cell rupture and more cell-free hemoglobin to destroy the NO.
"The destructive factors probably win the battle during a sickle cell crisis and it's tempting to speculate that women with sickle cell do better in this battle for NO because of estrogen," he says.
"We're very excited about this data because a number of therapies borrowed from the cardiology field have been shown to increase the amount of NO and its survival in the body. Principal among them is the cholesterol-lowering class of drugs called the statins," he says. Recent studies have indicated that statins provide protection against heart attack that seems to extend past their ability to lower cholesterol, perhaps through anti-inflammatory effects. A trial is expected to begin 2003 to test statins' effect on sickle cell disease, he says.
Co-authors are Alan Schechter, M.D.; Frederick P. Ognibene, M.D.; Wynona A. Coles; Chistopher D. Reiter, Ph.D.; William H. Schenke; Gyorgy Csako, M.D.; Myron A. Waclawiw, Ph.D; and Julio A. Panza, M.D.
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