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CSP News: Reduction of Iron Stores and Cardiovascular Outcomes in Patients With Peripheral Arterial Disease

Study suggests controlling iron levels early in life may cut future heart risk

JAMA, February 14, 2007—Vol 297, No. 6

WHITE RIVER JCT.,VT (2/14/2007) – A six-year study by Veterans Affairs researchers suggests that reducing the body's excess iron stores—in this case, by drawing blood—may improve clinical outcomes for people with symptomatic but stable peripheral arterial disease (PAD), but only if iron reduction begins at a relatively young age. The findings appear in the Feb. 14 Journal of the American Medical Association.

"While our study did not show that reducing iron led to across-the-board decreases in overall mortality, or combined death plus non-fatal myocardial infarction and stroke, it did support the theory that vascular health might be preserved into later life by maintaining low levels of iron over time," said lead author Leo R. Zacharski, MD, a physician-researcher at the White River Junction (Vt.) VA Medical Center and Dartmouth Medical School.

Excess iron in the blood is thought to promote free-radical damage to arteries, particularly in the early stages of atherosclerosis, a major risk factor for heart attack and stroke. Researchers posited in the 1980s that premenopausal women have lower cardiovascular risk than men because they regularly lose blood—and excess iron—through menstruation.

At least two large studies in the late 1990s seemed to support this notion: They found that men who donated blood—and thereby lowered their iron levels—had fewer cardiac problems than men who didn't donate. But other studies have yielded mixed results, and the topic is still debated among doctors.

Controlling Iron Levels Early in Life May Cut Future Heart Risk 2-2-2-2

The VA clinical trial involved 1,277 men and postmenopausal women with PAD, ages 43 to 87, studied between May 1999 and April 2005 at 24 VA medical centers. Patients were randomly assigned to either a control group (no iron reduction) or a group undergoing iron reduction by phlebotomy, with removal of defined volumes of blood at six-month intervals. The amounts of blood drawn were carefully calculated to avoid iron deficiency. Participants were defined by several subgroups: age, smoking status, diagnosis of diabetes mellitus, ratio of high-density to low-density lipoprotein cholesterol level, and initial ferritin (iron) level.

Phlebotomy was the iron-removal method of choice, said Zacharski, because it is "safe and inexpensive, and correlates to routine blood donation, an �over-the-counter' procedure that appears to contribute to improved vascular health." He emphasized, though, that pending further research, people should not seek to donate blood simply to lower their iron levels, and that similar effects could be achieved through dietary restrictions or drug treatment.

By the end of the study follow-up period in 2005, there had been 273 deaths from all causes, occurring roughly equally between the iron-reduced (125) and control (148) groups. In terms of the secondary outcome measure—death from any cause, or nonfatal heart attack or stroke—there was also no statistically significant difference: 180 in the iron-reduction group and 205 in the control group. The overall findings thus did not support the theory that iron-reduction therapy could improve outcomes for PAD patients across all of the study subgroups.

However, when the researchers analyzed the results for younger patients in the study—those ages 43 to 61—they found 54-percent fewer deaths from all causes in the iron-reduction group, and 57-percent fewer deaths plus nonfatal heart attacks and strokes. Iron reduction also appeared to somewhat improve the outcomes for smokers and those without diabetes.

Regarding the age-linked finding, Zacharski said, "We suspect that the toxic effect of excess ferritin may become permanent at an older age, such that the benefits of iron reduction are realized only if it is started early and continued over time." Future studies, he said, should aim to test this theory by investigating the impact of iron-reduction partnered with an overall iron maintenance program—including diet modification, education, and other interventions—on men and women under age 60.

More research, added Zacharski, is also needed to better define the overall relationship between iron and cardiovascular disease, clarify the biological mechanisms by which the two interact, and determine how best to counter what are conclusively shown to be harmful effects of iron.

"Our data suggest that iron may contribute to the development of atherosclerosis relatively early in its course, and that long-term iron maintenance—in combination with other lifestyle modifications—may help slow or reverse the process," Zacharski said. "But ours is just a beginning, and more controlled studies are required."

The study was funded by VA's Cooperative Studies Program. Study coauthors included researchers at VA sites in Palo Alto and Gainesville, Fla., and at Dartmouth Medical School, Stanford University Medical School and the University of Florida College of Medicine.

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