For Release: February 13, 2007
Contact: DMS Communications 603-650-1492

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Age Effect: Controlling Iron Levels Early in Life May Cut Future Heart Risk

HANOVER, NH—Lowering the body's excess iron stores--in this case, by drawing blood--may improve outcomes for people with symptomatic but stable peripheral arterial disease (PAD), but only if iron reduction begins at a relatively young age. Those are the findings of a six-year Veterans Affairs clinical trial reported in the Feb. 14 Journal of the American Medical Association.

Dr. Leo R. Zacharski
(Photo by Mark Washburn)

"The beauty of our study was that we could see the graded effect by age. We therefore confirmed the past negative epidemiology that didn't take age into consideration, but we also confirmed the positive studies showing an effect of iron on disease risk. The secret is the age effect," said lead author Leo R. Zacharski, MD, a Dartmouth Medical School professor of medicine at the White River Junction (VT) VA Medical Center.

"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, " added Zacharski, a member of the Norris Cotton Cancer Center.

Excess iron in the blood may promote free-radical damage to arteries, particularly in early stages of arteriosclerosis, a major risk factor for heart attack and stroke. Researchers posited 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 study results are mixed, and the topic is still debated.

The VA clinical trial involved 1,277 men and postmenopausal women with PAD, ages 43 to 87, 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 defined volumes of blood removed at six-month intervals. Blood levels 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 iron (ferritin) 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, 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, 273 deaths from all causes had occurred roughly equally between the iron-reduced (125) and control (148) groups. The secondary outcome measure--death from any cause, or nonfatal heart attack or stroke--also had no statistically significant difference: 180 in the iron-reduction group and 205 in the control group. The overall findings thus did not support the iron-reduction therapy to improve outcomes for PAD patients across all study subgroups.

However, when the researchers analyzed the results for younger patients--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 benefit 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 investigate iron-reduction partnered with an overall iron maintenance program--including diet modification, education and other interventions--on those 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 of interaction and determine how best to counter the shown harmful effects of iron. Furthermore, he suggested considering the potential of iron-reduction to help "protect smokers from the ravages of tobacco use."

"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."

More on the Dartmouth Iron Surveillance Program is at:

The study was funded by VA's Cooperative Studies Program. Co-authors included John Barron, and David Malenka of DMS, Paula Howes of the White River Junction VA and researchers at VA sites in Palo Alto and Gainesville, Fla., Stanford University Medical School and the University of Florida College of Medicine.

For further information, contact Anselm Beach at 802-295-9363, ext. 5424.


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