More than three decades ago, the “iron hypothesis” was proposed; it suggested elevated iron levels in the body could promote atherosclerosis (hardening of the arteries). It was based on the observation that all men and postmenopausal women have both higher body iron levels and higher rates of atherosclerosis than premenopausal women. The premise was that elevated iron levels could promote oxidative stress; thus, promoting inflammation. Countering that theory were subsequent studies that reported that individuals with diseases that comprised higher iron levels did not have higher atherosclerosis rates than individuals who did not have these diseases. UCLA researchers conducted a study to clarify this issue. They published their findings on December 17 in the journal Cell Reports.
“Understanding risk factors for atherosclerosis progression is important for better prevention and treatment of the disease,” explained senior author Elizabeta Nemeth, a professor of medicine at the David Geffen School of Medicine at UCLA and co-director of the UCLA Center for Iron Disorders. She added, “For many years, there has been a belief that higher iron levels might contribute to, or worsen, atherosclerosis. We found no such connection.”
The UCLA researchers noted that the hypothesis was refined over the last decade because of the discovery of hepcidin, which is a hormone that plays a central role in iron metabolism; they explain that hepcidin plays a similar role as that of insulin for control of blood sugar. This refined iron hypothesis, which proposed that because hepcidin is increased by the inflammation associated with atherosclerosis; this elevated hepcidin level promotes the accumulation of iron in macrophages, which are cells tht are significantly involved in the development of atherosclerosis.
The researchers made an unexpected finding: they discovered that the hepcidin level was not increased in mice at any stage of atherosclerosis progression. In addition, when the investigatorss increased the iron levels in the macrophage cells, they found no effect on atherosclerosis progression. The study authors note that their study is the first to evaluate hepcidin expression during atherosclerosis progression in mice; in addition, it is the first to measure the impact on atherosclerosis of iron-loading macrophages through genetic manipulation and/or injection of intravenous iron.
“The surprise was that we found no evidence that iron excess exacerbates atherosclerosis or that hepcidin is influenced at all by atherosclerosis,” explained first author Léon Kautz, a postdoctoral fellow in Dr. Nemeth’s laboratory. He added, “However, it is important to keep in mind that this is a mouse model. We need to see whether the same is true in humans.”
Dr. Nemeth noted that other researchers have begun analyzing hepcidin in atherosclerosis patients. She explained that among the additional questions raised by the study is whether significantly lowering iron below normal levels could reduce the progression of atherosclerosis.
Atherosclerosis involves thickening or hardening of the arteries due to a buildup of plaque in the inner lining of an artery. Plaque is made up of deposits of fatty substances, cholesterol, cellular waste products, calcium, and fibrin; it can develop in medium or large arteries. The artery wall becomes thickened and stiff. It is a slow, progressive disease that may start as early as childhood. However, the disease has the potential to progress rapidly.
It is unknown exactly how atherosclerosis begins or what causes it. Some scientists think that certain risk factors may be associated with atherosclerosis, including:
- Elevated cholesterol and triglyceride levels
- High blood pressure
- Type 1 diabetes
- Physical inactivity
- High saturated fat diet
The disease progresses by a gradual buildup of plaque or thickening of the inside of the walls of the artery, causing a decrease in the amount of blood flow, and a decrease in the oxygen supply to the vital body organs and extremities. A heart attack may occur if the oxygenated blood supply is reduced to the heart. A stroke may occur if the oxygenated blood supply is cut off to the brain. Severe pain and gangrene may occur if the oxygenated blood supply is reduced to the arms and legs.
Signs and symptoms of atherosclerosis may develop gradually, and may be few, as the plaque builds up in the artery. Symptoms may also vary depending on the affected artery. However, when a major artery is blocked, signs and symptoms may be severe, such as those occurring with heart attack, stroke, aneurysm, or blood clot. The symptoms of atherosclerosis may resemble other heart conditions; thus, one should consult a physician for a diagnosis.
Take home message:
A too high or too low level of iron can be harmful. A low iron level is a common cause of anemia. An elevated iron level can cause hemochromatosis, which involves the deposit of iron in vital organs, causing damage. Before the menopause, women rarely have elevated iron levels because they lose blood—and iron—during menstruation. Men and postmenopausal women are susceptible to a high iron level if they take iron supplements or use iron cookware in which iron is released into the food. A simple blood test can measure the serum iron level.
Appropriate lifestyle choices that include a healthy diet and exercise program can reduce the risk—or progression—of atherosclerosis.