Old Drug Works New Tricks For Iron Overload Heart Disease

The scientists have found that oral medications currently used to treat hypertension are also effective at blocking excessive iron from entering certain critical organs and causing permanent damage. Their new research is published in the Sept. 15 issue of Nature Medicine.

"Hereditary hemochromatosis and secondary iron overload due to illnesses such thalassemia and sickle cell anemia are genetic disorders associated with elevated iron levels that particularly affect people of North American, European, Mediterranean or Asian descent," says Dr. Peter Backx, professor of physiology and medicine at U of T in the Heart & Stroke/Richard Lewar Centre of Excellence and senior author of the paper. "What was never understood was why individuals with this genetic disorder are very susceptible to developing heart disease and dysfunction of the pancreas and pituitary gland. Why were these tissues so sensitive to elevated iron levels? We found that for these people, the same calcium channels that are critical for functioning in these organs by transporting calcium into the cells are also the culprits responsible for transporting iron and ultimately causing the damage."

L-type calcium channels are part of the body's natural functioning, explains Dr. Gavin Oudit, a PhD student in the clinician investigator program at U of T, a cardiology resident at Toronto General Hospital, University Health Network, and lead author of the paper. In the case of the heart, these channels allow calcium into the heart and cause it to contract. "For people with genetic disorders who have excess iron in their blood, however, the unfortunate byproduct of these calcium channels is that they also allow iron into the heart cells. In iron overload disorders, a large percentage of those patients end up dying of cardiomyopathy (disease of the heart), which is now reaching epidemic levels worldwide."

Oral medications like calcium channel blockers amlodipine, verapamil and diltiazem were tested on mice with iron overload cardiomyopathy. "This surprisingly simple and effective strategy may potentially open an entirely new door to treatment for patients worldwide suffering from iron overload. This is particularly important for patients in many countries who currently could not afford any treatment at all for this deadly condition because of the cost," says Dr. Peter Liu, director of the Heart & Stroke/Richard Lewar Centre of Excellence and professor of medicine and physiology at U of T, cardiologist at Toronto General Hospital and a senior investigator of the study.

However, Liu cautions that before rushing to this new treatment, scientists and physicians still need to do careful and systematic testing on a larger patient sample to understand who benefits the most from calcium channel blockers and how much to use. "Since the drugs being considered have already been approved for human use, the potential for clinical benefit could be realized much earlier than other treatment strategies."

The current method of treating iron overload in the heart is chelation therapy, a difficult and cumbersome process involving infusions of a solution containing compounds that bind to the iron, which can then excrete the iron from the body. However, the researchers say this method is playing catch up, not a preventative method in dealing with iron overload.

"For patients with iron overload right now, the choices are either nightly needles under the skin for hours on end to remove the iron or face certain death from heart failure. The drugs currently used are also extremely expensive, so many patients around the world die at a young age from heart failure" says Liu.

According to the researchers, iron-related disorders are a modern disease. In the case of genetic blood disorders, iron overload results directly from regular transfusions that the patients receive in order to sustain life. In other cases, a common genetic defect in the control of iron intake into the body leads to excessive iron deposits into critical organs such as the heart. Our overall exposure to iron has increased through changes in diet and nutrition, they say. With grains and cereals now fortified with iron, and people consuming much more meat than in the past, these many sources of iron are causing damage to those who are genetically unable to adequately metabolize and excrete it.

Other researchers on this paper are Hui Sun, Maria Trivieri, Fayez Dawood and Mehrdad Yazdanpanah of the Heart & Stroke/Richard Lewar Centre of Excellence and the Departments of Medicine and Physiology at U of T; Cameron Ackerley and Greg Wilson of pathology at The Hospital for Sick Children; and Sheryl Koch and Arnold Schwartz of the Institute of Molecular Pharmacology and Biophysics at the University of Cincinnati Medical Center.

Support for this research was provided by Canadian Institutes of Health Research, Heart and Stroke Foundation of Ontario and National Institutes of Health.