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About SickKids

October 26, 2005

Researchers discover gene involved in heart arrhythmia

TORONTO - An international team of researchers led by The Hospital for Sick Children (SickKids) and the University of Toronto has discovered that the cardiac expression of a gene called Irx5 controls the heart's electrical pattern. Alterations in the electrical pattern of the heart lead to electrical disturbances in the heart, a life-threatening condition called cardiac arrhythmias. This research is reported in the October 2005 issue of Cell .

Normal electrical rhythms in the heart are essential to coordinate proper mechanical pumping action of the heart. Cardiac arrhythmias cause the heart to beat too fast, too slow or irregularly leading to pump malfunction, much like the engine failure seen in automobiles with electrical breakdown. While some cardiac arrhythmias are harmless and easily managed, others are life-ending. Indeed, cardiac arrhythmias are the major cause of sudden-death in patients with heart failure and heart attack. Cardiac arrhythmias are also a common cause of sudden death in seemingly healthy young individuals, often athletes, without signs of cardiovascular disease.

In the study the authors explored the role of Irx5, a transcriptional factor on electrical properties of the heart. Transcription factors are proteins that regulate other genes by turning them on or off. The new findings show that Irx5 is integral in controlling the number and distribution of selected types of ion channel proteins (i.e. potassium channels) that are critical determinants of the heart's normal electrical pattern. Specifically, the study found in an animal model, that Irx5 preferentially turns off potassium channels on the inside layers of the heart compared to the outside layers, thereby creating a necessary electrical gradient required for normal heart function.

"We found that Irx5 controls pathways in the heart that are key in keeping the heart arrhythmia free.” said Dr. Benoit Bruneau, co-principal investigator in the study, a scientist in Cardiovascular Research at SickKids, Assistant Professor of Molecular and Medical Genetics at the University of Toronto and Canada Research Chair in Developmental Cardiology. "The Irx5 protein is expressed in different intensities on the interior and exterior of the heart, creating a repolarization gradient. When this differential is in the proper balance the heart functions properly. If the gradient is not working properly, then arrhythmias can occur.”

“Researchers have speculated for many years on how the electrical gradient in the heart is formed and our results solve this mystery,” said Dr. Peter H Backx, co-principal investigator of the study, senior scientist in the Division of Cellular & Molecular Biology at the Toronto General Research Institute (TGRI) and Professor of Physiology and Medicine at the University of Toronto. "Remarkably, the electric properties of the hearts that are regulated by Irx5 are precisely those that are altered in most forms of heart disease, a condition where arrhythmias cause death in 50 per cent of the patient deaths. Clearly, these results identify an important new target in our fight against the high mortality in heart disease. Our discovery further suggests that Irx5 might underlie some of the inherited forms of sudden-death whose genetic basis is currently unknown.”

Other members of the research team include Dr. Chi-chung Hui, Dr. Gil Gross, Eric Arruda, Pooja Ararwal, Yonghong Zhu, Wei Zhu, Melanie Lebel and Chi Wa Cheng from SickKids, Danny Contantini, Mansoor Husain, Kyoung-Han Kim and M.Golam Kabir of the Heart & Stroke/Richard Lewar Centre of Excellence and the Department of Physiology at the University of Toronto, Stephanie Pierce and Deepak Srivastava of the University of Texas Southwestern Medical Centre, Alejandra Guerchicoff, Guido D. Pollevick and Charles Antzelevitch of the Masonic Medical Research Laboratory, Shuk Hen Cheng of the City University of Hong Kong and Toby Y. Chan of TGRI .

This research was supported by the Canadian Institutes of Health Research, the National Institutes of Health, the Research Grants Council of Hong Kong, the National Science and Engineering Council of Canada, the Heart & Stroke Foundation of Ontario, the National Cancer Institute of Canada, the Canada Research Chairs program and SickKids Foundation.

The Hospital for Sick Children, affiliated with the University of Toronto , is Canada 's most research-intensive hospital and the largest centre dedicated to improving children's health in the country. Its mission is to provide the best in family-centred, compassionate care, to lead in scientific and clinical advancement, and to prepare the next generation of leaders in child health. For more information, please visit www.sickkids.ca.

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