Defusing the heart "time bomb"

McGill researchers identify protein associated with deadly Long QT Syndrome
Researchers at McGill University have identified a protein important to the understanding of a mysterious and often fatal disorder of the heart’s electrical rhythm known as Long QT Syndrome (LQTS). The syndrome takes its name from the prolonged interval between the Q and T pulses on a sufferer’s electrocardiogram.

In a study published June 15 in The Journal of Biological Chemistry, the lead author, PhD candidate Valerie Walker, senior and corresponding author Dr. Alvin Shrier, and colleagues in the Department of Physiology’s Cardiac Dynamics Research Laboratory report that a protein called FKB38 may play an important role in the onset of hereditary LQTS. There are two basics forms of the syndrome, an inheritable genetic type and an acquired type caused by side-effects to a number of different pharmaceuticals.

Colloquially known as the “time bomb in your chest,” the syndrome usually occurs in otherwise healthy children and young adults, and can lead to sudden death. Women are two-to-three times more likely than men to display LQTS symptoms and are usually the first members of a family to be diagnosed.

In heart cells of healthy individuals, potassium ions are passed from cell nucleus to outer membrane through the HERG gene, a specialized ’potassium channel’. “You can think of potassium channels as doughnuts floating around in the cell membrane and the potassium ions flow through the hole in the doughnut,“ said Shrier. In LQTS sufferers, those HERG genes, or doughnuts, are improperly folded and cannot perform this function. ”These ’doughnuts’ may never make it out of the cooking oil at all,“ continued Shrier. ”They get stuck in the machinery, so you’re entirely missing ion channels on the cell surface"

To date, no one has understood precisely how LQTS acts to malform the HERG gene in the first place. Now, Walker and Shrier have discovered that FKB38 is in fact a so-called chaperone protein, a genetic sidekick which helps genes fold into the proper shape. They have also discovered that FKB38 assists misshapen mutant HERG genes not affected by LQTS to fold properly. This suggests that something may be blocking FKB38’s actions in LQTS cases, though Shrier cautions that these are very preliminary steps on the long road to a possible treatment.

According to the Mayo Clinic and researchers at the University of Illinois College of Medicine, the syndrome affects one in 5000 to one in 7000 Americans and is thought to cause about 4000 deaths in the United States annually. Sufferers are frequently unaware that they have LQTS but when diagnosed early it is characterized by an abnormally long interval between the Q and T pulses on a patient’s electrocardiogram (ECG), which gives the syndrome its name. LQTS sufferers are prone to irregular heart rhythms, fainting spells and, most seriously, sudden, fatal heart arrhythmias. In late 2006, Colorado Avalanche forward Steve Konowalchuk was forced to end his hockey career after he was diagnosed with LQTS. The previous year, world-renowned wildlife photojournalist Windland “Wendy” Smith Rice died of a sudden LQTS-induced arrhythmia.

These discoveries, exciting as they are, are still very preliminary cautioned Shrier, with any potential treatment for LQTS still several steps down the road. “We don’t know all of the players or mechanism yet, so that’s what we’re pursuing now,” he explained. “We’re trying to work out how these proteins are interacting, whether they’re interacting with any other channels, what implications this has functionally for the cell, and ultimately how this might affect the heart.”