Link Between Common Virus And Heart Failure Discovered

(Toronto, April 1, 2000) - The gene that allows one of most common and highly-contagious viral infections to trigger deadly heart disease has been discovered for the first time by researchers at Princess Margaret Hospital's Ontario Cancer Institute, Toronto General Hospital, the AMGEN Research Institute and University of Toronto's Heart & Stroke/Richard Lewar Centre of Excellence.

Researchers discovered the role of a key gene called p56Ick that allows a common coxsackievirus to attack the heart causing heart failure and even death in some patients. The finding paves the way for future research into how to better predict who is at serious risk of cardiovascular disease and how to prevent it, and is reported in today's issue of Nature Medicine. The research was funded in part by Amgen, the Medical Research Council of Canada and the Heart and Stroke Foundation of Canada.

"This finding could lead to a much more targeted way to determine who is at very high risk for developing heart disease," said senior author and world expert on inflammation and heart disease Dr. Josef Penninger, an immunologist at Princess Margaret Hospital's Ontario Cancer Institute and the AMGEN Institute and a member of the Departments of Medical Biophysics and Immunology at the University of Toronto. "Rather than guessing at potential risk factors, we will be able to say much more definitively who's likely to get heart disease by testing for the presence of one gene."

According to the paper's lead author Dr. Peter Liu, a cardiologist at Toronto General Hospital and Director of the Heart and Stroke/Richard Lewar Centre of Excellence at the University of Toronto, "this finding may also open the door to new treatment strategies for virus-induced heart failure. We are thrilled at the potential of these findings."

No cure Coxsackieviruses are part of an extremely common family of viruses that live in the human digestive tract and are highly contagious. An estimated 70 percent of the population has been exposed to Coxsackievirus B which spreads easily from person to person like the flu. There is no vaccine against coxsackievirus infections (in contrast to its famous cousin, the polio virus) and no cure. Although the most common result of a coxsackievirus infection is the flu, they can also cause pancreatitis leading to diabetes, arthritis, meningitis and myocarditis (an infection of the heart muscle) leading to heart failure. Children with coxsackieviral myocarditis can develop flu-like symptoms followed quickly by heart failure and death. Coxsackievirus B can be detected in the hearts of between 30 and 50 percent of all adults with heart failure due to heart muscle weakness, a condition that frequently leads to the need for a heart transplant. In a mouse model, Drs. Penninger and Liu discovered that the difference between suffering minor flu symptoms and developing heart disease comes down to the p56Ick gene.

"Nearly all of us have been exposed to Coxsackievirus B at some time in our lives and experienced nothing more than the flu," said Dr. Liu. "However, in those people at risk, the p56Ick gene helps the virus to trigger the immune system to turn against the heart muscle. Without the p56Ick gene, the virus cannot replicate and remains relatively harmless."

Hitch-hiking Virus

The body's immune system is designed to recognize foreign agents and destroy them. When infection is detected by the body, the immune system, or T-cells, sets out to attack it. Coxsackievirus B uses t-cells to hitch a ride into the system. When a coxsackievirus infection causes mild flu-like symptoms and inflammation, T-cells head to the site of the infection to fight it. As T-cells travel to the heart to fight off the infection, the virus goes along for the ride on the back of T-cells, ultimately reaching the heart. Once in the heart, the virus stimulates the immune system to attack the heart muscle.

Drs. Penninger and Liu engineered special "knockout mice" that lacked the p56Ick gene. When injected with coxsackievirus B, mice with the p56Ick gene developed severe inflammation of the heart muscle and die from heart failure. Those mice without p56Ick were completely immune to heart disease despite being exposed to large doses of the virus leading to the conclusion that p56Ick is the crucial key gene that controls the effect the virus has on the heart.

Heart disease is the number one killer in the Western world and according to Dr. Liu, one in eight cases of heart failure may be blamed on coxsackievirus B. Last year, Dr. Penninger led a research team in the first discovery of link between heart disease Chlamydia infections, one of the most common infections contracted by humans. With that study, Dr. Penninger and his colleagues found that the best predictor of future heart disease might not be lack of exercise, poor diet or high cholesterol, but inflammation.

"For years we have associated various risk factors with heart disease including high cholesterol levels, smoking, stress, high blood pressure and obesity," said Dr. Liu, "and now infections are thought to play a very critical role in many heart diseases. In this study we have shown for the first time how a common infection with coxsackievirus B may cause severe heart disease. "

"Coxsackievirus B is just one in a large family of related viruses that cause a great number of symptoms, from common colds and diarrhea, to paralysis and even diabetes in children," said Dr. Penninger. "Now that we have discovered the cellular factor that controls the body's reaction to a coxsackievirus B infection, we can build on it to find the genetic trigger, and eventual block for, the viruses that cause the common cold, diabetes or diarrheas as well."

Preventing Heart Disease

The finding may pave the way for the future engineering of antibiotics to prevent, treat or even cure cardiovascular disease by blocking the effects of the virus. "It's not the virus that kills you, its your body's response to the virus that kills you," said Dr. Penninger. "We found that you don't need to worry about stopping the virus at all. All you need to do is change one single molecule in the body and the virus can harmlessly come and go with no effect on the host. In effect we cure the disease by preventing its action in the first place without doing anything at all to the virus itself."

Princess Margaret Hospital, a teaching hospital of the University of Toronto, has achieved an international reputation as a global leader in the fight against cancer and is considered one of the top comprehensive cancer research and treatment centres in the world. PMH is a member of the University Health Network, which also includes Toronto General Hospital and Toronto Western Hospital. Toronto General Hospital has a long established tradition of excellence in cardiovascular care and research. The Heart & Stroke/Richard Lewar Centre of Excellence is a University of Toronto Research Centre that seeks the prevention and cure of heart disease through novel approaches such as genomic medicine. The AMGEN Research Institute is an integral part of AMGEN, the world's largest biotechnology company and an innovative and pioneering world-wide organization dedicated to the research and development, manufacture and marketing of human proteins for therapeutic use, using recombinant DNA technology.

-30-

For more information, please contact :Keri Schoonderwoerd, Public Affairs, Princess Margaret Hospital416.946.4501 ext 5771