"We've shown a clear link between the genetic mutation of a protein called phospholamban and the disruption of calcium regulation in the heart," says Dr. David MacLennan, U of T professor in the Banting and Best Department of Medical Research and one of the senior authors in a Feb. 28 paper in Science. "Scientists at U of T and elsewhere have learned how this process functioned in mice but this is the first time we've seen the same mechanism in people."
Muscle contractions are triggered by calcium. For the heart to contract, calcium must be released into the main body of each heart cell. The more calcium released into each cell, the stronger the force of the contraction of the overall heart. For the heart to relax, calcium is pumped out of the main body of the heart cell by a protein known as a calcium pump. Phospholamban is a second protein that regulates this calcium pump, explains MacLennan, who is the J.W. Billes Professor of Medical Research at U of T and investigator of the Canadian Genetic Diseases Network. The protein slows the calcium pump when the body is at rest but it lets the pump work at full speed when the body is active.
At Harvard University, geneticists and senior authors on the paper Drs. Christine Seidman and Jonathan Seidman sequenced the phospholamban gene in 20 unrelated individuals with inherited dilated cardiomyopathy (a condition where the ventricles of the heart enlarge and lose their ability to pump blood adequately through the body, which eventually leads to heart failure). Of this group, one individual carried the gene mutation. An evaluation of the person's family history revealed a striking difference between members who carried the mutation and those who didn't. Carriers of the normal phospholamban gene were healthy while those who carried the mutant gene developed dilated cardiomyopathy and heart failure.
MacLennan and U of T post-doctoral fellow Michio Asahi, one of the first authors on the paper, brought to the project their expertise in phospholamban and its relationship with the calcium pump. Using biochemical approaches that they had pioneered years earlier, they found that genetic mutations of phospholamban chronically inhibited the calcium pump, which led to dilated cardiomyopathy and heart failure.
"This phospholamban gene mutation is quite rare, accounting for less than one per cent of dilated cardiomyopathy," says MacLennan. "But it can be deadly, striking people in their teens and 20s. While we've known that phospholamban mutations can cause dilated cardiomyopathy in mice, this is the first study showing that this mutation can cause dilated cardiomyopathy in humans."
"An example of an analogy would be how the thermostat in your home must work in a very finely tuned manner and when it is defective, it can lead to dramatic disturbances," says Dr. Peter Liu, director of the Heart & Stroke/Richard Lewar Centre of Excellence at U of T and spokesperson for the Heart and Stroke Foundation of Ontario. "Phospholamban is the equivalent of the calcium thermostat in the heart cell. We have always known that calcium is the master switch for function within the heart. When there is a mutation in the switch regulation, it leads to heart failure. This research represents a piece in the jigsaw puzzle that heart specialists have been looking for in terms of one of the master regulators of heart function."
Previous research has identified seven or eight different genes mutations that cause heart failure. This particular phospholamban gene mutation is a dominant one - inheriting the gene from one parent is enough to predispose offspring, says MacLennan.
Dr. Michael Hayden, scientific director of the Canadian Genetic Diseases Network, emphasizes that this discovery is important in understanding how these genes work and contribute to heart failure. "This is a wonderful result. It is hoped that this result highlights pathways that will have relevance for many Canadians who suffer from heart failure."
Heart failure is the leading cause of death in Canada. An estimated one in four Canadians suffers from heart disease and more than 70,000 Canadians will die from heart ailments in 2003. Dilated cardiomyopathy affects both the elderly and the young. Moreover, the outcome for patients with the disease is poor - 70 per cent will die within five years of diagnosis.
This research was supported by the National Institutes of Health, the Henrietta and Frederick Bugher Fund, the Heart and Stroke Foundation of Ontario, the Canadian Genetic Diseases Network of Centers of Excellence and the Canadian Institutes of Health Research.