FRIDAY, March 14, 2003 (HealthDayNews) -- In a little jolt to conventional wisdom, American researchers are reporting that a genetic heart mutation that does little damage in mice is fatal in humans.
Two studies by Evangelia G. Kranias and her colleagues at the University of Cincinnati say that knocking out a gene for a protein that plays a central role in heart function leaves mice alive and well, while a mutated gene for that protein in humans causes early heart failure.
The findings, published in the March 14 issue of the Journal of Clinical Investigation, are a warning flag to researchers, who generally depend on mouse studies for early evaluation of treatments and other aspects of human disease.
The protein is phospholamban (PLN). It helps regulate the flow of calcium ions in and out of heart cells, a flow that causes the regular contraction and relaxation of heart muscle. PLN has been intensely studied in several laboratories because of work indicating that knocking out the gene is beneficial in mouse models of heart failure, a major killer in humans.
But now Kranias and her colleagues report that, contrary to their expectations, the absence of the PLN gene in mice bred to have cardiac hypertrophy, which is overgrowth of the heart muscle and can lead to heart failure, does not produce the expected enhancement of calcium cycling and heart function.
"The surprise is that when we made mice that were missing the gene, they were healthy, their function was extremely good and they could exercise just as well as normal mice," says Kranias, a professor of cardiovascular biology.
But a second paper on a study of two human families finds that a harmful mutation of the PLN gene, leading to loss of the protein, causes a severe heart condition that can be treated only by transplantation early in life.
"It was quite a surprise," says Dr. David MacLennan, a professor of medicine at the University of Toronto and a leading phospholamban researcher.
A close look at the difference between the way human hearts and mice hearts work explains why the surprise is not overwhelming, MacLennan adds.
"The main difference between mice and humans is cardiac reserve," he says. "In humans, the contractility of the heart, the pressure it can develop, is not maximized under ordinary circumstances. If you exercise, the heart rate goes up and the contractility of the heart goes up. Humans have this cardiac reserve to draw on."
And PLN acts to provide this cardiac reserve, MacLennan adds.
By contrast, "the mouse goes through life already using most of its cardiac reserve," he says, and therefore the absence of PLN is not all that damaging.
Researchers will continue to use mice because "the only animal we can manipulate genetically is the mouse," Kranias says. "If we find something interesting in the mouse, we can go on from there.
While mouse studies have produced an enormous amount of useful information, the lesson of the latest studies is that "now and then you can't go directly from mouse to human," MacLennan says.
More information
You can learn more about phospholamban research. And the American Heart Association has more on heart failure.
