Despite advances in treatment, heart disease remains the leading cause of death in the United States, accounting for almost 41 percent of all deaths. In the United States, nearly five million people are diagnosed with heart failure. More than a half million new cases are diagnosed annually and 250,000 deaths are attributed to the disease.
William Stanley, Ph.D., associate professor of physiology and biophysics at the Case medical school, is the principal investigator of the new research program which will build on a foundation of findings that came out of his laboratory and those of his co-investigators. Normally, the heart obtains its energy from fat (readers should not misconstrue this as an endorsement for a fatty diet). During heart failure, however, the researchers found that the dying heart at the end of life doesn't use much fat for energy. In fact, different genes turn on and literally change the heart cells to consume glucose (a type of sugar) for energy, which is actually a more efficient fuel.
This phenomenon does not occur in early stages of heart failure, only in the end stage of the disease. The finding raised the questions of whether or not this change is good for the heart, and what would happen if the change occurred earlier. If it did, could the heart pump more blood and help heart failure patients feel better? That is what the researchers hope to answer with four projects that comprise this new program.
Stanley will lead a project that he said "will change the fuel that is used by the heart and see if we get an improvement in pumping function."
In the second project, Hani N. Sabah, Ph.D., professor of medicine at Case, director of the Cardiovascular Research Laboratories of the Henry Ford Heart and Vascular Institute and co-principal investigator of the program, will manipulate the energy use of the heart over four to five months and study if lowering the amount of fat fed to the heart slows down or reverses heart failure.
In the third project, Fabio A. Recchia, M.D., Ph.D., associate professor of physiology in the New York Medical College, will look at the transition from early stage heart failure to end-stage failure. He will manipulate which genes are activated in the heart to alter the energy use of the heart away from or towards fat to test the hypothesis that fat is really a bad thing which contributes to the progression of end-stage heart failure and death.
The fourth project, led by Charles Hoppel, M.D., professor of medicine and pharmacology and a mitochondria expert at Case, will look at the mitochondria, which burn the energy in cells. "They are dysfunctional in heart failure in many ways that are poorly understood," said Hoppel, "and we're trying to understand what happens to them over the progression of heart failure, and if we can prevent the abnormalities by manipulating the energy metabolism early in failure."
"We hope that by describing all these changes in pump function, energy source, molecular biology, and gene expression, it will give clinical investigators insight into what drugs should be developed and used in clinical trials to test our hypotheses in patients," said Stanley, who researched heart failure for many years in the pharmaceutical industry before joining Case. "This is a bridge between the human genome project and all the mouse work that gets done, and what gets done in the clinic. Right now there's a gap in knowledge. We know a little bit about this from mice and rats, and we know what the clinical problem is, but we don't know how to go from the basic genetic and biochemistry data to treating patients with a new therapy."