Cardiologist Richard N. Kitsis, MD, has been fascinated by cell death for nearly two decades, and with good reason. “Cell death is crucial to the field of cardiology,” said Dr. Kitsis, who is the Dr. Gerald and Myra Dorros Professor of Cardiovascular Disease at Einstein, professor of medicine and of cell biology, and director of the new Wilf Family Cardiovascular Research Institute. “It helps to explain why heart attacks kill some people and can cause heart failure in those who survive.”
In a heart attack, clots obstruct arteries that nourish the heart muscle, causing heart-muscle cells to die from lack of oxygen. All too often, this death of heart-muscle tissue leaves heart attack survivors with heart failure—a decline in the heart’s pumping ability. Typically in heart failure, heart cells continue dying over subsequent months and years. Because the weakened heart does not empty efficiently, blood sometimes backs up in the lungs and veins that return blood to the heart, causing fluid to leak into the legs and ankles.
Heart failure’s symptoms include leg swelling, shortness of breath, fatigue and an inability to perform normal daily activities. In the United States, six million people are living with heart failure at any given time, and 450,000 people die from it each year. “Dying from heart failure is not a pleasant death,” said Dr. Kitsis.
The ABCs of Cell Death
One form of cell death, apoptosis, has already been widely explored and is well understood. Triggered by heart attacks as well as strokes and in heart failure, apoptosis also serves some useful functions. It helps the body eliminate old, unnecessary or unhealthy cells and is actually essential for normal development. But it’s not the only type of cell death. Necrosis, for example, operates alongside apoptosis and in conjunction with it. Dr. Kitsis and his team are exploring how these other cell death mechanisms interact with apoptosis to damage the heart.
Understanding the molecular pathways that end with cell death may lead to therapies for preventing cells from dying. “The trick is to try to find a choke point where you can stop cell death before significant damage is done,” said Dr. Kitsis. In his lab in the Samuel H. and Rachel Golding Building, Dr. Kitsis and his colleagues have focused on a protein called apoptosis repressor with caspase recruitment domain (ARC). This protein, said Dr. Kitsis, “seems to be at a nexus where cardiac muscle cells make a lot of decisions about whether to live or to die.”
ARC is abundant in heart-muscle cells, where it prevents cell death by blocking several different molecular pathways. In fact, a major reason for the cell death following heart attacks is that the attacks degrade the ARC in cells.
Seeking New Treatments
By gaining a better understanding of the cell death mechanisms linked to ARC, Dr. Kitsis hopes to develop therapies for heart attack and heart failure—the final stop in the long journey from bench to bedside. For example, a substance that prevents ARC breakdown—and thereby prevents cell death—could be developed into a drug delivered as soon as possible after a heart attack, perhaps as a companion to today’s angioplasty and stenting.
He and his team are now evaluating a number of small molecules, looking for one that specifically blocks the breakdown of ARC. In addition to his NIH research grants, Dr. Kitsis recently received a $1.25 million extension of a NIH grant to support trainees interested in researching cell death and other aspects of cardiovascular disease through the year 2014.
Like many basic scientists at Einstein, Dr. Kitsis has a vision that extends beyond the microscope, the lab and the campus. “Our goal,” he said, “is to improve cardiovascular health in our families, our neighbors and the world.”