P&S Journal: Spring 1994, Vol.14, No.2
Centering on Heart Failure
New Animal Models for Heart Failure
The center's research agenda also includes development of new animal models of heart failure, elucidation of the role of vascular physiology in the disease, understanding of exercise physiology and intolerance in heart failure, and clarification of heart failure health care outcomes.
Animal models must be developed to understand the pathophysiology and molecular events of heart failure because tissue culture experiments do not provide the complete picture and most studies cannot be performed on human subjects. Dr. Daniel Burkhoff, assistant professor of medicine, is creating animal models of heart failure that better mimic human heart failure. To simulate heart failure, Dr. Burkhoff has devised a method of injecting microspheres in the small arteries of a dog's heart. The animals develop heart attacks and their hearts weaken and change in a manner similar to humans.
Preliminary data from these animals reveal a previously unappreciated aspect of the role of relaxation of the heart muscle in heart failure. Dr. Burkhoff plans to study the peripheral vasculature in these animals and the effect of exercise on slowing heart failure progression and improving quality of life.
Dr. Stuart Katz, assistant professor of medicine, studies the role of the vasculature in heart failure to clarify how the blood vessels affect the health of patients. "There is evidence that abnormal blood vessel function contributes to the overall health of heart failure patients," says Dr. Katz. "If the blood vessels are acting in a beneficial manner, the patient is healthier. If they are acting detrimentally, the patient is sicker."
His particular interest is the endothelium, the blood vessel layer that faces and separates the muscular layer from the blood. "It was originally believed that the endothelium's most important role was in clotting, or repairing damage to a cut vessel," he says, "but now we know the endothelium is involved in making and releasing substances that control the vessel wall muscle tone."
He studies the role of nitric oxide, one endothelial substance that regulates tone. Recent research by Dr. Katz reveals that low levels of nitroglycerin may act synergistically with endothelial nitric oxide to create enough nitric oxide to help peripheral blood vessel dilation. Higher dosages of nitroglycerin are normally used by physicians to treat heart failure and angina because the drug causes vasculature smooth muscle to make nitric oxide and vasodilate. This new finding may be important to a heart failure patient, Dr. Katz says, because patients develop tolerance for nitroglycerin at high levels. "Smaller dosages may be sufficient to get a beneficial effect." This work, however, focused on nitroglycerin's effect in one small region of the body, while future studies will analyze low nitroglycerin levels in the entire circulation.
Dr. Katz also examines the role cytokines, growth factors released by the immune system, play in heart failure and cardiovascular disease. There has been some evidence that immunological factors are involved in heart failure. The immune system plays a role in damaging the heart when the heart muscle is damaged by infection, Dr. Katz says, but Dr. Packer suggests that damaged heart muscle without infection releases some triggering substances that act on the neurohormonal environment to activate the immune system to release cytokines that further harm the heart muscle.
Tumor necrosis factor (TNF), released by activated macrophages in the immune system, is one cytokine under investigation by Dr. Katz. TNF is thought to act on nitric oxide metabolism. In septic shock, in response to an endotoxin, the body overproduces TNF, nitric oxide dilates blood vessels, and the person goes into shock. Recently, however, Dr. Katz has found that high levels of TNF might not be detrimental in heart failure and TNF may preserve endothelial vasodilation.