The purpose of this grant proposal is to develop an animal model of congestive heart failure secondary to a left-to-right shunt in immature minipigs. In approximately one-half of the 26,000 children born annually in the US with a congenital heart defect, the major hemodynamic abnormality is a left-to-right shunt which results in increased pulmonary blood flow and chronic volume overload of the heart. The long term effects of these abnormal hemodynamics are poorly understood and well-controlled studies of the effects of new potentially useful medical therapies have not been feasible because repeated hemodynamic studies in children are not possible at the present time. To overcome this problem, we will develop an animal model of a common congenital heart defect, patent ductus arteriosus, by surgically inserting a conduit from the descending aorta to the main pulmonary artery in 4-week-old minipigs. Measurements of ventricular volumes and ejection fractions from these animals will be compared to those of a control group to determine whether these parameters deteriorate with length of exposure to the shunt. In one group of animals, the shunt will be surgically closed after six months to determine whether ventricular volumes and function can be expected to return to normal. Two orally effective vasodilators, prazosin (an alpha blocking agent) and hydralazaine (a direct vasodilator) will be tested in these animals, one month, three months, and six months following operation. If these agents reduce systemic resistance without reducing pulmonary resistance to the same degree, then it may be possible to actually decrease the amount of blood flowing across a shunt. Because pulmonary blood flow and total work of the heart would be reduced, this approach to treatment of a left-to-right shunt could significantly improve our medical management of children with certain congenital heart defects. To obtain the repeated hemodynamic studies in these animals, we will use a prototype system for nuclear cardiology studies which has far better resolution than any commercially available system, and uses only 1/25th of the radiation. If this system is capable of detecting early irreversible changes in ventricular function or changes in pulmonary and systemic blood flow in response to drugs, then it will be possible to repeat many of these animal studies safely and noninvasively in children.
|Wu, X; Latson, L A; Driscoll, D J et al. (1987) Dynamic three-dimensional anatomy of pulmonary arteries in pigs with aorto-to-pulmonary artery shunts. Am J Physiol Imaging 2:169-75|