The unique fragility of the neonatal circulation in response to disease states and various physiologic stimuli is apparent clinically, although underlying mechanisms have not been explored. Accordingly, this report examines and compares the influence on cardiac performance of changes in left ventricular (LV) filling pressure in six conscious, unscdated newborn lambs studied serially at 1 and 3 weeks of age and five adult sheep. All animals were instrumented chronically to assess LV internal dimensions and pressures and cardiac output. At constant heart rate, infusion of saline to comparably high LV end diastolic pressure was associated in the younger newborns with significantly elevated mean arterial pressures (MAP), reduced LV stroke volume, stroke work, and mean fiber shortening when compared to older newborns or adults. A separate analysis of the LV pressure-dimension relationships showed lowest LV compliance in the youngest animals with a progressive increase with age. Thus, these results suggest that the youngest newborns have limited preload reserve related to reduced LV compliance. With volume infusion, sacromeres are stretched fully; the rise in peripheral resistance creates a mismatch between aftcrload and the level of inotropic state. These findings provide a framework for viewing cardiocirculatory adaptation to left-to-right shunt lesions in the human newborn and support the contention that age-dependent, disadvantageous myocardial mechanical factors play a critical role in their clinical course.Speculation The determinants of LV performance can best be described in terms of preload, afterload, and contractile state. The dynamic transition after birth from a single, parallel fetal circulation into separate, independent pulmonary and systemic circuits imposes marked loading alterations on the left ventricle of the newborn. Thus, preload increases dramatically in parallel with a 3-to 4-fold augmentation in pulmonary blood flow; systemic vascular resistance rises when clamping the umbilical cord removes the low resistance placental circulation, and when constriction of the ductus arteriosus occurs. Of course, the presence of a cardiac malformation may further accentuate either preload or aftcrload.