Selective and specific changes in gene expression characterize the end-stage failing heart. However, the pattern and relation of these changes to evolving systolic and diastolic dysfunction during development of heart failure remains undefined. In the present study, we assessed steady-state levels of mRNAs encoding a group of cardiac proteins during the early development of left ventricular dysfunction in dogs with pacing-induced cardiomyopathy. Corresponding hemodynamic assessments were made in the conscious state in the same animals and at the same time points at baseline, after 1 week of ventricular pacing, and at the onset of clinical heart failure. Systolic dysfunction dominated after 1 week of pacing, whereas diastolic dysfunction was far more pronounced with the onset of heart failure. Atrial natriuretic factor mRNA was undetectable in 7 of 12 hearts at baseline but was expressed in all hearts at 1 week (P<.01 by x2 test), and it increased markedly with progression to failure (P=.05). Creatine kix xrTilliam Osler1 first observed more than a cen-\J/ J tury ago that the pathophysiology of human VY s heart failure could be divided into three stages: (1) initial damage to the contractile apparatus, resulting in ventricular dysfunction, (2) a phase during which cardiovascular compensatory mechanisms are activated, and (3)

The impact of repeated umbilical cord occlusion on the normal maturation of fetal heart rate (FHR) and mean arterial pressure (MAP) and the cardiovascular responses to successive umbilical cord occlusion was investigated over a 21 day period in the latter part of gestation. Fifteen chronically instrumented sheep (control group n = 6; occlusion group n = 9) were studied for 21 days (113‐133 days of gestation, term = 145 days) with umbilical cord occlusions (90 s duration) performed every 30 min for 1‐4 h each day. On days 1, 9 and 18, FHR, FHR variation and MAP were monitored continuously and fetal arterial blood gases, pH and metabolites were measured at predetermined intervals. The baroreflex response to 75‐100 μg phenylephrine (i.v.) was tested on days 1 and 18. Basal FHR decreased (ΔFHR: control, 34.6 ± 3.6 beats min−1; occlusion, 36.9 ± 2.7 beats min−1) and MAP increased (ΔMAP: control, 3.1 ± 1.7 mmHg; occlusion, 5.2 ± 2.1 mmHg) to a similar extent in control and occlusion groups between days 1 and 21 of the study. There was a small decline in FHR variation over the 21 day study in occlusion, but not control, group fetuses. The magnitude of the fall in FHR decreased and the rise in MAP increased, despite similar changes in blood gases in response to umbilical cord occlusion, over the course of the 21 day study. Despite a significant decline in the ratio of ΔFHR to ΔMAP on days 9 and 18 compared to day 1, there was no difference between control and occlusion groups in baroreflex sensitivity. However ΔFHR/ΔPO2, an index of chemoreceptor sensitivity, had decreased by day 9 and 18 compared to day 1. The cardiovascular responses to umbilical cord occlusion are altered with repetitive occlusions during the latter part of gestation, with a decrease in ΔFHR/ΔMAP, which does not involve changes in baroreflex sensitivity, but may involve changes in chemoreceptor sensitivity. However, repeated umbilical cord occlusion appears to have no impact on baseline cardiovascular control since there was no change in the normal maturational decrease in FHR and rise in MAP.

Repetitive umbilical cord occlusion in the preterm ovine fetus resulted in the activation of the HPA axis, with increased adrenocortical responsiveness over time, and involved differential regulation of POMC mRNA expression in the pars distalis and pars intermedia of the pituitary, but with no change in GR.