Chronic Maternal Hypercortisolemia in Late Gestation Impairs Fetal Cardiac Function

Previous studies in our lab found that a modest yet chronic increase in maternal cortisol concentration significantly increases the incidence of peripartum fetal death. Transcriptomic analysis of the fetal hearts revealed that these dramatic outcomes could be due in part to changes in fetal cardiac function, as there were significant changes in gene expression in pathways related to cardiac metabolism and cardiac ion channels. Thus, we tested the hypothesis that chronic maternal hypercortisolemia in late gestation impairs fetal cardiac function, evident by reduced heart rate and blood pressure, and altered ECG in late gestation and during labor. Four ewes carrying singleton fetuses were infused with 1mg/kg/d cortisol (CORT) from 115 days of gestation (d) to term. Five similar ewes were not treated (CON). At 119±1d, DSI PAD70 PCTP radiotelemetry devices were implanted into the fetuses for continuous monitoring of ECG, heart rate (HR), and aortic and amniotic fluid pressures through delivery. DSI Ponemah 5.00 and DSI Dataquest Open A.R.T 4.31 software were used to analyze ECG, HR, pulse height (PH), and mean aortic pressure (MAP). HR, PH, and MAP were analyzed using 24h means of each day for 14d before birth, 1h means during the last 24h of fetal life and 10m means in the final 1h of fetal life. ECG was analyzed using 1h means on each day for 14d before birth, 1h means during the last 24h of fetal life and 10m means in the final 1h of fetal life. Two‐way analysis of variance corrected for repeated measures across time was used to analyze the data and between treatments comparisons at individual time points was performed by posthoc t‐test with Bonferroni adjustment. Fetal plasma cortisol was increased by maternal cortisol infusion. CORT fetuses delivered at 143±2d, and CON at 144±2d. There were no significant effects of cortisol on the parameters of the ECG, MAP, HR or PH in the period from −14d to birth. The P and P‐R intervals of the ECG were both significantly elongated in CORT at both 24h and 1h before birth. HR was significantly reduced and the Tpe:QTcf ratio (The ratio of Tpe (the interval from the peak to the end of the T wave) to the corrected QT interval (QTcf)) was significantly greater in CORT 1h before birth. Our results indicate that chronic maternal hypercortisolemia during late gestation increases fetal cortisol concentration and induces pathophysiological changes in the cardiac conduction pathways of the fetus, which manifest during the perinatal period. These changes include elongation of the P and P‐R intervals, a greater Tpe:QTc ratio, and a slower HR. Furthermore, the results indicate that these fetuses may have first‐degree heart block, delayed activation of the left atrium and may be at an increased risk for arrhythmias and sudden cardiac death. Support or Funding Information This work was funded by grants from the National Institutes of Health: HD 057871 and the American Heart Association: 14GRNT2042004814 Days Before Birth 24 Hours Before Birth 1 Hour Before BirthControl Cortisol Control Cortisol Control CortisolMean Aortic Pressure (mmHg) 51±3 44±3 56±4 49±4 57±4 48±4 Heart Rate (BPM) 164±6 160±7 153±7 149±7 162±8 135±9 * Pulse Height (msec) 20±1 18±2 23±2 19±2 23±3 22±2 ST Interval (msec) 163±8 167±9 164±8 173±9 156±6 178±7 PR Interval (msec) 78±2 83±2 75±3 90±3 * 73±4 96±5 * QTcf Interval (msec) 259±8 267±9 244±7 249±7 237±6 246±6 QRS Interval (msec) 27±3 31±3 31±2 28±2 29±3 29±3 P Interval (msec) 30±2 35±2 33±3 43±3 * 33±3 51±3 * Tpe/QTcf ratio 0.103±0.006 0.105±0.007 0.094±0.017 0.115±0.019 0.092±0.013 0.142±0.015 *Values are mean±SEM; * p<0.05 by Two‐way ANOVA with Bonferroni Adjustment