P48Heart rate changes mediate the embryotoxic effects of antiarrhythmic drugs in the chick embryo

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Beta-blocking agents are frequently used cardiovascular drugs. With increasing average age of pregnant women we face the need of drug treatment duringpregnancy more frequently. As the heart rate is the most important determinant of cardiac output in the embryonic heart, we hypothesized that drug-induced bradycardia is the leading mechanism of heart failure.

ED4 and ED8 chick embryos were studied by video microscopy and ultrasound biomicroscopy ex ovo after intraamniotic injection of 200 μl of metoprolol or ivabradine or 200 μl of normal saline for a period of 30 minutes. Stroke volume was calculated by Simpson method from long parasternal short axis view in ED 8 embryos and prolate ellipsoid formula in video recordings (ED4). Cardiac output was then calculated from equation CO(μl/min) = SV(μl)*HR(BPM). Embryotoxicity was tested in ovo after administration of various doses of metoprolol or ivabradine compared to normal saline between ED3-ED8.

Metoprolol and ivabradine are drugs with strong negative chronotropic effect leading to 40% decrease of heart rate compared to normal saline within 30 minutes in ED 4 embryos. In more mature ED 8 embryos this effect was even more pronounced, with the heart rate decreased by 88% in metoprolol group and by 43% in ivabradine group. CO in ED 4 embryos decreased by 1% in the control group, by 11% in metoprolol group and by 43% in ivabradine group at 30 minutes. In ED 8 embryos the decrease in CO was 34% for normal saline group, 92% decrease for metoprolol group and 63% decrease for ivabradine group. There was no significant difference in stroke volume at either time point. A significant dose-dependent mortality (80%) was achieved in ED 4 embryos injected by 200 μl of ivabradine. In ED 8 embryos this effect was less pronounced with only 10% mortality at the same dose. No significant mortality was observed in ED 4 embryos injected by different doses of metoprolol but 39% mortality was achieved in ED 8 embryos injected by 200 ul of metoprolol.

Sensitivity to negative chronotropic effect of metoprolol and ivabradine increases with development. The embryonic heart has limited potential to vary stroke volume and significant bradycardia is followed by a significant decrease in cardiac output, likely leading to embryonic death. Metoprolol in usual doses appears to be relatively safe in pregnancy whereas ivabradine might have potential adverse effect on fetus.

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