Embryonic Blood Flow Research Articles

Class III antiarrhythmics and phenytoin: teratogenicity due to embryonic cardiac dysrhythmia and reoxygenation damage.

Class III antiarrhythmic drugs, like almokalant, dofetilide and ibutilide, cause a spectrum of malformations in experimental teratology studies. The pattern of developmental toxic effects is very similar to those reported for phenytoin, which is an established human and animal teratogen. The toxic effects are characterised by embryonic death, decreased fetal weights, and stage specific malformations, such as distal digital reductions, orofacial clefts and cardiovascular defects. Class III antiarrhythmics decrease the excitability of cardiac cells by selectively blocking the rapid component of the delayed rectified potassium channel (IKr), resulting in prolongation of the repolarisation phase of the action potential. Phenytoin, which decrease the excitability of neurones, has recently also been shown to block IKr, in addition to its known blockade of sodium channels. Animal studies indicate that IKr is expressed in the embryo and that the embryonic heart is extremely susceptible to IKr-blockers during a restricted period in early development. At concentrations not affecting the maternal heart, the embryonic heart reacts with bradycardia, arrhythmia and cardiac arrest when exposed to such drugs. Available studies strongly support the idea that birth defects after in utero exposure to both selective and non-selective IKr-blockers (like phenytoin) are initiated by concentration dependent embryonic bradycardia/arrhythmia resulting in 1) hypoxia; explaining embryonic death and growth retardation, 2) episodes of severe hypoxia, followed by generation of reactive oxygen species within the embryo during reoxygenation, causing orofacial clefts and distal digital reductions, and 3) alterations in embryonic blood flow and blood pressure, inducing cardiovascular defects.

Magnetic resonance microscopy of mouse embryos in utero.

Magnetic resonance microscopy (MRM) was used to study mouse embryonic development in utero. MRM is a non-invasive imaging technique to study normal and abnormal embryonic development. To overcome image blurring as a result of embryonic movement, fast imaging sequences were used (less than 1 min scanning time). Clear morphologic proton images were obtained by diffusion spin echo and by rapid acquisition with relaxation enhancement (RARE), revealing living mouse embryos with great anatomical detail. In addition, functional information about embryonic blood flow could be obtained, in the absence of a contrast agent. This was achieved by combining two imaging sequences, RARE and very fast gradient echo. We expect that MRM will soon become a feasible method to study longitudinally both normal and abnormal (transgenic) mouse development.

Doppler Characterization of Murine Embryonic Umbilical Blood Flow: Insights into Developing Embryonic-Placental Circulation and Cardiac Function

Doppler Characterization of Murine Embryonic Umbilical Blood Flow: Insights into Developing Embryonic-Placental Circulation and Cardiac Function

Umbilical arterial blood flow in the mouse embryo during development and following acutely increased heart rate

In anesthetized, pregnant ICR mice, we measured embryonic umbilical arterial velocity at baseline and during bipolar atrial or ventricular pacing. Pregnant mice were anesthetized with pentobarbital (60 mg/kg intraperitoneal) and ventilation was mechanically supported via a tracheotomy. Embryos were exposed through a mid-line laparotomy and regional hysterotomy. We recorded umbilical velocity using a 1-mm diameter piezoelectric crystal and 20-MHz, pulsed Doppler velocimeter at embryo day (ED) 10.5 ( n = 8), 12.5 ( n = 10), 13.5 ( n = 27), 14.5 ( n = 12), and 16.5 ( n = 17). We then acutely altered embryonic heart rate in n = 8 ED 13.5 mouse embryos by bipolar atrial and ventricular pacing. Embryonic heart rate in this experimental preparation increased from 123 ± 7 to 193 ± 11 beats/min from ED 10.5 to 16.5 ( p < 0.05). Peak instantaneous average velocity increased from 21 ± 2 to 55 ± 6 mm/s from ED 10.5 to 16.6 ( p < 0.05), as did stroke volume and blood flow ( p < 0.05 for each). In contrast to human umbilical arterial velocity profiles, significant forward diastolic flow was not seen at these stages, suggesting higher placental resistance in mice versus humans at comparable developmental time points. As previously noted for the chick embryo, murine embryonic umbilical arterial velocity decreased after atrial pacing and disappeared after ventricular pacing. Thus, we can determine embryonic umbilical blood flow during the overlapping periods of murine cardiac and placental morphogenesis.

Ethyl alcohol reduces cardiac output, stroke volume, and end diastolic volume in the embryonic chick.

It has been established that ethanol causes both human congenital cardiac malformations and structural intracardiac abnormalities in the embryonic chick. In view of a theory that reduced embryonic tissue hemodynamics are associated with the development of malformations, we attempted to determine whether or not a) ethanol altered cardiac blood flow and b) altered hemodynamics were a function of ethanol dose in the chick embryo. Cardiac function in Hamburger-Hamilton stage 19 chick embryos was recorded on videotape before and up to 10 hours after exposure to graded doses of ethanol. Parameters of cardiac function, including cardiac output, were determined from videotaped images by means of computer assistance. Cardiac output decreased in a linear fashion with dose for up to 3 hours after exposure to ethanol. The maximum relative percent decrease in cardiac output was directly related to the dose of ethanol administered. Furthermore, the time required after ethanol treatment for mean cardiac output to return to pretreatment and control values was also dose-dependent--lower doses of ethanol required less time for mean cardiac output to return to pretreatment and control values. Although relatively high doses of ethanol depress cardiac rate, we attribute the significant decrease in cardiac output primarily to parallel dose-dependent decreases in both stroke volume and end diastolic volume. Our data are consistent with the hypothesis that reduced embryonic cardiac blood flow during cardiogenesis is associated with the development of ethanol-induced intracardiac defects in chick embryos.

Congenital cardiovascular malformations: Questions on inheritance

The Baltimore-Washington Infant Study, an epidemiologic investigation of congenital heart disease, searches for genetic and environmental risk factors. Among 2,102 infants with heart disease, 17.5% had a noncardiac abnormality of chromosomal or genetic origin, whereas among 2,328 control infants, only 0.7% had a genetic abnormality.Familial cardiovascular malformations encountered can be grouped into five distinct etiologic mechanisms. Single gene effects may be responsible for the specific histologic and biochemical changes in familial atrial septal defect with conduction disturbance and also in idiopathic ventricular hypertrophy. Left heart lesions showed familial concordance by the presumed morphogenetic mechanism of abnormal embryonic blood flow with phenotypes of varying severity. Pulmonary stenosis appeared with familial heritable disorders, as well as a partially concordant lesion with tetralogy of Fallot. Ventricular septal defect with transposition of the great arteries (one sibling pair) and with truncus arteriosus (two sibling pairs) indicate forme fruste expression of conotruncal defects. Endocardial cushion defect occurred with and without Down's syndrome in members of three families, suggesting inheritance of a defect affecting cellular migration. Heritable blood coagulopathies occurred in case families and not in control families. The association of hemophilia and transposition, observed also by others, is extremely unlikely by chance and suggests genetic errors of endothelial cell function.The description of specific families from a populationbased study emphasizes biologic questions on the nature of the inheritance of cardiovascular malformations.

Relations between afterload, stroke volume, and descending limb of Starling's curve.

Relations between afterload, stroke volume, and descending limb of Starling's curve.