Published online before print October 9, 2003, doi: 10.1161/01.RES.0000100389.57520.1A
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Submitted on March 6, 2003
Revised on September 29, 2003
Accepted on September 30, 2003
Developmental Changes in Ventricular Diastolic Function Correlate With Changes in Ventricular Myoarchitecture in Normal Mouse Embryos
Takahiro Ishiwata ;
From the Cardiovascular Division (T.I., S.I.), Beth Israel Deaconess Medical Center, and Department of Medicine (T.I., S.I.), Harvard Medical School, Boston, Mass; Department of Pediatric Cardiology (M.N.), The Heart Institute of Japan, Tokyo Women’s Medical University, Tokyo, Japan; Department of Cardiology (W.T.P.), Children’s Hospital, and Department of Pediatrics (W.T.P.), Harvard Medical School, Boston, Mass; and the Department of Genetics (S.G.T.), Dartmouth Medical School, Hanover, New Hampshire.
* To whom correspondence should be addressed. E-mail: sizumo{at}bidmc.harvard.edu.
Both genetic and epigenetic factors, such as abnormal hemodynamics, affect cardiac morphogenesis and the pathogenesis of congenital heart disease. Diastolic function is an important determinant of cardiac function, and tools for evaluating diastolic function in the embryo would be very valuable for assessment of cardiac performance. Using histological measurements of ventricular myoarchitecture, Doppler assessment of ventricular inflow velocities, and direct measurement of ventricular pressure, we investigated developmental changes of ventricular diastolic function in the mouse embryos from embryonic days 9.5 to 19.5. Regression analysis showed that peak velocity of A wave (an index of passive compliance) correlated with the area of trabecular myocardium in right ventricle (RV) (r=0.92, P<0.0001) and left ventricle (LV) (r=0.93, P<0.0001). Peak velocity of E wave (an index of active relaxation) exponentially correlated with the area of compact myocardium in RV (r=0.98, P<0.0001) and LV (r=0.97, P<0.0001). We used these techniques to analyze FOG-2 null embryos. FOG-2 null embryos had thin compact myocardium, higher EDP and E/A ratio, smaller -dP/dt, and diminished sucking pressure than wild-type littermates, indicating that decreased ventricular diastolic function might be the primary cause of embryonic lethality. In conclusion, during embryogenesis the development of compact myocardium tightly regulates the development of ventricular distensibility. Our study in normal mice forms the basis for future studies of embryonic cardiac function in genetically manipulated mice with abnormalities of the cardiovascular system.
Key words: cardiac development • embryonic circulation • diastolic function • myocardial architecture • gene targeting mouse
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