TY - JOUR
T1 - Embryonic heart failure in NFATc1-/- mice novel
T2 - Mechanistic insights from in utero ultrasound biomicroscopy
AU - Phoon, Colin K.L.
AU - Ji, Rui Ping
AU - Aristizábal, Orlando
AU - Worrad, Diane M.
AU - Zhou, Bin
AU - Baldwin, H. Scott
AU - Turnbull, Daniel H.
PY - 2004/7/9
Y1 - 2004/7/9
N2 - Gene targeting in the mouse has become a standard approach, yielding important new insights into the genetic factors underlying cardiovascular development and disease. However, we still have very limited understanding of how mutations affect developing cardiovascular function, and few studies have been performed to measure altered physiological parameters in mouse mutant embryos, Indeed, although in utero lethality due to embryonic heart failure is one of the most common results of gene targeting experiments in the mouse, the underlying physiological mechanisms responsible for embryonic demise remain elusive. Using in utero ultrasound biornicroscopy (UBM), we studied embryonic day (E) 10.5 to 14.5 NFATc1-/- embryos and control littermates. NFATc1-/- mice, which lack outflow valves, die at mid-late gestation from presumed defects in forward blood flow with resultant heart failure. UBM showed increasing abnormal regurgitant flow in the aorta and extending into the embryonal-placental circulation, which was evident after E12.5 when outflow valves normally first develop. Reduced NFATc1-/- net volume flow and diastolic dysfunction contributed to heart failure, but contractile function remained unexpectedly normal. Among 107 NFATc1-/- embryos imaged, only 2 were observed to be in acute decline with progressive bradyarrhythmia, indicating that heart failure occurs rapidly in individual NFATc1-/- embryos. This study is among the first linking a specific physiological phenotype with a defined genotype, and demonstrates that NFATc1-/- embryonic heart failure is a complex phenomenon not simply attributable to contractile dysfunction.
AB - Gene targeting in the mouse has become a standard approach, yielding important new insights into the genetic factors underlying cardiovascular development and disease. However, we still have very limited understanding of how mutations affect developing cardiovascular function, and few studies have been performed to measure altered physiological parameters in mouse mutant embryos, Indeed, although in utero lethality due to embryonic heart failure is one of the most common results of gene targeting experiments in the mouse, the underlying physiological mechanisms responsible for embryonic demise remain elusive. Using in utero ultrasound biornicroscopy (UBM), we studied embryonic day (E) 10.5 to 14.5 NFATc1-/- embryos and control littermates. NFATc1-/- mice, which lack outflow valves, die at mid-late gestation from presumed defects in forward blood flow with resultant heart failure. UBM showed increasing abnormal regurgitant flow in the aorta and extending into the embryonal-placental circulation, which was evident after E12.5 when outflow valves normally first develop. Reduced NFATc1-/- net volume flow and diastolic dysfunction contributed to heart failure, but contractile function remained unexpectedly normal. Among 107 NFATc1-/- embryos imaged, only 2 were observed to be in acute decline with progressive bradyarrhythmia, indicating that heart failure occurs rapidly in individual NFATc1-/- embryos. This study is among the first linking a specific physiological phenotype with a defined genotype, and demonstrates that NFATc1-/- embryonic heart failure is a complex phenomenon not simply attributable to contractile dysfunction.
KW - Cardiac development
KW - Embryonic circulation
KW - Heart failure
KW - NFAT
KW - Ultrasound biomicroscopy
UR - http://www.scopus.com/inward/record.url?scp=3142738008&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=3142738008&partnerID=8YFLogxK
U2 - 10.1161/01.RES.0000133681.99617.28
DO - 10.1161/01.RES.0000133681.99617.28
M3 - Article
C2 - 15166096
AN - SCOPUS:3142738008
SN - 0009-7330
VL - 95
SP - 92
EP - 99
JO - Circulation research
JF - Circulation research
IS - 1
ER -