Published online before print May 27, 2004, doi: 10.1161/01.RES.0000133681.99617.28
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Submitted on February 12, 2004
Revised on April 26, 2004
Accepted on May 18, 2004
Embryonic Heart Failure in NFATc1-/- Mice. Novel Mechanistic Insights From In Utero Ultrasound Biomicroscopy
Colin K.L. Phoon *;
From the Pediatric Cardiology Program (C.K.L.P.), Skirball Institute of Biomolecular Medicine (C.K.L.P., R.P.J., O.A., D.H.T.), and Departments of Radiology and Pathology (D.H.T.), New York University School of Medicine, New York, NY; Division of Cardiothoracic Surgery (D.M.W.), Children’s Hospital of Philadelphia, Philadelphia, Pa; and Division of Pediatric Cardiology (B.Z., S.B.), Vanderbilt University School of Medicine, Nashville, Tenn.
* To whom correspondence should be addressed. E-mail: colin.phoon{at}med.nyu.edu.
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 biomicroscopy (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.
Key words: cardiac development • embryonic circulation • heart failure • NFAT • ultrasound biomicroscopy
This article has been cited by other articles:
 |
|
 |
|
  A. Nomura-Kitabayashi, C. K. L. Phoon, S. Kishigami, J. Rosenthal, Y. Yamauchi, K. Abe, K.-i. Yamamura, R. Samtani, C. W. Lo, and Y. Mishina Outflow tract cushions perform a critical valve-like function in the early embryonic heart requiring BMPRIA-mediated signaling in cardiac neural crest Am J Physiol Heart Circ Physiol, November 1, 2009; 297(5): H1617 - H1628. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Sedmera Pathways to embryonic heart failure Am J Physiol Heart Circ Physiol, November 1, 2009; 297(5): H1578 - H1579. [Full Text] [PDF]
|
|
|
|
|
|
R. B. Hinton Jr., C. M. Alfieri, S. A. Witt, B. J. Glascock, P. R. Khoury, D. W. Benson, and K. E. Yutzey Mouse heart valve structure and function: echocardiographic and morphometric analyses from the fetus through the aged adult Am J Physiol Heart Circ Physiol, June 1, 2008; 294(6): H2480 - H2488. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Mu, D. Qu, A. Bartczak, M. J. Phillips, J. Manuel, W. He, C. Koscik, M. Mendicino, L. Zhang, D. A. Clark, et al. Fgl2 deficiency causes neonatal death and cardiac dysfunction during embryonic and postnatal development in mice Physiol Genomics, September 11, 2007; 31(1): 53 - 62. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. T Butcher and R. R Markwald Valvulogenesis: the moving target Phil Trans R Soc B, August 29, 2007; 362(1484): 1489 - 1503. [Abstract] [Full Text] [PDF]
|
|