Congenital heart defects are among the most common birth defects and the leading cause of death in children born with congenital defects. Understanding how the early embryonic heart functions and what regulatory mechanisms are involved in early cardiogenesis is highly important for advancement of heart defects research. Biomechanical stimuli, including blood flow and heart contraction, are important regulators of cardiovascular development. Thus, defining how these mechanisms coordinate mammalian heart tube function and morphogenesis is critically important for the diagnosis of congenital heart defects and for the development of new therapeutic interventions to treat/prevent them. Such analysis can only be performed through live high- resolution embryonic imaging. At present, nearly nothing is known about the biomechanics of the early mammalian heart. In this proposal, we will not only identify key relationships between wall motion and fluid movement needed to characterize the pump, but we will also utilize mouse mutants and embryonic interventions to elucidate the mechanism by which valveless mammalian heart tube propels blood. Traditionally, it has been believed that the early heart tube uses peristalsis to move blood through the heart and early vessels. However, more recently, an alternative theory has emerged that the heart tube functions as a Liebau pump, which works by the means of an asymmetrically-located, single, active compression site and the generation of bidirectional elastic waves through the tube. There is still controversy among researchers as to which of these two mechanisms better describes the heart tube, and further studies are needed to fully evaluate the early heart pump. Also, studies to understand the heart pump have never been performed in mammalian embryos, and the mechanisms that regulate early mammalian heart tube function may not fully replicate those of avians or teleosts. The major hypothesis of this project is that early mammalian embryonic heart tube acts neither as a peristaltic pump nor as a classical Liebau pump with a single point of compression, though it utilizes suction mechanism and functions via resonance of contractile waves from multiple sites. We propose to directly and unambiguously assess this complex, dynamic process by direct visualization and analysis of the heartbeat and blood flow during embryonic development using the live OCT mouse embryo imaging approach which we developed. This proposal will provide novel highly valuable quantitative information about the pumping mechanism of the early mammalian heart tube. It will set a basis for a broad range of research projects on live dynamic analysis of mammalian cardiogenesis, morphogenesis and teratology, contributing to better understanding, prevention and treatment of cardiac birth defects and embryonic failures in humans.

Public Health Relevance

Understanding the mechanism by which early mammalian heart circulates blood through the vascular system is critically important to advance diagnostics, prevention and treatment of congenital heart defects. The major objective of this proposal is to characterize mouse embryonic heartbeats and hemodynamics to elucidate the pumping mechanisms of the mammalian heart tube using highly innovative methodology. Successful implementation of this project will provide a basis for studying functional aspects of cardiac birt defects and embryonic failure in mouse models.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL120140-01
Application #
8547440
Study Section
Special Emphasis Panel (ZRG1-CB-F (57))
Program Officer
Evans, Frank
Project Start
2013-07-01
Project End
2018-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
1
Fiscal Year
2013
Total Cost
$386,700
Indirect Cost
$113,000
Name
Baylor College of Medicine
Department
Physiology
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
Udan, Ryan S; Piazza, Victor G; Hsu, Chih-Wei et al. (2014) Quantitative imaging of cell dynamics in mouse embryos using light-sheet microscopy. Development 141:4406-14