Congenital Heart Disease (CHD) is the most common birth defect in humans affecting nearly one out of every one-hundred live births and is responsible for the vast majority of prenatal losses. Although several cardiac gene regulatory programs are known to play an important role in cardiac development, our understanding of how biophysical forces act alone, together, or in concert with these cardiac transcriptional programs to modulate heart morphogenesis is far from complete. Thus, studies which illuminate the underlying cellular, molecular, and physiologic mechanisms of how biophysical forces impact cardiac morphogenesis may ultimately aid in diagnosis and treatment of patients predisposed for CHD. Past studies have shown that biomechanical forces such as cardiomyocyte contractility and intracardiac hemodynamic flow may regulate this process in vivo. Though in vitro studies suggest that cardiomyocytes can realign themselves according to electrical conduction directionality, it remains unclear as to whether these natural cardiac conduction currents can generate electric fields sufficient to direct cardiomyocyte cell shape and migration and subsequent cardiac morphogenesis in vivo. Recent animal studies have suggested that electrical conduction may influence overall architecture of the developing vertebrate heart;however, assessing the individual contributions of electrical cardiac conduction, mechanical cardiac contraction and hemodynamic forces to overall heart morphogenesis is difficult because these biophysical forces are intimately coupled in the intact heart through excitation- contraction coupling. As a result, to uncouple these biophysical factors in vivo, we have recently exploited the silent heart zebrafish cardiac mutant, which displays nonbeating, but electrically conducting hearts due to a mutation in the sarcomeric gene, cardiac troponin T, and discovered that electrical conduction exclusive of contractile and hemodynamic forces can directly participate in in vivo remodeling and morphogenesis of the vertebrate heart. Thus, we hypothesize that cardiac electrical forces play a critical role toward maintaining cardiomyocyte morphology and overall cardiac morphogenesis during vertebrate heart development through regulation of cardiomyocyte calcium transient patterns/gradients.
Our specific aims are: 1) to investigate the impact of electrical forces on cardiac morphogenesis in vivo;2) to investigate whether cardiac electrical forces may regulate cellular proteins involved in cardiomyocyte morphology;and 3) to investigate the influences of cardiac electrical forces on the spatiotemporal organization of cardiomyocyte calcium transients/flickers. Overall, our interdisciplinary approach including the utilization of a genetically tractable yet optically transparent animal system as well as novel bioengineering and imaging tools will provide in vivo mechanistic insight into how electrical forces may directly impact cardiac morphogenesis. These studies may not only prove rewarding towards our understanding of CHD, but also provide additional insight towards optimizing integration and alignment of engrafted embryonic cardiomyocytes in injured myocardium for future cardiac cell-based therapy.

Public Health Relevance

Congenital Heart Disease (CHD) is the most common birth defect in humans affecting nearly one out of every one-hundred live births and is responsible for the vast majority of prenatal losses. Although several cardiac gene regulatory programs are known to play an important role in cardiac development, our understanding of how biophysical forces act alone, together, or in concert with these cardiac transcriptional programs to modulate heart morphogenesis is far from complete. Thus, these studies will illuminate the underlying cellular, molecular, and physiologic mechanisms of how electrical forces may impact cardiac morphogenesis and thus may ultimately aid in diagnosis and treatment of patients predisposed for CHD.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD069305-03
Application #
8507263
Study Section
Special Emphasis Panel (ZRG1-CB-P (55))
Program Officer
Mukhopadhyay, Mahua
Project Start
2011-09-10
Project End
2016-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
3
Fiscal Year
2013
Total Cost
$311,629
Indirect Cost
$93,118
Name
University of California San Diego
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
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