Despite current treatment regimens, heart failure remains the leading cause of morbidity and mortality in the US and developed world due to failure to adequately replace lost ventricular myocardium from ischemia- induced infarct. Adult mammalian ventricular cardiomyocytes have a limited capacity to divide, and this proliferation is insufficient to overcome the significant loss of myocardium from ventricular injury. However, zebrafish (Danio rerio) possess the remarkable capacity to regenerate a significant amount of myocardium in injured hearts, and thus, represent an emerging vertebrate model for regenerative medicine and cardiovascular research. While the small size of zebrafish system allows for high-throughput research, the small heart size (1-2 mm in length) renders it challenging to perform functional physiological analyses. Toward this end, our collaborated efforts have enabled the applications of the micro-electrical cardiogram (ECG) and high-frequency ultrasonic transducers (>45 MHz) to further investigate the electrical and mechanical attributes of regenerating myocardium in injured zebrafish hearts. We have observed that ventricular repolarization (ST intervals and T waves) failed to normalize despite fully regenerated myocardium at 60 days post ventricular amputation, suggesting further cardiac remodeling may be required to fully integrate regenerating myocardium with host myocardium. We hypothesize that early regenerating cardiomyocytes may lack the electrical and mechanical cardiac phenotypes, and thus may require additional cardiac cellular remodeling for full electrical and mechanical integration into injured hearts. To assess the restoration of cardiac function during cardiac regeneration, we propose to interface implantable flexible micro-electrode arrays with high- frequency ultrasonic transducers and optical voltage mapping to test the conduction and mechanical phenotypes, followed by mechanistic assessment by conditionally blocking or activating Wnt/2-catenin and FGF signaling pathways. The development and application of implantable and flexible micro-electrode arrays, high frequency ultrasonic transducers hold a great promise in the era of stem cell and regenerative medicine. In sum, our concerted efforts will likely provide both novel technology and new mechanistic insights into cardiac conduction and mechanical phenotypes in response to genetic, epigenetic, and pharmaceutical perturbations with relevance to regenerative medicine.

Public Health Relevance

In the era of stem cell and regenerative medicine, there is a considerable interest to assess the phenotypes of injured and early regenerated cardiomyocytes. The advent of Micro-electro-mechanical systems (MEMS) sensors has enabled us to measure conduction and mechanical phenotypes of injured and regenerating hearts with both high spatial and temporal resolution in the small animal system. Thus, our goal is to test the hypothesis that regenerating myocardium may require additional cardiac cellular remodeling for full electrical and mechanical integration into injured hearts.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL111437-02
Application #
8433326
Study Section
Bioengineering, Technology and Surgical Sciences Study Section (BTSS)
Program Officer
Adhikari, Bishow B
Project Start
2012-03-01
Project End
2016-02-29
Budget Start
2013-03-01
Budget End
2014-02-28
Support Year
2
Fiscal Year
2013
Total Cost
$367,542
Indirect Cost
$49,210
Name
University of Southern California
Department
Biomedical Engineering
Type
Schools of Engineering
DUNS #
072933393
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
Ma, Jianguo; Luo, Yuan; Sevag Packard, René R et al. (2016) Ultrasonic Transducer-Guided Electrochemical Impedance Spectroscopy to Assess Lipid-Laden Plaques. Sens Actuators B Chem 235:154-161
Fei, Peng; Lee, Juhyun; Packard, René R Sevag et al. (2016) Cardiac Light-Sheet Fluorescent Microscopy for Multi-Scale and Rapid Imaging of Architecture and Function. Sci Rep 6:22489
Guan, Zeyi; Lee, Juhyun; Jiang, Hao et al. (2016) Compact plane illumination plugin device to enable light sheet fluorescence imaging of multi-cellular organisms on an inverted wide-field microscope. Biomed Opt Express 7:194-208
Packard, René R Sevag; Zhang, XiaoXiao; Luo, Yuan et al. (2016) Two-Point Stretchable Electrode Array for Endoluminal Electrochemical Impedance Spectroscopy Measurements of Lipid-Laden Atherosclerotic Plaques. Ann Biomed Eng 44:2695-706
Li, Rongsong; Navab, Kaveh; Hough, Greg et al. (2015) Effect of exposure to atmospheric ultrafine particles on production of free fatty acids and lipid metabolites in the mouse small intestine. Environ Health Perspect 123:34-41
Cao, Hung; Kang, Bong Jin; Lee, Chia-An et al. (2015) Electrical and Mechanical Strategies to Enable Cardiac Repair and Regeneration. IEEE Rev Biomed Eng 8:114-24
Zhang, Xiaoxiao; Beebe, Tyler; Jen, Nelson et al. (2015) Flexible and waterproof micro-sensors to uncover zebrafish circadian rhythms: The next generation of cardiac monitoring for drug screening. Biosens Bioelectron 71:150-7
Lee, Juhyun; Packard, René R Sevag; Hsiai, Tzung K (2015) Blood flow modulation of vascular dynamics. Curr Opin Lipidol 26:376-83
Yang, Hongbo; Fang, Longhou; Zhan, Rui et al. (2015) Polo-like kinase 2 regulates angiogenic sprouting and blood vessel development. Dev Biol 404:49-60
Zhao, Yu; Cao, Hung; Beebe, Tyler et al. (2015) Dry-contact microelectrode membranes for wireless detection of electrical phenotypes in neonatal mouse hearts. Biomed Microdevices 17:40

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