Sudden Cardiac Death (SCD) remains a leading cause of death in the western world. Estimates suggest that roughly 10-20% of all annual mortality in the U.S. results from SCD and that approximately 5% of the middle-aged U.S. population has a significant predisposition to SCD. The major causes of SCD in adults age 35 and older are coronary artery disease (CAD;~ 80%) and dilated cardiomyopathy (~10-15%), with risk increasing dramatically with age. While implantable cardioverter defibrillators (ICDs) are proving to be effective in reducing the occurrence of SCD, wholesale deployment of ICDs in large patient populations is impractical economically and ignores the facts that the majority of patients with ICDs are likely never to require them and that there are as yet no effective means for identifying patients at highest risk for SCD. Working both from the top-down (whole heart optical mapping, anatomical reconstruction and simulation) and from the bottom up (mitochondrial and cellular imaging and modeling), our aim is to achieve an unprecedented level of integration of structure and function in order to understand and model the ways in which coupling between metabolic and electrophysiological processes in the myocyte contribute to risk of cardiac arrhythmias under conditions of metabolic stress. We refer to this as the metabolic sink hypothesis. Cluster Project 1 will test the hypothesis that metabolic sinks may be formed by producing local regions of IKATP activation in the intact-perfused guinea pig (GP) heart and will assess their impact on ventricular conduction and arrhythmia generation. Cluster Project 2 will test the hypothesis that metabolically stressed myocardium is particularly susceptible to formation of metabolic sinks leading to arrhythmia in the setting of heart failure. Cluster Project 3 will develop novel biophysically, metabolically and anatomically detailed computational models of electrical conduction and, in conjunction with Cluster Projects 1 &2, test hypotheses regarding the ways in which the interplay between metabolic and electrophysiological function contributes to generation of arrhythmias under conditions of metabolic stress. The metabolic sink hypothesis has never been tested directly by producing metabolic uncoupling of mitochondria in local regions of myocardium and measuring effects on electrical conduction and generation of arrhythmias. Whether or not failing myocytes are susceptible to metabolic oscillations, whether or not failing tissue is more or less susceptible to formation of metabolic sinks than is normal tissue, and whether or not metabolic sinks form a substrate for reentry in failing myocardium is unknown. This project will test these hypotheses and the results will have major importance for our understanding of the mechanisms and treatment of arrhythmias.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Exploratory/Developmental Grants Phase II (R33)
Project #
5R33HL087345-03
Application #
7673580
Study Section
Special Emphasis Panel (ZHL1-CSR-K (M1))
Program Officer
Lathrop, David A
Project Start
2007-09-01
Project End
2011-08-31
Budget Start
2009-09-01
Budget End
2011-08-31
Support Year
3
Fiscal Year
2009
Total Cost
$268,676
Indirect Cost
Name
Johns Hopkins University
Department
Biomedical Engineering
Type
Schools of Engineering
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Barth, Andreas S; Kumordzie, Ami; Tomaselli, Gordon F (2016) Orchestrated regulation of energy supply and energy expenditure: Transcriptional coexpression of metabolism, ion homeostasis, and sarcomeric genes in mammalian myocardium. Heart Rhythm 13:1131-1139
Gauthier, Laura D; Greenstein, Joseph L; Cortassa, Sonia et al. (2013) A computational model of reactive oxygen species and redox balance in cardiac mitochondria. Biophys J 105:1045-56
Gauthier, Laura D; Greenstein, Joseph L; O'Rourke, Brian et al. (2013) An integrated mitochondrial ROS production and scavenging model: implications for heart failure. Biophys J 105:2832-42
Wei, An-Chi; Aon, Miguel A; O'Rourke, Brian et al. (2011) Mitochondrial energetics, pH regulation, and ion dynamics: a computational-experimental approach. Biophys J 100:2894-903
Winslow, Raimond L; Cortassa, Sonia; O'Rourke, Brian et al. (2011) Integrative modeling of the cardiac ventricular myocyte. Wiley Interdiscip Rev Syst Biol Med 3:392-413
Barth, Andreas S; Kumordzie, Ami; Frangakis, Constantine et al. (2011) Reciprocal transcriptional regulation of metabolic and signaling pathways correlates with disease severity in heart failure. Circ Cardiovasc Genet 4:475-83
Hashambhoy, Yasmin L; Winslow, Raimond L; Greenstein, Joseph L (2011) CaMKII-dependent activation of late INa contributes to cellular arrhythmia in a model of the cardiac myocyte. Conf Proc IEEE Eng Med Biol Soc 2011:4665-8
Anderson, Troy; Wulfkuhle, Julia; Petricoin 3rd, Emanuel et al. (2011) High resolution mapping of the cardiac transmural proteome using reverse phase protein microarrays. Mol Cell Proteomics 10:M111.008037
Winslow, Raimond L; Greenstein, Joseph L (2011) Cardiac myocytes and local signaling in nano-domains. Prog Biophys Mol Biol 107:48-59
Zhou, Lufang; Aon, Miguel A; Liu, Ting et al. (2011) Dynamic modulation of Ca2+ sparks by mitochondrial oscillations in isolated guinea pig cardiomyocytes under oxidative stress. J Mol Cell Cardiol 51:632-9

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