Heart failure (HF) is the leading cause of mortality and morbidity, which afflicts 5.7 million Americans. HF management includes surgery, implantable device and pharmacological therapy targeting angiotensin and adrenergic signaling. Numerous animal models of heart failure have been generated and studied for decades in effort to identify therapeutic targets for treatment of human HF patients. However, it is becoming increasingly evident that this strategy has yielded limited therapeutic options for the treatment o HF. Significant genetic, molecular, cellular, anatomical, and systemic differences among species are likely to be responsible for failure of translation from cell lines and animal models t humans. Cardiac rhythm disorders are striking examples of such translational failure. Despite deep knowledge of the biophysical properties of numerous ion channels, pumps, and exchangers gained over half a century of research conducted at huge expense, current pharmacological therapies used to treat arrhythmias are nonspecific and often ineffective. The main reason for this failure is the complexity of human cardiac physiology at the molecular, cellular and tissue levels. It is paradoxical, but we know much more about ion channels and action potentials in the mouse, rat, guinea pig, rabbit, and canine as compared to our own species - Homo sapiens. We have recently developed a program, which allows investigation of the mechanisms of arrhythmogenic remodeling in live human hearts in vitro. In this project we will investigate a number of mechanistic hypothesis linking HF and arrhythmia in live cardiac tissue from donors and patients with HF. In summary, we will develop, refine and extend experimental methodology, which is currently applied only to animal cardiac preparations in basic physiology laboratories, to deepen our understanding of human cardiac pathophysiology. This approach will modify and enhance the currently dominant translational paradigm and provide new important directions of research, which will stimulate and reinvigorate a biomedical research community that has ignored human physiology and thus delayed effective translation of needed therapies for HF and sudden cardiac death.

Public Health Relevance

Our project aims to bridge the gap between fundamental discoveries in animal models of human heart failure and its validation in clinical trials. We will develop methodology to produce critically important new physiological knowledge about the cardiac function of the human species, using explanted hearts of transplantation patients and donor hearts rejected from transplantation. These precious gifts of live human hearts will yield critically important new knowledge about pathological processes occurring during heart failure in humans that lead to sudden cardiac death of hundreds of thousands of patients.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL114395-02
Application #
8529268
Study Section
Special Emphasis Panel (ZRG1-CVRS-E (02))
Program Officer
Boineau, Robin
Project Start
2012-08-15
Project End
2016-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
2
Fiscal Year
2013
Total Cost
$521,188
Indirect Cost
$164,948
Name
Washington University
Department
Biomedical Engineering
Type
Schools of Engineering
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Sulkin, Matthew S; Boukens, Bas J; Tetlow, Megan et al. (2014) Mitochondrial depolarization and electrophysiological changes during ischemia in the rabbit and human heart. Am J Physiol Heart Circ Physiol 307:H1178-86
Rutledge, Cody A; Ng, Fu Siong; Sulkin, Matthew S et al. (2014) c-Src kinase inhibition reduces arrhythmia inducibility and connexin43 dysregulation after myocardial infarction. J Am Coll Cardiol 63:928-34
Gutbrod, Sarah R; Sulkin, Matthew S; Rogers, John A et al. (2014) Patient-specific flexible and stretchable devices for cardiac diagnostics and therapy. Prog Biophys Mol Biol 115:244-51
Xu, Lizhi; Gutbrod, Sarah R; Bonifas, Andrew P et al. (2014) 3D multifunctional integumentary membranes for spatiotemporal cardiac measurements and stimulation across the entire epicardium. Nat Commun 5:3329
Ng, Fu Siong; Holzem, Katherine M; Koppel, Aaron C et al. (2014) Adverse remodeling of the electrophysiological response to ischemia-reperfusion in human heart failure is associated with remodeling of metabolic gene expression. Circ Arrhythm Electrophysiol 7:875-82
Chung, Hyun-Joong; Sulkin, Matthew S; Kim, Jong-Seon et al. (2014) Stretchable, multiplexed pH sensors with demonstrations on rabbit and human hearts undergoing ischemia. Adv Healthc Mater 3:59-68
Holzem, Katherine M; Madden, Eli J; Efimov, Igor R (2014) Human cardiac systems electrophysiology and arrhythmogenesis: iteration of experiment and computation. Europace 16 Suppl 4:iv77-iv85
Sulkin, Matthew S; Yang, Fei; Holzem, Katherine M et al. (2014) Nanoscale three-dimensional imaging of the human myocyte. J Struct Biol 188:55-60
Boukens, Bas J; Efimov, Igor R (2014) A century of optocardiography. IEEE Rev Biomed Eng 7:115-25
Walmsley, John; Rodriguez, Jose F; Mirams, Gary R et al. (2013) mRNA expression levels in failing human hearts predict cellular electrophysiological remodeling: a population-based simulation study. PLoS One 8:e56359

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