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 #
1R01HL114395-01A1
Application #
8400879
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
2012-08-15
Budget End
2013-07-31
Support Year
1
Fiscal Year
2012
Total Cost
$504,647
Indirect Cost
$131,590
Name
Washington University
Department
Biomedical Engineering
Type
Schools of Engineering
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Tsutsui, Kenta; Monfredi, Oliver J; Sirenko-Tagirova, Syevda G et al. (2018) A coupled-clock system drives the automaticity of human sinoatrial nodal pacemaker cells. Sci Signal 11:
Fang, Hui; Yu, Ki Jun; Gloschat, Christopher et al. (2017) Capacitively Coupled Arrays of Multiplexed Flexible Silicon Transistors for Long-Term Cardiac Electrophysiology. Nat Biomed Eng 1:
Matkovich, Scot J; Al Khiami, Belal; Efimov, Igor R et al. (2017) Widespread Down-Regulation of Cardiac Mitochondrial and Sarcomeric Genes in Patients With Sepsis. Crit Care Med 45:407-414
Vigmond, Edward J; Efimov, Igor R; Rentschler, Stacey L et al. (2017) Fractionated electrograms with ST-segment elevation recorded from the human right ventricular outflow tract. HeartRhythm Case Rep 3:546-550
Kang, C; Badiceanu, A; Brennan, J A et al. (2017) ?-adrenergic stimulation augments transmural dispersion of repolarization via modulation of delayed rectifier currents IKs and IKr in the human ventricle. Sci Rep 7:15922
Gloschat, C R; Koppel, A C; Aras, K K et al. (2016) Arrhythmogenic and metabolic remodelling of failing human heart. J Physiol 594:3963-80
Holzem, Katherine M; Gomez, Juan F; Glukhov, Alexey V et al. (2016) Reduced response to IKr blockade and altered hERG1a/1b stoichiometry in human heart failure. J Mol Cell Cardiol 96:82-92
Nadadur, Rangarajan D; Broman, Michael T; Boukens, Bastiaan et al. (2016) Pitx2 modulates a Tbx5-dependent gene regulatory network to maintain atrial rhythm. Sci Transl Med 8:354ra115
Kang, C; Qiao, Y; Li, G et al. (2016) Human Organotypic Cultured Cardiac Slices: New Platform For High Throughput Preclinical Human Trials. Sci Rep 6:28798
Kang, C; Brennan, J A; Kuzmiak-Glancy, S et al. (2016) Technical advances in studying cardiac electrophysiology - Role of rabbit models. Prog Biophys Mol Biol 121:97-109

Showing the most recent 10 out of 47 publications