Heart failure (HF) claims ~250,000 lives per year in the US, and nearly half of these deaths are sudden and presumably due to ventricular tachyarrhythmias. However, the mechanisms by which electrical remodeling leads to arrhythmogenesis in human HF remain incompletely understood. Action potential (AP) prolongation is a hallmark electrophysiologic change of the failing myocardium, and repolarizing potassium currents are critical determinants of AP duration. However, repolarization changes in the failing myocardium have not been clearly associated with in vivo arrhythmia risk, the early steps in human HF electrical remodeling are unknown, and there are many contradictory findings attributable to different HF models. Our unique research program at Washington University in St. Louis enables us to study living donor and failing human hearts and to obtain detailed clinical information associated with every heart we examine. Thus, we will apply functional electrophysiology and molecular studies to hearts grouped by specific clinical phenotypes in order to pursue the following specific aims: 1) to investigate repolarizing current abnormalities in human HF and 2) to contrast repolarization remodeling among nonfailing, prefailing, and end-stage failing hearts and between HF patients with and without arrhythmia history. We predict that prefailing hearts will have decreased potassium channel gene and protein expression compared with nonfailing hearts and that functional, cell-surface expression of repolarizing currents will be most decreased in HF patients with clinical arrhythmia history. Thus, we hope to show that early HF remodeling involves gene and protein expression changes and that later functional ion channel derangements promote arrhythmogenesis in HF patients. Because we aim to study early HF remodeling and relate our findings to in vivo arrhythmia risk, we may be able to identify reversible changes and potential targets for therapeutic intervention in human HF.

Public Health Relevance

There are approximately 5 million Americans who currently suffer from heart failure, and the numbers of affected individuals are increasing with the aging population and as interventions for acute cardiovascular incidents improve. More than 250,000 people in the US die of heart failure every year, and nearly half of these deaths are sudden and presumably due to ventricular tachyarrhythmias. Thus, arrhythmogenic remodeling in heart failure is a major cause of disease mortality, and elucidation of the electrophysiologic alteration in human heart failure may lead to targeted therapies to prevent sudden death.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
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Special Emphasis Panel (ZRG1)
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Wang, Wayne C
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Washington University
Biomedical Engineering
Biomed Engr/Col Engr/Engr Sta
Saint Louis
United States
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Holzem, Katherine M; Vinnakota, Kalyan C; Ravikumar, Vinod K et al. (2016) Mitochondrial structure and function are not different between nonfailing donor and end-stage failing human hearts. FASEB J 30:2698-707
Holzem, Katherine M; Marmerstein, Joseph T; Madden, Eli J et al. (2015) Diet-induced obesity promotes altered remodeling and exacerbated cardiac hypertrophy following pressure overload. Physiol Rep 3:
Lang, Di; Holzem, Katherine; Kang, Chaoyi et al. (2015) Arrhythmogenic remodeling of ?2 versus ?1 adrenergic signaling in the human failing heart. Circ Arrhythm Electrophysiol 8:409-19
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
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
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
Sulkin, Matthew S; Widder, Emily; Shao, Connie et al. (2013) Three-dimensional printing physiology laboratory technology. Am J Physiol Heart Circ Physiol 305:H1569-73