Defibrillation therapy is routinely used in patients but it may fail, especially after long duration ventricular fibrillation (LDVF), it can be painful and damaging to myocardium. Targeted improvement of defibrillation requires better understanding of electrophysiological changes during LDVF and the effects of electrical shocks on myocardium. This project will address three fundamental questions: (1) how do shocks affect intramural Vm and Cai2+? (2) what is the role of membrane electroporation in defibrillation? (3) why does defibrillation fail to restore normal heartbeat after LDVF? To answer these questions, we will use novel methods including intramural optrode recordings and dual optical mapping to measure Vm and Cai2+ in whole hearts, wedge preparations and cell cultures.
Four Specific Aims will be addressed: 1) To determine the effects of shocks on intramural Vm in whole hearts using fiber optics technology. Understanding defibrillation requires knowledge of shock effects on intramural Vm but experimental measurements in intact hearts are lacking. Using a novel technique based on fiber optics technology, we will measure intramural Vm changes (?Vm) and shock-induced tissue activation in porcine hearts. We hypothesize that defibrillation-strength shocks produce wide-spread intramural ?Vm that are sufficient for direct and rapid excitation of tissue bulk. 2) To determine the effects of shocks on Cai2+ in intact myocardium using low-affinity dyes. The effects of shocks on Cai2+, which is one of the most important parameters of cardiac function, are controversial. We will use a novel method of Cai2+ measurements with low-affinity Ca2+ dyes that have linear Cai2+ response to measure shock-induced Cai2+ changes and Cai2+ overload in myocardium. 3) To determine the role of electroporation in defibrillation. Electroporation may cause shock failure but whether it occurs during defibrillation is not known. We will use optrode recordings and dye uptake measurements to measure the threshold of electroporation and its transmural distribution in porcine hearts. We hypothesize that (i) the electroporation threshold is comparable with the shock strength used for defibrillation;(ii) electroporation is not limited to the epicardium and endocardium but is present across the whole heart wall;(iii) electroporation and shock-induced arrhythmias can be inhibited by application of membrane sealing agents. 4) To determine the mechanisms of shock failure to restore a normal heartbeat after LDVF. Survival after defibrillation rapidly decreases with increasing the duration of fibrillation. We hypothesize that heart failure is caused by malfunctions in Cai2+ handling developed during/or after LDVF. We will measure intramural Cai2+ and Vm during and after LDVF to test whether LDVF leads to: (i) Vm/Cai2+ desynchronization, (ii) loss of Cai2+ transients, (iii) spontaneous Cai2+ oscillations after LDVF termination that are followed by extra beats and VF re-initiation.

Public Health Relevance

Cardiac defibrillation using electrical shocks can be painful, damaging to the heart or it may fail, especially after prolonged fibrillation. The goal of this project is to understand the effects of electrical shocks on the heart and the role of the calcium-handling system in shock failure using novel methods for intramural optical measurements of membrane potential and intracellular calcium. The successful fulfillment of this project will improve understanding of both ventricular fibrillation and defibrillation which may provide foundation for targeted improvement of defibrillation therapy.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Electrical Signaling, Ion Transport, and Arrhythmias Study Section (ESTA)
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Lathrop, David A
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University of Alabama Birmingham
Biomedical Engineering
Schools of Engineering
United States
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Li, Qince; Ni, Rong Ruby; Hong, Huixian et al. (2017) Electrophysiological Properties and Viability of Neonatal Rat Ventricular Myocyte Cultures with Inducible ChR2 Expression. Sci Rep 7:1531
Kong, Wei; Fast, Vladimir G (2014) The role of dye affinity in optical measurements of Cai(2+) transients in cardiac muscle. Am J Physiol Heart Circ Physiol 307:H73-9
Yan, Jiajie; Kong, Wei; Zhang, Qiang et al. (2013) c-Jun N-terminal kinase activation contributes to reduced connexin43 and development of atrial arrhythmias. Cardiovasc Res 97:589-97
Kong, Wei; Ideker, Raymond E; Fast, Vladimir G (2012) Intramural optical mapping of V(m) and Ca(i)2+ during long-duration ventricular fibrillation in canine hearts. Am J Physiol Heart Circ Physiol 302:H1294-305
Sowell, Brittany; Fast, Vladimir G (2012) Ionic mechanism of shock-induced arrhythmias: role of intracellular calcium. Heart Rhythm 9:96-104
Kong, Wei; Pollard, Andrew E; Fast, Vladimir G (2011) A new optrode design for intramural optical recordings. IEEE Trans Biomed Eng 58:3130-4
Dosdall, Derek J; Fast, Vladimir G; Ideker, Raymond E (2010) Mechanisms of defibrillation. Annu Rev Biomed Eng 12:233-58
Kong, Wei; Ideker, Raymond E; Fast, Vladimir G (2009) Transmural optical measurements of Vm dynamics during long-duration ventricular fibrillation in canine hearts. Heart Rhythm 6:796-802
Bourgeois, Elliot B; Fast, Vladimir G; Collins, Rueben L et al. (2009) Change in conduction velocity due to fiber curvature in cultured neonatal rat ventricular myocytes. IEEE Trans Biomed Eng 56:855-61
Kong, Wei; Fakhari, Nadia; Sharifov, Oleg F et al. (2007) Optical measurements of intramural action potentials in isolated porcine hearts using optrodes. Heart Rhythm 4:1430-6

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