The goal of this revised application is to study the relationships between intracellular Ca (Cai) dynamics and the mechanisms of ventricular fibrillation (VF) and defibrillation. In the present funding period, we discovered that Cai dynamics and spontaneous diastolic sarcoplasmic reticulum (SR) Ca release are important to the initial defibrillation success or failure. Whether or not Cai dynamics play a role in the recurrent spontaneous VF after initial successful defibrillation remains unclear. Spontaneous VF episodes are known to occur frequently during cardiopulmonary resuscitation and in patients with VF storms. Preliminary studies from the laboratory of SR Wayne Chen suggested that store overload induced Ca release (SOICR) is an important mechanism of spontaneous SR Ca release. They also found that carvedilol and its analog (VK-II-36) can effectively reduce the sensitivity of type 2 ryanodine receptor (RyR2) to luminal Ca and suppress SR Ca release in rat ventricular myocytes. These findings suggest that inhibition of SOICR may provide a novel approach to improve defibrillation efficacy and prevent postshock spontaneous VF. However, SOICR may not be the only mechanism for postshock arrhythmias. Our preliminary studies showed that late phase 3 EAD may also play a role in postshock arrhythmias in failing and ischemic hearts. The late phase 3 EAD occurs because of the coexistence of shortened action potential duration (APD) and persistently elevated Cai. This Cai elevation is induced by Ca induced Ca release, not SOICR. If late phase 3 EAD is an important mechanism for postshock arrhythmias, then SOICR inhibition alone may not achieve antiarrhythmic effects in the postshock period. We hypothesize that (1) Spontaneous (non-voltage gated) SR Ca release and late phase 3 EAD are both important mechanisms for the development of the postshock arrhythmias and (2) Inhibition of SOICR can improve initial efficacy of ventricular defibrillation and prevent recurrent SVF after successful defibrillation attempts. We will perform dual optical mapping of Cai and membrane potential (Vm) on rabbit ventricular endocardium to document SOICR-induced delayed after depolarization in normal ventricles and in ischemic ventricles. We will also study the effects of VK-II-36, a SOICR inhibitor, on postshock arrhythmias. These studies will provide us new insights into the mechanisms of VF and defibrillation, and help test the hypothesis that inhibition of SOICR is a novel approach to arrhythmia control.

Public Health Relevance

To perform dual optical mapping of Cai and membrane potential (Vm) on rabbit ventricular endocardium to document late phase 3 EAD and SOICR-induced DADs in ventricles with global ischemia. We will also study the effects of VK-II-36 on the postshock arrhythmias in these preparations. Recurrent ventricular fibrillation occurs frequently during cardiopulmonary resuscitation. We plan to study the importance of intracellular calcium dynamics in the mechanisms of recurrent fibrillation. These studies have significant relevance to sudden cardiac death, which is a major public health problem of this country.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL078932-05A1
Application #
7741761
Study Section
Electrical Signaling, Ion Transport, and Arrhythmias Study Section (ESTA)
Program Officer
Lathrop, David A
Project Start
2005-02-01
Project End
2011-08-31
Budget Start
2009-09-01
Budget End
2010-08-31
Support Year
5
Fiscal Year
2009
Total Cost
$385,000
Indirect Cost
Name
Indiana University-Purdue University at Indianapolis
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
603007902
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
Shen, Mark J; Coffey, Arthur C; Straka, Susan et al. (2017) Simultaneous recordings of intrinsic cardiac nerve activity and skin sympathetic nerve activity from human patients during the postoperative period. Heart Rhythm 14:1587-1593
Jiang, Zhaolei; Zhao, Ye; Doytchinova, Anisiia et al. (2015) Using skin sympathetic nerve activity to estimate stellate ganglion nerve activity in dogs. Heart Rhythm 12:1324-32
Choi, Eue-Keun; Shen, Mark J; Lin, Shien-Fong et al. (2014) Effects of carvedilol on cardiac autonomic nerve activities during sinus rhythm and atrial fibrillation in ambulatory dogs. Europace 16:1083-91
Shinohara, Tetsuji; Kim, Daehyeok; Joung, Boyoung et al. (2014) Carvedilol analog modulates both basal and stimulated sinoatrial node automaticity. Heart Vessels 29:396-403
Shen, Mark J; Hao-Che Chang; Park, Hyung-Wook et al. (2013) Low-level vagus nerve stimulation upregulates small conductance calcium-activated potassium channels in the stellate ganglion. Heart Rhythm 10:910-5
Hsueh, Chia-Hsiang; Chang, Po-Cheng; Hsieh, Yu-Cheng et al. (2013) Proarrhythmic effect of blocking the small conductance calcium activated potassium channel in isolated canine left atrium. Heart Rhythm 10:891-8
Turker, Isik; Yu, Chih-Chieh; Chang, Po-Cheng et al. (2013) Amiodarone inhibits apamin-sensitive potassium currents. PLoS One 8:e70450
Lee, Young Soo; Chang, Po-Cheng; Hsueh, Chia-Hsiang et al. (2013) Apamin-sensitive calcium-activated potassium currents in rabbit ventricles with chronic myocardial infarction. J Cardiovasc Electrophysiol 24:1144-53
Chang, Po-Cheng; Turker, Isik; Lopshire, John C et al. (2013) Heterogeneous upregulation of apamin-sensitive potassium currents in failing human ventricles. J Am Heart Assoc 2:e004713
Maruyama, Mitsunori; Xiao, Jianmin; Zhou, Qiang et al. (2013) Carvedilol analogue inhibits triggered activities evoked by both early and delayed afterdepolarizations. Heart Rhythm 10:101-7

Showing the most recent 10 out of 107 publications