[637] Increasing Gap Junction Conductance with ZP123 Improves Defibrillation Success in Experimental Cardiac Arrest

Paul Dorian, MD, FRCPC, Jingquan Zhong, MD, PhD, Xudong Hu, MD, PhD, Petsy P-S So, BSc, Donna Debicki, BSc, James K Hennan, PhD. St. Michael's Hospital, Toronto, ON, Canada; University of Toronto, Toronto, ON, Canada; Wyeth Research, Collegeville, PA

Ventricular fibrillation (VF) leads rapidly to tissue hypoxia, ischemia, and acidosis. These factors lead to intercellular uncoupling, and may contribute to conduction slowing and wavelet fragmentation during VF. We hypothesized that improving cellular coupling would improve the ability to defibrillate. Methods: Thirty two rabbits were anesthetized and ventilated. Arterial blood pressure (BP), ECG and left ventricular effective refractory period (VERP) were recorded. Following 4 min of electrically induced and untreated VF, animals were defibrillated with biphasic shocks delivered to subcutaneous chest wall patches, starting at 300 volts (V) (n = 16) or 500 V (n = 16), increasing in 200 V increments to 900 V in case of failure. Sixteen rabbits received a bolus of 1.5 μg/kg, followed by 0.09 μg/min/kg (for 15 min) of ZP123, a peptide which selectively increases gap junctional conductance; 16 control rabbits received saline, by random assignment. Electrophysiologic measures (heart rate (HR), QRS, QT interval and VERP), and BP were recorded pre and post drug or saline administration. Results: ZP123 improved defibrillation efficacy: 12/16 rabbits receiving saline were defibrillated, vs 16/16 after ZP123. Average cumulative voltage of all shocks was 1949 ± 1950 V for controls vs 844 ± 547 V for ZP123. One minute following defibrillation, 87% of ZP123-treated vs 13% of control rabbits had a supraventricular rhythm (p = 0.018). ZP123 has no effect on BP or any electrophysiologic measures.

	Electrophysiologic Effects of ZP123
	HR (bpm)	PR (ms)	QRS (ms)	QT (ms)	VERP (ms)
pre saline	241 ± 14	78 ± 7	46 ±13	163 ±12	99 ± 18
post saline	242 ± 31	80 ± 8	46 ± 7	161 ± 9	100 ± 8
pre ZP123	246 ± 31	77 ± 15	43 ± 5	159 ± 11	100 ± 26
post ZP123	248 ± 31	76 ± 15	42 ± 4	163 ± 17	101 ± 12

	Percent Defibrillation Success
	300 V	500V	700 V	900 V
Saline	25%	36%	56%	0%
ZP123	50%	50%	83%	100%
ZP123: greater proportion of successful shocks, p = 0.006

Conclusion: Enhancing gap junction conductance with ZP123 during VF improves the ability to defibrillate. Cellular uncoupling may play a role in electrical disorganization during VF.

Session Info: Gap Junctions and Cellular Electrophysiology - Monday, November 14, 2005, 10:45 AM - 12:00 PM
Presentation Time: 11:15 AM
Room: Dallas Convention Center, D170/172