Cardiac contractility modulation increases action potential duration dispersion and decreases ventricular fibrillation threshold via β1-adrenoceptor activation in the crystalloid perfused normal rabbit heart

James Winter; Kieran E Brack; John H Coote; G André Ng

doi:10.1016/j.ijcard.2013.12.184

Cardiac contractility modulation increases action potential duration dispersion and decreases ventricular fibrillation threshold via β1-adrenoceptor activation in the crystalloid perfused normal rabbit heart

James Winter, Kieran E Brack, John H Coote, G André Ng

Research output: Contribution to journal › Article › peer-review

8 Citations (Scopus)

121 Downloads (Pure)

Abstract

BACKGROUND/OBJECTIVES: Cardiac contractility modulation (CCM) is a new treatment being developed for heart failure (HF) involving application of electrical current during the absolute refractory period. We have previously shown that CCM increases ventricular force through β1-adrenoceptor activation in the whole heart, a potential pro-arrhythmic mechanism. This study aimed to investigate the effect of CCM on ventricular fibrillation susceptibility.

METHODS: Experiments were conducted in isolated New Zealand white rabbit hearts (2.0-2.5 kg, n=25). The effects of CCM (± 20 mA, 10 ms phase duration) on the left ventricular basal and apical monophasic action potential duration (MAPD) were assessed during constant pacing (200 bpm). Ventricular fibrillation threshold (VFT) was defined as the minimum current required to induce sustained VF with rapid pacing (30 × 30 ms). Protocols were repeated during perfusion of the β1-adrenoceptor antagonist metoprolol (1.8 μM). In separate hearts, the dynamic and spatial electrophysiological effects of CCM were assessed using optical mapping with di-4-ANEPPS.

RESULTS: CCM significantly shortened MAPD close to the stimulation site (Basal: 102 ± 5 [CCM] vs. 131 ± 6 [Control] ms, P<0.001). VFT was reduced during CCM (2.6 ± 0.6 [CCM] vs. 6.1 ± 0.8 [Control] mA, P<0.01) and was correlated (r(2)=0.40, P<0.01) with increased MAPD dispersion (26 ± 4 [CCM] vs. 5 ± 1 [Control] ms, P<0.01) (n=8). Optical mapping revealed greater spread of CCM induced MAPD shortening during basal vs. apical stimulation. CCM effects were abolished by metoprolol and exogenous acetylcholine. No evidence for direct electrotonic modulation of APD was found, with APD adaptation occurring secondary to adrenergic stimulation.

CONCLUSIONS: CCM decreases VFT in a manner associated with increased MAPD dispersion in the crystalloid perfused normal rabbit heart.

Original language	English
Pages (from-to)	144-154
Number of pages	11
Journal	International Journal of Cardiology
Volume	172
Issue number	1
Early online date	8 Jan 2014
DOIs	https://doi.org/10.1016/j.ijcard.2013.12.184
Publication status	Published - 1 Mar 2014

Keywords

Acetylcholine
Action Potentials
Adrenergic beta-1 Receptor Antagonists
Animals
Autonomic Nervous System
Cardiac Pacing, Artificial
Cholinergic Agonists
Electrophysiologic Techniques, Cardiac
Ganglia, Autonomic
Heart
Male
Metoprolol
Myocardial Contraction
Perfusion
Potassium Compounds
Rabbits
Receptors, Adrenergic, beta-1
Ventricular Fibrillation
Journal Article
Research Support, Non-U.S. Gov't
Cardiac contractility modulation
Non-excitatory stimulation (NES)
Ventricular arrhythmia
Action potential duration dispersion

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Winter, J., Brack, K. E., Coote, J. H., & Ng, G. A. (2014). Cardiac contractility modulation increases action potential duration dispersion and decreases ventricular fibrillation threshold via β1-adrenoceptor activation in the crystalloid perfused normal rabbit heart. International Journal of Cardiology, 172(1), 144-154. Advance online publication. https://doi.org/10.1016/j.ijcard.2013.12.184

@article{cda9273a440747a386e6b1e758685d54,

title = "Cardiac contractility modulation increases action potential duration dispersion and decreases ventricular fibrillation threshold via β1-adrenoceptor activation in the crystalloid perfused normal rabbit heart",

abstract = "BACKGROUND/OBJECTIVES: Cardiac contractility modulation (CCM) is a new treatment being developed for heart failure (HF) involving application of electrical current during the absolute refractory period. We have previously shown that CCM increases ventricular force through β1-adrenoceptor activation in the whole heart, a potential pro-arrhythmic mechanism. This study aimed to investigate the effect of CCM on ventricular fibrillation susceptibility.METHODS: Experiments were conducted in isolated New Zealand white rabbit hearts (2.0-2.5 kg, n=25). The effects of CCM (± 20 mA, 10 ms phase duration) on the left ventricular basal and apical monophasic action potential duration (MAPD) were assessed during constant pacing (200 bpm). Ventricular fibrillation threshold (VFT) was defined as the minimum current required to induce sustained VF with rapid pacing (30 × 30 ms). Protocols were repeated during perfusion of the β1-adrenoceptor antagonist metoprolol (1.8 μM). In separate hearts, the dynamic and spatial electrophysiological effects of CCM were assessed using optical mapping with di-4-ANEPPS.RESULTS: CCM significantly shortened MAPD close to the stimulation site (Basal: 102 ± 5 [CCM] vs. 131 ± 6 [Control] ms, P<0.001). VFT was reduced during CCM (2.6 ± 0.6 [CCM] vs. 6.1 ± 0.8 [Control] mA, P<0.01) and was correlated (r(2)=0.40, P<0.01) with increased MAPD dispersion (26 ± 4 [CCM] vs. 5 ± 1 [Control] ms, P<0.01) (n=8). Optical mapping revealed greater spread of CCM induced MAPD shortening during basal vs. apical stimulation. CCM effects were abolished by metoprolol and exogenous acetylcholine. No evidence for direct electrotonic modulation of APD was found, with APD adaptation occurring secondary to adrenergic stimulation.CONCLUSIONS: CCM decreases VFT in a manner associated with increased MAPD dispersion in the crystalloid perfused normal rabbit heart.",

keywords = "Acetylcholine, Action Potentials, Adrenergic beta-1 Receptor Antagonists, Animals, Autonomic Nervous System, Cardiac Pacing, Artificial, Cholinergic Agonists, Electrophysiologic Techniques, Cardiac, Ganglia, Autonomic, Heart, Male, Metoprolol, Myocardial Contraction, Perfusion, Potassium Compounds, Rabbits, Receptors, Adrenergic, beta-1, Ventricular Fibrillation, Journal Article, Research Support, Non-U.S. Gov't, Cardiac contractility modulation, Non-excitatory stimulation (NES), Ventricular arrhythmia, Action potential duration dispersion",

author = "James Winter and Brack, {Kieran E} and Coote, {John H} and Ng, {G Andr{\'e}}",

year = "2014",

month = mar,

day = "1",

doi = "10.1016/j.ijcard.2013.12.184",

language = "English",

volume = "172",

pages = "144--154",

journal = "International Journal of Cardiology",

issn = "0167-5273",

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Winter, J, Brack, KE, Coote, JH & Ng, GA 2014, 'Cardiac contractility modulation increases action potential duration dispersion and decreases ventricular fibrillation threshold via β1-adrenoceptor activation in the crystalloid perfused normal rabbit heart', International Journal of Cardiology, vol. 172, no. 1, pp. 144-154. https://doi.org/10.1016/j.ijcard.2013.12.184

Cardiac contractility modulation increases action potential duration dispersion and decreases ventricular fibrillation threshold via β1-adrenoceptor activation in the crystalloid perfused normal rabbit heart. / Winter, James; Brack, Kieran E; Coote, John H et al.
In: International Journal of Cardiology, Vol. 172, No. 1, 01.03.2014, p. 144-154.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Cardiac contractility modulation increases action potential duration dispersion and decreases ventricular fibrillation threshold via β1-adrenoceptor activation in the crystalloid perfused normal rabbit heart

AU - Winter, James

AU - Brack, Kieran E

AU - Coote, John H

AU - Ng, G André

PY - 2014/3/1

Y1 - 2014/3/1

N2 - BACKGROUND/OBJECTIVES: Cardiac contractility modulation (CCM) is a new treatment being developed for heart failure (HF) involving application of electrical current during the absolute refractory period. We have previously shown that CCM increases ventricular force through β1-adrenoceptor activation in the whole heart, a potential pro-arrhythmic mechanism. This study aimed to investigate the effect of CCM on ventricular fibrillation susceptibility.METHODS: Experiments were conducted in isolated New Zealand white rabbit hearts (2.0-2.5 kg, n=25). The effects of CCM (± 20 mA, 10 ms phase duration) on the left ventricular basal and apical monophasic action potential duration (MAPD) were assessed during constant pacing (200 bpm). Ventricular fibrillation threshold (VFT) was defined as the minimum current required to induce sustained VF with rapid pacing (30 × 30 ms). Protocols were repeated during perfusion of the β1-adrenoceptor antagonist metoprolol (1.8 μM). In separate hearts, the dynamic and spatial electrophysiological effects of CCM were assessed using optical mapping with di-4-ANEPPS.RESULTS: CCM significantly shortened MAPD close to the stimulation site (Basal: 102 ± 5 [CCM] vs. 131 ± 6 [Control] ms, P<0.001). VFT was reduced during CCM (2.6 ± 0.6 [CCM] vs. 6.1 ± 0.8 [Control] mA, P<0.01) and was correlated (r(2)=0.40, P<0.01) with increased MAPD dispersion (26 ± 4 [CCM] vs. 5 ± 1 [Control] ms, P<0.01) (n=8). Optical mapping revealed greater spread of CCM induced MAPD shortening during basal vs. apical stimulation. CCM effects were abolished by metoprolol and exogenous acetylcholine. No evidence for direct electrotonic modulation of APD was found, with APD adaptation occurring secondary to adrenergic stimulation.CONCLUSIONS: CCM decreases VFT in a manner associated with increased MAPD dispersion in the crystalloid perfused normal rabbit heart.

AB - BACKGROUND/OBJECTIVES: Cardiac contractility modulation (CCM) is a new treatment being developed for heart failure (HF) involving application of electrical current during the absolute refractory period. We have previously shown that CCM increases ventricular force through β1-adrenoceptor activation in the whole heart, a potential pro-arrhythmic mechanism. This study aimed to investigate the effect of CCM on ventricular fibrillation susceptibility.METHODS: Experiments were conducted in isolated New Zealand white rabbit hearts (2.0-2.5 kg, n=25). The effects of CCM (± 20 mA, 10 ms phase duration) on the left ventricular basal and apical monophasic action potential duration (MAPD) were assessed during constant pacing (200 bpm). Ventricular fibrillation threshold (VFT) was defined as the minimum current required to induce sustained VF with rapid pacing (30 × 30 ms). Protocols were repeated during perfusion of the β1-adrenoceptor antagonist metoprolol (1.8 μM). In separate hearts, the dynamic and spatial electrophysiological effects of CCM were assessed using optical mapping with di-4-ANEPPS.RESULTS: CCM significantly shortened MAPD close to the stimulation site (Basal: 102 ± 5 [CCM] vs. 131 ± 6 [Control] ms, P<0.001). VFT was reduced during CCM (2.6 ± 0.6 [CCM] vs. 6.1 ± 0.8 [Control] mA, P<0.01) and was correlated (r(2)=0.40, P<0.01) with increased MAPD dispersion (26 ± 4 [CCM] vs. 5 ± 1 [Control] ms, P<0.01) (n=8). Optical mapping revealed greater spread of CCM induced MAPD shortening during basal vs. apical stimulation. CCM effects were abolished by metoprolol and exogenous acetylcholine. No evidence for direct electrotonic modulation of APD was found, with APD adaptation occurring secondary to adrenergic stimulation.CONCLUSIONS: CCM decreases VFT in a manner associated with increased MAPD dispersion in the crystalloid perfused normal rabbit heart.

KW - Acetylcholine

KW - Action Potentials

KW - Adrenergic beta-1 Receptor Antagonists

KW - Animals

KW - Autonomic Nervous System

KW - Cardiac Pacing, Artificial

KW - Cholinergic Agonists

KW - Electrophysiologic Techniques, Cardiac

KW - Ganglia, Autonomic

KW - Heart

KW - Male

KW - Metoprolol

KW - Myocardial Contraction

KW - Perfusion

KW - Potassium Compounds

KW - Rabbits

KW - Receptors, Adrenergic, beta-1

KW - Ventricular Fibrillation

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

KW - Cardiac contractility modulation

KW - Non-excitatory stimulation (NES)

KW - Ventricular arrhythmia

KW - Action potential duration dispersion

U2 - 10.1016/j.ijcard.2013.12.184

DO - 10.1016/j.ijcard.2013.12.184

M3 - Article

C2 - 24456882

SN - 0167-5273

VL - 172

SP - 144

EP - 154

JO - International Journal of Cardiology

JF - International Journal of Cardiology

IS - 1

ER -