Cardiac contractility modulation increases action potential duration dispersion and decreases ventricular fibrillation threshold via β1-adrenoceptor activation in the crystalloid perfused normal rabbit heart.
OBJECTIVE
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.
Cardiology Group, Department of Cardiovascular Sciences, University of Leicester, UK.
James
J
Winter
Cardiology Group, Department of Cardiovascular Sciences, University of Leicester, UK.
Kieran E
KE
Brack
School of Clinical and Experimental Medicine, University of Birmingham, UK.
John H
JH
Coote
Cardiology Group, Department of Cardiovascular Sciences, University of Leicester, UK; NIHR Leicester Cardiovascular Biomedical Research Unit, Leicester, UK; University Hospitals of Leicester NHS Trust, Leicester, UK. Electronic address: gan1@le.ac.uk.
G André
GA
Ng
D000109:Acetylcholine / Q000494:pharmacology; D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D058671:Adrenergic beta-1 Receptor Antagonists / Q000494:pharmacology; D000818:Animals; D001341:Autonomic Nervous System / Q000502:physiology; D002304:Cardiac Pacing, Artificial; D018679:Cholinergic Agonists / Q000494:pharmacology; D022062:Electrophysiologic Techniques, Cardiac; D005725:Ganglia, Autonomic / Q000502:physiology; D006321:Heart / Q000187:drug effects / Q000294:innervation / Q000502:physiology; D008297:Male; D008790:Metoprolol / Q000494:pharmacology*; D009200:Myocardial Contraction / Q000187:drug effects* / Q000502:physiology*; D010477:Perfusion; D017680:Potassium Compounds / Q000494:pharmacology; D011817:Rabbits; D018342:Receptors, Adrenergic, beta-1 / Q000502:physiology*; D014693:Ventricular Fibrillation / Q000188:drug therapy* / Q000503:physiopathology*
D058671:Adrenergic beta-1 Receptor Antagonists; D018679:Cholinergic Agonists; D017680:Potassium Compounds; D018342:Receptors, Adrenergic, beta-1; C018369:potassium cardioplegic solution; D008790:Metoprolol; D000109:Acetylcholine
Action potential duration dispersion; Cardiac contractility modulation; Non-excitatory stimulation (NES); Ventricular arrhythmia; Ventricular fibrillation