title: The acute inotropic effects of cardiac contractility modulation (CCM) are associated with action potential duration shortening and mediated by β1-adrenoceptor signalling.
abstract: Despite promising results in clinical trials conducted to date, little is known about how cardiac contractile modulation (CCM) mediated inotropic enhancement occurs and how CCM affects the electrophysiological characteristics of the heart. The aims of the present study were to 1) investigate how the stimulation parameters of the CCM signal and the location of stimulus delivery influence the contractile response, 2) characterise the effect of CCM on ventricular electrophysiology, and 3) investigate the potential physiological mechanisms underlying these acute inotropic and electrophysiological effects. Experiments were conducted in isolated rabbit hearts with simultaneous measurement of ventricular contractility and monophasic action potential duration (MAPD). Biphasic square wave pulses were applied to the left ventricle, timed to coincide with the absolute refractory period. CCM mediated responses were assessed over a range of signal amplitudes (2-30 mA), durations (2-15 ms) and delays from the activation of the locally recorded monophasic action potential (0-30 ms). Responses were assessed during perfusion with the β1-adrenoceptor antagonist metoprolol (1.8 μM) and HMR 1556 (500 nM), an inhibitor of the slow delayed rectifying potassium current. Norepinephrine content was collected and assessed by ELISA from samples of coronary effluent collected during CCM. CCM induced a significant increase in left ventricular pressure (LVP) in a manner dependent upon the amplitude and duration of the CCM signal but independent of the delay of the stimulus within the action potential plateau and was associated with an increase in norepinephrine in coronary effluent (Mean: 46±9 pg/ml). CCM promoted a shortening of MAPD-90% close to the site of stimulation (-19±3%) but had no effect on those recorded at distant sites (0±1%). The increase in LVP (4.7±1.8 vs. 0.7±0.9%, P<0.01) and shortening of local MAPD-90% (-15±3 vs. 1±1%, P<0.01) was abolished with metoprolol. Perfusion with HMR 1556 caused a significant inhibition of local MAPD shortening (-27±2 vs. -21±3 ms, P<0.05). CCM is associated with a shortening of ventricular MAPD in a manner dependent upon β-adrenoceptor stimulation resulting from catecholamine release, a finding which may be of clinical significance in regard to the development of malignant ventricular arrhythmias. This article is part of a Special Issue entitled Possible Editorial.
authors.affiliation: Cardiology group, Department of Cardiovascular Sciences, University of Leicester, LE3 9QP, UK.
authors.forename: James
authors.initials: J
authors.lastname: Winter
authors.forename: Kieran E
authors.initials: KE
authors.lastname: Brack
authors.forename: G André
authors.initials: GA
authors.lastname: Ng
mesh_terms: D000200:Action Potentials / Q000187:drug effects*; D058671:Adrenergic beta-1 Receptor Antagonists / Q000494:pharmacology*; D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology*; D022062:Electrophysiologic Techniques, Cardiac; D006352:Heart Ventricles / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008790:Metoprolol / Q000494:pharmacology*; D009200:Myocardial Contraction / Q000187:drug effects*; D011817:Rabbits; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D058671:Adrenergic beta-1 Receptor Antagonists; D002316:Cardiotonic Agents; D011943:Receptors, Adrenergic, beta; D008790:Metoprolol