Proceedings of The Physiological Society

University of Oxford (2011) Proc Physiol Soc 23, PC37

Poster Communications

Inotropic Changes From Cardiac Contractility Modulation (CCM) Are Associated With Catecholamine Release And Activation Of The Slow Delayed Rectifying Potassium Current

J. Winter1, K. E. Brack1, G. Ng1,2

1. Department of Cardiovascular Sciences, University of Leicester, Leicester, United Kingdom. 2. Leicester NIHR Biomedical Research Unit in Cardiovascular Disease, Glenfield Hospital, Leicester, United Kingdom.

Cardiac contractility modulation (CCM) is being developed as a potential electrical treatment for heart failure, whereby an electrical current is applied to the ventricle during the absolute refractory period. However mechanistic information on this inotropic therapy is lacking. The aim of this study was to investigate the inotropic and electrophysiological effects of CCM in isolated rabbit hearts. Experiments were conducted in Langendorff perfused isolated rabbit hearts under conditions of constant flow (2.0-3.0 kg, n=8). Animals were euthanised by pentobarbitone overdose (160mg/kg, i.v.) following sedation with ketamine (10mg/kg), medetomidine hydrochloride (0.2mg/kg) and butorphanol (0.05mg/kg) (i.m.). Biphasic square wave pulses (Duration=20ms, Amplitude=20mA) were applied to the basal region of the left ventricle, timed to coincide with the absolute refractory period as measured from locally recorded monophasic action potentials (MAPs). Inotropic enhancement was assessed as the change in peak left ventricular pressure (LVP) from baseline values (steady state response). Basal (local) and apical (distal) MAP duration at 90% repolarisation (MAPD90) were measured at steady state before CCM and at the end of 120 s of CCM. Responses were assessed during perfusion with metropolol (1.8μM, β1 adrenoceptor antagonist) and HMR1556 (500nM, inhibitor of the slow delayed rectifying potassium channel (IKs)). Norepinephrine content was measured by ELISA from coronary effluent collected during CCM. CCM produced a 5±1% increase in peak LVP and resulted in a shortening of local MAPD90 (-19±3%) but had no effect on on distal regions (0±1%). The reduction in local MAPs was abolished with metoprolol (-15±3 [CCM] vs. 1±1% [CCM+metoprolol], P<0.01) and was associated with norepinephrine accumulation the coronary effluent (Mean=53±11 pg/ml). Metoprolol also abolished the CCM induced inotropic response. Perfusion with HMR1556 resulted in a significant reduction of CCM mediated local MAPD90 shortening (-27±2 vs. [CCM] vs. -21±3% [CCM+HMR1556], P<0.05). Inotropic changes with CCM are associated with a shortening of left ventricular action potential duration, partly via IKs activation, and in a manner dependent upon β-adrenoceptor stimulation resulting from local catecholamine release in isolated rabbit hearts. These data may be of clinical importance in the further development of this mode of therapy in heart failure.

Where applicable, experiments conform with Society ethical requirements