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MECHANOELECTRIC FEEDBACK (MEF) IN INTACT HEART NEURO- HUMORAL
MECHANOELECTRIC FEEDBACK (MEF) IN INTACT HEART: NEURO- HUMORAL CONTRIBUTION AND CROSS-TALK Max Lab Imperial College School of Science Technology & Medicine, National Heart & Lung Institute, Charing Cross Campus, Margravine Road, London, W6 8RF, UK. Since their definitive description, using patch electrophysiology in skeletal muscle,  stretch activated channels (SACS – depicted in the membrane channel, fig) have been described in heart . Characteristics of the channel electrophysiology have found equivalence in intact heart, where monophasic action potentials (MAPs) can be used to gain qualitative insights into cellular electrophysiology: for example isolated perfused heart of: frog , and mammals [4-6]. Notably, there is a “reversal” potential, [3, 7] where a stretch early in the action potential produces a repolarising tendency, whereas late it produces depolarisation. There is no change at the “reversal potential”. The equivalence extends to intact heart in situ, in experimental preparations, , and to man . MEF could be a homeostatic feedback mechanism (see ) and has also been mathematically modelled . Of particular relevance is that an exacting mechanical perturbation in the feedback loop can give rise to clinically relevant premature beats not only in left ventricle, but in right ventricle,  as well as in atria (reviewed in ). Ventricular premature beats can lead to life threatening arrhythmia. MEF is increasingly being highlighted as a possible cause of sudden arrhythmic cardiac death in man, (see reviews: [14-16]). If this is the case MEF should also feature in clinical correlations or predictors of mortality. This is apparent in correlations with ventricular ejection fraction - a purely mechanical rather than electrophysiological predictor [17-19]. How does MEF relate to other factors related to mortality? For example β blockade is one of the few pharmacological interventions that curtail mortality. We investigated this aspect, suspecting that alternative mechanoelectric transducers may reside in cell “signalsomes” associated with the β receptor (see fig, cell signal, SACs/channels/receptors). We have shown that this signalsome is involved in mechanically induced electrophysiological changes. This includes: the electrical restitution curve ; exacerbating by β agonism (unpublished), or blocking by β blockade  mechanically induced arrhythmia. This notion has been further supported: . Raised intraventricular pressure releases catecholamines from the ventricle  and this could affect the cell signal chain involving β agonist/receptor, ATP, cAMP, and Ca channels. In support of catecholamine release our laboratory has found that catecholamine store depletion, either pharmacologically , or by chronic sympathetic denervation  curtails mechanoarrhythmia. Is there evidence of further crosstalk? Any membrane channel associated with the cytoskeleton could provide a candidate (see fig, Cell stress/strain is distributed to several potential mechanotransducers to affect electrophysiology. SACs/channels/receptors), for stress-strain could be transmitted to the channel in this way. The ATP activated potassium (KATP) channel is Cytoskeleton attached to the cytoskeleton, and has been suggested to be * Integrin mechanosensitive , as is possibly the L type Ca channel . * Stress strain Cell signal Action potential Recently, our laboratory  has shown that several ion channels are * - tn-c Ca regionally fixed in the membrane over time, implicating the cytoskeleton. * Extracell This means that they could potentially be subject to transmitted forces. Mechanotransducer * matrix SAC/channel/receptor Although this makes them candidates for mechanoelectric transduction, * Sites/complexes Ion/ligand we have yet to investigate this aspect. However, several other channels may be mechanosensitive, including sodium channels  and potassium channels such as TREK-1 (, which appears not to involve the cytoskeleton), and IKAA , ion exchangers . Other cell signalsomes have also been implicated as being mechanosensitive and, mostly via intracellular Ca, affect membrane electrophysiology. Crosstalk could be provided by AT2 and ET1 receptors, (see brief overview ) which would affect PLC via Gq. This can alter intracellular Ca, first, via IP3 and SR Ca release, and second through PLC to facilitate membrane translocation (DAG/RACK/PKC) to influence Na/H exchange, and so intracellular Na to affect electrogenic Na/Ca exchange. An under-investigated but potentially important mechanism invokes mechanically-induced changes in ATP . In conclusion, mechanoelectric crosstalk embraces a plethora of channels, exchangers, and cell “signalsomes”. 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