DIASTOLIC (DYS-)FUNCTION AND ELECTROPHYSIOLOGY - 05/09/11
Résumé |
Mechanical diastole, the process of myocardial relaxation and filling of the cardiac chambers, is a pump-priming process in more than one respect. Most evidently, the extent of diastolic filling is a major determinant of the stroke volume, ejected from each chamber during the subsequent beat. There are, however, less apparent consequences of diastolic changes in tissue stress-strain distribution that provide direct and indirect effects on cardiac electrophysiology. These effects may be more or less immediate and affect the diastole during which they occur, develop over a number of beats, or arise secondary to stretch-induced changes in gene expression, protein synthesis, or tissue architecture.
This article focuses on the swiftly occurring electrical responses to mechanical stimulation, also referred to as cardiac mechano-electric feedback.54 For other effects of mechanical stimulation on cardiac function see the recent review articles on calcium handling and contraction,17 gene expression and protein synthesis,75, 98 and tissue architecture.85
Clinical manifestations of mechanically induced changes in cardiac electrophysiology have been reported in the European medical literature of the past two centuries, and experimental studies into mechano-electric feedback also have a long history. Still, the cellular and molecular mechanisms involved in the heart's electrical response to changes in the mechanical environment are uncertain.
Generalizing the available data one can state that diastolic stretch causes instantaneous depolarization of cardiac cells and tissues.34, 53 This response is believed to be mediated through stretch-activated ion channels (SACs).
SACs form an independent class of ion channels (equivalent to voltage activated channels or receptor activated channels). The known channels in this category are located in the outer cell membrane and permit exclusively cation movement into, or out of, the cell.* Their stretch-sensitivity is accomplished by an increase in open probability during mechanical stimulation (Figure 1).†
SACs in the mammalian heart are either relatively nonselective for different cations such as Na+ and K+, or have a preference for K+.* This ion selectivity lays basis to their effect on diastolic electrophysiology, because it determines the reversal potential, i.e., the membrane voltage at which the direction of current flow through a particular ion channel population changes direction (see Figure 1.
The reversal potential of cation nonselective ion channels (usually between −35 mV and 0 mV in physiological solutions) is positive to the diastolic membrane potential levels in cardiomyocytes (typically between −55 mV and −95 mV, depending on cell type). Any stretch-induced increase in SAC open probability during diastole will therefore depolarize cardiac cells.
Potassium-selective SACs, on the other hand, will be of less prominent impact on diastolic electrophysiology, as their reversal potential is close to the resting membrane potential, so that little or no additional current flow would result from their diastolic activation. Their systolic activation, however, would be a powerful mechanism to cause stretch-induced reduction in action potential duration.
It is important to mention another group of cardiac ion channels that are frequently assumed to be mechanically operated: cell-volume activated channels. Unlike SACs, these channels require changes in cytosolic volume for their activation. A large number of cell-volume activated channels are selective for anions, although cation-selective channels have also been reported in the mammalian heart. These channels are believed to be involved in the heart's response to swelling, for example during myocardial ischemia and reperfusion, and to be upregulated during chronic pathologies such as congestive heart failure. They are of little bearing, however, in the context of beat-by-beat variations in length and tension of cardiac tissue, because cell volume is not assumed to change during cardiac relaxation or contraction. Cell-volume activated channels will therefore not be addressed in detail here; for more information see earlier articles on the subject.21, 90
SACs provide a sub-cellular structure that could explain the immediate effects of diastolic stretch on cardiac electrophysiology. Any extrapolation, however, from findings at the ion channel or even cellular level to tissue and organ electrophysiology has to be done with great care, as in vitro and in vivo effects may considerably differ. Also, many facets of cardiac behavior cannot be reproduced on the single cell level, as they depend on propagation of excitation (e.g., re-entry). For this reason, a fair body of experimental evidence on this subject has been obtained in isolated tissue preparations, in situ, or in Langendorff perfused hearts.
The interpretation of these macroscopic findings on stretch-induced responses, and their correlation with SAC characteristics is also not without pitfalls. This task would benefit immensely from the availability of selective pharmacologic blockers or activators of SACs; however, no such drugs had been identified until very recently.
The most widely used substance, gadolinium, is a potent (at micro-molar concentrations) but highly nonspecific blocker of nonselective SACs.99 Side effects of gadolinium include block of important voltage-gated ion channels such as the L-type calcium channel, ICa,L, and the rapidly activating delayed rectifier potassium current, IK,r.55, 66 Furthermore, gadolinium precipitates almost completely in physiological, phosphate- or bicarbonate-buffered solutions,56, 93 which may explain why the use of gadolinium in radiograph examinations does not yield clinically eminent responses. The precipitation in the presence of phosphate or bicarbonate also increases solution acidity, which may account for some of the partially controversial results in the published literature.18
Other blockers of SACs include streptomycin and similar cationic antibiotics of the aminoglycoside family, and the venom of the tarantula Grammostola spatulata.39, 42 Again, these substances have been found to also block ICa,L,36, 65 which makes it difficult to cleanly dissect the contribution of SACs to stretch-induced responses in multicellular preparations.
In a very recent development, the active peptide sequence responsible for blocking SACs has been isolated from the crude Grammostola spatulata toxin.88 This has been shown to be highly specific for the cation nonselective SACs. This development, together with the successful cloning of mechano-sensitive ion channels completed thus far for bacterial SACs,13 is hoped to promote sufficiently our understanding of channel structure and function to allow targeted interventions to prevent stretch-induced arrhythmias.
In summary, diastolic stretch generally causes cardiac depolarization. It is uncertain whether the observations in multi-cellular preparations may be fully explained on the basis of the known behavior of SACs (for the deficit in selective blockers). Most of the tissue and organ behavior is fully consistent with being brought about primarily by SACs. The next section reviews fundamental research findings on the effects of diastolic (dys-)function on electrophysiology, and then addresses related observations in man.
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| Address reprint requests to Peter Kohl, MD, PhD, Laboratory of Physiology, University of Oxford, Parks Road, Oxford OX1 3PT, United Kingdom, e-mail: peter.kohl@physiol.ox.ac.uk This work was supported by grants from the British Heart Foundation, The Wellcome Trust, and the United Kingdom Medical Research Council. |
Vol 18 - N° 3
P. 637-651 - août 2000 Retour au numéro
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