HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Abstract Full Text (PDF) All Versions of this Article: 91/2/307    most recent expphysiol.2005.031062v1 Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kohl, P. Articles by Garny, A. Search for Related Content PubMed PubMed Citation Articles by Kohl, P. Articles by Garny, A. Related Collections Heart/Cardiac Muscle

¹ The Cardiac Mechano-Electric Feedback Group, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3PT, UK

	Abstract

Top Abstract Introduction References

 
The heart is an electrically driven mechanical pump, somewhat like an electric motor. Interestingly, like an electric motor in ‘dynamo mode’, the heart can also convert mechanical stimuli into electrical signals. This feedback from cardiac mechanics to electrical activity involves mechanosensitive ion channels, whose properties and pathophysiological relevance are reviewed in the context of experimental and theoretical modelling of ventricular beat-by-beat electromechanical function.

(Received 13 October 2005; accepted after revision 10 January 2006; first published online 11 January 2006)
Corresponding author P. Kohl: The Cardiac Mechano-Electric Feedback Group, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3PT, UK. Email: peter.kohl{at}physiol.ox.ac.uk

	Introduction

Top Abstract Introduction References

 
Mechanosensitive ion channels (MSC) have been reported in a wide range of species and tissues, and are implicated in vital responses ranging from the regulation of cell volume and contractile activity of muscle cells to proprioreception and senses such as touch and hearing. MSC are defined by their pronounced ability to change open probability in response to a mechanical stimulus (usually increasing with stretch, although stretch-inactivated channels have also been reported), thereby translating mechanical energy into an electrochemical signal. Alternatively, the conformational change encountered by MSC upon mechanical stimulation might, in its own right, serve as a catalytic event for signalling cascades involved in mechanoreception. For a more detailed introduction to MSC and their clinical relevance, see Kohl et al. (2005b).

MSC have been roughly divided into channels that normally require an increase in cell volume for activation (volume-activated channels; VAC) and those that respond to cell deformation in the absence of cell volume changes (stretch-activated channels; SAC). The mechanical entities responsible for channel activation (such as stress, strain, membrane curvature or thickness) are, as yet, unresolved. SAC and VAC can be further separated into subgroups, defined by their ion selectivity, such as cation-non-selective, potassium-selective or chloride-selective channels (e.g. SAC_NS, SAC_K, VAC_Cl). This ion selectivity also determines characteristic electrophysiological properties of MSC, such as their reversal potential which, for potassium-selective channels, is negative to the resting membrane potential and for cation-non-selective MSC lies somewhere between resting and action potential (AP) plateau levels. Thus, activation of potassium-selective channels will generally cause membrane repolarization/hyperpolarization, while activation of cation-non-selective channels will tend to depolarize resting cells and to repolarize cells at more positive membrane potentials during the AP. Like many functional classifications, MSC division is rather arbitrary and not based on definite mechanistic or structural insight. Nonetheless, it has proven to be of some practical value and aided conceptual developments in the field, so that it will be adhered to in the present report.

VAC play important roles in ischaemia/postischaemic responses. In addition, they are overexpressed and show background activity in hypertrophied myocardium. It is assumed, however, that overall cell volume does not change significantly on a beat-by-beat basis. Sarcolemmal VAC are therefore not discussed in detail here, and the reader is referred to reviews such as Baumgarten & Clemo (2003) and Baumgarten (2005). SAC are largely either cation-non-selective (Craelius et al. 1988) or potassium selective (Kim, 1992). They tend to show swift activation (unlike VAC, whose response to cell swelling tends to occur after a lag time of 1 min or more (Sorota & Du, 1998), and they are understood to contribute to ventricular electrophysiology on a beat-by-beat basis (Kohl & Sachs, 2001).

In cardiac cells, MSC, or their whole-cell equivalent currents, have been studied using a wide range of different interventions. These include: sarcolemmal membrane patch deformation (Guharay & Sachs, 1984; Craelius et al. 1988); local cell distortion (Sachs, 2004); compression (Isenberg et al. 2003); shrinkage or swelling (Baumgarten & Clemo, 2003); fluid sheer (Kong et al. 2005); centrifugal membrane plucking by magnetic beads (Glogauer et al. 1995; Browe & Baumgarten, 2004); bi-axial stretch of cells grown on elastic membranes (de Jonge et al. 2002); and axial distension of single cells (Le Guennec et al. 1990; Tung & Zou, 1995). In the absence of an experimental ‘gold standard’ for mechanical stimulation of cells, and given the scarcity of commercially available tools, most studies have been based on tailor-made (hence unique) experimental facilities. In addition, most studies have been conducted on ‘bulk-isolated’ myocardial cells (not taking into account regional differences in cellular electromechanics; Bryant et al. 1997; Natali et al. 2002), isolated from different species. These factors, together with differences in electrophysiological recording techniques (e.g. ruptured versus perforated patch), have yielded MSC data that are variable and, at times, contradictory.

Experiments at the (sub)cellular level have further shown that several ion channels and transporters, which are customarily defined via their voltage sensitivity or ligand sensitivity, are also modulated by mechanical events. Examples include currents through hyperpolarization-activated channels (Morris & Laitko, 2005) and the ATP-inactivated potassium current, i_KATP (van Wagoner, 1993). In both cases, ion channel mechanosensitivity might explain some of the differences between channel activation properties in vitro (usually studied in mechanically unloaded cells) and their apparent functional relevance for pacemaking or responses to ischaemia in situ (where cells experience significant and dynamically changing mechanical loads). Both ion channels have been implicated in pathophysiological responses in situ at voltage or ligand levels that would not allow very significant channel activation in vitro. Thus, i_KATP appears to contribute to cardiac tissue responses to ischaemic insults at a time when ATP concentration is still high enough to inhibit the current in isolated cells. Similarly, the hyperpolarization-activated ‘funny’ current, i_f, appears to contribute to cardiac pacemaker activity at membrane potentials where the current is very small or absent in isolated cells. This discrepancy may be related, in part, to the profoundly different mechanical environments experienced by cells in native tissue and after isolation.

‘Non-MSC’ mechanosensitivity may seem surprising at first. However, any ion channel whose opening coincides with an increase in its spatial projection in the plane of the membrane in which it is embedded should be sensitive to changes in the mechanical environment in that very plane (Sachs, 2005). One might argue, therefore, that the surprise (if any) is that some channels appear to be reasonably well protected from mechanical stimulation. This may, however, be related to the fact that cardiomyocyte cell membranes respond to stretch more like a concertina (i.e. by unfolding of membrane invaginations and, during excessive stretch, by membrane incorporation of caveolae; Kohl et al. 2003), rather than like a homogeneous, elastic membrane.

Studies at higher levels of structural and functional integration, such as in isolated tissue (Deck, 1964) and whole heart (Franz et al. 1989; Zabel et al. 1996), as well as animal- and human-based research (Lab & Woollard, 1978; Taggart, 1996), have shown that mechanical stimuli may affect both the origin and the spread of cardiac electrical excitation. This process has been termed Mechano-Electric Feedback (MEF; Kaufmann & Theophile, 1967), and its effects range from physiological heart rate modulation (such as during fluctuations in venous return to the heart) to the mechanical induction of heart rhythm disturbances or their mechanical termination (for review see Kohl et al. 1999).

Linking insight from these ‘systemic’ investigations to subcellular mechanisms has not been straightforward, though, mainly because of a lack in specific drugs to probe MSC in native tissue. The early favourite, gadolinium, is highly non-specific (Pascarel et al. 1998) and precipitates almost completely in physiological buffers (Caldwell et al. 1998). Streptomycin, an efficient MSC blocker in isolated cells at concentrations near 40 µM (Gannier et al. 1994), is not very selective at higher concentrations (Belus & White, 2002), and may be inefficient for acute interventions in native tissue (Cooper et al. 2006). This inability of streptomycin to acutely block MSC in situ will have been a prerequirement for human prescription of this drug as an antibiotic; otherwise vestibular side-effects of the drug would probably be more acute and more common. More recently, a 35 amino acid peptide (GsMTx-4), isolated from the Chilean tarantula Grammostola spatulata, has been shown to block MSC with high selectivity and to be suitable for native tissue application (Bode et al. 2001). However, limited availability and high cost of the peptide still pose limitations for more general use as the MSC blocker of choice.

Thus, for more detailed insight both into MSC effects on cardiac function and into the pathophysiological relevance of cardiac MEF, there is a requirement to link isolated pockets of factual knowledge at different levels of structural and functional integration. This situation calls for the improvement of experimental tools to interrelate effects of the mechanical environment on cardiac function to underlying mechanisms, and for quantitative theoretical reintegration of mechanistic insight towards an understanding of systems' behaviour.

Models: general considerations

Models, simplified representations of reality, can be compared to utensils in a toolbox: they are designed with a specific function in mind, restricted by their intrinsic properties, and inherently incapable of addressing all possible applications individually.

In biological research, model selection is guided by factors such as relevance, reproducibility of data, and cost (not only in terms of finance, but also time and ethical dimensions; see Fig. 1 and Hearse & Sutherland, 2000). These parameters possess different weight at the various levels of structural integration, from molecule to man. Most investigations are inherently method driven (horizontal lines in Fig. 1), in that we can only conduct studies using tools and techniques to which we have suitably well-qualified access. This has contributed to the aforementioned development of pockets of factual insight in cardiac MSC research.

View larger version (24K): [in this window] [in a new window]   Figure 1.  Levels of investigation and inherent compromises between relevance, data amount/reproducibility and cost of biomedical research Individual studies are often method driven, as indicated by the horizontal arrows. Hypothesis-driven research, in particular if ‘translational’ (i.e. projecting from fundamental research to practical application), necessitates vertical integration. This can be achieved by application of advanced engineering techniques to develop models, at lower levels of structural and functional integration, that maintain essential aspects of a system's pathophysiological function (down arrow), thereby increasing the relevance of lower level research. Theoretical reintegration, in turn, allows one to project from detailed insight at lower levels to high-level relevance (up arrow), thereby potentially reducing the cost of higher level studies. This view is simplified for clarity, since model development and wet/dry experimentation naturally involve both up- and downward projections, as well as iteration between model and experiment. Illustration inspired by Hearse & Sutherland (2000).

Bottom-up reintegration of data, in contrast, benefits from theoretical modelling. This direction has gathered momentum in recent years under various umbrellas, such as the IUPS Physiome Initiative (http://www.physiome.org.nz/), the Giome Project (http://www.giome.com/), and the Visible Human (http://www.nlm.nih.gov/research/visible/). Theoretical modelling of cardiac mechano-electrical interactions and MSC, in particular, has already guided data interpretation, hypothesis formation, and informed experimental design (Kohl & Sachs, 2001). Modelling that is based on experimental data input and that is developed, validated and applied in continuous iteration between ‘dry’ and ‘wet’ research, has the power of reducing the cost of biomedical research, thereby supporting a better balance between individual horizontal research efforts.

Thus, the toolbox of biological studies contains a multitude of parallel ‘horizontal’ models, both experimental and computational, whose ‘vertical’ integration holds the key to translation between basic research and clinical relevance.

Experimental models for cardiac MSC research

This section illustrates the utility and limitations of individual horizontal models in the context of research into cardiac MEF. As already indicated, mechanical stimulation, e.g. by impacts to the precordial chest, may both initiate and terminate heart rhythm disturbances. This is similar to the setting of electrical energy delivery, where pro- and antiarrhythmic responses can be induced. The type of response depends on the stimulus and conditioning parameters, as discussed below.

Systems-level experimental models of mechanical induction of arrhythmias.  The mechanical induction of heart rhythm disturbances (including sudden cardiac death) that occur in the absence of structural damage to the chest and its organs has been termed Commotio cordis (CC; for history and definition see Nesbitt et al. 2001).

First descriptions of CC can be traced in the European medical literature to the late 19th century (Nélaton, 1876; Meola, 1879). In the early 20th century, CC has been successfully modelled in extensive experiments on over 800 anaesthetized mammals (Schlomka, 1934). Key insights from this research included the following: (i) impact severity and location affect the type of heart rhythm disturbance caused; (ii) electrophysiological responses to mechanical stimulation require direct impulse transmission from the chest to the heart; and (iii) the mechanisms that give rise to mechanical induction of arrhythmias are intracardiac in nature (as confirmed by autonomic denervation). The last observation, together with frequently observed ST segment elevation, changed the then prevailing explanation of CC as an expression of a ‘pronounced vagal reflex’ (Nélaton, 1876) to the ‘vascular crisis concept’, where mechanically induced coronary vasospasms were thought to mediate cardiac electrophysiological responses (Schlomka, 1934).

In the late 20th century, this concept was shown to be flawed, aided significantly by technological improvements in whole-animal experimentation. Crucial developments included more precise control over impact mechanical characteristics and timing, and the ability to assess coronary circulation non-invasively in a near-acute setting. Using coronary angiography, it was shown that there is no visible change in coronary perfusion shortly after arrhythmogenic precordial impacts in an anaesthetized pig model (thereby invalidating the vascular crisis concept). Furthermore, it was revealed that the type of arrhythmia caused is strongly affected by impact timing relative to the cardiac cycle (Fig. 2). The most severe outcome, ventricular fibrillation (VF), occurred only upon impacts delivered during a 15 ms time window prior to the peak of the ECG T wave, when mechanical induction of VF is instantaneous (Fig. 3; Link et al. 1998).

View larger version (21K): [in this window] [in a new window]   Figure 2.  Schematic representation of the timing-dependent character of precordial impact effects on heart rhythm Labels above the ECG outline number and timing of impacts; markers below denote number and type of rhythm disturbances caused. CHB, complete heart block; ST, ST segment elevation; LBBB, left bundle branch block; VF, ventricular fibrillation; and NSVT, non-sustained ventricular tachycardia. Reproduced with permission from Maron et al. (1999).

View larger version (12K): [in this window] [in a new window]   Figure 3.  ECG (lead I, top) and left ventricular pressure (LVP, bottom), obtained from an anaesthetized pig, subjected to a precordial impact that coincided with the first half of the T wave Note the swiftness of mechanical induction of VF, witnessed by the loss of LVP (within one cardiac cycle). Reproduced with permission from Link et al. (1998).

Indeed, whole-animal experiments have shown that pharmacological block of the mechanosensitive i_KATP by glibenclamide prevented VF upon impacts delivered during a very narrow time window just before the peak of the ECG T wave (Link et al. 1999). In these experiments, T wave timed impacts still triggered premature ventricular contractions in all animals (Link et al. 1999), so that glibenclamide also uncovered an excitatory response that may act as the trigger for VF induction, and which would normally be hidden by the instantaneous onset of VF. In contrast, application of streptomycin in an attempt to block SAC_NS (Gannier et al. 1994) did have no effect on the mechanical inducibility of arrhythmias in this animal model (Garan et al. 2005).

Thus, the available systems-level data would suggest that activation of SAC_K may be arrhythmogenic in the context of CC, while that of SAC_NS might not. This is somewhat counter-intuitive, if one assumes that the instantaneous induction of VF upon T wave timed impact (see Fig. 3) requires a critical combination of both a trigger and an arrhythmia-sustaining substrate. Mechanical activation of potassium-selective channels may very well underlie arrhythmia sustenance (by changing electrical excitability, refractoriness and load), but it cannot reasonably explain the excitatory response triggered by the impact. The latter would be compatible with the effects of cation-non-selective channels, and this riddle will be revisited below in the context of lower-level insight.

Systems-level experimental models of mechanical termination of arrhythmias.  Precordial thumps (PT) have been part of documented European clinical practice for nearly a century (Schott, 1920), and they are still used for emergency resuscitation of victims of witnessed cardiac arrest (Caldwell et al. 1985; Kohp, et al. 2005). Initially described as an intervention to pace asystolic hearts, PT was subsequently applied to revert ventricular tachycardia (VT) and VF (Lown & Taylor, 1970; Befeler, 1978). Both fist-pacing (of bradycardiac hearts) and PT (for monitored cardiac arrest) are interventions recommended in the latest guidelines of the International Liaison Committee on Resuscitation (2005).

Precordial thumps have been modelled in a number of whole-animal experiments on anaesthetized dogs and pigs, with success rates ranging from 0% in an asphyxiated dog model (Yakaitis & Redding, 1973) to 95% in a postinfarction pig model (Gertsch et al. 1989). Unfortunately, none of these investigations provided detailed quantification of impact mechanics. Information from research on human volunteers, obtained using a modified industrial stapling gun, established that premature ventricular beats can be triggered by diastolic impacts with a total kinetic energy of just 0.04–1.5 J (Zoll et al. 1976). Interestingly, even at 10 times the threshold energy (which is still 1–2 orders of magnitude below the energy levels associated with CC in the adult), no negative side-effects on heart rhythm are caused in the anaesthetized dog, even if impacts are applied during the vulnerable window (Zoll et al. 1976). This is important for PT safety considerations (Kohl et al. 2005a).

Interestingly, the worst PT outcome (0% success rate) has been observed in settings where particularly severe hypoxia will have occurred (asphyxiation model; Yakaitis & Redding, 1973). It is plausible that in this setting, i_KATP may have been preactivated by the prevailing myocardial ischaemia, reducing PT efficacy. Thus, i_KATP activation would again (as in CC) be potentially pro-arrhythmic in the context of mechanical stimulation; a hypothesis that will be revisited in detail below.

Lower-level experimental models of cardiac mechanosensitivity.  Cardiac MEF can regularly be observed as a side-effect of handling Langendorff-perfused isolated hearts, which often stop or restart rhythmic contractions upon touch. This has been more systematically investigated in rabbit isolated heart, using a left ventricular balloon to manipulate cardiac volume acutely (Franz et al. 1992). Balloon inflations caused volume-dependent depolarizations of the resting ventricle which, once suprathreshold (at about 500 µl), triggered regular ventricular beats.

Data on mechanical induction or termination of sustained arrhythmias in isolated heart are, as yet, relatively rare. It has been shown, for example, that atrial fibrillation (induced by burst-pacing) occurs more readily during pressure overload, and that this link between cardiac chamber stretch and arrhythmogenesis can be removed via SAC block by GsMTx-4 (Bode et al. 2001). Mechanical termination of arrhythmias has been demonstrated in a study using finger-flicks to cardiovert postischaemic VT or VF. Mechanical and electrical cardioversion were equally efficient in this model, but mechanical interventions were not quantified in terms of timing or intensity, and they regularly caused additional cell damage (Kawakami et al. 1999), highlighting the need to control impact characteristics better.

More recently, an impactor has been developed that can be used to subject isolated hearts and/or tissue fragments to controlled and localized mechanical stimulation. This soft tissue impact characterization kit offers independent control over impact timing and energy, projectile mass and speed, as well as impact surface and location (Cooper et al. 2006). It also provides accurate information on mechanical probe deceleration parameters, which is crucial for quantitative characterization of probe–tissue interactions. The impactor has already been used to introduce mechanically short runs of VF in isolated guinea-pig hearts (Fig. 4), and it provides a complementary, more economical study design (compared to whole-animal experiments), in particular in as far as pharmacological interventions are concerned.

View larger version (12K): [in this window] [in a new window]   Figure 4.  ECG from a Langendorff-perfused guinea-pig heart, illustrating the electrophysiological response to controlled left ventricular mechanical impact during the T wave The stimulus (arrow) causes a short run of ventricular fibrillation (VF), preceded and followed by normal sinus rhythm (NSR). Reproduced with permission from Cooper et al. (2006).

At the cellular level, and under near-physiological conditions, effects of mechanical stimulation have been studied using a wide variety of tools and techniques (see Introduction). Mechanical effects on cell electrophysiology are generally characterized by: (i) diastolic depolarization (Franz et al. 1992), which may trigger AP (Craelius, 1993) or affect pacemaker beating rate (Cooper et al. 2000); and (ii) changes in AP shape/duration. The latter include AP plateau reduction (Hu & Sachs, 1997) and AP shortening (White et al. 1993), although AP lengthening (Zeng et al. 2000) and cross-over of the repolarization curve have also been reported (Zabel et al. 1993). Given that depolarizing effects dominate under control conditions at negative membrane potentials, stretch can also give rise to early and delayed after-depolarization-like events (Levine et al. 1988; Kohl et al. 2001). All of these physiological effects of mechanical stimulation are compatible with, and possibly dominated by, activation of SAC_NS.

The situation may be different in ischaemic myocardium. In patch-clamp investigations of rat atrial myocytes, i_KATP has been found to be mechanosensitive (van Wagoner, 1993). This mechanosensitivity is potentiated by ischaemia (van Wagoner & Lamorgese, 1994). Vice versa, the ATP dependence of i_KATP may be modulated by the mechanical environment. This would be in keeping with the observation that prevention of paradoxical segment lengthening of ischaemic myocardium, avoided using a mechanical restraining device, delays extracellular potassium accumulation in the ischaemic pig ventricle (Lab, 2005). To validate the possible link between tissue distension and i_KATP activation, experiments involving axial stretch of ventricular cardiomyocytes are required. A number of experimental techniques, such as the carbon fibre method (Le Guennec et al. 1990), allow one to control both length and tension of individual isolated cells. Combining this technique with simulated ischaemia (via uncoupling of oxidative phosphorylation using carbonyl cyanide p-trifluoromethoxyphenylhydrazone; FCCP) has confirmed that axial stretch of guinea-pig ventricular cardiomyocytes amplifies i_KATP (Fig. 5).

View larger version (19K): [in this window] [in a new window]   Figure 5.  Amplication of iKATP by axial stretch of ventricular cardiomyocytes A, metabolic uncoupling of resting guinea-pig ventricular myocytes by FCCP (1 µM) causes a significant increase in whole-cell current, carried by iKATP, from < 0.5 to > 5 nA (compare a and b). Axial stretch (by 8–9% of sarcomere length; SL) increases iKATP by 20–25% (see c), which is fully reversible (d; n = 5). B, left panel, voltage-clamp protocol of depolarizing steps from –80 mV to values between –40 and +40 mV; and right panel, sample currents during voltage steps from –80 to +40 mV, recorded during phases a–d; each point in A represents the current amplitude recorded during one such voltage step. All recordings at 37°C.

Theoretical models for reintegration of cardiac MSC findings

Cell-level theoretical models of cardiac mechanosensitivity.  All principal experimentally observed cellular expressions of cardiac MEF have been reproduced using theoretical models (Sachs, 1994; Kohl et al. 1998; Kohl & Sachs, 2001). It appears to be sufficient to account for the electrical current passing through SAC, rather than the ion movements, to reproduce experimentally observed acute changes in cellular electrophysiology (Kohl et al. 1998). Cellular representations of cardiac mechano-electrical interactions are continuously being developed and updated, to account in addition for more recent insight into SAC function and mechanical modulation of non-SAC currents (Healy & McCulloch, 2005) and other stretch-sensitive cellular processes (Markhasin et al. 2003).

Despite treating SAC essentially as a ‘black box’ in terms of mechanisms of activation and functional states, single-cell models have been successfully applied to theoretical experimentation (Riemer & Tung, 2003), data interpretation (Cooper et al. 2000) and design of further wet experimental research (Lei & Kohl, 1998), as reviewed in detail elsewhere (Kohl & Sachs, 2001).

Higher level theoretical models of mechanical induction of arrhythmias.  Projecting from cellular AP behaviour to the ECG (the clinically most-relevant form of cardiac electrophysiology monitoring) has been attempted both qualitatively and quantitatively.

Figure 6 illustrates an example of qualitative projection from cell- to organ-level electrophysiology, here in the context of arrhythmia induction by a mechanical stimulus during the critical window of the cardiac cycle (grey band in Fig. 6). During the T wave, cells in different regions of the ventricle show variable degrees of repolarization (see Fig. 6A–C). A mechanical stimulus, applied during the critical window, will therefore affect some cells while their transmembrane potential is still near AP plateau levels, while others will be partly or fully repolarized. In this setting, the pre-existing physiological gradient in cardiac electrical properties will be overlaid with a non-homogeneous mechanically induced gradient of variable response patterns. Cells, affected by stretch during AP plateau, will change the time course of repolarization (Fig. 6A), which may furnish an arrhythmia-sustaining substrate. Cells that, at the time of impact, have repolarized further may give rise to ectopic foci of excitation and so provide a trigger for arrhythmogenesis (Fig. 6B and C). The illustrated changes in AP plateau and duration may be caused via activation of either/both SAC_NS and SAC_K. The triggering of extra beats requires a net shift in the transmembrane current towards depolarization. This may be achieved either via a reduction of repolarizing currents or via additional activation of depolarizing currents, for which SAC_NS form a plausible substrate.

View larger version (30K): [in this window] [in a new window]   Figure 6.  Schematic representation of the potential arrhythmogenic effects of mechanical stimulation, acting on mechanosensitive channels, during a critical time window in early ventricular repolarization (upstroke of the T wave; see schematic ECG trace) Effects on action potential shape depend on the transmembrane potential of individual cardiomyocytes in different regions of the heart. Action potentials in A–C indicate the simplified view that cells that are activated first (A) repolarize last, and vice versa (C). For detail see text. Reproduced with permission from Kohl et al. (2001).

View larger version (24K): [in this window] [in a new window]   Figure 7.  Two-dimensional model of a ventricular tissue slice, subjected to external mechanical stimulation just before repolarization has progressed halfway from epicardium to endocardium Impact effects on electrophysiology are modelled via stretch-activation of cation-non-selective (SACNS) and potassium-selective channels (SACK) in the region outlined by the white curve (see text for detail). A, regional activation of SACNS (conductance 35 nS; reversal potential –10 mV). B, regional activation of SACK (35 nS, –95 mV). Endo, endocardium; and Epi, Epicardium. Transmembrane potential is colour coded; see scale bar at left. Reproduced from Garny & Kohl (2004) with permission from Annals of the New York Academy of Sciences, USA (2004).

View larger version (89K): [in this window] [in a new window]   Figure 8.  Effect of mechanical stimulation of the epicardial ventricular free wall at different time points during repolarization in a 2-D ventricular tissue model A, mechanically induced sustained re-entry, following SACNS activation at 40% repolarization. B, lack of arrhythmogenic effect of early impacts (< 10% repolarization). C, late impact (60% repolarization) likewise does not cause re-entry, but yields a single ectopic beat. Reproduced with permission from Garny & Kohl (2004).

These discrepancies illustrate how wet and dry experimentation may inform and stimulate each other, to aid the design of new investigations and to further insight. For example, 2-D modelling findings would ideally be matched to 2-D experimental investigations, perhaps using structured cell cultures grown on elastic membranes for control of the mechanical environment (Camelliti et al. 2005). Furthermore, the antiarrhythmic action of SAC_K block, experimentally established in whole animals, should be elucidated in more detail using a combination of wet and dry studies at lower levels of integration. Possible explanations for the efficient arrhythmia prevention by SAC_K block include the removal of a required arrhythmia-sustaining mechanism (perhaps a reduction in mechanically induced AP shortening in the presence of SAC_K blockers) or a drug-induced shift of the critical time window for mechanical VF induction (perhaps outside the timings identified before application of blockers). In addition, SAC_NS block by GsMTx-4 has been found to have pronounced antiarrhythmic effects, for example in atrial tissue (Bode et al. 2001) and cell cultures (Itabashia et al. 2005), and it will be interesting to assess the effects of this blocker in the context of CC, modelled experimentally in the isolated heart or in vivo.

Higher level theoretical models of mechanical termination of arrhythmias.  The mechanism underlying mechanical termination of arrhythmias, proposed in the 1970s, involves obliteration of the excitable gap by mechanically induced depolarization and/or ectopic excitation (Befeler, 1978; Bierfeld et al. 1979; Wirtzfeld et al. 1979). This can be simulated in multicellular models of cardiac tissue via activation of SAC_NS (Fig. 9A and B). Brief opening of SAC_NS (here for 5 ms) causes diastolic depolarization of tissue that has regained excitability. If large enough, this depolarization will eradicate the excitable gap (Fig. 9B, dotted arrows in frame B1), or even trigger ectopic foci of excitation (Fig. 9B, continuous arrows in frame B2), leading to annihilation of the re-entrant wave and successful cardioversion.

View larger version (88K): [in this window] [in a new window]   Figure 9.  Reduction of PT efficacy in ischaemic heart in a 2-D model of ventricular tissue A, control re-entrant behaviour before application of PT. B, termination of re-entry by PT, simulated via brief (5 ms) SACNS activation. This causes depolarization of tissue in the excitable gaps (dotted arrows in frame B1), potentially giving rise to foci of excitation (continuous arrows in frame B2) that collide with the re-entrant wave and instantaneously terminate the arrhythmia (frame B4). C, PT after simulated ischaemic sensitization of SACK to mechanical stimulation, which shifts the net mechanically induced reversal potential from –10 to –35 mV. This reduces depolarization of resting tissue and prevents development of ectopic foci (see arrows in frames C1 and C2) and shortens action potential duration, thereby enlarging the excitable gap (dotted vertical lines from frame A2 to C2). All of these changes favour continued re-entry and render PT potentially less efficient.

These modelling-derived suggestions may be of interest for PT safety considerations. Given that PT impact energies in man do not usually exceed 4–8 J (Kohl et al. 2005a), and taking into account that precordial mechanical stimuli at these energies do not trigger repetitive responses (such as VT and VF) in large mammals, even if applied during the vulnerable window (Zoll et al. 1976), it is conceivable that the energy of a precordial impact must first exceed a certain threshold (probably significantly higher than 10 J in healthy adult humans) before impact timing relative to the cardiac cycle becomes the decisive factor in determining outcome. In severely hypoxic hearts, however, the threshold demarcating ‘safe’ precordial impact may be shifted towards lower energy levels or be absent altogether (Fig. 10), possibly as a consequence of additional recruitment of SAC_K.

View larger version (13K): [in this window] [in a new window]   Figure 10.  Potential ischaemia-induced changes in the energy dependence of precordial impact effects on heart rhythm Pale blue represents lack of effect of precordial mechanical stimulation on heart rhythm. Green represents expected therapeutic range of precordial thumps. Red represents potential mechanical induction of arrhythmia, if ill timed. Panels symbolizing therapeutic precordial thump (far left) and arrhythmogenic Commotio cordis (far right, showing precordial impact sites that caused lethal heart rhythm disturbances upon) are reproduced with permission from Gordon (1973) and Maron et al. (1999), respectively.

As before, the given example illustrates how iteration between experimental and theoretical modelling may advance conceptual development and clinically relevant insight into complex biological systems, such as coupled cardiac electromechanics.

Future directions

This review provides a focused (and thus necessarily incomplete) overview of some recent advances in the development of experimental and theoretical model systems for the study of the pathophysiological relevance of cardiac MSC for acute responses of the heart to mechanical stimulation. The field is of course much wider and more complex. For example, we still know little about the actual mechanisms of MSC activation which, in addition to membrane forces (Gullingsrud & Schulten, 2004) or membrane–cytoskeleton interactions (Suchyna & Sachs, 2005), may involve spatial rearrangements such as membrane unfolding (Kohl et al. 2003) or be linked to the T-tubular system or z-line behaviour (Knöll et al. 2002). At least some of these possibilities could be addressed if the channel structures for mammalian cardiac MSC were known, such as it is the case for the cloned bacterial MSC (Chiang et al. 2005). In addition, sarcolemmal MSC that link the cell interior to the extracellular space are probably complemented by MSC in cellular organelles. Furthermore, connexin semi-channels (at least in the case of connexin46) have been shown to be mechanosensitive (Bao et al. 2004). If the same holds true for cardiac connexin channels, in particular after assembly into functional intercellular conduction pathways, it would add another level of complexity to MEF effects, in addition to cardiomyocyte responses or those caused by their interaction with mechanosensitive non-myocytes (Camelliti et al. 2003). Also, more emphasis should be placed on identifying regional differences in MSC distribution and function by combining modelling (Stevens & Hunter, 2003) and experimental research (Cazorla et al. 2000). As far as single-cell studies are concerned, cells would ideally be held in a mechanical environment that is more similar to the in situ setting than is achieved by either leaving them mechanically unchallenged or subjecting them to static loads only. Multicellular experimental models are increasingly capable of addressing cardiac structural and functional heterogeneities and their effect on MEF (Markhasin et al. 2003; Protsenko et al. 2005). In terms of clinical relevance, a fair body of evidence points towards antiarrhythmic effects of MSC block, in vitro (Itabashia et al. 2005), in situ (Bode et al. 2001) and in vivo (Yeung et al. 2005). Combining wet and dry model applications can aid data interpretation, hypothesis formation and the design of further research, potentially linking an understanding of passive and active tissue mechanics, fluidics and tissue architecture to the regulation of electrophysiology in the heterologous, interacting cell populations of normal and diseased heart.

	References

Top Abstract Introduction References

 
Bao L, Sachs F & Dahl G (2004). Connexins are mechanosensitive. Am J Physiol Cell Physiol 287, C1389–C1395.[Abstract/Free Full Text]

Baumgarten CM (2005). Cell volume-sensitive ion channels and transporters in cardiac myocytes. In Cardiac Mechano-Electric Feedback and Arrhythmias: from Pipette to Patient, ed. Kohl P, Sachs F & Franz MR, pp. 21–32. Elsevier (Saunders), Philadelphia.

Baumgarten CM & Clemo HF (2003). Swelling-activated chloride channels in cardiac physiology and pathophysiology. Prog Biophys Mol Biol 82, 25–42.[CrossRef][Medline]

Befeler B (1978). Mechanical stimulation of the heart: its therapeutic value in tachyarrhythmias. Chest 73, 832–838.[CrossRef][Medline]

Belus A & White E (2002). Effects of streptomycin sulphate on I_CaL, I_Kr and I_Ks in guinea-pig ventricular myocytes. Eur J Pharmacol 445, 171–178.[CrossRef][Medline]

Bierfeld JL, Rodriguez-Viera V, Aranda JM, Castellanos ACJ, Lazzara R & Befeler B (1979). Terminating ventricular fibrillation by chest thump. Angiology 30, 703–707.[Medline]

Bode F, Sachs F & Franz MR (2001). Tarantula peptide inhibits atrial fibrillation. Nature 409, 35–36.[CrossRef][Medline]

Browe DM & Baumgarten CM (2004). Angiotensin II (AT1) receptors and NADPH oxidase regulate Cl^– current elicited by ß1 integrin stretch in rabbit ventricular myocytes. J Gen Physiol 124, 273–287.[Abstract/Free Full Text]

Bryant SM, Shipsey SJ & Hart G (1997). Regional differences in electrical and mechanical properties of myocytes from guinea-pig hearts with mild left ventricular hypertrophy. Cardiovasc Res 35, 315–323.[Abstract/Free Full Text]

Calaghan SC, Belus A & White E (2003). Do stretch-induced changes in intracellular calcium modify the electrical activity of cardiac muscle? Prog Biophys Mol Biol 82, 81–95.[CrossRef][Medline]

Caldwell RA, Clemo HF & Baumgarten CM (1998). Using gadolinium to identify stretch-activated channels: technical considerations. Am J Physiol 275, C619–C621.[Medline]

Caldwell G, Millar G, Quinn E, Vincent R & Chamberlain DA (1985). Simple mechanical methods for cardioversion: defence of the precordial thump and cough version. Br Med J 291, 627–630.[Medline]

Camelliti P, Kohl P & Green C (2003). Functional coupling of fibroblasts in rabbit sino-atrial node. Biophys J 84, 406–407A.

Camelliti P, McCulloch AD & Kohl P (2005). Microstructured co-cultures of cardic myocytes and fibroblasts: a two-dimensional in vitro model of cardiac tissue. Microsc Microanal 11, 249–259.[Medline]

Cazorla O, Le Guennec J-Y & White E (2000). Length-tension relationships of sub-epicardial and sub-endocardial single ventricular myocytes from rat and ferret hearts. J Mol Cell Cardiol 32, 735–744.[CrossRef][Medline]

Chiang CS, Shirinian L & Sukharev S (2005). Capping transmembrane helices of MscL with aromatic residues changes channel response to membrane stretch. Biochemistry 44, 12589–12597.[CrossRef][Medline]

Cooper PJ, Epstein A, Macleod IA, Schaaf ST, Sheldon J et al. (2006). Soft tissue impact characterisation kit (STICK) for ex situ investigation of heart rhythm responses to acute mechanical stimulation. Prog Biophys Mol Biol 90, 444–468.[CrossRef][Medline]

Cooper PJ & Kohl P (2005). Species- and preparation-dependence of stretch effects on sino-atrial node pacemaking. Annals of the New York Academy of Sciences 1047, 324–335.[Abstract/Free Full Text]

Cooper PJ, Lei M, Cheng L-X & Kohl P (2000). Axial stretch increases spontaneous pacemaker activity in rabbit isolated sinoatrial node cells. J Appl Physiol 89, 2099–2104.[Abstract/Free Full Text]

Craelius W (1993). Stretch-activation of rat cardiac myocytes. Exp Physiol 78, 411–423.[Abstract]

Craelius W, Chen V & el-Sherif N (1988). Stretch activated ion channels in ventricular myocytes. Biosci Rep 8, 407–414.[CrossRef][Medline]

Deck KA (1964). Effects of stretch on the spontaneously beating, isolated sinus node [in German]. Pflügers Arch Gesamte Physiol Menschen Tiere 280, 120–130.[CrossRef][Medline]

de Jonge HW, Dekkers DH, Tilly BC & Lamers JM (2002). Cyclic stretch and endothelin-1 mediated activation of chloride channels in cultured neonatal rat ventricular myocytes. Clin Sci (Lond) 103, 148S–151S.[Medline]

Franz MR, Burkhoff D, Yue DT & Sagawa K (1989). Mechanically induced action potential changes and arrhythmia in isolated and in situ canine hearts. Cardiovasc Res 23, 213–223.[Medline]

Franz MR, Cima R, Wang D, Profitt D & Kurz R (1992). Electrophysiological effects of myocardial stretch and mechanical determinants of stretch-activated arrhythmias. Circulation 86, 968–978.[Abstract/Free Full Text]

Gannier F, White E, Lacampagne A, Garnier D & Le Guennec JY (1994). Streptomycin reverses a large stretch induced increases in [Ca²⁺]_i in isolated guinea pig ventricular myocytes. Cardiovasc Res 28, 1193–1198.[Abstract/Free Full Text]

Garan AR, Maron BJ, Wang PJ, Estes NME III & Link MS (2005). Role of streptomycin-sensitive stretch-activated channel in chest wall impact induced sudden death (commotio cordis). J Cardiovasc Electrophysiol 16, 433–438.[Medline]

Garny A & Kohl P (2004). Mechanical induction of arrhythmias during ventricular repolarisation: modeling cellular mechanisms and their interaction in two dimensions. Ann N Y Acad Sci 1015, 133–143.[Abstract/Free Full Text]

Garny A, Noble D & Kohl P (2005). Dimensionality in cardiac modelling. Prog Biophys Mol Biol 87, 47–66.[CrossRef][Medline]

Gertsch M, Hottinger S, Mettler D, Leupi F & Gurtner HP (1989). Conversion of induced ventricular tachycardia by single and serial chest thumps: a study in domestic pigs 1 week after experimental myocardial infaction. Am Heart J 118, 248–255.[CrossRef][Medline]

Glogauer M, Ferrier J & McCulloch CAG (1995). Magnetic fields applied to collagen-coated ferric oxide beads induce stretch-activated Ca²⁺ flux in fibroblasts. Am J Physiol 38, C1093–C1104.

Gordon AS (1973). Standards for cardiopulmonary resuscitation and emergency cardiac care. In National Conference on Cardiopulmonary Resuscitation and Emergency Cardiac Care, p. 95. Amercian Heart Association and National Academy of Sciences, Washington.

Guharay F & Sachs F (1984). Stretch-activated single ion channel currents in tissue-cultured embryonic chick skeletal muscle. J Physiol 352, 685–701.[Abstract/Free Full Text]

Gullingsrud J & Schulten K (2004). Lipid bilayer pressure profiles and mechanosensitive channel gating. Biophys J 86, 3496–3509.[CrossRef][Medline]

Healy SN & McCulloch AD (2005). An ionic model of stretch-activated and stretch-modulated currents in rabbit ventricular myocytes. Europace 7, S128–S134.

Hearse DJ & Sutherland FJ (2000). Experimental models for the study of cardiovascular function and disease. Pharmacol Res 41, 597–603.[CrossRef][Medline]

Hu H & Sachs F (1997). Stretch-activated ion channels in the heart. J Mol Cell Cardiol 29, 1511–1523.[CrossRef][Medline]

International Liaison Committee on Resuscitation I (2005). Consensus conference on cardiopulmonary resuscitation and emergency cardiovascular care science with treatment recommendations. Circulation 112, III/1–III/54.

Isenberg G, Kazanski V, Kondratev D, Gallitelli MF, Kiseleva I & Kamkin A (2003). Differential effects of stretch and compression on membrane currents and [Na⁺]_c in ventricular myocytes. Prog Biophys Mol Biol 82, 43–56.[CrossRef][Medline]

Itabashi Y, Miyoshi S, Yuasa S, Fujita J, Shimizu T, Okano T et al. (2005). Analysis of the electrophysiological properties and arrhythmias in directly contacted skeletal and cardiac muscle cell sheets. Cardiovasc Res 67, 561–570.[Abstract/Free Full Text]

Kaufmann R & Theophile U (1967). Autonomously promoted extension effect in Purkinje fibers, papillary muscles and trabeculae carneae of rhesus monkeys [in German]. Pflügers Arch Gesamte Physiol Menschen Tiere 297, 174–189.[CrossRef][Medline]

Kawakami T, Löwbeer C, Valen G & Vaage J (1999). Mechanical conversion of post-ischaemic ventricular fibrillation: effects on function and myocyte injury in isolated rat hearts. Scand J Clin Lab Invest 59, 9–16.[Medline]

Kim D (1992). A mechanosensitive K⁺ channel in heart cells. Activation by arachidonic acid. J Gen Physiol 100, 1021–1040.[Abstract/Free Full Text]

Knöll R, Hoshijima M, Hoffman HM, Person V, Lorenzen-Schmidt I, Bang ML et al. (2002). The cardiac mechanical stretch sensor machinery involves a Z disc complex that is defective in a subset of human dilated cardiomyopathy. Cell 111, 943–955.[CrossRef][Medline]

Kohl P, Cooper PJ & Holloway H (2003). Effects of acute ventricular volume manipulation on in situ cardiomyocyte cell membrane configuration. Prog Biophys Mol Biol 82, 221–227.[CrossRef][Medline]

Kohl P, Day K & Noble D (1998). Cellular mechanisms of cardiac mechano-electric feedback in a mathematical model. Can J Cardiol 14, 111–119.[Medline]

Kohl P, Hunter P & Noble D (1999). Stretch-induced changes in heart rate and rhythm: clinical observations, experiments and mathematical models. Prog Biophys Mol Biol 71, 91–138.[CrossRef][Medline]

Kohl P, King AM & Boulin C (2005a). Antiarrhythmic effects of acute mechanical stimulation. In Cardiac Mechano-Electric Feedback and Arrhythmias: from Pipette to Patient, ed. Kohl P, Sachs F & Franz MR, pp. 304–314. Elsevier (Saunders), Philadelphia.

Kohl P, Nesbitt AD, Cooper PJ & Lei M (2001). Sudden cardiac death by Commotio cordis: role of mechano-electric feedback. Cardiovasc Res 50, 280–289.[Abstract/Free Full Text]

Kohl P & Sachs F (2001). Mechanoelectric feedback in cardiac cells. Philosoph Trans Royal Soc Lond Series A Mathemat Phys Eng Sci 359, 1173–1185.[CrossRef]

Kohl P, Sachs F & Franz MR (eds) (2005b). Cardiac Mechano-Electric Feedback and Arrhythmias: from Pipette to Patient. Elsevier (Saunders), Philadelphia.

Kong CR, Bursac N & Tung L (2005). Mechanoelectrical excitation by fluid jets in monolayers of cultured cardiac myocytes. J Appl Physiol 98, 2328–2336; discussion 2320.[Abstract/Free Full Text]

Lab MJ (2005). Regional stretch effects in pathological myocardium. In Cardiac Mechano-Electric Feedback and Arrhythmias: from Pipette to Patient, ed. Kohl P, Sachs F & Franz MR, pp. 108–118. Elsevier (Saunders), Philadelphia.

Lab MJ & Woollard KV (1978). Monophasic action potentials, electrocardiograms and mechanical performance in normal and ischaemic epicardial segments of the pig ventricle in situ. Cardiovasc Res 12, 555–565.[Medline]

Le Guennec JY, Peineau N, Argibay JA, Mongo KG & Garnier D (1990). A new method of attachment of isolated mammalian ventricular myocytes for tension recording: length dependence of passive and active tension. J Mol Cell Cardiol 22, 1083–1093.[CrossRef][Medline]

Lei M & Kohl P (1998). Swelling-induced decrease in spontaneous pacemaker activity of rabbit isolated sino-atrial node cells. Acta Physiol Scand 164, 1–12.[CrossRef][Medline]

Levine JH, Guarnieri T, Kadish AH, White RI, Calkins H & Kan JS (1988). Changes in myocardial repolarisation in patients undergoing balloon valvuloplasty for congenital pulmonary stenosis: evidence for contraction-excitation feedback in humans. Circulation 77, 70–77.[Abstract/Free Full Text]

Li W, Kohl P & Trayanova N (2004). Induction of ventricular arrhythmias following a mechanical impact: a simulation study in 3D. J Mol Histol 35, 679–686.[CrossRef][Medline]

Li W, Kohl P & Trayanova N (2006). Myocardial ischemia lowers precordial thump efficacy: an inquiry into mechanisms using 3D simulations. Heart Rhythm 3, 179–186.[CrossRef][Medline]

Link MS, Wang PJ, Pandian NG, Bharati S, Udelson JE, Lee M-Y et al. (1998). An experimental model of sudden cardiac death due to low-energy chest-wall impact (Commotio cordis). N Engl J Med 338, 1805–1811.[Abstract/Free Full Text]

Link MS, Wang PJ, VanderBrink BA, Avelar E, Pandian NG et al. (1999). Selective activation of the K⁺_ATP channel is a mechanism by which sudden death is produced by low-energy chest-wall impact (commotio cordis). Circulation 100, 413–418.[Abstract/Free Full Text]

Lown B & Taylor J (1970). Thump-version. N Engl J Med 283, 1223–1224.[Medline]

Markhasin VS, Solovyova O, Katsnelson LB, Protsenko Y, Kohl P & Noble D (2003). Mechano-electric interactions in heterogeneous myocardium: development of fundamental experimental and theoretical models. Prog Biophys Mol Biol 82, 207–220.[CrossRef][Medline]

Maron BJ, Link MS, Wang PJ & Estes NAM III (1999). Clinical profile of Commotio cordis: An under appreciated cause of sudden death in the young during sports and other activities. J Cardiovasc Electrophysiol 10, 114–120.[Medline]

Meola F (1879). La commozione toracica. Giornale Internazionale Delle Scienze Mediche 1, 923–937.

Morris CE & Laitko U (2005). The mechanosensitivity of voltage-gated channels may contribute to cardiac mechano-electric feedback. In Cardiac Mechano-Electric Feedback and Arrhythmias: from Pipette to Patient, ed. Kohl P, Sachs F & Franz MR, pp. 33–41. Elsevier (Saunders), Philadelphia.

Natali A, Wilson L, Peckham M, Turner D, Harrison S & White E (2002). Different regional effects of voluntary exercise on the mechanical and electrical properties of rat ventricular myocytes. J Physiol 541, 863–875.[Abstract/Free Full Text]

Nélaton A (1876). Elements de Pathologie Chirurgicale, vol. 4. Librairie Germer Bateliere et Co., Paris.

Nesbitt AD, Cooper PJ & Kohl P (2001). Rediscovering commotio cordis. Lancet 357, 1195–1197.[CrossRef][Medline]

Pascarel C, Hongo K, Cazorla O, White E & Le Guennec JY (1998). Different effects of gadolinium on I_KR, I_KS and I_K1 in guinea-pig isolated ventricular myocytes. Br J Pharmacol 124, 356–360.[CrossRef][Medline]

Protsenko YL, Routkevitch SM, Guriev VY, Katsnelson LB, Solovyova O, Lookin ON et al. (2005). Hybrid duplex – a novel method to study the contractile function of heterogeneous myocardium. Am J Physiol Heart Circ Physiol 289, 2733–2746.

Riemer TL & Tung L (2003). Stretch-induced excitation and action potential changes of single cardiac cells. Prog Biophys Mol Biol 82, 97–110.[CrossRef][Medline]

Sachs F (1994). Modeling mechanical-electrical transduction in the heart. In Cell Mechanics and Cellular Engineering, ed. Mow V, Guliac F, Tran-Son-Tray R & Hochmuth R, pp. 308–328. Springer Verlag, New York.

Sachs F (2004). Mechanoelectric Transduction. In Cardiac Electrophysiology: from Cell to Bedside, 4th edn, eds. Zipes DP & Jalife J, pp. 96–102.

Sachs F (2005). Stretch-activated channels in the heart. In Cardiac Mechano-Electric Feedback and Arrhythmias: from Pipette to Patient, ed. Kohl P, Sachs F & Franz MR, pp. 2–10. Elsevier (Saunders), Philadelphia.

Schlomka G (1934). Commotio cordis und ihre Folgen. Die Einwirkung stumpfer Brustwandtraumen auf das Herz. Ergebnisse Inneren Med Kinderheilkunde 47, 1–91.

Schott E (1920). Über Ventrikelstillstand (Adams-Stokes'sche Anfälle) nebst Bemerkungen über andersartige Arhythmien passagerer Natur. Deutsches Arch Klinische Med 131, 211–229.

Sorota S & Du X-Y (1998). Delayed activation of cardiac swelling-induced chloride current after step changes in cell size. J Cardiovasc Electrophysiol 9, 825–831.[Medline]

Stevens C & Hunter P (2003). Sarcomere length changes in a model of the pig heart. Prog Biophys Mol Biol 82, 229–241.[CrossRef][Medline]

Suchyna TM & Sachs F (2005). Membrane–cytoskeleton interface and mechanosensitive channels. In Cardiac Mechano-Electric Feedback and Arrhythmias: from Pipette to Patient, ed. Kohl P, Sachs F & Franz MR, pp. 42–52. Elsevier (Saunders), Philadelphia.

Taggart P (1996). Mechano-electric feedback in the human heart. Cardiovasc Res 32, 38–43.[Medline]

Tung L & Zou S (1995). Influence of stretch on excitation threshold of single frog ventricular cells. Exp Physiol 80, 221–235.[Abstract]

van Wagoner DR (1993). Mechanosensitive gating of atrial ATP-sensitive potassium channels. Circ Res 72, 973–983.[Abstract/Free Full Text]

van Wagoner DR & Lamorgese M (1994). Ischemia potentiates the mechanosensitive modulation of atrial ATP-sensitive potassium channels. Ann N Y Acad Sci 723, 392–395.[Medline]

White E, Le Guennec J-Y, Nigretto JM, Gannier F, Argibay JA & Garnier D (1993). The effects of increasing cell length on auxotonic contractions; membrane potential and intracellular calcium transients in single guinea-pig ventricular myocytes. Exp Physiol 78, 65–78.[Abstract]

Wirtzfeld A, Himmler FC, Forßmann B, Hepp W, Erhardt W, Wriedt-Lübbe I et al. (1979). External mechanical cardiac stimulation: methods and possible application [in German]. Z Kardiologie 68, 583–589.

Yakaitis RW & Redding JS (1973). Precordial thumping during cardiac resusitation. Crit Care Med 1, 22–26.[Medline]

Yeung EW, Whitehead NP, Suchyna TM, Gottlieb PA, Sachs F & Allen DG (2005). Effects of stretch-activated channel blockers on [Ca²⁺]_i and muscle damage in the mdx mouse. J Physiol 562, 367–380.[Abstract/Free Full Text]

Zabel M, Koller BS & Franz MR (1993). Amplitude and polarity of stretch-induced systolic and diastolic voltage changes depend on the timing of stretch: a means to characterize stretch-activated channels in the intact heart. Pacing Clin Electrophysiol 16, 886.[CrossRef]