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Kamkin A, Kiseleva I, editors. Mechanosensitivity in Cells and Tissues. Moscow: Academia; 2005.

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Mechanosensitivity in Cells and Tissues.

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Mechano-Electric Feedback in the Heart: Evidence from Intracellular Microelectrode Recordings on Multicellular Preparations and Single Cells from Healthy and Diseased Tissue

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,1,2,* ,1,2 ,3 and 2.

1 Department of Fundamental and Applied Physiology, State Medical University of Russia, Ostrovitjanova Str. 1, 117997 Moscow, Russia
2 Institute of Physiology, Humboldt-University, Charité, Tucholskystrasse 2, 10117 Berlin, Germany
3 INSERM U636, Centre de Biochimie, Université de Nice, Parc Valrose, 06108 Nice, France
*Corresponding author: Andre Kamkin, M.D., Ph.D., Dr.med.habil, Department of Fundamental and Applied Physiology, Russian State Medical University, Ostrovitjanova Str. 1, 117997 Moscow, Russia, Phone: 007095-131 4863, Telefax: 007095-131 4863, e-mail: ur.mocler.32g@A.nikmaK

We report on studies applying intracellular microelectrode recordings and whole-cell current measurements to investigate the effect of mechanical stretch on the electrical properties of cells from normal and diseased heart. Imposing physical stretch on atrial and ventricular tissue specimens elicited stretch-induced depolarizations (SID) of cardiomyocytes. Extra-action potentials occurred in the multicellular tissue preparations when the SIDs reached a threshold potential. Isolated cardiomyocytes responded to stretch with membrane depolarization, prolongation of their action potential (AP) and extra-APs that correlated with the amplitude of a non-selective stretch-activated current (ISAC). At negative potentials, ISAC was negative and carried by a transmembrane influx of Na+ ions, which induced diastolic depolarization or SID. Whilst the reaction of cardiomyocytes to mechanical stretch was independent of their spatial orientation (edgewise or broadwise), their response to compression was different and determined by the relative position of each cell. The sensitivity of the AP to mechanical stretch was significantly increased in hypertrophied myocardium, and this could be related to the expression of SACs.

Introduction

Mechanoelectric feedback [36, 37] describes the situation in which a mechanical stimulus is transduced into an electrical signal. Several electrophysiological alterations in the heart, which were ascribed to mechanoelectric feedback has been reported. They include: (1) changes of the monophasic action potential duration (MAPD), (2) a decrease in the resting membrane potential, (3) a decrease in monophasic action potential amplitude, (4) development of stretch-induced depolarizations, (5) ectopic beats originating from stretch induced depolarization (which reached the threshold potential for depolarization) in myocardium sustaining the stretch, (6) other changes of the cardiac potentials [13], and changes in intercellular interaction through gap junctions [24]. However, in most studies of mechanoelectric feedback, the monophasic action potential recording method was used [13], since it is extremely difficult to maintain a glass-microelectrode positioned stably within a cell of a beating heart and even harder to ascertain the effects of simultaneously imposed mechanical perturbations [12]. Dudel and Trautwein [11] stretched papillary muscle while measuring the microelectrode action potential (AP).

In this review we will discuss some of the recent advances from intracellular recordings of the bioelectrical activity of cardiomyocytes during mechanical stretch of healthy and diseased tissues from animals and human. Furthermore, we will discuss some open questions about mechano-sensitive ionic currents in isolated cardiomyocytes. For a more comprehensive review of the effects of mechanical deformation on ionic currents in isolated cardiomyocytes, the reader is referred to reviews by Isenberg et al. and Youm et al. in this book.

Methods to stretch isolated cardiac tissue specimens and to mechanically deform isolated cardiomyocytes

Registration of membrane potentials in cardiomyocytes

The method of intracellular recordings of membrane potentials in cardiomyocytes by means of standard microelectrodes was used to study spontaneously contracting and artificially stimulated cardiac tissue specimens during application of mechanical stretch. The task is difficult to perform, since it requires keeping the microelectrode properly positioned not only in contracting, but also in mechanically stretched specimens. We managed to solve this problem technically and to carry out stable registrations from cardiomyocytes of various animal species and human myocardium for long times [28, 33]. During the registration of membrane potentials of cardiomyocytes, the tissue was stretched, and the degree of stretching was monitored simultaneously in terms of resting force and active force.

Electrophysiological changes were evoked by application of long-lasting mechanical stretch, which was imposed slowly. This was done, because the amplitude of stretch is more important, than its velocity and duration. In our experiments, stretch-induced depolarization (SID) was the typical response of the membrane potential of atrial and ventricular cardiomyocytes to mechanical stretch. The configuration of SID was variable depending on the type of AP.

Application and measurement of mechanical stretch of atrial myocardium

Developed force, which was measured at a baseline preload of 1 mN, was approx. 0.3 mN because always small pieces of tissue of a strictly certain size have been used. A preload of 1 mN corresponded to a lengthening of approximately 6 % of the preparations in healthy and disease rats and human. To simulate changes in length of right atrial myocardium caused by changes of blood flow, we used long-lasting stretch (length changes), which was applied by a micromanipulator. Stepwise changes in length were established slowly to maintain a stable position of the microelectrode during the experiments [28]. Clearly, individual cells in the tissue were exposed to different levels of stretch, which is similar to the situation in situ.

Measurement of mechanical stretch of ventricular myocardium

The adjusted resting force was not comparable in both groups – healthy rats and rats with myocardial infarction – because 50% of the post-infarcted ventricular tissue specimen usually consisted of scar tissue with indefinable visco-elastic properties. In an attempt to standardise the mechanical test stimulus, we used the increase in isometric force amplitude (active force: AF) due to the applied stretch (Starling mechanism) as an indirect measure. This stimulus was used to provoke the electrophysiological response of the myocytes. The preload was adjusted to produce stable force development of 0.5 mN [33].

Application and measurement of mechanical deformation of isolated cardiomyocytes from healthy and diseased tissues

A simple and effective method for mechanical deformation of isolated cardiomyocytes (local stretch or local compression) has been developed by Kamkin, Kiseleva, and Isenberg in 1999 and published in 2000 [22]. Later this method was used effectively in different works [23, 26]. For a more comprehensive review on different methods of stretching isolated cells, the reader is referred to the chapter «Isolated cardiomyocytes: Mechano-sensitivity of action potential, membrane current, and ion concentration» by Isenberg et al. in this book.

After seal formation and whole cell access of the patch pipette, a fire- polished glass stylus was attached to the membrane [22]. A motorized micromanipulator increased the distance between the patch pipette (P) and glass stylus (S) by 2 to 10 μm, causing a local stretch (Fig. 1A) or local compression (Fig. 1B). The patch-electrode served as a fix-point. The stretch- relaxation and compression-relaxation experiments could be repeated on the same cell three to five times, on average.

Figure 1. Mechanical deformation of ventricular myocyte with two glass tools.

Figure 1

Mechanical deformation of ventricular myocyte with two glass tools. P: patch pipette, fixing the myocyte to the glass coverslip. S: fire polished glass stylus. (A) Axial stretch. The distance of 36 μm (A1) is increased to 43 μm (A2, 7 (more...)

It is necessary to note that brick-like isolated cardiomyocytes stuck to the bottom of the perfusion chamber in two different positions: edgewise, staying on the narrow side or broad-wise. In some experiments after seal formation and whole cell access, cardiomyocytes were rolled [08] using the patch-pipette to attach to the glass bottom from edgewise, staying on the narrow side (Fig. 2A) to broad-wise (Fig. 2D). This allows to analyze the whole-cell current during stretch and compression at different positions on the same cardiomyocyte.

Figure 2. Brick-like myocytes were rolled to attach to the glass bottom in two different positions.

Figure 2

Brick-like myocytes were rolled to attach to the glass bottom in two different positions. A - edgewise, staying on the narrow side, B - and C – turning of the cell by patch-pipette, D – broadwise, staying on the broad side. (Kamkin and Kiseleva, (more...)

As we have shown - a proportion of the data will be presented below - the reaction to stretch was identical in cardiomyocytes, occupying both position (edgewise and broad-wise). However, the reaction to compression was different and determined by the position of a cell [20].

Mechano-electric feedback in atrium from healthy and diseased animals and human

Mechano-electric feedback in right atrial tissue in healthy rats

The intact atrial tissue shows mechano-electric transduction, as has been reviewed from experiments with extracellular registration (see for example ref. [37, 41]). Mechanoelectric feedback in atrial cardiomyocytes, studied by the intracellular microelectrode technique has been shown in rat hearts [28, 29]. Figure 3 demonstrates one representative example of the effect of sustained stretch (1.75 ± 0.04 mN) in sham operated rats on AP duration at three different time points of repolarization. APD25 was unaffected, APD50 was shortened, whereas APD90 was increased significantly. The increase in APD90 was due to delayed repolarization resulting from SID.

Figure 3. Superimposed action potentials from right atrial cardiomyocytes in sham operated rats at a preload of 1 mN (dotted line) and 1.

Figure 3

Superimposed action potentials from right atrial cardiomyocytes in sham operated rats at a preload of 1 mN (dotted line) and 1.7 mN (solid line) of stretch. Stretch produces depolarization (SID) near APD90. (Reprinted from Kamkin et al. [28], with permission (more...)

A further increase in stretch to 2 mN evoked extra-APs (Fig. 4). These effects were completely reversible upon release of stretch. Resting membrane potentials (Em) and AP amplitudes were not significantly changed by mechanical stretch (only a depolarization of approximately 5 mV was observed). These findings demonstrate that the electrical properties of right atrial tissue from normal heart are sensitive to mechanical stretch.

Figure 4. Response of the resting membrane potential (Em) and action potential (AP) of an atrial cardiomyocyte from a sham operated rat to mechanical stretch.

Figure 4

Response of the resting membrane potential (Em) and action potential (AP) of an atrial cardiomyocyte from a sham operated rat to mechanical stretch. Stepwise increases in resting force due to physical stretch (indicated by ↑) up to 1.7 mN significantly (more...)

Mechano-electric feedback in isolated right atrial cardiomyocytes in healthy rats

We will not discuss this topic here, since it is described in detail in the chapter by Youm et al. entitled «Role of stretch-activated channels in the heart: Action potential and Ca2+ transients» in this book. These authors have been the first who described mechanically induced potentials and currents on isolated cardiomyocytes from rat atria [56]. In their review in this book, they discuss recent progress and analyze the role of stretch-activated channels based on the experimental findings from the rat atrial cardiomyocytes.

Mechano-electric feedback in right atrial tissue from animals with cardiac hypertrophy after infarction and human atria

Whilst myocardial infarction (MI) is a regional pathology, it can lead to alterations in global hemodynamic load of the heart, thereby inducing cardiac hypertrophy. Consequently, changes in systemic hemodynamics may cause phenotype modulation of right atrial cardiomyocytes after left ventricular myocardial infarction [43].

There is considerable evidence to suggest electrophysiological abnormalities in hypertrophied cardiac myocytes after myocardial infarction. Data from other models of cardiac hypertrophy indicate that arrhythmia develops more readily in hypertrophied ventricular and atrial myocardium than in healthy tissue [3, 15, 44].

After phenotype modulation of atrial myocardium, a close correlation between atrial size and the occurrence of atrial fibrillations has been observed (for review see: [41, 42]). Moreover, congestive heart failure is frequently associated with atrial fibrillation, which has been reported recently as an important predictor for the mortality of patients with myocardial infarction [10]. Therefore, we investigated action potential characteristics after myocardial infarction and a potential role for atrial fibrillation.

Two types of APs could be monitored in the atria from animals with myocardial infarction. The first type of AP had a similar time course like APs at APD25 and APD50 in sham operated rats, but was considerably lengthened near APD90 (Fig. 5A). The second type of AP showed substantial enlargement during APD25, APD50, and APD90 (Fig. 5B) [28, 31].

Figure 5. Superimposed action potentials in a right atrial cardiomyocyte from a sham operated rat (1) and a rat after myocardial infarction (2).

Figure 5

Superimposed action potentials in a right atrial cardiomyocyte from a sham operated rat (1) and a rat after myocardial infarction (2). The preload was set to 1mN. Remodeling after infarction revealed two types of action potentials (AP). A: the first type (more...)

These two types of APs responded differently to application of stretch (Fig. 6). Thus, the first type of AP was associated with SID, which arose at APD90 (AP-SID90, Fig. 6A), whereas the second type of AP developed SIDs at APD50 (AP-SID50, Fig. 6B).

Figure 6. Action potentials from right atrial cardiomyocytes at a preload of 1 mN in rats after myocardial infarction.

Figure 6

Action potentials from right atrial cardiomyocytes at a preload of 1 mN in rats after myocardial infarction. Two types of stretch-induced depolarization (SID), arising either at APD90 (A) or at APD50 (B) could be monitored.

Although compensatory hypertrophy of the surviving myocardium is considered as an important adaptive response of the heart [43], it can have potentially adverse effects. Ultrastructural alterations, such as swelling and destruction of mitochondria and the sarcoplasmic reticulum, cellular edema, and loss of clear structure and enlargement of myofilaments have been described for hypertrophied myocardium after MI [14, 52]. The lowered frequency of spontaneous contractions in the MI group might reflect a specific phenomenon of the interaction of cardiomyocytes through connexons with cardiac fibroblasts, which significantly hyperpolarize after myocardial infarction (see review Kamkin at al. titled «The role of mechanosensitive fibroblasts in the heart» in this book).

Consistent with data obtained in other models of cardiac hypertrophy [4, 16], we found prolongation of the APD. Hypertrophy has been reported to increase APD dispersion possibly due to structural heterogeneity [45]. The two types of APs may result from non-uniform remodelling causing heterogeneous APs in cardiomyocytes. This mechanism would provide an explanation for the moderate increase in APD90, which was seen in the type AP-SID90s only, and the more general increase in APD25, APD50, and APD90 in the type AP-SID50s. That is, the AP-SID90 types may be recorded from myocytes being affected by remodelling in a different way than cells showing the AP-SID50 type characteristics.

Most importantly, SIDs could be elicited at a much lower level of stretch (0.19 ± 0.02 mN) in tissue preparations that were obtained from rats with myocardial infarction compared to specimens from sham operated animals (1.75 ± 0.04 mN) [28].

After myocardial infarction, a significantly lower level of stretch (0.19 ± 0.02 mN) was sufficient to elicit SIDs in both types of APs. Figure 7 shows the effect of increasing stretch (myocardial infarction group) on SIDs near APD90 (AP-SID90 type). Figure 7A was recorded at the standard preload of 1 mN. Whilst application of a weak stretch (0.15 mN) did not produce SIDs in sham-operated rats, the same amount of stretch induced a SID after myocardial infarction (Fig. 7B). Stretch did not change APD25. APD50 was minimally shortened, whereas APD90 was significantly increased. The increase in APD90 was due to the SID. Moreover, only a small increase in stretch (up to 0.2 mN) produced SIDs, which were accompanied by extra-APs (Fig. 7C). These premature excitations, taking a paired or bigeminal form, had reduced amplitudes as would be expected in the case of a partially depolarized cell membrane. However, these effects on AP configuration were seen at an approx. 10-fold lower degree of stretch as compared to sham operated rats. The effects were completely reversible upon cessation of stretch (Fig. 7D).

Figure 7. Example of one type of response of the membrane potential of a cardiomyocyte to stretch applied by the micrometer to right atrial tissue in the post- infarction group.

Figure 7

Example of one type of response of the membrane potential of a cardiomyocyte to stretch applied by the micrometer to right atrial tissue in the post- infarction group. Stepwise increases in resting force due to stretch (indicated by ↑) up to 0.15 (more...)

Increasing stretch to more than 0.2 mN prolonged APD90 due to SID and produced extra-APs in the SID90 types. Although we did not record an electrogram, these extra-APs seemed to even elicit atrial tachyarrhythmia (Fig. 8 - same preparation as in Fig. 7). The irregular amplitude of the potentials and the barely visible and irregular global contractions suggested atrial fibrillation. Note that the two large AF records were associated with an initial large AP, but the following three or so small rapid APs occurred within each force trace. Apparent tachyarrhythmia as well as atrial fibrillation was observed in the preparations after MI. Tachyarrhythmia and atrial fibrillations were never observed in sham operated rats. That is, in addition to the greater sensitivity of the atrial AP configuration to stretch, the appearance of fibrillations is a particular characteristic of this preparation of post-infarction atrial myocardium. These effects were also reversible upon release of stretch.

Figure 8. Example of stretch-induced atrial fibrillation in the group with myocardial infarction.

Figure 8

Example of stretch-induced atrial fibrillation in the group with myocardial infarction. The terminal action potential of the first brief episode of tachyarrhythmia shows a clear SID. The next episode of tachyarrhythmia is maintained. Initially, it shows (more...)

Figure 9A demonstrates the dynamics of development of one extra-AP in the cardiomyocyte of the rat right atrium after myocardial infarction. The preparation was exposed to increasing stretch (2–4) up to 0.2 mN. The second potential arises, when SID reaches the critical level of depolarization (Ec = -66.6 mV) [28]. A similar effect but with two additional APs is demonstrated in Fig. 9B.

Figure 9. Superimposed action potentials during stepwise increases in stretch.

Figure 9

Superimposed action potentials during stepwise increases in stretch. AP SID90 types A: Trace 1 was recorded at a preload of 1 mN. Stepwise increases in length produced SIDs (2 – 4). The highest stretch SID induced an extra action potential (5) (more...)

Exposure to 40 μmol/l of Gd3+, a dose, which is normally used to suppress stretch-activated events [18, 50], had only little effect on contractile activity in all preparations. Developed peak force decreased to 95 % of control, but, importantly, gadolinium had already exerted its suppressing effect on SIDs approximately 5 min before.

In the AP-SID50 types, stretch induced a membrane potential response near APD50 (Fig. 10). Very small amounts of stretch, less than 0.2 mN, increased developed peak force and produced SIDs near APD50, which significantly prolonged APD50. Stretch also increased APD90, whereas APD25 remained unaffected. The increases in APD50 and APD90 may result from the SIDs. The APD50 possibly represents another type of response to stretch because these very early SIDs were never followed by extra-APs. However, premature APs were also observed most likely after the refractory period and near to the threshold potential (Fig. 11). Release of stretch completely reversed the effects.

Figure 10. Example of another type of response of cardiomyocyte membrane potential to stretch applied by the micrometer to right atrial tissue in the post-ventricular infarction group.

Figure 10

Example of another type of response of cardiomyocyte membrane potential to stretch applied by the micrometer to right atrial tissue in the post-ventricular infarction group. Stretch (↑) induced a depolarization (SID) during the plateau of action (more...)

Figure 11. Superimposed action potentials during stepwise increases in stretch.

Figure 11

Superimposed action potentials during stepwise increases in stretch. APs were of the SID50 type. Recordings were performed at a preload of 1 mN (1), and during stepwise increases of stretch, which produced a stepwise rise of the SIDs (2 – 4). (more...)

In the AP-SID50 type, increases in stretch produced increments in SID (steps 2–4 in Fig. 11). We also observed generation of extra-APs not at APD50, but with some delay. These additional APs occurred immediately upon mechanical stimulation, i.e. as soon as the threshold potential was reached (steps 2–4 in Fig. 11). Also in this case, exposure to 40 μmol/l of Gd3+ blocked the stretch-induced effects.

In human atrial myocardium, baseline electrophysiological parameters recorded in cardiomyocytes are as follows: AP amplitude 71 ± 8 mV, resting potential -63 ± 10 mV, overshoot 8 ± 6 mV, duration 452 ± 65 ms [25].

Figure 12 demonstrates a representative example of the effect of sustained stretch on AP configuration at three different levels of repolarization in human atrial tissue. APD25 and APD50 were unaffected, whereas APD90 was significantly increased. The increase in APD90 was associated with stretch-activated depolarization (SID).

Figure 12. Simultaneous recording of the isometric force development – resting force (RF), active force (AF) of a human atrial trabecula (upper trace) and action potential (AP) of a cardiomyocyte (lower trace).

Figure 12

Simultaneous recording of the isometric force development – resting force (RF), active force (AF) of a human atrial trabecula (upper trace) and action potential (AP) of a cardiomyocyte (lower trace). Superimposed action potentials at a preload (more...)

Long-lasting stretch increased active force development. In human atrial tissue, lengthening increased the isometric peak force from 1.9 ± 0.3 mN (curve 1) to 2.1 ± 0.2 mN (curve 2). These effects were completely reversible upon removal of stretch. The resting membrane potential and the AP amplitude were not affected by stretch.

The SIDs at APD90 were suppressed completely after 10 min of application of 40 μM Gd3+. These experiments with Gd3+, which blocked the stretch-induced electrophysiological changes, strongly suggest the involvement of SACs.

Mechano-electric feedback in isolated right atrial cardiomyocytes from patients with cardiac hypertrophy

We performed electrophysiological recordings on cardiac myocytes that were freshly isolated from patients with various heart diseases [26]. Our findings show, that human atrial myocytes indeed contain stretch-activated ion channels. It was demonstrated that transmembrane influx, presumably of sodium ions, through non-selective cation channels may have a role in cardiac arrhythmogenesis.

Replacement of K+ by Cs+ ions in the bathing and electrode solutions for suppression of inwardly rectifying K+ currents allowed the separation of net currents into current components. A typical current-voltage relationship for the late current IL and ICa-L is shown in Fig. 13B.

Figure 13. Example of L-type Ca2+ channel current, ICa-L, and late current, IL, measured at the end of the depolarizing 140 ms pulse in a human atrial myocyte during suppression of IK.

Figure 13

Example of L-type Ca2+ channel current, ICa-L, and late current, IL, measured at the end of the depolarizing 140 ms pulse in a human atrial myocyte during suppression of IK. A – original current registration in the whole-cell configuration. The (more...)

The example in Fig. 14 illustrates the voltage-dependence of the membrane late currents before and during application of mechanical stretch. Stretch-induced currents increased with the intensity of stretch. Increasing stretch at -45 mV by 2 μm, 4 μm, and 6 μm caused stretch-induced late currents of -38 ± 6 pA, -254 ± 17 pA, and -595 ± 22 pA, respectively. These effects were reversible upon release of stretch (Fig. 14A).

Figure 14. Modulation of net membrane currents by stretch during suppression of IK.

Figure 14

Modulation of net membrane currents by stretch during suppression of IK. A - current-voltage relation of the late current IL measured at the end of the test pulse (empty squares - before stretch; empty triangles - after removal of stretch; filled squares (more...)

Upon stretching the atrial myocytes, the stretch-activated difference currents ISAC followed an almost linear voltage-dependence and crossed the voltage axis at a reversal potential Erev of 0 mV (Fig. 14B). At -45 mV, ISAC was -54 ± 18 pA with 2 μm of stretch, -272 ± 22 pA with 4 μm of stretch and -613 ± 22 pA with 6 μm of stretch.

Stretch-induced late currents were suppressed within 8–10 min after application of 5 μM Gd3+ [46] (Fig. 15). ISAC was insensitive to substitution of Cl- by aspartate ions suggesting that ISAC is carried by cations rather than by Cl-. Thus, the linear voltage-dependence, the value of Erev, Gd3+ sensitivity, and Cl- insensitivity suggest that stretch-activated ISAC flows through mechanically sensitive non-selective cation channels.

Figure 15. Gd3+-sensitivity of stretch activated currents during suppression of IK.

Figure 15

Gd3+-sensitivity of stretch activated currents during suppression of IK. Stretch-induced late currents were calculated from the current-voltage relation at a holding potential of -45 mV. Voltage–dependence of stretch-induced late currents before (more...)

During application of stretch, the sustained inward current ISAC of approximately -500 pA is expected to cause intracellular accumulation of Na+ and Ca2+ ions, which may affect other current components. Indeed, our findings made with Cs+ dialyzed cells (suppression of IK) showed that mechanical stretch suppressed the L-type Ca2+ channel current ICa-L (Fig. 13). Inhibition of ICa-L was not observed when the cells were dialyzed with 5 mM BAPTA for 5 min prior to application of stretch, whilst ISAC remained unchanged by this maneuver. For example, imposing a stretch of 3 μm at a holding potential of -45 mV produced ISAC of -140 ± 10 and -148 ± 20 pA in the presence or absence of 5 mM BAPTA, respectively (not significant). The effect of BAPTA is likely due to chelation of Ca2+ ions. Hence, the observed stretch-induced reduction of ICa-L can be explained as "Ca2+ inactivation" due to intracellular Ca2+ accumulation [53, 57].

It was shown recently that application of mechanical stretch to atrial cardiac tissue and isolated atrial cardiomyocytes [28, 41, 56] increased the AP duration, induced diastolic depolarization, and caused extra-APs. These phenomena were at least in part due to activation of stretch-operated ion channels. We demonstrated that stretch-activated non-selective cation channels are also contained in human atrial myocytes and potentially are related to the pathophysiology of the diseased heart.

In the current-clamp mode, human atrial cardiomyocytes responded to stretch with membrane potential depolarization, and increasing stretch by 2 μm (S1 in Fig. 16A) and 3 μm (S2 in Fig. 16A) induced stretch-induced depolarizations at APD90. Remarkably, extra-APs were observed upon stretching of atrial cardiac myocytes by 4 μm (S3 in Fig. 16B) and 6 μm (S4 in Fig. 16B) under current-clamp conditions.

Figure 16. Membrane depolarization, prolongation of the action potential and extra-action potentials in response to mechanical stretch.

Figure 16

Membrane depolarization, prolongation of the action potential and extra-action potentials in response to mechanical stretch. Right atrial cardiomyocytes from patients undergoing open-heart surgery were stretched from the control value (C) by 2 μm (more...)

Thus, the negative ISAC that was presumably carried by influx of Na+ ions at negative membrane potentials may cause depolarization and extra-APs, if the depolarization reaches threshold.

Mechano-electric feedback in ventricle from healthy and diseased animals and human

Mechano-electric feedback in left ventricular tissue in healthy rats

This role of mechanoelectric feedback in ventricle has been previously studied by extracellular recording and reviewed for animals (see for example ref. [12, 36]), and human [48]). Investigation at the cellular level demonstrates that stretch can raise intracellular calcium by affecting mechanosensitive channels [9, 39, 47, 54] and activation of Na+-H+ exchange [8].

Mechanoelectric feedback in ventricular cardiomyocytes, studied by the microelectrode technique has been shown in rat heart [27, 32, 33]. Figure 17 demonstrates the typical APs, which were registered in left ventricular tissue of rats.

Figure 17. Continuous recordings of active force (AF), resting force (RF) and action potentials (AP) from the sham operated group (A,).

Figure 17

Continuous recordings of active force (AF), resting force (RF) and action potentials (AP) from the sham operated group (A,). A single AP from a sham-operated rat is shown at higher resolution (B). Note that the ventricular preparations from sham-operated (more...)

In normal hearts, AP configurations of different cardiomyocytes in the endocardial region of the ventricle were relatively uniform.

Long-lasting stretch of the tissue led to an increase in active force development, which could modulate the electrophysiological function of the cardiac myocytes. The resting membrane potential and the AP amplitude were not affected by stretch.

Figure 18 illustrates the typical effect of prolonged stretch of the ventricular preparations from a sham-operated rat. Application of physical stretch resulted in an increase in active force. APD25 and APD50 remained constant, whereas APD90 was significantly increased during stretch. The rise in APD90 was associated with stretch-activated depolarization (SID).

Figure 18. Response of the membrane potential of a cardiomyocyte to long-lasting mechanical stretch of the left ventricular preparation from a sham-operated rat.

Figure 18

Response of the membrane potential of a cardiomyocyte to long-lasting mechanical stretch of the left ventricular preparation from a sham-operated rat. Increasing stretch (indicated by ↑) caused a membrane depolarisation, which was completely reversible upon (more...)

Application of 40 μM Gd3+ reduced the active force only insignificantly by 5% but completely suppressed SIDs near to APD90. The resting membrane potential and the AP amplitude were unaffected by Gd3+.

Mechano-electric feedback in isolated ventricular cardiomyocytes from healthy rats

For studying whole cell currents, ventricular cardiomyocytes for the first time have been stretched by Kamkin, Kiseleva, Isenberg [21, 22] and Zeng, Bett, Sachs [55] and further whole cell currents have been studied in detail [20, 22, 23]. Also other effects of stretch on isolated cardiomyocytes have been reported [5, 8, 9, 19, 34, 35]. We will discuss these findings only briefly, since a detailed description is provided by Isenberg et al. in their review «Isolated cardiomyocytes: Mechanosensitivity of AP, membrane current and ion concentration» in this book.

We studied the reaction to stretch of whole-cell currents and it was shown that the reaction to stretch was identical in cardiomyocytes, occupying both positions (Fig. 2: edgewise and broadwise). However, reaction to compression was different and was determined by the position of a cell.

In this chapter, we will review some of the recent advances in the electrophysiology of isolated ventricular cardiomyocytes during local compression.

Stretch of isolated ventricle cardiomyocytes

In these experiments, membrane whole-cell currents were recorded. Figure 19 shows membrane currents by means of on-line pen records.

Figure 19. Induction of net inward currents by local stretch is graded and reversible.

Figure 19

Induction of net inward currents by local stretch is graded and reversible. On-line pen records of membrane current; K+ currents are not suppressed. Membrane potential clamped to a holding potential of -45 mV, 140 ms pulses to 0 mV at 1 Hz. Amplitude (more...)

A 6 μm stretch shifted the holding current at -45 mV by -0.16 nA to more negative values (Fig. 19A). The stretch induced current change completed during the time of mechanical movement (usually 200 ms), i.e. an activation time course could not be observed. Stretches by 2 μm and 4 μm did not change the currents (not illustrated). During stretches of 6, 8, 10, and 12 μm, the amount of negative current increased with the extent of stretch (Fig. 19 from A to D). During continuous stretch, the inward current remained constant (tested up to 15 min), i.e. inactivation with time was not observed (Fig. 19E). The effect of stretch on the current was reversible, i.e. the current returned to the value before stretch when the stretch was relaxed by moving the stylus to its position before stretch (Fig. 19E). Fig. 19 shows furthermore that the amplitude of the stretch induced inward current gradually increased with the extent of stretch.

As an example, we depicted only the effect of stretch on the time-dependent net membrane currents in Kin/Kout configuration, which is shown in Fig. 20A.

Figure 20. Voltage-dependence of stretch-induced membrane currents, K+ currents not suppressed.

Figure 20

Voltage-dependence of stretch-induced membrane currents, K+ currents not suppressed. A: Holding potential -45 mV, 140 ms pulses to -80 mV (A1) or 0 mV (A2). Traces of currents before (label C) and during 12 μm stretch (label S), and stretch induced (more...)

Figure 20 demonstrates that the value of the late current and stretch induced inward current gradually increased with the extent of stretch.

The nature of ISAC is analyzed in the review by Isenberg and co-authors in this book and ref. [20].

Compression of isolated ventricular cardiomyocytes

It is obvious, that each cardiomyocyte in multicellular preparations is disposed to different extent of stretch or compression even in the pause between contraction and relaxation of the myocardium. Most cardiomyocytes are compressed during each contraction (during a systole). The brick-like cardiomyocytes have narrow and wide sides. Therefore, we considered two variants of a compression of cardiomyocytes - a compression on the narrow side and a compression on the wide side. It was not difficult to perform these experiments, because brick-like isolated cardiomyocytes, stuck to a bottom of perfusion chamber in two positions: edgewise, staying on the narrow side or broadwise. In some experiments after seal formation and whole cell access, cardiomyocytes were rolled by the patch-pipette to attach to the glass bottom from edgewise, staying on the narrow side (Fig. 2A) to broadwise (Fig. 2D). It allowed on the same cardiomyocyte, placed in different positions, to the study of whole-cell current during stretch and compression.

Myocytes were compressed by pressing the cell surface with the glass stylus towards the glass bottom of the chamber (Fig. 21). The effects of compression depended on the orientation of the myocyte (Fig. 21A or B).

Figure 21. Schematic drawing for the two variants of compression of cardiomyocytes - compression on the narrow side (A) and compression on the wide side (B).

Figure 21

Schematic drawing for the two variants of compression of cardiomyocytes - compression on the narrow side (A) and compression on the wide side (B).

Figure 22 demonstrated the effect of local pressure on the cardiomyocyte, with K+ ions in both, bath and electrode solution, which is in edgewise position. During compression, we registered depolarisation of the resting membrane and reduction of IK1. Voltage dependence of compression-induced currents reminded voltage dependence of stretch-induced currents (see Fig. 20B1). This reduction of IK1 was blocked by 8 μM of non-selective blocker Gd3+. Gadolinium also blocks L-type calcium channels in isolated ventricular myocytes of the guinea-pig [38], in mouse ventricular myocytes [23], and ventricular myocytes from human heart [22]. Moreover, gadolinium blocks the delayed rectifier potassium current in isolated guinea-pig ventricular myocytes [17]. Nevertheless, it was possible to assume the activation of IPA (pressure activated current – PA) through non-selective cation channels. Negative IPA appeared and decayed rapidly upon exposure/release of compression. IPA was -0.12 ± 0.04 nA at 2 μm, -0.28 ± 0.05 nA at 4 μm; -0.32 ± 0.02 nA at 6 μm, and -0.70 ± 0.1 nA at 8 μm compression (at -45 mV). Compression also reduced ICa. Since this effect was prevented by cell dialysis with 5 mM BAPTA, the reduced ICa may be caused by elevated [Ca2+]c (see also ref. [22, 23, 26]).

Figure 22. Pressure on the cell by 6 μm, which is in edgewise position with Kin+/Kout+ solutions.

Figure 22

Pressure on the cell by 6 μm, which is in edgewise position with Kin+/Kout+ solutions. A: Starting from -45 mV, the membrane potential was adjusted for 140 ms to -80 mV (A1) and 0 mV (A2), respectively. Shown are the net membrane currents before (more...)

Thus, edgewise attached cells responded to compression with depolarisation of the resting membrane, and reduction of IK1 through inwardly-rectifying K+-channels.

After block of K+-currents by substitution of both extracellular and intracellular K+-ions with Cs+-ions (Fig. 23A) even compression by 8 μm does not induce IPA. However, the stretch by 8 μm of the same cell in all cases caused the appearance of ISAC through non-selective cation channels (Fig. 23A). It is impossible to tell that the compression as against a stretch does not influence to the cell, because in absence of BAPTA in both cases (at a compression and a stretch) L-type calcium current decreases (Fig. 24). Gadolinium does not render influence on a late current IL of the cell subject to a compression even by 8 μm (Fig. 23B). All three curves - a control curve of a IL, that is before compression of a cell, IL curve on a background of a compression and IL curve after addition of gadolinium are similar in all of experiments. (Certainly, gadolinium eliminates ISAC through non-selective cation channels during the stretch of cardiomyocyte (see for ref. [22, 23, 26]). Thus, negative to -45 mV, IK1 rectified inwardly, and was blocked by replacing extracellular and intracellular K+ by Cs+ ions.

Figure 23. Mechanosensitive currents in edgewise attached cells after block of K-currents by substitution of both extracellular and intracellular K+-ions with Cs+-ions.

Figure 23

Mechanosensitive currents in edgewise attached cells after block of K-currents by substitution of both extracellular and intracellular K+-ions with Cs+-ions. A: Compression by 8 μm does not induce IPA for example through through non-selective (more...)

Figure 24. Pressure on the cell, which is in broad-wise position with Kin+/Kout+ solutions.

Figure 24

Pressure on the cell, which is in broad-wise position with Kin+/Kout+ solutions. A: Starting from -45 mV, the membrane potential was adjusted for 140 ms to -80 mV (A1) and 0 mV (A2), respectively. Shown are the net membrane currents before (labelled as (more...)

As a whole, pressure on the cell, which is in edgewise position with Kin+/Kout+ solutions modulated IK1 through inwardly-rectifying K-channels. The effect of compression of edgewise cells is not shown in Csin+/Csout+, though the cell reacted to deformation as IL-Ca decreased and reacted to stretch.

Figure 24 depicts the effect of local pressure on the cardiomyocyte, with K+ ions in both bath and electrode solution, which is in broad-wise position. Hyperpolarization is seen as shift of the zero current potential from -75 to -80 mV. When pressure was applied to broad-wise attached myocytes, it increased IK1 through inwardly-rectifying K+-channels. Nevertheless, it was possible to assume the inactivation of IPA (pressure activated current – PA) through non-selective cation channels.

Thus, pressure on the cell, which is in broadwise position with Kin+/Kout+ solutions increased IK1 through inwardly-rectifying K-channels. It could be possibly also deactivation of a background INS. Compression did not reduced ICa.

When broadwise-attached cells with blocked K+ currents were studied, compression by 4 μm decreased late current IL. It could be deactivation of INS (Fig. 25B). However, the stretch by 4 μm of the same cell in all cases causes the appearance of ISAC through non-selective cation channels (Fig. 25B). After compression by 4 μm, the curve of late current IL takes a position, which is inconveniently to explain for us. Stronger compression does not result in change of the IL curve. If on the cell to apply a smaller compression by 2 μm, typical reduction of a late current is registered (Fig. 25C). However, addition of gadolinium results in a curve that takes the same position as the one at a compression by 4 μm (Fig. 25C).

Figure 25. Broad-wise attached cell with blocked K-currents (Csin/Csout solution).

Figure 25

Broad-wise attached cell with blocked K-currents (Csin/Csout solution). A: Starting from -45 mV, the membrane potential was adjusted for 140 ms to -80 mV (A1) and 0 mV (A2). Shown are the net membrane currents before (labelled as C) and during application (more...)

Pressure upon the outer cell surface can modify several ionic currents. It is known, for example, that some mechanosensitive channels are activated, when force of pressure is directed in relation to the nucleus of a cell. This has been reported for glial cells [6, 7], smooth muscle cells [30], and endothelial cells [40].

Our results suggested that compression modulates inwardly-rectifying K+-channels. Whether the conductance is activated or deactivated depends on the orientation of the compression in regard to the long or short diameter of the cell. Compression has different effects, dependent on the angle to the width and height of the cell (edge- and broadwise attached cells).

Later it has been shown [20] by analyzing compression with a ramp command, that edgewise attached myocytes responded to compression with a decrease of the K+ currents IKo and IK1. When pressure was applied to broad-wise attached myocytes, it increased the two potassium currents IK1 and IKo (Fig. 26). The opportunity of activation of a INS during a local compression of cardiomyocytes in different position is not clear and demands further experiments.

Figure 26. Currents before and during 3 μm compression, broad-wise attached myocytes.

Figure 26

Currents before and during 3 μm compression, broad-wise attached myocytes. Note: hyperpolarisation is seen as shift of the zero current potential from -80 to -84 mV. Note: Currents measured before and during compression with a ramp command from +60 (more...)

In broad-wise attached cells, the deformation has a lower working space of e.g. 6 μm only, i.e. high amplitudes of stretch damage more easily. The stress may be translated up to the interface between the cell button and the coverslip. There might be less bulging at the lateral side because the distance from glass stylus to outer membrane is longer, or it might be more energy dissipated inside the cell.

The dependence on the direction of the effects of local deformation can be explained as follows: a similar standard movement of the stylus will reduce the height in broad-wise attached cells more than in edgewise attached cell, however, it will increase the local diameter that stretches the cell surface more in the edgewise than in the broad-wise attached cells [20].

The asymmetry of the response is difficult to explain with the current models that attribute channel gating to changes in the surface tension of the lipid bilayer. The responses are easier to understand on the assumption that the energy of local compression is transferred by cytoskeletal elements to the channel protein [23]. Treatment of the cells with cytochalasin D, which is thought to disrupt F-actin reduced the amplitude of ISAC during continuous stretch [23]. It attenuated the activation of IK1 by pressure of broad-wise attached cells. When the cells were pre-treated before application of stretch, the mechanosensitivity was reduced or abolished, i.e. the mechanical stimuli (stretch or pressure) became ineffective [23]. Nearly identical results were obtained by cell dialysis with 5 μM colchicin, i.e. depolymerisation of tubulin reduced or abolished the mechanosensitivity of INS and IK1 [20]. From these observations, we concluded that an intact cytoskeleton is necessary for the mechanosensitive gating of ion channels and K+ gating. We might see the cytoskeleton as part of a pathway that transforms the exogenous mechanical energy into activation energy of membrane channels. This hypothesis is in line with the increased mechanosensitivity of INS in hypertrophied cells [22, 28, 33] with enhanced stiffness resulting from a pathological high expression of tubulin in the cytoskeletal cortex [51].

Mechano-electric feedback in ventricular tissue from animals with cardiac hypertrophy after infarction

Remodelling of the heart after myocardial infarction is associated with phenotypic changes and hypertrophy of the surviving myocardium [45]. Structural remodelling may include an increase in myocyte cross-sectional area and length of the left ventricular myocytes [1, 2].

Approximately 90% of the preparations from rats with myocardial infarction (16.5 ± 0.6 % of the left ventricular endocardial surface) generated spontaneous APs and contractile activity, which was never observed in the tissue of sham operated rats. Representative examples of APs in myocardial preparations after infarction are depicted in Fig. 27. The preload was adjusted to a level, which allowed active force development of 0.5 mN. Post-infarct remodelling was associated with typical changes of AP configuration in ventricular cardiomyocytes. In comparison to sham-operated rats, cardiomyocytes from animals with myocardial infarction had a similar AP amplitude, a more negative resting membrane potential (-95.2 ± 1.3 mV vs. -88.6 ± 0.8 mV, P < 0.005), and a prolonged AP duration at progressing levels of repolarization (APD90: 129 ± 15 ms vs. 86±3 ms, P < 0.05).

Figure 27. Continuous recordings of active force (AF), resting force (RF), and action potentials (AP) in ventricular cardiomyocytes from rats with myocardial infarction (A).

Figure 27

Continuous recordings of active force (AF), resting force (RF), and action potentials (AP) in ventricular cardiomyocytes from rats with myocardial infarction (A). Single APs are shown in Figs. B and C. Note that the ventricular preparations after sham (more...)

The configuration of APs was more heterogeneous in the cardiac myocytes from rats with myocardial infarction than in cells that were recorded from sham-operated rats. Consistent with previous findings, the duration of APs was increased and the time course of repolarization showed marked heterogeneity in left ventricular myocytes in the remodelling heart after myocardial infarction [45]. Prolongation of the APD was explained by decreased K+ outward currents, rather than by changes in Ca2+ inward currents [45]. The electrophysiological heterogeneity may result from differences in remodelling between individual cells. The scar tissue and the adjacent myocardium are less distensible and more resistant to mechanical stretch than the cells at a distance from the infarcted area. It is known from the classical work by Tennant and Wiggers [49] that mechanical forces can deform the non-contracting scar region. These forces act differently on both, the necrotic and the non-infarcted myocardium, which may account for the observed electrophysiological heterogeneity in the myocardium adjacent to the scar tissue.

Application of mechanical stretch led to an increase in active force development, which could provide a trigger for changes in the electrical function of cardiac myocytes. In comparison to the extensive stretch that was required to change the configuration of APs in the myocardium of sham-operated rats (150 μm; increase in active force from 0.48 to 0.88 mN), a far weaker mechanical stimulation was sufficient to produce increases in APD90 in tissue preparations from rats with myocardial infarction (20 μm; increase in active force from 0.5 to 0.57 mN). These effects were completely reversible upon removal of stretch. The resting membrane potential and the AP amplitudes were not affected by stretch.

In the cases of relatively short APD, the SIDs appeared near to APD90 (Fig. 28). In the cases of extremely prolonged APs, SID was already observed close to APD50 (Fig. 29) at similar intensities of mechanical stretch as in the experiments with SIDs near to APD90. Application of weak stretch caused SIDs with small amplitudes. Increasing stretch led to a further rise in the SID. Removal of stretch demonstrated the complete reversibility of alterations in AP configuration. SID at APD90 and APD50 were completely suppressed after application of 40 μM Gd3+.

Figure 28. Representative example of the response of the cardiomyocyte membrane potential to long-lasting stretch in rats with myocardial infarction.

Figure 28

Representative example of the response of the cardiomyocyte membrane potential to long-lasting stretch in rats with myocardial infarction. The increase in stretch (indicated by ↑) led to depolarization near to APD90. This effect was completely (more...)

Figure 29. Response of the membrane potential of a cardiomyocyte to long-lasting mechanical stretch in a left ventricular preparation from a rat with myocardial infarction.

Figure 29

Response of the membrane potential of a cardiomyocyte to long-lasting mechanical stretch in a left ventricular preparation from a rat with myocardial infarction. The increase in stretch (indicated by ↑) caused depolarization near to APD50. Removal (more...)

One major finding of this study is that in remodelled myocardium adjacent to the scar, stretch elicited SIDs more readily compared to ventricular myocardium from sham-operated rats.

Mechano-electric feedback in isolated ventricular cardiomyocytes from animals and patients with cardiac hypertrophy

Based on the observations in multicellular ventricular preparations, we investigated the sensitivity to stretch in isolated ventricular cardiomyocytes from hypertrophied hearts of animals and humans in the Department of Physiology Martin-Luther-University of Halle, Germany together with Professor G. Isenberg [22]. The data obtained from isolated hypertrophied cardiomyocytes completely agreed with our experiments on ventricular fragments of hypertrophied tissues. The results for isolated hypertrophied cardiomyocytes are reviewed by Isenberg et al. in «Isolated cardiomyocytes: Mechanosensitivity of action potential, membrane current and ion concentration» in this book.

Conclusions and perspectives

In summary, our findings indicate that (i) stretch of the tissue lead to appearance of SID of cardiomyocytes in tissue fragments, which could be in APD50 and APD90 in atrial cardiomyocytes as well as in ventricular cardiomyocytes; (ii) increment of stretch causes proportional and reversible changes in the AP associated with SID; (iii) in the level of APD90 appear extra-action potentials when SID amplitude reach threshold; (iv) isolated cardiomyocytes respond to mechanical stimulation with membrane depolarization, prolongation of the action potential and extra-APs; (v) ISAC is the major cause of these stretch-induced events. At negative potentials, ISAC was negative and carried by influx of Na+ ions, and induced diastolic depolarization or SID; (vi) reaction to a stretch was identical in cardiomyocytes, occupying both positions (edgewise and broad-wise). However, reaction to compression was different and was determined by the position of a cell; (vii) the sensitivity of the AP to mechanical stretch is significantly increased in hypertrophied myocardium; (viii) this increase in the sensitivity to stretch could be related to expression of SACs.

Further work is required to elucidate signalling pathways, which regulate mechanosensitive channel function and intercellular interactions. Special interest represents interaction of cardiomyocytes with cardiac fibroblasts and signaling pathways of its regulation.

Acknowledgement

This study was supported by the Alexander von Humboldt-Stiftung, the Deutsche Forschungsgemeinschaft (DFG), and a travel grant from the Humboldt University (Germany).

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