Mechanical Induction of Nonphysiologic Rhythms

The fact that mechanical stimuli of sufficient amplitude can be used to pace otherwise quiescent hearts has been illustrated by Franz et al., using Langendorff-perfused rabbit heart preparations where the ventricles (rendered asystolic by ablation of the atrioventricular node) were stimulated by periodic inflation of an intraventricular balloon (Figure 14-2, A).

Similar behavior is believed to underlie “fist pacing” in asystolic patients. Energy levels required for mechanical PVB induction by precordial impact have been established by defibrillation pioneer Zoll et al.³ in human volunteers as 0.04 to 1.5 J. For comparison, the lower end of this energy range is equivalent to dropping a golf ball (46 g) from a height of 9 cm (3.5 in).

The study by Zoll et al.³ found that, in anaesthetized dogs, impacts with energies tenfold greater than the PVB-induction threshold do not induce repetitive responses, ventricular tachycardia (VT), or VF, even if applied in the relative refractory period.³ Overall, this is in keeping with the notion that arrhythmogenesis requires the combination of trigger and sustaining mechanisms, so that consequences of isolated ectopic beats, whether mechanically induced or not, are usually benign.

Although these examples illustrate the effects of the external mechanical environment on cardiac MEC (see Figure 14-1, bottom box), mechanical PVB induction can also arise because of the heart’s own contractile activity (see Figure 14-1, middle box). This is illustrated in Figure 14-2, B, which shows MAP recordings from a patient undergoing pulmonary balloon valvuloplasty. In this procedure, the stenosed RV outflow valve is widened by insertion and inflation of a balloon. During balloon inflation, RV contractions are isovolumic (no ejection) and give rise to significantly increased RV peak-pressures. This increase is generally associated with AP-shortening, diastolic depolarization, and occurrence of early afterdepolarization (EAD)-like events. If supra-threshold, these depolarization can give trigger PVB.⁴ As before, against an otherwise inconspicuous myocardial background, self-sustained repetitive activity is not normally induced.

In contrast, in the presence of preexisting pathologies, PVB can give rise to sustained arrhythmias, as shown in whole-animal studies of pathologically prolonged QT intervals, conducted by Volders et al. In their model, QT-prolongation was induced acutely by pharmacologic block of the slowly activating delayed rectifier potassium current. On this background, additional β-adrenergic stimulation by bolus injection of isoproterenol gives rise to ventricular after contractions of increasing amplitude (up to 25 mm Hg). Originating from near-endocardial locations, their onset precedes (by tens of milliseconds) EAD-like epicardial potentials and alterations in descending T-wave morphology. With increasing amplitude, these apparently contraction-induced afterdepolarizations eventually reach threshold for PVB-induction, followed by torsades de pointes arrhythmic activity.⁵

Under certain conditions, acute mechanical stimulation can be sufficient to give rise to both trigger and sustaining mechanisms for maintained arrhythmias, even in otherwise healthy myocardium. A prominent example of this is Commotio cordis. A number of risk factors for the mechanical induction of such rhythm disturbances have been identified, based on experimental observations from the pioneering work of Schlomka⁶ to modern studies by Link.⁷ Key risk factors include (1) type of impact (impulse-like stimulation, whose arrhythmogenic risk is inversely related to projectile compliance and contact area); (2) impact energy (large subcontusional forces, reaching more than 100 J in competitive sports); (3) impact location (precordial, or in human also spinal, areas that offer efficient energy transmission from body surface to myocardium); and (4) impact timing. Factors 1 to 3 can be regarded as permissive: only if they are all present does timing become decisive.⁸ This presumably explains why the vast majority of precordial (or spinal) impacts result in relatively benign heart rhythm changes, if any.

The critical time-window for the worst possible outcome of Commotio cordis, induction of VF, overlaps with the T wave. The T wave, during which myocardial electrophysiologic heterogeneity is maximal, has long been associated with a period of increased susceptibility to arrhythmogenesis by electrical stimulation, the so-called vulnerable window. Compared with electrical stimulation, the vulnerable window for mechanical VF-induction is surprisingly narrow (∼15 ms, just before the peak of the T wave in anaesthetized pig).⁹

Quantitative computational modeling suggests that mechanically induced VF is favored during a short period of time only, when the mechanically stimulated tissue volume overlaps with the trailing wave of excitation.10,11 In this setting, sustained arrhythmogenesis occurs because, in addition to mechanical PVB induction in tissue that has regained excitability (trigger), the intersection of mechanically affected myocardium and the trailing repolarization wave gives rise to a functional block zone around which reentry develops (sustaining mechanism; Figure 14-3). In three-dimensional tissue, the ectopic activation front forms around a transmurally directed conelike volume of tissue in which mechanical activation reaches the AP threshold.¹² The more forceful the impact, the closer to fully transmural is the affected tissue cone. In addition, the more focal the stimulus, the closer to perpendicular is this ectopic wavefront, relative to the cardiac surface and, by implication, to the trailing wave-end. This relationship enhances the arrhythmogenic potential, as seen in classic S1/S2 cross-stimulus experiments, and could hold a key to understanding risk factors 1 and 2.

Risk factors 3 and 4 are related to the understanding that the critical window for mechanical VF-induction will differ, depending on where on the surface of the heart a stimulus is applied; therefore, this critical window exists in space and time. However, only a limited part of myocardial tissue is in close proximity to the precordium and, hence, accessible to extracorporeally applied local mechanical stimulation. Therefore, only a subset of the (location-specific) critical windows present throughout the heart form a mechanically accessible target in vivo. This is qualitatively different from electrical stimulation, which is less focused and less dependent on proximity, and therefore potentially arrhythmogenic over a longer part of the T-wave duration.

In contrast to acute effects, MEC-contributions to arrhythmogenesis in chronic cardiac overload are more difficult to uncover. Usually, pathologies that involve cardiac pressure or volume overload develop slowly, and they are associated with pronounced structural and functional remodeling. In addition, the causes of overload and tissue remodeling could be proarrhythmogenic in their own right. Nonetheless, mechanical factors have been implicated in the domestication of atrial fibrillation (AF),¹³ whose dominant frequency in patients correlates with atrial pressure.¹⁴ Similarly, ventricular arrhythmogenesis has been linked to pressure and volume overload.^15,16

A conceptually interesting approach to probing the relevance of mechanical factors for arrhythmogenesis in the chronically overloaded heart is the temporary removal of tissue strain. This can be achieved with the Valsalva maneuver, an attempt to forcefully exhale against the closed glottis. Intrathoracic pressure increases during the strain phase of the maneuver, reducing venous return and favoring arterial drainage from the chest. This condition leads to measurable reductions in cardiac dimensions. On this background, VT has been found to convert to sinus rhythm.¹⁷ In this study, 7 of 15 patients showed sustained and 2 showed transient cardioversion. Relief of ventricular wall stress, rather than autonomic nervous system–mediated responses, appears to be a causal contributor to this antiarrhythmic effect, because successful cardioversion can also be observed in the presence of pharmacologic¹⁷ or surgical denervation of the heart, such as in transplant recipients.¹⁸

Thus, acute stretch can cause diastolic depolarization, which can trigger ectopic excitation. Systolic or sustained stretch can contribute to arrhythmia sustenance by enhancing heterogeneities in excitability, refractoriness, and electrical load. These MEC effects have implications for preventive measures (e.g., chest protector design for sports involving fast-moving projectiles) and for interventions such as hemodynamic unloading, active and passive cardiac assist, or biventricular pacing. In addition, defibrillation threshold increases with ventricular preload,¹⁹ apparently not only because of geometric factors,²⁰ but also because of regionally differing MEC-mediated strain effects that raise background electrophysiologic heterogeneity.²¹ Cardiac mechanosensitivity therefore adds an interesting dimension to the present discussion about whether a period of chest compressions should precede defibrillation attempts in cardiac arrest victims with prolonged delays to intervention.

Mechanical Termination of Nonphysiologic Rhythms

Acute mechanical stimulation, usually by precordial thump (PT), can be used as a means of cardiopulmonary resuscitation. PT has been reported to terminate arrhythmias, including asystole, VT, and rarely VF (Figure 14-4).

In the emergency resuscitation setting, PT is often the fastest resuscitative procedure available. PT is delivered with the ulnar side of the clinched fist, from a height of approximately 20 cm (8 in), followed by active retraction to emphasize the impulse like nature of the stimulus. The energy levels required for PT-based termination of VT and VF are one to two orders of magnitude higher than those involved in mechanical pacing of the acutely asystolic ventricle (4 to 10 J vs. 0.04 to 1.5 J in adults).²² The more powerful thumps are applied preferentially to the lower sternum, rather than the left sternal edge, which is targeted for fist-pacing or precordial percussion.²³

Efficacy of PT in real-life settings is difficult to calibrate and compare, because patient backgrounds vary, mechanical impact properties are not normally monitored, controlled study designs are not usually possible, and single case reports in particular suffer from positive data publication bias. The available information from case series involving tens²⁴ to 100 patients²⁵ suggest that fist-pacing of the bradycardic heart has higher success rates (up to 90%)²⁵ than PT-version of tachyarrhythmias (1% to 60%).^24,26 Only three small prospective studies have investigated the clinical utility of PT.^26–28 They showed that PT is ineffective in most tachyarrhythmias, that acutely-asystolic arrest (for which PT was initially described in 1920)²⁹ may be the most amenable target for mechanical cardioversion, and that negative side effects are rare (none in >700 cases).^26–28

In cases where PT causes successful termination of tachyarrhythmias, it is believed to act primarily via depolarizing excitable tissue in the excitable gaps.³⁰ However, as these gaps may be in myocardium at sites distant from the tissue underneath the precordium, high PT energy levels are necessary and, if there is a multitude of them (e.g., in VF), positive outcomes are rare.

In the asystolic heart, fist-pacing can trigger cardiac excitation and active contraction. The hemodynamic efficacy of such mechanically induced cardiac contractions is not different from electrically stimulated beats,³¹ and both are about twice as productive (in terms of volume output) as chest compressions, even if performed optimally.³² This efficacy confers resuscitatory value to fist-pacing even when normal sinus rhythm is not immediately reinstated; of course, PT should not delay implementation of other established resuscitation measures.

The most common manifestation of PT effects in ECG recordings, in particular in the asystolic heart, is an impact-induced electrical artifact with an electrical axis that tends to resemble the direction of normal QRS-complexes. This manifestation suggests that mechanically induced excitation in the quiescent heart can proceed along a pathway that has an overall trajectory similar to that of normal activation. It is possible, therefore, that earliest excitation is triggered preferentially either in cells of the secondary/tertiary pacemaker/conduction tissue of the heart (e.g., Purkinje fibers that have long been known to be mechanosensitive),³³ or in subendocardial locations, which appear to be more mechanosensitive than subepicardial tissue.⁵ This possibility is supported by transmural differences in expression levels of potassium-selective SAC (SAC_K) such as TREK-1³⁴ and cation nonselective SAC (SAC_NS) such as TRPC1.³⁵

Overall, the range of cardiac electrophysiologic responses to mechanical stimulation is not principally different from those caused by electrical energy delivery. Both can be used to pace, cardiovert, or arrest the heart. Concepts such as the vulnerable window for VF-induction apply to both electrical and mechanical stimuli. Even the effective energy ranges required for pacing, cardioversion and defibrillation are not entirely dissimilar. For example, external electrical defibrillation is usually achieved by extracorporeal energy application of 150 to 250 J; of this, only 4% traverses the heart,³⁶ yielding a cardiac energy delivery of 6 to 10 J, similar to that for the PT-version of tachyarrhythmia. These similarities should not be surprising, because mechanical energy can be converted into a transmembrane current by ion fluxes through SAC at the intervention’s target site: the cardiac cell.

Mechanical Modulation of Pacemaking

Diastolic stretch of cardiac tissue causes membrane depolarization, if strong enough to induce any change. In working myocardium, such depolarization may trigger PVB (see Figure 14-2), while in conduction³³ and pacemaker tissue³⁷ of many species an increase in beating rate (BR) is observed (Figure 14-5). This positive chronotropic response to stretch is seen predominantly in mammals with low resting heart rates, such as guinea pigs, rabbits, cats, dogs, and humans. In fast-beating murine hearts, in contrast, sustained stretch reduces BR, although apparently via the same underlying mechanism: SAC_NS activation.³⁸

From a systematic point of view, early induction of the next heartbeat in response to increased venous return is advantageous, unless volume throughput is limited by inflow, such as in species with already very high heart rates. In species with an upright body posture, however, a chief and evidently overriding requirement for survival is the control of cardiac output pressure to ensure brain perfusion. Therefore, heart rate responses to hemodynamic stimuli that affect both venous return and arterial pressure, such as most changes in body posture (including standard tilt-table experiments), will be determined primarily by arterial pressure control patterns. This obscured the identification of the positive chronotropic response to stretch in human until Donald and Shepherd³⁹ dissociated the increase in venous return from arterial pressure changes, by passively elevating the legs of healthy volunteers in supine position, confirming the positive chronotropic response in humans.³⁹

Similar mechanosensitive behavior is believed to underlie the nonnervous component of respiratory sinus arrhythmia (RSA). Dynamic changes in thoracoabdominal pressure gradients favor venous blood return to the heart during inspiration, causing a relative increase in right atrial filling and an associated rise in heart rate. Although this mechanical component contributes little to RSA at rest (when modulation of vagal innervation is the dominant driver), it is a major cause of RSA during peak exercise in healthy subjects (when vagal tone is reduced, while respiratory effort and associated pressure gradients are enhanced),40,41 and explains the presence of RSA in heart transplant recipients.⁴¹

If mechanical modulation of the heart rate was the only physiologically relevant effect, one might be tempted to wonder why cardiac MEC has been preserved during evolution, against its pro-arrhythmic potential that could have exerted a negative selection bias. This question is somewhat misleading, of course, because we do not know the evolutionary cost of removing any trait (in particular if that trait per se does not conflict with reproductive probability). It is possible, however, that the deleterious electrophysiologic manifestations of cardiac MEC are side effects rather than main targets of underlying mechanisms, akin to the arrhythmogenic potential of the sodium-calcium exchanger in calcium-overloaded cells, as a consequence of its electrogenicity, whereas its physiologic function is to maintain ion concentration gradients. Therefore, it is conceivable that MEC is a side effect of mechano-mechanic coupling, perhaps required for the adjustment of individual cells’ calcium concentration to external mechanical demand (see Summary and Outlook).

Transsarcolemmal Channels

Mechanosensitive ion channels can be found in the sarcolemma of most prokaryotic and eukaryotic cell types. The open probability of these channels is primarily modulated by mechanical stimuli, such as stretch (e.g., SAC) or cell volume changes (volume-activated channels; VACs). VACs in particular are believed to be a phylogenetically ancient theme, required to allow single-cell organisms to adapt to potentially drastic changes in osmotic pressure in their external environment.

The mammalian heart contains both SACs and VACs. SACs respond instantaneously to mechanical stimuli, whereas VACs tend to show a significant lag-time (up to minutes) between the onset of cell volume changes and ion channel response. VACs, possibly encoded by CIC-3,⁴² are understood to be important contributors to cardiac electrophysiology in chronic settings, such as ischemic or postischemic cell swelling and hypertrophy (where VAC are constitutionally active).⁴³ In the context of electrophysiologic responses to beat-by-beat changes in the mechanical environment, however, SACs are implied as a key mechanism underlying MEC.

SACs were discovered in the 1980s, initially in cultured avian skeletal muscle by Guhara and Sachs,² and confirmed in mammalian cardiomyocytes by Craelius et al.⁴⁴ SACs show either little selectivity for (predominantly monovalent) cations (SAC_NS, for nonselective), or they preferentially conduct potassium ions (SAC_K). These selectivity profiles determine their transmembrane current reversal potentials, which are half-way between AP-plateau and resting potentials for SAC_NS (usually between 0 and –25 mV), and close to the potassium equilibrium-potential for SAC_K (approximately –95 mV in cardiomyocytes).

Like other phenomenological classifications, mechanosensitive ion channel categories are not absolute, and there is overlap with other types of ion channels. Several mechanosensitive channels are also voltage or ligand sensitive, and vice versa, voltage or ligand activated channels can be modulated by their mechanical environment. Thus, the hyperpolarization-activated cyclic nucleotide gated (HCN) channel is mechanically modulated,⁴⁵ as is the adenosine triphosphate (ATP)-inactivated potassium channel (K_ATP), whose open probability is increased by stretch in atrial⁴⁶ and ventricular myocytes.⁴⁷ Mechanosensitivity could explain why these two ion channel populations appear to be less active when studied in vitro, compared with predictions based on in situ observations. The contribution of the funny current, i_f (HCN equivalent in cardiac pacemaker cells) to pacemaking, for example, could be underestimated under conditions of reduced external load, such as in isolated cell and tissue preparations. Likewise, in vitro activation of K_ATP channels can occur only after reaching abnormally low ATP levels in mechanically unloaded cells. This would be in keeping with the in situ observation that prevention of systolic stretch (or paradoxical segment lengthening) of ischemic myocardium, achieved using a tripodlike mechanical clamp, reduces or delays extracellular potassium accumulation in the anaesthetized pig.¹⁶

For practicality, SACs are therefore regarded as the channels whose open probability is primarily affected by the mechanical environment, and for whom mechanical stimulation in the absence of cell volume changes is sufficient to promote opening.

SACs typically respond to a range of mechanical stimuli, including local membrane deformation, changes in cell curvature, lateral compression, and axial stretch. Whether transfer of mechanical energy to the ion channel protein occurs mainly via the cytoskeleton, or via the lipid bilayer, is a matter of debate. It is likely that both are involved to individually varying degrees. Some SACs, such as the transient receptor potential channel (TRPC1), can be activated in pure lipid bilayers.⁴⁸ Other SACs are sensitive to cytoskeletal integrity, which could either promote or prevent their opening.⁴⁹

The actual mechanisms of cardiac SAC activation are not well established. Open and closed state data from large conductance prokaryotic mechanosensitive channels (MscL) have identified one mode of action. This action involves an irislike increase in pore dimensions during channel opening, involving an increase in the outer circumference of the protein in the plane of the sarcolemma, combined with a reduction in transsarcolemmal dimensions.⁵⁰ These configurational changes would be favored by increased lipid bilayer tension and by membrane thinning, both of which could underlie the mechanosensitive gating of the channel. In this context, any channel whose area projection in the plane of the cell membrane increases during opening should be sensitive to lipid bilayer tension. The question “why do SAC channels exist?” could be replaced, therefore, by asking “should not more channels be at least modulated by their mechanical environment?” Recent reports indicate that the range of mechanically modulated ion channels is indeed significantly larger than generally assumed.^45,51

At the same time, no sequence or structure homologues of MscL have been identified in mammalian myocardium. However, recent evidence suggests that TRPC channels (such as TRPC1⁴⁸ or TRPC6⁵²) underlie cardiac sarcolemmal SAC_NS, whereas cardiac SAC_K appear to include two pore-domain channels (e.g., TREK-1),⁵³ inwardly rectifying channels (e.g., K_ir),⁵⁴ and ligand-activated channels (e.g., K_ATP, BK_Ca).^46,55 Another promising candidate is formed by piezo proteins that have been shown recently to assemble into large (protein-tetramers containing more than 100 transmembrane domains) mechanosensitive channels in a range of species, from flies to mammals.⁵⁶

Detailed functional description of SAC has been complicated by the fact that some of them (in particular SAC_NS) appear to be located in membrane areas that are not easily accessible to patch-clamp investigations in adult mammalian ventricular cells, such as T-tubules⁵⁷ and caveolae.⁵⁸ Single-ion channel data have therefore been obtained mainly on neonatal or atrial cells.

Nontranssarcolemmal Channels

In addition to transsarcolemmal SACs that allow ion flux between cell interior and extracellular spaces, ion channels in certain subcellular compartments may be mechanosensitive. These compartments include the sarcoplasmic reticulum (SR), mitochondria, and the nuclear envelope.

Calcium release from and reuptake into the SR have been shown to be modulated in cardiac cells by the mechanical environment, chiefly invoking length-dependent changes in calcium buffer capacity of contractile filaments and direct or secondary effects of transsarcolemmal ion fluxes (e.g., Ca²⁺-fluxes, or Na⁺-fluxes that affect the Ca²⁺-balance via sodium-calcium exchange). However, SR calcium release events (“sparks”) become more frequent during acute axial stretch, even in resting cardiomyocytes and in the absence of extracellular sodium and calcium (Figure 14-6).⁵⁹ Similarly, stimulation of cultured atrial and ventricular cardiomyocytes by the application of small fluid jets can increase calcium spark rate in a way that appears to draw on mitochondrial calcium.⁶⁰

In other cell types, the nuclear envelope has been found to contain SACs that contribute to calcium signaling in this domain,⁶¹ and it would not be surprising if the same applied to the heart.

Finally, connexin channels can be mechanosensitive. Connexins are best known for linking the cytosols of two contacting cells; although “sarcolemmal,” they do not connect a cell’s inside to the outside in this configuration. Noncardiac connexin46 has been shown to be mechanosensitive.⁶² It will be interesting to see whether the same applies to cardiac isoforms, such as connexin43, whether located in the sarcolemmal or in the internal membranes of cardiac mitochondria.⁶³ In fact, mitochondria could be more important players in cardiac MEC than customarily assumed, because they are able to generate significant intracellular forces during mitochondrial swelling,⁶⁴ and hence possibly link metabolic disturbances to mechanisms involved in MEC.

Cell-Level Responses

Whole-cell SAC currents have been recorded from most cardiomyocyte types, including SAN pacemaker cells, Purkinje fibers, and atrial and ventricular myocytes. Their effects on cellular electrophysiology depend on the effective stretch target (SAC_NS or SAC_K), stretch timing (relative to the cardiac cycle), and stretch characteristics (e.g., rate of rise, amplitude).

As a rule, diastolic stretch gives rise to depolarization if it is of sufficient amplitude to cause any changes in membrane potential (V_m; Figure 14-8). This can best be explained by the activation of SACs whose reversal potential is positive to the resting cell membrane (i.e., SAC_NS).

The effects of stretch during the AP are less clear, because AP shortening, crossover of repolarization, and delayed repolarization have all been reported. Some of this discrepancy could be explained by differences in recording techniques, which can affect stretch targets. For instance, sharp electrodes and a perforated or ruptured patch can give rise to opposite AP duration changes, hinging on differential effects of these techniques on the interaction between SACs and calcium handling.⁶⁸ Stretch configuration matters as well, because moderate stretch initially affects only AP duration (the AP plateau is electrophysiologically more labile than the resting potential), whereas more severe distension alters diastolic behavior, potentially causing crossover of late AP repolarization and EAD-like behavior (see Figure 14-8). Another confounding aspect is related to the repolarization level at which AP duration is measured. Because early AP shortening may coincide with late AP-prolongation, this can give rise to apparently contradictory changes in reported AP duration.

Whereas stretch of normal myocardium appears to preferentially target SAC_NS (whose block fully eradicates whole-cell current responses in isolated cells; see Figure 14-7), this could be different under conditions of metabolic impairment. Thus, K_ATP channels that are normally quiescent in atrial and ventricular cardiomyocytes respond to pipette suction⁴⁶ and axial stretch⁴⁷ when preactivated by a reduction in ATP concentration. Coactivation of a potassium-selective channel by ATP reduction and stretch will give rise to a less-positive reversal potential of the “net whole-cell current” induced by stretch in the ATP-starved heart. This might explain the reduced efficacy of PT (less efficient eradication of excitable gaps by reduced net inward current) in myocardium with severe metabolic impairment.⁴⁷

Stretch effects may vary not only with disease, but also with species, age, cell type, and location. For example, subendocardial ventricular cardiomyocytes appear to be more likely than subepicardial cells to respond to mechanical stimulation with EAD-like behavior.⁵ Differences in mechanosensitivity can be caused by (1) regionally or transmurally varying levels of relevant mechanical stimuli; (2) different mechanical properties of cell and tissue components involved in the transmission of external mechanical stimuli to the actual mechanotransducers; (3) variable expression or responsiveness of mechanotransducers; and (4) distinct electrophysiologic background properties of affected cells and tissues. The latter appears to underlie species differences in SAN pacemaker responses to mechanical stimulation.

The response of the SAN pacemaker cells to stretch seems to chiefly involve SAC_NS activation, as shown in rabbit SAN isolated cells during axial stretch.⁶⁹ The principal effects of stretch on SAN cell AP-morphology are qualitatively equivalent to those observed in SAN tissue (see Figure 14-5). They include (in addition to truncation of diastolic and systolic V_m-maxima) acceleration of spontaneous diastolic depolarization and of early AP repolarization, which can both act to increase pacemaker rate, combined with a slowing of late AP repolarization when V_m is below the SAC_NS reversal potential, which would prolong the pacemaker cycle and reduce beating rate if it dominated the response. In other words, SAN pacemaker potential changes that move toward the reversal potential of SAC_NS (–11 mV in rabbit SAN cells)⁶⁹ are accelerated by stretch, whereas those that move away from the reversal potential are slowed.

If one compares the SAN pacemaker potential waveforms of slow- and fast-beating mammalian heart (e.g., guinea pig or rabbit versus mouse or rat), it is apparent that murine SAN pacemaker potentials have a very different AP morphology: both upstroke and initial repolarization are extremely fast, followed by an extended late repolarization phase. The percentage of the pacemaker cycle during which V_m moves away from the SAC_NS reversal potential dominates murine SAN pacemaking (71% in mouse, compared to 46% in rabbit)⁶⁶; this might underlie the negative chronotropic response to sustained stretch, observed in murine hearts. Importantly, both negative and positive chronotropic responses to sustained stretch can be abolished by the application of GsMTx-4,⁶⁶ confirming the pivotal contribution of SAC_NS. Thus, identical mechanisms can give rise to opposite responses, depending on the electrophysiologic background of affected cells. This reemphasizes the need for caution when extrapolating observations between species, such as from mouse to human.

Of course, SAN tissue in situ will not normally be stretched throughout the entire cycle, and more refined experimental study designs are needed to apply mechanical stimulation in a cycle-dependent manner. In addition, it will be interesting to explore whether individual components of the “voltage- and calcium-clocks” that drive pacemaking are directly mechanosensitive in native SAN cells (e.g., HCN or SR-release channels) and whether effects secondary to other MEC-actions, such as changes in intracellular calcium concentration, determine pacemaker responses to stretch.⁷⁰

Tissue- and Organ-Level Effects

Cardiac arrhythmias are inherently multicellular phenomena, and it is therefore necessary to understand mechanisms, modulators, and outcomes of cardiac MEC at tissue and organ levels. However, linking macroscopic to microscopic events is not without challenges in multicellular biologic systems.

On the “input side,” quantification of mechanical interventions is even more difficult in tissue than it is in cells, where sarcomere length can be used as an indicator of strain, or in membrane patches where deformation can be optically monitored, at least in principle. In most tissue preparations—except for trabeculae, thin papillary muscles, and live tissue slices—mechanical deformation usually cannot be quantified or graded with respect to subcellular or cellular strains. In the absence of cell deformation data, the characterization of externally applied mechanical stimuli is helpful. However, because of complex viscoelastic tissue properties that confer a strong time-varying component to the translation of external interventions to effective stimuli for MEC, this is a restricted surrogate measure only.

On the “output side,” many of the standard techniques used to record electrophysiologic consequences of mechanical stimulation in tissue and organ preparations report ensemble properties (including ECG, MAP, and optical mapping). In this context, it is important to recall that the heart contains a large number of different cell types, the majority of which are not cardiomyocytes. These types include endothelial cells, fibroblasts, smooth muscle, and intracardiac neurons, all of which are mechanosensitive and can affect cardiac electrophysiologic responses to mechanical stimulation. In addition, stretch can influence conduction velocity (reports in the literature are divided between increase, reduction, and no change, whereas reported effects depend on stretch amplitudes and could differ in conduction system versus working muscle),⁷⁰ which would be important for the interpretation of electrophysiologic ensemble data, and for their pathophysiologic relevance.

Given this complexity, the identification of SAC contributions to cardiac MEC in multicellular preparations has relied largely on pharmacologic probes. For most SAC types, specific and efficient openers are not available, whereas available blockers suffer from a lack of cardiomyocyte specificity, as well as the limitations discussed earlier. In addition, it is not sufficient for a blocker to be SAC specific at the single cell level, but it must also be effective upon acute application to native tissue. This is not necessarily the case for streptomycin,⁶⁶ which calls for careful interpretation, in particular of apparently negative observations at the tissue level.

Despite these notes of caution, the available evidence overwhelmingly demonstrates that block of SAC_NS abolishes stretch-induced changes in SAN pacemaker rate. It can also prevent the mechanical induction of arrhythmogenic triggers, such as single PVB,⁷¹ and the mechanical promotion of sustained arrhythmias, such as the preload-dependent amplification of burst-pacing–induced AF.⁷² In contrast, block of SAC_K can increase PVB inducibility.⁵⁵ Interestingly, however, SAC_K block may still prevent mechanically induced development of VF.⁷³ Whether this is caused by removal of an arrhythmia-sustaining effect (ectopic excitation is still observed), a shift in the space-time sensitive narrow vulnerable window for mechanical VF-induction, or another mechanism, remains to be confirmed.

So—What Next?

In addition to populating and interconnecting the pockets of current insight into MEC effects and mechanisms, there are a number of key challenges. These include:

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