Cardiac Mechano-Gated Ion Channels and Arrhythmias
Abstract
Mechanical forces will have been omnipresent since the origin of life, and living organisms have evolved mechanisms to sense, interpret, and respond to mechanical stimuli. The cardiovascular system in general, and the heart in particular, is exposed to constantly changing mechanical signals, including stretch, compression, bending, and shear. The heart adjusts its performance to the mechanical environment, modifying electrical, mechanical, metabolic, and structural properties over a range of time scales. Many of the underlying regulatory processes are encoded intracardially and are, thus, maintained even in heart transplant recipients. Although mechanosensitivity of heart rhythm has been described in the medical literature for over a century, its molecular mechanisms are incompletely understood. Thanks to modern biophysical and molecular technologies, the roles of mechanical forces in cardiac biology are being explored in more detail, and detailed mechanisms of mechanotransduction have started to emerge. Mechano-gated ion channels are cardiac mechanoreceptors. They give rise to mechano-electric feedback, thought to contribute to normal function, disease development, and, potentially, therapeutic interventions. In this review, we focus on acute mechanical effects on cardiac electrophysiology, explore molecular candidates underlying observed responses, and discuss their pharmaceutical regulation. From this, we identify open research questions and highlight emerging technologies that may help in addressing them.
Introduction to Cardiac Mechanosensitivity
History and Scope
The heart’s propensity to respond to mechanical stimuli with acute changes in its activity has been known for centuries. Early reports in the European medical literature describing mechanical effects on human heart rhythm date back to the 19th century, such as the communications by Nélaton1 and Meola2 on sudden death caused by precordial impact.3,4
At about the same time, Langendorff5 developed his isolated perfused heart model which, by the way, offers vivid illustrations of mechanosensitivity (eg, touch-induced ectopy). Building on the Langendorff-method, physiologists like Henry Bowditch, Joseph Coats, and Elias Cyon described effects of cardiac volume loading on contractility,6 nowadays commonly credited to subsequent defining work by Frank7 and Starling.8 Astonishingly, given the long history and vast importance of this mechano-mechanical feedback for autoregulation of cardiac output, the mechanisms underlying the Frank–Starling effect are still subject of debate.9
In parallel, first experimental evidence of mechano-electric feedback (MEF)10 was reported by Bainbridge,11 who showed that stretch of the right atrium, containing the heart’s primary pacemaker tissue, increases spontaneous beating rate. This “Bainbridge effect” is seen in the denervated heart, including human transplants,12–14 ex situ animal hearts,15–17 isolated tissue,18,19 and even single isolated pacemaker cells,20 highlighting the intrinsic nature of at least some of the underlying mechanisms. Conceptually related MEF effects are seen in cardiac myocytes21–24 and nonmyocytes,25–27 highlighting the potential relevance of cardiac MEF for heart function (more details on MEF are available in the collection of works from leading teams edited by Kohl et al28).
This review will focus on one of the contributors to mechanically induced acute changes in cardiac electrophysiology. Their effects are instantaneous, as opposed to more slowly occurring mechanical modulation of contractility, or even longer term mechanically induced changes in gene expression and cell/tissue remodeling. Several mechanosensors of potential relevance for acute MEF responses have been identified. They include enzymes (eg, mechanosensitive kinases), structural elements from molecules (eg, cytoskeletal and transmembrane linkage proteins) to membrane domains (eg, caveolae), or more complex assemblies (eg, contractile filament lattice and z-disks), but of particular interest are ion translocation mechanisms afforded by mechanically gated channels (MGC).
MGC may serve both as sensors and as effectors of MEF responses. Embedded in membranes, they convert mechanical stimuli, putatively including in-plane membrane tension, membrane thickness and curvature, as well as matrix–protein interactions, into electrical and biochemical signals. MGC can affect, therefore, a wide range of cellular processes, with response times in the millisecond domain relevant for acute cardiac MEF.
MGC were discovered in 1984 by Guharay and Sachs29 in embryonic chick skeletal myocytes. Four years later, Craelius et al30 published the first MGC recordings from mammalian cardiomyocytes. Since then, in addition to stretch-activated whole-cell currents, single-channel activity has been identified in a wide range of cardiac cells,31 including atrial myocytes,32 foetal,30 and (for potassium-selective MGC at least) adult ventricular myocytes,33 as well as cardiac nonmyocytes.27
In the 1990s, the first MGC was cloned from Escherichia coli (mechanosensitive channel of large conductance [MscL]),34 and the molecular nature of the first mammalian MGC was reported.35 Since then, an increasing number of MGC has been identified and a large proportion of them are expressed and functional in the heart (Figure 1).
Figure 1. Mechanically gated channel (MGC) and mechanically modulated channel (MMC) candidates are present throughout living organisms. Several mammalian channels have homologues in other organisms: for example, NOMPC, OSM9, TRP4, TRPY1, and LOV-1 are transient receptor potential (TRP) homologues; MEC channels are members of the DEG/ENaC (degenerin/epithelial Na+ channel) superfamily whose mammalian representatives are acid-sensing ion channels (ASIC); TPK is a homologue of K2P channels; Mid1 (mating induced death) is homologous to voltage-gated calcium channels. In red, channels expressed in the heart; underlined, channels clearly identified as MGC; *, channels with no known mammalian homologues. Only a selection of the more well-known channels and receptors is presented; protein names for mammals are explained in Cardiac SAC: Molecular Candidates section of this article. AchR, acetylcholine receptor; BK, big K+ channels; CFTR, cystic fibrosis transmembrane conductance regulator; CLC, chloride channels; KCNQ, K+ channel, voltage-gated, KQT-like; LOV, location of vulva; MCA, mechanosensitive Ca2+ channel; MscA, mechansosensitive channel archaeon; MSC, mechanosensitive channel of small conductance homolog in Chlamydomonas reinhardtii; MscK, L, M, S, mechansosensitive channel of K+, large, medium, small conductance, MscMJ, mechansosensitive channel of Methanococcus jannashii; mito, mitochondria; MSL, mechansosensitive channel of small conductance like; Msy, MscS homologues in fission yeast; NOMPC, no mechanoreceptor potential C; NMDA, N-methyl-d-aspartate; SACNS, stretch-activated channels, cation nonselective; SACK, stretch-activated channels, potassium selective; SR, sarcoplasmic reticulum; TREK, TWIK-related K+ channel; TRPA, M, N, P, and V, transient receptor potential ankyrin, melastatin, NOMP, polycystin, and vanilloid; TPK, 2-pore domain K+ channels; OSM, OSMotic avoidance abnormal family.
Because block of MGC in the mammalian heart can prevent certain forms of mechanically induced heart rhythm disturbances in the experimental setting,36,37 they form a putative therapeutic target. This has motivated the present assessment of what we know about them so far.
Channel Activation: Mechanical Modulation Versus Mechanical Gating
Mechanically Modulated Ion Channels Versus Mechano-Gated Ion Channels
Nomenclature
Ion channels, relevant for MEF, are characterized by their ability to change open probability in direct response to mechanical stimulation. Traditionally, mechanically gated ion channels have been classed according to the stimulus by which they were activated (eg, cell volume-activated channels [VAC], stretch-activated channels [SAC]; Figure 2). However, it is difficult to apply perturbations in a way that alters only one mechanical parameter, even if techniques for controlled mechanical stimulation of membrane patches have improved.38–40 In this paper, we refer to MGC as channels that can be activated by a mechanical stimulus alone. Channels that are normally activated by a different type of stimulus but with a gain that is affected by the mechanical environment, or those that require coactivation by nonmechanical stimuli, will be referred to as mechanically modulated channels (MMC).
Figure 2. Mechanically modulated channels (MMC) versus mechanically gated channels (MGC). Presentation includes channels understood to be activated by transmembrane voltage, ligands, stretch (stretch-activated channel, SAC) or intracellular volume change (cell volume-activated channel, VAC). In red: channels expressed in the heart. AchR, acetylcholine receptor; ASIC, acid-sensing ion channel; BK, big K+ channels; NMDA, N-methyl-d-aspartate; TREK, TWIK-related K+ channel; TRAAK, TWIK-related arachidonic acid-activated K+ channel; TRPA, C, M, and V, transient receptor potential ankyrin, canonical, melastatin, and vanilloid.
Voltage-Gated MMC
MMC normally classed as voltage-gated include potassium,41 calcium,42–44 and sodium45–47 channels. Mechanical modulation of Kv channels (K+ channel, voltage-gated) ranges from mechanically induced redistribution (eg, integration of Kv1.5 channels into the sarcolemma of rat atrial myocytes),48 to direct stretch-induced gating (eg, of Kir channels [K+ inwardly rectifying channel] in murine ventricular myocytes).49 Similarly, voltage-sensitive sodium channels can be affected by the mechanical environment (such as NaV1.5 [Na+ channel, voltage-gated] in human embryonic kidney cells).50 Modification of the channel stability at the membrane is another type of modulation and has recently been exemplified for the L-type calcium channel: polycystin-1, well-known to act as a mechanosensor in several cell types, can stabilize the entire pool of L-type channel proteins in rat cardiomyocytes.51
Mechanical modulation of voltage-sensitive channel gating is perhaps less surprising than often assumed, given that voltage sensing requires conformational rearrangements of the channel protein.52 If channel opening is associated with an increase in protein dimensions in the membrane plane, then the open state should be favored by increased membrane tension. That said the precise conformational changes of many ion channels are not known, and it is clear that not all channels are mechanosensitive in standard experimental conditions (eg, TWIK-related acid-sensitive K+ channels with TWIK standing for tandem of 2-pore K+ domains in a weak inwardly rectifying K+ channel).53
Ligand-Activated MMC
Both γ-aminobutyric acid and purinergic (P2X) receptors (P2X3 and P2X4 subtypes in particular) are expressed in the heart, although not in cardiomyocytes but in neurons and smooth muscle cells, respectively.54,55 They were suggested to participate in mechanotransduction processes, but their direct mechanosensitivity remains to be established. P2X4 is not activated by shear stress alone, and their role in mechanotransduction is suggested to stem from ATP release that can be mechanically induced by them, as shown in endothelial cells.56
Sarcolemmal KATP channels (K+ channel, ATP inactivated), discovered in cardiac myocytes in the early 1980s,57 are sensitive to their mechanical environment.58 These KATP channels are hetero-octamers comprising 2 subunits: the pore-forming subunit with 2 membrane-spanning regions (K+ inwardly rectifying channel [Kir6.1 or Kir6.2]) and the regulatory subunit sulfonylurea receptor (SUR1, SUR2A, or SUR2B).59,60 KATP channels are highly expressed in atrial and ventricular cardiomyocytes of murine models61,62 and in human heart.63
In normal metabolic conditions, KATP channels are inactivated. If ATP levels fall, KATP open probability increases. In the presence of stretch, this increase occurs at less reduced ATP levels.64 This may explain the difference between in vitro studies (where ATP levels have to be severely reduced to open KATP) and the in vivo setting (where stretch of cardiac tissue is present at all times and presumably elevated in regions with reduced ATP). It is thought that KATP channels are gated by local bilayer tension, and that this is affected by the cytoskeleton.65
KATP channels may have a protective role in ischaemia.66 Interestingly, stretch preconditioning, known to reduce ischaemia-reperfusion injury, is abolished by blocking KATP channels.67 Of note, cardiac KATP channels are also present and active in fibroblasts, suggesting that one must consider cardiac pre/postconditioning effects on cells other than just cardiomyocytes.68–70 As with other K+ channels, KATP opening favors re/hyperpolarization. Although beneficial in preventing spurious excitation of resting cells, this also shortens action potential (AP) duration and reduces the refractory period. The latter could help to establish an arrhythmogenic substrate and support re-entry.
Channel Activation: Cell Volume Versus Stretch
VAC are generally regarded to be MGC. That said, their mechanism of activation in the heart is poorly understood. What is known is that increases in cell volume, whether by swelling71 or pipette-based cell inflation,72 tend to activate chloride71 or potassium conductances.32 Although cell volume changes undoubtedly cause mechanical deformation, VAC-activation tends to occur with significant lag times (tens of seconds to minutes) after the onset of cell volume changes.73 This has put into question the role of direct mechanical stimuli as drivers of VAC gating, and it has been suggested that swelling-induced changes in cytoskeletal structures must take place before mechanosensitive electrophysiological responses are seen.74
In terms of pathophysiological settings, cell swelling can be observed in ischaemia, particularly upon reperfusion,75 and VAC are understood to affect cardiac electrical behavior in these conditions. Interestingly, VAC-like Cl− conductances are constitutively activated in hypertrophied cardiomyocytes,71 lending credence to the notion that structural aspects of cardiomyocyte organization matter. Recently, LRRC8A (a leucine-rich repeat containing protein 8A, aka SWELL1) has been identified by two independent groups as an essential component of the ubiquitous volume-regulated anion channels.76,77 This discovery has been a result of genome-wide RNAi screens and provided a new molecular candidate to better understand cell volume regulation.
At the same time, the normal cycle of cardiomyocyte contraction and relaxation is not generally assumed to be associated with pronounced changes in cell volume. This, and the lag time for VAC activation, makes it unlikely that these channels are main contributors to acute, beat-by-beat MEF (for more information on cardiac VAC see review by Baumgarten and Clemo71).
SAC—the quintessential MGC—increase their open probability in direct response to membrane deformation. Evidence demonstrating that lipid bilayer forces are sufficient to gate SAC was obtained for several bacterial, fungal,78 and two vertebrate channels, TWIK-related K+ channels (TREK-1) and TWIK-related arachidonic acid-activated K+ channels (TRAAK).79,80 The small number of channels tested in this way is caused in part by technical difficulties to purify or produce functional channel reconstitutes in pure lipid bilayers. Also, several SAC are likely to require cytoskeletal and linker proteins,81 and/or possibly soluble factors or messengers for activation.82 Interestingly, mutations in cytoskeletal proteins have been linked to cardiac pathologies,83–86 including rhythm disturbances,87,88 though, thus far, this would not seem to act via effects on MGC but rather through effects on voltage-dependent channels and transporters that indirectly affect cardiac excitation–contraction coupling. Several biophysical models have been proposed to address energetic interactions at the membrane–protein interface and contributions of lipid organization or, in addition to in-plane stress, changes such as membrane thinning have been suggested as relevant atomistic-level stimuli.89–91 These models, mainly obtained from bacterial channels reconstituted in liposomes, suggest that MGC can be gated by forces from lipids in the range of hundreds of piconewton (eg, 220 pN for MscL).92 More broadly, including eukaryotic channels in the cellular context (ie, in the presence of the cytoskeleton), it seems that MGC are sensitive to a wide range of force intensities characteristic for living cells, from 2 to 10 mN/m (data acquired on cultured cells).93,94 To understand the mechanical gating of SAC, structural data are needed. So far, the structure of MscL95 and mechanosensitive channel of small conductance (MscS),96,97 as well as of mammalian TRAAK,98 Piezo1,99 and Big K+ (BK)100 channels, has been resolved at atomic resolution.
Channel Location: Sarcolemmal Versus Nonsarcolemmal
Sarcolemmal MGC
Single-channel patch clamp investigations require direct access of the pipette tip to the membrane containing channels, such as MGC. As the outer surface of the sarcolemma is easily accessible, it is the membrane from which most electrophysiological MGC data have been reported, so much so, that the notion of MGC seems synonymous with sarcolemmal ion channel. However, not all sarcolemmal channels are present at the accessible cell surface, as “hidden” cell surface membrane, such as in transverse tubules (T-tub) and caveolae, contains ion channels.101 In addition, MGC are present also on endomembranes of organisms such as plants102 and yeast,103 and there is evidence to suggest that the same may hold true for mammalian heart cells.21,104 Apart from BK channels, which appear in a range of endomembranes and whose mechano-gating is discussed controversially (see section on BK channels, below), the following MGC are interesting examples that warrant further investigation.
Nonsarcolemmal MGC: Sarcoplasmic Reticulum
Calcium handling in cardiac cells is mechanosensitive, involving mechanisms from changes in Ca2+ buffering and troponin-C binding, to Ca2+ fluxes.105,106 This includes Ca2+ releasability from the sarcoplasmic reticulum (SR), such as evident in an increased frequency of SR Ca2+ release events (sparks) upon acute mechanical stimulation, whether using axial cell stretch or local application of fluid puffs to deform isolated cells.21,104 Mechanisms underlying the stretch-induced increase in spark rate continue to be investigated and may include mechanical modulation of ryanodine receptor Ca2+-release channels of the SR.
This could have functional relevance not only for priming SR Ca2+ release and/or terminating it upon successful cell shortening, but it would also have the potential of affecting cardiac electrophysiology. If stretch promoted Ca2+ release from the SR, this could affect trans-sarcolemmal Na+/Ca2+ exchange and—in particular, in cells that are already Ca2+ overloaded (eg, in ischaemic conditions)—trigger ectopic excitation.34
Nonsarcolemmal MGC: Other Organelles
Mitochondrial KATP channels contribute to ischemic pre-107 and postconditioning,108,109 potentially protecting cells by maintaining ATP production during hypoxic episodes.110 Although the molecular identity of the cardiac mitochondrial KATP is still debated, it is possible that it shares mechanical modulation with its sarcolemmal counterpart (discussed in Ligand-Activated MMC section of this article).
The nuclear envelope shows significant deformation during application of mechanical forces to a cell.111–113 Nuclear mechanosensing is an underappreciated research area with significant importance for the understanding of mechanically induced changes in cell behavior.114 In terms of ion channels, TRPV4 (transient receptor potential channel, vallinoid, #4) was localized in cultured neonatal rat ventricular myocytes in the nucleus only,115 although functional data confirming actual ion channel activity of this protein are still outstanding.
Of course, for MEF to affect heart rhythm, transmembrane potential changes must occur, and the focus on sarcolemmal MGC is, therefore, not merely a consequence of conceptual restrictions or technical constraints (in terms of channel accessibility by recording tools) but related to the focus on functional responses of interest and, thus, the topic of this review.
Beyond cardiomyocytes: another questionable preconception is that the normal heart consists chiefly of cardiomyocytes. Although true in terms of volume fraction, nonmyocytes, such as endothelial and interstitial cells, outnumber muscle cells in the heart. Endothelial cells of the cardiovascular system possess MGC,116–118 and so do fibroblasts.119–121 Although presumably required for functions, such as shear sensing and directional extracellular matrix protein deposition in response to mechanical clues,122 ion channels in nonmyocytes may affect cardiac electrophysiology in the presence of heterotypic cell coupling in the heart. Such coupling seems to exist in native myocardium, both in normal123–125 and fibrotic/scarred tissue,126,127 as reviewed in detail elsewhere.128
Cardiac SAC: Molecular Candidates
Criteria and Terminology
Knowledge about molecular candidates for cardiac MGC has seen significant improvements over the past decade. Candidate proteins and protein families have emerged, and new, often complex regulatory contributions have been proposed. At the same time, specific information about mechanotransduction pathways remains relatively limited. To address present controversies, Arnadóttir and Chalfie129 suggested 4 criteria to establish whether or not a protein forms an ion channel that transduces mechanical forces and is relevant for organ function: 1) the protein must be expressed and localized in the mechanosensory organ; 2) the channel is required for mechanosensitive responses but not merely for normal development of the mechanoreceptor cell or signaling downstream of the stimulus; 3) alteration of channel properties (conductance, kinetics, sensitivity, and selectivity) alter the properties of mechanical responses; and 4) the channel should be gated mechanically in heterologous expression system. In the mammalian heart, proteins have not generally been assessed as yet for these 4 criteria, highlighting avenues for further investigation.
In this review, SAC are subdivided by their ion selectivity into K+-selective (SACK) and cation nonselective channels (SACNS).
Stretch-Activated Channels, K+-Selective
Kim32 described first whole-cell SACk currents (ISAC,K) in cardiac cells. SACK are outwardly rectifying and allowing potassium ions to move more easily out of the cell than into it. They have large single-channel conductances and inactivate in a time-dependent manner. Their activation causes membrane re- or hyperpolarization.64 Single-channel recordings of ISAC,K in adult mammalian cardiac myocytes have been obtained from atrial32 and ventricular myocytes.33,130,131 ISAC,K is thought to be carried by K2P (K+, 2 P domain; a P domain is a short amino acid segment between 2 transmembrane helices that contributes to formation of the inner part of the pore, acting as a selectivity filter) channels expressed in the mammalian heart.132 The most studied among them is TREK-1.
TREK and TREK-Like Channels
TREK-1 is active over a range of physiological membrane voltages. Channel gating is polymodal, activated by an impressive number of stimuli including intra- and extracellular pH, temperature, fatty acids, anesthetics, and crucially, membrane deformation (curvature) or stretch.133
TREK-1 expression appears distinctly heterogeneous in the heart, with a gradient of mRNA expression that increases transmurally, from subepicardial to subendocardial myocytes.134,135 This heterogeneity seems to correlate with transmural changes in MEF sensitivity, whereas stretch causes the most pronounced AP shortening in the subendocardium.136,137 However, although TREK-1 mRNA expression was observed in murine atria and ventricles,132,134,138,139 it has not, to our knowledge, been found in the human heart.140,141 That said, whole-tissue mRNA, and even protein assays, are not necessarily true reflections of presence, let alone relevance, of a target, which may derive importance from high expression in a minority cell population (cardiac Purkinje fibers would be an example).
Where observed, TREK-1 protein appears to be arranged in longitudinal stripes on the surface of cardiomyocytes: a pattern that could support directional stretch sensing.131 Whole-cell currents exhibiting the characteristics of recombinant TREK-1 (including sensitivity to volatile anesthetics, arachidonic acid, pH, internal acidification, and stretch) have been observed in atrial and ventricular myocytes of several species including rat, mouse, and pig.137,142
In terms of functional relevance, TREK-1 contributes to the “leak” potassium conductance in cardiomyocytes.137,143 As such, it aids normal repolarization and diastolic stability. However, increased TREK-1 current, for example during stretch, could shorten AP duration to a degree where this becomes proarrhythmic.136 In keeping with this, several well-established antiarrhythmic drugs, including lidocaine, mexiletine, propafenone, carvedilol, dronedarone, and vernakalant, inhibit TREK-1.142
TREK-2 shares functional similarity with TREK-1, although little is known about its functional relevance in the heart. It appears active in chicken embryonic atrial myocytes,144 and it is expressed in rat atria.132
TRAAK is a TREK-1 homologue with similar biophysical properties and regulation,145 expressed in the human heart132,146 TRAAK might form a human TREK-1 homologue, but its specific functional relevance in the heart is not yet known.
The similarity of electrophysiological properties of TREK-1, TREK-2, and TRAAK, and the overwhelmingly high expression levels of TREK-1 in murine model systems, may explain the paucity of experimental data on TREK-2 and TRAAK function. It is possible to differentially study them, as volatile anesthetics activate TREK-1 and -2, but not TRAAK,147 whereas extracellular acidification inhibits TREK-1 but activates TREK-2.148 Detailed characterization of the functional relevance of these MGC in mammalian heart in general, and in human tissue in particular, is a prerequirement for consideration of their pathophysiological relevance and therapeutic target potential. This has, by and large, yet to occur.
BK Channels
BK channel activation is polymodal for a range of gating stimuli, which has given rise to different names for the same type of ion channel in a variety of studies (eg, SAKCA, BKCa, SLO1, MaxiK).149 They are present in a number of cell and tissue types, including vascular smooth muscle, atrium, and ventricles.150 BK channels are found not only in the sarcolemma but also in membranes of the endoplasmic reticulum, the Golgi apparatus, and mitochondria.149
Mechanosensitivity of BK channels was established in membrane patches excised from cultured embryonic chick ventricular myocytes.151 However, as BK channels are activated by voltage changes and by alterations in intracellular Ca2+ concentration,150 it has been suggested that their mechanosensitivity is indirect, occurring secondary to stretch-induced changes in intracellular Ca2+ concentration.152
As implied by their name, BK channels have large conductances. They have been suggested to contribute to heart rate control153 and to offer cardioprotection during ischaemia.154 Genetic variants of BK have been related with increased severity of systolic and general hypertension, as well as increased risk of myocardial infarction.155
Stretch-Activated Channels, Cation Nonselective
Following on from the discovery by Guharay and Sachs29 of stretch-activated ion currents in avian skeletal muscle, Craelius et al30 identified SAC whole-cell currents in mammalian heart muscle. This current had the typical linear current–voltage relationship of weakly selective ion channels, which we now attribute to SACNS (ISAC,NS). In contrast to SACK, SACNS have smaller conductances and a reversal potential closer to 0 mV. With the reversal potential being positive to the resting potential of working cardiomyocytes, activation of SACNS will depolarize resting heart muscle cells, potentially triggering premature or ectopic excitation.64
In contrast to SAKK, no SACNS single-channel recordings have been obtained from freshly isolated adult ventricular cardiomyocytes. This has led to the suggestion that SACNS may be hidden from patch pipette access, in membrane regions such as T-tub,156 caveolae, or at intercalated discs.157 A recent report suggests that α1A adrenergic agonists may cause translocation of a putative SACNS (transient receptor potential channel, canonical [TRPC]6) from T-tub to the sarcolemma.158 Whether this occurs physiologically, and the extent to which it might serve as a useful experimental intervention to facilitate single-channel recordings of TRPC6 in adult ventricular myocytes, remains to be explored.
The main molecular candidates for SACNS are Piezo and transient receptor potential (TRP) channels.
Piezo1 and 2
The discovery of Piezo1 and 2 by Coste et al40 represents a breakthrough in the field of mechanotransduction. Piezo proteins form true SAC that meet the 4 criteria listed above. Stretch activation was demonstrated by heterologous expression of Piezo1 in human embryonic kidney cells, which induced robust ISAC,NS. Purified Piezo1, reconstituted into asymmetric bilayers and liposomes, forms ruthenium-red (a well-established pore blocker) sensitive ion channels, demonstrating that Piezo1 proteins are a pore-forming subunit of the channel.159 Further investigation is required to clarify whether Piezo1 ion channel subunits are intrinsically mechanosensitive.
Currently, no functional data have been published on Piezo1 or Piezo 2 in the heart. However, as Piezo channel properties are similar to those of endogenous cardiac SACNS, including (weak) voltage dependency, single-channel conductance, inactivation, and sensitivity to Grammostola spatulata mechanotoxin #4 (GsMTx-4),160 it is tempting to think that Piezo contributes to cardiac MEF.161
In terms of mRNA expression, Piezo1 has been observed in murine heart,40 albeit at low levels in comparison with expression in lung, bladder, or skin. However, mRNA or protein expression in tissue should be interpreted with caution. The two do not necessarily correlate to one another,162 and even if protein expression is confirmed, it does not necessarily prove the presence of functional ion channels. Vice versa, low expression levels do not rule out functional relevance of a protein, in particular, if it is present in a minority cell population (such as Purkinje fibers, whose mechanosensitivity was subject of the paper that coined the term cardiac MEF).10
This is an exciting and area of dynamic development. Basic science questions concerning structure, protein partners, and regulation of Piezo channels need to be addressed, as does the question of whether they are present in, and relevant for, the human heart.
TRP Channels
Most mammalian TRP channels act as nonselective cation channels, passing Na+, K+, and in some cases Ca2+. They are widely expressed, involved in a variety of cell functions, and characterized by polymodal regulation.163 Although the presence and extent of direct stretch activation of these channels have remained controversial, results from heterologous expression systems suggest that some TRP are good SACNS candidates.
TRPC6 stretch activation was characterized in human embryonic kidney cells164 but was not confirmed in CHO and COS cells (CHO is a Chinese hamster ovary cell line; COS is a transformed monkey kidney fibroblast cell line).82 It has been suggested that TRPC6 requires the angiotensin II type 1 receptor to be mechanosensitive.163,165 TRPC6 is among a small number of SAC candidates that are highly expressed in human heart homogenates.166 In mouse heart, TRPC6 appears localized in T-tub and, in agreement with this observation, detubulation inhibits ISAC,NS in murine ventricular cardiomyocytes.49 Whole-cell patch clamp experiments on mouse cardiomyocytes identified robust ISAC,NS in response to shear stimuli, which was inhibited by pore-blocking TRPC6 antibodies.49 Murine TRPC6 knockout models suggest that the channel contributes to the slow force response and may be involved in Duchenne muscular dystrophy,167 highlighting the potential clinical relevance of TRPC6 manipulation. In nonmyocytes, TRPC6 is proposed to promote myofibroblast transdifferentiation, and it could act as a positive regulator in wound healing.168 Putative roles, both in myocytes and nonmyocytes, make this channel an interesting target for therapeutic intervention.
TRPC1 mechanosensitivity is discussed controversially. Stretch activation of TRPC1 was first shown in Xenopus oocytes169 but has not been confirmed in other expression systems.82 Like TRPC6, this channel is likely to require the presence of a partner protein. Caveolin 1 has been reported to be a trafficking regulator of TRPC1.170,171 As caveolae are highly dynamic membrane regions, whose sarcolemmal integration is dynamically modulated by acute and sustained stretch,172,173 this observation points to the possibility that TRPC1 is mechano-modulated but not mechano-gated.
TRPC3 protein has been identified in rat ventricular myocytes, where it is located in T-tub.174 In mouse neonatal cardiomyocytes, this channel is involved in reactive oxygen species production in response to mechanical stimulation or to perfusion of 1-oleoyl-2-acetyl-sn-glycerol (OAG), a nonspecific activator of MGC.174 Recently, TRPC3/4 and 6 channels have been shown to contribute to pathological structural and functional remodeling after myocardial infarction.175 Blocking these channels is suggested to reduce pathological remodeling and to improve contractility, making TRPC channels new therapeutic targets in the context of postmyocardial infarction.
TRPV2 is expressed in mouse heart157,176 and has been reported to be activated by both cell volume changes and patch pipette suction.177 Using the TRPV2 agonist probenecid in wild-type and TRPV2 constitutive knockout mice, it was proposed that this channel contributes to baseline function of the cardiac calcium-handling machinery.176 Like TRPC6, TRPV2 combines this putative physiological role with potential contributions to dystrophic cardiomyopathies in pathological settings. TRPV2 is overexpressed in dystrophic cardiomyocytes and contributes to Ca2+ influx. Interestingly, in cardiomyocytes challenged by osmotic shock, TRPV2 trafficking is impaired, leading to an accumulation of the protein on the sarcolemma and along T-tub, instead of their normal preferred location in the membranes of internal Ca2+ stores.178
TRP melastatin (TRPM) 4 is expressed in cardiomyocytes of several species including mouse, rat, and human.165 It has been implicated in stretch-activated responses of vascular smooth muscle.179 Overexpression of TRPM4 may be involved in an inheritable form of progressive familial heart block type I,67 though perhaps via mechanisms not directly related to TRPM4 mechanosensitivity. Its physiological role in the heart is currently unknown.
TRP polycystin (TRPP) 2 is primarily found on the endoplasmic/SR and in primary cilia.180 However, a TRPP2-like protein seems to function as a channel in the plasma membrane of rat ventricular cardiomyocytes,181 acting as a modulator of the cardiac ryanodine receptor.182 Given its contribution to intracellular calcium cycling, TRPV2 dysregulation has been suggested to be involved in the development of heart failure.183
Pharmacological Modulators
The best-known pharmacological tools to alter SAC activity are blockers of limited specificity, including gadolinium ions, amiloride, and cationic antibiotics (streptomycin, penicillin, and kanamycin). Caution is needed, in this context, when interpreting research on stretch effects in cultured cells, as standard media contain antibiotics that may alter (reduce) background availability of SAC.
Despite of their limited selectivity, the above SAC blockers have been highly productive for experimental cell research, as reviewed elsewhere.93,184 Their utility in whole animal or human studies is limited though. Thus, gadolinium is chelated almost completely in solutions that contain physiological pH-buffer systems,185 while clinically used compounds (amiloride, antibiotics) exert their effect primarily and predominantly via their established pharmacological targets, rather than possible (side-)effects on SAC. Also, not always is in vitro behavior indicative of in situ response patterns. Thus, streptomycin’s ability to block stretch responses in isolated cells185 is not necessarily preserved over the same concentration ranges and response times in native tissue,186 highlighting the possibility of false-negative findings on SAC contributions probed using the antibiotic in more integrative model systems.
A number of other clinically applied compounds affect molecular SAC candidates with a relatively narrow spectrum of action. TREK-1 activity, for example, is modulated by the neuroprotective agent riluzole (10−100 μM), the antidepressant fluoxetine (Prozac; IC50–10 μM), and millimolar concentrations of volatile halogenated and gaseous general anesthetics,145 in the case of channel activation with the potential for unexpected false-positive effects in studies on anaesthetized mammals.
Among the few specific SAC inhibitors identified is the peptide GsMTx-4,160 isolated by the team of Fred Sachs from a Chilean tarantula venom.187 In contrast to SACK, SACNS are distinctly sensitive to this peptide, although the mechanism of this specificity is unknown. GsMTx-4 inhibits TRPC5,73,188 TRPC6,164,189 and Piezo1 channels, when applied to the external membrane.190,191 Both the d and l enantiomers of GsMTx-4 block SACNS, showing that the mechanism of action is not stereospecific or chiral.192 Instead, the action of GsMTx-4 is thought to involve insertion into the outer membrane leaflet (GsMTx-4 is an amphipath) in the proximity of the channel, relieving lipid stress sensed by the channel and favoring the closed state of SAC.192 Counterintuitively, GsMTx-4 sensitizes bacterial MscS and MscL to increased tension,193 although it has no effect on TREK-1.190 The mode of action of GsMTx-4 on SAC requires further elucidation.
A SACK specific blocker is Spadin. It inhibits TREK-1 mechano-gating,194 without affecting TREK-2 and TRAAK.194 Additional TREK-1 modulators, including activators, have recently been identified by Bagriantsev et al,195 and the utility of these compounds for cardiac MEF research awaits exploration. Cardiac potassium-selective MMC that have been probed using specific inhibitors include KATP channels. The mitochondrial KATP is inhibited by the 5-hydroxydecanoate (5-HD), whereas HMR-1098 (Aventis Pharma) has been identified as an antagonist for the sarcolemmal KATP.110,196 Glibenclamide is also a popular pharmacological tool, inhibiting sarcolemmal KATP from either side of the membrane.197
Concerning TRP channels, TRPC6 antibodies have been used as specific inhibitors of stretch responses in isolated cells.49 More generally, TRPC6 is modulated by hyperforin,198 TRPV1 by capsaicin,199 TRPV2 by probenecid,200 and TRPM4 by 9-phenanthrol.201
If specific inhibitors are rare, even fewer specific activators have been identified. Recently, Yoda1 has been shown to be an agonist for both human and mouse Piezo1, affecting sensitivity and inactivation kinetics of the channel. This compound does not act via protein partners of the channel as it is still efficient in artificial bilayers.202 If confirmed in native heart tissue, it would represent a powerful tool to investigate Piezo1 functions in integrated systems, especially if the channel was closed in physiological conditions.
The potential for MGC and MMC modulators as pharmacological tools in heart rhythm management has been expertly reviewed by White.106 Considering the ubiquitous presence of these channels in all cell types of the human body, pharmacological interventions targeting a specific organ are challenging, requiring selective delivery and avoidance of side-effects on other body functions. A possibility here is genetic targeting, with the potential of not only aiming for a specific organ, but for a specific cell type in that organ (cardiomyocytes, endothelial, interstitial or immune cells, etc.) or a defined disease progression stage. Again, this is a domain of research requiring additional effort/focus.
Mechanistic Projection Between Levels of Investigation
The heart generates, experiences, and responds to a highly dynamic mechanical environment. Parameters relevant for cardiac mechanoreception change dynamically and on a range of different time scales, from years (eg, ontogenesis, disease development, or aging) to fluctuations that are circadian (eg, physical activity), spread over tens of seconds (eg, respiratory cycle induced alternations in venous return), or happen in milliseconds (eg, mechanical activation during a heartbeat). MGC are, jointly with phototransduction systems, among the most rapid sensors in biological systems, although they may make contributions over the whole range of time scales mentioned above.
Knowledge about SAC contributions to chronic cardiac conditions is limited, although they have been implicated in the development of cardiac hypertrophy and heart failure.203–205 Identification of causal chains of events is difficult in chronic disease, as a host of relevant parameters, from tissue and cell viscoelastic properties to ion channel expression,206 remodel.
Projection from SAC activity to cell and tissue levels during acute stretch-induced changes in cardiac electrophysiology is more straightforward. Activation of SACK, with their reversal potential negative to the resting membrane potential of cardiac cells, will tend to hyperpolarize resting cells. SACNS, in contrast, with reversal potentials typically between 0 and −20 mV in cardiac cells, will depolarize resting cells, if sufficient current flow is generated.207 Interestingly, all stretch-induced changes in resting membrane potential of cardiac myocytes reported so far involve depolarization, up to and including mechanical induction of AP.15 Resting membrane depolarization can be explained by SACNS but not by SACK, suggesting that the latter do not normally determine acute electrophysiological response patterns of the heart to diastolic mechanical stimulation.
Matters get more complicated during the AP, when timing of mechanical stimuli warrants closer examination. Although SACK activation would continue to have a re- or hyperpolarizing effect, SACNS will do so only while membrane potential levels are positive to the SACNS reversal potential. As a consequence, SACNS activation will shorten AP duration during early repolarization but may, if sustained or applied late in the AP, give rise to late AP prolongation, or even after-depolarization-like events (Figure 3). Indeed, both early and late stretch-induced after-depolarization-like behavior have been reported in cardiac research.64 If suprathreshold, these may mechanically trigger ectopic excitation.208
Figure 3. Stretch greatly modifies the action potential (AP). Representative recordings showing the effect of stretch intensity on AP and resting membrane potential in single isolated cardiomyocytes. Stretch was applied during the entire duration of recordings, scaled to control cell length (left, moderate stretch; right, large stretch); black, control recordings; red, stretch. Red arrows indicate putative contributions of SACNS and blue arrows represent potential effects of SACK. Based on Kohl et al.3
Timing dependence of stretch effects on cellular electrophysiology matters also for the projection from cell to organ/organism levels, as both electrical activation and repolarization are characterized by a wave-like behavior across the heart. This means that the ECG offers an inherently limited temporal reference for characterization of local events, as illustrated in more detail in Clinical Relevance section of this article.
Quantitative projection from molecule to organism, including elucidation of spatiotemporal modulators of stretch responses, has benefitted from computational modelling.209–211 Interestingly, the vast majority of observed acute electrophysiological responses of the heart to stretch can be successfully reproduced simply by invoking SACNS.212
Of course, computational demonstration of quantitative plausibility is neither proof nor replacement of experimental validation. Occasionally, validation trails computational predictions by a decade or more. An example is models of impact-induced arrhythmogenesis (aka Commotio cordis [CC], agitation of the heart, without structural damage),3,4 which—using 2D213 and 3D214 simulations—concluded that the rare but devastating CC-induced ventricular fibrillation (VF) requires spatiotemporal overlap of mechanically affected tissue with the trailing edge of the repolarization wave. This has now been confirmed experimentally (see also Clinical Relevance section of this article).215
Among the present challenges in projecting from protein to pathology is the difficulty of assessing and comparing actual effective mechanical parameters of ion channel stimulation. Few studies have quantified the stretch imparted upon patch-clamped membranes during SAC investigations.216 At the cell and tissue level, cell or sarcomere length are used as a readout of strain,217 and occasionally as an input parameter to gauge mechanical modulation of cardiomyocytes.24,218 In native heart, implanted ultrasonic transducers,219 echo, and magnetic resonance imaging220 have all been applied to characterize transmural deformation patterns. But, and this is a crucial limitation, none of these techniques allows one to actually measure stress/force inside the preparation (whether a membrane patch, a cell, or a tissue/organ). An exciting development here is the advent of fluorescent force reporters,221 whose application to cardiac MEF research could revolutionize concepts and understanding of cardiac mechanosensitivity.
Clinical Relevance
In terms of physiological beat-by-beat effects, activation of SAC has been shown to underlie the non-neural component of the stretch-induced increase in spontaneous sinoatrial node cell pacemaking rate, aka the Bainbridge effect.20 Block of SAC using GsMTx-4 (but not using streptomycin, see Pharmacological Modulators section of this article) terminates this positive chronotropic response in native sinoatrial node tissue explants186 which, in its guise of a respiratory sinus arrhythmia, persists at whole body level—even in heart transplant recipients and/or after additional pharmacological denervation.222
Surprisingly, this is about all we know for sure regarding the physiological relevance of SAC in heart rate and rhythm regulation.
It is possible, perhaps probable, that the key role of cardiac SAC under normal conditions is related to autoregulation of contractile behavior. This could occur via stretch-dependent adjustment of trans-sarcolemmal Ca2+ influx,223 preservation of intracellular Ca2+ secondary to stretch-induced trans-sarcolemmal influx of Na+,152,224 and/or stretch-modulated grading of Ca2+ release from the SR.21 Any or all of these mechanisms could contribute to both acute (Frank–Starling response)225 and sustained (slow force response)226 adjustments of cardiac contractility to changes in the heart’s mechanical environment (highly relevant for contractile cells in the heart, given that they are not controlled via neuromuscular junctions, such as is the case in skeletal muscle), whereas their effects on cardiac electrophysiology would be secondary.
In contrast, SAC have been implicated in a host of clinically relevant scenarios, from acute arrhythmogenesis to sustenance and termination of arrhythmias, as explored next.
Mechanical Induction of Arrhythmias (Acute)
As mentioned before, stretch of resting myocardium, if strong enough to cause any change in membrane potential, gives rise to depolarization, potentially triggering ectopic excitation. In human volunteers, this has been shown to occur upon external mechanical energy delivery, such as by precordial tapping, at energy levels as low as 0.04 J (equivalent to dropping a golf ball [46 g] from a height of 9 cm).227,228 Mechanically induced ectopy is a common adjunct to intracardiac device-tissue interactions such as during cardiac catheterization,229 and it may even be triggered by the heart’s own mechanical activity, such as upon acute obstruction of ventricular outflow during balloon valvuloplasty.230
Mechanically induced ectopy is usually benign, but in the context of pre-existing pathologies, it may give rise to sustained tachyarrhythmias. In a porcine model of pathologically prolonged QT-intervals, for example, β-adrenergic stimulation by bolus injection of isoproterenol can give rise to ventricular after-contractions, originating from near-endocardial locations. These after-contractions precede early after-depolarization-like behavior in near-epicardial tissue. Upon reaching threshold for induction of ectopic excitation, this can initiate torsades de pointes.231
Much rarer than mechanically induced ectopy, but more widely known, is CC, in particular, in its most severe form of CC-induced VF. Here, a mechanical impact on the precordium, usually by a projectile such as an ice hockey puck or baseball, gives rise to acute MEF responses that, during a very narrow critical window of about 15–20 ms, can cause instantaneous induction of VF.232 The mechanisms underlying VF induction are discussed controversially, with focus either on abnormal repolarization233 or on abnormal excitation overlapping the trailing edge of normal repolarization.3 Also, the role of the impact-associated surge in intraventricular pressure is subject of debate, although it is accepted that local mechanically induced ectopy occurs in myocardium nearest to the site of mechanical stimulation, both in isolated heart215,234 and whole animal.234
Recent optical mapping studies of isolated heart models of CC have confirmed that SACNS are involved in the generation of ectopic excitation, and that deterioration into VF is seen only if ectopy occurs right on the edge of the preceding normal repolarization wave.215 This confirms prior modeling-based predictions213 and sheds further light on the unusually narrow critical window for mechanical induction of VF in whole animal studies: the precondition for overlap of mechanical stimulus and trailing repolarization edge is met for any specific precordial impact location for a brief part of the ECG cycle only (if one could mechanically stimulate other parts of the heart by extracorporeal impact, the accompanying critical time window would be shifted). Thus, the critical window for VF induction during CC exists in time and in space, highlighting that systemic (ECG) and local (AP) timings are not interchangeable.
Mechanical Sustenance of Arrhythmias (Chronic)
Mechanical contributions to chronic arrhythmias have been implicated in the perpetuation of both atrial235–237 and ventricular tachycardias.238 Mechanisms here may range from activation of SAC that alter AP duration,239 slow conduction velocity,173,235,238 or increase dispersion of repolarization,238 over changes in expression of mechanically modulated ion channels206 and alterations in connexin phosphorylation240 to remodeling of tissue architecture, composition,241 and innervation.242
Given the multiplicity of mechanisms and pathways involved and the variable time scales over which they manifest themselves, this area is understudied, in particular, with regard to ventricular arrhythmogenesis. A conceptually interesting approach to probing effects of sustained ventricular stretch in cardiac arrhythmogenesis has been employed by Waxman et al,243 who used the Valsalva manoeuvre to temporarily reduce ventricular volume overload in tachycardic patients, achieving spontaneous return to normal sinus rhythm. Because the intervention also works in heart transplant recipients,12 the most probable explanation is that sustained stretch is proarrhythmogenic.
The demonstration of tachycardia termination by temporary reduction in ventricular load highlights that chronic mechanical effects on heart electrophysiology are a clinically relevant target for further research. A perhaps particularly important aspect is the border zone of local (post-)ischaemic foci,244 where mechanically promoted arrhythmogenesis245 has been prevented in whole animal studies by application of a mechanical constraint that curtails ischaemic segment lengthening during contraction of the surrounding healthy myocardium.246 The same intervention delayed extracellular potassium accumulation, suggesting mechanical modulation of transmembrane ion fluxes, perhaps involving sarcolemmal KATP channels.
Mechanical Termination of Arrhythmias
Beyond removal of sustained overload, acute mechanical interventions, such as by precordial thump (“fist-aid”), have been known for at least a century to be of therapeutic potential.247 It is assumed that the short sharp impact on the chest is transmitted to the heart, where—presumably via activation of SACNS—it triggers ectopic activation in excitable tissue.248 Such activation can be used to pace the quiescent heart or to obliterate excitable gaps in hearts containing re-entrant activation waves.
The latter scenario is less straightforward, given that excitable gaps, in particular, in the presence of multiple re-entry pathways, are unlikely to be accessible from the limited extent of precordial impact locations. In addition, in conditions of severe pre-existing ischaemia, the depolarizing effect of SACNS activation may be off-set, in part, by ischaemic and mechanical coactivation of KATP channels,58 potentially rendering mechanically induced depolarization less effective.229 Accordingly, early hopes, based predominantly on (publication-bias prone) case reports249 for thump version of tachyarrhythmias, have not been sustained in more recent prospective human study designs.250–253 Accordingly, precordial thump application has been discouraged in recent advice by the International Liaison Committee on Resuscitation (ILCOR).254
Precordical thump-pacing in bradycardia or primary asystole, however, remains a potentially productive intervention,255,256 for example, to bridge between witnessed asystolic arrest and application of electrical device-based rhythm management.257 As evident form the 2010 ILCOR statement, precordial thump in asystole warrants further investigation, taking us full circle to the original 1920 paper by Schott,247 who kept patients with Stokes–Adams syndrome during episodes of intermittent atrioventricular conduction block conscious for extended periods of time by mechanical fist-pacing only.247
Outlook
By and large, acute electrophysiological responses of the heart to mechanical stimulation can be explained, qualitatively and quantitatively, through activation of SAC. This in itself does not prove that they are sole or main drivers of responses. But, given the ability of increasingly selective pharmacological tools to probe responses in model systems from patch to patient, it seems reasonable to consider these ion channels as clinically relevant targets for management or correction of cardiac electrical activity.
So—What Are the Challenges?
At the basic science end, the perhaps most important question relates to the mechanism(s) of activation of MGC. Mechanical stimuli span all scales form nano to macro (an overview of the sizes of main mechanosensitive structures and proteins can be found in Figure 4). Their quantification in living systems is particularly challenging at cellular and subcellular levels.
Figure 4. Size matters. Strain is greatly influenced by size and shape of affected structures and spans all scales from nano to macro. Tools to study mechanosensors are listed on the left in parallel with milestones. Membrane (blue), cytoskeleton (red), measuring probes (green), and others structures (black) are annotaed. Ø indicates diameter; AFM, atomic fore microscopy; MRI, magnetic resonance imaging; MSC, mechanosensitive channel; MscL, mechanosensitive channel of large conductance; TREK-1, TWIK-related K+ channel; T-tub, transverse tubule.
It is known from in vitro experiments that sarcolemmal in-plane tension, curvature and thickness, as well as lipid composition, affect MGC activity. In addition, the cytoskeleton can gate MGC. Nonsarcolemmal responses, such as the stretch-induced increase in calcium spark rate, require the integrity, here of microtubules.21 Sarcolemmal TREK channels are inhibited by actin,143 whereas Piezo1 channels need the actin cytoskeleton to fully activate.258 In addition, Piezo1 can be inhibited by the cytoskeleton-protein cross-linker filamin A in smooth muscle.259 Thus, the cytoskeleton may, cause MGC activation or protect them from opening. An additional layer of complexity arises from the fact that cytoskeletal integrity affects membrane tension and shape of the cell and its organelles.260 This may provide a further, potentially indirect, path to affecting MGC gating. Thus, even though MGC were discovered 3 decades ago, the actual biophysics of channel activation in vivo has remained elusive.261
That said, membrane stretch is usually taken to be the obvious driver of MGC activation, but what are the relevant properties and descriptors of such stretch? Existence and extent of in-plane tension in membranes of cardiac cells is not known. What is known is that lipid bilayers are not distensible (strain exceeding 2–3% of slack area causes membrane failure),262–264 so reservoirs (membrane invaginations, vesicles, caveolae)172,173,265 are known to buffer membrane tension variations via quick (<100 ms)266 membrane surface adaptation.267 Thus, in-plane membrane tension may not increase linearly with stretch, rising more prominently when some of the membrane reserves have been extinguished.268 This condition may be present in vitro more frequently than in vivo, as cells swell upon isolation, “losing” structurally identifiable caveolae, and hence, potentially biasing experimental observations. This could include either heighted mechanoresponsiveness or reduce differential stretch effects, as a result of preactivation of certain mechanosensitive pathways.
Related to tension (via the law of Laplace), but presumed to be an independent activator of MGC, membrane curvature is present both in the plasma- and in endomembranes. Effective strains are related to size and shape of mechanosensitive structures, and it is thought that curvatures only with radii in the range of ion channel dimensions (ie, few nanometers)269 will act as directly relevant signals. Although optical monitoring of membrane curvature in live samples (membrane patches and cells) is possible, this tracks larger radii only. A real understanding, therefore, of the biophysics involved in translating a macroscopic mechanical stimulus into a microscopic event, capable of increasing the open probability of an ion channel, is one of the key missing ingredients in developing a mechanistic understanding of mechano-electric coupling.
Thankfully, techniques are emerging that will allow quantification of mechanical properties experienced by individual cells in the tissue.
Förster resonance energy transfer-based tension probes have started to be used to assess dynamic changes in cytoskeletal tension, thus far in noncardiac cells. This measuring approach is based on the energy transfer between 2 chromophores whose distance changes as a function of the mechanical environment. As the efficacy of energy transfer (which is measured as a shift in emitted fluorescence) is inversely proportional to this distance with a power of 106, Förster resonance energy transfer probes are highly sensitive to minute changes in strain, and they can be used in vivo to characterize cytoskeletal tension in real time.221,277,278 A conceptually similar approach is being taken toward assessment membrane mechanical properties in native cells. Using a Förster resonance energy transfer tension probe, inserted into a mechanosensitive protein, it has been possible to track conformational changes at the ion channel level in living cells.279 Constructs like this could be used as tension reporters for various lipid bilayers, including nonsarcolemmal membranes.
At the applied end, one of the key challenges is to identify the molecular nature of individual ion channels involved in electrophysiological responses of the human heart to changes in the mechanical environment. Building on that, intervention tools that are organ-, or better cell- and/or disease-state specific, may hold a key to novel therapeutic opportunities.
A more long-term aim will be to decipher the complex pathways of mechanically induced changes in cell and tissue structure and function, which contribute to chronic responses to mechanical overload. Given that we are still unsure whether stress or strain is the key activators of MGC, it is difficult to decipher response patterns driven by volume- and pressure-challenges (or by pre- and afterload) in the whole organ.
The most complex setting—chronic overload combined with acute stretch (such as may occur in ischaemic border zone tissue)—is perhaps the clinically most relevant immediate target, as focal excitation occurs acutely and in relation to local stretch maxima. An MGC modulator that would be metabolic state specific (eg, perhaps pH-dependent) could potentially be applied systemically, yet act where needed. This is an area deserving targeted study.
Another challenge lies in the multiplicity of nonchannel structures that are mechanosensitive,280 making an understanding of the roles of mechanical forces more complex.
Caveolae are known to act as membrane reserves that can buffer variation of membrane tension. They were shown to limit VAC (ICl,swell) activation in rat ventricular myocytes267 and were implied as the substrate for stretch-induced conduction slowing (acting via mechanical unfolding, increasing effective surface membrane area).173
Also, caveolin 3 can modify integrin function and mechanotransduction in cardiomyocytes and intact heart,281 whereas caveolin 1 in endothelial cells of murine coronary arteries is a critical requirement for shear stress-mediated vasodilatation.282 Caveolins are also tightly linked to some TRP channels, making caveolae another most interesting component of mechanical transduction pathways, including those relevant for MEF.
Last, but not least, T-tub—sarcolemmal membrane invaginations that dive deep into the centre of cardiac myocytes—contains MGC (eg, TRPC6) and MMC (eg, Kir2.3).49 They deform rhythmically on a beat-by-beat basis172,283 and may be one of the more underestimated physiologically relevant mechanotransducers in the heart. For a more extensive overview of nonchannel structures involved in mechanotransduction processes, we refer to Hirata et al.280
Conclusion
MGC in the heart affect cardiac electrophysiology. Although mechanical activation of ion transport pathways may be an evolutionary inheritance of the need, even for the earliest cells to respond to osmotic challenges, SAC in (osmotically more stable) multicellular systems may have conferred other advantages. For muscle cells, this may include the adjustment of contractility to local mechanical demand. The fact that MGC carry ion currents that can affect heart rate and rhythm may, thus, be a side effect. But, even if so, it is one that matters for maintenance of normal heart rate and for the induction or termination of heart rhythm disturbances. Any therapeutic targeting will need to involve a 3-pronged approach that considers potential electrophysiological benefits in the context of the need to maintain volume regulatory capacity (say in ischaemia, and even more so, reperfusion) and the ability to tune cell contractility to the mechanical environment.284 In fact, the latter is particularly important for the heart as, in contrast to skeletal muscle, individual myocytes must match their mechanical performance to that of their neighbors in the absence of neuromuscular junctions or other cell external mechanisms to grade contractile activity. What is clear, therefore, is that any concept of cardiac electro-mechanical activity that ignores the information flow from mechanics to electrics is unnecessarily limited—and outdated.
This Review is in a thematic series on Mechanotransduction, which includes the following articles:
The Hippo Pathway in Heart Development, Regeneration, and Diseases [Circ Res. 2015;116:1431–1447]
Role of Mechanotransduction in Vascular Biology: Focus on Thoracic Aortic Aneurysms and Dissections [Circ Res. 2015;116:1448–1461]
Mechanotransduction in Cardiac Hypertrophy and Failure [Circ Res. 2015;116:1462–1476]
Mechanical Forces Reshape Differentiation Cues that Guide Cardiomyogenesis
Cardiac Mechano-Gated Ion Channels and Arrhythmias
Mechanotransduction in Myocyte Biology
Andrew McCulloch, Guest Editor
Nonstandard Abbreviations and Acronyms
| AP | action potential |
| BK | big K+ channels |
| CC | Commotio cordis |
| GsMTx-4 | Grammostola spatulata mechanotoxin 4 |
| KATP | K+ channel, ATP inactivated |
| MEF | mechano-electrical feedback |
| MGC | mechanically gated channels |
| MMC | mechanically modulated channels |
| MscL | bacterial mechanosensitive channel of large conductance |
| MscS | bacterial mechanosensitive channel of small conductance |
| SAC | stretch-activated channels |
| SACK | SAC, K+-selective |
| SACNS | SAC, cation nonselective |
| SR | sarcoplasmic reticulum |
| TPK | two-pore K+ channels |
| TRAAK | TWIK-related arachidonic acid-activated K+ channel |
| TREK | TWIK-related K+ channel |
| TRP | transient receptor potential |
| TRPA, C, M, N, P, V, Y | transient receptor potential ankyrin, canonical, melastatin, NOMP, polycystin, vanilloid, yeast |
| T-tub | transverse tubule |
| TWIK | tandem of two-pore K+ domains in a weak inwardly rectifying K+ channel |
| VAC | cell volume-activated channels |
| VF | ventricular fibrillation |
Sources of Funding
This study was supported by
Disclosures
None.
Footnotes
References
- 1.
Nélaton A. Elements de pathologie chirurgicale. Librairie Germer Bateliere et Co; 1876.Google Scholar - 2.
Meola F. La commozione toracica.Gior Internaz Sci Med. 1879; 1:923–37.Google Scholar - 3.
Kohl P, Nesbitt AD, Cooper PJ, Lei M. Sudden cardiac death by Commotio cordis: role of mechano-electric feedback.Cardiovasc Res. 2001; 50:280–289.CrossrefMedlineGoogle Scholar - 4.
Nesbitt AD, Cooper PJ, Kohl P. Rediscovering commotio cordis.Lancet. 2001; 357:1195–1197. doi: 10.1016/S0140-6736(00)04338-5.CrossrefMedlineGoogle Scholar - 5.
Langendorff O. Untersuchungen am überlebenden Säugethierherzen.Pflügers Archiv Eur J Phys. 1895; 61:291–332.CrossrefGoogle Scholar - 6.
Zimmer HG. Who discovered the Frank–Starling mechanism?News Physiol Sci. 2002; 17:181–184.MedlineGoogle Scholar - 7.
Frank O. Die Grundform des arteriellen Pulses.Z Biol. 1899; 37:483–526.Google Scholar - 8.
Starling E. The law of the heart (Linacre Lecture, given at Cambridge).Nature. 1918; 101: 43.Google Scholar - 9.
Campbell KS. Impact of myocyte strain on cardiac myofilament activation.Pflugers Arch. 2011; 462:3–14. doi: 10.1007/s00424-011-0952-3.CrossrefMedlineGoogle Scholar - 10.
Kaufmann R, Theophile U. Autonomously promoted extension effect in Purkinje fibers, papillary muscles and trabeculae carneae of rhesus monkeys.Pflugers Arch Gesamte Physiol Menschen Tiere. 1967; 297:174–189.CrossrefMedlineGoogle Scholar - 11.
Bainbridge FA. The influence of venous filling upon the rate of the heart.J Physiol. 1915; 50:65–84.CrossrefMedlineGoogle Scholar - 12.
Ambrosi P, Habib G, Kreitmann B, Faugère G, Métras D. Valsalva manoeuvre for supraventricular tachycardia in transplanted heart recipient.Lancet. 1995; 346:713.CrossrefMedlineGoogle Scholar - 13.
Bernardi L, Salvucci F, Suardi R, Soldá PL, Calciati A, Perlini S, Falcone C, Ricciardi L. Evidence for an intrinsic mechanism regulating heart rate variability in the transplanted and the intact heart during submaximal dynamic exercise?Cardiovasc Res. 1990; 24:969–981.CrossrefMedlineGoogle Scholar - 14.
Bernardi L, Keller F, Sanders M, Reddy PS, Griffith B, Meno F, Pinsky MR. Respiratory sinus arrhythmia in the denervated human heart.J Appl Physiol (1985). 1989; 67:1447–1455.CrossrefMedlineGoogle Scholar - 15.
Franz MR, Cima R, Wang D, Profitt D, Kurz R. Electrophysiological effects of myocardial stretch and mechanical determinants of stretch-activated arrhythmias.Circulation. 1992; 86:968–978.LinkGoogle Scholar - 16.
Blinks JR. Positive chronotropic effect of increasing right atrial pressure in the isolated mammalian heart.Am J Physiol. 1956; 186:299–303.CrossrefMedlineGoogle Scholar - 17.
Keatinge WR. The effect of increased filling pressure on rhythmicity and atrioventricular conduction in isolated hearts.J Physiol. 1959; 149:193–208.CrossrefMedlineGoogle Scholar - 18.
Markhasin VS, Solovyova O, Katsnelson LB, Protsenko Y, Kohl P, Noble D. Mechano-electric interactions in heterogeneous myocardium: development of fundamental experimental and theoretical models.Prog Biophys Mol Biol. 2003; 82:207–220.CrossrefMedlineGoogle Scholar - 19.
ter Keurs HE, Shinozaki T, Zhang YM, Zhang ML, Wakayama Y, Sugai Y, Kagaya Y, Miura M, Boyden PA, Stuyvers BD, Landesberg A. Sarcomere mechanics in uniform and non-uniform cardiac muscle: a link between pump function and arrhythmias.Prog Biophys Mol Biol. 2008; 97:312–331. doi: 10.1016/j.pbiomolbio.2008.02.013.CrossrefMedlineGoogle Scholar - 20.
Cooper PJ, Lei M, Cheng LX, Kohl P. Selected contribution: axial stretch increases spontaneous pacemaker activity in rabbit isolated sinoatrial node cells.J Appl Physiol (1985). 2000; 89:2099–2104.CrossrefMedlineGoogle Scholar - 21.
Iribe G, Ward CW, Camelliti P, Bollensdorff C, Mason F, Burton RA, Garny A, Morphew MK, Hoenger A, Lederer WJ, Kohl P. Axial stretch of rat single ventricular cardiomyocytes causes an acute and transient increase in Ca2+ spark rate.Circ Res. 2009; 104:787–795. doi: 10.1161/CIRCRESAHA.108.193334.LinkGoogle Scholar - 22.
Gannier F, White E, Lacampagne A, Garnier D, Le Guennec JY. Streptomycin reverses a large stretch induced increases in [Ca2+]i in isolated guinea pig ventricular myocytes.Cardiovasc Res. 1994; 28:1193–1198.CrossrefMedlineGoogle Scholar - 23.
Craelius W. Stretch-activation of rat cardiac myocytes.Exp Physiol. 1993; 78:411–423.CrossrefMedlineGoogle Scholar - 24.
Iribe G, Helmes M, Kohl P. Force-length relations in isolated intact cardiomyocytes subjected to dynamic changes in mechanical load.Am J Physiol Heart Circ Physiol. 2007; 292:H1487–H1497. doi: 10.1152/ajpheart.00909.2006.CrossrefMedlineGoogle Scholar - 25.
Kohl P, Kamkin AG, Kiseleva IS, Streubel T. Mechanosensitive cells in the atrium of frog heart.Exp Physiol. 1992; 77:213–216.CrossrefMedlineGoogle Scholar - 26.
Kiseleva I, Kamkin A, Kohl P, Lab MJ. Calcium and mechanically induced potentials in fibroblasts of rat atrium.Cardiovasc Res. 1996; 32:98–111.CrossrefMedlineGoogle Scholar - 27.
Kamkin A, Kirischuk S, Kiseleva I. Single mechano-gated channels activated by mechanical deformation of acutely isolated cardiac fibroblasts from rats.Acta Physiol (Oxf). 2010; 199:277–292. doi: 10.1111/j.1748-1716.2010.02086.x.CrossrefMedlineGoogle Scholar - 28.
Kohl P, Sachs F, Franz MR. Cardiac Mechano-Electric Coupling and Arrhythmias. 2nd ed. Oxford: Oxford University Press; 2011.CrossrefGoogle Scholar - 29.
Guharay F, Sachs F. Stretch-activated single ion channel currents in tissue-cultured embryonic chick skeletal muscle.J Physiol. 1984; 352:685–701.CrossrefMedlineGoogle Scholar - 30.
Craelius W, Chen V, el-Sherif N. Stretch activated ion channels in ventricular myocytes.Biosci Rep. 1988; 8:407–414.CrossrefMedlineGoogle Scholar - 31.
Reed A, Kohl P, Peyronnet R. Molecular candidates for cardiac stretch-activated ion channels.Glob Cardiol Sci Pract. 2014; 2014:9–25. doi: 10.5339/gcsp.2014.19.CrossrefMedlineGoogle Scholar - 32.
Kim D. A mechanosensitive K+ channel in heart cells. Activation by arachidonic acid.J Gen Physiol. 1992; 100:1021–1040.CrossrefMedlineGoogle Scholar - 33.
Wang W, Zhang M, Li P, Yuan H, Feng N, Peng Y, Wang L, Wang X. An increased TREK-1-like potassium current in ventricular myocytes during rat cardiac hypertrophy.J Cardiovasc Pharmacol. 2013; 61:302–310. doi: 10.1097/FJC.0b013e318280c5a9.CrossrefMedlineGoogle Scholar - 34.
Sukharev SI, Martinac B, Blount P, Kung C. Functional reconstitution as an assay for biochemical isolation of channel proteins: application to the molecular identification of a bacterial mechanosensitive channel.Methods. 1994; 6:51–59.CrossrefGoogle Scholar - 35.
Patel AJ, Honoré E, Maingret F, Lesage F, Fink M, Duprat F, Lazdunski M. A mammalian two pore domain mechano-gated S-like K+ channel.EMBO J. 1998; 17:4283–4290. doi: 10.1093/emboj/17.15.4283.CrossrefMedlineGoogle Scholar - 36.
Bode F, Sachs F, Franz MR. Tarantula peptide inhibits atrial fibrillation.Nature. 2001; 409:35–36. doi: 10.1038/35051165.CrossrefMedlineGoogle Scholar - 37.
Hansen DE, Borganelli M, Stacy GP, Taylor LK. Dose-dependent inhibition of stretch-induced arrhythmias by gadolinium in isolated canine ventricles. Evidence for a unique mode of antiarrhythmic action.Circ Res. 1991; 69:820–831.LinkGoogle Scholar - 38.
McBride DW, Hamill OP. Pressure-clamp: a method for rapid step perturbation of mechanosensitive channels.Pflugers Arch. 1992; 421:606–612.CrossrefMedlineGoogle Scholar - 39.
Hurwitz CG, Segal AS. Application of pressure steps to mechanosensitive channels in membrane patches: a simple, economical, and fast system.Pflugers Arch. 2001; 442:150–156. doi: 10.1007/s004240100541.CrossrefMedlineGoogle Scholar - 40.
Coste B, Mathur J, Schmidt M, Earley TJ, Ranade S, Petrus MJ, Dubin AE, Patapoutian A. Piezo1 and Piezo2 are essential components of distinct mechanically activated cation channels.Science. 2010; 330:55–60. doi: 10.1126/science.1193270.CrossrefMedlineGoogle Scholar - 41.
Laitko U, Morris CE. Membrane tension accelerates rate-limiting voltage-dependent activation and slow inactivation steps in a Shaker channel.J Gen Physiol. 2004; 123:135–154. doi: 10.1085/jgp.200308965.CrossrefMedlineGoogle Scholar - 42.
Farrugia G, Holm AN, Rich A, Sarr MG, Szurszewski JH, Rae JL. A mechanosensitive calcium channel in human intestinal smooth muscle cells.Gastroenterology. 1999; 117:900–905.CrossrefMedlineGoogle Scholar - 43.
Calabrese B, Tabarean IV, Juranka P, Morris CE. Mechanosensitivity of N-type calcium channel currents.Biophys J. 2002; 83:2560–2574. doi: 10.1016/S0006-3495(02)75267-3.CrossrefMedlineGoogle Scholar - 44.
Kraichely RE, Strege PR, Sarr MG, Kendrick ML, Farrugia G. Lysophosphatidyl choline modulates mechanosensitive L-type Ca2+ current in circular smooth muscle cells from human jejunum.Am J Physiol Gastrointest Liver Physiol. 2009; 296:G833–G839. doi: 10.1152/ajpgi.90610.2008.CrossrefMedlineGoogle Scholar - 45.
Tabarean IV, Juranka P, Morris CE. Membrane stretch affects gating modes of a skeletal muscle sodium channel.Biophys J. 1999; 77:758–774. doi: 10.1016/S0006-3495(99)76930-4.CrossrefMedlineGoogle Scholar - 46.
Morris CE, Juranka PF. Nav channel mechanosensitivity: activation and inactivation accelerate reversibly with stretch.Biophys J. 2007; 93:822–833. doi: 10.1529/biophysj.106.101246.CrossrefMedlineGoogle Scholar - 47.
Wang JA, Lin W, Morris T, Banderali U, Juranka PF, Morris CE. Membrane trauma and Na+ leak from Nav1.6 channels.Am J Physiol Cell Physiol. 2009; 297:C823–C834. doi: 10.1152/ajpcell.00505.2008.CrossrefMedlineGoogle Scholar - 48.
Boycott HE, Barbier CS, Eichel CA, Costa KD, Martins RP, Louault F, Dilanian G, Coulombe A, Hatem SN, Balse E. Shear stress triggers insertion of voltage-gated potassium channels from intracellular compartments in atrial myocytes.Proc Natl Acad Sci U S A. 2013; 110:E3955–E3964. doi: 10.1073/pnas.1309896110.CrossrefMedlineGoogle Scholar - 49.
Dyachenko V, Husse B, Rueckschloss U, Isenberg G. Mechanical deformation of ventricular myocytes modulates both TRPC6 and Kir2.3 channels.Cell Calcium. 2009; 45:38–54. doi: 10.1016/j.ceca.2008.06.003.CrossrefMedlineGoogle Scholar - 50.
Beyder A, Rae JL, Bernard C, Strege PR, Sachs F, Farrugia G. Mechanosensitivity of Nav1.5, a voltage-sensitive sodium channel.J Physiol. 2010; 588:4969–4985. doi: 10.1113/jphysiol.2010.199034.CrossrefMedlineGoogle Scholar - 51.
Pedrozo Z, Criollo A, Battiprolu PK, Morales CR, Contreras-Ferrat A, Fernández C, Jiang N, Luo X, Caplan MJ, Somlo S, Rothermel BA, Gillette TG, Lavandero S, Hill JA. Polycystin-1 Is a cardiomyocyte mechanosensor that governs L-type Ca2+ channel protein stability.Circulation. 2015; 131:2131–2142. doi: 10.1161/CIRCULATIONAHA.114.013537.LinkGoogle Scholar - 52.
Schmidt D, MacKinnon R. Voltage-dependent K+ channel gating and voltage sensor toxin sensitivity depend on the mechanical state of the lipid membrane.Proc Natl Acad Sci U S A. 2008; 105:19276–19281. doi: 10.1073/pnas.0810187105.CrossrefMedlineGoogle Scholar - 53.
Peyronnet R, Sharif-Naeini R, Folgering JH, . Mechanoprotection by polycystins against apoptosis is mediated through the opening of stretch-activated K2P channels.Cell Rep. 2012; 1:241–250. doi: 10.1016/j.celrep.2012.01.006.CrossrefMedlineGoogle Scholar - 54.
Bentzen BH, Grunnet M. Central and peripheral GABA(A) receptor regulation of the heart rate depends on the conscious state of the animal.Adv Pharmacol Sci. 2011; 2011:578273. doi: 10.1155/2011/578273.CrossrefMedlineGoogle Scholar - 55.
Ralevic V. P2X receptors in the cardiovascular system.Wiley Interdiscip Rev Membr Transp Signal. 2012; 1:663–674.CrossrefGoogle Scholar - 56.
Kessler S, Clauss WG, Fronius M. Laminar shear stress modulates the activity of heterologously expressed P2X(4) receptors.Biochim Biophys Acta. 2011; 1808:2488–2495. doi: 10.1016/j.bbamem.2011.07.010.CrossrefMedlineGoogle Scholar - 57.
Noma A. ATP-regulated K+ channels in cardiac muscle.Nature. 1983; 305:147–148.CrossrefMedlineGoogle Scholar - 58.
Van Wagoner DR. Mechanosensitive gating of atrial ATP-sensitive potassium channels.Circ Res. 1993; 72:973–983.LinkGoogle Scholar - 59.
Inagaki N, Gonoi T, Clement JP, Namba N, Inazawa J, Gonzalez G, Aguilar-Bryan L, Seino S, Bryan J. Reconstitution of IKATP: an inward rectifier subunit plus the sulfonylurea receptor.Science. 1995; 270:1166–1170.CrossrefMedlineGoogle Scholar - 60.
Aguilar-Bryan L, Nichols CG, Wechsler SW, Clement JP, Boyd AE, González G, Herrera-Sosa H, Nguy K, Bryan J, Nelson DA. Cloning of the beta cell high-affinity sulfonylurea receptor: a regulator of insulin secretion.Science. 1995; 268:423–426.CrossrefMedlineGoogle Scholar - 61.
Morrissey A, Rosner E, Lanning J, Parachuru L, Dhar Chowdhury P, Han S, Lopez G, Tong X, Yoshida H, Nakamura TY, Artman M, Giblin JP, Tinker A, Coetzee WA. Immunolocalization of KATP channel subunits in mouse and rat cardiac myocytes and the coronary vasculature.BMC Physiol. 2005; 5:1. doi: 10.1186/1472-6793-5-1.CrossrefMedlineGoogle Scholar - 62.
Miki T, Suzuki M, Shibasaki T, Uemura H, Sato T, Yamaguchi K, Koseki H, Iwanaga T, Nakaya H, Seino S. Mouse model of prinzmetal angina by disruption of the inward rectifier Kir6.1.Nat Med. 2002; 8:466–472. doi: 10.1038/nm0502-466.CrossrefMedlineGoogle Scholar - 63.
Fedorov VV, Glukhov AV, Ambrosi CM, Kostecki G, Chang R, Janks D, Schuessler RB, Moazami N, Nichols CG, Efimov IR. Effects of KATP channel openers diazoxide and pinacidil in coronary-perfused atria and ventricles from failing and non-failing human hearts.J Mol Cell Cardiol. 2011; 51:215–225. doi: 10.1016/j.yjmcc.2011.04.016.CrossrefMedlineGoogle Scholar - 64.
Kohl P, Bollensdorff C, Garny A. Effects of mechanosensitive ion channels on ventricular electrophysiology: experimental and theoretical models.Exp Physiol. 2006; 91:307–321. doi: 10.1113/expphysiol.2005.031062.CrossrefMedlineGoogle Scholar - 65.
Huang H, Liang L, Liu P, Wei H, Sachs F, Niu W, Wang W. Mechanical effects on KATP channel gating in rat ventricular myocytes.PLoS One. 2013; 8:e63337. doi: 10.1371/journal.pone.0063337.CrossrefMedlineGoogle Scholar - 66.
Cole WC, McPherson CD, Sontag D. ATP-regulated K+ channels protect the myocardium against ischemia/reperfusion damage.Circ Res. 1991; 69:571–581.LinkGoogle Scholar - 67.
Takahashi K, Kakimoto Y, Toda K, Naruse K. Mechanobiology in cardiac physiology and diseases.J Cell Mol Med. 2013; 17:225–232. doi: 10.1111/jcmm.12027.CrossrefMedlineGoogle Scholar - 68.
Benamer N, Vasquez C, Mahoney VM, Steinhardt MJ, Coetzee WA, Morley GE. Fibroblast KATP currents modulate myocyte electrophysiology in infarcted hearts.Am J Physiol Heart Circ Physiol. 2013; 304:H1231–H1239. doi: 10.1152/ajpheart.00878.2012.CrossrefMedlineGoogle Scholar - 69.
Bell RM, Yellon DM. Conditioning the whole heart–not just the cardiomyocyte.J Mol Cell Cardiol. 2012; 53:24–32. doi: 10.1016/j.yjmcc.2012.04.001.CrossrefMedlineGoogle Scholar - 70.
Abrial M, Da Silva CC, Pillot B, Augeul L, Ivanes F, Teixeira G, Cartier R, Angoulvant D, Ovize M, Ferrera R. Cardiac fibroblasts protect cardiomyocytes against lethal ischemia-reperfusion injury.J Mol Cell Cardiol. 2014; 68:56–65. doi: 10.1016/j.yjmcc.2014.01.005.CrossrefMedlineGoogle Scholar - 71.
Baumgarten CM, Clemo HF. Swelling-activated chloride channels in cardiac physiology and pathophysiology.Prog Biophys Mol Biol. 2003; 82:25–42.CrossrefMedlineGoogle Scholar - 72.
Matsuda N, Hagiwara N, Shoda M, Kasanuki H, Hosoda S. Enhancement of the L-type Ca2+ current by mechanical stimulation in single rabbit cardiac myocytes.Circ Res. 1996; 78:650–659.LinkGoogle Scholar - 73.
Gomis A, Soriano S, Belmonte C, Viana F. Hypoosmotic- and pressure-induced membrane stretch activate TRPC5 channels.J Physiol. 2008; 586:5633–5649. doi: 10.1113/jphysiol.2008.161257.CrossrefMedlineGoogle Scholar - 74.
Bett GC, Sachs F. Whole-cell mechanosensitive currents in rat ventricular myocytes activated by direct stimulation.J Membr Biol. 2000; 173:255–263.CrossrefMedlineGoogle Scholar - 75.
Vandenberg JI, Rees SA, Wright AR, Powell T. Cell swelling and ion transport pathways in cardiac myocytes.Cardiovasc Res. 1996; 32:85–97.CrossrefMedlineGoogle Scholar - 76.
Qiu Z, Dubin AE, Mathur J, Tu B, Reddy K, Miraglia LJ, Reinhardt J, Orth AP, Patapoutian A. SWELL1, a plasma membrane protein, is an essential component of volume-regulated anion channel.Cell. 2014; 157:447–458. doi: 10.1016/j.cell.2014.03.024.CrossrefMedlineGoogle Scholar - 77.
Voss FK, Ullrich F, Münch J, Lazarow K, Lutter D, Mah N, Andrade-Navarro MA, von Kries JP, Stauber T, Jentsch TJ. Identification of LRRC8 heteromers as an essential component of the volume-regulated anion channel VRAC.Science. 2014; 344:634–638. doi: 10.1126/science.1252826.CrossrefMedlineGoogle Scholar - 78.
Opsahl LR, Webb WW. Transduction of membrane tension by the ion channel alamethicin.Biophys J. 1994; 66:71–74. doi: 10.1016/S0006-3495(94)80751-9.CrossrefMedlineGoogle Scholar - 79.
Brohawn SG, Su Z, MacKinnon R. Mechanosensitivity is mediated directly by the lipid membrane in TRAAK and TREK1 K+ channels.Proc Natl Acad Sci U S A. 2014; 111:3614–3619. doi: 10.1073/pnas.1320768111.CrossrefMedlineGoogle Scholar - 80.
Berrier C, Pozza A, de Lacroix de Lavalette A, Chardonnet S, Mesneau A, Jaxel C, le Maire M, Ghazi A. The purified mechanosensitive channel TREK-1 is directly sensitive to membrane tension.J Biol Chem. 2013; 288:27307–27314. doi: 10.1074/jbc.M113.478321.CrossrefMedlineGoogle Scholar - 81.
Bett GC, Sachs F. Activation and inactivation of mechanosensitive currents in the chick heart.J Membr Biol. 2000; 173:237–254.CrossrefMedlineGoogle Scholar - 82.
Gottlieb P, Folgering J, Maroto R, Raso A, Wood TG, Kurosky A, Bowman C, Bichet D, Patel A, Sachs F, Martinac B, Hamill OP, Honoré E. Revisiting TRPC1 and TRPC6 mechanosensitivity.Pflugers Arch. 2008; 455:1097–1103. doi: 10.1007/s00424-007-0359-3.CrossrefMedlineGoogle Scholar - 83.
Moulik M, Vatta M, Witt SH, Arola AM, Murphy RT, McKenna WJ, Boriek AM, Oka K, Labeit S, Bowles NE, Arimura T, Kimura A, Towbin JA. ANKRD1, the gene encoding cardiac ankyrin repeat protein, is a novel dilated cardiomyopathy gene.J Am Coll Cardiol. 2009; 54:325–333. doi: 10.1016/j.jacc.2009.02.076.CrossrefMedlineGoogle Scholar - 84.
Lammerding J, Schulze PC, Takahashi T, Kozlov S, Sullivan T, Kamm RD, Stewart CL, Lee RT. Lamin A/C deficiency causes defective nuclear mechanics and mechanotransduction.J Clin Invest. 2004; 113:370–378. doi: 10.1172/JCI19670.CrossrefMedlineGoogle Scholar - 85.
van Tintelen JP, Entius MM, Bhuiyan ZA, . Plakophilin-2 mutations are the major determinant of familial arrhythmogenic right ventricular dysplasia/cardiomyopathy.Circulation. 2006; 113:1650–1658. doi: 10.1161/CIRCULATIONAHA.105.609719.LinkGoogle Scholar - 86.
Stroud MJ, Banerjee I, Veevers J, Chen J. Linker of nucleoskeleton and cytoskeleton complex proteins in cardiac structure, function, and disease.Circ Res. 2014; 114:538–548. doi: 10.1161/CIRCRESAHA.114.301236.LinkGoogle Scholar - 87.
Ackerman MJ, Mohler PJ. Defining a new paradigm for human arrhythmia syndromes: phenotypic manifestations of gene mutations in ion channel- and transporter-associated proteins.Circ Res. 2010; 107:457–465. doi: 10.1161/CIRCRESAHA.110.224592.LinkGoogle Scholar - 88.
Smith SA, Sturm AC, Curran J, . Dysfunction in the βII spectrin-dependent cytoskeleton underlies human arrhythmia.Circulation. 2015; 131:695–708. doi: 10.1161/CIRCULATIONAHA.114.013708.LinkGoogle Scholar - 89.
Steinbacher S, Bass R, Strop P, Rees DC. Structures of the prokaryotic mechanosensitive channels MscL and MscS.Curr Top Membr. 2007; 58:1–24.CrossrefGoogle Scholar - 90.
Haswell ES, Phillips R, Rees DC. Mechanosensitive channels: what can they do and how do they do it?Structure. 2011; 19:1356–1369. doi: 10.1016/j.str.2011.09.005.CrossrefMedlineGoogle Scholar - 91.
Hamilton ES, Schlegel AM, Haswell ES. United in diversity: mechanosensitive ion channels in plants.Annu Rev Plant Biol. 2015; 66:113–137. doi: 10.1146/annurev-arplant-043014-114700.CrossrefMedlineGoogle Scholar - 92.
Anishkin A, Loukin SH, Teng J, Kung C. Feeling the hidden mechanical forces in lipid bilayer is an original sense.Proc Natl Acad Sci U S A. 2014; 111:7898–7905. doi: 10.1073/pnas.1313364111.CrossrefMedlineGoogle Scholar - 93.
Sachs F, Morris CE. Mechanosensitive ion channels in nonspecialized cells.Rev Physiol Biochem Pharmacol. 1998; 132:1–77.CrossrefMedlineGoogle Scholar - 94.
Peyronnet R, Tran D, Girault T, Frachisse JM. Mechanosensitive channels: feeling tension in a world under pressure.Front Plant Sci. 2014; 5:558. doi: 10.3389/fpls.2014.00558.CrossrefMedlineGoogle Scholar - 95.
Sukharev SI, Blount P, Martinac B, Blattner FR, Kung C. A large-conductance mechanosensitive channel in E. coli encoded by mscL alone.Nature. 1994; 368:265–268. doi: 10.1038/368265a0.CrossrefMedlineGoogle Scholar - 96.
Chang G, Spencer RH, Lee AT, Barclay MT, Rees DC. Structure of the MscL homolog from Mycobacterium tuberculosis: a gated mechanosensitive ion channel.Science. 1998; 282:2220–2226.CrossrefMedlineGoogle Scholar - 97.
Bass RB, Strop P, Barclay M, Rees DC. Crystal structure of Escherichia coli MscS, a voltage-modulated and mechanosensitive channel.Science. 2002; 298:1582–1587. doi: 10.1126/science.1077945.CrossrefMedlineGoogle Scholar - 98.
Brohawn SG, del Mármol J, MacKinnon R. Crystal structure of the human K2P TRAAK, a lipid- and mechano-sensitive K+ ion channel.Science. 2012; 335:436–441. doi: 10.1126/science.1213808.CrossrefMedlineGoogle Scholar - 99.
Ge J, Li W, Zhao Q, Li N, Chen M, Zhi P, Li R, Gao N, Xiao B, Yang M. Architecture of the mammalian mechanosensitive Piezo1 channel.Nature. 2015; 527:64–69. doi: 10.1038/nature15247.CrossrefMedlineGoogle Scholar - 100.
Wu Y, Yang Y, Ye S, Jiang Y. Structure of the gating ring from the human large-conductance Ca2+-gated K+ channel.Nature. 2010; 466:393–397. doi: 10.1038/nature09252.CrossrefMedlineGoogle Scholar - 101.
Bhargava A, Lin X, Novak P, Mehta K, Korchev Y, Delmar M, Gorelik J. Super-resolution scanning patch clamp reveals clustering of functional ion channels in adult ventricular myocyte.Circ Res. 2013; 112:1112–1120. doi: 10.1161/CIRCRESAHA.111.300445.LinkGoogle Scholar - 102.
Haswell ES, Meyerowitz EM. MscS-like proteins control plastid size and shape in Arabidopsis thaliana.Curr Biol. 2006; 16:1–11. doi: 10.1016/j.cub.2005.11.044.CrossrefMedlineGoogle Scholar - 103.
Nakayama Y, Yoshimura K, Iida H. Organellar mechanosensitive channels in fission yeast regulate the hypo-osmotic shock response.Nat Commun. 2012; 3:1020. doi: 10.1038/ncomms2014.CrossrefMedlineGoogle Scholar - 104.
Belmonte S, Morad M. Shear fluid-induced Ca2+ release and the role of mitochondria in rat cardiac myocytes.Ann N Y Acad Sci. 2008; 1123:58–63. doi: 10.1196/annals.1420.007.CrossrefMedlineGoogle Scholar - 105.
Traister A, Li M, Aafaqi S, . Integrin-linked kinase mediates force transduction in cardiomyocytes by modulating SERCA2a/PLN function.Nat Commun. 2014; 5:4533. doi: 10.1038/ncomms5533.CrossrefMedlineGoogle Scholar - 106.
White E. Mechanosensitive channels: therapeutic targets in the myocardium?Curr Pharm Des. 2006; 12:3645–3663.CrossrefMedlineGoogle Scholar - 107.
O’Rourke B. Evidence for mitochondrial K+ channels and their role in cardioprotection.Circ Res. 2004; 94:420–432. doi: 10.1161/01.RES.0000117583.66950.43.LinkGoogle Scholar - 108.
Yang XM, Proctor JB, Cui L, Krieg T, Downey JM, Cohen MV. Multiple, brief coronary occlusions during early reperfusion protect rabbit hearts by targeting cell signaling pathways.J Am Coll Cardiol. 2004; 44:1103–1110. doi: 10.1016/j.jacc.2004.05.060.CrossrefMedlineGoogle Scholar - 109.
Mykytenko J, Reeves JG, Kin H, Wang NP, Zatta AJ, Jiang R, Guyton RA, Vinten-Johansen J, Zhao ZQ. Persistent beneficial effect of postconditioning against infarct size: role of mitochondrial KATP channels during reperfusion.Basic Res Cardiol. 2008; 103:472–484. doi: 10.1007/s00395-008-0731-2.CrossrefMedlineGoogle Scholar - 110.
Swyers T, Redford D, Larson DF. Volatile anesthetic-induced preconditioning.Perfusion. 2014; 29:10–15. doi: 10.1177/0267659113503975.CrossrefMedlineGoogle Scholar - 111.
Guilak F. Compression-induced changes in the shape and volume of the chondrocyte nucleus.J Biomech. 1995; 28:1529–1541.CrossrefMedlineGoogle Scholar - 112.
Versaevel M, Grevesse T, Gabriele S. Spatial coordination between cell and nuclear shape within micropatterned endothelial cells.Nat Commun. 2012; 3:671. doi: 10.1038/ncomms1668.CrossrefMedlineGoogle Scholar - 113.
Rowat AC, Lammerding J, Ipsen JH. Mechanical properties of the cell nucleus and the effect of emerin deficiency.Biophys J. 2006; 91:4649–4664. doi: 10.1529/biophysj.106.086454.CrossrefMedlineGoogle Scholar - 114.
Fedorchak GR, Kaminski A, Lammerding J. Cellular mechanosensing: getting to the nucleus of it all.Prog Biophys Mol Biol. 2014; 115:76–92. doi: 10.1016/j.pbiomolbio.2014.06.009.CrossrefMedlineGoogle Scholar - 115.
Zhao Y, Huang H, Jiang Y, Wei H, Liu P, Wang W, Niu W. Unusual localization and translocation of TRPV4 protein in cultured ventricular myocytes of the neonatal rat.Eur J Histochem. 2012; 56:e32. doi: 10.4081/ejh.2012.e32.CrossrefMedlineGoogle Scholar - 116.
Lansman JB, Hallam TJ, Rink TJ. Single stretch-activated ion channels in vascular endothelial cells as mechanotransducers?Nature. 1987; 325:811–813. doi: 10.1038/325811a0.CrossrefMedlineGoogle Scholar - 117.
Popp R, Hoyer J, Meyer J, Galla HJ, Gögelein H. Stretch-activated non-selective cation channels in the antiluminal membrane of porcine cerebral capillaries.J Physiol. 1992; 454:435–449.CrossrefMedlineGoogle Scholar - 118.
Naruse K, Yamada T, Sokabe M. Involvement of SA channels in orienting response of cultured endothelial cells to cyclic stretch.Am J Physiol. 1998; 274:H1532–H1538.CrossrefMedlineGoogle Scholar - 119.
Yue Z, Zhang Y, Xie J, Jiang J, Yue L. Transient receptor potential (TRP) channels and cardiac fibrosis.Curr Top Med Chem. 2013; 13:270–282.CrossrefMedlineGoogle Scholar - 120.
Stockbridge LL, French AS. Stretch-activated cation channels in human fibroblasts.Biophys J. 1988; 54:187–190. doi: 10.1016/S0006-3495(88)82944-8.CrossrefMedlineGoogle Scholar - 121.
Glogauer M, Ferrier J, McCulloch CA. Magnetic fields applied to collagen-coated ferric oxide beads induce stretch-activated Ca2+ flux in fibroblasts.Am J Physiol. 1995; 269:C1093–C1104.CrossrefMedlineGoogle Scholar - 122.
Blaauw E, Lorenzen-Schmidt I, Babiker FA, Munts C, Prinzen FW, Snoeckx LH, van Bilsen M, van der Vusse GJ, van Nieuwenhoven FA. Stretch-induced upregulation of connective tissue growth factor in rabbit cardiomyocytes.J Cardiovasc Transl Res. 2013; 6:861–869. doi: 10.1007/s12265-013-9489-5.CrossrefMedlineGoogle Scholar - 123.
Camelliti P, Green CR, LeGrice I, Kohl P. Fibroblast network in rabbit sinoatrial node: structural and functional identification of homogeneous and heterogeneous cell coupling.Circ Res. 2004; 94:828–835. doi: 10.1161/01.RES.0000122382.19400.14.LinkGoogle Scholar - 124.
Kohl P, Camelliti P. Fibroblast-myocyte connections in the heart.Heart Rhythm. 2012; 9:461–464. doi: 10.1016/j.hrthm.2011.10.002.CrossrefMedlineGoogle Scholar - 125.
Camelliti P, Borg TK, Kohl P. Structural and functional characterisation of cardiac fibroblasts.Cardiovasc Res. 2005; 65:40–51. doi: 10.1016/j.cardiores.2004.08.020.CrossrefMedlineGoogle Scholar - 126.
Camelliti P, Devlin GP, Matthews KG, Kohl P, Green CR. Spatially and temporally distinct expression of fibroblast connexins after sheep ventricular infarction.Cardiovasc Res. 2004; 62:415–425. doi: 10.1016/j.cardiores.2004.01.027.CrossrefMedlineGoogle Scholar - 127.
Kohl P, Camelliti P, Burton FL, Smith GL. Electrical coupling of fibroblasts and myocytes: relevance for cardiac propagation.J Electrocardiol. 2005; 38:45–50. doi: 10.1016/j.jelectrocard.2005.06.096.CrossrefMedlineGoogle Scholar - 128.
Kohl P, Gourdie RG. Fibroblast-myocyte electrotonic coupling: does it occur in native cardiac tissue?J Mol Cell Cardiol. 2014; 70:37–46. doi: 10.1016/j.yjmcc.2013.12.024.CrossrefMedlineGoogle Scholar - 129.
Arnadóttir J, Chalfie M. Eukaryotic mechanosensitive channels.Annu Rev Biophys. 2010; 39:111–137. doi: 10.1146/annurev.biophys.37.032807.125836.CrossrefMedlineGoogle Scholar - 130.
Tan JH, Liu W, Saint DA. Trek-like potassium channels in rat cardiac ventricular myocytes are activated by intracellular ATP.J Membr Biol. 2002; 185:201–207. doi: 10.1007/s00232-001-0123-0.CrossrefMedlineGoogle Scholar - 131.
Xian Tao Li, Dyachenko V, Zuzarte M, Putzke C, Preisig-Müller R, Isenberg G, Daut J. The stretch-activated potassium channel TREK-1 in rat cardiac ventricular muscle.Cardiovasc Res. 2006; 69:86–97. doi: 10.1016/j.cardiores.2005.08.018.CrossrefMedlineGoogle Scholar - 132.
Liu W, Saint DA. Heterogeneous expression of tandem-pore K+ channel genes in adult and embryonic rat heart quantified by real-time polymerase chain reaction.Clin Exp Pharmacol Physiol. 2004; 31:174–178.CrossrefMedlineGoogle Scholar - 133.
Honoré E, Patel A. The mechano–gated K2p channel TREK-1 in the cardiovascular system., P. Kohl, F. Sachs, Franz MR Cardiac Mechano-Electric Coupling and Arrhythmias. 2nd ed. Oxford: Oxford University Press; 2011: 19–26.CrossrefGoogle Scholar - 134.
Tan JH, Liu W, Saint DA. Differential expression of the mechanosensitive potassium channel TREK-1 in epicardial and endocardial myocytes in rat ventricle.Exp Physiol. 2004; 89:237–242. doi: 10.1113/expphysiol.2003.027052.CrossrefMedlineGoogle Scholar - 135.
Stones R, Calaghan SC, Billeter R, Harrison SM, White E. Transmural variations in gene expression of stretch-modulated proteins in the rat left ventricle.Pflugers Arch. 2007; 454:545–549. doi: 10.1007/s00424-007-0237-z.CrossrefMedlineGoogle Scholar - 136.
Kelly D, Mackenzie L, Hunter P, Smaill B, Saint DA. Gene expression of stretch-activated channels and mechanoelectric feedback in the heart.Clin Exp Pharmacol Physiol. 2006; 33:642–648. doi: 10.1111/j.1440-1681.2006.04392.x.CrossrefMedlineGoogle Scholar - 137.
Goonetilleke L, Quayle J. TREK-1 K+ channels in the cardiovascular system: their significance and potential as a therapeutic target.Cardiovasc Ther. 2012; 30:e23–e29. doi: 10.1111/j.1755-5922.2010.00227.x.CrossrefMedlineGoogle Scholar - 138.
Terrenoire C, Lauritzen I, Lesage F, Romey G, Lazdunski M. A TREK-1-like potassium channel in atrial cells inhibited by beta-adrenergic stimulation and activated by volatile anesthetics.Circ Res. 2001; 89:336–342.LinkGoogle Scholar - 139.
Aimond F, Rauzier JM, Bony C, Vassort G. Simultaneous activation of p38 MAPK and p42/44 MAPK by ATP stimulates the K+ current ITREK in cardiomyocytes.J Biol Chem. 2000; 275:39110–39116. doi: 10.1074/jbc.M008192200.CrossrefMedlineGoogle Scholar - 140.
Medhurst AD, Rennie G, Chapman CG, Meadows H, Duckworth MD, Kelsell RE, Gloger II, Pangalos MN. Distribution analysis of human two pore domain potassium channels in tissues of the central nervous system and periphery.Brain Res Mol Brain Res. 2001; 86:101–114.CrossrefMedlineGoogle Scholar - 141.
Gurney A, Manoury B. Two-pore potassium channels in the cardiovascular system.Eur Biophys J. 2009; 38:305–318. doi: 10.1007/s00249-008-0326-8.CrossrefMedlineGoogle Scholar - 142.
Schmidt C, Wiedmann F, Tristram F, Anand P, Wenzel W, Lugenbiel P, Schweizer PA, Katus HA, Thomas D. Cardiac expression and atrial fibrillation-associated remodeling of K2P2.1 (TREK-1) K+ channels in a porcine model.Life Sci. 2014; 97:107–115. doi: 10.1016/j.lfs.2013.12.006.CrossrefMedlineGoogle Scholar - 143.
Patel AJ, Honoré E. Properties and modulation of mammalian 2P domain K+ channels.Trends Neurosci. 2001; 24:339–346.CrossrefMedlineGoogle Scholar - 144.
Zhang H, Shepherd N, Creazzo TL. Temperature-sensitive TREK currents contribute to setting the resting membrane potential in embryonic atrial myocytes.J Physiol. 2008; 586:3645–3656. doi: 10.1113/jphysiol.2008.153395.CrossrefMedlineGoogle Scholar - 145.
Noel J, Sandoz G, Lesage F. Molecular regulations governing TREK and TRAAK channel functions.Channels (Austin). 2011; 5:402–409.CrossrefMedlineGoogle Scholar - 146.
Ozaita A, Vega-Saenz de Miera E. Cloning of two transcripts, HKT4.1a and HKT4.1b, from the human two-pore K+ channel gene KCNK4. Chromosomal localization, tissue distribution and functional expression.Brain Res Mol Brain Res. 2002; 102:18–27.CrossrefMedlineGoogle Scholar - 147.
Patel AJ, Honoré E, Lesage F, Fink M, Romey G, Lazdunski M. Inhalational anesthetics activate two-pore-domain background K+ channels.Nat Neurosci. 1999; 2:422–426. doi: 10.1038/8084.CrossrefMedlineGoogle Scholar - 148.
Sandoz G, Douguet D, Chatelain F, Lazdunski M, Lesage F. Extracellular acidification exerts opposite actions on TREK1 and TREK2 potassium channels via a single conserved histidine residue.Proc Natl Acad Sci U S A. 2009; 106:14628–14633. doi: 10.1073/pnas.0906267106.CrossrefMedlineGoogle Scholar - 149.
Ge L, Hoa NT, Wilson Z, Arismendi-Morillo G, Kong XT, Tajhya RB, Beeton C, Jadus MR. Big Potassium (BK) ion channels in biology, disease and possible targets for cancer immunotherapy.Int Immunopharmacol. 2014; 22:427–443. doi: 10.1016/j.intimp.2014.06.040.CrossrefMedlineGoogle Scholar - 150.
Takahashi K, Naruse K. Stretch-activated BK channel and heart function.Prog Biophys Mol Biol. 2012; 110:239–244.CrossrefMedlineGoogle Scholar - 151.
Kawakubo T, Naruse K, Matsubara T, Hotta N, Sokabe M. Characterization of a newly found stretch-activated KCa,ATP channel in cultured chick ventricular myocytes.Am J Physiol. 1999; 276:H1827–H1838.CrossrefMedlineGoogle Scholar - 152.
Iribe G, Jin H, Kaihara K, Naruse K. Effects of axial stretch on sarcolemmal BKCa channels in post-hatch chick ventricular myocytes.Exp Physiol. 2010; 95:699–711. doi: 10.1113/expphysiol.2009.051896.CrossrefMedlineGoogle Scholar - 153.
Imlach WL, Finch SC, Miller JH, Meredith AL, Dalziel JE. A role for BK channels in heart rate regulation in rodents.PLoS One. 2010; 5:e8698. doi: 10.1371/journal.pone.0008698.CrossrefMedlineGoogle Scholar - 154.
Xu W, Liu Y, Wang S, McDonald T, Van Eyk JE, Sidor A, O’Rourke B. Cytoprotective role of Ca2+- activated K+ channels in the cardiac inner mitochondrial membrane.Science. 2002; 298:1029–1033. doi: 10.1126/science.1074360.CrossrefMedlineGoogle Scholar - 155.
Tomás M, Vázquez E, Fernández-Fernández JM, Subirana I, Plata C, Heras M, Vila J, Marrugat J, Valverde MA, Sentí M. Genetic variation in the KCNMA1 potassium channel alpha subunit as risk factor for severe essential hypertension and myocardial infarction.J Hypertens. 2008; 26:2147–2153. doi: 10.1097/HJH.0b013e32831103d8.CrossrefMedlineGoogle Scholar - 156.
Huang H, Wang W, Liu P, Jiang Y, Zhao Y, Wei H, Niu W. TRPC1 expression and distribution in rat hearts.Eur J Histochem. 2009; 53:e26. doi: 10.4081/ejh.2009.e26.CrossrefMedlineGoogle Scholar - 157.
Iwata Y, Katanosaka Y, Arai Y, Komamura K, Miyatake K, Shigekawa M. A novel mechanism of myocyte degeneration involving the Ca2+-permeable growth factor-regulated channel.J Cell Biol. 2003; 161:957–967. doi: 10.1083/jcb.200301101.CrossrefMedlineGoogle Scholar - 158.
Mohl MC, Iismaa SE, Xiao XH, Friedrich O, Wagner S, Nikolova-Krstevski V, Wu J, Yu ZY, Feneley M, Fatkin D, Allen DG, Graham RM. Regulation of murine cardiac contractility by activation of α1A-adrenergic receptor-operated Ca2+ entry.Cardiovasc Res. 2011; 91:310–319. doi: 10.1093/cvr/cvr081.CrossrefMedlineGoogle Scholar - 159.
Coste B, Xiao B, Santos JS, Syeda R, Grandl J, Spencer KS, Kim SE, Schmidt M, Mathur J, Dubin AE, Montal M, Patapoutian A. Piezo proteins are pore-forming subunits of mechanically activated channels.Nature. 2012; 483:176–181. doi: 10.1038/nature10812.CrossrefMedlineGoogle Scholar - 160.
Suchyna TM, Johnson JH, Hamer K, Leykam JF, Gage DA, Clemo HF, Baumgarten CM, Sachs F. Identification of a peptide toxin from Grammostola spatulata spider venom that blocks cation-selective stretch-activated channels.J Gen Physiol. 2000; 115:583–598.CrossrefMedlineGoogle Scholar - 161.
Volkers L, Mechioukhi Y, Coste B. Piezo channels: from structure to function.Pflugers Arch. 2015; 467:95–99. doi: 10.1007/s00424-014-1578-z.CrossrefMedlineGoogle Scholar - 162.
Vogel C, Marcotte EM. Insights into the regulation of protein abundance from proteomic and transcriptomic analyses.Nat Rev Genet. 2012; 13:227–232. doi: 10.1038/nrg3185.CrossrefMedlineGoogle Scholar - 163.
Inoue R, Jian Z, Kawarabayashi Y. Mechanosensitive TRP channels in cardiovascular pathophysiology.Pharmacol Ther. 2009; 123:371–385. doi: 10.1016/j.pharmthera.2009.05.009.CrossrefMedlineGoogle Scholar - 164.
Spassova MA, Hewavitharana T, Xu W, Soboloff J, Gill DL. A common mechanism underlies stretch activation and receptor activation of TRPC6 channels.Proc Natl Acad Sci U S A. 2006; 103:16586–16591. doi: 10.1073/pnas.0606894103.CrossrefMedlineGoogle Scholar - 165.
Vennekens R. Emerging concepts for the role of TRP channels in the cardiovascular system.J Physiol. 2011; 589:1527–1534. doi: 10.1113/jphysiol.2010.202077.CrossrefMedlineGoogle Scholar - 166.
Riccio A, Medhurst AD, Mattei C, Kelsell RE, Calver AR, Randall AD, Benham CD, Pangalos MN. mRNA distribution analysis of human TRPC family in CNS and peripheral tissues.Brain Res Mol Brain Res. 2002; 109:95–104.CrossrefMedlineGoogle Scholar - 167.
Seo K, Rainer PP, Lee DI, Hao S, Bedja D, Birnbaumer L, Cingolani OH, Kass DA. Hyperactive adverse mechanical stress responses in dystrophic heart are coupled to transient receptor potential canonical 6 and blocked by cGMP-protein kinase G modulation.Circ Res. 2014; 114:823–832. doi: 10.1161/CIRCRESAHA.114.302614.LinkGoogle Scholar - 168.
Davis J, Burr AR, Davis GF, Birnbaumer L, Molkentin JD. A TRPC6-dependent pathway for myofibroblast transdifferentiation and wound healing in vivo.Dev Cell. 2012; 23:705–715. doi: 10.1016/j.devcel.2012.08.017.CrossrefMedlineGoogle Scholar - 169.
Maroto R, Raso A, Wood TG, Kurosky A, Martinac B, Hamill OP. TRPC1 forms the stretch-activated cation channel in vertebrate cells.Nat Cell Biol. 2005; 7:179–185. doi: 10.1038/ncb1218.CrossrefMedlineGoogle Scholar - 170.
Pani B, Ong HL, Brazer SC, Liu X, Rauser K, Singh BB, Ambudkar IS. Activation of TRPC1 by STIM1 in ER-PM microdomains involves release of the channel from its scaffold caveolin-1.Proc Natl Acad Sci U S A. 2009; 106:20087–20092. doi: 10.1073/pnas.0905002106.CrossrefMedlineGoogle Scholar - 171.
Ingueneau C, Huynh UD, Marcheix B, Athias A, Gambert P, Nègre-Salvayre A, Salvayre R, Vindis C. TRPC1 is regulated by caveolin-1 and is involved in oxidized LDL-induced apoptosis of vascular smooth muscle cells.J Cell Mol Med. 2009; 13:1620–1631.CrossrefMedlineGoogle Scholar - 172.
Kohl P, Cooper PJ, Holloway H. Effects of acute ventricular volume manipulation on in situ cardiomyocyte cell membrane configuration.Prog Biophys Mol Biol. 2003; 82:221–227.CrossrefMedlineGoogle Scholar - 173.
Pfeiffer ER, Wright AT, Edwards AG, Stowe JC, McNall K, Tan J, Niesman I, Patel HH, Roth DM, Omens JH, McCulloch AD. Caveolae in ventricular myocytes are required for stretch-dependent conduction slowing.J Mol Cell Cardiol. 2014; 76:265–274. doi: 10.1016/j.yjmcc.2014.09.014.CrossrefMedlineGoogle Scholar - 174.
Friedrich O, Wagner S, Battle AR, Schürmann S, Martinac B. Mechano-regulation of the beating heart at the cellular level–mechanosensitive channels in normal and diseased heart.Prog Biophys Mol Biol. 2012; 110:226–238. doi: 10.1016/j.pbiomolbio.2012.08.009.CrossrefMedlineGoogle Scholar - 175.
Makarewich CA, Zhang H, Davis J, Correll RN, Trappanese DM, Hoffman NE, Troupes CD, Berretta RM, Kubo H, Madesh M, Chen X, Gao E, Molkentin JD, Houser SR. Transient receptor potential channels contribute to pathological structural and functional remodeling after myocardial infarction.Circ Res. 2014; 115:567–580. doi: 10.1161/CIRCRESAHA.115.303831.LinkGoogle Scholar - 176.
Rubinstein J, Lasko VM, Koch SE, Singh VP, Carreira V, Robbins N, Patel AR, Jiang M, Bidwell P, Kranias EG, Jones WK, Lorenz JN. Novel role of transient receptor potential vanilloid 2 in the regulation of cardiac performance.Am J Physiol Heart Circ Physiol. 2014; 306:H574–H584. doi: 10.1152/ajpheart.00854.2013.CrossrefMedlineGoogle Scholar - 177.
Muraki K, Iwata Y, Katanosaka Y, Ito T, Ohya S, Shigekawa M, Imaizumi Y. TRPV2 is a component of osmotically sensitive cation channels in murine aortic myocytes.Circ Res. 2003; 93:829–838. doi: 10.1161/01.RES.0000097263.10220.0C.LinkGoogle Scholar - 178.
Lorin C, Vögeli I, Niggli E. Dystrophic cardiomyopathy: role of TRPV2 channels in stretch-induced cell damage.Cardiovasc Res. 2015; 106:153–162. doi: 10.1093/cvr/cvv021.CrossrefMedlineGoogle Scholar - 179.
Morita H, Honda A, Inoue R, Ito Y, Abe K, Nelson MT, Brayden JE. Membrane stretch-induced activation of a TRPM4-like nonselective cation channel in cerebral artery myocytes.J Pharmacol Sci. 2007; 103:417–426.CrossrefMedlineGoogle Scholar - 180.
Watanabe H, Murakami M, Ohba T, Ono K, Ito H. The pathological role of transient receptor potential channels in heart disease.Circ J. 2009; 73:419–427.CrossrefMedlineGoogle Scholar - 181.
Volk T, Schwoerer AP, Thiessen S, Schultz JH, Ehmke H. A polycystin-2-like large conductance cation channel in rat left ventricular myocytes.Cardiovasc Res. 2003; 58:76–88.CrossrefMedlineGoogle Scholar - 182.
Anyatonwu GI, Estrada M, Tian X, Somlo S, Ehrlich BE. Regulation of ryanodine receptor-dependent calcium signaling by polycystin-2.Proc Natl Acad Sci U S A. 2007; 104:6454–6459. doi: 10.1073/pnas.0610324104.CrossrefMedlineGoogle Scholar - 183.
Paavola J, Schliffke S, Rossetti S, Kuo IY, Yuan S, Sun Z, Harris PC, Torres VE, Ehrlich BE. Polycystin-2 mutations lead to impaired calcium cycling in the heart and predispose to dilated cardiomyopathy.J Mol Cell Cardiol. 2013; 58:199–208. doi: 10.1016/j.yjmcc.2013.01.015.CrossrefMedlineGoogle Scholar - 184.
Hamill OP, McBride DW The pharmacology of mechanogated membrane ion channels.Pharmacol Rev. 1996; 48:231–252.MedlineGoogle Scholar - 185.
Caldwell RA, Clemo HF, Baumgarten CM. Using gadolinium to identify stretch-activated channels: technical considerations.Am J Physiol. 1998; 275:C619–C621.CrossrefMedlineGoogle Scholar - 186.
Cooper PJ, Kohl P. Species- and preparation-dependence of stretch effects on sino-atrial node pacemaking.Ann N Y Acad Sci. 2005; 1047:324–335. doi: 10.1196/annals.1341.029.CrossrefMedlineGoogle Scholar - 187.
Bowman CL, Gottlieb PA, Suchyna TM, Murphy YK, Sachs F. Mechanosensitive ion channels and the peptide inhibitor GsMTx-4: history, properties, mechanisms and pharmacology.Toxicon. 2007; 49:249–270. doi: 10.1016/j.toxicon.2006.09.030.CrossrefMedlineGoogle Scholar - 188.
Lembrechts R, Brouns I, Schnorbusch K, Pintelon I, Timmermans JP, Adriaensen D. Neuroepithelial bodies as mechanotransducers in the intrapulmonary airway epithelium: involvement of TRPC5.Am J Respir Cell Mol Biol. 2012; 47:315–323. doi: 10.1165/rcmb.2012-0068OC.CrossrefMedlineGoogle Scholar - 189.
Pan NC, Ma JJ, Peng HB. Mechanosensitivity of nicotinic receptors.Pflugers Arch. 2012; 464:193–203. doi: 10.1007/s00424-012-1132-9.CrossrefMedlineGoogle Scholar - 190.
Bae C, Sachs F, Gottlieb PA. The mechanosensitive ion channel Piezo1 is inhibited by the peptide GsMTx4.Biochemistry. 2011; 50:6295–6300. doi: 10.1021/bi200770q.CrossrefMedlineGoogle Scholar - 191.
Peyronnet R, Martins JR, Duprat F, Demolombe S, Arhatte M, Jodar M, Tauc M, Duranton C, Paulais M, Teulon J, Honoré E, Patel A. Piezo1-dependent stretch-activated channels are inhibited by polycystin-2 in renal tubular epithelial cells.EMBO Rep. 2013; 14:1143–1148. doi: 10.1038/embor.2013.170.CrossrefMedlineGoogle Scholar - 192.
Suchyna TM, Tape SE, Koeppe RE, Andersen OS, Sachs F, Gottlieb PA. Bilayer-dependent inhibition of mechanosensitive channels by neuroactive peptide enantiomers.Nature. 2004; 430:235–240. doi: 10.1038/nature02743.CrossrefMedlineGoogle Scholar - 193.
Kamaraju K, Gottlieb PA, Sachs F, Sukharev S. Effects of GsMTx4 on bacterial mechanosensitive channels in inside-out patches from giant spheroplasts.Biophys J. 2010; 99:2870–2878. doi: 10.1016/j.bpj.2010.09.022.CrossrefMedlineGoogle Scholar - 194.
Gil V, Gallego D, Moha Ou Maati H, Peyronnet R, Martínez-Cutillas M, Heurteaux C, Borsotto M, Jiménez M. Relative contribution of SKCa and TREK1 channels in purinergic and nitrergic neuromuscular transmission in the rat colon.Am J Physiol Gastrointest Liver Physiol. 2012; 303:G412–G423. doi: 10.1152/ajpgi.00040.2012.CrossrefMedlineGoogle Scholar - 195.
Bagriantsev SN, Ang KH, Gallardo-Godoy A, Clark KA, Arkin MR, Renslo AR, Minor DL A high-throughput functional screen identifies small molecule regulators of temperature- and mechano-sensitive K2P channels.ACS Chem Biol. 2013; 8:1841–1851. doi: 10.1021/cb400289x.CrossrefMedlineGoogle Scholar - 196.
Zaugg M, Lucchinetti E, Spahn DR, Pasch T, Schaub MC. Volatile anesthetics mimic cardiac preconditioning by priming the activation of mitochondrial KATP channels via multiple signaling pathways.Anesthesiology. 2002; 97:4–14.CrossrefMedlineGoogle Scholar - 197.
Ripoll C, Lederer WJ, Nichols CG. On the mechanism of inhibition of KATP channels by glibenclamide in rat ventricular myocytes.J Cardiovasc Electrophysiol. 1993; 4:38–47.CrossrefMedlineGoogle Scholar - 198.
Harteneck C, Gollasch M. Pharmacological modulation of diacylglycerol-sensitive TRPC3/6/7 channels.Curr Pharm Biotechnol. 2011; 12:35–41.CrossrefMedlineGoogle Scholar - 199.
O’Neill J, Brock C, Olesen AE, Andresen T, Nilsson M, Dickenson AH. Unravelling the mystery of capsaicin: a tool to understand and treat pain.Pharmacol Rev. 2012; 64:939–971. doi: 10.1124/pr.112.006163.CrossrefMedlineGoogle Scholar - 200.
Koch SE, Gao X, Haar L, . Probenecid: novel use as a non-injurious positive inotrope acting via cardiac TRPV2 stimulation.J Mol Cell Cardiol. 2012; 53:134–144. doi: 10.1016/j.yjmcc.2012.04.011.CrossrefMedlineGoogle Scholar - 201.
Guinamard R, Hof T, Del Negro CA. The TRPM4 channel inhibitor 9-phenanthrol.Br J Pharmacol. 2014; 171:1600–1613. doi: 10.1111/bph.12582.CrossrefMedlineGoogle Scholar - 202.
Syeda R, Xu J, Dubin AE, Coste B, Mathur J, Huynh T, Matzen J, Lao J, Tully DC, Engels IH, Petrassi HM, Schumacher AM, Montal M, Bandell M, Patapoutian A. Chemical activation of the mechanotransduction channel Piezo1.Elife. 2015; 4:. doi: 10.7554/eLife.07369.CrossrefGoogle Scholar - 203.
Seth M, Zhang ZS, Mao L, Graham V, Burch J, Stiber J, Tsiokas L, Winn M, Abramowitz J, Rockman HA, Birnbaumer L, Rosenberg P. TRPC1 channels are critical for hypertrophic signaling in the heart.Circ Res. 2009; 105:1023–1030. doi: 10.1161/CIRCRESAHA.109.206581.LinkGoogle Scholar - 204.
Ohba T, Watanabe H, Murakami M, Takahashi Y, Iino K, Kuromitsu S, Mori Y, Ono K, Iijima T, Ito H. Upregulation of TRPC1 in the development of cardiac hypertrophy.J Mol Cell Cardiol. 2007; 42:498–507. doi: 10.1016/j.yjmcc.2006.10.020.CrossrefMedlineGoogle Scholar - 205.
Stiber JA, Seth M, Rosenberg PB. Mechanosensitive channels in striated muscle and the cardiovascular system: not quite a stretch anymore.J Cardiovasc Pharmacol. 2009; 54:116–122. doi: 10.1097/FJC.0b013e3181aa233f.CrossrefMedlineGoogle Scholar - 206.
Clemo HF, Stambler BS, Baumgarten CM. Swelling-activated chloride current is persistently activated in ventricular myocytes from dogs with tachycardia-induced congestive heart failure.Circ Res. 1999; 84:157–165.LinkGoogle Scholar - 207.
Kohl P, Hunter P, Noble D. Stretch-induced changes in heart rate and rhythm: clinical observations, experiments and mathematical models.Prog Biophys Mol Biol. 1999; 71:91–138.CrossrefMedlineGoogle Scholar - 208.
Zabel M, Koller BS, Sachs F, Franz MR. Stretch-induced voltage changes in the isolated beating heart: importance of the timing of stretch and implications for stretch-activated ion channels.Cardiovasc Res. 1996; 32:120–130.CrossrefMedlineGoogle Scholar - 209.
Quinn TA, Kohl P. Combining wet and dry research: experience with model development for cardiac mechano-electric structure-function studies.Cardiovasc Res. 2013; 97:601–611. doi: 10.1093/cvr/cvt003.CrossrefMedlineGoogle Scholar - 210.
Healy SN, McCulloch AD. An ionic model of stretch-activated and stretch-modulated currents in rabbit ventricular myocytes.Europace. 2005; 7 (suppl 2):128–134. doi: 10.1016/j.eupc.2005.03.019.CrossrefMedlineGoogle Scholar - 211.
Trayanova NA, Constantino J, Gurev V. Models of stretch-activated ventricular arrhythmias.J Electrocardiol. 2010; 43:479–485. doi: 10.1016/j.jelectrocard.2010.05.014.CrossrefMedlineGoogle Scholar - 212.
Kohl P, Day K, Noble D. Cellular mechanisms of cardiac mechano-electric feedback in a mathematical model.Can J Cardiol. 1998; 14:111–119.MedlineGoogle Scholar - 213.
Garny A, Kohl P. Mechanical induction of arrhythmias during ventricular repolarization: modeling cellular mechanisms and their interaction in two dimensions.Ann N Y Acad Sci. 2004; 1015:133–143. doi: 10.1196/annals.1302.011.CrossrefMedlineGoogle Scholar - 214.
Li W, Kohl P, Trayanova N. Induction of ventricular arrhythmias following mechanical impact: a simulation study in 3D.J Mol Histol. 2004; 35:679–686. doi: 10.1007/s10735-004-2666-8.CrossrefMedlineGoogle Scholar - 215.
Quinn TA, Kohl P. Critical window for mechanically-induced arrhythmias exists in time and in space.Circulation. 2012; 126:21. Supplement A11162.Google Scholar - 216.
Sokabe M, Sachs F, Jing ZQ. Quantitative video microscopy of patch clamped membranes stress, strain, capacitance, and stretch channel activation.Biophys J. 1991; 59:722–728. doi: 10.1016/S0006-3495(91)82285-8.CrossrefMedlineGoogle Scholar - 217.
Le Guennec JY, Peineau N, Argibay JA, Mongo KG, Garnier D. A new method of attachment of isolated mammalian ventricular myocytes for tension recording: length dependence of passive and active tension.J Mol Cell Cardiol. 1990; 22:1083–1093.CrossrefMedlineGoogle Scholar - 218.
Nishimura S, Seo K, Nagasaki M, Hosoya Y, Yamashita H, Fujita H, Nagai R, Sugiura S. Responses of single-ventricular myocytes to dynamic axial stretching.Prog Biophys Mol Biol. 2008; 97:282–297. doi: 10.1016/j.pbiomolbio.2008.02.011.CrossrefMedlineGoogle Scholar - 219.
Omens JH, MacKenna DA, McCulloch AD. Measurement of strain and analysis of stress in resting rat left ventricular myocardium.J Biomech. 1993; 26:665–676.CrossrefMedlineGoogle Scholar - 220.
Hales PW, Schneider JE, Burton RA, Wright BJ, Bollensdorff C, Kohl P. Histo-anatomical structure of the living isolated rat heart in two contraction states assessed by diffusion tensor MRI.Prog Biophys Mol Biol. 2012; 110:319–330. doi: 10.1016/j.pbiomolbio.2012.07.014.CrossrefMedlineGoogle Scholar - 221.
Guo J, Sachs F, Meng F. Fluorescence-based force/tension sensors: a novel tool to visualize mechanical forces in structural proteins in live cells.Antioxid Redox Signal. 2014; 20:986–999. doi: 10.1089/ars.2013.5708.CrossrefMedlineGoogle Scholar - 222.
Slovut DP, Wenstrom JC, Moeckel RB, Wilson RF, Osborn JW, Abrams JH. Respiratory sinus dysrhythmia persists in transplanted human hearts following autonomic blockade.Clin Exp Pharmacol Physiol. 1998; 25:322–330.CrossrefMedlineGoogle Scholar - 223.
Dibb KM, Graham HK, Venetucci LA, Eisner DA, Trafford AW. Analysis of cellular calcium fluxes in cardiac muscle to understand calcium homeostasis in the heart.Cell Calcium. 2007; 42:503–512. doi: 10.1016/j.ceca.2007.04.002.CrossrefMedlineGoogle Scholar - 224.
Gannier F, White E, Garnier , Le Guennec JY. A possible mechanism for large stretch-induced increase in [Ca2+]i in isolated guinea-pig ventricular myocytes.Cardiovasc Res. 1996; 32:158–167.MedlineGoogle Scholar - 225.
Cannell MB. Pulling on the heart strings: a new mechanism within Starling’s law of the heart?Circ Res. 2009; 104:715–716. doi: 10.1161/CIRCRESAHA.109.195511.LinkGoogle Scholar - 226.
Calaghan S, White E. Activation of Na+-H+ exchange and stretch-activated channels underlies the slow inotropic response to stretch in myocytes and muscle from the rat heart.J Physiol. 2004; 559:205–214. doi: 10.1113/jphysiol.2004.069021.CrossrefMedlineGoogle Scholar - 227.
Zoll PM, Belgard AH, Weintraub MJ, Frank HA. External mechanical cardiac stimulation.N Engl J Med. 1976; 294:1274–1275. doi: 10.1056/NEJM197606032942307.CrossrefMedlineGoogle Scholar - 228.
Cohn PF, Angoff GH, Zoll PM, Sloss LJ, Markis JE, Graboys TB, Green LH, Braunwald E. A new, noninvasive technique for inducing post-extrasystolic potentiation during echocardiography.Circulation. 1977; 56:598–605.LinkGoogle Scholar - 229.
Pellis T, Kohl P. Antiarrhythmic effects of acute mechanical stimulation.Cardiac Mechano-Electric Coupling and Arrhythmias. 2nd ed. Oxford: Oxford University Press; 2011: 361–368.CrossrefGoogle Scholar - 230.
Levine JH, Guarnieri T, Kadish AH, White RI, Calkins H, Kan JS. Changes in myocardial repolarization in patients undergoing balloon valvuloplasty for congenital pulmonary stenosis: evidence for contraction-excitation feedback in humans.Circulation. 1988; 77:70–77.LinkGoogle Scholar - 231.
Gallacher DJ, Van de Water A, van der Linde H, Hermans AN, Lu HR, Towart R, Volders PG. In vivo mechanisms precipitating torsades de pointes in a canine model of drug-induced long-QT1 syndrome.Cardiovasc Res. 2007; 76:247–256. doi: 10.1016/j.cardiores.2007.06.019.CrossrefMedlineGoogle Scholar - 232.
Link MS, Wang PJ, Pandian NG, Bharati S, Udelson JE, Lee MY, Vecchiotti MA, VanderBrink BA, Mirra G, Maron BJ, Estes NA An experimental model of sudden death due to low-energy chest-wall impact (commotio cordis).N Engl J Med. 1998; 338:1805–1811. doi: 10.1056/NEJM199806183382504.CrossrefMedlineGoogle Scholar - 233.
Link MS. Commotio cordis: ventricular fibrillation triggered by chest impact-induced abnormalities in repolarization.Circ Arrhythm Electrophysiol. 2012; 5:425–432. doi: 10.1161/CIRCEP.111.962712.LinkGoogle Scholar - 234.
Alsheikh-Ali AA, Akelman C, Madias C, Link MS. Endocardial mapping of ventricular fibrillation in commotio cordis.Heart Rhythm. 2008; 5:1355–1356. doi: 10.1016/j.hrthm.2008.03.009.CrossrefMedlineGoogle Scholar - 235.
Walters TE, Lee G, Spence S, Larobina M, Atkinson V, Antippa P, Goldblatt J, O’Keefe M, Sanders P, Kistler PM, Kalman JM. Acute atrial stretch results in conduction slowing and complex signals at the pulmonary vein to left atrial junction: insights into the mechanism of pulmonary vein arrhythmogenesis.Circ Arrhythm Electrophysiol. 2014; 7:1189–1197. doi: 10.1161/CIRCEP.114.001894.LinkGoogle Scholar - 236.
Sparks PB, Mond HG, Vohra JK, Yapanis AG, Grigg LE, Kalman JM. Mechanical remodeling of the left atrium after loss of atrioventricular synchrony. A long-term study in humans.Circulation. 1999; 100:1714–1721.LinkGoogle Scholar - 237.
Wijffels MC, Kirchhof CJ, Dorland R, Power J, Allessie MA. Electrical remodeling due to atrial fibrillation in chronically instrumented conscious goats: roles of neurohumoral changes, ischemia, atrial stretch, and high rate of electrical activation.Circulation. 1997; 96:3710–3720.LinkGoogle Scholar - 238.
Quintanilla JG, Moreno J, Archondo T, Usandizaga E, Molina-Morúa R, Rodríguez-Bobada C, González P, García-Torrent MJ, Filgueiras-Rama D, Pérez-Castellano N, Macaya C, Pérez-Villacastín J. Increased intraventricular pressures are as harmful as the electrophysiological substrate of heart failure in favoring sustained reentry in the swine heart.Heart Rhythm. 2015; 12:2172–2183. doi: 10.1016/j.hrthm.2015.05.017.CrossrefMedlineGoogle Scholar - 239.
Franz MR, Burkhoff D, Yue DT, Sagawa K. Mechanically induced action potential changes and arrhythmia in isolated and in situ canine hearts.Cardiovasc Res. 1989; 23:213–223.CrossrefMedlineGoogle Scholar - 240.
Salameh A, Karl S, Djilali H, Dhein S, Janousek J, Daehnert I. Opposing and synergistic effects of cyclic mechanical stretch and α- or β-adrenergic stimulation on the cardiac gap junction protein Cx43.Pharmacol Res. 2010; 62:506–513. doi: 10.1016/j.phrs.2010.08.002.CrossrefMedlineGoogle Scholar - 241.
John B, Stiles MK, Kuklik P, Brooks AG, Chandy ST, Kalman JM, Sanders P. Reverse remodeling of the atria after treatment of chronic stretch in humans: implications for the atrial fibrillation substrate.J Am Coll Cardiol. 2010; 55:1217–1226. doi: 10.1016/j.jacc.2009.10.046.CrossrefMedlineGoogle Scholar - 242.
Mondry A, Swynghedauw B. Biological adaptation of the myocardium to chronic mechanical overload. Molecular determinants of the autonomic nervous system.Eur Heart J. 1995; 16 (suppl I):64–73.CrossrefMedlineGoogle Scholar - 243.
Waxman MB, Wald RW, Finley JP, Bonet JF, Downar E, Sharma AD. Valsalva termination of ventricular tachycardia.Circulation. 1980; 62:843–851.LinkGoogle Scholar - 244.
Ashikaga H, Mickelsen SR, Ennis DB, Rodriguez I, Kellman P, Wen H, McVeigh ER. Electromechanical analysis of infarct border zone in chronic myocardial infarction.Am J Physiol Heart Circ Physiol. 2005; 289:H1099–H1105. doi: 10.1152/ajpheart.00423.2005.CrossrefMedlineGoogle Scholar - 245.
Jie X, Gurev V, Trayanova N. Mechanisms of mechanically induced spontaneous arrhythmias in acute regional ischemia.Circ Res. 2010; 106:185–192. doi: 10.1161/CIRCRESAHA.109.210864.LinkGoogle Scholar - 246.
Lab CBM. Stretch effects on potassium accumulation and alternans in pathological myocardium.Cardiac Mechano-Electric Coupling and Arrhythmias. 2nd ed. Oxford: OUP; 2011: 173–179.CrossrefGoogle Scholar - 247.
Schott E. Über Ventrikelstillstand (Adam-Stokes’sche Anfälle) nebst Bemerkungen über andersartige Arrhythmien passagerer Natur. (“On Ventricular Standstill (Adam-Stokes Attacks) together with other Arrhythmias of Temporary Nature.”).Dt Arch klin Med. 1920:211–229.Google Scholar - 248.
Li W, Kohl P, Trayanova N. Myocardial ischemia lowers precordial thump efficacy: an inquiry into mechanisms using three-dimensional simulations.Heart Rhythm. 2006; 3:179–186. doi: 10.1016/j.hrthm.2005.10.033.CrossrefMedlineGoogle Scholar - 249.
Pellis T, Kohl P. Extracorporeal cardiac mechanical stimulation: precordial thump and precordial percussion.Br Med Bull. 2010; 93:161–177. doi: 10.1093/bmb/ldp045.CrossrefMedlineGoogle Scholar - 250.
Nehme Z, Andrew E, Bernard SA, Smith K. Treatment of monitored out-of-hospital ventricular fibrillation and pulseless ventricular tachycardia utilising the precordial thump.Resuscitation. 2013; 84:1691–1696. doi: 10.1016/j.resuscitation.2013.08.011.CrossrefMedlineGoogle Scholar - 251.
Pellis T, Kette F, Lovisa D, Franceschino E, Magagnin L, Mercante WP, Kohl P. Utility of pre-cordial thump for treatment of out of hospital cardiac arrest: a prospective study.Resuscitation. 2009; 80:17–23. doi: 10.1016/j.resuscitation.2008.10.018.CrossrefMedlineGoogle Scholar - 252.
Amir O, Schliamser JE, Nemer S, Arie M. Ineffectiveness of precordial thump for cardioversion of malignant ventricular tachyarrhythmias.Pacing Clin Electrophysiol. 2007; 30:153–156. doi: 10.1111/j.1540-8159.2007.00643.x.CrossrefMedlineGoogle Scholar - 253.
Haman L, Parizek P, Vojacek J. Precordial thump efficacy in termination of induced ventricular arrhythmias.Resuscitation. 2009; 80:14–16. doi: 10.1016/j.resuscitation.2008.07.022.CrossrefMedlineGoogle Scholar - 254.
Sayre MR, Koster RW, Botha M, Cave DM, Cudnik MT, Handley AJ, Hatanaka T, Hazinski MF, Jacobs I, Monsieurs K, Morley PT, Nolan JP, Travers AH ; Adult Basic Life Support Chapter Collaborators. Part 5: adult basic life support: 2010 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science with Treatment Recommendations.Circulation. 2010; 122:S298–S324. doi: 10.1161/CIRCULATIONAHA.110.970996.LinkGoogle Scholar - 255.
Eich C, Bleckmann A, Schwarz SK. Percussion pacing–an almost forgotten procedure for haemodynamically unstable bradycardias? A report of three case studies and review of the literature.Br J Anaesth. 2007; 98:429–433. doi: 10.1093/bja/aem007.CrossrefMedlineGoogle Scholar - 256.
Madias C, Maron BJ, Alsheikh-Ali AA, Rajab M, Estes NA, Link MS. Precordial thump for cardiac arrest is effective for asystole but not for ventricular fibrillation.Heart Rhythm. 2009; 6:1495–1500. doi: 10.1016/j.hrthm.2009.06.029.CrossrefMedlineGoogle Scholar - 257.
Monteleone PP, Alibertis K, Brady WJ. Emergent precordial percussion revisited–pacing the heart in asystole.Am J Emerg Med. 2011; 29:563–565. doi: 10.1016/j.ajem.2010.01.030.CrossrefMedlineGoogle Scholar - 258.
Gottlieb PA, Bae C, Sachs F. Gating the mechanical channel Piezo1: a comparison between whole-cell and patch recording.Channels (Austin). 2012; 6:282–289. doi: 10.4161/chan.21064.CrossrefMedlineGoogle Scholar - 259.
Retailleau K, Duprat F, Arhatte M, Ranade SS, Peyronnet R, Martins JR, Jodar M, Moro C, Offermanns S, Feng Y, Demolombe S, Patel A, Honoré E. Piezo1 in smooth muscle cells is involved in hypertension-dependent arterial remodeling.Cell Rep. 2015; 13:1161–1171. doi: 10.1016/j.celrep.2015.09.072.CrossrefMedlineGoogle Scholar - 260.
Sheetz MP. Cell control by membrane-cytoskeleton adhesion.Nat Rev Mol Cell Biol. 2001; 2:392–396. doi: 10.1038/35073095.CrossrefMedlineGoogle Scholar - 261.
Sachs F. Mechanical transduction by ion channels: a cautionary tale.World J Neurol. 2015; 5:74–87. doi: 10.5316/wjn.v5.i3.74.CrossrefMedlineGoogle Scholar - 262.
Evans EA, Skalak R. Mechanics and thermodynamics of biomembranes: part 1.CRC Crit Rev Bioeng. 1979; 3:181–330.MedlineGoogle Scholar - 263.
Nichol JA, Hutter OF. Tensile strength and dilatational elasticity of giant sarcolemmal vesicles shed from rabbit muscle.J Physiol. 1996; 493 (pt 1):187–198.CrossrefMedlineGoogle Scholar - 264.
Morris CE, Homann U. Cell surface area regulation and membrane tension.J Membr Biol. 2001; 179:79–102.CrossrefMedlineGoogle Scholar - 265.
Groulx N, Boudreault F, Orlov SN, Grygorczyk R. Membrane reserves and hypotonic cell swelling.J Membr Biol. 2006; 214:43–56. doi: 10.1007/s00232-006-0080-8.CrossrefMedlineGoogle Scholar - 266.
Raucher D, Sheetz MP. Characteristics of a membrane reservoir buffering membrane tension.Biophys J. 1999; 77:1992–2002. doi: 10.1016/S0006-3495(99)77040-2.CrossrefMedlineGoogle Scholar - 267.
Kozera L, White E, Calaghan S. Caveolae act as membrane reserves which limit mechanosensitive ICl,swell channel activation during swelling in the rat ventricular myocyte.PLoS One. 2009; 4:e8312. doi: 10.1371/journal.pone.0008312.CrossrefMedlineGoogle Scholar - 268.
Dai J, Sheetz MP, Wan X, Morris CE. Membrane tension in swelling and shrinking molluscan neurons.J Neurosci. 1998; 18:6681–6692.CrossrefMedlineGoogle Scholar - 269.
Sachs F. Stretch-activated ion channels: what are they?Physiology (Bethesda). 2010; 25:50–56. doi: 10.1152/physiol.00042.2009.CrossrefMedlineGoogle Scholar - 270.
Bigay J, Casella JF, Drin G, Mesmin B, Antonny B. ArfGAP1 responds to membrane curvature through the folding of a lipid packing sensor motif.EMBO J. 2005; 24:2244–2253. doi: 10.1038/sj.emboj.7600714.CrossrefMedlineGoogle Scholar - 271.
Eyckmans J, Boudou T, Yu X, Chen CS. A Hitchhiker’s guide to mechanobiology.Dev Cell. 2011; 21:35–47. doi: 10.1016/j.devcel.2011.06.015.CrossrefMedlineGoogle Scholar - 272.
Cruickshank CC, Minchin RF, Le Dain AC, Martinac B. Estimation of the pore size of the large-conductance mechanosensitive ion channel of Escherichia coli.Biophys J. 1997; 73:1925–1931. doi: 10.1016/S0006-3495(97)78223-7.CrossrefMedlineGoogle Scholar - 273.
Wagner E, Lauterbach MA, Kohl T, . Stimulated emission depletion live-cell super-resolution imaging shows proliferative remodeling of T-tubule membrane structures after myocardial infarction.Circ Res. 2012; 111:402–414. doi: 10.1161/CIRCRESAHA.112.274530.LinkGoogle Scholar - 274.
Savio-Galimberti E, Frank J, Inoue M, Goldhaber JI, Cannell MB, Bridge JH, Sachse FB. Novel features of the rabbit transverse tubular system revealed by quantitative analysis of three-dimensional reconstructions from confocal images.Biophys J. 2008; 95:2053–2062. doi: 10.1529/biophysj.108.130617.CrossrefMedlineGoogle Scholar - 275.
Cannell MB, Crossman DJ, Soeller C. Effect of changes in action potential spike configuration, junctional sarcoplasmic reticulum micro-architecture and altered t-tubule structure in human heart failure.J Muscle Res Cell Motil. 2006; 27:297–306. doi: 10.1007/s10974-006-9089-y.CrossrefMedlineGoogle Scholar - 276.
Suchyna TM, Markin VS, Sachs F. Biophysics and structure of the patch and the gigaseal.Biophys J. 2009; 97:738–747. doi: 10.1016/j.bpj.2009.05.018.CrossrefMedlineGoogle Scholar - 277.
Meng F, Suchyna TM, Sachs F. A fluorescence energy transfer-based mechanical stress sensor for specific proteins in situ.FEBS J. 2008; 275:3072–3087. doi: 10.1111/j.1742-4658.2008.06461.x.CrossrefMedlineGoogle Scholar - 278.
Meng F, Sachs F. Visualizing dynamic cytoplasmic forces with a compliance-matched FRET sensor.J Cell Sci. 2011; 124:261–269. doi: 10.1242/jcs.071928.CrossrefMedlineGoogle Scholar - 279.
Wang Y, Liu Y, Deberg HA, Nomura T, Hoffman MT, Rohde PR, Schulten K, Martinac B, Selvin PR. Single molecule FRET reveals pore size and opening mechanism of a mechano-sensitive ion channel.Elife. 2014; 3:e01834. doi: 10.7554/eLife.01834.CrossrefMedlineGoogle Scholar - 280.
Hirata H, Tatsumi H, Hayakawa K, Sokabe M. Non-channel mechanosensors working at focal adhesion-stress fiber complex.Pflugers Arch. 2015; 467:141–155. doi: 10.1007/s00424-014-1558-3.CrossrefMedlineGoogle Scholar - 281.
Israeli-Rosenberg S, Chen C, Li R, Deussen DN, Niesman IR, Okada H, Patel HH, Roth DM, Ross RS. Caveolin modulates integrin function and mechanical activation in the cardiomyocyte.FASEB J. 2015; 29:374–384. doi: 10.1096/fj.13-243139.CrossrefMedlineGoogle Scholar - 282.
Chai Q, Wang XL, Zeldin DC, Lee HC. Role of caveolae in shear stress-mediated endothelium-dependent dilation in coronary arteries.Cardiovasc Res. 2013; 100:151–159. doi: 10.1093/cvr/cvt157.CrossrefMedlineGoogle Scholar - 283.
McNary TG, Spitzer KW, Holloway H, Bridge JH, Kohl P, Sachse FB. Mechanical modulation of the transverse tubular system of ventricular cardiomyocytes.Prog Biophys Mol Biol. 2012; 110:218–225. doi: 10.1016/j.pbiomolbio.2012.07.010.CrossrefMedlineGoogle Scholar - 284.
Solovyova O, Katsnelson LB, Konovalov P, . Activation sequence as a key factor in spatio-temporal optimization of myocardial function.Philos Trans A Math Phys Eng Sci. 2006; 364:1367–1383.CrossrefMedlineGoogle Scholar
eLetters(0)
eLetters should relate to an article recently published in the journal and are not a forum for providing unpublished data. Comments are reviewed for appropriate use of tone and language. Comments are not peer-reviewed. Acceptable comments are posted to the journal website only. Comments are not published in an issue and are not indexed in PubMed. Comments should be no longer than 500 words and will only be posted online. References are limited to 10. Authors of the article cited in the comment will be invited to reply, as appropriate.
Comments and feedback on AHA/ASA Scientific Statements and Guidelines should be directed to the AHA/ASA Manuscript Oversight Committee via its Correspondence page.