Cardiac Mechano-Electric Coupling Physrev.00036.2019

TITLE
Cardiac Mechano-Electric Coupling: Acute Effects of Mechanical Stimulation on Heart Rate and
Rhythm
RUNNING HEAD
Cardiac Mechano-Electric Coupling
AUTHORS
T. Alexander Quinn, PhD1,2
Peter Kohl, MD PhD3,4
AFFILIATIONS
1Department of Physiology and Biophysics and 2School of Biomedical Engineering, Dalhousie
University, 5850 College St, Lab 4J, Halifax, NS, B3H 4R2, Canada
3Institute for Experimental Cardiovascular Medicine, University Heart Centre Freiburg/ Bad
Krozingen, Medical Faculty of the University of Freiburg, Elsässer Str. 2Q, 79110, Freiburg,
Germany
4CIBSS – Centre for Integrative Biological Signalling Studies, University of Freiburg,
Schänzlestraße 18, 79104, Freiburg, Germany
CORRESPONDING AUTHOR
T Alexander Quinn, PhD
Department of Physiology and Biophysics
Dalhousie University
5850 College St, Lab 3F
Halifax, NS B3H 4R2
Phone: +1 902 494 4349
Email: alex.quinn@dal.ca
(1)
Downloaded from journals.physiology.org/journal/physrev by Julio Hilario-Vargas (179.007.193.198) on August 27, 2020.
DISCLOSURES
The authors declare no conflicts of interest, financial or otherwise.
FUNDING
This work was supported by the Canadian Institutes of Health Research (MOP 342562 to TAQ),
the Natural Sciences and Engineering Research Council of Canada (RGPIN-2016-04879 to
TAQ), and the European Research Council Advanced Grant CardioNECT (323099 to PK). TAQ
is a National New Investigator of the Heart and Stroke Foundation of Canada.
ACKNOWLEDGEMENTS
We thank both the present and past members of our research groups, as well as our colleagues
and mentors, from all of whom we have learned along the way. Special thanks go to Remi
Peyronnet, PhD, for critical comments on the manuscript. While we have tried to be
comprehensive, we have been unable to include all published communications on the topic. We
apologise for any omissions – they were not intended.
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TABLE OF CONTENTS
ABSTRACT .................................................................................................................. 5
GRAPHICAL ABSTRACT ............................................................................................ 5
CLINICIAN CALL-OUT BOX ........................................................................................ 6
GLOSSARY .................................................................................................................. 7
ABBREVIATIONS ........................................................................................................ 9
I. CARDIAC MECHANO-ELECTRIC COUPLING (MEC) ........................................... 10
A. MEC and the Mechano-electric Regulatory Loop ............................................... 10
B. Brief History of MEC Research........................................................................... 12
II. PHYSIOLOGICAL AND CLINICAL RELEVANCE OF MEC .................................. 14
A. Modulation of Heart Rate ................................................................................... 14
1. Mechanisms of SAN Automaticity................................................................... 14
2. SAN Mechano-Sensitivity ............................................................................... 17
3. SAN Dysfunction ............................................................................................ 19
4. Summary ........................................................................................................ 20
B. Transient Effects on Whole Heart Electrical Activity ........................................... 21
1. Diastolic Stretch.............................................................................................. 21
2. Systolic Stretch ............................................................................................... 23
3. Summary ........................................................................................................ 24
C. Induction of Sustained Arrhythmias .................................................................... 25
1. Tissue-Level Mechanisms of Stretch-Induced Arrhythmias ............................ 25
2. Commotio Cordis ............................................................................................ 26
3. Acute Regional Ischaemia .............................................................................. 28
4. Mitral Valve Prolapse ...................................................................................... 29
5. Chronic Pathophysiological States ................................................................. 30
6. Atrial Fibrillation .............................................................................................. 32
5. Summary ........................................................................................................ 34
D. Arrhythmia Termination ...................................................................................... 34
1. Tachyarrhythmias ........................................................................................... 34
2. Bradycardia and Asystole ............................................................................... 36
3. Advantages and Limitations of MEC-based Anti-Arrhythmic Interventions ..... 39
4. Summary ........................................................................................................ 43
C. Knowledge Gaps and Future Directions ............................................................. 44
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III. MOLECULAR MECHANISMS OF MEC ................................................................ 44
A. Pacemaker Cells ................................................................................................ 44
1. Mechano-Sensitivity of ‘Mechanical Oscillator’ Components .......................... 44
2. Mechano-Sensitivity of Vm Oscillator Components ......................................... 48
3. Mechano-Sensitivity of Ca2+ Oscillator Components ...................................... 49
4. Summary ........................................................................................................ 50
B. Working Cardiomyocytes.................................................................................... 50
1. SACNS ............................................................................................................. 50
2. SACK .............................................................................................................. 53
3. Mechano-Sensitivity of Intra-Cellular Ca2+ Handling ....................................... 53
4. Summary ........................................................................................................ 54
C. Cardiac Non-Myocytes ....................................................................................... 55
1. SACNS ............................................................................................................. 55
2. Summary ........................................................................................................ 56
D. Molecular Candidates for SAC ........................................................................... 56
1. SACNS ............................................................................................................. 56
2. SACK .............................................................................................................. 59
3. Considerations for the Use of Pharmacological Probes ................................. 60
4. Summary ........................................................................................................ 62
IV. INTEGRATIVE COMPUTATIONAL MODELS OF MEC ....................................... 63
A. Single Cell .......................................................................................................... 63
1. Consequences of SAC Activation ................................................................... 63
2. Consequences of Altered Intra-Cellular Ca2+ Handling .................................. 65
3. Summary ........................................................................................................ 66
B. Multi-cellular ....................................................................................................... 67
1. Physiological Mechanical Activity and Electrical Instability ............................. 67
2. Triggering and Sustenance of Arrhythmias .................................................... 68
3. Modifying and Terminating Arrhythmias ......................................................... 69
3. Summary ........................................................................................................ 71
V. SUMMARY AND CONCLUSIONS ......................................................................... 71
VI. REFERENCES ...................................................................................................... 73
(4)
ABSTRACT
The heart is vital for biological function in almost all chordates, including human. It beats
continually throughout our life, supplying the body with oxygen and nutrients while removing
waste products. If it stops – so does life. The heartbeat involves precise coordination of the
activity of billions of individual cells, as well as their swift and well-coordinated adaption to
changes in physiological demand. Much of the vital control of cardiac function occurs at the level
of individual cardiac muscle cells, including acute beat-by-beat feedback from the local
mechanical environment to electrical activity (as opposed to longer-term changes in gene
expression, and functional or structural remodelling). This process is known as Mechano-Electric
Coupling (MEC). In the current review, we: present evidence for, and implications of, MEC in
health and disease in human; summarise our understanding of MEC effects gained from whole
animal, organ, tissue, and cell studies; identify potential molecular mediators of MEC responses;
and demonstrate the power of computational modelling in developing a more comprehensive
understanding of ‘what makes the heart tick’.
GRAPHICAL ABSTRACT
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CLINICIAN CALL-OUT BOX
Mechanical Induction and Termination of Arrhythmias
1. Normal cardiac rhythm requires the coordination of billions of individual heart cells’ activity, as
well as their swift and well-coordinated adaption to changes in physiological demand. A critical
factor for beat-by-beat control of cardiac function is an intracardiac, electro-mechanical auto-
regulatory loop, involving feed-forward and feed-back interactions between the heart’s electrical
and mechanical behaviour. This includes acute feedback from the local mechanical environment
to cellular electrophysiology via mechano-sensitive sub-cellular components, a process known
as Mechano-Electric Coupling (MEC).
2. In cardiac pacemaker cells, acute stretch (e.g., in the primary pacemaker of the sinoatrial node,
caused by an increase in venous return) results in more rapid spontaneous diastolic
depolarisation (e.g., increasing rate of sinoatrial node excitation; the Bainbridge effect). This
MEC response is intrinsic to the pacemaker cells themselves (i.e., independent of autonomic
reflexes) and it is critical for the adaptation of heart rate to beat-by-beat changes in venous
return. Age- and disease- related changes in myocardial mechanics can affect associated auto-
regulatory mechanisms, and thus contribute to sinoatrial node dysfunction and disturbances of
cardiac rhythm.
3. In the atria, acute stretch due to volume or pressure overload increases the vulnerability to, and
sustainability of, atrial fibrillation – whether tissue remodelling is already present or not. This
MEC effect has been attributed to heterogeneous, mechanically-induced changes in excitability,
action potential duration, refractoriness, and/or conduction.
4. In the ventricles, acute mechanical stimulation, whether global (due to volume or pressure
overload) local (due to contact of intra-cardiac devices with the endocardium, such as tips of
catheters or pacing leads), or caused by external impacts (e.g., in the setting of Commotio
cordis) can lead to premature excitation and induce tachyarrhythmias, including ventricular
fibrillation. Outcomes depend on the interrelation of the mechanical stimulus with underlying
substrate electrophysiology, creating an individually varying, spatio-temporally defined
vulnerable window. In chronic diseases with ventricular overload, stretch contributes to the
sustenance of ventricular arrhythmias, as evidenced by the anti-arrhythmic effect of a temporary
reduction in ventricular loading (e.g., by the Valsalva manoeuvre).
5. Transcutaneous mechanically-induced excitation, whether by extracorporeal or epicardial

impact, high-intensity focused ultrasound, or catheter-based device approaches, may be an
effective means for transient pacing of the asystolic or severely bradycardic heart, potentially to
the point of recovery of normal sinus rhythm. Current International Liaison Committee on
Resuscitation (ILCOR) guidelines state that: “fist pacing may be considered in
haemodynamically unstable bradyarrhythmias until an electric pacemaker (transcutaneous or
transvenous) is available” and that: ““there is insufficient evidence to recommend for or against
the use of the precordial thump for witnessed onset of asystole caused by atrioventricular
conduction disturbance”. This is an area requiring targeted research.
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GLOSSARY
Key Specialised Terminology
A potassium channel that is activated both a

ATP-sensitive potassium current (IK,ATP) reduction in intracellular adenosine triphosphate and
modulated by stretch.
Atrial fibrillation (AF) Rapid, irregular excitation of some or all of the atria.
Bradycardia Slow heart rate.
Intracellular calcium cycling contribution to sinoatrial

‘Calcium (Ca2+) clock’
node automaticity.
Mechanical “agitation of the heart” [Latin], usually by

a precordial impact of sub-contusional energy, that
Commotio cordis
may give rise to heart rhythm disturbances of varying
severity and duration, including ventricular fibrillation.
Membrane potential at which there is no net flow

Reversal potential (Erev)
through an ion channel.
Chemical element that is a non-specific blocker of

Gadolinium (Gd3+)
cation nonselective stretch-activated ion channels.
Peptide isolated from the venom of the Grammostola

Grammostola spatulata rosea spider that is currently the most selective
mechanotoxin-4 (GsMTx-4) blocker of cation-nonselective stretch-activated
channels.
Hyperpolarisation-activated depolarising ‘inward’

‘Funny’ current (If) current passed by cyclic nucleotide-gated channels,
for example in sinoatrial node cells.
Condition in which repolarisation of (part of) the

Long QT syndrome ventricles is delayed, causing an increase in the QT
interval of the electrocardiogram.
Most negative membrane potential reached by

Maximum diastolic potential pacemaker cells during their spontaneous cycle of
de- and repolarisation.
Most positive membrane potential reached by

Maximum systolic potential pacemaker cells during their spontaneous cycle of
de- and repolarisation.
(7)
Acute feedback from the mechanical status of the
Mechano-electric coupling (MEC)
heart to its electrical activity.
System of mechano-sensitive mechanisms that

‘Mechanics clock’
contributes to sinoatrial node automaticity.
A single fist impact, generally applied to the left of the

Precordial thump lower half of the sternum, to re-set disturbed heart
rhythms.
Physiological fluctuation in heart rate that is

Respiratory sinus arrhythmia
synchronous with the respiratory cycle.
A region of tissue in the right atrium that contains the

Sinoatrial node (SAN)
primary cardiac pacemaker.
Automaticity-providing shift in membrane potential in

Spontaneous diastolic depolarisation
cardiac pacemaker cells.
Automaticity-providing shift in membrane potential in

Spontaneous diastolic depolarisation
cardiac pacemaker cells.
Ion channel which is gated by a mechanical stimulus

Stretch-activated channel (SAC)
(in the absence of cell volume changes).
Ion channel whose activity is altered by a mechanical

Stretch-modulated channel
stimulus.
Tachyarrhythmia Abnormally rapid heart rhythm.
Ventricular fibrillation (VF) Rapid irregular excitation of the ventricles.
System of sarcolemma-bound ion flux mechanisms

‘Voltage (Vm) clock’
that contributes to sinoatrial node automaticity.
A narrow period during which the heart is particularly

Vulnerable window
susceptible to the induction of arrhythmias.
(8)
ABBREVIATIONS
2D two-dimensional
3D three-dimensional
AF atrial fibrillation
AP action potential
APD action potential duration
ATP adenosine triphosphate
BK big potassium channel
Ca2+ calcium ion
CaV voltage-gated calcium
ECG electrocardiogram
Erev reversal potential
Gd3+ gadolinium ion
GsMTx-4 Grammostola spatulata mechanotoxin-4
HR heart rate
Ib,Na background sodium current
ICa,L long-lasting calcium current
ICa,T transient calcium current
ICl,swell swelling-activated chloride current
If ‘funny’ current
IK,ATP adenosine triphosphate-sensitive potassium current
INa fast sodium current
INCX sodium-calcium exchanger current
ISAC,K potassium-selective stretch-activated current
ISAC,NS cation-nonselective stretch-activated current
K+ potassium ion
K2P 2 P-domain potassium channel
MEC mechano-electric coupling
Na+ sodium ion
ROS reactive oxygen species
RyR ryanodine receptor
SAC stretch-activated channel
SACK potassium-selective stretch-activated channel
SACNS cation-nonselective stretch-activated channel
SAN sinoatrial node
SR sarcoplasmic reticulum
TnC troponin C
TRAAK TWIK-related arachidonic acid-activated potassium channel
TREK-1 TWIK-related potassium channel-1
TRP transient receptor potential channel
TRPC transient receptor potential channel, canonical protein
TRPM transient receptor potential channel, melastatin protein
TRPP transient receptor potential channel, polycystic protein
TRPV transient receptor potential channel, vanilloid protein
TWIK 2-pore domain weak inwardly rectifying potassium channel
VF ventricular fibrillation
Vm transmembrane potential
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I. CARDIAC MECHANO-ELECTRIC COUPLING (MEC)
A. MEC and the Mechano-electric Regulatory Loop

The heart is a remarkably dynamic, robust organ. It beats approximately once per second,
and about 3-4 billion times in one’s lifetime. In doing so, it pumps the equivalent to the volume
contained in an Olympic-sized swimming pool each year. The human heart is composed of
billions of individual muscle cells (cardiomyocytes), as well as a host of other cell types (e.g.,
fibroblasts, endothelial, fat, nerve, and immune cells). For effective pumping, this myriad of cells
functions in a tightly controlled and well-orchestrated manner. Cardiomyocytes are electrically
excited and mechanically contract in a well-coordinated pattern, while simultaneously adjusting
their activity on a beat-by-beat basis to fluctuating haemodynamic conditions, so that local
mechanical activity matches global circulatory demand. This demand is altered by exercise,
when we change posture, and even with every breath we take, affecting the passive mechanical
stretch of cells before contraction (referred to as ‘strain’ when normalised to resting length) and
the load against which cells actively contract (referred to as ‘stress’ when expressed as force per
cross-sectional area). In the ventricles, pre-contraction stretch can be approximated by end-
diastolic volume (called ‘preload’), and the force opposing ventricular ejection is determined by
the pressure in the downstream aortic or pulmonary vessels (called ‘afterload’). One result of the
inherent cardiac mechano-sensitivity is the fact that cardiac output (ejection) matches venous
return (filling), maintaining balanced cardiovascular system performance, while also matching
the throughput of left and right sides of the heart over any period of time.
Incredibly, the heart’s coordinated activity and its adaption to haemodynamic changes occur
in the absence of the kind of neuro-muscular junctions that organise skeletal muscle activity
(although neuro-muscular interaction sites with the autonomic nervous system may be much
more wide-spread and regular in the heart than previously thought (478)). And while heart
function is clearly influenced by extra-cardiac factors such as sympathetic and parasympathetic
innervation and circulating hormones, beat-by-beat adaptation of cardiac function to changes in
the mechanical environment continues even when the heart is removed from the body, or when
it lacks nervous system inputs such as in freshly transplanted hearts. This is possible because
the heart possesses highly efficient intrinsic (intra-cardiac) auto-regulatory mechanisms that are
based on feed-forward and feed-back interactions between the heart’s electrical and mechanical
activity.
In the direction classically regarded as feed-forward, electrical excitation of the myocardium,
physiologically initiated by the leading pacemaker in the sinoatrial node (SAN, a region of the
(10)
right atrium), results in a spreading wave of cellular action potentials (AP) that, through a
process known as excitation contraction coupling, give rise to mechanical activation (47, 168). In
the opposite direction, the heart’s mechanical status, including internal and external mechanical
perturbations, affects cardiac electrical activity. This acute feedback (as opposed to medium-
term gene expression changes or longer-term electrophysiological, mechanical, and structural
remodelling that occur with chronic mechanical alterations and during heart disease (397)) has
been termed ‘Mechano-Electric Feedback’ (which, strictly, considers only cardiac mechanical
activity as an input signal), or more broadly, ‘Mechano-Electric Coupling’ (MEC, which
encompasses mechanical perturbations of the heart irrespective of their origin) (318, 499)
(illustrated in FIGURE 1).
Figure 1. The feed-forward and feed-back links between cardiac electrophysiology and
mechanics, forming the intra-cardiac mechano-electric regulatory loop. The feed-forward between
electrical excitation and mechanical contraction involving intra-cellular calcium (Ca2+) handling and actin-
myosin cross-bridge cycling, is a process known as ‘Excitation-Contraction Coupling’. Feedback from
myocardial deformation to cell electrophysiology and intra-cellular Ca2+ dynamics occurs via multiple
interdependent mechano-sensitive mechanisms, which in turn affect the origin and spread of excitation, a
phenomenon known as ‘Mechano-Electric Feedback’ (which, strictly, would consider only cardiac
mechanical activity as an input signal) or more broadly ‘Mechano-Electric Coupling’ (which encompasses
mechanical perturbations of the heart irrespective of their origin). [Adapted from (487).]
(11)
MEC is an expression of the heart’s exquisite mechano-sensitivity. It is evident at all levels
of structural and functional integration (from sub-cellular to whole organ), in numerous cell types
(ventricular and atrial myocytes, SAN and Purkinje pacemaker cells, as well as cardiac non-
myocytes), and it is present both in invertebrates and vertebrates from fish to human (318).
Mechanical stimuli, acting through stretch-activated ion channels (SAC, which are directly gated
by a mechanical stimulus), stretch-modulated ion channels (whose primary mechanism of
activation is non-mechanical, but whose activity is modulated, usually increased, by mechanical
stimulation), changes in calcium handling, and second messenger systems have far-ranging
physiological effects on the heart, from altered electrophysiological properties including
excitability, refractoriness, and electrical load, to changes in heart rate (HR) and rhythm, AP
shape, and electrical conduction. These effects have important clinical consequences, including
the induction or termination of arrhythmias.
In this review, following a brief look at the history of MEC research, we will present the
evidence for and implications of MEC in human, summarise insight into MEC effects that have
been gleaned from whole animal, organ, tissue, and cell studies, explore potential molecular
mechanisms of MEC, and reflect upon the utility of integration of mechano-electric interaction
data by computational modelling.
B. Brief History of MEC Research

Early case reports on mechanically-induced changes in heart rhythm date back, in the
European medical literature, at least to the late 19th century (e.g., on mechanically-induced
sudden death by Felice Meola (394), Auguste Nelaton (426), and Ferdinand Riedinger (519)). At
the turn of the 20th century, systematic experimental studies in whole animals explored
phenomena ranging from Commotio cordis (e.g., Georg Schlomka (543)) to stretch-induced
increase in HR (23). Mechanistic insight from AP recordings in isolated cardiac tissue started to
emerge in the 1960s, when Klaus Deck characterised the stretch-induced positive chronotropic
response in isolated SAN from rabbit and cat (147). These intra-cardiac, mechanically-induced
electrophysiological effects (discussed in ‘II.A. Modulation of Heart Rate’) were recognised as an
expression of Mechano-Electric Feedback (“Mechano-Elektrische Rückkoppelung”) in a paper
by Raimund Kaufmann and Ursula Ravens (née Theophile) that reported a stretch-induced
increase in automaticity of Purkinje fibres from rhesus monkeys (292).
Stretch-induced electrophysiological effects in working myocardium (e.g., acceleration of early
repolarisation, depolarisation in later phases of the AP, and the potential of triggering ectopic
beats) were demonstrated in frog by Max Lab in the 1970s (329). Ten years later, Michael Franz
(12)
and colleagues showed that an acute increase in intra-ventricular volume in hearts from dogs
caused diastolic depolarization that could be used to pace the asystolic heart (180). Around the
same time, direct evidence for the presence of MEC in human ventricles came from Peter
Taggart and colleagues, who reported an acute decrease in AP duration upon increased left
ventricular pressure in patients being weaned from cardiopulmonary bypass (593), and Joseph
Levine and colleagues, who showed similar results during acute right ventricular outflow tract
occlusion in patients undergoing balloon valvuloplasty ((347); these observations are discussed
in ‘II.B. Transient Effects on Whole Heart Electrical Activity’). Another ten years on, similar MEC
responses were shown to exist in the atria by Flavia Ravelli and Maurits Allessie ((507);
described in the section on ‘II.C.6. Atrial Fibrillation’)).
Molecular MEC mechanisms started to emerge in 1984, with single channel recordings of
currents through SAC in cultured embryonic chick skeletal muscle by Falguni Guharay and
Frederick Sachs (209). This was followed soon after by recordings of SAC currents in rat
isolated ventricular myocytes ((133); discussed in ‘II.A. Modulation of Heart Rate’)), and later by
cloning of SAC ion channels (accomplished in Escherichia coli (580)) and structural analysis
using x-ray crystallography (99). At the tissue and whole heart level, investigations of the role of
SAC currents in observed MEC responses have involved the use of pharmacological blockers
(described in ‘III. Molecular Mechanisms of MEC’), while the structural homologue to the
bacterial SAC in the mammalian heart remains unknown (a particular focus of recent research
has been on determining its molecular identity). At the same time, significant attention has been
paid to non-sarcolemmal mediators of MEC, particularly stretch-effects on intracellular calcium
(Ca2+) handling (described in ‘III.B.3. Mechano-Sensitivity of Intra-Cellular Ca2+ Handling’).
Importantly, the experimental innovations mentioned above have been complemented by
rapid advancement of computational modelling, which has enabled the integration and
interpretation of data, and the generation of novel, experimentally-testable hypotheses (312,
493, 616) (described in ‘IV. Integrative Computational Models of MEC’). Thus, building from a
strong history, the present and future of MEC presents exciting possibilities, as is elucidated
below.
(13)
II. PHYSIOLOGICAL AND CLINICAL RELEVANCE OF MEC
A. Modulation of Heart Rate
1. Mechanisms of SAN Automaticity

The perhaps clearest example of a physiological role for MEC is the response of the heart’s
primary intrinsic pacemaker to stretch (23, 147). Normal excitation of the heart originates from
the SAN, a tissue region located in the wall of the right atrium that displays spontaneous
rhythmic excitation (295). At the whole cell level, SAN electrophysiology has been well described
(269): rhythmic SAN firing requires spontaneous diastolic depolarisation of the transmembrane
potential (Vm) from its most negative value (maximum diastolic potential) towards threshold for
AP firing (illustrated in FIGURE 2, A).
Early spontaneous diastolic depolarisation is driven by a depolarising inward current through
hyperpolarisation-activated cyclic nucleotide-gated channels (‘funny’ current, If) and background
conductances (e.g., for sodium [Na+], Ib,Na (438)), facilitated by a continual reduction in
repolarising outward potassium (K+) currents (152). As diastole progresses, spontaneous
diastolic depolarisation rate increases by activation of inward Ca2+ flux through voltage-gated
‘transient’ Ca2+ channels (CaV3.1 carrying ICa,T) and, upon further depolarisation, long-lasting
Ca2+ channels (CaV1.2/1.3 carrying ICa,L), whose activation ultimately drives the AP upstroke in
SAN cells of large mammals (395) (in mice, fast Na+ channels carrying INa also contribute to
SAN AP upstroke (342), affecting the utility of mice for translational studies into SAN electrical
function). This system of membrane-bound ion channels can independently give rise to cyclic
spontaneous AP generation, as illustrated by quantitative computational models (680). This cardiac
pacemaker mechanism has been referred to as a ‘voltage clock’ (Vm clock (380); summarised,
along with potential stretch effects, in FIGURE 2, C).
Spontaneous diastolic depolarisation of SAN cells is also facilitated by Ca2+ release from the
sarcoplasmic reticulum (SR), occurring either spontaneously or triggered by Ca2+-induced Ca2+-
release upon activation of ICa,L (612). Cytosolic Ca2+, extruded from the cell by the Na+-Ca2+
exchanger (INCX), gives rise to membrane depolarisation, as INCX is ‘electrogenic’ in that it moves
three Na+ ions into the cell for each Ca2+ ion removed. As SR Ca2+ release remains rhythmic for
a period of time, even in the absence of cyclic changes in Vm, this electrogenic effect is also
sufficient to drive SAN pacemaking (335), and it has been referred to as the ‘Ca2+ clock’ of
cardiac pacemaking (380); summarised, along with potential stretch effects, in FIGURE 2, B
AND C).
(14)
Figure 2. The coupled voltage (Vm)/calcium (Ca2+)-oscillator system in sinoatrial node cells and its
modulation by the mechanical environment. A and B: SAN Vm (A) and intracellular calcium
concentration ([Ca2+]I, B) under normal conditions (solid line) and during stretch (dashed line). Time
intervals of spontaneous diastolic depolarisation (SDD) and spontaneous Ca2+ release are indicated; note
that SDD largely overlaps with the period of maximal mechanical distension of the sinoatrial node in situ.
C: Transmembrane ionic currents associated with the V m/Ca2+-oscillator system. Shaded currents (‘funny’
current [If], transient calcium current [ICa,T]) and the cation-nonselective stretch-activated current (ISAC,NS)
refer to the 20 pA scale, while solidly filled current plots (sodium-calcium exchanger current [INCX], long-
lasting calcium current [ICa,L], delayed rectifier potassium current [IK]) refer to the 200 pA scale. [Adapted
from (496).]
When considering mechanisms that drive pacemaker activity, it is important to remember

that pacemaker function adapts to changes in haemodynamic load on a beat-by-beat basis. The
Vm and Ca2+ ‘clocks’ do not inherently account for this rapid response to circulatory demand
(cellular Ca2+ balance changes over multiple beats, while mechanically-driven variation of
sarcolemmal ion channel expression takes even longer). Thus, another set of mechanisms,
(15)
sensitive to the SAN’s cyclically changing mechanical environment, must contribute to
spontaneous diastolic depolarisation. In analogy to the above terminology, this may be
considered a ‘mechanics-clock’ (496, 622). Of course, the concept of multiple ‘clocks’ providing
one ‘time’ (initiation of each heartbeat) is somewhat counterintuitive: if one considers SAN
activation as the uniform ‘time’ output, then the various underlying mechanisms may better be
conceptualised as a system of three coupled oscillators.
Pacemaker electrophysiology has been studied largely in isolated, unloaded cells. In vivo,
the SAN is subjected to cyclic yet variable changes in its mechanical environment. During atrial
diastole the SAN is stretched by the downward shift of the atrioventricular valve-plane during
ventricular contraction (214) and the associated filling by venous return. Peak stretch levels
coincide with spontaneous diastolic depolarisation, which is affected by stretch-induced inward
currents (120) (discussed further in ‘III. Molecular Mechanisms of MEC’), thus ‘priming’ SAN
cells during the very period when their Vm moves towards threshold for excitation.
The contribution of mechanical load to spontaneous diastolic depolarisation and SAN
excitation timing was established in 1964, when Klaus Deck reported microelectrode recordings
of Vm during equi-biaxial stretch of cat and rabbit isolated SAN tissue, demonstrating an
increase in spontaneous diastolic depolarisation and spontaneous beating rate (147). The
critical nature of the mechanical environment for spontaneous, rhythmic SAN excitation was
confirmed soon after, as it was shown that slack isolated SAN tissue often shows no, or
irregular, excitation, while moderate stretch restores rhythmic pacemaker activity in previously
quiescent or arrhythmic SAN tissue (73, 337) (FIGURE 3). Preload may in fact be critical to SAN
Figure 3. Effects of stretch on isolated sinoatrial node beating rate. Floating microelectrode
recordings of transmembrane potential in cat isolated sinoatrial node, showing a stretch-induced shift of
the maximum diastolic potential towards less negative values, resulting in restoration of regular rhythm in
a preparation with irregular activity at slack length (A), or initiation of spontaneous excitation in a
previously quiescent preparation (B). In both examples, tissue length was increased by ~40% from slack,
with periods of stretch indicated by the lower horizontal lines. [Adapted from (337).]
(16)
pacemaker activity from the very first heartbeat during embryonic development (e.g., day 22 in
the human embryo), as physiological loading (fluid pressure build-up in the quiescent cardiac
tube) may be a pre-requirement for initiation and pre-neuronal control of cardiac excitation
during ontogenesis (104, 504, 505).
Ultimately, through the combined actions of the various pacemaking oscillators,
spontaneous diastolic depolarisation causes Vm to cross the activation threshold for AP
generation, resulting in the initiation and spread of a new wave of cardiac excitation (395). While
the roles and interrelation of the mechanisms of SAN automaticity are still debated (Vm, Ca2+,
and mechanics oscillators can, in the experimental setting, each independently induce SAN
excitation (153, 379, 525)), they represent overlapping and redundant systems that do not
operate in isolation. Their interplay supports a robust and flexible system that integrates multiple
functionally relevant inputs to provide a reliable basis for cardiac rhythmicity (259).
2. SAN Mechano-Sensitivity
SAN automaticity is influenced by extrinsic cues, such as biochemical signals from the
autonomic nervous system and circulating hormones (374), as well as biophysical factors
including preload. Mechano-sensitivity of SAN pacemaking was first established in the
laboratory of Albert von Bezold, who reported sinus tachycardia induced by an increase in
venous return in rabbits in whom the heart’s sympathetic and parasympathetic connections with
the nervous system had been cut (‘denervated’) (570). More generally known is the work by
Francis Bainbridge, who demonstrated that right-atrial distension by intravenous fluid injection in
anaesthetised dogs causes an increase in HR (23) – a response now known as the ‘Bainbridge
effect’.
Demonstrating that the Bainbridge effect also occurs in humans was difficult, as most non-
invasive interventions that raise central venous pressure (such as tilt-table studies) tend to also
increase arterial pressure and trigger the (dominant) baroreceptor-mediated depressor reflex. It
was not until 1978 that David Donald and John Shepherd overcame this challenge by passively
elevating the legs of volunteers in the supine position (155), which raised central venous
pressure (by favouring venous return) without a simultaneous rise in arterial pressure. This
resulted in an increase in HR that unequivocally established the presence of a positive
chronotropic response to stretch in humans.
Under most conditions, the degree of filling of the right atrium, and thus the extent of stretch
of the SAN, is primarily determined by venous return. Venous return is modulated, for example,
by breathing, posture, physical activity, and vascular tone. Through the Bainbridge effect, HR in
(17)
large mammals is raised in response to an increase in right atrial filling. Along with cell length-
dependent changes in stroke volume (a consequence of the ‘Frank-Starling Law’ – for further
discussion of ‘Mechano-Mechanical Coupling’ see (81, 428, 497)), this stretch-induced response
helps match cardiac output (HR u stroke volume) to changes in venous return. The Bainbridge
effect also opposes the baroreceptor response (the ‘Bezold-Jarisch’ or ‘depressor’ reflex, which
reduces HR when arterial blood pressure is increased (271, 636)), thus preventing excessive
slowing of beating rate or diastolic (over-)distension of the right atrium, while maintaining cardiac
output and adequate circulation during haemodynamic changes that increase both venous
return and arterial pressure. Interestingly, a response similar to the Bainbridge effect may also
occur in cells of lower order pacemaker and conduction system, where Purkinje fibres –
stretched during ventricular diastole (91) – show a mechanically-induced increase in
automaticity (292, 536) and conduction velocity (146, 154, 524).
The fundamental importance of SAN mechano-sensitivity is indicated by its presence across
the invertebrate (546) and vertebrate phyla (464). Originally assumed to be a neurally-mediated
reflex (the near-instantaneous response suggests that circulating humoral factors are not
responsible), it can be observed not only in intact animals, but also in isolated hearts, tissue, and
single pacemaker cells, indicating that intra-cardiac mechanisms are indeed key contributors
(489, 496).
Ex vivo evidence has added further support to the notion of a nervous system-independent
mechanism for the stretch-induced increase in HR, as the chronotropic response to stretch is
insensitive to ablation of intra-cardiac neurons (663) and pharmacological block of Na+ channels
(103, 663) or adrenergic and cholinergic receptors (30, 52, 61, 72, 73, 103, 337, 465, 663).
There is evidence, however, for an interaction between mechanical and autonomic HR
modulation. Stretch causes both an increase in HR and a decrease in the response to vagus
nerve stimulation in whole animals (62) and isolated tissue (664). Conversely, when HR is
reduced by vagus nerve stimulation, the stretch-induced increase in HR is enhanced (61, 72,
664), possibly in part through stretch-inactivation of the stretch-modulated acetylcholine-
activated K+ current (219). The stretch response is similarly enhanced when HR is first reduced
by pharmacological parasympathetic or cholinergic stimulation, and diminished when HR is
increased by adrenergic stimulation (30, 60, 72, 147, 219, 527, 664). In the case of excessive
adrenergic stimulation, the direction of stretch-induced changes in HR may reverse (i.e., give
rise to slowing (30)), similar to the response seen in mouse (a species with an inherently high
HR (119), limiting the utility of mice for translational studies of cardiac MEC responses). Yet,
(18)
whether these changes in chronotropic stretch-responses are driven by an interaction of intrinsic
(stretch) and extrinsic (autonomic nervous system) effects, or simply result from HR-dependent
differences in the electrophysiological response to stretch is difficult to tell (several studies have
reported that the positive chronotropic response to stretch is enhanced at lower HR, regardless
of the nature of the HR reduction (113, 119)).
Combined actions of stretch- and neuronally-mediated effects on HR are evident also from
variations in HR that are synchronous with the respiratory cycle: HR rises during inspiration and
declines during expiration. This phenomenon, noted in humans more than 170 years ago by Carl
Ludwig (372) and referred to as ‘respiratory sinus arrhythmia’ (even though it is a physiological
fluctuation in heart rhythm, not an arrhythmia per se), has long been considered to be a
consequence – and, hence, useful clinical indicator – of ‘vagal tone’. Yet, respiratory sinus
arrhythmia continues to exist, albeit at a reduced magnitude, in the transplanted (i.e.,
denervated) human heart (44, 45, 502), during autonomic block (558, 569), and in acutely
vagotomised animals (472), indicating a contribution of intrinsic, mechanically-mediated
mechanisms.
The MEC contribution to respiratory sinus arrhythmia is driven by fluctuations in right atrial
volume during respiration, as venous return is favoured – by reduced intra-thoracic and
increased abdominal pressure – during inspiration and impeded during expiration. During
physical activity, non-neuronal responses appear to dominate respiratory sinus arrhythmia -
mediated fluctuations in HR even in healthy volunteers, as cyclic fluctuations in venous return
are increased with increased respiratory effort, while ‘vagal tone’ is reduced during physical
activity (45, 95). In keeping with this, during positive pressure ventilation, which reverses the
thoraco-abdominal pressure gradients relative to the respiratory cycle, respiratory sinus
arrhythmia can switch phase, so that HR decreases during inspiration, as intrathoracic positive
pressure application impedes venous return to the heart below levels present during passive
expiration (370).
3. SAN Dysfunction
Mechanical modulation of HR appears to be functional only within a certain range of
mechanical loads, as excessive stretch can result in irregular rhythms (337) and multifocal
activity (234). This may be relevant in cardiac pathologies associated with atrial volume overload
(417, 535, 565), where natural occurring HR variability is reduced by SAN stretch (240, 391) –
an adverse prognostic marker. Decreased SAN distension upon increased myocardial stiffness,
resulting from cardiac fibrosis or structural remodelling in advanced age (410, 530), atrial
(19)
fibrillation (AF) (170, 325) or other cardiac pathologies (2, 53, 322, 421), may also contribute to
SAN dysfunction, and may be further exacerbated by mechano-sensitive non-myocytes (315,
317). The potential importance of age-related SAN remodelling for stretch-induced responses is
supported by the greater increase in HR that occurs with similar stretch of the SAN from younger
versus older animals (147).
Another important consideration in the context of SAN mechanics is the structural
heterogeneity of the SAN, which results in regional differences in tissue stiffness and stretch
(433). Changes in HR have been shown to correlate best with maximum SAN stretch, which
occurs at its periphery, a region more distensible than the central node (279). This regional
difference may be important for transmission of electrical activity from the SAN to atrium (195),
as the SAN periphery is where (the possibly stretch-modulated) If is thought to play the largest
role in SAN pacemaking. This is due, in part at least, to the more negative maximum diastolic
potential in that region (caused by electrotonic influences from coupled working
cardiomyocytes), which activates more If and increases the driving force for cation-nonselective
stretch-activated channels (SACNS) (323, 431). These regional differences in SAN mechano-
sensitivity may be exasperated by heterogeneous changes in SAN mechanical properties, or by
variable expression and activity of SAC and stretch-modulated ion channels during disease or
ageing (65, 575, 600).
It is important to note, however, that it is not entirely clear what constitutes a normal or a
pathophysiologically-altered SAN mechanical environment. In this context, questions that should
be explored in further research include: whether the key mechanical parameter for changes in
SAN function is stretch (279, 536), stress (14, 73, 103), or a combination of both (337); whether
the rate of change in mechanical load affects SAN electrophysiology (73, 337) or not (103); and
whether certain spatial loading patterns (e.g., linear, equi-biaxial, multi-axial) are more
appropriate than others (147). Additionally, as mechanical-responses, at least in ventricular
myocytes, are AP shape- and phase-dependent (86, 181, 222, 437), the timing of mechanical
stimulation is an important variable that may be affected by disease. This could help to explain
species differences in the chronotropic response to stretch (i.e., mouse versus larger mammals
(119), as discussed further in ‘III.A.1. Mechano-Sensitivity of ‘Mechanical Oscillator’
Components’).
4. Summary
The SAN, the heart’s intrinsic pacemaker, initiates the heartbeat. Its rate of firing is
determined by the interaction of multiple oscillators (Vm, Ca2+, mechanics) whose integrated
(20)
activity sets the clock for robust automaticity and regular heart rhythm. The chronotropic
response to SAN stretch (Bainbridge effect) allows HR to be tuned to haemodynamic demand
on a beat-by-beat basis, governed by effects intrinsic to SAN pacemaker cells. Abnormal stretch
can result in a disturbance of rhythm, representing a potential contributor to SAN dysfunction
with age and in disease. While much is understood about SAN function and its control by the
mechanical environment, most ex vivo studies are performed in unloaded preparations, leaving
questions regarding the (patho-)physiological importance of MEC in the SAN unanswered, thus
warranting further investigation.
B. Transient Effects on Whole Heart Electrical Activity
1. Diastolic Stretch
Electrophysiological effects of acute mechanical stimulation are cardiac electrical cycle-
dependent. In ‘electrical diastole’ (here used to describe the period when cells of the working
myocardium are at their resting Vm), a sufficiently large mechanical stimulus will cause
depolarisation, in a stretch-amplitude dependent manner. If supra-threshold, this can trigger
excitation in whole heart (FIGURE 4, A), tissue, and cells (495). In the whole heart, this is true
both for transient increases in intra-ventricular volume (54, 150, 151, 161, 180, 181, 221-223,
245, 301, 424, 459, 460, 513, 547, 568, 650, 688) and for local tissue deformation, such as upon
contact of intra-cardiac devices (e.g., the tips of catheters or pacing leads) with the endocardium
(35) or by epicardial and precordial impact (492, 494) (FIGURE 4, B). Interestingly, both for
global and local mechanical stimuli it appears that depolarisation depends on tissue stretch,
rather than stress. With an increase in intra-ventricular volume, the amount of volume required
for excitation is remarkably consistent between hearts of the same species, while the associated
change in intra-ventricular pressure shows high variability (222), depending on the speed of
volume changes applied (in contrast, stretch-induced changes in refractoriness have been
shown to correlate best with ventricular wall stress (215)). With local impact-induced tissue
deformation, the extent of tissue indentation needed for excitation is similar between subjects
and for various regions in a given heart, while the pressure under the probe can be highly
variable (117, 492), depending on probe contact surface area and impact location.
Depolarisation also appears to depend on the rate of stretch application (320), which increases
the magnitude of stretch needed to cause excitation at lower deformation rates (172, 181). This
application rate-dependence may be a consequence of myocardial visco-elasticity, where faster
application of an external mechanical stimulus will be associated with a larger transient
(21)
overshoot in local peak stretch levels, while slow application of a mechanical stimulus may
cause mild depolarisation and partial inactivation of INa (in keeping with experimental
observations showing that the threshold for electrical stimulation is also affected by stretch
dynamics, being reduced due to stretch-induced Vm depolarisation (620)).
It should be noted that in the setting of a ‘global’ stimulus, such as an increase in intra-
ventricular volume, there will be spatially heterogeneous mechanical effects. Myocardial
stiffness varies regionally throughout the heart, resulting in non-uniform stretch and
depolarisation (101, 547). Upon global mechanical stimulation, excitation originates from areas
where the largest stretch is observed, typically in the left ventricular free-wall or the right
ventricular outflow tract, depending on the cardiac chamber affected (101, 181, 547) (FIGURE 4,
C). This again highlights the notion that stretch, not stress, is a main input signal for MEC.
Figure 4. Mechanically-induced excitation upon diastolic stimulation of rabbit isolated whole

heart. A, top row: Monophasic action potential recording from the left ventricular (LV) epicardium (EPI;
top trace) during intraventricular volume pulses ('VOL; bottom trace) by inflation of an intraventricular
balloon (schematic on left) during complete heart block, showing transient membrane depolarisations
upon each balloon inflation whose amplitude increases with pulse volume; above a certain amplitude,
each LV balloon-inflation causes LV excitation (note: first two action potentials are spontaneous ‘escape
beats’ of the preparation). [Adapted from (181).] A, bottom row: Optical mapping of right ventricle near-
epicardial membrane potential showing focal excitation at the site of maximum stretch during an intra-
ventricular volume pulse (scale bar = 4 mm). [Adapted from (547).] B, top row: Optical mapping of LV
near-epicardial membrane potential showing focal excitation resulting from a sub-contusional local impact
of the epicardium. B, bottom row: LV excitation pattern with an electrical stimulus applied to the same site
as the local impact, showing a similar activation pattern (scale bar = 5 mm). [Adapted from (492).]
(22)
2. Systolic Stretch
When an increase in intra-ventricular volume is applied during ‘electrical systole’ (i.e., during
the AP), or maintained over the entire cardiac cycle, electrophysiological effects are generally
characterised by a heterogeneous decrease in AP duration (APD) and refractoriness (54, 76, 86,
87, 101, 129, 130, 144, 161, 208, 215, 238, 331, 346, 511, 513, 514, 583, 642, 644, 688, 689),
although some studies have reported an increase in both (40, 42, 131, 143, 655). These effects
are also HR dependent (238, 511, 644) and generally thought to be accompanied by a decrease
in tissue conduction velocity (150, 403, 554, 583, 655, 689), though an increase in conduction
velocity has been seen in isolated ventricular tissue and engineered myocyte strands (252, 392).
The stretch-induced decrease in conduction velocity has been attributed to effects on passive
cable properties of interconnected cardiomyocytes through an increase in axial tissue resistance
(75), caused by an increase in sarcoplasm resistance (116, 652), as well as to an increase in
cardiomyocyte membrane capacitance caused by incorporation of sub-sarcolemmal caveolae
into the cell surface membrane (311, 477). The reported discrepancies in electrophysiological
responses to systolic or sustained stretch mentioned above (some of which come from the same
groups) may relate to differences in species (e.g., small versus large animal), preparation (e.g.,
intact animal versus isolated heart or tissue or cell), physiological factors (e.g., baseline heart
rate, AP morphology), experimental considerations (e.g., mechanical stimulus magnitude,
measurement technique, temperature), or data handling (e.g., measurement algorithms).
Similar effects of acute changes in ventricular preload have been seen in humans (448). For
instance, an increase in intra-ventricular volume upon discontinuation of cardiopulmonary
bypass results in a heterogeneous decrease in APD (593). In contrast, however, acutely
reducing intra-ventricular volume (over 15 s) by the Valsalva manoeuvre (which involves forced
expiration against a closed glottis, causing an increase in intrathoracic pressure that impedes
venous return) in patients undergoing routine cardiac catheterisation procedures has been
shown to also decrease APD, even in transplant recipients with denervated hearts, in whom a
concomitant autonomic response is eliminated (590). This decrease in APD with reduced intra-
ventricular volume has been suggested to relate to a reduction in myocardial shortening (rather
than the change in intra-ventricular volume), as APD changes correlated with ventricular wall-
motion changes (589). A similar decrease in APD occurs in experimental studies when
myocardial shortening is restricted during isometric contraction (293, 329, 571). Naturally
occurring oscillations in ventricular preload, much like for respiratory sinus arrhythmia in the
(23)
SAN, may also cause respiratory-related (225, 625) and lower-frequency (‘Mayer wave’)
fluctuations (224, 484) in ventricular repolarisation.
An acute increase in ventricular afterload, on the other hand, for instance due to aortic
constriction (449, 591) or pulmonary balloon valvuloplasty (347), also results in a heterogeneous
decrease in APD, and can lead to after-depolarisation-induced ectopy (347). Ectopic excitation
also occurs in experiments involving rapid increases in aortic blood pressure (550, 552, 553),
potentially due to post-systolic myocardial deformation (212), which is reduced by anti-
hypertensive treatment (551, 553). Conversely, an acute reduction in ventricular pressure
overload, as occurs following balloon valvuloplasty or angioplasty, increases APD (347)
(although this may partly reflect mechanically-induced after-depolarisation) and decreases
dispersion of repolarisation (538).
MEC may play a role in coordinating whole heart electrical activity by helping to generate
homogeneity out of the complex, physiologically-necessary electrophysiological and mechanical
heterogeneity that exists across the heart (291). The interplay of regional mechanical effects of a
contraction-induced intra-ventricular pressure wave and the phase of the AP in early and late
activated regions may act to regionally synchronise ventricular repolarisation (446, 486). A
similar effect has been shown using duplexes of individually controlled, mechanically interacting
(in-parallel or in-series) cardiac muscle segments that allow for the simulation of mechano-
electric interactions in heterogeneous myocardium (382, 561). This experimental model has
demonstrated that mechanical heterogeneity contributes differently to APD changes when
muscle segments are coupled in in-parallel or in-series, which may play a role in mechanical
tuning of electrical activity in distant tissue regions. Also, the electro-mechanical activity of
interacting contractile elements is affected by their activation sequence, which may optimise
myocardial performance by reducing intrinsic APD differences. Pathophysiological, non-uniform
ventricular contractions, on the other hand, can lead to electrocardiogram (ECG) T-wave vector
displacement (563) and, along with increased intra-ventricular volume, may be partly
responsible generation of the ECG U-wave (105, 124, 185, 542, 584-586).
3. Summary
Acute electrophysiological effects of MEC depend on the timing of mechanical stimulation
relative to the AP cycle of affected cells. Mechanical stimulation, whether local or global, during
electrical diastole will – if large enough to give rise to any change in electrophysiology – cause
depolarisation of Vm. This may trigger premature and/or ectopic excitation. If instead timed
during the AP, or sustained over the entire cardiac cycle, mechanical stimulation affects APD,
(24)
refractoriness, conduction, and the dispersion of those parameters across the heart, potentially
causing a pathological increase in electrophysiological heterogeneity, while otherwise playing a
physiological coordinating role. While these effects are well established, critical parameters
determining MEC outcomes, such as the relative importance of stretch versus stress, the actual
levels of stretch or stress experienced by individual cells within the tissue, the rate of mechanical
stimulus application, and underlying mechanical and electrical heterogeneities are unclear,
necessitating future research.
C. Induction of Sustained Arrhythmias
1. Tissue-Level Mechanisms of Stretch-Induced Arrhythmias

As mentioned above (in ‘II.B.1. Transient Effects on Whole Heart Electrical Activity’),
diastolic mechanical stimulation may cause depolarisation and trigger excitation (FIGURE 5, A).
While extra beats in healthy heart will mostly have benign consequences, ectopic excitation
accompanied by mechanically-induced effects on electrophysiological tissue properties during
an AP can interact with underlying electrical activity to cause severe tachyarrhythmias (487).
Ventricular tachyarrhythmias are thought to arise as a result of untoward interactions of an
arrhythmogenic trigger and a substrate for re-entry (699). Both of these may be favoured by, or
result from, MEC effects (268, 330, 510). Across the heart, electrical systole involves dispersion
of Vm, as cells in atria and ventricles de- (P- and QRS-waves of the ECG) and repolarise
sequentially (atrial repolarisation is not normally discernible on the ECG, ventricular
repolarisation is reflected by the T-wave). This gives rise to electrical tissue gradients that are
relatively short upon activation, and more drawn-out upon repolarisation, as witnessed for
ventricles by the smaller-amplitude broad ECG T-wave, compared to the QRS complex. As a
result, mechanical stimuli during electrical systole tend to encounter locally differing stages of
the underlying cellular AP, which – during repolarisation – can furnish a substrate for re-entry,
creating a vulnerable window for mechanically-induced ventricular tachyarrhythmia (FIGURE 5,
B).
Early studies of MEC, where intra-ventricular volume was acutely increased in ex vivo whole
hearts, reported a decrease in the threshold for electrically-induced excitation and
tachyarrhythmias (including ventricular fibrillation, VF) (265, 513, 526); the same holds for AF
inducibility during acute atrial dilatation (179, 506) (discussed in more detail in ‘II.C.6. Atrial
Fibrillation’). Also in isolated hearts, mechanically-induced excitation resulting from intra-
ventricular volume pulses can trigger ventricular ectopy and tachyarrhythmias (54, 222, 547,
(25)
568). In vivo, an acute increase in intra-ventricular volume in experimental preparations (101,
180, 208), in patients during balloon valvuloplasty (347), or as a consequence of mitral valve
prolapse, stenosis, or insufficiency (31, 122, 348) is associated with a high incidence of
arrhythmias. Outcomes are typically mechanical stimulus magnitude- and ECG timing-
dependent and may in part result from heterogeneous stress-stretch patterns due to the spatio-
temporal dissociation between a globally uniform stimulus and its regional effect. In the volume
overloaded ventricle, there may also be a contribution of excessive Purkinje fibre stretch to
arrhythmias, as it has been suggested to contribute to reduced conduction velocity (524) or loss
of AP conduction (158, 292), sub-threshold after-depolarisations (175) and ectopic excitation
(158, 234, 557), or rapid firing-induced tachycardia (158, 515, 608).
Similarly, local mechanical stimulation can result not only in ectopic excitation, but also in
ventricular tachyarrhythmias, as reported upon tissue contact of central venous and pulmonary
artery catheter tips (140, 169, 176, 251, 326, 340, 567, 577) or intra-cardiac catheters and
electrodes (58, 339, 359, 398). The same is true for extra-corporeal mechanical stimuli, such as
chest compressions during cardio-pulmonary resuscitation (43), or impacts to the precordium
(97) for instance in the setting of non-contusional mechanical stimuli causing Commotio cordis
(FIGURE 6, A) (316, 385, 427).
2. Commotio Cordis
Commotio cordis may be the most dramatic example of the consequences of mechanically-
induced ventricular tachyarrhythmias, having been reported to result in VF-related sudden death
at least as far back as the 1870s (394, 426). Even though VF by Commotio cordis is a rare
event, it is one of the most common causes of sudden death in youth athletes in the US (383).
Electrophysiological outcomes of Commotio cordis are determined by mechanical stimulus
characteristics such as anatomical location and impact area, duration, and energy (363, 364,
543). Studies in pigs have characterised mechanical inducibility of VF as inversely-related to
impact area and duration, rising with projectile stiffness and occurring only when impact-induced
ectopy occurs during a vulnerable window that exists during a 10-20 ms period immediately prior
to the peak of the ECG T-wave (360, 361, 365, 383) (FIGURE 6, B). Results indicate the
susceptibility to VF by Commotio cordis is subject-specific (8) and, as for the chronotropic
effects of stretch on SAN rate, is not affected by autonomic block (576) or denervation (543).
Computational modelling has helped to explain how precordial impact in the vulnerable
window may lead to VF. Two- (2D) and three-dimensional (3D) simulations have demonstrated
that Commotio cordis-induced VF should arise only when a supra-threshold mechanical stimulus
(26)
occurs at the trailing edge of the preceding wave of repolarisation, such that the mechanically-
induced premature excitation forms directly adjacent to tissue that is functionally refractory (still
repolarising). This results in the generation of both a trigger (ectopy, via SACNS in the model)
Figure 6. Mechanically-induced ventricular fibrillation in the setting of Commotio cordis. A:

Summary of location of lethal precordial impacts in victims of Commotio cordis. [Adapted from (384).] B:
Global endocardial activation map (right anterior oblique, RAO, orientation) of impact-induced electrical
excitation preceding ventricular fibrillation, highlighting the focal nature of the initial trigger event.
[Adapted from (7).] C: Electrocardiogram recording of instantaneous, impact-induced ventricular
fibrillation in an anesthetised pig model of Commotio cordis. [Adapted from (360).] D: Surface
electrocardiogram from rabbit isolated heart showing the effect of local epicardial mechanical stimulation
applied to the left ventricle (LV) during the early T-wave, resulting in instantaneous ventricular fibrillation.
E: Spatial interrelation of mechanical stimulation site and 50% repolarisation isochrone of the preceding
sinus beat, obtained from epicardial voltage mapping (green) in those cases where sub-contusional
mechanical stimulation did trigger ventricular fibrillation: only when mechanically-induced excitation (red)
occurs directly adjacent to still inexcitable tissue (yellow) is a region of functional block (black rectangle)
formed, around which re-entry can occur (as predicted from computational modelling shown in FIGURE
5, C). [Adapted from (492).]
(27)
and a substrate (conduction block) around which sustained re-entry can occur (194, 355)
(FIGURE 5, C; discussed further in ‘IV.B.2. Triggering and Sustenance of Arrhythmias’).
Conceptually, this is similar to the vulnerable window for extracorporeal electrical stimulation,
which was systematically studied since the 1930s (660), but whose duration is significantly
larger (t100 ms in large animals (549)) than that described for precordial impacts (365). The
difference in the length of the two vulnerable windows is a consequence of the fact that
repolarisation is spatially heterogeneous across the ventricles. Therefore, the condition for
overlap of mechanically-induced excitation with the trailing wave of repolarisation will be met in
different cardiac locations at different time-points of the cardiac cycle, and at each of these
locations for brief periods only. This means that the vulnerable window for mechanical VF
induction is determined by space and time (as is also the case for point electrical stimulation).
This theoretical concept has been tested in ex vivo rabbit hearts (492), demonstrating that
local epicardial stimulation causes focal excitation underneath the contact site (as seen with
intra-cardiac mapping during extracorporeal impacts in the pig model of Commotio cordis (7)).
As predicted by modelling, this ectopic excitation results in VF if, and only if, the stimulus
overlaps with the trailing edge of repolarisation from the preceding sinus beat (492) (FIGURE 6,
C).
3. Acute Regional Ischaemia

Mechanical heterogeneity is thought to contribute to the induction of arrhythmias in regional
ischaemia (267). In patients with myocardial ischaemia, there is a strong correlation between the
presence of regional wall motion abnormalities and arrhythmogenesis (84, 557). In the acute
phase, a large proportion of ectopic beats originates from the ischaemic border zone (123, 328)
(FIGURE 7, A), an area of particularly high stretch due to ‘paradoxical segment lengthening’ of
the ischaemically-weakened myocardium during mechanical systole (189, 479, 533, 609, 626).
Also, in ischaemic hearts that develop VF, stretch magnitude is related to the timing of VF onset
(232). Similarly, the end-diastolic length of the ischaemic region is a strong predictor of VF (26,
27, 29). In acute regional ischaemia, a contribution of MEC to arrhythmogenesis is further
supported by an increase in the incidence of ectopic activity in isolated hearts with elevated left
ventricular pre- and afterload (established by an intraventricular balloon, connected to a fluid
filled column with a clamp to control ejection resistance), compared to an unloaded ventricle
(FIGURE 7, B). In addition, it has been shown that following a potentiated contraction due to an
increased diastolic interval (which is presumed to increase stretch at the ischaemic border) there
is an increase in the likelihood of ectopic excitation (123), which is also seen after an increase in
(28)
intra-ventricular volume (123, 459). These findings are supported by computational modelling
that suggests mechanically-induced depolarisation originating from the ischaemic border zone
(through SACNS) contributes to the formation of ectopic foci (if supra-threshold), or to the slowing
and block of conduction (if sub-threshold) (274) (FIGURE 7, C; discussed further in ‘IV.B.2.
Triggering and Sustenance of Arrhythmias’).
Figure 7. Mechanically-induced arrhythmias during acute regional ischaemia. A: Activation map of

ventricular premature excitation (VPE) originating at the ischaemic border in a pig isolated heart model.
B: Plots summarising greater frequency of arrhythmias in loaded versus unloaded pig hearts. [Adapted
from (123).] C: Computational simulation of mechanically-induced ventricular ectopy (black circle) and re-
entry during acute regional ischaemia (top) and simulated activation patterns without re-entry when
omitting from the model either stretch-activated channels (SAC) or ischaemic electrophysiological
changes (bottom). [Adapted from (274).]
4. Mitral Valve Prolapse

Another pathological setting, in which regional changes in ventricular mechanics are thought
to contribute to arrhythmogenesis, is mitral valve prolapse (31, 442). In mitral valve prolapse,
one or both leaflets of the mitral valve bulge into the left atrium during ventricular systole,
resulting in stretch of the leaflets, chordae tendinae, papillary muscles, and infero-basal
ventricular wall (471). The resulting arrhythmias that occur in some patients involve complex
premature ventricular excitation, arising from sites close to the anchor points of prolapsing
leaflets and supporting structures, such as the papillary muscles, fascicular tissue, LV outflow
tract, or mitral annulus, which can lead to sudden cardiac death (32). This excitation appears to
occur due to mechanically-induced after-depolarisations of tissue associated with the mitral
valve (662) (particularly the papillary muscles (186, 204, 248)), by contact of the prolapsing
leaflets snapping back against the ventricular myocardium during diastole (136), or by stretch of
the valve itself (muscle fibres in the mitral valve leaflet have been shown to develop diastolic
depolarisation when stretched, potentially leading to automatic activity that may propagate into
(29)
the surrounding myocardium (668)). The key role of abnormal mechanical forces is further
supported by a series of cases in which surgical correction of bi-leaflet mitral valve prolapse
resulted in a reduction of ventricular arrhythmias by relieving myocardial stretch (623).
5. Chronic Pathophysiological States

In a host of chronic cardiovascular diseases, alterations in myocardial mechanical properties
may contribute to electrophysiological changes that promote arrhythmogenesis. This had initially
proposed based on the observation that ventricular tachyarrhythmias are frequently encountered
in pathologies associated with volume or pressure overload (327, 592). It is difficult, however, to
identify causal relationships between tissue mechanics, MEC, and cardiac rhythm disturbances
in chronic disease settings, as structural and functional remodelling, as well as fluctuations in
metabolic and autonomic state, may be arrhythmogenic in their own right. Considering effects of
acute changes in mechanical load, and in particular the temporary removal of chronic overload,
on ventricular electrophysiology in chronic pathophysiological states has been an alternative, yet
effective way to elucidate the potential relevance of MEC in the induction and sustenance of
ventricular arrhythmias.
One of the most striking examples is the anti-arrhythmic effect of an acute temporary
decrease in intra-ventricular volume in patients suffering from chronic ventricular volume
overload and tachyarrhythmias. In these patients, acute haemodynamic unloading (249), or a
temporary reduction in cardiac chamber volume by the Valsalva manoeuvre (341, 648), rapid
pacing (473), or repeated forceful coughs (651) can result in temporary termination of ventricular
tachyarrhythmias (for as long as the reduced load is maintained) (FIGURE 8), even in transplant
recipients (10). In a similar vein, in patients with a dilated left atrium due to mitral stenosis, the
associated arrhythmogenic dispersion and delays of conduction can be immediately reversed
upon normalisation of pressure gradients by percutaneous transvenous mitral balloon valvotomy
(122).
In the opposite direction, an increased mechanical load on top of a chronic disease
background can be pro-arrhythmic (587). For instance, in heart failure patients average daily
median pulmonary artery pressure has been shown to correlate with the risk of ventricular
tachyarrhythmias (512). In the setting of heart failure, acute increases in afterload occur on the
background of pro-arrhythmic metabolic (mitochondrial oxidative capacity, fatty acid and glucose
oxidation, rate of glycolysis), humoral (circulating catecholamines), electrophysiological (APD,
conduction velocity, repolarisation) and mechanical (structural remodelling, volume overload)
changes, and it has been shown that an acute increase in intra-ventricular pressure alone may
(30)
be as arrhythmogenic as the acidified catecholamine-rich milieu, or the electrical remodelling
associated with heart failure (500).
Figure 8. Temporary termination of ventricular tachyarrhythmia with acute haemodynamic

unloading. A: X-ray images of the thoracic cavity of a patient in ventricular tachycardia after deep
inspiration (INSP., top left) and after an identical inspiration followed by a strong Valsalva manoeuvre (top
right, timing corresponding to label in B), with a tracing of the cardiac silhouettes below (solid line =
INSP., dashed line = INSP.+VALSALVA). B: Surface electrocardiogram leads 1, 2, 3 (L1-3), bipolar right
atrial electrogram (BAE), and aortic blood pressure (BP) from the same patient showing as background
activity atrioventricular dissociation and ventricular tachycardia. During the Valsalva manoeuvre, there is
an initial increase in BP (corresponding to a period of blood redistribution away from the chest cavity,
reducing heart size), followed by a decrease in BP, which is associated with a return to normal sinus
rhythm. After the Valsalva manoeuvre is stopped, BP and cardiac volume return to control levels, and
arrhythmia resumes. [From (648).]
Similarly, increased intraventricular preload may help in sustaining established ventricular

tachyarrhythmias, as stretch accelerates activation and increases the complexity of ventricular
tachyarrhythmias, potentially by producing more areas of transmural excitation breakthrough
and/or conduction block (68, 106, 108-111, 413, 614). These effects can be eliminated by
stabilising ryanodine receptors (RyR) in their closed state (148), highlighting the crucial
contributions of intra-cellular Ca2+ handling to MEC (discussed further in ‘III.B.3. Mechano-
Sensitivity of Intra-Cellular Ca2+ Handling’). Interestingly, an increase in intra-ventricular volume
has also been shown to acutely reduce the effectiveness of antiarrhythmic drugs (514), while
Na+ channel block by flecainide may be potentiated by atrial distension (166).
In the case of ischaemia, if infarction occurs, viable myocardium is replaced by scar tissue
(518). The consequence is considerable mechanical heterogeneity (and stretch) at the infarct
border zone (16), such that acute increases in intra-ventricular volume result in ventricular
tachyarrhythmias, arising from the site of the largest stretch-induced change in repolarisation
(87). This effect of post-infarction mechanical heterogeneity on electrophysiology may be
enhanced by mechano-sensitive non-myocytes in cardiac lesions, if electrically-coupled to
surviving cardiomyocytes (317), and may explain why, in patients with myocardial infarction,
(31)
acute afterload reduction can abolish arrhythmias (159, 419). Yet, little direct evidence exists
regarding the role of MEC in post-infarction arrhythmias, and while mechanical heterogeneity
does overlap with sites of arrhythmogenesis suggesting MEC could be involved, computational
models have demonstrated that arrhythmias can arise from such regions without evoking MEC
(15, 115, 393). Moreover, in the case of wall motion abnormalities, while non-uniform ventricular
contraction is associated with increased dispersion of repolarisation, dispersion appears to
increase primarily in normally contracting regions of hearts, independent of the presence of
infarction (447).
Potential contributions of MEC to arrhythmogenesis in chronic cardiac diseases may also be
related to an increase in tissue mechano-sensitivity, as demonstrated in various animal models
(272, 273, 281, 304, 485, 646). Chronic disease-related hyper-sensitivity of MEC may result
from: increased expression or sensitivity of SACNS current (ISAC,NS; (281)); increased microtubule
density (460), altered viscoelastic properties (646), a reduced compensatory response to
increased load (345); altered intra-cellular Ca2+ handling, including changes in mechano-
sensitive RyR function (273) due to impaired regulation (287) or to mitochondria function due to
microtubule rearrangement (405).
Some chronic diseases, attributed primarily to cardiac electrical dysfunction, may also
include underappreciated beat-by-beat mechanical contributions. An example is long QT
syndrome, in which spatially heterogeneous prolongation of repolarisation results in increased
dispersion of APD, QT prolongation, and a propensity for developing polymorphic ventricular
tachyarrhythmias that may give rise to sudden cardiac death (522). Both in transgenic and
pharmacological models of long QT syndrome, there is a spatial correlation between regional
APD changes and diastolic dysfunction (443), also seen in patients (66), whose extent
correlates with individual arrhythmic risk (336). In fact, diagnosis of long QT syndrome may be
more straightforward and accurate using spatially-resolved deformation imaging (e.g., by MRI)
than the more global read-outs provided by ECG. This regional mechanical heterogeneity may
contribute to disturbed electrical activity (309). One possible scenario, observed in whole animal
models of pharmacologically-induced long QT syndrome, are after-contractions in the ventricular
sub-endocardium which stretch (17) and depolarise sub-epicardial tissue regions, causing after-
depolarisations that may give rise to torsades de pointes (188, 601).
6. Atrial Fibrillation
While severe ventricular arrhythmias are lethal, an increasing proportion of our ‘aging
population’ lives with AF. Many factors contribute to the initiation and progression of AF,
(32)
including atrial dilatation, with left atrial enlargement being an independent risk factor for the
development of the disease (483, 629, 630). Atrial overload can be acute (e.g., acute pulmonary
embolus, myocardial ischaemia), transient (e.g., pregnancy), and chronic (e.g., mitral valve
disease, hypertension, or changes secondary to HF) (630). Experimental studies of AF have
confirmed that acute atrial dilatation increases AF inducibility and sustenance (FIGURE 9, A
AND B) (55, 56, 107, 166, 167, 179, 184, 351, 399, 434-436, 506, 621, 672, 673, 691), while an
acute reduction of atrial dilatation reduces the vulnerability to AF (263). The increase in AF
vulnerability upon acute atrial dilatation is thought to occur due to stretch-induced AP shortening
and altered refractoriness (285, 507, 555). Other pro-arrhythmic effects of atrial tissue distension
Figure 9. Acute stretch increases AF inducibility. A: Photographs of the right atrium of a rabbit
isolated heart during acute atrial stretch caused by raising intra-atrial pressures from 0 (left) to 10 cm H2O
(right, scale bar = 1 cm; expanding atria highlighted by dashed circle). [Adapted from (506).] B: Bipolar
atrial electrograms showing an increase in atrial fibrillation (AF) inducibility (triggered by bursts of high-
frequency pacing, end of burst-pacing indicated by arrow) with increasing intra-atrial pressure. C: Effect
of application of the cation-nonselective stretch-activated channel blocker Grammostola spatulata
mechanotoxin-4 (GsMtx-4, 170 nM) on AF inducibility (top panel: open circles = control, filled circles =
GsMtx-4, dashed line = washout) and AF duration (bottom panel) as a function of intra-atrial pressure (* =
p < 0.05 versus baseline). [Adapted from (56).]
(33)
include decreased conduction velocity (107, 562) and altered APD, refractoriness, and
conduction – effects that vary locally, in part as a result of highly heterogeneous atrial wall
thickness (20, 167, 246, 540).Consequently , regions of altered re-entrant cycle length (679) and
conduction block (167) can be observed. AF inducibility is also increased upon removal of the
pericardium, adding weight to the suggestion that electrophysiological effects of acute atrial
dilatation depend on stretch, rather than tissue stress (435).
Some of the above experimental findings have been confirmed in human. Increased atrial
pressure promotes the induction of AF (12), while atrial stretch modulates re-entrant cycle length
(508, 649). In patients undergoing cardiac surgery, rapid atrial dilatation decreases conduction
velocity and causes signal fractionation (640), while atrial loading modified by atrioventricular
pacing decreases the refractory period, conduction velocity, and increases the vulnerability to
AF (85, 509, 618). In keeping with these reports, relief of chronic atrial stretch after
percutaneous mitral balloon commissurotomy results in an increase in refractoriness and a
decrease in its heterogeneity (564).
5. Summary
Depending on magnitude and timing, as well as on the underlying electrical and mechanical
background, global and local mechanical stimulation can generate excitation and a substrate for
re-entry (resulting in sustained arrhythmias during a narrow and regionally varying vulnerable
window for mechanically-induced tachyarrhythmias), or lower the threshold for electrically-
induced arrhythmias, both in experimental models and humans. This occurs, for example, in the
settings of Commotio cordis, acute regional ischaemia, mitral valve prolapse, and AF. In chronic
diseases associated with mechanical changes, such as an increase in preload (end-diastolic
volume overload) of afterload (increased arterial blood pressure or outflow resistance), there
may also be a contribution of MEC to arrhythmogenesis that is additional to the existing pro-
arrhythmic substrate, as evidenced by temporary changes in arrhythmia incidence with acute
changes in load. Determining direct causal effects of MEC on cardiac rhythm is challenging and
requires further experimental and computational consideration.
D. Arrhythmia Termination
1. Tachyarrhythmias
The anti-arrhythmic potential of cardiac mechanical stimulation had been first noted
anecdotally as far back as the 1930s. Mechanical interaction of needles with the myocardium in
the context of the then so-called ‘intra-cardiac therapy’ (for adrenalin injections to ‘revive the
(34)
dead’) were shown to have the potential of re-starting the asystolic heart even in the absence of
drug injections (250). Later on, targeted myocardial contact of intra-cardiac catheters has been
used to terminate atrial, junctional, and ventricular tachycardia (35, 57, 94, 381, 444, 466, 669),
as well as AF (338). Several reports have also found a link between an abrupt increase in intra-
thoracic pressure, due to coughing (135) or during the Valsalva manoeuvre (648) and
termination of ventricular tachyarrhythmias.
The potential for extracorporeal mechanical stimulation for termination of tachyarrhythmias,
on the other hand, received little attention until the 1970s, when a paper detailing the use of
precordial thump (a single forceful blow to the lower half of the sternum using the lateral aspect
of a closed fist) to defibrillate the tachycardic heart was published (470). It has been shown
since that precordial thump may be used in some settings to terminate a host ventricular
tachyarrhythmias, as reported in case reports and uncontrolled studies (summarised in (469),
with additional reports since (266, 560, 624, 656)).
Few prospective studies of precordial thump have been published, all of which
demonstrated extremely low success for termination of ventricular tachyarrhythmia (below 2%;
(11, 82, 216, 467)). In contrast, precordial thump applied to the heart in primary asystole may
make relevant contributions to restoration of spontaneous circulation in patients (467) (as
discussed in ‘II.D.2. Bradycardia and Asystole’). It is important to note that the clinical utility of
precordial thump in emergency settings is a function of time-since-collapse, as all reported
successful cases of precordial thump-induced cardioversion occurred early during the
development of ventricular tachycardia or in early VF (21, 35). Animal models of precordial
thump have shown a matching disparity of results, with success rates ranging from 0% in an
asphyxiated dog model of VF (equivalent to very late application; (675)) to 95% in a post-
infarction pig model (198), suggesting that the utility of precordial thump may be inversely
related to myocardial tissue energy availability.
Computational modelling has helped in understanding probable mechanisms of successful
precordial thump. In these models, successful precordial thump interrupts tachyarrhythmias by
stretch-induced excitation of cells in the excitable gap(s), which obliterates re-entrant activity and
results in return to sinus rhythm if no re-entrant waves survive or are created (310) (discussed
further in ‘IV.B.3. Modifying and Terminating Arrhythmias’). However, when the heart is severely
ischaemic, as will often be the case in out-of-hospital VF, the mechanical augmentation of
metabolically pre-activated adenosine triphosphate (ATP)-sensitive K+ current (IK,ATP) can
(35)
account for the reduced efficacy of precordial thump (310) (discussed further in ‘IV.B.2.
Triggering and Sustenance of Arrhythmias’).
2. Bradycardia and Asystole

One of the first reports in the Western medical literature of the anti-arrhythmic effects of
precordial mechanical stimulation was published in 1920, when Eduard Schott demonstrated
that rhythmic fist thumps, applied to the precordium (now commonly referred to as ‘precordial
percussion’, ‘percussion pacing’, or ‘fist pacing’), each triggered competent ventricular
contractions, which maintained patient consciousness during acute Stokes-Adams attacks
(disturbances in atrio-ventricular conduction that decrease cardiac output and can give rise to
loss of consciousness and death; (545)). Unlike the utility of precordial thump for termination of
ventricular tachyarrhythmias, which has been generally disappointing, triggering contractions in
the bradycardic or asystolic heart seems to work more reliably, so that the use of precordial
percussion pacing to treat asystole in the emergency setting has been a well-received concept
(396, 541, 661).
In a number of case reports (3, 41, 134, 156, 157, 164, 165, 199, 200, 396, 411, 445, 537,
619) percussion pacing has been shown to be relatively effective in triggering electrical
activation and competent contractions in the bradycardic or asystolic heart. In the few case
series of precordial percussion pacing reported in the literature, a total of 139 patients have
been mechanically paced, with a 93% success rate (306, 692, 701). Similarly, finger-tapping of
the heart is generally an effective means for cardiac surgeons to restore rhythmic contractile
activity while weaning the heart from cardio-pulmonary bypass, especially when electrical
defibrillation attempts have put the heart into asystole.
Experimental studies of the asystolic post-electrical defibrillation shock period (377) or of
cardiac standstill due to complete atrioventricular block (637) have also demonstrated that
percussion pacing is a relatively effective means of mechanically stimulating heart beats
(FIGURE 10). It has also been shown that passive chest compressions, applied for cardio-
pulmonary resuscitation, can lead to ventricular excitation, resulting in active cardiac
contractions (451, 452). However, since its inception, interest in percussion pacing has always
been contrasted by questions about its utility (675, 702), fuelled by a lack of prospective clinical
studies (469) and mechanistic explanations.
Overall, it appears that single or serial precordial thump (often called precordial percussion)
may have some utility in the asystolic or severely bradycardic heart. Importantly, ventricular
(36)
contractions resulting from mechanically-induced excitation (which triggers active contraction)
are haemodynamically more productive than external chest compressions (which generate
circulation by passive ventricular ejection): cardiac output is 77% of baseline for mechanically-
induced excitation, compared to 38% of baseline even with optimally performed chest
compressions (98, 262). Thus, percussion pacing could have some utility in maintaining
adequate circulation in the asystolic heart in emergency setting.
Figure 10. Precordial fist thumps for mechanical pacing. A: Technique of percussion pacing, using
short sharp blows with the ulnar side of the clenched fist from a height of about 30 cm to the lower left
sternal edge. [From (200).] B: Termination of ventricular fibrillation by external defibrillator shock in an
anesthetised pig, followed by a single premature ventricular contraction and two seconds of asystole. A
series of chest thumps then results in active ventricular depolarisation (electrocardiogram Lead 2; top
row) and left ventricular (LV) contractions (LV pressure; bottom row). [From (377).]
Based on the potential of precordial mechanical stimulation as a rapid and non-invasive

means of cardiac pacing, several techniques for applying mechanical stimuli to the heart have
been developed (488). In 1976, pacemaker, defibrillator, and resuscitation pioneer Paul Zoll
developed a device for temporary mechanical pacing (the “Cardiac Thumper”) (700), which was
effective in evoking repetitive heartbeats in patients with asystole after VF, with AF, or with
atrioventricular block, as well as in dogs with normal sinus rhythm or atrioventricular block (701)
(FIGURE 11). Other mechanical stimulation devices have been devised, including patents for an
extracorporeal mechanical pacer that stimulates the heart via pressure waves applied to the
precordium (228), and an implantable mechanical defibrillator that applies a mechanical shock to
the heart by a piezo-transducer generated pressure wave transmitted through a hydraulic line to
a balloon-head in contact with the myocardium (233).
(37)
Figure 11. “Cardiac Thumper” device for temporary mechanical pacing. A: Mechanic pacing device
(fashioned from a modified electrically powered stapling gun). B: Electrocardiogram of an anesthetised
dog in complete heart block (top) and a patient in cardiac arrest (bottom) being mechanically paced by
the external mechanical pacemaker (mechanical stimuli marked by spike-like artefacts). [From (701).]
While precordial percussion is an immediately accessible form of extracorporeal pacing that

is potentially well-suited for out-of-hospital emergency settings, more recent device-based efforts
have focused on the use of extracorporeal high-intensity focused ultrasound (319) as a
potentially more controlled means of externally applying mechanical stimuli to specific regions of
the myocardium, over longer periods. The bio-effects of ultrasound have been extensively
studied (motivated by the assessment of its safety for use in echocardiography), and are
dependent on tissue properties (e.g., density, attenuation, absorption), exposure (e.g.,
frequency, intensity, pulse duration / duty cycle), and beam configuration (137). Ultrasound-
induced tissue deformation can occur as a result of acoustic radiation force (a consequence of
momentum transfer from the ultrasound wave to the tissue) which can lead to excitation of the
heart - one of the known side-effects of high-intensity focused ultrasound lithotripsy (121, 138,
149, 162, 207, 286, 665, 667). The first report of the excitatory effects of ultrasound on the heart
came from E. Newton Harvey in 1929, who noted that in frog and turtle hearts high frequency
ultrasound caused an increase in HR or the resumption of regular beating of an otherwise
quiescent ventricle (226). Subsequent studies have shown similar ultrasound-induced excitation
in frog (139), mouse (376), and rat (229) hearts, as well as cultured neonatal ventricular
cardiomyocytes (177), which, as for direct mechanical stimulation, appears to be driven by
activation of SAC (324). Short periods of mechanical pacing by repetitive high-intensity focused
ultrasound-induced have also been used for excitation in pigs with hypoxia-induced bradycardia
(613), in anesthetised rats (368), and in ex vivo and in vivo pig hearts, occasionally using intra-
ventricular contrast agents to enhance energy transfer (387) (FIGURE 12, A).
(38)
Beyond precordial percussion and high-intensity focused ultrasound, there have been
reports of the use of time-varying magnetic fields to excite the heart, which by-and-large has
proven to be impractical due to high energy requirements and unreliable pacing capture (63,
260, 418, 653, 676-678). These have inspired an alternative approach for the delivery of cardiac
mechanical stimulation using electromagnet-manipulated intravenously-injected magnetic
microparticles (528). Using an electromagnet to localise intravenously-injected magnetic
microparticles in the ventricles, and then periodically forcing them against the myocardium using
an alternating magnetic field, allowed mechanical pacing in ex vivo and in vivo rat hearts, as well
as in vivo in pigs (FIGURE 12, B).
Figure 12. Mechanical pacing. A: Electrocardiogram from right atrium (RA) and left ventricle (LV) and
haemodynamic recordings (LV pressure) of ultrasonic LV pacing in a pig isolated heart, showing that
upon ultrasound application LV excitation and pressure development precede atrial excitation. [Adapted
from (387).] B: Arterial pressure (blue line) and the current through an electromagnet coil (red line) during
mechanical pacing using electromagnet-manipulated intravenously-injected magnetic microparticles in an
anesthetised pig (+ signs indicate pacing capture). [From (528).]
3. Advantages and Limitations of MEC-based Anti-Arrhythmic Interventions

The above discussion highlights the potential utility of mechanical pacing for the asystolic or
severely bradycardic heart. Perhaps most importantly for its use, by triggering active
contractions, mechanical pacing generates a greater stroke volume than external chest
compressions that passively squeeze blood from the cardiac chambers (98, 262). On top of this,
extracorporeal mechanical pacing is more targeted, has low energy requirements (0.04-1.5 J
(701), compared to 150 J or more that are used for electrical defibrillation (572)), and it is less
painful than transthoracic (transcutaneous) electric stimulation (the alternative available method
for temporary extracorporeal pacing), so it has some advantages that ideally one would wish to
garner in the clinical setting. For instance, due to nerve and skeletal muscle activation causing
(39)
painful spasms, transthoracic electric stimulation typically necessitates the use of a sedative or
aesthetic agent, which may further impair the critical haemodynamic condition of a patient (416).
However, mechanical pacing is not without its own limitations. High-intensity focused
ultrasound has been shown to cause cell and tissue damage (352, 353, 400-402, 690), and
direct mechanical stimulation may give rise to contusional effects (117, 492, 494), so stimulation
energy levels must be carefully considered and well controlled (not usually possible with manual
application – though the maximum energy most physicians will be able to apply by fist thumps
from the recommended 30 cm height is below 10J (468)). Another major concern for cardiac
mechanical stimulation is the potential for the induction of sustained arrhythmias (discussed in
‘II.C. Induction of Sustained Arrhythmias’). Precordial thump, for instance, has been shown to
carry a risk of causing rhythm deterioration (425, 559) and, while rare, ventricular
tachyarrhythmias have been reported to occur with precordial percussion (306), high-intensity
focused ultrasound (when used with an intra-ventricular contrast agent) (387), and even with
chest compressions (451, 452). Thus, in applications of mechanical pacing, timing relative to
any underlying rhythm should be considered – as is common for cardiac electrical stimulation.
For mechanical pacing with magnetic microparticles, there are additional concerns relating to
particle biocompatibility and their excretion, as well potential coronary blockage and vascular
embolism (528).
Another important consideration for the utility of mechanical pacing is the loss of capture that
has been observed in many studies upon repeat application of mechanical stimuli. High-intensity
focused ultrasound-based mechanical pacing in anesthetised rats, for example, was effective for
a maximum of 7 consecutive stimuli, despite low pacing rates (once per breathing cycle (368)).
Mechanical pacing in the presence of magnetic microparticles in the heart was marginally more
successful, with ~30 stimulated beats in anesthetised rats and pigs before loss of 1:1 capture
occurred (528) (FIGURE 12, B). Even though fist-pacing has been reported to be possible over
longer periods in severely bradycardic patients (described in ‘IV.D.2. Bradycardia and Asystole’),
the published case reports generally did not monitor whether 1:1 capture was indeed sustained,
and in many cases, treatment was interspersed with periods of spontaneous circulation, so the
sustainability of mechanical pacing in human is currently unknown.
The apparent lack of sustainability of mechanical pacing in the above studies was attributed
to a loss of magnetic microparticles (528) or contrast agent (when used to enhance the effects of
high-intensity focused ultrasound-based stimulation) (387) at the pacing site, or to disruption of
myocyte homeostasis (such as a mechanically-induced increase in intra-cellular Ca2+ levels)
(40)
(368). Studies of mechanical pacing by gentle mechanical contact with the epicardium of ex vivo
hearts have corroborated a loss of capture (494, 696) and demonstrated that this effect is pacing
rate dependent, suggesting that loss of mechanical stimulation efficacy may be a fundamental
biological limitation of mechanical stimulation itself (494) (FIGURE 13). While the mechanisms
for the loss of capture with repetitive mechanical stimulation have not yet been identified, loss of
capture appears to relate to an MEC adaptation period during which mechanical, but not
electrical, excitability is reduced. As capture with mechanical stimulation is restored after a
period of normal sinus rhythm, it appears mechanical and electrical stimulation are limited by
different types of ‘refractoriness’. This concept is supported by: i) ex vivo studies of intra-
ventricular balloon inflation (151) and stimulation of myocyte monolayers by fluid jets (320), in
which repeat stimulations were effective only after periods of rest up to 1 min for full recovery of
mechanically-induced excitability; and ii) in vivo studies of repetitive local ventricular stimulation
that demonstrated a decrease in the effective refractory period with electrical but not mechanical
stimulation (18), in which mechanical stimulation during the (electrically-established) relative
refractory period resulted in excitation only with every second or third mechanical stimulus (71).
Figure 13. Loss of mechanical pacing capture. A: Electrocardiogram (ECG, top curve) and left
ventricular pressure (LVP, bottom curve) recorded from an isolated Langendorff-perfused rabbit heart
during sinus rhythm, followed by a train of focal left-ventricular mechanical stimulations (MS; see short
pressure spikes preceding mechanically-induced contractions, bottom curve), with a transient period of
1:1 capture, followed by return to sinus rhythm with intermittent MS beats. B: Effect of varying rate of MS
on the number of stimulations to loss of 1:1 capture. [Adapted from (494).]
There are several potential mechanisms that could account for mechanical refractoriness
that is distinct from electrical refractoriness, including effects of mechanical stimulation on tissue
mechanical properties, ion distributions in cardiac cells, or SAC or stretch-modulated ion
channel activity.
(41)
Mechanical stimulation is known to affect myocardial mechanics. Repeated axial stretch of
ventricular myocardium (by 5 - 15%) has been reported to cause a small decrease in muscle
stiffness, which recovers after ~30 s of rest (302). This apparent viscoelastic effect could
contribute to formation of an MEC adaptation period, especially considering that loss of capture
with mechanical pacing is accelerated as stimulation frequency is increased. On the other hand,
a possible role for changes in cellular ion balance(s) in the loss of mechanical pacing capture,
specifically via mechanical modulation of Ca2+ handling (81), could be based on an acute
stretch-induced increase in localised SR Ca2+-release events (‘Ca2+ sparks’), which may reduce
SR Ca2+ levels (190, 257, 258, 474, 481, 482), or on Ca2+-release from mitochondria, whose
intra-organelle Ca2+ concentrations may also be affected (36, 37, 405, 412). If Ca2+ is involved in
mechanically-induced excitation, then a depletion of mechanically releasable sub-pools of Ca2+
could affect the efficacy of mechanical stimulation. Stretch-induced Ca2+-release from the SR
may result either from direct mechanical stimulation of RyR (258) or arise via effects mediated
by mechanically-stimulated reactive oxygen species (ROS) production (481). Both mechanisms
could be affected by the frequency of cyclic mechanical stimulation, which could help to explain
the decrease in the number of mechanical stimulations before a loss of pacing capture when
stimulation rate is increased (494).
Perhaps the most convincing potential mechanism contributing to pacing loss, however, is
the fact that SACNS themselves show ‘mechanical refractoriness’ in the heart (i.e., the first
response to stretch is larger than subsequent ones). This is supported by the observation in
cardiac cells that repeated mechanical stimulation causes a cumulative reduction in ISAC,NS due
to channel inactivation, unless stimulations are spaced minutes apart (48, 49, 242). At the whole
heart level, this reduction in ISAC,NS results in a continuously increasing delay between
mechanical stimulation and excitation with successive stimuli (696). Although it has not been
studied in cardiac myocytes, mechanically-induced current through Piezo channels has been
shown to decrease with repetitive stimulation (e.g., in HEK293t cells expressing the ion
channel). In sensory dorsal root ganglion neurons this leads to a stimulation frequency
dependent loss of mechanically-induced excitation (349), as seen with mechanical pacing in the
heart. SAC ‘desensitisation’ or ‘rundown’ is in fact a broadly reported phenomenon and a
common observation in patch clamp studies. It has been observed, for instance, in the 2-pore K+
domains in a weak inwardly rectifying K+ (TWIK)-related K+ channel-1 (TREK-1) (237). A similar
use-dependent decrease in SAC could be responsible for the inverse dependence of the
(42)
number of mechanical stimulations to a loss of pacing capture on the mechanical stimulation
rate.
Even though it appears that 1:1 capture may not be maintainable for extended periods of
repetitive mechanical stimulation at physiological rates, it is possible that mechanical pacing is
effective at rates below normal sinus rhythm, accounting for clinical case reports on its utility in
patients with bradycardic or asystolic hearts, who have been kept conscious during prolonged
ventricular asystole for periods of close to 3 hours (3).
4. Summary
Precordial mechanical stimulation, whether by precordial impact, high-intensity focused
ultrasound, or other device-based means, can cause excitation of the heart and may hold
important therapeutic potential for temporary pacing or, less compellingly, tachyarrhythmia
termination in emergency settings. Mechanical rhythm management is not without limitations,
however, including lack of sustainability, safety, and ethical (hitting a patient) concerns. Based
on the 2010 International Consensus on Cardiopulmonary Resuscitation and Emergency
Cardiovascular Care Science with Treatment Recommendations (440), current International
Liaison Committee on Resuscitation (ILCOR) (321, 582) and American Heart Association (74,
362) guidelines state that: “precordial thump may be considered for patients with witnessed,
monitored, unstable ventricular tachyarrhythmias, including pulseless ventricular tachycardia if a
defibrillator is not immediately ready for use” (74), but ”should not be used for unwitnessed out-
of-hospital cardiac arrest” (74). The need for further research into the utility of mechanical heart
rhythm management in severe bradycardia is highlighted as follows: “there is insufficient
evidence to recommend for or against the use of the precordial thump for witnessed onset of
asystole caused by atrioventricular conduction disturbance” (321). Regarding percussion pacing,
the guidelines state that: “fist pacing may be considered in haemodynamically unstable
bradyarrhythmias until an electric pacemaker (transcutaneous or transvenous) is available”
(582), but that “there is insufficient evidence to recommend percussion pacing during typical
attempted resuscitation from cardiac arrest” (96). These recommendations reflect a paucity of
prospective data and a general lack of understanding of the efficacy, limitations, and
mechanisms of mechanical rhythm management, justifying future study of its optimisation and
potential clinical utility in particular in asystole and severe bradycardia – the rhythm disturbance
for which precordial thump was originally reported.
(43)
C. Knowledge Gaps and Future Directions
x The critical characteristics of mechanical stimulation, such as timing, force versus
deformation, rate, and site of application are largely unexplored, deserving further
exploration.
x The mechanisms and importance of SAN mechano-sensitivity for maintaining normal sinus
rhythm, and mechanical contributions to SAN dysfunction with age and disease, are
unknown; this, and the interplay of Vm, Ca2+, and mechanics oscillators in sustaining SAN
activity and autoregulation warrant further investigation in experimental models and human
studies.
x For ventricular mechanical stimulation, observed responses include a wide variety of
electrophysiological changes, but the source of this variability is unclear; aspects relating to
differences in species, mechanical stimulation characteristics, or underlying physiology will
need to be explored.
x The potential role of non-myocytes (such as fibroblasts, macrophages, or intracardiac
neurons) in MEC responses is just emerging, and much remains to be explored; the use of
innovative targeted technologies, such as optogenetics, holds promise for addressing this
new frontier.
x While hallmark examples of the arrhythmogenic and anti-arrhythmic potential of MEC in the
acute settings have driven conceptual and computational model development to link
molecular and clinical observations, mechanistic insight into MEC-mediated behaviour in
chronic diseases, their mechanisms of action, and potential for therapeutic exploitation, have
not been established; this is a critical area for targeted investigation.
x MEC contributions to anti-arrhythmic interventions seem most relevant in the asystolic or
severely bradycardic heart. The source of the observed loss of mechanical trigger efficacy
with repetitive stimulation is unknown; further investigations are essential for the clinical
translation of mechanically-based pacing.
III. MOLECULAR MECHANISMS OF MEC
A. Pacemaker Cells
1. Mechano-Sensitivity of ‘Mechanical Oscillator’ Components

In the microelectrode recording experiments of Klaus Deck (FIGURE 14, A), the increase of
spontaneous diastolic depolarisation and beating rate during SAN stretch were accompanied by
a decrease in the absolute values of both maximum diastolic and maximum systolic potentials
(44)
(147). In other experiments, the need for a minimum mechanical preload to establish rhythmic
SAN excitation also involved a progressive reduction in the absolute value of the maximum
diastolic potential with stretch, which resulted initially in the appearance of sub-threshold
oscillations of Vm, followed by spontaneous beating (337) (FIGURE 3, A). Isolated Purkinje fibres
also responded to stretch with diastolic depolarisation, which, once it exceeds a certain level,
gives rise to arrhythmic AP generation, followed by loss of excitation (292)).
Figure 14. Stretch-induced increase in SAN beating rate. A: Intra-cellular sharp electrode recordings
of transmembrane potential (top) and applied and generated force (bottom; passive stretch and active
contraction pointing upwards) in cat isolated sinoatrial node tissue, showing an increase in beating rate
during stretch, combined with a reduction in absolute values of maximum diastolic and maximum systolic
potential. [From (147).] B: Axial stretch, applied to a spontaneously beating rabbit sinoatrial node cell
using a pair of carbon fibres (scale bar = 10 mm). C: Patch-clamp recordings of transmembrane potential
showing a stretch-induced increase in spontaneous beating rate of the pacemaker cell, accompanied by
a reduction in the absolute values of maximum diastolic and maximum systolic potential (light curve =
before stretch, dark curve = during stretch). [From (120).] D: Whole-cell stretch-induced current (I) /
voltage (V) relation (I is the difference current in absence versus. presence of streptomycin to block
cation-nonselective stretch-activated channels, normalised to cell capacitance) from rabbit isolated
sinoatrial node cells, showing a reversal potential of ~11 mV (dotted lines = 95% confidence limits). [From
(120).]
These findings helped in narrowing the range of plausible molecular mechanisms involved in
the chronotropic response to stretch, as any components affecting Vm would be expected to
have their reversal potential (Erev) somewhere between maximum diastolic and systolic
potentials. Initial targeted electrophysiology studies used positive pressure inflation (via the
(45)
patch pipette in whole-cell model) of rabbit isolated SAN cells, which activated the swelling-
activated chloride current (ICl,swell) (213), as well as ICa,L (389). With an Erev near 0 mV in cardiac
myocytes, ICl,swell could theoretically account for the observed stretch-induced changes in SAN
electrophysiology. However, there is a time-lag between the onset of cell swelling and activation
of ICl,swell (usually exceeding 1 min), rendering it too slow for the near-instantaneous changes
upon acute stretch. Additional studies using hypo-osmotic swelling of spontaneously beating
rabbit SAN cells in perforated patch mode demonstrated a reduction, rather than the expected
increase, in beating rate (343). These experiments were accompanied by computational
simulations suggesting that the decrease in beating rate is caused by cytosol dilution (343). It
was shown that this effect, via a decrease in intra-cellular K+ concentration, could have reduced
the rapid delayed rectifier K+ current, shifting the maximum diastolic potential towards more
depolarised levels and reducing the hyperpolarisation-activated depolarising ‘funny’ current If, as
confirmed experimentally in voltage-clamped SAN cells (343).
It should be noted that cell inflation, whether by positive pressure inflation or swelling, is
mechanically different from axial stretch, as swelling is associated with an increase in cell
diameter and negligible changes in length. In contrast, axial stretch causes cell lengthening, a
reduction in diameter (as cell volume is understood to remain constant during acute length
changes), and an increase in beating rate of spontaneously beating rabbit SAN cells (120). Even
in isolated cells, this is accompanied by a reduction in the absolute values of maximum diastolic
and maximum systolic potential, as seen in SAN tissue (FIGURE 14, B AND C).
Subsequent Vm-clamp studies revealed that stretch of single SAN cells indeed gives rise to
a stretch-activated current with an Erev near -11 mV (120) (FIGURE 14, D). This current is
compatible with SACNS (133, 209) (FIGURE 15), whose block indeed causes a reduction of the
chronotropic response to SAN stretch (119).
Interestingly, while in larger mammals with inherently slow background HR the chronotropic
response to SAN stretch is ‘positive’ (increase in beating rate), in smaller mammals such as
mouse and rat with resting HR of 600 bpm or more, SAN stretch can decrease beating rate
(119). Perhaps counterintuitively, both responses may be accounted for by activation of SAC NS.
In mammals with slower background HR, the SAN AP is characterised by a relatively slow AP
upstroke (carried mainly by ICa,L) and a relatively prominent plateau-like early repolarisation
phase, while mammals with faster HR exhibit faster upstrokes (often carried by a mix of Na + and
Ca2+ currents (344)) and swift initial repolarisation, giving rise to a more spike-like AP shape.
(46)
Figure 15. Cation-nonselective stretch-activated channel current in cardiac cells. A: Cell-attached
patch-clamp recording of a neonatal rat ventricular myocyte during application of negative pressure (~2
cm Hg) to the patch pipette, indicated by the horizontal line. B: Current (I) / voltage (V) relationship of
resulting stretch-activated current. [Adapted from (133).]
Consequently, ‘slower’ SAN AP spend the majority of each cycle moving their V m towards the
Erev of SACNS, while ‘faster’ SAN AP spend a larger proportion of time moving their V m away
from it (FIGURE 16). Thus, activation of ISAC,NS, which ‘pulls’ Vm in the direction of its Erev, would
be expected to increase slower and reduce faster beating rates (118), a concept that has been
supported quantitatively by computational modelling (120) (discussed in ‘IV.A.1. Consequences
of SAC Activation’). This concept is also supported by recent experimental data from zebrafish,
whose HR (~120 bpm) is closer to that of mammals larger than mice, and whose SAN AP show
a relatively slow upstroke and a prominent plateau: stretch of the zebrafish SAN causes a
stretch-amplitude dependent increase in beating rate (375). The difference in the chronotropic
stretch response between mouse and other mammals may also relate in part to species-specific
structural and mechanical SAN properties, in particular distinct collagen architecture and acute
changes that occur with stretch.
(47)
Figure 16. Conceptual model of cation-nonselective stretch-activated channel (SACNS) effects on
the action potential (AP) of sinoatrial node (SAN) pacemaker cells in different species.
Experimental recordings of transmembrane potential from rabbit (A) and mouse (B) show the interrelation
of key electrophysiological parameters (maximum diastolic [MDP] and maximum systolic [MSP] potential)
and the reversal potential of SACNS (ESAC,NS). The time periods during which opening of SACNS would
either accelerate (nV) or slow (pV) intrinsic changes in transmembrane potential are indicated at the
bottom. In rabbit, SACNS would accelerate changes during ~70% of the pacemaker cycle, while in mouse
this would occur only for ~45% of the time. [From (118).]
2. Mechano-Sensitivity of Vm Oscillator Components

Quantitative plausibility is no substitute for experimental validation (498), and SAN stretch
responses might also result from direct effects on stretch-modulated components of the Vm
and/or Ca2+-oscillators (summarised in FIGURE 2, C). In cell expression systems, mechanical
stimulation increases the amplitude (88) and both activation and deactivation rates (358) of If.
Interestingly, these effects are dependent on background beating rate: when membrane patches
are AP-clamped to cyclic SAN or Purkinje cell AP waveforms, membrane deformation causes an
increase in If at higher, and a decrease at lower beating rates, which would be expected to have
opposite effects to the observed direction of stretch-induced chronotropic effects. Similarly, ICa,L
but not ICa,T (77, 373, 594), several K+ currents (via Kv1, Kv3, Kv7, KvCa) (415), and the Na+
window current (50) have been shown to be mechanically modulated. This means that their
opening probability is sensitive to the mechanical environment, even though stretch per se is not
normally sufficient to trigger channel openings on its own. In the beating heart, ICa,L and the Na+
window current could be involved in accelerating SAN (390, 409) and Purkinje fibre pacemaking
rates (173, 270, 422, 450). In pathological settings associated with myocardial ischaemia, IK,ATP
may also become important in the mechanical modulation of pacemaker function (51). This
current, whose activity – if pre-activated by a reduction in ATP-levels – is increased by stretch in
atrial and ventricular myocytes (627, 628), has been shown to be present in rabbit isolated SAN
(48)
cells (220). Activation of IK,ATP in the ischaemic SAN could be expected to hyperpolarise V m,
opposing spontaneous diastolic depolarisation and, potentially at least, the positive chronotropic
effect of stretch, yet the ultimate effect on beating rate is unclear, as SAN beating rate is set by
competing changes in several current systems whose partially reciprocal dependence on the
maximum diastolic potential can stabilise beating rate (such as If and Ib,Na (438)).
3. Mechano-Sensitivity of Ca2+ Oscillator Components

Stretch-effects on intra-cellular Ca2+ handling may also modulate SAN beating rate. Stretch
has been shown to directly affect intra-cellular Ca2+ handling in cardiac cells (5, 81, 480, 602). In
keeping with a contribution of these mechanisms to beating rate regulation, it has been reported
that the response to stretch is reduced by interventions that decrease SR Ca 2+ content by
lowering extracellular Ca2+ concentration or blocking sarco/endoplasmic reticulum Ca2+-ATPase
(14), inhibit SR Ca2+ release by RyR block (14), or decrease trans-sarcolemmal Ca2+ fluxes,
such as upon ICa,L block (230). As mentioned above (in ‘II.D.3. Advantages and Limitations of
MEC-based Anti-arrhythmic Interventions’), axial stretch of ventricular myocytes causes an
acute increase in Ca2+ spark rate (258) (FIGURE 17). In ventricular cells, this may further involve
mechanically-induced mitochondrial Ca2+ release through mitochondrial INCX (36, 37, 405, 412).
If similar stretch-effects on Ca2+ handling are present in SAN cells, they could be relevant for
mechanical modulation of SAN activity, as changes in SAN intra-cellular Ca2+ concentration
(682) or mitochondrial INCX-mediated changes in Ca2+ spark rate (683) may affect beating rate.
Figure 17. Effect of axial stretch on calcium (Ca 2+) spark rate in rat ventricular myocytes. A:
Confocal images of intra-cellular Ca2+ concentration showing an acute increase in Ca 2+ spark activity
upon axial stretch (change in sarcomere length of 8% from control) applied by carbon fibres to only one
half (right side, see arrow marks) of an isolated cardiomyocyte. B: Time course of relative intra-cellular
Ca2+ concentration signal intensity, illustrating the local nature of the stretch-induced (at time-point 0 s)
increase in in Ca2+ spark rate in the distended part of the cell only (individual spark dynamics remain
unchanged; scale bars = 20 Pm). [From (258).]
(49)
In addition, there may be secondary effects of altered Ca 2+ handling through store-operated
Ca2+ channel current (an inward Ca2+ current whose magnitude depends on the level of
depletion of SR Ca+ stores (548)). While not generally included as a component of the Ca2+-
oscillator, this current has been implicated in modulation of SAN beating rate, both directly via a
background inward current that is modulated by beat-by-beat changes in SR Ca2+ content (277),
and through secondary effects via electrogenic INCX activity (276). Moreover, it has been
suggested that the store-operated Ca2+ channel may be accounted for by transient receptor
potential (TRP) canonical protein (TRPC) expression (277). Since type 1 of TRPC has been
suggested to underlie SACNS (386), it could play a much more important role in direct
mechanical effects on cardiac pacemaker activity than hitherto appreciated.
4. Summary
Mechanical activation of SACNS can explain most aspects of the chronotropic response to
SAN stretch. Stretch causes an increase of spontaneous diastolic depolarisation and a decrease
in the absolute values of maximum diastolic and maximum systolic potentials, due to the Erev of
SACNS between -20 and 0 mV. As a result, beating rate is increased with stretch in most
animals. In species with high HR and fast early repolarisation such as mouse, however, beating
rate can be decreased with SAN stretch, even though this response may be explained by the
same molecular mechanism – SACNS activity. While SACNS can explain most aspects of the
chronotropic response to SAN stretch, there may be important contributions of mechanical
effects on components of the Vm and Ca2+ oscillators. Many factors involved have been shown
to be subject to mechanical modulation, including various ion currents (If, ICa,L, the Na+ window
current, and several K+ currents) and intra-cellular Ca2+ handling, although most of the related
evidence comes from other cardiac cell types or expression systems, so direct confirmation of
their involvement in SAN mechano-sensitivity is missing.
B. Working Cardiomyocytes
1. SACNS
Stretch-induced changes in Vm of working cardiomyocytes can be explained by ISAC,NS
(FIGURE 5A). Due to an Erev at levels that are somewhere half-way between peak AP and
resting Vm, activation of ISAC,NS depolarises Vm in resting cells (132), causing after depolarisation-
like events in isolated cardiomyocytes (308) and, if supra-threshold, premature excitation (521,
658). During the AP plateau, ISAC,NS accelerates Vm repolarisation, causing a shortening of early
APD (659, 688). As a result, AP shortening has frequently been observed with sustained stretch
(50)
(659). However, as the cell membrane repolarises and becomes more negative than the Erev of
SACNS, this can give rise to late AP prolongation (693), potentially resulting in a cross-over of the
repolarisation curve (687).
The role of SACNS in causing the typical stretch-induced changes in cardiac
electrophysiology is further supported by studies using pharmacological blockers (657) (although
results must be interpreted with caution, as discussed in ‘III.D.3. Considerations for the Use of
Pharmacological Probes’). Gadolinium (Gd3+) and amiloride, two non-specific blockers of SAC,
have been shown to reduce the incidence of stretch-induced ectopy in ex vivo hearts (221, 245,
547), and to prevent stretch-induced changes in electrophysiology in myocyte monolayers (320),
single myocytes (281, 556, 693), cardiovascular smooth muscle cells (670), and expression
systems (217). More specific compounds have shown similar inhibition of stretch effects, such
as streptomycin (20, 40, 150, 161, 192, 245, 320, 371, 423, 614, 644, 650), which at low-
concentrations serves as a reasonably selective SAC blocker (657), and the selective SACNS
inhibitor Grammostola spatulata mechanotoxin-4 (GsMTx-4(578)) (28, 430, 492, 578, 641).
SACNS have also been implicated in mechanically-induced ventricular arrhythmias. In the
rabbit isolated heart model of Commotio cordis, it was shown that impact-induced excitation was
dependent on SACNS (492), as it was blocked by GsMTx-4. This is in apparent contrast to
results from an anaesthetised pig model of Commotio cordis, where streptomycin did not alter
the probability of VF induction after precordial impact (193). The rabbit heart study, however,
also showed no effect of streptomycin on mechanically-induced excitation (492), which may
reflect the limited efficacy of streptomycin for acute SACNS block in native myocardium (119) (for
a discussion of utility and limitations of SAC blockers, see ‘III.D.3. Considerations for the Use of
Pharmacological Probes’).
During acute ischaemia, a role of SACNS in stretch-induced excitation has been suggested
by computational modelling (274). This is in contrast to recent experimental reports, where
application of Gd3+ (25) or GsMTx-4 (28) did not alter the incidence of arrhythmias in whole
animal (pig) experimental models. The interpretation of data from pharmacological intervention
in whole animals is challenging, of course, as the lack of an observation of an effect is not the
same as observation of a lack of an effect, given that pharmacological agents used to target
SAC have a number of restrictions that affect their utility in vivo (discussed further in ‘III.D.3.
Considerations for the Use of Pharmacological Probes’). In particular, Gd3+ has been shown to
precipitate almost completely upon interaction with anions in physiological buffers, causing a
drastic reduction in its free concentration (83), so that it cannot be recommended for in vivo
(51)
MEC studies. In the pig experiments using GsMTx-4, the effective concentration at the level of
cardiac cells would have been extremely low, given that the peptide is diluted not only in plasma
(which would have yielded 170 nM, a concentration that has been found to be effective in some,
but not all, in vitro studies), but also in interstitial fluid (which has a 3 times greater volume than
plasma), yielding an effective concentration of GsMTx-4 of less than 50 nM; this may not have
blocked SACNS effectively.
Along with SACNS, additional stretch-modulated mechanisms may contribute to
arrhythmogenesis in acute ischaemia (239), such as the stretch-modulated IK,ATP (acting as a K+-
selective stretch-activated channel, SACK) (627, 628), sympathetic stimulation (241), or altered
Ca2+ handling (33). In particular, a role for mechanical augmentation of IK,ATP in ischaemia is
supported by the fact that preventing paradoxical segment lengthening of affected tissue in a pig
model of myocardial ischaemia using a mechanical splinting device delays K + accumulation in
the ischaemic zone, and prevents electrophysiological changes such as APD shortening and
occurrence of alternans (59).
In the atria, the importance of SACNS for stretch-induced excitation is supported by
experiments showing that Gd3+, (which blocks ISAC,NS in isolated atrial cells; (698)) suppresses
ectopy (599). Indeed, in stretch-augmented rapid pacing-induced AF models, Gd3+,
streptomycin, and GsMTx-4 all reduce AF inducibility (FIGURE 9, C), without affecting
refractoriness (55, 56, 179, 436). Interestingly, the stretch-mediated increase in AF inducibility
can be reduced by altering the fatty acid composition of cardiac cell membranes with dietary fish
oil, possibly by changing physical membrane properties and altering mechanical stimulus
transmission from macroscopic input (pressure/volume overload) to SAC and stretch-modulated
currents as molecular sensors (434).
There may also be a contribution of stretch-induced excitation, mediated via SACNS, in
pulmonary vein automaticity, a key clinical contributor to AF. Here, stretch results in an
increased incidence and rate of firing (278), which is blocked by Gd3+ and streptomycin (100)
(although with Gd3+, simultaneous block of INa may also contribute to suppression of excitation
(350)). Streptomycin, on the other hand, can also block L-type Ca2+ channels (39) and Ca2+
influx via L-type Ca2+ channels may be one of the contributors to the decrease in refractoriness
with atrial dilatation, as changes in refractoriness and AF inducibility are also prevented by block
of ICa,L (618, 691). Interestingly, a recent report has implicated caveolae-mediated activation of
stretch-activated ICl,swell as a critical cause of pulmonary vein automaticity with stretch, however
(52)
based on the considerations of a role of ICl,swell in a stretch-induced increase in automaticity
discussed above, this finding requires further investigation (163).
2. SACK
While all of the known acute stretch-induced effects on cardiac electrophysiology in healthy
myocardium can be reproduced in quantitative computational models by simply invoking ISAC,NS,
there is strong evidence supporting a contribution by SACK, specifically in ATP-deprived tissue.
During systole, activation of SACK (whose Erev is close to the reversal potential of K+) would be
expected to enhance APD shortening (297) and, if activated in resting cells, to hyperpolarise Vm.
The latter has not been reported, which suggests that SACK do not dominate MEC responses in
healthy cardiomyocytes. In ischaemia, there may be an additional contribution to APD
shortening by the stretch-modulated IK,ATP (627, 628). IK,ATP has additionally been implicated in
VF induction in the setting of Commotio cordis, as administration of the non-specific IK,ATP-
blocker glibenclamide reduced the incidence of VF-induction in pigs upon precordial impact
(366). That said, under conditions of normal oxygen supply IK,ATP is inactivated (441) and not
responsive to mechanical stimulation (627, 628) (in fact, the combined sensitivity to stretch and
ATP-reduction may explain why to cause channel opening in vitro ATP concentrations must be
reduced far more than might be expected to occur in vivo). In keeping with non-specific effects
of the blocker used (glibenclamide) (19, 501), the decrease in the incidence of mechanically-
induced VF may instead represent IK,ATP-induced changes in repolarisation timing and
refractoriness, causing a shift in the exceedingly narrow vulnerable window for mechanically-
induced re-entry (492) and, hence, a potentially false-positive conclusion regarding
glibenclamide effects on cardiac mechano-sensitivity. In the case of increased AF incidence with
atrial dilatation, K+ influx via SACK may contribute to decreased refractoriness and it has been
shown that acidotic conditions, which amplify stretch activation of K + channels such TREK-1
(378), cause an additional reduction in refractory period and increase in AF susceptibility with
atrial dilatation (436).
3. Mechano-Sensitivity of Intra-Cellular Ca2+ Handling

Stretch directly affects intra-cellular Ca2+ handling in cardiac cells. Stretch has been shown
to acutely increase SR Ca2+ release in guinea pig (257), rat (190, 258, 482), and mouse (481)
ventricular myocytes, via either direct mechanical (258), ROS-mediated (481), or mitochondrial
Ca2+-related (36, 37, 405, 412) influences on RyR open probability, which may contribute to
Ca2+-induced after-depolarisations (182). This stretch-induced increase in SR Ca2+ release may
(53)
be especially important in acute ischemia as it is enhanced, along with the stretch-induced
increase in ROS production, in that setting (90). Intra-cellular free Ca2+ is also acutely affected
by a length-dependent change in the affinity of troponin C (TnC) for Ca2+ (4), such that with
increased stretch (4, 6) or tension (685) more Ca2+ is in the bound state. Upon rapid shortening
during relaxation, the dissociation of Ca2+ from TnC causes a surge in intra-cellular Ca2+ (638).
In this period RyR can have sufficiently recovered to allow additional Ca2+-induced Ca2+-release
from the SR (24), which can cause propagating Ca2+ waves (FIGURE 18, A). Cellular excitation
may then occur (141, 605, 639) by depolarisation of Vm via electrogenic Ca2+ removal through
INCX (408). It is important to note that in the given example, it is the relaxation of stretched
muscle, rather than the stretch per se, that causes this Ca2+-mediated arrhythmic trigger. Such
response would be in keeping with the observation that Ca2+ release is enhanced by increasing
the rate of relaxation (639), independently of the involvement of SACNS (407). Importantly, in the
case of non-uniformly contracting myocardium, for instance with regional-changes in contraction
as occurs in ischaemia or long QT syndrome, acute mechanically-induced changes in Ca2+
dynamics may give rise to arrhythmogenic Ca2+ waves (406, 603, 604, 606). These waves
themselves can then result in after-contractions that cause after-depolarisations in other cardiac
tissue segments that may trigger tachyarrhythmias (188, 601) (FIGURE 18, B).
4. Summary
SACNS can explain most electrophysiological MEC responses in working myocytes of the
heart. With an Erev approximately half-way between peak AP and resting Vm, ISAC,NS can cause
depolarisation and excitation in resting cells, while during the AP plateau it can accelerate early
repolarisation and shorten APD. As a result, SACNS are implicated in atrial and ventricular
arrhythmogenesis, including settings such as AF, Commotio cordis, or acute ischaemia. These
effects may be reduced or prevented by SACNS blockers, but they must be used with careful
consideration to avoid false conclusions. Other sub-cellular stretch-modulated components may
also contribute to pro-arrhythmic stretch effects, including after depolarisations, ectopic
excitation, and tachyarrhythmias, including SACK (such as the stretch-modulated IK,ATP) and
intra-cellular Ca2+ handling (via changes in SR Ca2+ release and the affinity of TnC for Ca2+).
(54)
Figure 18. Effects of non-uniform contraction on rat ventricular cardiomyocyte intracellular
calcium concentration ([Ca2+]i) and electrical activity. A: Three- (top) and two-dimensional (bottom)
spatio-temporal representations of [Ca2+]i showing electrically stimulated [Ca2+]i transients (white arrows)
in a ventricular trabecula, followed by a surge in [Ca 2+]i at the border between normal and weakened
muscle (by perfusion with 2,3- butanedione monoxime, BDM, across the central part of the trabecula),
triggering a propagating [Ca2+]i wave. [Adapted from (638).] B: After-contractions of increasing amplitude
during E-adrenergic stimulation in the left ventricle (see arrows in the bottom trace of left ventricular
pressure, LVP) of an anesthetised dog model of acute long QT syndrome (induced by pharmacological
inhibition of the slow component of the delayed-rectifier potassium current by HMR1556), preceding after-
depolarisations (blue segments in middle trace of left ventricle epicardial monophasic action potentials,
LV MAP). These mechanically-induced depolarisations eventually reach the threshold for ventricular
excitation (red in LV MAP trace), triggering torsades de pointes (upper trace of the electrocardiogram,
ECG). Green and orange lines illustrate that onset and peak of LV after-contractions, respectively,
precede depolarisations. [Adapted from (188).]
C. Cardiac Non-Myocytes
1. SACNS
While electrophysiological responses to stretch in native cardiac tissue can be explained
generally by direct MEC effects on myocytes, they may also be mediated through mechano-
sensitivity of electrically-coupled non-myocytes, such as macrophages (which have been shown
to both express SACNS (455) and electrically-couple to myocytes (247)) or fibroblasts (313).
Fibroblasts are relatively depolarised cells that possess SAC NS (573). They have been shown to
form structural connexin-based links with SAN cells (89) that support active electrotonic coupling
with cardiomyocytes (490, 529) in native tissue. In cell cultures, fibroblasts can act as current
(55)
sinks that affect cardiomyocyte excitability, repolarisation, and conduction (305, 404), and they
may serve as passive conductors between structurally separate myocyte groups (196, 205).
Stretch has been shown to cause fibroblast depolarisation (282, 315, 317), a response that
is sensitive to pharmacological depletion or buffering of fibroblast intra-cellular Ca2+ (303), and
that has been implicated in mechanically-induced electrophysiological changes in fibrotic cardiac
tissue (610). A role for non-myocytes in stretch-induced electrophysiological responses may
underlie the observation that the magnitude of mechanical effects on HR increases with
structural complexity of the biological model: isolated SAN cells ~5%, whole-heart/SAN tissue
~15%, intact dog up to 30% (even though the inherent reduction in beating rate that occurs with
more reduced preparations should have the opposite effect, i.e., the largest chronotropic
response in isolated cells) (119). This phenomenon suggests a loss of contributory factors
involved in transmission or sensing of mechanical stimuli as one moves towards more reduced
biological model systems (which, in denervated preparations, will also include loss of autonomic
nervous system contributions).
2. Summary
Mechano-sensitivity of non-myocytes, electrically coupled to cardiomyocytes, may contribute
to MEC responses in the heart. Fibroblasts in particular have been shown to express SACNS and
to electrically connect with cardiomyocytes, which may give rise to mechanically-induced
changes in cardiac electrophysiology.
D. Molecular Candidates for SAC
1. SACNS
The first single channel recordings of depolarising ISAC,NS were reported in 1984 by Falguni
Guharay and Frederick Sachs, in cultured embryonic chick skeletal muscle (209). Since then,
ISAC,NS has been recorded in isolated ventricular myocytes from various mammalian species,
including human (133, 281, 283, 539). This current has a near-linear current-voltage relationship
(as is typical for weakly selective ion channels), a single channel conductance between 10 and
30 pS, and an Erev somewhere between -20 and 0 mV. In contrast to atrial cells, where single-
channel recordings of SACNS have been reported (300), SACNS channels in adult ventricular
cardiomyocytes appear to be hidden from direct patch pipette access, for example in membrane
regions of the transverse tubular system (244), caveolae, or at intercalated discs (264). Two
principal families of candidates for SACNS have been identified: TRP and Piezo channels, both of
(56)
which have been shown to be expressed in the plasma membrane of numerous human and
animal cell types (476) (FIGURE 19).
Most TRP channels found in mammals are cation non-selective, and depending on the
specific channel, pass some combination of Ca 2+, Mg2+, Na+, K+, and Cs+. They are generally
widely expressed, play a critical role in sensory physiology by enabling cells to sense changes in
their local environment (including chemicals, temperature, osmolarity, vibration, and pressure).
They can be activated by multiple factors, including mechanical stimuli (such as osmotic stress,
shear force, and membrane stretch (255), although direct stretch activation of TRP channels is
controversial (432)). Particularly interesting candidates for cardiac SAC NS include members of
the TRPC, TRP vanilloid (TRPV), TRP melastatin (TRPM), and TRP polycystic (TRPP) protein
sub-families.
Figure 19. A selection of the more well-known mechano-sensitive ion channels and receptors in
different organisms. Channels in red are expressed in the heart, underlined channels have been clearly
identified as mechano-gated, while channels with an asterisk have no known mammalian homologues.
Examples of mammalian channels with homologues in other organisms include: NOMPC, OSM9, TRP4,
TRPY1, and LOV-1, which are transient receptor potential homologues; MEC channels, which are
members of the degenerin / epithelial sodium channel superfamily that in mammals are Asic; TPK which
is a homologue of K2P channels; and Mid1 which is homologous to voltage-gated calcium channels.
AchR, acetylcholine receptor; Asic, acid-sensing ion channels; BK, big potassium (K+) channels; CFTR,
cystic fibrosis transmembrane conductance regulator; CLC, chloride channels; K ATP, ATP-inactivated K+
channel; KCNQ, KQT-like voltage-gated K+ channel; LOV, location of vulva; Mid1, mating induced death;
MCA, mechanosensitive Ca2+ channel; MSC, mechanosensitive channel of small conductance homolog
in Chlamydomonas reinhardtii; MscA, K, L, M, MJ, S, mechano-sensitive channel of archaeon, K+, large,
medium, Methanococcus jannashii, small conductance, 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, cation-nonselective stretch-activated
channel; SACK, stretch-activated K+-selective channel; SR, sarcoplasmic reticulum; TRAAK, TWIK-
related arachidonic acid-activated K+ channel; TREK, TWIK-related K+ channel; TRPA, C, M, N, P, V, and
Y, transient receptor potential ankyrin, canonical, melastatin, NOMP, polycystin, vanilloid, and yeast
channels; TPK, 2-pore domain K+ channels; OSM, OSMotic avoidance abnormal family; TWIK, 2-pore K+
domains in a weak inwardly rectifying K+ channel. [From (476).]
(57)
In terms of candidates in the TRPC sub-family of channels, TRPC6 is highly expressed in
the human heart (516), being localised in transverse tubules of mouse ventricular myocytes
(160). Stretch activation of TRPC6 was first characterised in human embryonic kidney cells
(566). Lack of mechano-sensitivity of TRPC6 expressed in Chinese hamster ovary (CHO) or
monkey kidney fibroblast (COS) cell lines (206) may be attributed to the requirement for co-
expression of angiotensin II receptor type 1 to yield SAC activity (255, 631). ISAC,NS in mouse
cardiomyocytes during shear stress is reduced by pore-blocking TRPC6 antibodies or de-
tubulation (160). TRPC3 expression has been shown in rat ventricular myocytes, where – like
TRPC6 – it is found in the transverse tubular system (183). In mouse neonatal cardiomyocytes,
the channel is involved in ROS production upon mechanical stimulation or application of 1-
oleoyl-2-acetyl-sn-glycerol (OAG), a non-specific activator of SAC (183). Stretch activation of
TRPC1 is controversial. It was initially demonstrated in Xenopus oocytes (386), however like for
TRPC6, it was not confirmed in other expression systems (206), suggesting that this channel
may also require the presence of a partner protein. Caveolin 1 may be a trafficking regulator of
TRPC1 (254, 458). As caveolae can be integrated into the sarcolemmal surface membrane of
ventricular cardiomyocytes in response to stretch (311, 477), TRPC1 mechano-sensitivity may
be linked to stretch-induced changes in membrane topology, including knock-on effects on
conduction velocity (due to a stretch-induced increase in membrane capacitance) rather than ion
channel function of the protein.
Regarding candidates in other TRP sub-families, TRPV2, expressed in the mouse heart
(264, 531), is activated by patch pipette suction and cell volume changes (420), and it has been
proposed to contribute to Ca2+-handling in cardiac cells (531). TRPM4 is expressed in
cardiomyocytes of several species, including mouse, rat, and human (631), and it has been
implicated in stretch-activated responses of vascular smooth muscle (414), though its
physiological role in the heart is currently unknown. TRPP2 is primarily found on the
endoplasmic/SR and in primary cilia (647), but a TRPP2-like protein seems to function as an ion
channel in the sarcolemma of rat ventricular myocytes (634), potentially acting as a modulator of
RyR activity (13).
The discovery of Piezo channels (Piezo 1 and 2) constituted a breakthrough in the field of
mechano-transduction (127). Stretch activation of Piezo 1 has been demonstrated with
heterologous expression in human embryonic kidney cells, resulting in ISAC,NS (128). While Piezo
has not been detected at the protein level in cardiomyocytes, and no functional data have been
published for the Piezo in the heart at the time of writing (34), low level Piezo1 mRNA
(58)
expression (compared to lung, bladder, or skin) has been observed in mouse heart tissue
homogenates (127). As Piezo current properties are similar to those of cardiac ISAC,NS, including
weak voltage dependency, single-channel conductance, inactivation, and sensitivity to GsMTx-4
(635), it is tempting to think that Piezo may indeed contribute to cardiac MEC. Whether this is
through a direct involvement in cardiomyocyte function, or via non-myocyte mediated effects
(which would be in keeping with the low-level tissue homogenate mRNA data) remains to be
elucidated.
2. SACK
A whole cell SACK current (ISAC,K) in cardiac cells was first reported by Kim in 1992 (299).
SACK is outwardly rectifying, allowing K+ to move out of the cell more easily than in, has a
relatively large single-channel conductance (~100 pS), and inactivates in a time-dependent
manner. Single-channel ISAC,K recordings have been made in adult mammalian atrial (299) and
ventricular myocytes (597, 643). ISAC,K is thought to be carried primarily by 2 P-domain K+
channels (K2P) in the mammalian heart (367) (FIGURE 19).
One of the most studied K2P channel is K2P2.1 (TREK-1). TREK-1 is active over a range of
physiological Vm and activated by a number of stimuli, including intra- and extra-cellular pH,
temperature, fatty acids, anesthetics, and membrane deformation or stretch (46, 70, 236).
TREK-1 in the rat heart is arranged in longitudinal stripes on the surface of cardiomyocytes, a
pattern that could support directional stretch sensing (671). TREK-1 shows heterogeneous
expression in rat heart, increasing transmurally from sub-epi to sub-endocardium (574, 596).
This heterogeneity seems to correlate with transmural differences in mechanical sensitivity of
myocardium, where stretch causes the most pronounced AP shortening in the sub-endocardium
(203, 297). While TREK-1 mRNA expression has been reported in rat atria and ventricles (1,
367, 596, 607), it has not yet been identified in human heart (1, 211). Whole-cell currents
exhibiting the characteristics of TREK-1, including sensitivity to internal acidification, anesthetics,
and stretch, have been observed in atrial and ventricular myocytes of several mammalian
species including rat, mouse, and pig (203, 544). TREK-1 contributes to the “leak” K+
conductance in cardiomyocytes, aiding in repolarisation and diastolic stability (203, 463). During
stretch, increased K+ current could cause excessive, pro-arrhythmic AP shortening (297). TREK-
1 can be particularly pro-arrhythmic in patients with channel mutations. In a patient with right
ventricular outflow tract tachycardia, a heterozygous point mutation in the selectivity filter of
TREK-1 has been identified, which increased Na+ permeability and mechano-sensitivity of the
channel (145). TREK-2 shares functional similarity with TREK-1, is expressed in rat atria (367)
(59)
and appears active in chick embryonic atrial myocytes (695), yet little is known about its
relevance in the heart. The TWIK-related arachidonic acid-activated K+ channel (TRAAK) is a
TREK-1 homologue with similar biophysical properties and regulation (439). TRAAK is
expressed in human heart (367, 454) and might form the human TREK-1 homologue, although
its functional relevance has not yet been demonstrated.
There may also be a contribution to ISAC,K from big K+ (BK) channels, which are activated by
various stimuli and which therefore have been given multiple names (e.g., SAKCA, BKCa, SLO1,
MaxiK) (197). BK channels have a large conductance (100 - 300 pS), are present in many
cardiovascular cell types, including vascular smooth muscle and atrial and ventricular
cardiomyocytes (595). They are found in the sarcolemma, as well as in membranes of the
endoplasmic reticulum, the Golgi apparatus, and mitochondria (197). Stretch-activation of BK
channels was observed in membrane patches excised from cultured embryonic chick ventricular
myocytes (294). However, as BK channels are activated also by V m changes and by intra-
cellular Ca2+ (595), it has been suggested that their mechano-sensitivity may be indirect,
occurring secondary to stretch-induced changes in intra-cellular Ca2+ concentration caused by
ISAC,NS (256). In terms of their physiological role, BK channels have been suggested to contribute
to HR control (253) and to offer cardio-protection during ischaemia (674), along with IK,ATP.
3. Considerations for the Use of Pharmacological Probes

Pharmacological modulators are among the most effective tools available for investigating
molecular mechanisms of MEC (657). The principal agents for this are blockers and activators of
stretch-modulated sarcolemmal ion channels. The most widely used probes in the heart to date
have been two types of non-specific inhibitors of ISAC,NS: lanthanides and aminoglycosidic
antibiotics, which have been highly productive for experimental cell research in vitro. Caution is
needed, however, with their use, as limitations can lead to false-positive or -negative
conclusions.
Lanthanides, most commonly Gd3+, non-specifically reduce ISAC,NS at concentrations of 1 -
100 PM. Their mechanism of action is thought to be multi-site, involving open channel block of
SACNS (178) and screening of surface negative charges, which alters the properties of the lipid
bilayer (218). In isolated cardiac cells they have been shown to block whole cell ISAC,NS in atrial
(283, 698) and ventricular myocytes (261, 280, 281, 693), and to block the increase in sub-
sarcolemmal Ca2+ during cell prodding (556). However, in preparations where ISAC,NS cannot be
isolated from other currents, interpretations of results is difficult. Within the concentration range
used to inhibit ISAC,NS, Gd3+ is known to also inhibit ICa,L (IC50 = 1.4 PM) (332), INa (IC50 = 48 PM)
(60)
(350), IKr (although not IKs or IK1) (462), and INCX (IC50 = 20 - 30 PM, depending on Vm) (697).
Another important consideration is that fact that Gd3+ interacts with anions present in
physiological buffers (HCO3-, CO32-, HPO42-, and PO43-), forming precipitates that drastically
reduce its free concentration (addition of 1 PM to solutions containing standard amount so
phosphate and bicarbonate, results in a free concentration of less than 1 pM) (83). This can be a
problem even with solutions employing synthetic buffers, if continually exposed to room air (as
CO2 dissolves in water to form carbonic acid), and it will certainly alter available free Gd3+ in vivo.
Aminoglycosidic antibiotics are composed of two or more amino sugars joined to hexose by
glycosidic links; they are thought to act on SAC by partial occlusion of the channel pore (666).
The most commonly used compound is streptomycin. As for Gd3+, streptomycin is not specific
for SACNS and it has been shown to also block Ca2+ and K+ channels (39), as well as to reduce
Ca2+ transients and contraction (38). In cardiac cells, it inhibits ICa,L at relatively high
concentrations (IC50 = 1-2 mM), but not at concentrations that inhibit ISAC,NS (40 PM) (40),
demonstrating a superior demarcation between inhibition of SAC and other currents compared
to Gd3+, at least in vitro. ‘Pure’ streptomycin has a molecular weight of 581.6 g/mol, but the most
commonly available commercial form is streptomycin sulphate with a molecular weight of 1457.4
g/mol. This requires an extra level of attention, as streptomycin concentration may differ by a
factor of three if the wrong molecular weight is used for calculation (sadly, clear information
needed to replicate experiments is not always provided; (491)). A further consideration for the
use of streptomycin is its limited utility for use in tissue (if streptomycin was an effective SAC
blocker in vivo, it might not be suitable for prescription as an antibiotic). While it is an efficient
blocker of SACNS in isolated or cultured cardiac cells (40), it appears to have a limited efficacy in
native myocardium (119). This limitation results in the need for higher concentrations for effects
on stretch-induced responses (>200 PM) (161, 534) and a disparity of positive and negative
results, some of which may have been caused by lack of effect or off-target actions (492). It is
also important to note that streptomycin (and other aminoglycosidic antibiotics) are common
components of standard cell-culture media, so caution is needed when interpreting studies on
stretch effects in cultured cells, as background SACNS availability may be reduced in these
preparations. Thankfully, streptomycin seems to wash off reasonably well in vitro.
Among the more specific pharmacological agents for modulating SACNS activity, the best-
known is the 35 amino acid peptide toxin GsMTx-4 (64). In particular in its native (toxin-isolated)
form, it has been shown to be a highly-potent and specific inhibitor of ISAC,NS (578). GsMTx-4 has
been shown to effectively block the stretch-induced increase in AF inducibility at a concentration
(61)
of 170 nM (56) (2-3 orders of magnitude less than what is needed for similar effects by Gd3+ or
streptomycin (55)), while showing no effects on AP shape at concentrations up to 4 PM (532).
GsMTx-4 is an amphipath, having both hydrophobic and hydrophilic groups, and is thought to
act by insertion into the outer leaflet of the sarcolemma in the proximity of SAC NS, causing
deformation of the bilayer and preventing mechano-sensing by the channel (579). This
mechanism of action is not stereospecific or chiral, as both the D- and L-enantiomers of GsMTx-
4 inhibit ISAC,NS (579). GsMTx-4 cDNA has been sequenced and a cloned 34 amino acid version
of the wild-type toxin synthesised. In the hands of serval investigators, the synthesised version
has been found to require much higher concentrations to inhibit ISAC,NS, potentially indicative of
the difficulty in properly folding peptides ex vivo (453). It has been shown, though, that GsMTx-4
blocks the SACNS candidate proteins Piezo1 (22, 475) and TRPC6 (456, 566).
Specific activators (Yoda1 (334, 588) and Jedi (645)) and inhibitors (Dooku1 (171)) of
Piezo1 are also now available, offering a potentially powerful new tool for determining whether
Piezo1 is indeed a key player in cardiac MEC. Similarly, a number of activators and inhibitors of
various TRP channels have been reported (174), which will be useful in probing the role of those
ion channels in tissue- and organ-level MEC.
Another interesting class of pharmacological probes for investigating sub-cellular mediators
of MEC responses are those that target the cytoskeleton (657), although results have been
inconsistent. Cytochalasin D, which prevents actin polymerization, has been shown to cause an
increase in SACNS in atrial myocytes (300), but similar results were not seen by others (698).
Conversely, application of cytochalasin (280) and colchicine (which prevents microtubule
polymerisation) (261) causes a reduction in SACNS in ventricular cells. On the other hand, the
microtubule stabiliser paclitaxel has been shown to cause both an increase in the susceptibility
to stretch-induced arrhythmias in rabbit isolated hearts (460) and a decrease during acute
ischaemia in rat isolated hearts (93), while inhibiting the stretch-induced increase in AF
inducibility (673). Colchicine, however, had no effect (151, 460). Thus, overall there is no
general agreement regarding the role of the cytoskeleton in MEC effects. This lack of consensus
may in part be due to the fact that, as with other pharmacological agents discussed above, actin
and tubulin modulators are not specific to the cytoskeleton, and the degree to which they
actually disrupt the cytoskeleton is rarely monitored (79). Also, the individual molecular
components of the cytoskeleton may have their own, independent effects on intracellular Ca2+
handling and ion channel function (201, 202, 298), although this is debated (78, 80, 461).
4. Summary
(62)
While the electrophysiological consequences of stretching the heart have been well
characterised, the molecular mechanisms involved are still unclear. In particular, the specific
identities of cardiac SACNS and SACK in different cardiac cell types are largely unknown. Based
on the biophysical characteristics of ISAC,NS and ISAC,K in cardiac cells, there are numerous
candidates, including Piezo and various TRP channels (for SACNS), and K2P channels such as
TREK-1 and BK channels (for SACK). While pharmacological tools have been helpful in
narrowing down ion channel contributions, agents have been limited in their specificity and
applicability to whole heart and organisms, hindering progress; more reliable probes are
emerging, and they will drive further insight into sub-cellular mechanisms of MEC.

x The molecular mechanism(s) responsible for the chronotropic response to SAN stretch are
still unconfirmed, including the role of mechano-sensitivity of ion fluxes in SAN automaticity;
targeted genetic and pharmacological studies are needed to address this fundamental
aspect of cardiac function.
x It remains unclear how exactly the chronotropic response of the SAN to stretch differs
between animal species; this requires comparative studies utilising innovative approaches to
determine underlying causes.
x Novel, more specific pharmacological agonists and antagonists are becoming available,
which may lead to transformative insight into sarcolemmal and non-sarcolemmal SAC
effects in normal homeostasis, pathogenesis, and therapy.
IV. INTEGRATIVE COMPUTATIONAL MODELS OF MEC
A. Single Cell
1. Consequences of SAC Activation

In early computational studies of MEC, SAC currents were approximated either by
simulation of currents with an appropriate Erev through ohmic conductances – i.e., as structures
conducting charge not matter (ions) (315) – or by an increase in background Na+ and K+
conductances (191). Since then, more detailed models of SAC have been developed, which
include activation through biophysically-relevant parameters, allowing for simulation of stretch
effects in cells, tissue, and whole hearts. In these formulations, SAC-activation is scaled by
either: i) stretch (or strain) (227, 312, 693); ii) stretch (or strain) rate (274); or iii) tension (312),
reflecting the lack of agreement on which biophysical input determines SAC activity. While these
(63)
models have largely been successful in replicating known MEC responses, it is worth noting that
even when they consider ion movements, they account for effects on bulk cytosolic ion
concentrations only. If a subset of effectors interacted with physiologically-relevant sub-cellular
compartments, such as sub-membrane spaces like the dyadic cleft, or with SR and
mitochondrial Ca2+ stores, their influence on cardiac electrophysiology may not be captured by
current models. This is true, also, for close proximity effects of mechano-sensors, such as the
putative secondary activation of BK channels in response to Ca 2+ fluxes through co-localised
SAC (256).
SAC incorporated into cardiac electrophysiology models have been used extensively in
single cell simulation studies that recapitulate experimental data (307), occasionally in direct
iteration with experimental studies. For instance, computational simulations correctly suggested
that block of SAC with Gd3+ does not reduce the stretch-induced increase in resting Ca2+ in
single ventricular myocytes, due to additional effects of Gd3+ on the delayed rectifier K+ current
and Ca2+ extrusion via INCX (235). Similarly, stretch effects on the delayed rectifier K+ current,
along with a transmurally varying ISAC,K were shown to plausibly explain transmural differences in
AP changes with stretch (227). Differences in experimentally reported stretch effects (including
triggering of premature excitation and changes in AP shape and duration) have also been
explained by computational modelling, which suggested that the various responses relate to
different sub-cellular mechanisms (for instance SAC activation versus changes in the Ca2+
affinity of TnC versus modulation of SR Ca2+ handling) (312). These effects have been shown in
cellular models to be further exasperated in conditions of Ca 2+ overload, such as occurs with
decreased activity of the Na+-K+ pump (581).
The source of the experimentally established importance of stretch timing for cell-level
responses has also been elucidated with computational simulations. That transient stretch,
applied at the end of an AP or during diastole, causes depolarisation and premature excitation,
while stretch during the AP plateau causes early repolarisation (and during later repolarisation
has little effect), can be explained by the interrelation of SACNS Erev and cell Vm during those
phases of the AP (312, 520, 688). Simulations have also demonstrated that this relation can
explain the increase in beating rate of sinoatrial node cells with sustained stretch in rabbit (120),
and that this stretch response may be enhanced by effects of SAC NS activation in
electrotonically-coupled fibroblasts (315, 317).
Not only does MEC result in premature excitation and enhanced automaticity, it may also
modulate pro-arrhythmic electrical alternans. Computational simulations have shown that
(64)
increasing ISAC,NS suppresses electro-mechanically concordant alternans (positive Vm-Ca2+
coupling or voltage-driven alternans), while it promotes electro-mechanically discordant
alternans (negative Vm-Ca2+ coupling or Ca2+-driven alternans) (187). In addition, the interaction
of MEC with Mayer waves, involving oscillations in sympathetic nervous system activity and
changes in ventricular preload, enhance this alternans promoting effect, which can ultimately
result in premature excitation (484).
2. Consequences of Altered Intra-Cellular Ca2+ Handling

The increase in diastolic Ca2+ concentration, SR Ca2+ release, and TnC-Ca2+ affinity seen
with stretch have all been reproduced in computational models. A stretch-induced increase in
diastolic Ca2+ levels has been modelled on the basis of secondary effects of an increase in Na +
and K+ background conductances on INCX (191), highlighting the close interrelation of stretch
effects on SAC and Ca2+ handling, the importance of identifying secondary effects of mechanical
perturbations, and the relevance of further enhancing the 3D structural detail on sub-cellular
compartmentalisation of cardiac cells. The effect of stretch on SR Ca2+ release has been
simulated by including, in a formulation of RyR Ca2+ flux, an exponential dependence on
sarcomere length or tension (although the effect this has on cardiac electrophysiology was not
investigated) (312). This has been extended to specifically simulate the stretch-induced increase
in Ca2+ spark rate, linked to mechanically-stimulated ROS production, by developing an RyR
model that includes a ROS-dependent mode switch (357). This model has also not yet been
used to investigate the potential role this increase in Ca2+ spark rate may have on cardiac
electrophysiology, but it has been used to make relevant predictions. Simulations using this
model have demonstrated that stretch during diastole is expected to cause a local increase in
ROS near the RyR complex, which increases the magnitude of the subsequent Ca 2+ transient,
potentially helping to match contractile force to haemodynamic load (290) and coordinating
contraction across the heart (92). Further, it has been suggested that when the chemical
reducing capacity of cells is decreased, such as in ischaemia, mechanically-stimulated ROS
production contributes to global oxidative stress and enhances SR Ca 2+ leak, which may
increase the possibility of stretch-induced arrhythmias. Computational modelling has also
suggested that the above effects may be microtubule dependent (275). These computational
predictions, by and large, remain to be experimentally confirmed.
Stretch-induced changes in the Ca2+affinity of TnC have been studied extensively, using
computational simulations to understand effects on cardiac electrical activity (617). In the
context of MEC, simulations have shown that with constant stretch, changes in TnC-Ca2+ affinity
(65)
would be expected to delay repolarisation, due to elevated Ca 2+-buffering by TnC causing an
increase in total SR Ca2+ release and a delay in re-uptake that leads to an increase and
prolongation of INCX (312, 429, 598). These stretch-induced AP changes differ from those
predicted to arise from SAC activation, which, as described above, tends to cause AP
shortening or cross-over of the repolarisation curve. Differences in the extent to which stretch
effects are mediated by SAC or Ca2+ handling may therefore partly account for discrepancies in
experimental findings of stretch effects on APD. This could be the case due to differences in
timing or magnitude of applied stretch, differing (patho-)physiological states, or unintended
experimental influences (for example the ‘clamping’ of intra-cellular ion concentrations in whole-
cell patch, as opposed to sharp electrode recordings). In fact, with stretch applied during the late
plateau phase, TnC–Ca2+ binding (in contrast to SACNS-activation) shortens the AP (312, 611),
as the increase in Ca2+ buffering occurs at a time when SR Ca2+ release has terminated, thus
reducing cytosolic Ca2+ concentration and INCX (312, 429, 598). The effects of mechanically-
induced changes in TnC-Ca2+ affinity are also influenced by the mechanical state of the cell.
Computational simulations suggest, for example, that increased cellular viscosity results in the
occurrence of premature excitation due to an increase in intra-cellular Ca2+ levels, to the point of
triggering spontaneous Ca2+ releases from the SR (289), and that Ca2+ overload and the
ensuring incidence of arrhythmias can be enhanced by a decrease in the afterload imposed
upon auxotonically contracting cells, or a decrease in preload for isometrically contracting
cardiomyocytes (288). Again, many of the modelling-based hypotheses in this context still await
experimental validation.
3. Summary
Single cell computational simulations have been successfully used to reproduce observed
MEC effects. This has helped in integrating and interpreting experimental data to elucidate
underlying mechanisms, including the role of SACNS and SACK and of changes in intracellular
Ca2+ dynamics or ROS, the importance stretch timing, non-specific effects of pharmacological
agents, and the potential relevance of non-myocytes. That said, modelling of the effects of MEC
at the cell level remains limited by a lack of fundamental information about characteristics of
SAC function, such as mechanistic links between mechanical stimuli and channel opening,
including their dependence on cytoskeletal elements and membrane properties such tension
and curvature, as well as three-dimensional distribution in highly structured cardiac cells,
necessitating assumptions for model parameterisation. This is, of course, is a reflection of limits
in experimental insight. Technological developments, such as membrane (114) and protein
(66)
tension (125, 333, 681) sensors, their application to cardiac research, and improved 3D nano-
scale reconstructions of cells (67, 523, 686), are needed to obtain and integrate the required
information to further develop our conceptual and computational models.
B. Multi-cellular
1. Physiological Mechanical Activity and Electrical Instability

While single cell simulations are useful for recapitulating and explaining known cell-level
MEC effects, tissue and whole organ simulations are necessary for exploring mechanically-
induced changes in heart rhythm that involve more integrative mechanisms. This aids in the
understanding of causally-linked effects involving complex interactions between factors such as
tissue composition and structure, electrophysiological and mechanical heterogeneity, and
haemodynamics and organ geometry, while ideally allowing for the generation of novel
experimentally-testable hypothesis and predictions (493, 616).
2D computational simulations of MEC have been used to investigate the effects of
myocardial deformation caused by cardiac contraction. Theoretical studies have shown that
contraction-induced deformation affects AP conduction, due to effects of tissue inertia (126) and
stress-assisted diffusion (102, 369), which under pathological conditions can promote
vulnerability to re-entry (especially for curved wave-fronts) (314, 654). This effect can lead to
spiral wave breakup (457) and reduces the dispersion of repolarisation between adjacent
regions of interacting muscle (633). In addition, as in single cell simulations, stretch may
influence electrical alternans, as computational simulations have demonstrated that SAC NS can
cause a transition from concordant (in-phase) to discordant (out of-phase) alternations due to a
change in the slope of the conduction velocity restitution curve (503), while spatially distributed
stretch can instead suppress alternans (684).
3D computational simulations have also been useful for investigating experimentally
intractable questions. For instance, 3D simulations have allowed examination of the importance
of myocardial mechanics in MEC effects, suggesting that during ventricular loading AP changes
are mediated by stretch in both the longitudinal and transverse myocyte axes (632), and that
changes in conduction velocity are driven by reduced intercellular resistance and a concurrent
increase of effective membrane capacitance (142, 403), for example due to caveolar membrane
integration. The stability of sustained transmural scroll waves – whose 3D organisational centres
are only just becoming experimentally tractable (112) – has been explored during stretch using
biophysically-detailed 3D electro-mechanical models of the ventricles. These demonstrated that
(67)
MEC can cause deterioration of otherwise stable waves into turbulent patterns (296). In
particular, wave stability depends on the Erev and conductance of SAC: an Erev of -60 mV
reduces scroll wave breakup for all values of conductance by heterogeneously flattening the
APD restitution curve, while an Erev of -20 mV partially prevents scroll wave breakup at low
conductance values by heterogeneously flattening the conduction velocity restitution curve (but
not when conductance is increased, as INa inactivation in regions of large stretch leads to
conduction block, counteracting the increase in scroll wave stability (243)). The putative impact
of pathological states has also been investigated in a 3D electro-mechanical model of the
ventricles, suggesting an increased importance of MEC effects in failing hearts (9).
2. Triggering and Sustenance of Arrhythmias

By their very nature, re-entrant cardiac arrhythmias require multiple electrically connected
cells. A prime example of the utility of 2D and 3D computational modelling for the prediction of
mechanisms underlying mechanically-induced re-entry is Commotio cordis. Simulating the
application of a mechanical stimulus to a 2D sheet of ventricular myocytes by activating SAC NS
in a sub-population of cells at different timings after the preceding ‘normal’ wave of excitation
(and therefore with differing overlap on the trailing wave of repolarisation) demonstrated that
SACNS causes depolarisation in cells that have regained excitability, while it accelerates
repolarisation in cells at a Vm more positive than the Erev of SACNS. Mechanical stimuli applied
too early (i.e., when most of the tissue is still refractory) do not cause an excitatory response,
while stimuli timed to occur well after a previous excitation, when most of the tissue is
repolarised, trigger a single premature excitation. If, and only if, a mechanical stimulus overlaps
the trailing wave of repolarisation, it may provide both a trigger (premature excitation) and
sustaining mechanism (increased electrophysiological heterogeneity, including a functional block
line at the intersection of the new and preceding excitation) for the development of sustained
‘figure-of-eight’ re-entry (194) (FIGURE 5, C). This computationally-generated ‘overlap
hypothesis’ was confirmed in a 3D whole ventricle model by simulation of an epicardial
mechanical stimulation, which added confidence to the original prediction and highlighted the
fact that mechanical stimulus location (relative to the ventricular surface) is a variable that may
affect the absolute timing (though not the duration) of the vulnerable window for VF induction
(355). The modelling-based prediction that the vulnerable window for precordial impact-induced
VF exists in time and space gave rise to a subsequent targeted investigation, which
experimentally confirmed this hypothesis ten years later (492) (FIGURE 6, B).
(68)
A similar computational approach, using a combination of electrical trigger and subsequent
mechanical stimulus in a 2D sheet of ventricular myocytes, has been utilised to model the
stretch of mechanically weakened ventricular regions that occur in acute regional ischaemia. In
this case, when a mechanically-induced wave of excitation is initiated perpendicularly to an initial
excitation after it has propagated through almost the entire sheet of tissue, the mechanically-
induced excitation interferes with the trailing end of the original excitation, causing formation of a
`spiral' re-entrant wave (similar to the arrhythmic effect of a critically-timed S1-S2 stimulus)
(517). Alternatively, when a centrally located area of ischaemic tissue is simulated, the wave of
sinus excitation is slowed in the ischaemic area, causing the formation of two wave fronts that
circumvent the ischaemic region. In this case, subsequent contraction of the surrounding
myocardium that distends the ischaemic tissue (paradoxical segment lengthening) may lead to
SACNS activation and a mechanically-induced ectopic beat (314). These effects of acute
ischaemia may in fact be increased in diseased hearts where fibrosis is present, through
mechano-sensitive fibroblasts, as computational simulations suggest that relatively small
fibroblast-rich tissue and low levels of fibroblast-myocyte coupling are sufficient to give rise to
stretch-induced excitation in ventricular muscle (317, 694). As for studies of Commotio cordis,
the computationally-derived concept that stretch of the ischaemic border zone during acute
regional ischaemia may be responsible for mechanically-induced excitation and re-entry has
been supported by 3D computational modelling, which further showed that a combination of
MEC and ischaemic effects is necessary for the induction of ventricular tachyarrhythmias: when
SACNS are omitted from the model, ectopic excitation and block of conduction do not occur,
while when ischaemia-induced electrophysiological changes are absent, the mechanically-
induced ectopy and conduction effects do not result in re-entry (274) (FIGURE 7, C).
Computational modelling further suggests that an increase in intra-ventricular volume during
acute ischaemia can result in ectopic excitation from the more compliant ischaemic region (314),
which has since been shown experimentally (459).
3. Modifying and Terminating Arrhythmias

In the case of sustained arrhythmias, MEC can affect re-entry dynamics. 2D computational
simulations involving a fully-coupled electro-mechanical model have been used to investigate
mechanisms underlying the increased prevalence of VF in mechanically compromised heart.
These studies suggest that sustained stretch shortens APD and flattens the APD restitution
curve. Stretch applied specifically near an excitation wave-front, however, creates a distribution
of stretch during spiral re-entry that is characterised by a large gradient at the core of the spiral
(69)
wave, which then prolongs APD and creates an extended refractory region at the wave-end.
This localised effect facilitates wave breakup and the occurrence of VF (231). In terms of atrial
arrhythmias, computational simulations have suggested that MEC affects spiral wave
frequencies, trajectories, and stability in AF (69), acting as a major source of cycle length
variability during atrial flutter through effects of both respiration (as with respiratory sinus
arrhythmia) and ventricular contraction, as atrial flutter interval (time between consecutive atrial
activations) becomes phase-locked to ventricular contraction during periodic ventricular pacing
(388).
The mechanisms by which mechanical stimulation may instead terminate established re-
entry have also been investigated with computational modelling of precordial thump. When a
mechanical stimulus is applied to a simulated 2D sheet of tissue in which sustained re-entry is
occurring, activation of SACNS causes depolarisation of excitable tissue and, if stretch is large
enough, initiation of excitation in these regions. If the proportion of excitable gaps in the
simulated tissue in which stretch eradicates the excitable gap is large enough, this will terminate
the re-entrant wave (310). In cases of established VF however, the myocardium will often be in
an ischaemic state, due to a lack of coronary blood flow, resulting in co-activation of stretch-
modulated IK,ATP. Computational modelling suggests that the combined activation of SACK and
SACNS during mechanical stimulation will result in a more negative Erev of the overall stretch-
induced current, compared to control conditions (-35 mV versus -10 mV). This reduces excitable
gap depolarisation, prevents formation of ectopic foci, and shortens APD (310), thus explaining
one possible mechanism underlying the reduced efficacy of precordial thump in severely hypoxic
conditions (675). MEC may also play a role in reducing the efficacy of electrical defibrillation in
the arrested, volume-overloaded heart. 2D computational simulations have demonstrated that
SACNS activation in this setting results in a more positive Vm at the end of the effective refractory
period, a reduction in conduction velocity of shock-induced break excitations, and an increase in
the complexity of post-shock VF patterns. This leads to a flattening of the defibrillation dose-
response curve and an increase in the defibrillation threshold (210, 615).
Again, as for the examples of computational modelling of arrhythmia triggering above, for
the case of sustained arrhythmia termination by precordial thump, 3D results are similar to the
2D case, demonstrating that in the whole ventricle mechanical stimulation can obliterate
excitable gaps, thus terminating the arrhythmia, and that the efficacy of this intervention is
reduced by ischaemia (356). Similarly, the reduced efficacy of electrical defibrillation due to
(70)
SACNS activation shown with 2D modelling has been replicated in a 3D electro-mechanical
model of the acutely volume overloaded ventricle (354).
3. Summary
Multi-cellular computational models have been an effective means for quantitative
theoretical exploration of integrated (patho-)physiological MEC responses, especially
mechanisms of mechanically-induced and -terminated tachyarrhythmias, such as in the setting
of Commotio cordis, acute regional ischaemia, and precordial thump. These simulations have
predicted the critical importance of the relation of mechanical stimulation to underlying electrical
activity for (anti-)arrhythmic outcomes, generating novel hypotheses that have since been
experimentally verified. Moving forward, continually increasing computational power, combined
with advances in experimental insight, will make 2D and 3D simulations an increasingly powerful
tool for studies of MEC.

x Computational models continue to increase in complexity and sophistication, but they often
do not include MEC; this should become standard practice for relevant studies of cardiac
structure and function.
x Much of the fundamental information needed for the effective development and
parameterisation of computational models that include MEC is still lacking; nonetheless,
simulations of known MEC effects have be informative in identifying key knowledge gaps.
x Experimental and computational research should be conducted in close collaboration, using
computational simulations to interpret and integrate experimental data, to generate novel
experimentally testable hypotheses and predictions, and to guide experimental
investigations that test these theories and suggestions, providing novel input data for
computational model refinement.
V. SUMMARY AND CONCLUSIONS

In this review, we hope first and foremost to have conveyed the critical role of cardiac
mechano-sensitivity in the auto-regulation of the heart’s electro-mechanical activity, and the vital
importance of MEC in the acute adaptation of cardiac electrical behaviour to changes in the
mechanical environment. The feedback from mechanics to electrics is essential for the
maintenance of normal HR and rhythm. In cardiac pathologies, however, MEC can contribute to
the initiation and maintenance of arrhythmias, both in acute and chronic disease states. Finally,
(71)
and very much like electrical current delivery to the heart, MEC can have not only
arrhythmogenic effects, but also contribute to heart rhythm restoration.
Almost all clinical and experimental observations of MEC in the heart can be explained
quantitatively by invoking no other mechanism besides SACNS in cardiac myocytes. However,
one should be wary of the plausibility trap: simply because one mechanism may explain a
response does not mean that said mechanism is the major driver of a response, or even
involved at all. The mechanical modulation of other ion channels, as well as of intra-cellular Ca2+
handling and other signalling mechanisms (e.g., ROS) matter for MEC in healthy and diseased
myocardium. In addition, mechano-sensitive non-myocytes in the heart may play important roles
in MEC effects. This complexity, along with our lack of understanding of the role and interplay of
many molecular sensors and information pathways involved in MEC, leaves much to be
discovered.
MEC studies are hampered by several experimental limitations, such as our inability to
measure tension inside cardiac tissue, and by the lack of selective pharmacological probes that
can block or activate individual relevant players in native tissue, ideally in a cell-type specific
manner. This restricts our ability to link discrete islands of insight at molecular, cellular, tissue,
organ, and organism levels, and to project between species. At times, the setting reminds one of
the famous ‘street-light effect’ (284), where one looks for missing items not where they are most
likely to be found, but where it is most convenient to search for them. That said, bridges can be
built between experimentally-intractable questions and theoretical explanations using
computational models to quantitatively assess the plausibility of interpretations and novel
hypotheses, and to design new experimental research.
Finally, even based on our current partial understanding of mechanisms and importance of
cardiac MEC in health in disease, it is clear that exciting potential for therapeutic interventions
exists, for instance in the use of mechanical stimulation for heart rhythm management, in
controlling mechanical modifiers of electro-mechanical structure and function, and in
pharmacological targeting of sub-cellular players as novel means for anti-arrhythmic therapies.
Overall, the current state of cardiac MEC research warrants further investigation into acute
mechanical effects on HR and rhythm, to help us come closer to a comprehensive
understanding of the integrated electro-mechanical crosstalk that makes the heart tick in health
and disease.
(72)
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TITLE

Mechanical Induction and Termination of Arrhythmias

5. Transcutaneous mechanically-induced excitation, whether by extracorporeal or epicardial

Key Specialised Terminology

A potassium channel that is activated both a

Bradycardia Slow heart rate.

Intracellular calcium cycling contribution to sinoatrial

Mechanical “agitation of the heart” [Latin], usually by

Membrane potential at which there is no net flow

Chemical element that is a non-specific blocker of

Peptide isolated from the venom of the Grammostola

Hyperpolarisation-activated depolarising ‘inward’

Condition in which repolarisation of (part of) the

Most negative membrane potential reached by

Most positive membrane potential reached by

System of mechano-sensitive mechanisms that

A single fist impact, generally applied to the left of the

Physiological fluctuation in heart rate that is

A region of tissue in the right atrium that contains the

Automaticity-providing shift in membrane potential in

Automaticity-providing shift in membrane potential in

Ion channel which is gated by a mechanical stimulus

Ion channel whose activity is altered by a mechanical

Tachyarrhythmia Abnormally rapid heart rhythm.

Ventricular fibrillation (VF) Rapid irregular excitation of the ventricles.

System of sarcolemma-bound ion flux mechanisms

A narrow period during which the heart is particularly

A. MEC and the Mechano-electric Regulatory Loop

B. Brief History of MEC Research

A. Modulation of Heart Rate

1. Mechanisms of SAN Automaticity

When considering mechanisms that drive pacemaker activity, it is important to remember

B. Transient Effects on Whole Heart Electrical Activity

Figure 4. Mechanically-induced excitation upon diastolic stimulation of rabbit isolated whole

C. Induction of Sustained Arrhythmias

1. Tissue-Level Mechanisms of Stretch-Induced Arrhythmias

Figure 6. Mechanically-induced ventricular fibrillation in the setting of Commotio cordis. A:

3. Acute Regional Ischaemia

Figure 7. Mechanically-induced arrhythmias during acute regional ischaemia. A: Activation map of

4. Mitral Valve Prolapse

5. Chronic Pathophysiological States

Figure 8. Temporary termination of ventricular tachyarrhythmia with acute haemodynamic

Similarly, increased intraventricular preload may help in sustaining established ventricular

2. Bradycardia and Asystole

Based on the potential of precordial mechanical stimulation as a rapid and non-invasive

While precordial percussion is an immediately accessible form of extracorporeal pacing that

3. Advantages and Limitations of MEC-based Anti-Arrhythmic Interventions

III. MOLECULAR MECHANISMS OF MEC

1. Mechano-Sensitivity of ‘Mechanical Oscillator’ Components

2. Mechano-Sensitivity of Vm Oscillator Components

3. Mechano-Sensitivity of Ca2+ Oscillator Components

3. Mechano-Sensitivity of Intra-Cellular Ca2+ Handling

D. Molecular Candidates for SAC

3. Considerations for the Use of Pharmacological Probes

C. Knowledge Gaps and Future Directions

IV. INTEGRATIVE COMPUTATIONAL MODELS OF MEC

1. Consequences of SAC Activation

2. Consequences of Altered Intra-Cellular Ca2+ Handling

1. Physiological Mechanical Activity and Electrical Instability