Title: Mechano-electrical feedback in the clinical setting: Current perspectives.
M. Orini
1,2
, A. Nanda
3
, M. Yates
2
, C. Di Salvo
2
, N. Roberts
2
, P.D. Lambiase
1,2
, P. Taggart
1
1: Institute of Cardiovascular Science, University College London, London, UK
2: Barts Heart Centre, St Bartholomew’s Hospital, London, UK
3: Department of Medical Sciences, University of Oxford, UK
Corresponding author: Dr M. Orini, m.orini@ucl.ac.uk, UCL Institute of Cardiovascular
Science, Gower Street, London WC1E 6BT, UK
Abstract
Mechano-electric feedback (MEF) is an established mechanism whereby myocardial
deformation causes changes in cardiac electrophysiological parameters. Extensive animal,
laboratory and theoretical investigation has demonstrated that abnormal patterns of cardiac
strain can induce alteration of electrical excitation and recovery through MEF, which can
potentially contribute to the establishment of dangerous arrhythmias. However, the clinical
relevance of MEF in patients with heart disease remains to be established.
This paper reviews up-to date experimental evidence describing the response to different
types of mechanical stimuli in the intact human heart with the support of new data collected
during cardiac surgery. It discusses modulatory effects of MEF that may contribute to increase
the vulnerability to arrhythmia and describes MEF interaction with clinical conditions where
mechanically induced changes in cardiac electrophysiology are likely to be more relevant.
Finally, directions for future studies, including the need for in-vivo human data providing
simultaneous assessment of the distribution of structural, functional and electrophysiological
parameters at the regional level, are identified.
Keyword: Mechano-electrical coupling, cardiac stretch, arrhythmia mechanisms, in-vivo
human electrophysiology, cardiac mapping.
1. Introduction
The electrical activity and the mechanical function of the human heart are intertwined. In
normal conditions, electrical activation and repolarization ensure optimal cardiac contraction
and relaxation. This electro-mechanical interaction represents the direct pathway of the
mechano-electric coupling. However, this is not the only pathway of interaction. The mechano-
electric feedback (MEF), a mechanism whereby mechanical deformation of the heart induces
changes in the cardiac electrophysiology, has been studied for more than fifty years (Desk
and Williams, 1982; Franz, 1996; Kohl et al., 1999; Kohl and Ravens, 2003; Quinn et al.,
2014). However, the current understanding of MEF mechanisms derives almost entirely from
animal (Calkins et al., 1991; Chen et al., 2004; Franz et al., 1992; Zabel et al., 1996a), in-vitro
(Seo et al., 2010) and theoretical (Hu et al., 2013; Kuijpers et al., 2014; Quinn and Kohl, 2016)
studies. These suggest that MEF may be an important factor in arrhythmogenesis and
modulates cardiac risk (Quinn, 2014; Ravens, 2003). However, extrapolation to the in-vivo
human heart is not straightforward because important differences exist in-vitro and in-vivo as
well as between animal and human ventricular electrophysiology (O’Hara and Rudy, 2012).
The precise physiological role of MEF is undetermined, but a recent animal study has
suggested that MEF may also be important in the normal intact heart by synchronizing
ventricular repolarization, therefore reducing tissue susceptibility to arrhythmia (Opthof et al.,
2015). Extensive laboratory work has established that MEF can exacerbate arrhythmogenic
substrate irritability and induce potential arrhythmic triggers, especially in the diseased heart
(Franz, 1996). However, its pro-arrhythmic potential in the human heart and its precise clinical
relevance is still to be determined (Babuty and Lab, 2001; Taggart, 1996; Taggart and Lab,
2008; Taggart and Sutton, 1999).
In patients, mechanical deformation of the cardiac tissue can be due to structural and
functional abnormalities that cause an abnormal level of cardiac stretch, which can be acute
or chronic. Cardiac stretch modulates electrophysiological dynamics by interacting with
stretch-activated channels (Peyronnet et al., 2016) and calcium cycling (Calaghan et al., 2003;
Calaghan and White, 1999). Non-specific cation stretch-activated channels are responsible
for premature ventricular contractions, while both stretch-activated channels and calcium
dynamics cause MEF-mediated changes in repolarization, and shortening and lengthening of
local action potential duration (APD) depends on the precise modality and timing of cardiac
stretch (Zabel et al., 1996a).
In this paper, we review recent evidence of mechanically induced changes in human cardiac
electrophysiology focusing on recently published studies and using new unpublished data, we
discuss clinical implications and we suggest direction for future studies.
2. Mechano-electric contribution to arrhythmia mechanisms
Soon after been first described, the potential pathological effects of MEF became of interest.
It was observed that acute stretch of isolated animal hearts using left-ventricular balloons,
which mimics an increase in cardiac volume, causes premature ventricular excitation,
increases the propensity for arrhythmias (Stacy et al., 1992) that can transform into runs of
VT if the stretch is prolonged (Hansen et al., 1990). Although the changes in ventricular loading
simulated in these studies are not likely to occur in-vivo, this level of stretch may occur on a
regional basis in heart disease. The most direct evidence of the existence of a MEF pathway
to arrhythmia is commotio cordis, triggering of ventricular fibrillation by a mechanical impact
to the precordial region (Kohl et al., 2001, 1999). On the other hand, precordial thump can
terminate ventricular tachycardia (Barrett, 1971; Pennington et al., 1970). The link between
cardiac mechanical deformation and abnormal cardiac rhythm is not limited to traumatic
events. Several clinical observations suggest that long-term mechano-electric interactions
may also play an important role in arrhythmogenesis. For example, ventricular wall motion
abnormalities are one of the strongest clinical predictors of arrhythmic sudden death in
patients with heart disease (Cicala et al., 2007), and that reverse ventricular mechanical
remodelling is associated with reversal of electrical remodelling and a lower rate of arrhythmia
(Lellouche et al., 2011).
The establishment of dangerous ventricular arrhythmia requires a trigger, i.e. a premature
beat, and a substrate (Coumel et al., 1987; Janse, 1992; Mines, 1914; Weiss et al., 2015).
Established pro-arrhythmic substrates include spatially heterogeneous repolarization (Kuo et
al., 1983), temporal repolarization instabilities such as repolarization alternans (Pastore et al.,
1999; Zhou et al., 2016) and short term beat-to-beat repolarization variability (Baumert et al.,
2016; Thomsen et al., 2006), repolarization and conduction response to changes in heart rate
(Cao et al., 1999) and disturbances in the electrical conduction such as conduction slowing
(de Bakker et al., 1993; Stevenson et al., 1993) and late potentials (Breithardt et al., 1991).
An interaction between refractoriness and conduction dynamics rather than a single
mechanism acting in isolation determines the susceptibility to re-entry (Allessie et al., 1977;
Coronel et al., 2009). In fact, re-entry requires that a wave-front of excitation finds electrically
excitable tissue always ahead of it, and its likelihood depends on both conduction and
repolarization dynamics. A paradigm has emerged from laboratory and theoretical studies that
suggests that MEF provides a pathway to translate abnormal mechanical heterogeneity into
potentially arrhythmogenic abnormal electrophysiological inhomogeneity (Kuijpers et al.,
2014; Solovyova et al., 2016, 2014). Structural abnormalities such as fibrosis are relevant in
this context because they can potentially provide the conditions for establishing slow
conduction (through tissue uncoupling) and short repolarization (through MEF secondary to
abnormal contraction), therefore increasing vulnerability to re-entry (Mines, 1914). For
instance, MEF may potentially contribute to the interplay between premature activation,
conduction slowing and repolarization time that is critical for the establishment of re-entrant
tachycardia (Child et al., 2015; Coronel et al., 2009).
The hypothesis that MEF may favour the establishment of ventricular arrhythmia by increasing
spatial inhomogeneity of repolarization, or shortening repolarization and slowing conduction
at critical sites in not new (Reiter, 1996) and has been supported by laboratory studies (Seo
et al., 2010) but its clinical relevance has yet to be demonstrated in patients.
In conclusion, MEF may facilitate arrhythmia by simultaneously inducing ectopics and
promoting arrhythmogenic substrates (Quinn, 2014), especially when coupled with structural
or functional abnormalities, such as fibrosis, myocardial infarction and asynchronous
contraction.
In the following, we describe electrophysiological response to cardiac deformation that may
results in increased vulnerability to arrhythmia.
3. Experimental evidence describing cardiac human response
to different stimuli
Elegant animal and laboratory studies have demonstrated that the electrophysiological
response to cardiac stretch is complex and determined by its magnitude, the velocity of the
deformation, and the timing at which the stimulus is applied with respect to the action potential
dynamics (Franz et al., 1992; Opthof et al., 2015; Seo et al., 2010; Zabel et al., 1996a).
Experiments have shown that abrupt stretch during diastole can produce delayed
afterdepolarizations (Franz et al., 1992; Seo et al., 2010), stretch applied during the early
phase of repolarization causes an acceleration of the repolarization process and APD
shortening, while stretch applied during the later phase of repolarization causes APD
prolongation (Zabel et al., 1996a). In general, physiological ventricular loading provokes small
APD shortening (H Calkins et al., 1989), whereas acute ventricular overload has been shown
to increase dispersion of repolarization and induce arrhythmia in the lamb right ventricle (Chen
et al., 2004), and to facilitate arrhythmia induction in the rabbit heart (Jalal et al., 1992; Reiter
et al., 1997) and in a canine myocardial infarction model (H. Calkins et al., 1989).
The interaction between myocardial deformation and conduction velocity is controversial and
different studies have shown mixed results (McNary et al., 2008). Some animal (Dhein et al.,
2014; Quintanilla et al., 2015; Sung et al., 2003; Zabel et al., 1996b) and computational