Mechanoelectric Feedback Research Articles

SCARY ECG IN TAKOTSUBO CARDIOMYOPATHY

Abstract Takotsubo cardiomyopathy (TTC) is characterized by a transient ventricular wall motion abnormality and shares common features with acute coronary syndrome (ACS) with a wide spectrum of triggers, such as both emotional or physical, activating common toxic catecholamines–mediated pathways. TTC might be associated with severe clinical complications. We report a case of a 74–year female patient with circulatory shock with mixed phenotype, distributive due to sepsis and cardiogenic due to TTC. The patient presented to the emergency department with severe hypotension, pathological qSOFA score and clinical and laboratory findings consistent with severe sepsis. ECG showed diffuse lambda ST–segment elevation, also called “shark fin”(fig.1). According to hemodynamically unstable scenario and ECG pattern, emergency coronary angiography was performed, showing absence of coronary artery disease(fig. 2). Echocardiography revealed severe LV systolic disfunction (EF 20–25%) with apical ballooning and severe systolic anterior motion (SAM) of the anterior mitral leaflet eliciting dynamic LVOTO with peak gradient greater than 90 mmHg; fig. 3) and severe MR. Patient was treated with cautious fluid administration, hemotrasfusion and empiric large spectrum antibiotic therapy. According to TTC working diagnosis, even if septic state was thought to contribute to cardiogenic shock, norepinephrine was not administered due to concerns for LVOTO and SAM. After overcoming of dramatic first phase and after hemodynamic steadiness was achieved, beta blockade and ACEi were progressively administered. Seriate transthoracic echocardiogram revealed progressive improvement of LV systolic function, regression of apical ballooning, SAM and LVOTO. ECG monitoring showed regression of ischemic ST elevation. ST elevation has been described in about 56% of TTC cases, however with amplitude tipically lower than in STEMI. Lambda–wave ST elevation has been rarely reported. Vasospasm, local intermittent microvascular constriction, catecholamine–induced metabolic toxicity, transmural systolic wall tension and its the mechano–electric feedback can explain scaring ECG–pattern. Despite its rare prevalence in TTC “shark fin” pattern appears to relate to adverse outcome and it should be used as an early marker of potential further clinical deterioration, suggesting more intensive monitoring to avoid delays in possible therapy escalation.

Recurrence of ventricular fibrillation in out-of-hospital cardiac arrest: Clinical evidence and underlying ionic mechanisms.

Defibrillation remains the optimal therapy for terminating ventricular fibrillation (VF) in out-of-hospital cardiac arrest (OHCA) patients, with reported shock success rates of ∼90%. A key persistent challenge, however, is the high rate of VF recurrence (∼50-80%) seen during post-shock cardiopulmonary resuscitation (CPR). Studies have shown that the incidence and time spent in recurrent VF are negatively associated with neurologically-intact survival. Recurrent VF also results in the administration of extra shocks at escalating energy levels, which can cause cardiac dysfunction. Unfortunately, the mechanisms underlying recurrent VF remain poorly understood. In particular, the role of chest-compressions (CC) administered during CPR in mediating recurrent VF remains controversial. In this review, we first summarize the available clinical evidence for refibrillation occurring during CPR in OHCA patients, including the postulated contribution of CC and non-CC related pathways. Next, we examine experimental studies highlighting how CC can re-induce VF via direct mechano-electric feedback. We postulate the ionic mechanisms involved by comparison with similar phenomena seen in commotio cordis. Subsequently, the hypothesized contribution of partial cardiac reperfusion (either as a result of CC or CC independent organized rhythm) in re-initiating VF in a globally ischaemic heart is examined. An overview of the proposed ionic mechanisms contributing to VF recurrence in OHCA during CPR from a cellular level to the whole heart is outlined. Possible therapeutic implications of the proposed mechanistic theories for VF recurrence in OHCA are briefly discussed.

Differential effects of mechano-electric feedback mechanisms on whole-heart activation, repolarization, and tension.

The human heart is subject to highly variable amounts of strain during day-to-day activities and needs to adapt to a wide range of physiological demands. This adaptation is driven by an autoregulatory loop that includes both electrical and the mechanical components. In particular, mechanical forces are known to feed back into the cardiac electrophysiology system, which can result in pro- and anti-arrhythmic effects. Despite the widespread use of computational modelling and simulation for cardiac electrophysiology research, the majority of in silico experiments ignore this mechano-electric feedback entirely due to the high computational cost associated with solving cardiac mechanics. In this study, we therefore use an electromechanically coupled whole-heart model to investigate the differential and combined effects of electromechanical feedback mechanisms with a focus on their physiological relevance during sinus rhythm. In particular, we consider troponin-bound calcium, the effect of deformation on the tissue diffusion tensor, and stretch-activated channels. We found that activation of the myocardium was only significantly affected when including deformation into the diffusion term of the monodomain equation. Repolarization, on the other hand, was influenced by both troponin-bound calcium and stretch-activated channels and resulted in steeper repolarization gradients in the atria. The latter also caused afterdepolarizations in the atria. Due to its central role for tension development, calcium bound to troponin affected stroke volume and pressure. In conclusion, we found that mechano-electric feedback changes activation and repolarization patterns throughout the heart during sinus rhythm and lead to a markedly more heterogeneous electrophysiological substrate. KEY POINTS: The electrophysiological and mechanical function of the heart are tightly interrelated by excitation-contraction coupling (ECC) in the forward direction and mechano-electric feedback (MEF) in the reverse direction. While ECC is considered in many state-of-the-art computational models of cardiac electromechanics, less is known about the effect of different MEF mechanisms. Accounting for calcium bound to troponin increases stroke volume and delays repolarization. Geometry-mediated MEF leads to more heterogeneous activation and repolarization with steeper gradients. Both effects combine in an additive way. Non-selective stretch-activated channels as an additional MEF mechanism lead to heterogeneous diastolic transmembrane voltage, higher developed tension and delayed repolarization or afterdepolarizations in highly stretched parts of the atria. The differential and combined effects of these three MEF mechanisms during sinus rhythm activation in a human four-chamber heart model may have implications for arrhythmogenesis, both in terms of substrate (repolarization gradients) and triggers (ectopy).

Electrophysiological effects of stretch-activated ion channels: a systematic computational characterization.

Cardiac electrophysiology and mechanics are strongly interconnected. Their interaction is, among others, mediated by mechano-electric feedback through stretch-activated ion channels (SACs). The electrophysiological changes induced by SACs may contribute to arrhythmogenesis, but the precise SAC-induced electrophysiological changes remain incompletely understood. Here, we provide a systematic characterization of stretch effects through three distinguished SACs on cardiac electrophysiology using computational modelling. We implemented potassium-selective, calcium-selective and non-selective SACs in the Tomek-Rodriguez-O'Hara-Rudy model of human ventricular electrophysiology. The model was calibrated to experimental data from isolated cardiomyocytes undergoing stretch, considering inter-species differences, and disease-related remodelling of SACs. SAC-mediated effects on the action potential (AP) were analysed by varying stretch amplitude, application timing and/or duration. Afterdepolarizations of different amplitudes were observed with transient 10-ms stretch stimuli of 15-18% applied during phase 4, while stretch ≥18% during phase 4 elicited triggered APs. Longer stimuli shifted the threshold of AP trigger during phase 4 to lower amplitudes, while shorter stimuli increased it. Continuous stretch provoked electrophysiological remodelling. Furthermore, stretch shortened duration or changed morphology of a subsequent electrically evoked AP, and, if applied during a vulnerable time window with sufficient amplitude, prevented its occurrence because of stretch-induced modulation of sodium and L-type calcium channel gating. These effects were more pronounced with disease-related SAC remodelling due to increased stretch sensitivity of diseased hearts. We showed that SACs may induce afterdepolarizations and triggered activities, and prevent subsequent AP generation or change its morphology. These effects depend on cardiomyocyte stretch characteristics and disease-related SACs remodelling and may contribute to cardiac arrhythmogenesis. KEY POINTS: The interplay between cardiac electrophysiology and mechanics is mediated by mechano-electric feedback through stretch-activated ion channels (SACs). These channels may be pro-arrhythmic, but their precise effect on electrophysiology remains unclear. Here we present a systematic in silico characterization of stretch effects through three SACs by implementing inter-species differences as well as disease-related remodelling of SACs in a novel computational model of human ventricular cardiomyocyte electrophysiology. Our simulations showed that, at the cellular level, SACs may provoke electrophysiological remodelling, afterdepolarizations, triggered activities, change the morphology or shorten subsequent electrically evoked action potentials. The model further suggests that a vulnerable window exists in which stretch prevents the following electrically triggered beat occurrence. The pro-arrhythmic effects of stretch strongly depend on disease-related SAC remodelling as well as on stretch characteristics, such as amplitude, time of application and duration. Our study helps in understanding the role of stretch in cardiac arrhythmogenesis and revealing the underlying cellular mechanisms.

SIMULATED MICROGRAVITY CHANGES THE NUMBER OF MECHANICALLY GATED AND MECHANOSENSITIVE ION CHANNELS GENES TRANSCRIPTS IN RAT VENTRICULAR CARDIOMYOCYTES

The mechanoelectrical feedback in the heart is based on the work of mechanically gated (MGCs) and mechanosensitive (MSCs) channels. Since microgravity alters the heart’s morphological and physiological properties, we hypothesized that the expression of both MGCs and MSCs would be affected. We employed RNA transcriptome sequencing to investigate changes in the gene transcript levels of MGCs and MSCs in isolated rat ventricular cardiomyocytes under control conditions and in a simulated microgravity environment. For the first time, our findings demonstrated that simulated microgravity induces alterations in the gene transcript levels of specific MGCs, such as TRPM7, TRPV2, TRPP1, TRPP2, Piezo1, TMEM63A, TMEM36B, and known MSCs, including K2P2.1, K2P3.1, Kir6.1, Kir6.2, NaV1.5, CaV1.2, KV7.1. However, other voltage-gated channels and channels lacking a voltage sensor remained unaffected. These findings suggest that the altered expression of MGCs and MSCs could lead to changes in the net currents across the membrane, ultimately impacting the heart’s function.

A detailed mathematical model of the human atrial cardiomyocyte: integration of electrophysiology and cardiomechanics.

Mechano-electric regulations (MER) play an important role in the maintenance of cardiac performance. Mechano-calcium and mechano-electric feedback (MCF and MEF) pathways adjust the cardiomyocyte contractile force according to mechanical perturbations and affects electro-mechanical coupling. MER integrates all these regulations in one unit resulting in a complex phenomenon. Computational modelling is a useful tool to accelerate the mechanistic understanding of complex experimental phenomena. We have developed a novel model that integrates the MER loop for human atrial cardiomyocytes with proper consideration of feedforward and feedback pathways. The model couples a modified version of the action potential (AP) Koivumäki model with the contraction model by Quarteroni group. The model simulates iso-sarcometric and isometric twitches and the feedback effects on AP and Ca2+-handling. The model showed a biphasic response of Ca2+ transient (CaT) peak to increasing pacing rates and highlights the possible mechanisms involved. The model has shown a shift of the threshold for AP and CaT alternans from 4.6 to 4Hz under post-operative atrial fibrillation, induced by depressed SERCA activity. The alternans incidence was dependent on a chain of mechanisms including RyRs availability time, MCF coupling, CaMKII phosphorylation, and the stretch levels. As a result, the model predicted a 10% slowdown of conduction velocity for a 20% stretch, suggesting a role of stretch in creation of substrate formation for atrial fibrillation. Overall, we conclude that the developed model provides a physiological CaT followed by a physiological twitch. This model can open pathways for the future studies of human atrial electromechanics. KEY POINTS: With the availability of human atrial cellular data, interest in atrial-specific model integration has been enhanced. We have developed a detailed mathematical model of human atrial cardiomyocytes including the mechano-electric regulatory loop. The model has gone through calibration and evaluation phases against a wide collection of available human in-vitro data. The usefulness of the model for analysing clinical problems has been preliminaryly tested by simulating the increased incidence of Ca2+ transient and action potential alternans at high rates in post-operative atrial fibrillation condition. The model determines the possible role of mechano-electric feedback in alternans incidence, which can increase vulnerability to atrial arrhythmias by varying stretch levels. We found that our physiologically accurate description of Ca2+ handling can reproduce many experimental phenomena and can help to gain insights into the underlying pathophysiological mechanisms.

TREK channels in Mechanotransduction: a Focus on the Cardiovascular System.

Mechano-electric feedback is one of the most important subsystems operating in the cardiovascular system, but the underlying molecular mechanism remains rather unknown. Several proteins have been proposed to explain the molecular mechanism of mechano-transduction. Transient receptor potential (TRP) and Piezo channels appear to be the most important candidates to constitute the molecular mechanism behind of the inward current in response to a mechanical stimulus. However, the inhibitory/regulatory processes involving potassium channels that operate on the cardiac system are less well known. TWIK-Related potassium (TREK) channels have emerged as strong candidates due to their capacity for the regulation of the flow of potassium in response to mechanical stimuli. Current data strongly suggest that TREK channels play a role as mechano-transducers in different components of the cardiovascular system, not only at central (heart) but also at peripheral (vascular) level. In this context, this review summarizes and highlights the main existing evidence connecting this important subfamily of potassium channels with the cardiac mechano-transduction process, discussing molecular and biophysical aspects of such a connection.

Mechano-electrical interactions and heterogeneities in wild-type and drug-induced long QT syndrome rabbits.

Electromechanical reciprocity - comprising electro-mechanical (EMC) and mechano-electric coupling (MEC) - provides cardiac adaptation to changing physiological demands. Understanding electromechanical reciprocity and its impact on function and heterogeneity in pathological conditions - such as (drug-induced) acquired long QT syndrome (aLQTS) - might lead to novel insights in arrhythmogenesis. Our aim is to investigate how electrical changes impact on mechanical function (EMC) and vice versa (MEC) under physiological conditions and in aLQTS. To measure regional differences in EMC and MEC in vivo, we used tissue phase mapping cardiac MRI and a 24-lead ECG vest in healthy (control) and IKr-blocker E-4031-induced aLQTS rabbit hearts. MEC was studied in vivo by acutely increasing cardiac preload, and ex vivo by using voltage optical mapping (OM) in beating hearts at different preloads. In aLQTS, electrical repolarization (heart rate corrected RT-interval, RTn370) was prolonged compared to control (P<0.0001) with increased spatial and temporal RT heterogeneity (P<0.01). Changing electrical function (in aLQTS) resulted in significantly reduced diastolic mechanical function and prolonged contraction duration (EMC), causing increased apico-basal mechanical heterogeneity. Increased preload acutely prolonged RTn370 in both control and aLQTS hearts (MEC). This effect was more pronounced in aLQTS (P<0.0001). Additionally, regional RT-dispersion increased in aLQTS. Motion-correction allowed us to determine APD-prolongation in beating aLQTS hearts, but limited motion correction accuracy upon preload-changes prevented a clear analysis of MEC ex vivo. Mechano-induced RT-prolongation and increased heterogeneity were more pronounced in aLQTS than in healthy hearts. Acute MEC effects may play an additional role in LQT-related arrhythmogenesis, warranting further mechanistic investigations. KEY POINTS: Electromechanical reciprocity comprising excitation-contraction coupling (EMC) and mechano-electric feedback loops (MEC) is essential for physiological cardiac function. Alterations in electrical and/or mechanical heterogeneity are known to have potentially pro-arrhythmic effects. In this study, we aimed to investigate how electrical changes impact on the mechanical function (EMC) and vice versa (MEC) both under physiological conditions (control) and in acquired long QT syndrome (aLQTS). We show that changing the electrical function (in aLQTS) results in significantly altered mechanical heterogeneity via EMC and, vice versa, that increasing the preload acutely prolongs repolarization duration and increases electrical heterogeneity, particularly in aLQTS as compared to control. Our results substantiate the hypothesis that LQTS is an ‛electro-mechanical', rather than a 'purely electrical', disease and suggest that acute MEC effects may play an additional role in LQT-related arrhythmogenesis.

Prolonged Piezo1 Activation Induces Cardiac Arrhythmia

The rhythmical nature of the cardiovascular system constantly generates dynamic mechanical forces. At the centre of this system is the heart, which must detect these changes and adjust its performance accordingly. Mechanoelectric feedback provides a rapid mechanism for detecting even subtle changes in the mechanical environment and transducing these signals into electrical responses, which can adjust a variety of cardiac parameters such as heart rate and contractility. However, pathological conditions can disrupt this intricate mechanosensory system and manifest as potentially life-threatening cardiac arrhythmias. Mechanosensitive ion channels are thought to be the main proponents of mechanoelectric feedback as they provide a rapid response to mechanical stimulation and can directly affect cardiac electrical activity. Here, we demonstrate that the mechanosensitive ion channel PIEZO1 is expressed in zebrafish cardiomyocytes. Furthermore, chemically prolonging PIEZO1 activation in zebrafish results in cardiac arrhythmias. indicating that this ion channel plays an important role in mechanoelectric feedback. This also raises the possibility that PIEZO1 gain of function mutations could be linked to heritable cardiac arrhythmias in humans.

A comprehensive and biophysically detailed computational model of the whole human heart electromechanics

While ventricular electromechanics is extensively studied in both physiological and pathological conditions, four-chamber heart models have only been addressed recently; most of these works however neglect atrial contraction. Indeed, as atria are characterized by a complex anatomy and a physiology that is strongly influenced by the ventricular function, developing computational models able to capture the physiological atrial function and atrioventricular interaction is very challenging. In this paper, we propose a biophysically detailed electromechanical model of the whole human heart that considers both atrial and ventricular contraction. Our model includes: (i) an anatomically accurate whole-heart geometry; (ii) a comprehensive myocardial fiber architecture; (iii) a biophysically detailed microscale model for the active force generation; (iv) a 0D closed-loop model of the circulatory system, fully-coupled with the mechanical model of the heart; (v) the fundamental interactions among the different core models, such as the mechano-electric feedback or the fibers-stretch and fibers-stretch-rate feedbacks; (vi) specific constitutive laws and model parameters for each cardiac region. Concerning the numerical discretization, we propose an efficient segregated-intergrid-staggered scheme that includes a computationally efficient strategy to handle the non-conductive regions. We also propose extending recent stabilization techniques – regarding the circulation and the fibers-stretch-rate feedback – to the whole heart, demonstrating their cruciality for obtaining a stable formulation in a four-chamber scenario. We are able to reproduce the healthy cardiac function for all the heart chambers, in terms of pressure–volume loops, time evolution of pressures, volumes and fluxes, and three-dimensional cardiac deformation, with volumetric indexes within reference ranges for cardiovascular magnetic resonance. We also show the importance of considering atrial contraction, fibers-stretch-rate feedback and the proposed stabilization techniques, by comparing the results obtained with and without these features in the model. In particular, we show that the fibers-stretch-rate feedback, often neglected due to the numerical challenges that it entails, plays a fundamental role in the regulation of the blood flux ejected by ventricles. The proposed model represents the state-of-the-art electromechanical model of the iHEART ERC project – an Integrated Heart Model for the Simulation of the Cardiac Function – and is a fundamental step toward the building of physics-based digital twins of the human heart.

In silico analysis of the contribution of cardiomyocyte-fibroblast electromechanical interaction to the arrhythmia.

Although fibroblasts are about 5-10times smaller than cardiomyocytes, their number in the ventricle is about twice that of cardiomyocytes. The high density of fibroblasts in myocardial tissue leads to a noticeable effect of their electromechanical interaction with cardiomyocytes on the electrical and mechanical functions of the latter. Our work focuses on the analysis of the mechanisms of spontaneous electrical and mechanical activity of the fibroblast-coupled cardiomyocyte during its calcium overload, which occurs in a variety of pathologies, including acute ischemia. For this study, we developed a mathematical model of the electromechanical interaction between cardiomyocyte and fibroblasts and used it to simulate the impact of overloading cardiomyocytes. In contrast to modeling only the electrical interaction between cardiomyocyte and fibroblasts, the following new features emerge in simulations with the model that accounts for both electrical and mechanical coupling and mechano-electrical feedback loops in the interacting cells. First, the activity of mechanosensitive ion channels in the coupled fibroblasts depolarizes their resting potential. Second, this additional depolarization increases the resting potential of the coupled myocyte, thus augmenting its susceptibility to triggered activity. The triggered activity associated with the cardiomyocyte calcium overload manifests itself in the model either as early afterdepolarizations or as extrasystoles, i.e., extra action potentials and extra contractions. Analysis of the model simulations showed that mechanics contribute significantly to the proarrhythmic effects in the cardiomyocyte overloaded with calcium and coupled with fibroblasts, and that mechano-electrical feedback loops in both the cardiomyocyte and fibroblasts play a key role in this phenomenon.

Mechanoelectric effects in healthy cardiac function and under Left Bundle Branch Block pathology

Mechanoelectric feedback (MEF) in the heart operates through several mechanisms which serve to regulate cardiac function. Stretch activated channels (SACs) in the myocyte membrane open in response to cell lengthening, while tension generation depends on stretch, shortening velocity, and calcium concentration. How all of these mechanisms interact and their effect on cardiac output is still not fully understood. We sought to gauge the acute importance of the different MEF mechanisms on heart function.An electromechanical computer model of a dog heart was constructed, using a biventricular geometry of 500K tetrahedral elements. To describe cellular behavior, we used a detailed ionic model to which a SAC model and an active tension model, dependent on stretch and shortening velocity and with calcium sensitivity, were added. Ventricular inflow and outflow were connected to the CircAdapt model of cardiovascular circulation. Pressure–volume loops and activation times were used for model validation.Simulations showed that SACs did not affect acute mechanical response, although if their trigger level was decreased sufficiently, they could cause premature excitations. The stretch dependence of tension had a modest effect in reducing the maximum stretch, and stroke volume, while shortening velocity had a much bigger effect on both. MEF served to reduce the heterogeneity in stretch while increasing tension heterogeneity. In the context of left bundle branch block, a decreased SAC trigger level could restore cardiac output by reducing the maximal stretch when compared to cardiac resynchronization therapy. MEF is an important aspect of cardiac function and could potentially mitigate activation problems.

Development of a novel low-order model for atrial function and a study of atrial mechano-electric feedback

Numerical models of the cardiovascular system have largely focused on the function of the ventricles, with atrial function often neglected. Furthermore, the time-varying elastance method that prescribes the pressure–volume relationship rather than calculating it consistently is frequently used for the ventricles and atrium. This method has yet to be validated however, so its applicability for cardiac modelling is frequently questioned. To overcome this challenge, we propose a synergistic model of left atrium (LA) and left ventricle (LV) by self-consistently integrating various feedback mechanisms among the electro-mechanical and chemical functions of the micro-scale myofiber, the macro-scale dynamics of the LA and LV, the atrioventricular node (AV), and circulation. The model is tested and shown to reproduce the essential features of the atrium cycling, such as the characteristic figure of eight pressure–volume loops. Our model is further developed to investigate the effect of dysfunctions of the mechanical-electric feedback (MEF) in the atrium. Our model not only successfully reproduces key experimental MEF observations such as prolonged action-potential and increases in action-potential magnitude induced by atrial stretch but also shows how MEF and arrhythmia of the atrium lead to a degradation of cardiac output and pumping power with significant consequences. In particular, MEF reproduces arrhythmia such as ectopic and erratic cycling, missed heart beats and restricted function.

A mathematical model that integrates cardiac electrophysiology, mechanics, and fluid dynamics: Application to the human left heart.

We propose a mathematical and numerical model for the simulation of the heart function that couples cardiac electrophysiology, active and passive mechanics and hemodynamics, and includes reduced models for cardiac valves and the circulatory system. Our model accounts for the major feedback effects among the different processes that characterize the heart function, including electro-mechanical and mechano-electrical feedback as well as force-strain and force-velocity relationships. Moreover, it provides a three-dimensional representation of both the cardiac muscle and the hemodynamics, coupled in a fluid-structure interaction (FSI) model. By leveraging the multiphysics nature of the problem, we discretize it in time with a segregated electrophysiology-force generation-FSI approach, allowing for efficiency and flexibility in the numerical solution. We employ a monolithic approach for the numerical discretization of the FSI problem. We use finite elements for the spatial discretization of partial differential equations. We carry out a numerical simulation on a realistic human left heart model, obtaining results that are qualitatively and quantitatively in agreement with physiological ranges and medical images.

Effect of strain-dependent conduction slowing on the re-entry formation and maintenance in cardiac muscle: 2D computer simulation.

The effect of mechano-electrical feedback on re-entry formation and maintenance was studied using a model of myocardial electromechanics that accounts for two components of myocardial conductivity and delayed strain-dependent changes in membrane capacitance that causes a conduction slowing. Two scenarios were simulated in 2D numerical experiments: (i) propagation of an excitation-contraction wave beyond the edge of a nonconductive nonexcitable obstacle; (ii) circulation of a re-entry wave around a nonconductive nonexcitable obstacle. The simulations demonstrated that the delayed strain-dependent deceleration of the conduction waves promotes the detachment of the excitation-contraction waves from the sharp edge of an elongated obstacle and modulates the re-entry waves rotating around a compact obstacle. The data show that the mechano-electrical feedback, together with an increase in the stimulation frequency and an increase in the excitation threshold, is an arrhythmogenic factor that must be taken into account when analyzing the possibility of the re-entry formation.

TREK-1 in the heart: Potential physiological and pathophysiological roles.

The TREK-1 channel belongs to the TREK subfamily of two-pore domains channels that are activated by stretch and polyunsaturated fatty acids and inactivated by Protein Kinase A phosphorylation. The activation of this potassium channel must induce a hyperpolarization of the resting membrane potential and a shortening of the action potential duration in neurons and cardiac cells, two phenomena being beneficial for these tissues in pathological situations like ischemia-reperfusion. Surprisingly, the physiological role of TREK-1 in cardiac function has never been thoroughly investigated, very likely because of the lack of a specific inhibitor. However, possible roles have been unraveled in pathological situations such as atrial fibrillation worsened by heart failure, right ventricular outflow tract tachycardia or pulmonary arterial hypertension. The inhomogeneous distribution of TREK-1 channel within the heart reinforces the idea that this stretch-activated potassium channel might play a role in cardiac areas where the mechanical constraints are important and need a particular protection afforded by TREK-1. Consequently, the main purpose of this mini review is to discuss the possible role played by TREK -1 in physiological and pathophysiological conditions and its potential role in mechano-electrical feedback. Improved understanding of the role of TREK-1 in the heart may help the development of promising treatments for challenging cardiac diseases.

An Investigation of Left Ventricular Valve Disorders and the Mechano-Electric Feedback Using a Synergistic Lumped Parameter Cardiovascular Numerical Model.

Cardiac diseases and failure make up one of largest contributions to global mortality and significantly detriment the quality of life for millions of others. Disorders in the valves of the left ventricle are a prominent example of heart disease, with prolapse, regurgitation, and stenoses—the three main valve disorders. It is widely known that mitral valve prolapse increases the susceptibility to cardiac arrhythmia. Here, we investigate stenoses and regurgitation of the mitral and aortic valves in the left ventricle using a synergistic low-order numerical model. The model synergy derives from the incorporation of the mechanical, chemical, and electrical elements. As an alternative framework to the time-varying elastance (TVE) method, it allows feedback mechanisms at work in the heart to be considered. The TVE model imposes the ventricular pressure–volume relationship using a periodic function rather than calculating it consistently. Using our synergistic approach, the effects of valve disorders on the mechano-electric-feedback (MEF) are investigated. The MEF is the influence of cellular mechanics on the electrical activity, and significantly contributes to the generation of arrhythmia. We further investigate stenoses and regurgitation of the mitral and aortic valves and their relationship with the MEF and generation of arrhythmia. Mitral valve stenosis is found to increase the sensitivity to arrhythmia-stimulating systolic stretch, and reduces the sensitivity to diastolic stretch. Aortic valve stenosis does not change the sensitivity to arrhythmia-stimulating stretch, and regurgitation reduces it. A key result is found when valve regurgitation is accompanied by diastolic stretch. In the presence of MEF disorder, ectopic beats become far more frequent when accompanied by valve regurgitation. Therefore, arrhythmia resulting from a disorder in the MEF will be more severe when valve regurgitation is present.

Active force generation contributes to the complexity of spontaneous activity and to the response to stretch of murine cardiomyocyte cultures.

Cardiomyocyte cultures exhibit spontaneous electrical and contractile activity, as in a natural cardiac pacemaker. In such preparations, beat rate variability exhibits features similar to those of heart rate variability in vivo. Mechanical deformations and forces feed back on the electrical properties of cardiomyocytes, but it is not fully elucidated how this mechano‐electrical interplay affects beating variability in such preparations. Using stretchable microelectrode arrays, we assessed the effects of the myosin inhibitor blebbistatin and the non‐selective stretch‐activated channel blocker streptomycin on beating variability and on the response of neonatal or fetal murine ventricular cell cultures against deformation. Spontaneous electrical activity was recorded without stretch and upon predefined deformation protocols (5% uniaxial and 2% equibiaxial strain, applied repeatedly for 1 min every 3 min). Without stretch, spontaneous activity originated from the edge of the preparations, and its site of origin switched frequently in a complex manner across the cultures. Blebbistatin did not change mean beat rate, but it decreased the spatial complexity of spontaneous activity. In contrast, streptomycin did not exert any manifest effects. During the deformation protocols, beat rate increased transiently upon stretch but, paradoxically, also upon release. Blebbistatin attenuated the response to stretch, whereas this response was not affected by streptomycin. Therefore, our data support the notion that in a spontaneously firing network of cardiomyocytes, active force generation, rather than stretch‐activated channels, is involved mechanistically in the complexity of the spatiotemporal patterns of spontaneous activity and in the stretch‐induced acceleration of beating. Key points Monolayer cultures of cardiac cells exhibit spontaneous electrical and contractile activity, as in a natural cardiac pacemaker. Beating variability in these preparations recapitulates the power‐law behaviour of heart rate variability in vivo. However, the effects of mechano‐electrical feedback on beating variability are not yet fully understood.Using stretchable microelectrode arrays, we examined the effects of the contraction uncoupler blebbistatin and the non‐specific stretch‐activated channel blocker streptomycin on beating variability and on stretch‐induced changes of beat rate.Without stretch, blebbistatin decreased the spatial complexity of beating variability, whereas streptomycin had no effects.Both stretch and release increased beat rate transiently; blebbistatin attenuated the increase of beat rate upon stretch, whereas streptomycin had no effects.Active force generation contributes to the complexity of spatiotemporal patterns of beating variability and to the increase of beat rate upon mechanical deformation. Our study contributes to the understanding of how mechano‐electrical feedback influences heart rate variability.

Effects of blebbistatin and streptomycin on beat rate variability and mechano-electric feedback in spontaneously active cardiomyocyte cultures

Monolayer cultures of cardiac cells exhibit spontaneous electrical and contractile activity and represent an in vitro model of a natural cardiac pacemaker. In such preparations, it was shown previously that beat rate variability (BRV) exhibits features similar to those of heart rate variability in vivo. However, tissue deformation and mechanical forces feedback on the electrical properties of cardiomyocytes (mechano-electrical feedback) e.g., through stretch-activated channels (SACs), and it is not known how mechano-electrical feedback affects BRV in such preparations. Our objective was to assess the contribution of active force generation and SACs on BRV and on the response of neonatal or fetal murine ventricular cell cultures to mechanical deformation. Monolayer cultures were grown on stretchable microelectrode arrays. Spontaneous electrical activity was recorded without deformation and upon predefined deformation protocols (5% uniaxial and 2% biaxial strain, applied repeatedly for 1 min every 3 min), before and after the application of the myosin inhibitor blebbistatin (10 μmol/L) or the SAC blocker streptomycin (20 μmol/L). Without deformation, spontaneous activity originated from the edge of the preparations and the site of origin switched frequently in a complex manner. Blebbistatin did not change mean beat rate, but it decreased the spatial complexity of beating variability. In contrast, streptomycin did not exert any manifest effects on spontaneous activity. During the deformation protocols, beat rate transiently increased upon stretch, but paradoxically also upon release. Blebbistatin attenuated the response to stretch, while this response was not manifestly affected by streptomycin. These results indicate that any change of shape transiently increases beat rate. Importantly, active force generation, rather than SACs, appears to be mechanistically involved in this response as well as in the complexity of spatiotemporal BRV patterns. Our study thus contributes to understand how mechano-electric feedback may influence heart rate variability.

Understanding the contribution of stretch-activated ion channels to cardiac arrhythmogenesis using computational modelling

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Dutch heart foundation, ERA-CVD Introduction Cardiac electrophysiology and mechanics are strongly interconnected. Among other things, their interaction is mediated by cardiac mechano-electric feedback through stretch-activated ion-channels (SACs). These channels are also thought to contribute to the development of arrhythmias, but their precise role remains unclear. Purpose To elucidate the contribution of SACs to arrhythmias using a novel computational model of cardiac electromechanics. Methods We implemented two types of SACs in the O’Hara-Rudy model (ORd) of human ventricular electrophysiology: potassium-selective SACs and non-selective SACs (conducting sodium and potassium). The model was calibrated based on experimental human and rodent data of cardiomyocytes undergoing stretch. The calibration also considered inter-species differences, age, and upregulation of SACs under disease conditions. Subsequently, we varied the amplitude, duration, and timing of the simulated stretch to investigate their effects on action potential (AP). Results The model reproduced APs measured experimentally. Early afterdepolarizations, delayed afterdepolarizations, and ectopic beats were observed when applying stretch with short duration (e.g. 20ms) and high amplitude (e.g. 40%). When varying the time of application, stretch applied closer to the subsequent beat (cycle length: 1000ms) also shortened the following AP duration (APD) (shortening of 30ms with stretch at t=600ms, 130ms at t=800ms). Higher sensitivity to stretch was observed when simulating disease-related remodelling of SACs. Milder effects (no APD shortening with stretch at t=600ms and t=800ms) were seen with a lower stretch amplitude (e.g. 10% with SACs disease-related remodelling, 15% without). Failure of repolarization only occurred when sustained stretch (1000ms duration) of more than 10% (with SACs disease-related remodelling) or 15% (without) was applied. Conclusions Using a novel human electromechanical computational model, we quantified the contribution of SACs to cardiac AP changes. We showed that both disease-related SAC remodelling and variations of amplitude, timing, and duration of cardiomyocyte stretch modulated the effects on cardiac electrophysiology. We also showed that SACs may lead to afterdepolarizations and shorten the subsequent AP duration, factors which may potentially contribute to the generation of arrhythmias.