Mechanoelectric Feedback Research Articles

892 The potential role of L-type voltage-gated channels in rat cardiac mechanosensitivity

Background: Mechanosensitive channels (MSCs) have been determined to work as transducers of mechanoelectric feedback in the heart1), which play a non-negligible role in heart physiological development. Besides, MSCs may be also involved in cardiovascular pathophysiology such as hypertension, cardiac myopathy and so on2). It has been reported that cardiac myocyte voltage-gated channels (VGCs) contribute to convert mechanical signals into biochemical response in the heart3). However, which ion channel is responsible for the heart mechanosensitivity is not well understood. In this study, we hypothesized that L-type voltage gated calcium channel (L-type VGCC) is involved with the cardiac mechanosensitivity. Methods: Isolated langendorff-perfused rat heart was used to investigate whether L-type VGCC was concerned with the mechanosensitivity of the heart. Balloon catheter was inserted into the left ventricle, and left ventricular pressure (LVP) was recorded continuously. After 20 min of stabilization, volume of the left ventricle was increased sequentially by injecting water into the balloon (control group). 0.1 μM-nifedipine, a blocker of L-type VGCC, was used to examine if it can diminish the left ventricular developed pressure (LVDP) in response to the increase of the left ventricular volume. Results: The slope of volume-LVDP relationship in the nifedipine group was significantly reduced compared to the control group (0.94 ± 0.27 and 4.44 ± 0.47, respectively; P < 0.005). Conclusion: The result indicates that the L-type VGCC play an important role in the mechanosensitivity of the heart. Further study with electrophysiological experiments may reveal the mechanosensitivity of the L-type VGCC itself.References Nazir, S.A. & Lab, M.J., Mechanoelectric feedback and atrial arrhythmias. Cardiovasc Res 32 (1), 52-61 (1996). Lab, M.J., Mechanosensitivity as an integrative system in heart: an audit. Prog Biophys Mol Biol 71 (1), 7-27 (1999). Jaalouk, D.E. & Lammerding, J., Mechanotransduction gone awry. Nat Rev Mol Cell Biol 10 (1), 63-73 (2009).

Slow force response and auto-regulation of contractility in heterogeneous myocardium

Classically, the slow force response (SFR) of myocardium refers to slowly developing changes in cardiac muscle contractility induced by external mechanical stimuli, e.g. sustained stretch. We present evidence for an intra-myocardial SFR (SFRIM), caused by the internal mechanical interactions of muscle segments in heterogeneous myocardium. Here we study isometric contractions of a pair of end-to-end connected functionally heterogeneous cardiac muscles (an in-series muscle duplex). Duplex elements can be either biological muscles (BM), virtual muscles (VM), or a hybrid combination of BM and VM. The VM implements an Ekaterinburg–Oxford mathematical model accounting for the ionic and myofilament mechanisms of excitation–contraction coupling in cardiomyocytes. SFRIM is expressed in gradual changes in the overall duplex force and in the individual contractility of each muscle, induced by cyclic auxotonic deformations of coupled muscles. The muscle that undergoes predominant cyclic shortening shows force enhancement upon return to its isometric state in isolation, whereas average cyclic lengthening may decrease the individual muscle contractility. The mechanical responses are accompanied with slow and opposite changes in the shape and duration of both the action potential and Ca2+ transient in the cardiomyocytes of interacting muscles. Using the mathematical model we found that the contractility changes in interacting muscles follow the alterations in the sarcoplasmic reticulum loading in cardiomyocytes which result from the length-dependent Ca2+ activation of myofilaments and intracellular mechano-electrical feedback. The SFRIM phenomena unravel an important mechanism of cardiac functional auto-regulation applicable to the heart in norm and pathology, especially to hearts with severe electrical and/or mechanical dyssynchrony.

Ectopic and reentrant activation patterns in the posterior left atrium during stretch-related atrial fibrillation

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia in humans and is predicted to dramatically increase its prevalence in the future. There is experimental evidence that increasing stretch increases the dominance of the pulmonary veins (PVs) during AF in isolated hearts and ectopic activity in the isolated PVs, but the ionic mechanisms underlying such effects are not clear and the ability of the PVs to favorably host functional reentry during stretch cannot be excluded. We used a combination of endocardial–epicardial optical mapping with phase and spectral analysis to study stretch-related AF (SRAF) in normal isolated sheep hearts. We have found rapid AF sources in the posterior left atrium (PLA) and PV region and their activation frequency and level of organization correlated with intra-atrial pressure. Analysis of the surfaces' optical mapping data in the phase domain reveals that activation of the PLA consisted of alternating patterns of breakthroughs, reentries and relatively simple waves swiping across the mapped field. The patterns on the endocardial and epicardial PLA surface at any given moment of time of the SRAF could be either identical or not identical, and the activity in the thickness of the PLA wall is hypothesized to conform to either ectopic discharge or scroll waves, but a definite evidence for the presence of such mechanisms is currently lacking. Thus the understanding of the manner by which the mechano-electric feedback effects in the PLA, including the PVs, become important in the initiation and maintenance of AF requires further detailed investigation.

Dynamics of spiral waves in a cardiac electromechanical model with a local electrical inhomogeneity

Joint effect of electrical heterogeneity (e.g. induced by ischemia) and mechanical deformation is investigated for an anisotropic, quasi–incompressible model of cardiac electromechanical coupling (EMC) using the active strain approach and periodic boundary conditions. Three local inhomogeneities with different geometry are simulated. Under a specific stimulation protocol, the heterogeneities are able to induce spirals. The interplay between the dimension of the electrical inhomogeneity, the EMC and the mechano-electrical feedback provided by the stretch activated current (SAC) determines the dynamics of the spiral waves of excitation, which could extinguish (in the case of low SAC), or be stable (with the tip rotating inside the inhomogeneity), or drift and be annihilated (in the case of high SAC).

Mechanical modulation of the transverse tubular system of ventricular cardiomyocytes

In most mammalian cardiomyocytes, the transverse tubular system (t-system) is a major site for electrical signaling and excitation–contraction coupling. The t-system consists of membrane invaginations, which are decorated with various proteins involved in excitation–contraction coupling and mechano-electric feedback. Remodeling of the t-system has been reported for cells in culture and various types of heart disease. In this paper, we provide insights into effects of mechanical strain on the t-system in rabbit left ventricular myocytes. Based on fluorescent labeling, three-dimensional scanning confocal microscopy, and digital image analysis, we studied living and fixed isolated cells in different strain conditions. We extracted geometric features of transverse tubules (t-tubules) and characterized their arrangement with respect to the Z-disk. In addition, we studied the t-system in cells from hearts fixed either at zero left ventricular pressure (slack), at 30 mmHg (volume overload), or during lithium-induced contracture, using transmission electron microscopy. Two-dimensional image analysis was used to extract features of t-tubule cross-sections. Our analyses of confocal microscopic images showed that contracture at the cellular level causes deformation of the t-system, increasing the length and volume of t-tubules, and altering their cross-sectional shape. TEM data reconfirmed the presence of mechanically induced changes in t-tubular cross sections. In summary, our studies suggest that passive longitudinal stretching and active contraction of ventricular cardiomyocytes affect the geometry of t-tubules. This confirms that mechanical changes at cellular levels could promote alterations in partial volumes that would support a convection-assisted mode of exchange between the t-system content and extracellular space.

Kardiale Zwei-Porendomänen-Kaliumkanäle (K2P): Physiologie, Pharmakologie und therapeutisches Potenzial

Uncontrolled electrical activity caused by ion channel dysfunction produces arrhythmia in the heart. Despite recent advances in pharmaceutical research and development, effective and safe pharmacological management of cardiac arrhythmia still remains an unmet medical need. The emerging family of two-pore-domain potassium (K2P) channels stabilizes the resting membrane potential and facilitates action potential repolarization. In the heart, genetic inactivation or inhibition of two-pore-domain K + (K2P) currents by class III antiarrhythmic drugs results in action potential prolongation. In particular, human K2P3.1 channels are selectively expressed in the atria and represent targets for the pharmacological management of atrial fibrillation. Furthermore, stretch-sensitive K2P2.1 channels are implicated in mechanoelectrical feedback and arrhythmogenesis. The current knowledge on function, regulation, and cardiac significance of K2P channels is summarized in this work, and potential therapeutic implications are highlighted.

Mechano-electrical feedback explains T-wave morphology and optimizes cardiac pump function: Insight from a multi-scale model

In the ECG, T- and R-wave are concordant during normal sinus rhythm (SR), but discordant after a period of ventricular pacing (VP). Experiments showed that the latter phenomenon, called T-wave memory, is mediated by a mechanical stimulus. By means of a mathematical model, we investigated the hypothesis that slow acting mechano-electrical feedback (MEF) explains T-wave memory. In our model, electromechanical behavior of the left ventricle (LV) was simulated using a series of mechanically and electrically coupled segments. Each segment comprised ionic membrane currents, calcium handling, and excitation–contraction coupling. MEF was incorporated by locally adjusting conductivity of L-type calcium current (gCaL) to local external work. In our set-up, gCaL could vary up to 25%, 50%, 100% or unlimited amount around its default value. Four consecutive simulations were performed: normal SR (with MEF), acute VP, sustained VP (with MEF), and acutely restored SR. MEF led to T-wave concordance in normal SR and to discordant T-waves acutely after restoring SR. Simulated ECGs with a maximum of 25–50% adaptation closely resembled those during T-wave memory experiments in vivo and also provided the best compromise between optimal systolic and diastolic function. In conclusion, these simulation results indicate that slow acting MEF in the LV can explain a) the relatively small differences in systolic shortening and mechanical work during SR, b) the small dispersion in repolarization time, c) the concordant T-wave during SR, and d) T-wave memory. The physiological distribution in electrophysiological properties, reflected by the concordant T-wave, may serve to optimize cardiac pump function.

The zebrafish as a novel animal model to study the molecular mechanisms of mechano-electrical feedback in the heart

Altered mechanical loading of the heart leads to hypertrophy, decompensated heart failure and fatal arrhythmias. However, the molecular mechanisms that link mechanical and electrical dysfunction remain poorly understood. Growing evidence suggest that ventricular electrical remodeling (VER) is a process that can be induced by altered mechanical stress, creating persistent electrophysiological changes that predispose the heart to life-threatening arrhythmias. While VER is clearly a physiological property of the human heart, as evidenced by “T wave memory”, it is also thought to occur in a variety of pathological states associated with altered ventricular activation such as bundle branch block, myocardial infarction, and cardiac pacing. Animal models that are currently being used for investigating stretch-induced VER have significant limitations. The zebrafish has recently emerged as an attractive animal model for studying cardiovascular disease and could overcome some of these limitations. Owing to its extensively sequenced genome, high conservation of gene function, and the comprehensive genetic resources that are available in this model, the zebrafish may provide new insights into the molecular mechanisms that drive detrimental electrical remodeling in response to stretch. Here, we have established a zebrafish model to study mechano-electrical feedback in the heart, which combines efficient genetic manipulation with high-precision stretch and high-resolution electrophysiology. In this model, only 90 min of ventricular stretch caused VER and recapitulated key features of VER found previously in the mammalian heart. Our data suggest that the zebrafish model is a powerful platform for investigating the molecular mechanisms underlying mechano-electrical feedback and VER in the heart.

The effect of berberine on arrhythmia caused by stretch of myocardium, in vitro, of rats after myocardial ischemia

Objective To study the effect of berberine on arrhythmia caused by stretch of rats' myocardium,in vitro,after myocardial ischemia (MI) for 30 min.Methods The study was carried out in the laboratory of Heilongjiang traditional Chinese medicine university.A total of 40 Wistar rats were randomly (random number) divided into 4 groups,namely normal control group,berberine group、MI group and MI + berberine group.After perfusion of rat' s heart with Langendorff perfusion device,the model of MI was made with ligation of left anterior descending branch for 30 min.Berberine was dissolved in Tyrode' s solution to a concentration of 300 μmol/L.The hearts were stretched for 5 s by 0.2 ml.The effect of stretching was observed for 30 s to record 90％ monophasic action potential (MAPD90),premature ventricular beats (PVB) and ventricular tachycardia (VT).Quantitative data were compared with ANOVA.Qualitative data were compared with a x2 test.Differences with a value of P ＜ 0.05 were considered statistically significant.Results MAPD90 in normal control and MI group obviously prolonged after the hearts were stretched ( P ＜ 0.01 ).And MAPD90 in MI group was even longer than that of normal control group (P＜0.05).Berberine had no influence on MAPD90 before myocardiuml stretched (P ＞0.05),while it could reduce the degree of prolongation in MAPD90 after myocardium stretched (P ＜ 0.05 or P ＜0.01 ).The incidence rate of PVB and VT in normal control and MI group increased after stretched.The berberine in dose of 300 μmol/L could reduce the incidence of PVB and obviously inhibit the occurrence of VT ( P ＜ 0.01 ).Conclusions Berberine could obviously inhibit the occurrence of stretch-inducedarrhythmias after myocardial infarction. Key words: Berberine; Mechanoelectric feedback; Monophasic action potential; Myocardial infarction; Arrhythmias

Modèle unidimensionnel instationnaire de l’activité pacemaker cardiaque induite par le feedback mécano-électrique dans un environnement thermo-électromécanique

Aim of the studyIn a healthy heart, the mechanoelectric feedback (MEF) process acts as an intrinsic regulatory mechanism of the myocardium which allows the normal cardiac contraction by damping mechanical perturbations in order to generate a new healthy electromechanical situation. However, under certain conditions, the MEF can be a generator of dramatic arrhythmias by inducing local electrical depolarizations as a result of abnormal cardiac tissue deformations, via stretch-activated channels (SACs). Then, these perturbations can propagate in the whole heart and lead to global cardiac dysfunctions. In the present study, we qualitatively investigate the influence of temperature on autonomous electrical activity generated by the MEF. MethodWe introduce a one-dimensional time-dependent model containing all the key ingredients that allow accounting for the excitation-contraction coupling, the MEF and the thermoelectric coupling. ResultsOur simulations show that an autonomous electrical activity can be induced by cardiac deformations, but only inside a certain temperature interval. In addition, in some cases, the autonomous electrical activity takes place in a periodic way like a pacemaker. We also highlight that some properties of action potentials, generated by the mechanoelectric feedback, are significantly influenced by temperature. Moreover, in the situation where a pacemaker activity occurs, we also show that the period is heavily temperature-dependent. ConclusionsOur qualitative model shows that the temperature is a significant factor with regards to the electromechanical behavior of the heart and more specifically, with regards to the autonomous electrical activity induced by the cardiac tissue deformations.

Modifications of mechanoelectric feedback induced by 2,3‐butanedione monoxime and Blebbistatin in Langendorff‐perfused rabbit hearts

Myocardial stretching is an arrhythmogenic factor. Optical techniques and mechanical uncouplers are used to study the mechanoelectric feedback. The aim of this study is to determine whether the mechanical uncouplers 2,3-butanedione monoxime and Blebbistatin hinder or modify the electrophysiological effects of acute mechanical stretch. The ventricular fibrillation (VF) modifications induced by acute mechanical stretch were studied in 27 Langendorff-perfused rabbit hearts using epicardial multiple electrodes and mapping techniques under control conditions (n=9) and during the perfusion of 2,3-butanedione monoxime (15mM) (n=9) or Blebbistatin (10μm) (n=9). In the control series, myocardial stretch increased the complexity of the activation maps and the dominant frequency (DF) of VF from 13.1±2.0Hz to 19.1±3.1Hz (P<0.001, 46% increment). At baseline, the activation maps showed less complexity in both the 2,3-butanedione monoxime and Blebbistatin series, and the DF was lower in the 2,3-butanedione monoxime series (11.4±1.2Hz; P<0.05). The accelerating effect of mechanical stretch was abolished under 2,3-butanedione monoxime (maximum DF=11.7±2.4Hz, 5% increment, ns vs baseline, P<0.0001 vs. control series) and reduced under Blebbistatin (maximum DF = 12.9 ± 0.7 Hz, 8% increment, P<0.01 vs. baseline, P<0.0001 vs. control series). The variations in complexity of the activation maps under stretch were not significant in the 2,3-butanedione monoxime series and were significantly attenuated under Blebbistatin. The accelerating effect and increased complexity of myocardial activation during VF induced by acute mechanical stretch are abolished under the action of 2,3-butanedione monoxime and reduced under the action of Blebbistatin.

Effect of Nitric Oxide on Mechanoelectric Feedback in Rat Right Atrium

In situ microelectrode examination of rat right atrium showed that in physiologically prestretched tissue, NO donor SNAP modifies the repolarization phase of cardiomyocyte AP in a "hump-like" way provoking the development of arrhythmia. Gadolinium both prevents and eliminates this effect attesting to involvement of stretch-activated channels in the development of NO-induced abnormalities. Elevation of SNAP concentration or further stretch of the tissue (presumably, it increases NO concentration) eliminated the hump depolarization induced by moderate SNAP stimulation. Thus, low NO opens the stretch-activated channels while high NO inactivates them.

Effects of assisted and variable mechanical ventilation on cardiorespiratory interactions in anesthetized pigs

The physiological importance of respiratory sinus arrhythmia (RSA) and cardioventilatory coupling (CVC) has not yet been fully elucidated, but these phenomena might contribute to improve ventilation/perfusion matching, with beneficial effects on gas exchange. Furthermore, decreased RSA amplitude has been suggested as an indicator of impaired autonomic control and poor clinical outcome, also during positive-pressure mechanical ventilation (MV). However, it is currently unknown how different modes of MV, including variable tidal volumes (VT), affect RSA and CVC during anesthesia. We compared the effects of pressure controlled (PCV) versus pressure assisted (PSV) ventilation, and of random variable versus constant VT, on RSA and CVC in eight anesthetized pigs. At comparable depth of anesthesia, global hemodynamics, and ventilation, RSA amplitude increased from 20 ms in PCV to 50 ms in PSV (p < 0.05). CVC was detected (using proportional Shannon entropy of the interval between each inspiration onset and the previous R-peak in ECG) in two animals in PCV and seven animals in PSV. Variable VT did not significantly influence these phenomena. Furthermore, heart period and systolic arterial pressure oscillations were in phase during PCV but in counter-phase during PSV. At the same depth of anesthesia in pigs, PSV increases RSA amplitude and CVC compared to PCV. Our data suggest that the central respiratory drive, but not the baroreflex or the mechano-electric feedback in the heart, is the main mechanism behind the RSA increase. Hence, differences in RSA and CVC between mechanically ventilated patients might reflect the difference in ventilation mode rather than autonomic impairment. Also, since gas exchange did not increase from PCV to PSV, it is questionable whether RSA has any significance in improving ventilation/perfusion matching during MV.

Imprudent blow, catastrophic consequence: a case of commotio cordis associated with violence

Commotio cordis is a rare and catastrophic mechano-electric feedback syndrome, and it is especially apt to occur in male children, adolescents and youths during sports activities. The authors present a case of unexpected sudden death due to commotio cordis associated with violence. In a house of detention, a 19-year-old boy was punched and kicked in the face, neck and chest during a fight with another suspect in their ward. Unfortunately, his precordium was the major injured region. The victim turned pale, then lost the ability to resist and lost consciousness immediately. When the emergency medical personnel arrived, the victim was found in a condition of cardiac and respiratory arrest and he was pronounced dead at the scene without cardiopulmonary resuscitation. Both autopsy signs and forensic morphology were in accord with the criteria for commotio cordis diagnosis, showing no cardiac or other organic fatal lesions and no underlying cardiac diseases; moreover, the toxicological screening was negative for alcohol, drug and common toxicants. In the present case, the whole fight was seen by some witnesses in their ward, and it was recorded by the monitoring unit. Based on the statements of the witnesses and the monitoring videotape, combined with the forensic pathological and toxicological examinations, all the testimonies supported the conclusion that the cause of death was commotio cordis.

Autonomous Electrical Activity Induced By Cardiac Tissue Deformation In A Thermo-Electro-Mechanical Background*

In a healthy heart, the mechano-electric feedback (MEF) process acts as an intrinsic regulatory mechanism of the myocardium which allows the normal cardiac contraction by damping mechanical perturbations in order to generate a new healthy electromechanical situation. However, under certain conditions, the MEF can be a generator of dramatic arrhythmias by inducing local electrical depolarizations as a result of abnormal cardiac tissue deformations, via stretch-activated channels (SACs). Then, these perturbations can propagate in the whole heart and lead to global cardiac dysfunctions. In the present study, we examine the spatio-temporal behavior of the autonomous electrical activity induced by the MEF when the heart is subject to temperature variations. For instance, such a situation can occur during a therapeutic hypothermia. This technique is usually used to prevent neuronal injuries after a cardiac resuscitation. From this perspective, we introduce a one-dimensional time-dependent model containing all the key ingredients that allow accounting for excitation-contraction coupling, MEF and thermoelectric coupling. Our simulations show that an autonomous electrical activity can be induced by cardiac deformations, but only inside a certain temperature interval. In addition, in some cases, the autonomous electrical activity takes place in a periodic way like a pacemaker. We also highlight that some properties of the action potentials that are generated by the MEF, are significantly influenced by temperature. Moreover, in the situation where a pacemaker activity occurs, we also show that the period is heavily temperature-dependent.

Mid-Septal Hypertrophy and Apical Ballooning; Potential Mechanism of Ventricular Tachycardia Storm in Patients with Hypertrophic Cardiomyopathy

Medically refractory ventricular tachycardia (VT) storm can be controlled with radiofrequency catheter ablation (RFCA), however, it may be difficult to control in some patients with hemodynamic overload. We experienced a patient with intractable VT storm controlled by hemodynamic unloading. The patient had mid-septal hypertrophic cardiomyopathy with an implantable cardioverter defibrillator (ICD) back-up. Because of the severe mid-septal hypertrophy, his left ventricle (LV) had an hourglass-like morphology and showed apical ballooning; the focus of VT was at the border of apical ballooning. Although we performed VT ablation because of electrical storm with multiple ICD shocks, VT recurred 1 hour after procedure. As the post-RFCA monomorphic VT was refractory to anti-tachycardia pacing or ICD shock, we reduced the hemodynamic overload of LV with β-blockade, hydration, and sedation. VT spontaneously stopped 1.5 hours later and the patient has remained free of VT for 24 months with β-blockade alone. In patients with VT storm refractory to antiarrhythmic drugs or RFCA, the mechanism of mechano-electrical feedback should be considered and hemodynamic unloading may be an essential component of treatment.

New Mechanism of Spiral Wave Initiation in a Reaction-Diffusion-Mechanics System

Spiral wave initiation in the heart muscle is a mechanism for the onset of dangerous cardiac arrhythmias. A standard protocol for spiral wave initiation is the application of a stimulus in the refractory tail of a propagating excitation wave, a region that we call the “classical vulnerable zone.” Previous studies of vulnerability to spiral wave initiation did not take the influence of deformation into account, which has been shown to have a substantial effect on the excitation process of cardiomyocytes via the mechano-electrical feedback phenomenon. In this work we study the effect of deformation on the vulnerability of excitable media in a discrete reaction-diffusion-mechanics (dRDM) model. The dRDM model combines FitzHugh-Nagumo type equations for cardiac excitation with a discrete mechanical description of a finite-elastic isotropic material (Seth material) to model cardiac excitation-contraction coupling and stretch activated depolarizing current. We show that deformation alters the “classical,” and forms a new vulnerable zone at longer coupling intervals. This mechanically caused vulnerable zone results in a new mechanism of spiral wave initiation, where unidirectional conduction block and rotation directions of the consequently initiated spiral waves are opposite compared to the mechanism of spiral wave initiation due to the “classical vulnerable zone.” We show that this new mechanism of spiral wave initiation can naturally occur in situations that involve wave fronts with curvature, and discuss its relation to supernormal excitability of cardiac tissue. The concept of mechanically induced vulnerability may lead to a better understanding about the onset of dangerous heart arrhythmias via mechano-electrical feedback.

Electromechanical feedback with reduced cellular connectivity alters electrical activity in an infarct injured left ventricle: a finite element model study

Myocardial infarction (MI) significantly alters the structure and function of the heart. As abnormal strain may drive heart failure and the generation of arrhythmias, we used computational methods to simulate a left ventricle with an MI over the course of a heartbeat to investigate strains and their potential implications to electrophysiology. We created a fully coupled finite element model of myocardial electromechanics consisting of a cellular physiological model, a bidomain electrical diffusion solver, and a nonlinear mechanics solver. A geometric mesh built from magnetic resonance imaging (MRI) measurements of an ovine left ventricle suffering from a surgically induced anteroapical infarct was used in the model, cycled through the cardiac loop of inflation, isovolumic contraction, ejection, and isovolumic relaxation. Stretch-activated currents were added as a mechanism of mechanoelectric feedback. Elevated fiber and cross fiber strains were observed in the area immediately adjacent to the aneurysm throughout the cardiac cycle, with a more dramatic increase in cross fiber strain than fiber strain. Stretch-activated channels decreased action potential (AP) dispersion in the remote myocardium while increasing it in the border zone. Decreases in electrical connectivity dramatically increased the changes in AP dispersion. The role of cross fiber strain in MI-injured hearts should be investigated more closely, since results indicate that these are more highly elevated than fiber strain in the border of the infarct. Decreases in connectivity may play an important role in the development of altered electrophysiology in the high-stretch regions of the heart.

The interaction of Ca2+ with sarcomeric proteins: role in function and dysfunction of the heart.

The hallmarks of the normal heartbeat are both rapid onset of contraction and rapid relaxation as well as an inotropic response to both increased end-diastolic volume and increased heart rate. At the microscopic level, Ca(2+) plays a crucial role in normal cardiac contraction. This paper reviews the cycle of Ca(2+) fluxes during the normal heartbeat, which underlie the coupling between excitation and contraction and permit a highly synchronized action of cardiac sarcomeres. Length dependence of the response of the regulatory sarcomeric proteins mediates the Frank-Starling Law of the heart. However, Ca(2+) transport may go astray in heart disease such as in congestive heart failure, and both jeopardize systole and diastole and triggering arrhythmias. The interaction between weak and strong segments in nonuniform cardiac muscle allows partial preservation of force of contraction but may further lead to mechanoelectric feedback or reverse excitation-contraction coupling mediating an early diastolic Ca(2+) transient caused by the rapid force decrease during the relaxation phase. These rapid force changes in nonuniform muscle may cause arrhythmogenic Ca(2+) waves to propagate by the activation of neighboring sarcoplasmic reticulum by diffusing Ca(2+) ions.

Eicosapentaenoic acid reduces the pulmonary vein arrhythmias through nitric oxide

AimsOmega-3 polyunsaturated fatty acids can modulate cardiac electrophysiology and reduce the genesis of atrial fibrillation. This study investigates the potential mechanisms through which eicosapentaenoic acid (EPA) reduces pulmonary vein (PV) arrhythmogenesis. Main methodsConventional microelectrodes were used to record the action potentials (APs), before and after the EPA (0.1μM and 1.0μM) administration with and without the presence of a nitric oxide (NO) synthase inhibitor (L-NAME, 100μM) in isolated rabbit PV tissue preparations. Furthermore, indo-1 fluorimetric ratio technique was used to evaluate intracellular calcium in isolated single PV cardiomyocytes with or without incubation of EPA (1.0μM, 30min). Key findingsEPA concentration-dependently reduced the PV spontaneous beating rate (P<0.05). EPA (1.0μM) also reduced the amplitude of delayed afterdepolarizations (P<0.05). EPA hyperpolarized the maximal diastolic potential (MDP), shortened AP duration, increased AP amplitude (APA), and reduced diastolic tension and contractility. However, EPA in the presence of L-NAME or omega-9 fatty acids (oleic acid, 1.0μM) did not have any effect on PV spontaneous activity, AP morphology, or contractile force. A linear regression shows that the decrease in PV spontaneous beating rates induced by EPA correlated well with the changes of MDP, APA, diastolic tension, and contractile force of PVs. In addition, intracellular Ca2+ transient and sarcoplasmic reticulum Ca2+ content were significantly more decreased in the EPA-treated cardiomyocytes than in control PV cardiomyocytes as observed by indo-1 fluorescence. SignificanceEPA reduces PV arrhythmogenesis through the mechanoelectrical feedback generated by NO production.