Single cardiomyocytes from papillary muscles show lower preload-dependent activation of force compared to cardiomyocytes from the left ventricular free wall.

Efficient pumping of the healthy left ventricle (LV) requires heterogeneities in mechanical function of individual cardiomyocytes (CM). Deformation of sub-endocardial (Endo) tissue is greater than that of sub-epicardial (Epi) regions. Papillary muscles (PM), often considered to be part of Endo tissue, show lower beat-by-beat length variation than Epi (or Endo) regions, even though they contribute to the shift in atrio-ventricular valve plane, which is essential for LV pump function. Thus far, no comparative assessment of CM mechanics for PM and LV free wall has been published. Here, we investigate contractility and cytosolic calcium concentration ([Ca2+]c) transients in rabbit single CM, freshly isolated from PM, Endo and Epi regions of the LV (free wall tissue was further subdivided into near-basal [Base], equatorial [Centre], and near-apical [Apex] parts). Functional parameters were measured in the absence of external mechanical loads (non-loaded), or during afterloaded (auxotonic) CM contractions, initiated from different levels of preload (diastolic axial stretch), using the carbon fibre technique. We note significant differences in time-course and amplitudes of sarcomere shortening between PM, Endo and Epi CM. In non-loaded CM, sarcomere shortening between regions compares as follows: Endo > Epi and Endo > PM. During afterloaded contractions, the slope of auxotonic tension-length relation and the Frank-Starling gain index (preload-dependent increase in tension and shortening) follow the sequence of Endo > Epi > PM. In terms of apico-basal gradients, time-to-peak sarcomere shortening was greater in Apex compared to Centre and Base in non-loaded CM only. Thus, CM from PM show the least pronounced preload-dependent activation of force across the LV regions assessed, while CM from Endo regions show the strongest response. This is in keeping with prior in situ observations on the smaller extent of PM shortening and their thus lower functional requirement for sensitivity to preload, compared to LV free wall. The here identified regional differences in cellular Frank-Starling responses illustrate the extent to which CM mechanical responses appear to be in keeping with in situ differences in mechanical demand.

Right Ventricular Longitudinal Conduction Delay in Patients with Brugada Syndrome.

BACKGROUND: The mechanism of Brugada syndrome (BrS) is still unclear, with different researchers favoring either the repolarization or depolarization hypothesis. Prolonged longitudinal activation time has been verified in only a small number of human right ventricles (RVs). The purpose of the present study was to demonstrate RV conduction delays in BrS. METHODS: The RV outflow tract (RVOT)-to-RV apex (RVA) and RVA-to-RVOT conduction times were measured by endocardial stimulation and mapping in 7 patients with BrS and 14 controls. RESULTS: Patients with BrS had a longer PR interval (180 ± 12.6 vs. 142 ± 6.7 ms, P = 0.016). The RVA-to-RVOT conduction time was longer in the patients with BrS than in controls (stimulation at 600 ms, 107 ± 9.9 vs. 73 ± 3.4 ms, P = 0.001; stimulation at 500 ms, 104 ± 12.3 vs. 74 ± 4.2 ms, P = 0.037; stimulation at 400 ms, 107 ±12.2 vs. 73 ± 5.1 ms, P = 0.014). The RVOT-to-RVA conduction time was longer in the patients with BrS than in controls (stimulation at 500 ms, 95 ± 10.3 vs. 62 ± 4.1 ms, P = 0.007; stimulation at 400 ms, 94 ±11.2 vs. 64 ± 4.6 ms, P = 0.027). The difference in longitudinal conduction time was not significant when isoproterenol was administered. CONCLUSION: The patients with BrS showed an RV longitudinal conduction delay obviously. These findings suggest that RV conduction delay might contribute to generate the BrS phenotype.

Endocardial Cell Plasticity in Cardiac Development, Diseases and Regeneration.

Endocardial cells are specialized endothelial cells that form the innermost layer of the heart wall. By virtue of genetic lineage-tracing technology, many of the unexpected roles of endocardium during murine heart development, diseases, and regeneration have been identified recently. In addition to heart valves developed from the well-known endothelial to mesenchymal transition, recent fate-mapping studies using mouse models reveal that multiple cardiac cell lineages are also originated from the endocardium. This review focuses on a variety of different cell types that are recently reported to be endocardium derived during murine heart development, diseases, and regeneration. These multiple cell fates underpin the unprecedented roles of endocardial progenitors in function, pathological progression, and regeneration of the heart. Because emerging studies suggest that developmental mechanisms can be redeployed and recapitulated in promoting heart disease development and also cardiac repair and regeneration, understanding the mechanistic regulation of endocardial plasticity and modulation of their cell fate conversion may uncover new therapeutic potential in facilitating heart regeneration.

Endocardial Hippo signaling regulates myocardial growth and cardiogenesis.

The Hippo signaling pathway has been implicated in control of cell and organ size, proliferation, and endothelial-mesenchymal transformation. This pathway impacts upon two partially redundant transcription cofactors, Yap and Taz, that interact with other factors, including members of the Tead family, to affect expression of downstream genes. Yap and Taz have been shown to regulate, in a cell-autonomous manner, myocardial proliferation, myocardial hypertrophy, regenerative potential, and overall size of the heart. Here, we show that Yap and Taz also play an instructive, non-cell-autonomous role in the endocardium of the developing heart to regulate myocardial growth through release of the paracrine factor, neuregulin. Without endocardial Yap and Taz, myocardial growth is impaired causing early post-natal lethality. Thus, the Hippo signaling pathway regulates cell size via both cell-autonomous and non-cell-autonomous mechanisms. Furthermore, these data suggest that Hippo may regulate organ size via a sensing and paracrine function in endothelial cells.

Effects of Transendocardial Delivery of Bone Marrow-Derived CD133+ Cells on Left Ventricle Perfusion and Function in Patients With Refractory Angina: Final Results of Randomized, Double-Blinded, Placebo-Controlled REGENT-VSEL Trial.

RATIONALE: New therapies for refractory angina are needed. OBJECTIVE: Assessment of transendocardial delivery of bone marrow CD133+ cells in patients with refractory angina. METHODS AND RESULTS: Randomized, double-blinded, placebo-controlled trial enrolled 31 patients with recurrent Canadian Cardiovascular Society II-IV angina, despite optimal medical therapy, ≥1 myocardial segment with inducible ischemia in Tc-99m SPECT who underwent bone marrow biopsy and were allocated to cells (n=16) or placebo (n=15). Primary end point was absolute change in myocardial ischemia by SPECT. Secondary end points were left ventricular function and volumes by magnetic resonance imaging and angina severity. After 4 months, there were no significant differences in extent of inducible ischemia between groups (summed difference score mean [±SD]: 2.60 [2.6] versus 3.63 [3.6], P=0.52; total perfusion deficit: 3.60 [3.6] versus 5.01 [4.3], P=0.32; absolute changes of summed difference score: -1.38 [5.2] versus -0.73 [1.9], P=0.65; and total perfusion deficit: -1.33 [3.3] versus -2.19 [6.6], P=0.65). There was a significant reduction of left ventricular volumes (end-systolic volume: -4.3 [11.3] versus 7.4 [11.8], P=0.02; end-diastolic volume: -9.1 [14.9] versus 7.4 [15.8], P=0.02) and no significant change of left ventricular ejection fraction in the cell group. There was no difference in number of patients showing improvement of ≥1 Canadian Cardiovascular Society class after 1 (41.7% versus 58.3%; P=0.68), 4 (50% versus 33.3%; P=0.63), 6 (70% versus 50.0%; P=0.42), and 12 months (55.6% versus 81.8%; P=0.33) and use of nitrates after 12 months. CONCLUSION: Transendocardial CD133+ cell therapy was safe. Study was underpowered to conclusively validate the efficacy, but it did not show a significant reduction of myocardial ischemia and angina versus placebo. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01660581.

The face of epicardial and endocardial derived cells in zebrafish.

Zebrafish hearts can regenerate through activation of growth factors and trans-differentiation of fibroblasts, epicardial, myocardial and endocardial cells, all positive for GATA4 during the process. A possible model of regeneration of the whole heart and the regenerating cells in ex-vivo culture is presented here by a stimulation of cocktail of growth factors. In ex-vivo growth-factors-supplemented culture the heart regeneration was quite complete without signs of fibrosis. Epicardial- and endocardial-derived cells have been analyzed by electron microscopy evidencing two main types: 1) larger/prismatic and 2) small/rounded. Type (1) showed on the surface protein-sculptures, while type(2) was smooth with sparse globular proteins. To confirm their nature we have contemporarily analyzed their proliferative capability and markers-positivity. The cells treated by growth factors have at least two-fold more proliferation with GATA4-positivity. The type (1) cell evidenced WT1+(marker of embryonic epicardium); the type (2) showed NFTA2+(marker of embryonic endocardium); whereas cTNT-cardiotroponin was negative. Under growth factors stimulation, GATA4+/WT1+ and GATA4+/NFTA2+ could be suitable candidates to be the cells with capability to move in/out of the tissue, probably by using their integrins, and it opens the possibility to have long term selected culture to future characterization.

Ventricular Endocardial Tissue Geometry Affects Stimulus Threshold and Effective Refractory Period.

BACKGROUND: Understanding the biophysical processes by which electrical stimuli applied to cardiac tissue may result in local activation is important in both the experimental and clinical electrophysiology laboratory environments, as well as for gaining a more in-depth knowledge of the mechanisms of focal-trigger-induced arrhythmias. Previous computational models have predicted that local myocardial tissue architecture alone may significantly modulate tissue excitability, affecting both the local stimulus current required to excite the tissue and the local effective refractory period (ERP). In this work, we present experimental validation of this structural modulation of local tissue excitability on the endocardial tissue surface, use computational models to provide mechanistic understanding of this phenomena in relation to localized changes in electrotonic loading, and demonstrate its implications for the capture of afterdepolarizations. METHODS AND RESULTS: Experiments on rabbit ventricular wedge preparations showed that endocardial ridges (surfaces of negative mean curvature) had a stimulus capture threshold that was 0.21 ± 0.03 V less than endocardial grooves (surfaces of positive mean curvature) for pairwise comparison (24% reduction, corresponding to 56.2 ± 6.4% of the energy). When stimulated at the minimal stimulus strength for capture, ridge locations showed a shorter ERP than grooves (n = 6, mean pairwise difference 7.4 ± 4.2 ms). When each site was stimulated with identical-strength stimuli, the difference in ERP was further increased (mean pairwise difference 15.8 ± 5.3 ms). Computational bidomain models of highly idealized cylindrical endocardial structures qualitatively agreed with these findings, showing that such changes in excitability are driven by structural modulation in electrotonic loading, quantifying this relationship as a function of surface curvature. Simulations further showed that capture of delayed afterdepolarizations was more likely in trabecular ridges than grooves, driven by this difference in loading. CONCLUSIONS: We have demonstrated experimentally and explained mechanistically in computer simulations that the ability to capture tissue on the endocardial surface depends upon the local tissue architecture. These findings have important implications for deepening our understanding of excitability differences related to anatomical structure during stimulus application that may have important applications in the translation of novel experimental optogenetics pacing strategies. The uncovered preferential vulnerability to capture of afterdepolarizations of endocardial ridges, compared to grooves, provides important insight for understanding the mechanisms of focal-trigger-induced arrhythmias.

The effects of load on transmural differences in contraction of isolated mouse ventricular cardiomyocytes.

Mechanical properties of cardiomyocytes from different transmural regions are heterogeneous in the left ventricular wall. The cardiomyocyte mechanical environment affects this heterogeneity because of mechano-electric feedback mechanisms. In the present study, we investigated the effects of the mechanical load (preload and afterload) on transmural differences in contraction of subendocardial (ENDO) and subepicardial (EPI) single cells isolated from the murine left ventricle. Various preloads imposed via axial stretch and afterloads (unloaded and heavy loaded conditions) were applied to the cells using carbon fiber techniques for single myocytes. To simulate experimentally obtained results and to predict mechanisms underlying the cellular response to change in load, our mathematical models of the ENDO and EPI cells were used. Our major findings are the following. Our results show that ENDO and EPI cardiomyocytes have different mechanical responses to changes in preload to the cells. Under auxotonic contractions at low preload (unstretched cells), time to peak contraction (Tmax) and the time constant of [Ca2+]i transient decay were significantly longer in ENDO cells than in EPI cells. An increase in preload (stretched cells) prolonged Tmax in both cell types; however, the prolongation was greater in EPI cells, resulting in a decrease in the transmural gradient in Tmax at high preload. Comparing unloaded and heavy loaded (isometric) contractions of the cells we found that transmural gradient in the time course of contraction is independent of the loading conditions. Our mathematical cell models were able to reproduce the experimental results on the distinct cellular responses to changes in the mechanical load when we accounted for an ENDO/EPI difference in the parameters of cooperativity of calcium activation of myofilaments.

The developmental origins and lineage contributions of endocardial endothelium.

Endocardial development involves a complex orchestration of cell fate decisions that coordinate with endoderm formation and other mesodermal cell lineages. Historically, investigations into the contribution of endocardium in the developing embryo was constrained to the heart where these cells give rise to the inner lining of the myocardium and are a major contributor to valve formation. In recent years, studies have continued to elucidate the complexities of endocardial fate commitment revealing a much broader scope of lineage potential from developing endocardium. These studies cover a wide range of species and model systems and show direct contribution or fate potential of endocardium giving rise to cardiac vasculature, blood, fibroblast, and cardiomyocyte lineages. This review focuses on the marked expansion of knowledge in the area of endocardial fate potential. This article is part of a Special Issue entitled: Cardiomyocyte Biology: Integration of Developmental and Environmental Cues in the Heart edited by Marcus Schaub and Hughes Abriel.

Packaging of implantable accelerometers to monitor epicardial and endocardial wall motion.

Acceleration signals, collected from the inner and the outer heart wall, offer a mean of assessing cardiac function during surgery. Accelerometric measurements can also provide detailed insights into myocardial motion during exploratory investigations. Two different implantable accelerometers to respectively record endocardial and epicardial vibrations, have been developed by packaging a commercially available capacitive transducer. The same coating materials have been deposited on the two devices to ensure biocompatibility of the implants: Parylene-C, medical epoxy and Polydimethylsiloxane (PDMS). The different position-specific requirements resulted in two very dissimilar sensor assemblies. The endocardial accelerometer, that measures accelerations from the inner surface of the heart during acute animal tests, is a 2 mm-radius hemisphere fixed on a polymethyl methacrylate (PMMA) rod to be inserted through the heart wall. The epicardial accelerometer, that monitors the motion of the outer surface of the heart, is a three-legged structure with a stretchable polytetrafluoroethylene (PTFE) reinforcement. This device can follow the continuous motion of the myocardium (the muscular tissue of the heart) during the cardiac cycle, without hindering its natural movement. Leakage currents lower than 1 µA have been measured during two weeks of continuous operation in saline. Both transducers have been used, during animal tests, to simultaneously record and compare acceleration signals from corresponding locations on the inner and the outer heart wall of a female sheep.

What endocardial right ventricular pacing site shows better contractility and synchrony in children and adolescents?

AIMS: Right ventricular (RV) apical (RVA) pacing can induce left ventricular (LV) dyssynchrony, remodeling, and dysfunction in children with complete atrioventricular block (CAVB). We compared the functional outcome of RVA with RV alternative pacing sites (RVAPS), including para-Hisian, septal, and outflow tract sites. METHODS: This is a single-center, retrospective study. Data were collected before pacemaker implantation (transvenous leads), postoperatively, at 6 months, and at 1-2-3-4 years. Electrocardiogram evaluation included QRS duration, axis, QTc/JTc, and QTc dispersion. Echocardiographic evaluation included 2-D/3-D assessment of ventricular dimensions (Z-score of LV end-diastolic dimension), function (ejection fraction), and synchrony. RESULTS: From 2009 to 2015, 55 patients with CAVB, aged 3-17 years, with or without other congenital heart defects, underwent RVAPS (30 patients, median age 11 years) or RVA (25 patients, median 12 years). All leads were positioned into the septum. Before implantation, no significant differences in parameters were observed, except for higher Z-score in RVAPS than in RVA. After implantation, at a median follow-up of 2.5 (range 1-6) years, the two groups showed no significant differences in LV dimensions, contractility, and synchrony. QRS intervals of RVAPS were significantly shorter than RVA. Clinical status was good and contractility/synchrony indexes were normal or adequate in all patients. CONCLUSIONS: In pediatric patients, RVAPS and RVA showed no significant differences in LV dimensions, contractility, and synchrony. Preimplantation dilated patients showed LV reverse remodeling. RVAPS demonstrated shorter QRS intervals. Therefore, septal pacing sites, either RVA or RVAPS, seem to determine good contractility and synchrony at a mid-term follow-up.

Experimental study of cryofreezing energy applications on the ventricular myocardium using sheep hearts.

BACKGROUND: Cryofreezing energy has been utilized to abolish arrhythmogenic substrates of various kinds of tachyarrhythmias. However, systematic electrophysiological and histological investigations of cryothermia have never been performed. The aim of this study was to clarify those aspects using sheep beating hearts. METHODS: A total of eight adult sheep were utilized under total anesthesia, and a pericardial cradle was made by opening the pericardium. Eight epicardial plaque electrodes were sutured on the epicardial surface of the left ventricle 2∼3 cm apart from each other. A cryoprobe was inserted through a vent made in the left ventricular apex, and positioned so as to locate the probe tip at a site just opposite the center of the epicardial plaque electrodes. Ventricular electrograms and pacing threshold were measured during endocardial freezing. The volume of the necrotized lesion created by the cryofreezing was measured in the excised hearts after staining. RESULTS: The cryoprobe tip temperature was lowered to -50°C for 10 minutes. A significant increase in the pacing threshold and significant reduction in the ventricular electrograms were observed after endocardial freezing. The transmurality of the necrotized lesions varied depending on the situation of the cryoapplications, and the lesion depth and volume were significantly larger in the transmural lesions; however, there was no significant difference between the transmural and nontransmural lesions regarding the lesion width. CONCLUSIONS: Endocardial cryofreezing could provoke significant electrophysiological and injurious effects on the ventricular myocardium in the goat heart. Transmural cryolesions could be created when cryoprobe was appropriately applied.

Subendocardial viability ratio and ejection duration as parameters of early cardiovascular risk in children.

AIM: The purpose of this study was to investigate subendocardial viability ratio (SEVR) and ejection duration (ED) in children and adolescents with common cardiovascular risk factors such as arterial hypertension, obesity, and hypercholesterolemia. METHODS: Four groups of pediatric patients were analyzed: 31 children and adolescents had hypertension, 36 were overweight, 49 were overweight and had hypertension, and 70 had hypercholesterolemia. The patients were compared to a control group of 50 healthy individuals. Subjects were sampled by opportunity sampling at the Department of Pediatrics Maribor, Slovenia. In each patient, blood pressure, anthropometrical parameters, and pulse wave analysis (PWA) measurements using applanation tonometry technique were performed and calculated. RESULTS: The results show a statistically-significant difference in ED (p = 0.013) but not in SEVR (p = 0.074) in the hypercholesterolemia group in comparison to the control group. In other research groups, no statistically-significant differences were found. In all study groups, SEVR correlated significantly with age (positive, moderate) and heart rate (negative, strong) as well as with central mean pressure (CMP). CONCLUSIONS: Our study does not show a significant role of SEVR and ED in early cardiovascular risk determination in children. However, some results do indicate a potential role of both, at least in hypercholesterolemia, and should be further investigated.
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Ventricular stimulus site influences dynamic dispersion of repolarization in the intact human heart.

The spatial variation in restitution properties in relation to varying stimulus site is poorly defined. This study aimed to investigate the effect of varying stimulus site on apicobasal and transmural activation time (AT), action potential duration (APD) and repolarization time (RT) during restitution studies in the intact human heart. Ten patients with structurally normal hearts, undergoing clinical electrophysiology studies, were enrolled. Decapolar catheters were placed apex to base in the endocardial right ventricle (RVendo) and left ventricle (LVendo), and an LV branch of the coronary sinus (LVepi) for transmural recording. S1-S2 restitution protocols were performed pacing RVendo apex, LVendo base, and LVepi base. Overall, 725 restitution curves were analyzed, 74% of slopes had a maximum slope of activation recovery interval (ARI) restitution (Smax) > 1 (P < 0.001); mean Smax = 1.76. APD was shorter in the LVepi compared with LVendo, regardless of pacing site (30-ms difference during RVendo pacing, 25-ms during LVendo, and 48-ms during LVepi; 50th quantile, P < 0.01). Basal LVepi pacing resulted in a significant transmural gradient of RT (77 ms, 50th quantile: P < 0.01), due to loss of negative transmural AT-APD coupling (mean slope 0.63 ± 0.3). No significant transmural gradient in RT was demonstrated during endocardial RV or LV pacing, with preserved negative transmural AT-APD coupling (mean slope -1.36 ± 1.9 and -0.71 ± 0.4, respectively). Steep ARI restitution slopes predominate in the normal ventricle and dynamic ARI; RT gradients exist that are modulated by the site of activation. Epicardial stimulation to initiate ventricular activation promotes significant transmural gradients of repolarization that could be proarrhythmic.

Left ventricular twist mechanics in the context of normal physiology and cardiovascular disease: a review of studies using speckle tracking echocardiography.

The anatomy of the adult human left ventricle (LV) is the result of its complex interaction with its environment. From the fetal to the neonatal to the adult form, the human LV undergoes an anatomical transformation that finally results in the most complex of the four cardiac chambers. In its adult form, the human LV consists of two muscular helixes that surround the midventricular circumferential layer of muscle fibers. Contraction of these endocardial and epicardial helixes results in a twisting motion that is thought to minimize the transmural stress of the LV muscle. In the healthy myocardium, the LV twist response to stimuli that alter preload, afterload, or contractility has been described and is deemed relatively consistent and predictable. Conversely, the LV twist response in patient populations appears to be a little more variable and less predictable, yet it has revealed important insight into the effect of cardiovascular disease on LV mechanical function. This review discusses important methodological aspects of assessing LV twist and evaluates the LV twist responses to the main physiological and pathophysiological states. It is concluded that correct assessment of LV twist mechanics holds significant potential to advance our understanding of LV function in human health and cardiovascular disease.

Role of heart rate in the relation between regional body fat and subendocardial viability ratio in women.

Subendocardial viability ratio (SEVR) is a measure of left ventricular function, specifically; it is an index of myocardial perfusion relative to left ventricular workload. Women have lower SEVR than men, partly due to a faster resting heart rate that reduces diastolic time (i.e., time for myocardial perfusion). It is unclear if body fat relates to SEVR, thus the purpose of this study was to examine the relation between body fat and SEVR in women. Twenty-eight middle-aged (31-45 years) and 31 older (60-80 years) women were examined. Radial artery applanation tonometry was used to calculate SEVR from a synthesized central aortic pressure wave. Dual-energy X-ray absorptiometry was used to assess body composition including fat in the trunk, legs, android and gynoid regions. Body fat was not related (P>.05) with SEVR in older women. In middle-aged women, all measures of regional fat were correlated with heart rate (range, r=.49-.59, P≤.01) and SEVR (range, r=.43-.53, P≤.01). Android-to-gynoid ratio was identified as the strongest predictor (r(2) =-.26, P<.01) of SEVR among measures of regional fat. Middle-aged women with lower android-to-gynoid fat ratio had higher SEVR (1.96±0.33 vs 1.66±0.20, P=.009) than women with higher fat ratio, even after adjusting for age, height, daily physical activity, and aortic mean pressure (P=.02). Adjusting for heart rate or diastolic time abolished the difference in SEVR between groups (1.80±0.09 vs 1.82±0.09, P=.56). These results suggest that middle-aged women with a greater distribution of fat in the abdomen have poorer left ventricular function that is dependent on the negative influence of heart rate on diastolic time.

Myocardial Telocytes: A New Player in Electric Circuitry of the Heart.

The heart is an electrically conducting organ with networked bioelectric currents that transverse a large segment of interstitial space interspersed with the muscular parenchyma. Non-excitable connective cells in the interstitial space contributed importantly to many structural, biochemical, and physiological activities of cardiac homeostasis. However, contribution of interstitial cells in the cardiac niche has long been neglected. Telocyte is recently recognized as a distinct class of interstitial cell that resides in a wide array of tissues including in the epicardium, myocardium, and endocardium of the heart. They are increasingly described to conduct ionic currents that may have significant implications in bioelectric signaling. In this review, we highlight the significance of telocytes in such connectivity and conductivity within the interstitial bioelectric network in tissue homeostasis.

Transmural Differences in Mechanical Properties of Isolated Subendocardial and Subepicardial Cardiomyocytes.

We studied the differences in twitch force of subendocardial and subepicardial cardiomyocytes isolated from mouse left ventricular wall at different preloads using an original single cell stretch method recently developed by us. Then, we used our mathematical models of subendocardial and subepicardial cells to predict underlying cellular mechanisms. Transmural differences in the amplitudes of active tension of subendocardial and subepicardial cardiomyocytes were revealed that could be related to the differences in cooperative end-to-end interaction between the neighboring regulatory units of the thin filament.

[Numerical Simulation of Propagation of Electric Excitation in the Heart Wall Taking into Account Its Fibrous-Laminar Structure].

The propagation of excitation wave in the inhomogeneous anisotropic finite element model of cardiac muscle is investigated. In this model, the inhomogeneity stands for the rotation of anisotropy axes through the wall thickness and results from a fibrous-laminar structure of the cardiac muscle tissue. Conductivity of the cardiac muscle is described using a monodomain model and the Aliev-Panfilov equations are used as the relationships between the transmembrane current and transmembrane potential. Numerical simulation is performed by applying the splitting algorithm, in which the partial differential solution to the nonlinear boundary value problem is reduced to a sequence of simple ordinary differential equations and linear partial differential equations. The simulation is carried out for a rectangular block of the cardiac tissue, the minimal size of which is considered to be the thickness of the heart wall. Two types of distribution of the fiber orientation angle are discussed. The first case corresponds 'to the left ventricle of a dog. The endocardium and epicardium fibers are generally oriented in the meridional direction. The angle of fiber orientation varies smoothly through the wall thickness making a half-turn. A circular layer, in which the fibers are oriented in the circumferential direction locates deep in the cardiac wall. The results of calculations show that for this case the wave form strongly depends on a place of initial excitation. For the endocardial and epicardial initial excitation one can see the earlier wave front propagation in the endocardium and epicardium, respectively. At the intramural initial excitation the simultaneous wave front propagation in the endocardium and epicardium occurs, but there is a wave front lag in the middle of the wall. The second case refers to the right ventricle of a swine, in which the endocardium and epicardium fibers are typically oriented in the circumferential direction, whereas the subepicardium fibers undergo an abrupt change in the angle of orientation. For this case the dependence of the wave front on the location of initial excitation is weak. One can see the earlier wave front propagation in the middle of the wall. However, the wave front formation rate is different: with highest velocity for intramural initial excitation and with lowest one during excitation on the endocardial surface.