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Introduction: The assessment of left ventricular myocardial deformation and function by two-dimensional speckle tracking-derived strain analysis is an established method in human cardiology. It also progressively gains recognition in veterinary cardiology in both dogs and cats., Objectives: The objectives of this study were to create reference intervals for two-dimensional speckle tracking echocardiography (STE)-derived endocardial global longitudinal strain (GLS) in a population of healthy adult cats of different breeds. Influences of heart rate, body weight, and age were investigated., Animals: A total of 132 healthy, adult cats were included in this study., Materials and Methods: Left apical two-, three-, and four-chamber views were obtained prospectively for GLS measurements using two-dimensional speckle tracking performed with cardiac performance analysis. Potential influence of body weight, heart rate, and age was analyzed, and the interobserver and intra-observer variability of the measurements was determined., Results: Endocardial GLS values were not significantly influenced by body weight (P=0.102), heart rate (P=0.144), or age (P=0.075). A reference interval for GLS of -21.18% to -37.50% (±4.12) was determined. The interobserver and intra-observer variability showed excellent agreement., Discussion and Conclusions: Two-dimensional STE is a feasible technique for the evaluation of cardiac myocardial deformation and systolic function in cats. Showing an excellent interobserver and intra-observer agreement, two-dimensional STE is a promising method for clinical analysis of cardiac deformation in cats., Competing Interests: Conflict of Interest Statement The authors do not have any conflicts of interest to disclose., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

The structural development of the heart depends heavily on mechanical forces, and rhythmic contractions generate essential physical stimuli during morphogenesis. Cardiac cells play a critical role in coordinating this process by sensing and responding to these mechanical forces. In vivo, cells experience rhythmic spatial and temporal variations in deformation-related stresses throughout heart development. What impact do these mechanical forces have on heart morphogenesis? Recent work in zebrafish (Danio rerio) offers important insights into this question. This review focuses on endocardial (EdCs) and myocardial cells (cardiomyocytes, CMs), key cell types in the heart, and provides a comprehensive overview of forces and tissue mechanics in zebrafish and their direct influence on cardiac cell identity., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2025 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Spatial heterogeneity in repolarization plays an important role in generating and sustaining cardiac arrhythmias. Reliable determination of repolarization times remains challenging., Objectives: The goal of this study was to improve processing of densely sampled noncontact unipolar electrograms to yield reliable high-resolution activation and repolarization maps., Methods: Endocardial noncontact unipolar electrograms were both simulated and recorded in pig left ventricle. Electrical activity on the endocardial surface was processed in terms of a pseudo-electric field. Activation and repolarization times were calculated by using an amplitude-weighted average on QRS and T waves (ie, the E-field method). This was compared vs the conventional Wyatt method on unipolar electrograms. Timing maps were validated against timing on endocardial action potentials in a simulation study. In vivo, activation and repolarization times determined by using this alternative E-field method were validated against simultaneously recorded endocardial monophasic action potentials (MAPs)., Results: Simulation showed that the E-field method provides viable measurements of local endocardial action potential activation and repolarization times. In vivo, correlation of E-field activation times with MAP activation times (r E  = 0.76; P < 0.001) was similar to those of Wyatt (r Wyatt  = 0.80, P < 0.001; P[h 1 :r E > r Wyatt ] = 0.82); for repolarization times, correlation improved significantly (r E  = 0.96, P < 0.001; r Wyatt  = 0.82, P < 0.001; P[h 1 :r E > r Wyatt ] < 0.00001). This resulted in improved correlations of activation-repolarization intervals to endocardial action potential duration on MAP (r E  = 0.96, P < 0.001; r Wyatt  = 0.86, P < 0.001; P[h 1 :r E > r Wyatt ] < 0.00001). Spatial beat-to-beat variation of repolarization could only be calculated by using the E-field methodology and correlated well with the MAP beat-to-beat variation of repolarization (r E  = 0.76; P = 0.001)., Conclusions: The E-field method substantially enhances information from endocardial noncontact electrogram data, allowing for dense maps of activation and repolarization times and derived parameters., Competing Interests: Funding Support and Author Disclosures The work was supported by grants from KU Leuven BOF, C14/18/079, to Drs Willems and Claus and from Fund for Scientific Research-Flanders (FWO) G097021N to Drs Claus and Sipido. Dr Willems is supported as Senior Clinical Investigator and Dr Amoni as PhD fellow by the Fund for Scientific Research-Flanders (FWO)., (Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Computational modeling of electrophysiological properties of the rabbit heart is a commonly used way to enhance and/or complement findings from classic lab work on single cell or tissue levels. Yet, thus far, there was no possibility to extend the scope to include the resulting body surface potentials as a way of validation or to investigate the effect of certain pathologies. Based on CT imaging, we developed the first openly available computational geometrical model not only of the whole heart but also the complete torso of the rabbit. Additionally, we fabricated a 32-lead ECG-vest to record body surface potential signals of the aforementioned rabbit. Based on the developed geometrical model and the measured signals, we then optimized the activation sequence of the ventricles, recreating the functionality of the Purkinje network, and we investigated different apico-basal and transmural gradients in action potential duration. Optimization of the activation sequence resulted in an average root mean square error between measured and simulated signal of 0.074 mV/ms for all leads. The best-fit T-Wave, compared to measured data (0.038 mV/ms), resulted from incorporating an action potential duration gradient from base to apex with a respective shortening of 20 ms and a transmural gradient with a shortening of 15 ms from endocardium to epicardium. By making our model and measured data openly available, we hope to give other researchers the opportunity to verify their research, as well as to create the possibility to investigate the impact of electrophysiological alterations on body surface signals for translational research., Competing Interests: The authors have declared that no competing interests exist.

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 ([Ca 2+ ] 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., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Myocardial infarction and subsequent therapeutic interventions activate numerous intracellular cascades in every constituent cell type of the heart. Endothelial cells produce several protective compounds in response to therapeutic ultrasound, under both normoxic and ischemic conditions. How endothelial cells sense ultrasound and convert it to a beneficial biological response is not known. We adopted a global, unbiased phosphoproteomics approach aimed at understanding how endothelial cells respond to ultrasound. Here, we use primary cardiac endothelial cells to explore the cellular signaling events underlying the response to ischemia-like cellular injury and ultrasound exposure in vitro. Enriched phosphopeptides were analyzed with a high mass accuracy liquid chromatrography (LC) - tandem mass spectrometry (MS/MS) proteomic platform, yielding multiple alterations in both total protein levels and phosphorylation events in response to ischemic injury and ultrasound. Application of pathway algorithms reveals numerous protein networks recruited in response to ultrasound including those regulating RNA splicing, cell-cell interactions and cytoskeletal organization. Our dataset also permits the informatic prediction of potential kinases responsible for the modifications detected. Taken together, our findings begin to reveal the endothelial proteomic response to ultrasound and suggest potential targets for future studies of the protective effects of ultrasound in the ischemic heart., (Copyright © 2021 Elsevier B.V. All rights reserved.)

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., Competing Interests: The authors have no potential conflicts of interest to disclose., (© 2021 The Korean Academy of Medical Sciences.)

Life expectancy of contemporary cardiac pacemakers is limited due to the use of an internal primary battery. Repeated device replacement interventions are necessary, which leads to an elevated risk for patients and an increase of health care costs. The aim of our study is to investigate the feasibility of powering an endocardial pacemaker by converting a minimal amount of the heart's kinetic energy into electric energy. The intrinsic cardiac muscle activity makes it an ideal candidate as continuous source of energy for endocardial pacemakers. For this reason, we developed a prototype able to generate enough power to supply a pacing circuit at different heart rates. The prototype consists of a mass imbalance that drives an electromagnetic generator while oscillating. We developed a mathematical model to estimate the amount of energy harvested from the right ventricle. Finally, the implemented prototype was successfully tested during in-vitro and in-vivo experiments., Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: Dr. Reichlin is a consultant for Medtronic. He has received speaker’s honoraria or travel support from Abbott, Bayer, Biotronik, Biosense Webster, BMS, Boston Scientific, Daiichi, Medtronic, and Pfizer. He has received institutional support from Abbott, Biotronik, Biosense Webster, Boston Scientific, Medtronic, and Microport. Dr. Haeberlin has received travel grants from Medtronic. He is a consultant for Cairdac, co-founder and CEO of Act-Inno, and has received research funding from Novartis.

Important physiologic and anatomic differences exist between the epicardium and endocardium, particularly of the ventricles, and these differences affect ablation biophysics. Absence of passive convective effects conferred by circulating blood as well as the presence of epicardial fat and vessels and absence of intracavitary ridges and structures affect ablation lesion size when performing epicardial catheter-based ablation, whether using radiofrequency or cryothermal energy. Understanding differential effects in each environment is important in informing strategies to increase ablation lesion depth. When using actively cooled radiofrequency ablation, local impedance can be altered to selectively augment energy delivery., Competing Interests: Disclosure R. Debenham: Nothing to disclose. W.S. Tzou: Consultant or speaker honoraria from Abbott, Biosense Webster, Boston Scientific, Medtronic; Research funding from Boston Scientific, Biosense Webster, Abbott., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Understanding how coronary blood vessels form and regenerate during development and progression of cardiac diseases will shed light on the development of new treatment options targeting coronary artery diseases. Recent studies with the state-of-the-art technologies have identified novel origins of, as well as new, cellular and molecular mechanisms underlying the formation of coronary vessels in the postnatal heart, including collateral artery formation, endocardial-to-endothelial differentiation and mesenchymal-to-endothelial transition. These new mechanisms of coronary vessel formation and regeneration open up new possibilities targeting neovascularization for promoting cardiac repair and regeneration. Here, we highlight some recent studies on cellular mechanisms of coronary vessel formation, and discuss the potential impact and significance of the findings on basic research and clinical application for treating ischemic heart disease., (Copyright © 2020 Cold Spring Harbor Laboratory Press; all rights reserved.)

Understanding the depolarisation pattern of the equine heart under normal physiologic conditions, and its relationship to the surface electrocardiogram (ECG), is of uppermost importance before any further research can be done about the pathophysiology of complex arrhythmias. In the present study, a 3D electro-anatomical mapping system was used to evaluate the qualitative and quantitative depolarisation patterns and correlation to the surface ECG of both the atrial and ventricular endocardium in seven healthy horses in sinus rhythm under general anaesthesia. Bipolar activation maps of the endocardium were analysed. The first atrial activation was located at the height of the terminal crest. Only one interatrial conduction pathway was recognised. The first and second P wave deflections represent the right and left atrial depolarisation, respectively. Bundle of His electrograms could be recorded in 5/7 horses. Left ventricular activation started at the mid septum and right ventricular activation started apically from the supraventricular crest. This was followed by separate depolarisations at the height of the mid free wall. Further ventricular depolarisation occurred in an explosive pattern. Electrically active tissue could be found in all pulmonary veins. In contrast to findings of previous studies, all parts of the ventricular depolarisation contributed to the surface ECG QRS complex. This study provides a reference for the normal sinus impulse endocardial propagation pattern and for conduction velocities in equine atria and ventricles., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Defective coronary network function and insufficient blood supply are both cause and consequence of myocardial infarction. Efficient revascularization after infarction is essential to support tissue repair and function. Zebrafish hearts exhibit a remarkable ability to regenerate, and coronary revascularization initiates within hours of injury, but how this process is regulated remains unknown. Here, we show that revascularization requires a coordinated multi-tissue response culminating with the formation of a complex vascular network available as a scaffold for cardiomyocyte repopulation. During a process we term "coronary-endocardial anchoring," new coronaries respond by sprouting (1) superficially within the regenerating epicardium and (2) intra-ventricularly toward the activated endocardium. Mechanistically, superficial revascularization is guided by epicardial Cxcl12-Cxcr4 signaling and intra-ventricular sprouting by endocardial Vegfa signaling. Our findings indicate that the injury-activated epicardium and endocardium support cardiomyocyte replenishment initially through the guidance of coronary sprouting. Simulating this process in the injured mammalian heart should help its healing., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objectives: This study sought to determine new reference cutoffs for normal unipolar voltage (UV) and bipolar voltage (BV) that would be adjusted for the LV remodeling., Background: The definition of "normal" left ventricular (LV) endocardial voltage in patients with post-infarct scar is still lacking. The reference voltage of the noninfarcted myocardium (NIM) may differ between patients depending on LV structural remodeling and the ensuing interstitial fibrosis., Methods: Electroanatomic voltage mapping was integrated with isotropic late gadolinium-enhanced cardiac magnetic resonance in 15 patients with nonremodeled LV and 12 patients with remodeled LV (end-systolic volume index >50 ml/m 2 with ejection fraction <47% assessed by cardiac magnetic resonance). Reference voltages (fifth percentile values) were determined from pooled NIM segments without late gadolinium enhancement., Results: The cutoffs for normal BV and UV were ≥3.0 and ≥6.7 mV for nonremodeled LV and ≥2.1 and ≥6.4 mV for remodeled LV. Endocardial low-voltage area (LVA) defined by the adjusted cutoffs corresponded better to late gadolinium enhancement-detected scar than did LVA defined by uniform cutoffs. In 15 patients who underwent successful ablation of ventricular tachycardia, the LVA contained >97% of targeted evoked delayed potentials. Insights from whole-heart T1 mapping revealed more fibrotic NIM in patients with remodeled LV compared with nonremodeled LV., Conclusions: This study found substantial differences in endocardial voltage of NIM in post-infarct patients with remodeled versus nonremodeled LV. The new adjusted cutoffs for "normal" BV and UV enable a patient-tailored approach to electroanatomic voltage mapping of LV., (Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

In this study, we explore the use of low rank and sparse constraints for the noninvasive estimation of epicardial and endocardial extracellular potentials from body-surface electrocardiographic data to locate the focus of premature ventricular contractions (PVCs). The proposed strategy formulates the dynamic spatiotemporal distribution of cardiac potentials by means of low rank and sparse decomposition, where the low rank term represents the smooth background and the anomalous potentials are extracted in the sparse matrix. Compared to the most previous potential-based approaches, the proposed low rank and sparse constraints are batch spatiotemporal constraints that capture the underlying relationship of dynamic potentials. The resulting optimization problem is solved using alternating direction method of multipliers. Three sets of simulation experiments with eight different ventricular pacing sites demonstrate that the proposed model outperforms the existing Tikhonov regularization (zero-order, second-order) and L1-norm based method at accurately reconstructing the potentials and locating the ventricular pacing sites. Experiments on a total of 39 cases of real PVC data also validate the ability of the proposed method to correctly locate ectopic pacing sites.

Lower vertebrate and neonatal mammalian hearts exhibit the remarkable capacity to regenerate through the reprogramming of pre-existing cardiomyocytes. However, how cardiac injury initiates signaling pathways controlling this regenerative reprogramming remains to be defined. Here, we utilize in vivo biophysical and genetic fate mapping zebrafish studies to reveal that altered hemodynamic forces due to cardiac injury activate a sequential endocardial-myocardial signaling cascade to direct cardiomyocyte reprogramming and heart regeneration. Specifically, these altered forces are sensed by the endocardium through the mechanosensitive channel Trpv4 to control Klf2a transcription factor expression. Consequently, Klf2a then activates endocardial Notch signaling which results in the non-cell autonomous initiation of myocardial Erbb2 and BMP signaling to promote cardiomyocyte reprogramming and heart regeneration. Overall, these findings not only reveal how the heart senses and adaptively responds to environmental changes due to cardiac injury, but also provide insight into how flow-mediated mechanisms may regulate cardiomyocyte reprogramming and heart regeneration., Competing Interests: MG, DC, RZ, RS, CN, LZ, LN, EM, JV, CB, CB, Jd, NC No competing interests declared, (© 2019, Gálvez-Santisteban et al.)

Regional cardiac function analysis is important for the diagnosis and treatment planning of ischemic heart disease, but has not been sufficiently developed in the field of computed tomography (CT). Therefore, we propose a 3D endocardial tracking framework for cardiac CT using local point cloud registration based on the iterative closest point with an integrated scale estimation algorithm. We also introduce regional function descriptors that express the curvature and stretching of the endocardium: Surface distortion (E) and Scaling rate (S). For a region-to-region comparison, we propose endocardial segmentation according to coronary perfusion territories defined by the Voronoi partition based on coronary distribution. Our study of 65 endocardial segments in ten subjects showed that global endocardial deformation has a positive relationship with the stroke volume index (r  =  0.896 and 0.829 in [Formula: see text] and [Formula: see text], respectively) and ejection fraction (r  =  0.804 and 0.835), and a positive relationship with the brain natriuretic peptide level (r  =  0.690 and 0.776). A positive relationship between segmental E and S (r  =  0.845), a higher value of E in ischemic segments (p   =  0.021) that are determined by fractional flow reserve estimated from coronary CT data, and a higher value of S in the left circumflex artery territory (p   <  0.05) were also observed. The required radiation dose was 5.0  ±  0.7 mSv and the computation time was 7.2  ±  1.1 min. The result suggests that proposed endocardial deformation analysis using CT can be conducted on site and in time for the acute setting, and may be useful for the diagnosis of cardiac dysfunction or myocardial ischemia.

Purpose: Personalized computational simulations of the heart could open up new improved approaches to diagnosis and surgery assistance systems. While it is fully recognized that myocardial fiber orientation is central for the construction of realistic computational models of cardiac electromechanics, the role of its overall architecture and connectivity remains unclear. Morphological studies show that the distribution of cardiac muscular fibers at the basal ring connects epicardium and endocardium. However, computational models simplify their distribution and disregard the basal loop. This work explores the influence in computational simulations of fiber distribution at different short-axis cuts., Methods: We have used a highly parallelized computational solver to test different fiber models of ventricular muscular connectivity. We have considered two rule-based mathematical models and an own-designed method preserving basal connectivity as observed in experimental data. Simulated cardiac functional scores (rotation, torsion and longitudinal shortening) were compared to experimental healthy ranges using generalized models (rotation) and Mahalanobis distances (shortening, torsion)., Results: The probability of rotation was significantly lower for ruled-based models [95% CI (0.13, 0.20)] in comparison with experimental data [95% CI (0.23, 0.31)]. The Mahalanobis distance for experimental data was in the edge of the region enclosing 99% of the healthy population., Conclusions: Cardiac electromechanical simulations of the heart with fibers extracted from experimental data produce functional scores closer to healthy ranges than rule-based models disregarding architecture connectivity.

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., (Copyright © 2018 Biophysical Society. Published by Elsevier Inc. All rights reserved.)

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., (Copyright © 2018 Elsevier Inc. All rights reserved.)

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., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

The reconstruction of the ventricular cardiac conduction system (CCS) from patient-specific data is a challenging problem. High-resolution imaging techniques have allowed only the segmentation of proximal sections of the CCS from images acquired ex vivo. In this paper, we present an algorithm to estimate the location of a set of Purkinje-myocardial junctions (PMJs) from electro-anatomical maps, as those acquired during radio-frequency ablation procedures. The method requires a mesh representing the myocardium with local activation time measurements on a subset of nodes. We calculate the backwards propagation of the electrical signal from the measurement points to all the points in the mesh to define a set of candidate PMJs that is iteratively refined. The algorithm has been tested on several Purkinje network configurations, with simulated activation maps, subject to different error amplitudes. The results show that the method is able to build a set of PMJs that explain the observed activation map for different synthetic CCS configurations. In the tests, the average error in the predicted activation time is below the amplitude of the error applied to the data., (Copyright © 2018 John Wiley & Sons, Ltd.)

The mammalian heart must function as an efficient pump while simultaneously conducting electrical signals to drive the contraction process. In the ventricles, electrical activation begins at the insertion points of the Purkinje network in the endocardium. How does the diffusion component of the subsequent excitation wave propagate from the endocardium in a healthy heart wall without creating directional biases? We show that this is a consequence of the particular geometric organization of myocytes in the heart wall. Using a generalized helicoid to model fiber orientation, we treat the myocardium as a curved space via Riemannian geometry, and then use stochastic calculus to model local signal diffusion. Our analysis shows that the helicoidal arrangement of myocytes minimizes the directional biases that could lead to aberrant propagation, thereby explaining how electrophysiological principles are consistent with local measurements of cardiac fiber geometry. We discuss our results in the context of the need to balance electrical and mechanical requirements for heart function.

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., (© 2018 American Heart Association, Inc.)

Objective: cardiac pacemakers require regular medical follow-ups to ensure proper functioning. However, device replacements due to battery depletion are common and account for ∼25% of all implantation procedures. Furthermore, conventional pacemakers require pacemaker leads which are prone to fractures, dislocations or isolation defects. The ensuing surgical interventions increase risks for the patients and costs that need to be avoided., Methods: in this study, we present a method to harvest energy from endocardial heart motions. We developed a novel generator, which converts the heart's mechanical into electrical energy by electromagnetic induction. A mathematical model has been introduced to identify design parameters strongly related to the energy conversion efficiency of heart motions and fit the geometrical constraints for a miniaturized transcatheter deployable device. The implemented final design was tested on the bench and in vivo., Results: the mathematical model proved an accurate method to estimate the harvested energy. For three previously recorded heart motions, the model predicted a mean output power of 14.5, 41.9, and 16.9 μW. During an animal experiment, the implanted device harvested a mean output power of 0.78 and 1.7 μW at a heart rate of 84 and 160 bpm, respectively., Conclusion: harvesting kinetic energy from endocardial motions seems feasible. Implanted at an energetically favorable location, such systems might become a welcome alternative to extend the lifetime of cardiac implantable electronic device., Significance: the presented endocardial energy harvesting concept has the potential to turn pacemakers into battery- and leadless systems and thereby eliminate two major drawbacks of contemporary systems.

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 (T max ) and the time constant of [Ca 2+ ] i transient decay were significantly longer in ENDO cells than in EPI cells. An increase in preload (stretched cells) prolonged T max in both cell types; however, the prolongation was greater in EPI cells, resulting in a decrease in the transmural gradient in T max 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., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

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., (© 2017 Wiley Periodicals, Inc.)

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.

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., (© 2017 Wiley Periodicals, Inc.)

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., (© 2016 American Heart Association, Inc.)

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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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.

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., (Copyright © 2016 the American Physiological Society.)

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., (© 2016 John Wiley & Sons Australia, Ltd.)

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., (Copyright © 2016 the American Physiological Society.)

Mural cells of the vessel wall, namely pericytes and vascular smooth muscle cells, are essential for vascular integrity. The developmental sources of these cells and molecular mechanisms controlling their progenitors in the heart are only partially understood. Here we show that endocardial endothelial cells are progenitors of pericytes and vascular smooth muscle cells in the murine embryonic heart. Endocardial cells undergo endothelial-mesenchymal transition and convert into primitive mesenchymal progenitors expressing the platelet-derived growth factor receptors, PDGFRα and PDGFRβ. These progenitors migrate into the myocardium, differentiate and assemble the wall of coronary vessels, which requires canonical Wnt signalling involving Frizzled4, β-catenin and endothelial cell-derived Wnt ligands. Our findings identify a novel and unexpected population of progenitors for coronary mural cells with potential relevance for heart function and disease conditions.

Background: Noninvasive imaging of cardiac activation before ablation of the arrhythmogenic substrate can reduce electrophysiological procedure duration and help choosing between an endocardial or epicardial approach. A noninvasive imaging technique was evaluated that estimates both endocardial and epicardial activation from body surface potential maps. We performed a study in isolated and in situ pig hearts, estimating activation from body surface potential maps during sinus rhythm and localizing endocardial and epicardial stimulation sites., Methods and Results: From 3 Langendorff-perfused pig hearts, 180 intramural unipolar electrograms were recorded during sinus rhythm and ectopic activation, together with pseudo-body surface potential map ECGs in 2 of them. From 4 other anesthetized pigs, 64-lead body surface potential maps were recorded during sinus rhythm and ventricular stimulation from 27 endocardial and epicardial sites. The ventricular activation pattern was computed from the recorded QRS complexes. For both Langendorff-perfused hearts, the calculated epicardial and endocardial activation patterns showed good qualitative correspondence to the patterns obtained with needle electrodes. Absolute timing difference for sinus rhythm was 10±5 and 11±8 ms respectively, and for ectopic activation 6±5 and 7±6 ms, respectively. Calculated activation for the in situ hearts in sinus rhythm was similar to patterns recorded in Langendorff-perfused hearts. During stimulation, the distance between the stimulation site and calculated site of earliest activation was 18 (15-27) mm, and 23 of 27 stimulation sites were correctly mapped to either endocardium or epicardium., Conclusions: Noninvasive activation imaging is able to determine earliest ventricular activation and discriminate endocardial from epicardial origin of activation with clinically relevant accuracy., (© 2016 American Heart Association, Inc.)

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., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Epithelial-Mesenchymal Transformation (EMT) and the subsequent invasion of epicardial and endocardial cells during cardiac development is critical to the development of the coronary vessels and heart valves. The transformed cells give rise to cardiac fibroblasts and vascular smooth muscle cells or valvular interstitial cells, respectively. The Type III Transforming Growth Factor β (TGFβR3) receptor regulates EMT and cell invasion in both cell types, but the signaling mechanisms downstream of TGFβR3 are not well understood. Here we use epicardial and endocardial cells in in vitro cell invasion assays to identify common mechanisms downstream of TGFβR3 that regulate cell invasion. Inhibition of NF-κB activity blocked cell invasion in epicardial and endocardial cells. NF-κB signaling was found to be dysregulated in Tgfbr3(-/-) epicardial cells which also show impaired cell invasion in response to ligand. TGFβR3-dependent cell invasion is also dependent upon Activin Receptor-Like Kinase (ALK) 2, ALK3, and ALK5 activity. A TGFβR3 mutant that contains a threonine to alanine substitution at residue 841 (TGFβR3-T841A) induces ligand-independent cell invasion in both epicardial and endocardial cells in vitro. These findings reveal a role for NF-κB signaling in the regulation of epicardial and endocardial cell invasion and identify a mutation in TGFβR3 which stimulates ligand-independent signaling., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Ablation of cardiac tissue with pulsed electric fields is a promising alternative to current thermal ablation methods, and it critically depends on the electric field distribution in the heart., Methods: We developed a model that incorporates the twisted anisotropy of cardiac tissue and computed the electric field distribution in the tissue. We also performed experiments in rabbit ventricles to validate our model. We find that the model agrees well with the experimentally determined ablation volume if we assume that all tissue that is exposed to a field greater than 3 kV/cm is ablated. In our numerical analysis, we considered how tissue thickness, degree of anisotropy, and electrode configuration affect the geometry of the ablated volume. We considered two electrode configurations: two parallel needles inserted into the myocardium ("penetrating needles" configuration) and one circular electrode each on epi- and endocardium, opposing each other ("epi-endo" configuration)., Results: For thick tissues (10 mm) and moderate anisotropy ratio (a = 2), we find that the geometry of the ablated volume is almost unaffected by twisted anisotropy, i.e. it is approximately translationally symmetric from epi- to endocardium, for both electrode configurations. Higher anisotropy ratio (a = 10) leads to substantial variation in ablation width across the wall; these variations were more pronounced for the penetrating needle configuration than for the epi-endo configuration. For thinner tissues (4 mm, typical for human atria) and higher anisotropy ratio (a = 10), the epi-endo configuration yielded approximately translationally symmetric ablation volumes, while the penetrating electrodes configuration was much more sensitive to fiber twist., Conclusions: These results suggest that the epi-endo configuration will be reliable for ablation of atrial fibrillation, independently of fiber orientation, while the penetrating electrode configuration may experience problems when the fiber orientation is not consistent across the atrial wall.

Background: Unlike arteries, in which regionally distinct hemodynamics are associated with phenotypic heterogeneity, the relationships between endocardial endothelial cell phenotype and intraventricular flow remain largely unexplored. We investigated regional differences in left ventricular wall shear stress and their association with endocardial endothelial cell gene expression., Methods and Results: Local wall shear stress was calculated from 4-dimensional flow magnetic resonance imaging in 3 distinct regions of human (n=8) and pig (n=5) left ventricle: base, adjacent to the outflow tract; midventricle; and apex. In both species, wall shear stress values were significantly lower in the apex and midventricle relative to the base; oscillatory shear index was elevated in the apex. RNA sequencing of the endocardial endothelial cell transcriptome in pig left ventricle (n=8) at a false discovery rate ≤10% identified 1051 genes differentially expressed between the base and the apex and 327 between the base and the midventricle; no differentially expressed genes were detected at this false discovery rate between the apex and the midventricle. Enrichment analyses identified apical upregulation of genes associated with translation initiation including mammalian target of rapamycin, and eukaryotic initiation factor 2 signaling. Genes of mitochondrial dysfunction and oxidative phosphorylation were also consistently upregulated in the left ventricular apex, as were tissue factor pathway inhibitor (mean 50-fold) and prostacyclin synthase (5-fold)-genes prominently associated with antithrombotic protection., Conclusions: We report the first spatiotemporal measurements of wall shear stress within the left ventricle and linked regional hemodynamics to heterogeneity in ventricular endothelial gene expression, most notably to translation initiation and anticoagulation properties in the left ventricular apex, in which oscillatory shear index is increased and wall shear stress is decreased., (© 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.)

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.

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.

In vertebrates, heart pumping is required for cardiac morphogenesis and altering myocardial contractility leads to abnormal intracardiac flow forces and valve defects. Among the different mechanical cues generated in the developing heart, oscillatory flow has been proposed to be an essential factor in instructing endocardial cell fate toward valvulogenesis and leads to the expression of klf2a, a known atheroprotective transcription factor. To date, the mechanism by which flow forces are sensed by endocardial cells is not well understood. At the onset of valve formation, oscillatory flows alter the spectrum of the generated wall shear stress (WSS), a key mechanical input sensed by endothelial cells. Here, we establish that mechanosensitive channels are activated in response to oscillatory flow and directly affect valvulogenesis by modulating the endocardial cell response. By combining live imaging and mathematical modeling, we quantify the oscillatory content of the WSS during valve development and demonstrate it sets the endocardial cell response to flow. Furthermore, we show that an endocardial calcium response and the flow-responsive klf2a promoter are modulated by the oscillatory flow through Trpv4, a mechanosensitive ion channel specifically expressed in the endocardium during heart valve development. We made similar observations for Trpp2, a known Trpv4 partner, and show that both the absence of Trpv4 or Trpp2 leads to valve defects. This work identifies a major mechanotransduction pathway involved during valve formation in vertebrates., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: Because of the optical features of heart tissue, optical and electrical action potentials are only moderately associated, especially when near-infrared dyes are used in optical mapping (OM) studies., Objective: By simultaneously recording transmural electrical action potentials (APs) and optical action potentials (OAPs), we aimed to evaluate the contributions of both electrical and optical influences to the shape of the OAP upstroke., Methods and Results: A standard glass microelectrode and OM, using an near-infrared fluorescent dye (di-4-ANBDQBS), were used to simultaneously record transmural APs and OAPs in a Langendorff-perfused rabbit heart during atrial, endocardial, and epicardial pacing. The actual profile of the transmural AP upstroke across the LV wall, together with the OAP upstroke, allowed for calculations of the probing-depth constant (k ~2.1 mm, n = 24) of the fluorescence measurements. In addition, the transmural AP recordings aided the quantitative evaluation of the influences of depth-weighted and lateral-scattering components on the OAP upstroke. These components correspond to the components of the propagating electrical wave that are transmural and parallel to the epicardium. The calculated mean values for the depth-weighted and lateral-scattering components, whose sum comprises the OAP upstroke, were (in ms) 10.18 ± 0.62 and 0.0 ± 0.56 for atrial stimulation, 9.37 ± 1.12 and 3.01 ± 1.30 for endocardial stimulation, and 6.09 ± 0.79 and 8.16 ± 0.98 for epicardial stimulation; (n = 8 for each). For this dye, 90% of the collected fluorescence originated up to 4.83 ± 0.18 mm (n = 24) from the epicardium., Conclusions: The co-registration of OM and transmural microelectrode APs enabled the probing depth of fluorescence measurements to be calculated and the OAP upstroke to be divided into two components (depth-weighted and lateral-scattering), and it also allowed the relative strengths of their effects on the shape of the OAP upstroke to be evaluated.

Vagal nerve stimulation (VNS) has been proposed as a cardioprotective intervention. However, regional ventricular electrophysiological effects of VNS are not well characterized. The purpose of this study was to evaluate effects of right and left VNS on electrophysiological properties of the ventricles and hemodynamic parameters. In Yorkshire pigs, a 56-electrode sock was used for epicardial (n = 12) activation recovery interval (ARI) recordings and a 64-electrode catheter for endocardial (n = 9) ARI recordings at baseline and during VNS. Hemodynamic recordings were obtained using a conductance catheter. Right and left VNS decreased heart rate (84 ± 5 to 71 ± 5 beats/min and 84 ± 4 to 73 ± 5 beats/min), left ventricular pressure (89 ± 9 to 77 ± 9 mmHg and 91 ± 9 to 83 ± 9 mmHg), and dP/dtmax (1,660 ± 154 to 1,490 ± 160 mmHg/s and 1,595 ± 155 to 1,416 ± 134 mmHg/s) and prolonged ARI (327 ± 18 to 350 ± 23 ms and 327 ± 16 to 347 ± 21 ms, P < 0.05 vs. baseline for all parameters and P = not significant for right VNS vs. left VNS). No anterior-posterior-lateral regional differences in the prolongation of ARI during right or left VNS were found. However, endocardial ARI prolonged more than epicardial ARI, and apical ARI prolonged more than basal ARI during both right and left VNS. Changes in dP/dtmax showed the strongest correlation with ventricular ARI effects (R(2) = 0.81, P < 0.0001) than either heart rate (R(2) = 0.58, P < 0.01) or left ventricular pressure (R(2) = 0.52, P < 0.05). Therefore, right and left VNS have similar effects on ventricular ARI, in contrast to sympathetic stimulation, which shows regional differences. The decrease in inotropy correlates best with ventricular electrophysiological effects., (Copyright © 2014 the American Physiological Society.)

The postnatal coronary vessels have been viewed as developing through expansion of vessels formed during the fetal period. Using genetic lineage tracing, we found that a substantial portion of postnatal coronary vessels arise de novo in the neonatal mouse heart, rather than expanding from preexisting embryonic vasculature. Our data show that lineage conversion of neonatal endocardial cells during trabecular compaction generates a distinct compartment of the coronary circulation located within the inner half of the ventricular wall. This lineage conversion occurs within a brief period after birth and provides an efficient means of rapidly augmenting the coronary vasculature. This mechanism of postnatal coronary vascular growth provides avenues for understanding and stimulating cardiovascular regeneration following injury and disease., (Copyright © 2014, American Association for the Advancement of Science.)