Source-sink Mismatch Research Articles

Spontaneous termination of ventricular tachycardia in the human heart.

Understanding the spatiotemporal location of the spontaneous termination of ventricular tachycardia (VT) may provide new insights for ablation. To test the hypothesis that spontaneous VT termination most frequently occurs at the VT exit due to source-sink mismatch and to characterize electrophysiological properties of the sites termination during VT and with extra-stimulus technique. Retrospective analysis of intraoperative mapping studies of nine patients with ischemic cardiopathy or repaired tetralogy of Fallot. Simultaneous endocardial and epicardial mapping was performed in both ventricles using a custom mapping array during VT. Electrogram (EGM) characteristics before and at the moment of termination were analyzed including: cycle length oscillations, EGM heterogeneity and a variation in the systolic/diastolic path. The decrements to extra stimulus were analysed for termination sites and other diastolic sites. Nine VTs in seven patients demonstrated spontaneous VT termination. Seven VTs (77.8%) spontaneously terminated in the final third of the systolic interval, one (11.1%) in early diastole and one (11.1%) in mid diastole. Cycle length oscillations (prolongation, shortening, and no change) were seen in equal frequency. Four VTs (44.4%) showed alternans in the local EGM at the site of termination and this was more prevalent than alternans at other sites in the diastolic pathway (p < .001). Only one-third of VTs showed a change in activation pattern before termination. There was no difference based on etiology. During substrate characterization with extra-stimulus pacing, sites of spontaneous termination showed greater decrement than other sites of the VT circuit during pacing (43.5 ± 14.5 ms vs. 31.2 ± 31.2 ms; p = .003). The entrance zone rather than the exit is the commonest site for the spontaneous termination of VT in the human heart. These sites tend to demonstrate EGM alternans during VT and greater decrement during extrastimulus pacing. These findings may help guide future studies into improving the success of VT ablation.

Abstract We045: Development of SA Node Organoids: A Multicellular Approach to Biological Pacemaking

The rising prevalence of sinoatrial (SA) node dysfunction, attributed to the aging population, is emerging as a critical health issue. The SA node, a natural organoid within the heart, comprises the pacemaker cells embedded within a connective tissue matrix, insulated electrically from the surrounding atrial muscle cells. This isolated architecture, along with a heterogeneous cellular composition, is crucial for the SA node's robust pacemaking and electrical conduction. Developing methods to reconstruct this crucial heterogeneous structure could offer a long-term solution for individuals with SA node dysfunction. However, the use of current biological pacemakers, which typically involve a single cell type, has often led to unstable heart rhythms during one-month in vivo integration, challenging their long-term clinical application as biological pacemakers. To address existing SA node model limitations, we developed a SA node organoid that reproduces the human SA node's multicellular tissue structure. Initially, we developed a protocol for generating cardiac SA node organoids by employing a lentivirus to deliver dox-inducible genes for key pacemaker transcription factors, specifically TBX-18 or Shox-2. We mixed wild-type human-induced pluripotent stem cells (hiPSCs) with those modified to express TBX-18 or Shox-2. These cell mixtures were aggregated, embedded in a diluted Matrigel, and then exposed to a cardiac differentiation protocol, activating TBX-18 or Shox-2 at specific times (D1 or D7) via Dox administration. By D9, these organoids began to exhibit contraction, which lasted beyond 60 days, with notable upregulation of two transcription factors and pacemaker-specific genes following Dox treatment. Subsequently, we integrated the SA node organoid into 2D hiPSC-derived atrial muscle tissue constructs, maintaining geometric isolation within the cardiac tissue to enhance source-sink mismatch. This isolation allowed the SA node organoid to successfully trigger activity in adjacent dormant cardiomyocytes, preserving the rhythm for over 60 days. These findings could redefine the role of tissue architecture and cell diversity in the SA node's pacemaking function, potentially leading to a high-fidelity, tissue-level biological pacemaker as a new treatment strategy for SA node dysfunctions.

Wavefront curvature analysis derived from preprocedural imaging can identify the critical isthmus in patients with postinfarcted ventricular tachycardia

BackgroundWhere activation wavefront curvature is convexly shaped, functional conduction block can occur. ObjectiveThe purpose of this study was to determine whether left ventricular (LV) wall thickness determined from contrast-enhanced computed tomography (CT) is useful in localizing such areas in clinical postinfarction reentrant ventricular tachycardia (VT). MethodsWe evaluated data from 6 patients who underwent catheter ablation for postinfarction VT. CT imaging with inHEART processing was conducted 1–3 days before electrophysiological (EP) study to determine LV wall thickness (T). Activation wavefront curvature was approximated as ΔT/T, where ΔT represents wall thickness change. During EP study, bipolar LV VT electrograms were acquired using a high-density mapping catheter, and activation times were determined. Maps of T, ΔT/T, and VT activation were subsequently compared using statistical analyses. ResultsTwo of 6 cases exhibited dual circuit morphologies, resulting in a total of 8 VT morphologies analyzed. The LV wall near the VT isthmus location tended to be thin, on the order of a few hundred micrometers. Regions of largest ΔT/T partially coincided with the lateral isthmus boundaries where electrical conduction block occurred during VT. ΔT/T at the boundaries, measured from imaging, was significantly larger compared to values at the isthmus midline and to the global LV mean value (P <.001). ConclusionWavefront curvature measured by ΔT/T and caused by source–sink mismatch is dependent on ventricular wall thickness. Areas of high wavefront curvature partly coincide with and may be helpful in locating the VT isthmus in infarct border zones using preprocedural imaging analysis.

Source-sink mismatch and conduction block: simulation study

Abstract Background Source-sink mismatch is one of the key concepts in arrhythmia mechanism such as relationship between pulmonary veins and the left atrium in atrial fibrillation. We sought to find the condition for conduction block in various geometries. Methods To simulate cardiac atrial tissue, the finite element method was used to discretize the governing equation in a 2D mesh. We evaluated under the following conditions: 6 sizes of source width (0.1, 0.2, 0.3, 0.4, 0.5 and 0.6 mm), 64 types of angle (θ) at the junction (30-330 degrees), 3 conditions of conduction velocity (CV) (x0.5, x0.75, and x1 of normal CV of atrial myocardium). Results Conduction block was not observed with source width &amp;gt; 0.5 mm in any settings. In reduced CV condition, conduction block was not observed in θ &amp;lt; 300 degrees when source width &amp;gt; 0.3 mm. The higher CV, conduction block was observed in the narrower θ. In cases of CV of x1.0 and x0.75, conduction block was observed in θ &amp;lt; 180 degrees when source width &amp;lt; 0.3 mm. The smaller source width, conduction block was observed in the narrower θ. The wider θ, the easier conduction block occurred. Conclusion Conditions for conduction block due to source-sink mismatch are as follows: smaller source width, higher CV, and wider θ. Source with width &amp;gt; 0.5 mm may not be associated with source-sink mismatch in the atrial tissue. CV slowing by antiarrhythmic drugs can be effective in the aspect of source-sink mismatch.

Beyond source and sink control-toward an integrated approach to understand the carbon balance in plants.

A conceptual understanding on how the vegetation's carbon (C) balance is determined by source activity and sink demand is important to predict its C uptake and sequestration potential now and in the future. We have gathered trajectories of photosynthesis and growth as a function of environmental conditions described in the literature and compared them with current concepts of source and sink control. There is no clear evidence for pure source or sink control of the C balance, which contradicts recent hypotheses. Using model scenarios, we show how legacy effects via structural and functional traits and antecedent environmental conditions can alter the plant's carbon balance. We, thus, combined the concept of short-term source-sink coordination with long-term environmentally driven legacy effects that dynamically acclimate structural and functional traits over time. These acclimated traits feedback on the sensitivity of source and sink activity and thus change the plant physiological responses to environmental conditions. We postulate a whole plant C-coordination system that is primarily driven by stomatal optimization of growth to avoid a C source-sink mismatch. Therefore, we anticipate that C sequestration of forest ecosystems under future climate conditions will largely follow optimality principles that balance water and carbon resources to maximize growth in the long term.

Trapped re-entry challenges the binary view on cardiac arrhythmias

Abstract Background There is currently a binary view on cardiac arrhythmias: (1) arrhythmias are present and thereby affect the atria or ventricles as a whole, or (2) they are not present and therefore the heart is in sinus rhythm. However, complex fractionated atrial electrograms (CFAEs) under sinus rhythm (SR) are observed in patients with atrial fibrillation (AF), raising the question whether both cardiac states (arrhythmia and SR) could coexist. Although CFAEs in AF patients have been associated with functional and structural heterogeneities (e.g. dense fibrotic regions), the underlying mechanisms of fractionation under SR remain incompletely understood. Purpose To test the hypothesis that an arrhythmia can exist locally with the majority of cardiac tissue in sinus rhythm, made possible through dense local fibrotic regions forming a small electrically isolated re-entrant circuit that can "trap" excitation waves, which can only be "released" under dynamic tissue changes at an isthmus connected to the bulk of the tissue. Methods By harnessing the unique possibilities of light-gated depolarizing ion channels (CatCh) to precisely control in vitro cardiac excitability in time and space, complemented with advanced computational modelling of whole human atria, we explored the geometry of such an electrically isolated circuit and assessed its clinical relevance. Results Optical mapping studies, in monolayers of CatCh-activated neonatal rat atrial cardiomyocytes (n=8), revealed that re-entry can be established and trapped by creating an electrically isolated pathway with a bulk-connecting isthmus causing source-sink mismatch. A tachyarrhythmia was shown to exist locally with SR prevailing in the bulk of the monolayer. Next, conditions were found under which re-entry could escape this pathway, thereby converting a local dormant arrhythmic source into an active driver with global impact. Escape could be established by overcoming the source-sink mismatch through widening of the isthmus or a reduction of the gap junctional coupling. In a digital twin of the human atria, it was revealed that the conditions for "trapped re-entry" and its release can be realized as well. Unipolar pseudo-electrograms derived from these complementary computational 3D studies showed CFAEs at the site of "trapped re-entry" in coexistence with normal electrograms of SR in the bulk of the atria. Upon release of the re-entry, acute arrhythmia onset occurred, affecting the complete atria as evidenced by wave front and electrogram visualization. Conclusion Through the concept of "trapped re-entry", we not only present a new mechanism of acute manifestation of focal tachyarrhythmias, but also provide novel insight into the origin of fractionated electrograms. This insight may provide new rationales for treatment of cardiac arrhythmias, especially for ablation by site-directed targeting.Trapped re-entry in vitro and in silico

Unidirectional conduction characterizing epicardial connections in patients with atrial tachyarrhythmias.

Electrophysiological characteristics of epicardial connections (ECs) in atria and pulmonary veins (PVs) are unclear despite their important contributions to atrial fibrillation (AF). Unidirectional conduction associated with source-sink mismatch can occur in ECs due to their fine fibers with abrupt changes in orientation. We detailed the prevalence and electrophysiological characteristics of unidirectional conduction in the atria and investigated its association with the clinical manifestation of AF. This study retrospectively reviewed electrophysiological studies and radiofrequency catheter ablation in 261 consecutive patients with AF. Unidirectional conduction was observed during ablation encircling the PVs in eight (3.1%) patients, and all occurred in the suspected (N = 4) or definitively (N = 4) recognized ECs. These ECs included three intercaval bundles, four septopulmonary bundles, and one Marshall bundle, and were first manifested in a second procedure in 6 (75%) patients. The unidirectional property was from PV to atrium (exit conduction) in all intercaval bundles and three septopulmonary bundles, and from atrium to PV (entrance conduction) in the remaining two bundles. Intercaval bundles acted as a limb of bi-atrial macro-reentrant tachycardia (50%, three of the six including previous cases). Ablation of the exit outside the PVs, including the right atrium, eliminated ECs in three (38%) patients. All patients remain free from arrhythmia recurrence after a mean 13-month follow-up. A unidirectional conduction property was closely associated with the EC, as estimated by histological findings. Recognition of this fact by electrophysiologists may help to clarify mechanisms for AF and atrial tachycardia and guide the creation of efficient and safe ablation lesion sets.

Assessment of flood regulation service based on source–sink landscape analysis in urbanized watershed

AbstractFacing climate change and rapid urbanization, urban flooding has exposed human and properties to increasing disaster risks. The attention from researchers and decision‐makers to understand the key role of flood regulation service (FRS) in flood management has arisen. However, the mechanism of FRS supply–demand is little known from landscape scale. The FRS assessment methodology considering interacts between source, sink, and flow landscape was proposed in this study. The spatial distributions of surface runoff generation, runoff reduction capacity, and flood inundation were mapped using one‐dimensional rainfall–runoff method SCS‐CN and two‐dimensional flood propagation model CADDIES. Four 3‐hour designed rainfall scenarios ranging from nuisance to extreme events (3a, 11a, 56a, and 100a) were simulated. The Liuyang River Watershed in Changsha Municipality, China was selected for case study. The results showed that, the differences of runoff reduction coefficient and runoff generation volume between vegetation and built‐up landscape have shortened. The peak flood depth, extent of flood inundation, and peak flood velocity have increased continuously with the growing rainfall intensity. The number of source–sink mismatch catchment was the highest under 56 and 100a, and the most of source‐sink match catchments were observed under 3a. Under four rainfall scenarios, the changes of source–sink relationships were witnessed and the potentials of flow zone in source–sink mismatch catchments have increased. The FRS management framework concerning supply–demand connections has been proposed based on source–sink–flow analysis. These findings could provide a scientific basis for sustainable urban flood management and disaster risk mitigation.

Trapped re-entry: a dormant source of arrhythmia

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – EU funding. Main funding source(s): This study was supported by the European Research Council (Starting grant 716509) to D.A. Pijnappels. Background Diseased atria are characterized by functional and structural heterogeneities (e.g. dense fibrotic regions), which add to abnormal impulse generation and propagation, like ectopy and block. These heterogeneities are thought to play a role in the origin of complex fractionated atrial electrograms (CFAEs) under sinus rhythm (SR) in patients with atrial fibrillation (AF), but also in the onset and perpetuation (e.g. re-entry) of this disorder. The underlying mechanisms, however, remain incompletely understood. Objective To test the hypothesis that dense local fibrotic regions can create an electrically isolated conduction pathway in which re-entry can be established via ectopy and block to become "trapped" (giving rise to CFAEs under SR), only to be "released" under dynamic tissue changes at a connecting isthmus (causing acute onset of arrhythmia). Methods The geometry of such a pathway, under which re-entry could be trapped and released, was explored in vitro using optogenetics by creating conduction blocks of any shape by means of light-gated depolarizing ion channels (CatCh) and patterned illumination. Insight from these studies was used for complementary investigation in a digital twin of the human atria to assess clinical relevance. Results Optical mapping studies, in monolayers of CatCh-activated neonatal rat atrial cardiomyocytes, revealed that re-entry can be established and trapped by creating an electrically isolated pathway with a bulk-connecting isthmus causing source-sink mismatch. A tachyarrhythmia was shown to exist locally with SR prevailing in the bulk of the monolayer. Next, conditions were found under which re-entry could escape this pathway, thereby converting a local dormant arrhythmic source into an active driver with global impact. Escape could be established by overcoming the source-sink mismatch through widening of the isthmus or a reduction of the gap junctional coupling. In a digital twin of the human atria, it was revealed that the conditions for "trapped re-entry" and its release can be realized as well. Unipolar pseudo-electrograms derived from these complementary computational 3D studies showed CFAEs at the site of "trapped re-entry" in coexistence with normal electrograms of SR in the bulk of the atria. Upon release of the re-entry, acute arrhythmia onset occurred, affecting the complete atria as evidenced by wave front and electrogram visualization. Conclusion This study reveals that "trapped re-entry", a previously undesignated phenomenon, can explain the observation of two designated ones: CFAEs under SR and acute arrhythmia onset. Further exploration of the concept of "trapped re-entry" may not only expand our understanding of AF initiation and perpetuation, but also termination, including ablation strategies by site-directed targeting.

Structure and function of the ventricular tachycardia isthmus.

Catheter ablation of postinfarction reentrant ventricular tachycardia (VT) has received renewed interest owing to the increased availability of high-resolution electroanatomic mapping systems that can describe the VT circuits in greater detail, and the emergence and need to target noninvasive external beam radioablation. These recent advancements provide optimism for improving the clinical outcome of VT ablation in patients with postinfarction and potentially other scar-related VTs. The combination of analyses gleaned from studies in swine and canine models of postinfarction reentrant VT, and in human studies, suggests the existence of common electroanatomic properties for reentrant VT circuits. Characterizing these properties may be useful for increasing the specificity of substrate mapping techniques and for noninvasive identification to guide ablation. Herein, we describe properties of reentrant VT circuits that may assist in elucidating the mechanisms of onset and maintenance, as well as a means to localize and delineate optimal catheter ablation targets.

Calibration of single-cell model parameters based on membrane resistance improves the accuracy of cardiac tissue simulations

In the calibration process, replicating some cellular properties is the main focus, while the importance of membrane resistance (Rm) that is primal in the tissue-level modeling is often underestimated. Previously, we presented a framework in which Rm in addition to action potential (AP) waveform was considered in the cellular model fitting. In this paper, we test the hypothesis that this approach for tuning cellular model parameters improves the accuracy of simulations at the tissue level. In doing so, two different sets of single-cell models are generated via independent realizations of our multi-objective optimization approach. In the first set of calibration (Model I), root-mean-square error (RMSE) of AP, and absolute error (AE) of maximum upstroke velocity are included as optimization functions; however, in the second set of calibration (Model II), RMSE of Rm curve in the repolarization phase is also added to the optimization functions. The calibrated cell models are then used in several tissue configurations of physiological relevance. We adopt well-defined evaluation metrics to compare tissue models tuned using Models I and II. In the source-sink mismatch configuration, the average absolute relative error (ARE) of the critical transition border, defined as the smallest required window width between source and sink for AP propagation, is less than 4.7 % in Model II, while this error is increased to more than 8.9 % in Model I. In addition, in Model I, the average ARE of total time for activation of tissue is 3.3–6.3 %; however, in Model II, this error is reduced to 0.7–1.6 %. In the Purkinje-myocardium configuration, the average of RMSE of activation time map is reduced approximately 75 % in Model II. Finally, in the transmural APD heterogeneity configuration, the average AREs of AP duration (APD) and APD dispersion (i.e., the difference between maximum and minimum of APD) are about 13.2 % and 17.4 % in Model I and 5.8 % and 6.8 % in Model II, respectively. Overall, our results demonstrate that consideration of Rm in the single-cell optimization procedure yields a substantial improvement in the accuracy of tissue models.

Pka and CaMKII Signaling Synergistically Promotes Atrial Arrhythmia in Populations of Human Atrial Tissues

The β-adrenergic receptor (βAR)/cAMP/PKA and multifunctional Ca2+-calmodulin-dependent protein kinase II (CaMKII) signaling pathways are key mediators of cardiac excitation-contraction coupling (ECC) and share multiple downstream targets. Hyperactivation of both signaling pathways contributes to the initiation and maintenance of atrial fibrillation (AF), the world's most common arrhythmia. Using novel populations of computational models coupling atrial electrophysiology and Ca2+ handling with detailed descriptions of βAR-PKA and CaMKII pathways, we have previously shown that PKA and CaMKII effects on atrial ECC proteins synergistically promote a vicious cycle of Ca2+and membrane potential instabilities. Since both kinases are known to affect tissue-level modifiers of atrial electrophysiology, here we sought to test whether PKA and CaMKII signaling also synergize to mediate arrhythmias in tissue, and to determine the mechanisms underlying the increased vulnerability. Populations of 1D strand models revealed increased vulnerability to unidirectional block with hyperactive CaMKII, mediated by Na+ channel loss of function and cell-to-cell uncoupling, which was exacerbated by activation of βARs. Simulations of 2D heterogeneous tissues demonstrated synergistic enhancement of arrhythmia vulnerability by βAR stimulation and CaMKII hyperactivation through dysregulating conduction and modifying source-sink mismatch, as well as promoting tissue repolarization dispersion and invoking spontaneous Ca2+-overload-mediated action potentials. CaMKII inhibition substantially reduced the vulnerability. Collectively, our simulations reveal synergy in PKA and CaMKII effects on tissue-level outcomes, and depict a novel paradigm for Ca2+-CaMKII-dependent involvement in both enhanced triggered activity and conduction disturbances in AF. These findings suggest that interrupting the vicious cycle of ever-increasing CaMKII and Ca2+ (e.g., via CaMKII inhibition) may be a valuable pharmacotherapy approach to counteract both AF triggers and functional substrate.

“Trapped reentry” as a dormant source of acute focal arrhythmia and fractionated atrial electrograms under sinus rhythm

Abstract Background Diseased atria are characterised by functional and structural heterogeneities (e.g. dense fibrotic regions), which add to abnormal impulse generation and propagation, like ectopy and block. These heterogeneities are thought to play a role in the origin of complex fractionated atrial electrograms (CFAEs) under sinus rhythm (SR) in atrial fibrillation (AF) patients, but also in the onset and perpetuation (e.g. reentry) of this disorder. The underlying mechanisms, however, remain incompletely understood. Purpose To test the hypothesis that dense local fibrotic regions could create an electrically isolated conduction pathway in which reentry can be established via ectopy and block to become “trapped” (giving rise to CFAEs under SR), only to be “released” under dynamic changes at a connecting isthmus (causing acute focal arrhythmia (FA)). Methods The geometrical properties of such an electrically isolated pathway, under which reentry could be trapped and released, were explored in vitro using optogenetics by creating conduction blocks of any shape by means of light-gated depolarizing ion channels (CatCh) and patterned illumination. Insight from these studies was used for complementary computational investigation in virtual human atria to assess clinical translation and to provide deeper mechanistic insight. Results Optical mapping studies, in monolayers of CatCh-activated neonatal rat atrial cardiomyocytes, revealed that reentry could indeed be established and trapped by creating an electrically isolated pathway with a connecting isthmus causing source-sink mismatch. This proves that a tachyarrhythmia can exist locally with SR prevailing in the bulk of the monolayer. Next, it was confirmed under which conditions reentry could escape this pathway by widening of the isthmus (i.e. overcoming the source-sink mismatch), thereby converting this local dormant arrhythmic source into an active driver with global impact (i.e. acute monolayer-wide FA). This novel phenomenon was shown in circuits &amp;lt;0.7cm2, adding to their probability to exist in human atria. Computational 3D studies revealed that the conditions for “trapped reentry” and its release can indeed be realized in human atria. Unipolar epicardial pseudo-electrograms derived from these simulations showed CFAEs at the site of “trapped reentry” in coexistence with normal electrograms showing SR in the bulk of the atria. Upon release of the reentry through reduction of gap junctional coupling, acute FA occurred, affecting the complete atria as evidenced by wave front and electrogram visualization. Conclusion This study reveals that “trapped reentry”, a previously undesignated phenomenon, can explain the origin of two designated ones: the observation of CFAEs under SR and acute onset of FA. Further exploration of the concept of “trapped reentry” may not only expand our understanding of AF initiation and perpetuation, but also termination, including ablation strategies by site-directed targeting. Funding Acknowledgement Type of funding source: Public grant(s) – EU funding. Main funding source(s): This study was funded by the European Research Council (Starting grant 716509) to D.A. Pijnappels

Feeling the heat: source-sink mismatch as a mechanism underlying the failure of thermal tolerance.

A mechanistic explanation for the tolerance limits of animals at high temperatures is still missing, but one potential target for thermal failure is the electrical signaling off cells and tissues. With this in mind, here I review the effects of high temperature on the electrical excitability of heart, muscle and nerves, and refine a hypothesis regarding high temperature-induced failure of electrical excitation and signal transfer [the temperature-dependent deterioration of electrical excitability (TDEE) hypothesis]. A central tenet of the hypothesis is temperature-dependent mismatch between the depolarizing ion current (i.e. source) of the signaling cell and the repolarizing ion current (i.e. sink) of the receiving cell, which prevents the generation of action potentials (APs) in the latter. A source-sink mismatch can develop in heart, muscles and nerves at high temperatures owing to opposite effects of temperature on source and sink currents. AP propagation is more likely to fail at the sites of structural discontinuities, including electrically coupled cells, synapses and branching points of nerves and muscle, which impose an increased demand of inward current. At these sites, temperature-induced source-sink mismatch can reduce AP frequency, resulting in low-pass filtering or a complete block of signal transmission. In principle, this hypothesis can explain a number of heat-induced effects, including reduced heart rate, reduced synaptic transmission between neurons and reduced impulse transfer from neurons to muscles. The hypothesis is equally valid for ectothermic and endothermic animals, and for both aquatic and terrestrial species. Importantly, the hypothesis is strictly mechanistic and lends itself to experimental falsification.

Improved Accuracy of Cardiac Tissue-Level Simulations by Considering Membrane Resistance as a Cellular-Level Optimization Objective.

Cardiac cellular models are utilized as the building blocks for tissue simulation. One of the imprecisions of conventional cellular modeling, especially when the models are used in tissue-level modeling, stems from the mere consideration of cellular properties (e.g., action potential shape) in parameter tuning of the model. In our previous work, we put forward an accurate framework in which membrane resistance (Rm) reflecting inter-cellular characteristics, i.e., electrotonic effects, was considered alongside cellular features in cellular model fitting. This paper, for the first time, examines the hypothesis that considering Rm as an additional optimization objective improves the accuracy of tissue-level modeling. To study this hypothesis, after cellular-level optimization of a well-known model, source-sink mismatch configurations in a 2-dimensional model are investigated. The results demonstrate that including Rm in the optimization protocol yields a substantial improvement in the relative error of the critical transition border which is defined as the minimum window size between source and sink that wave propagates. Model developers can utilize the proposed concept during parameter tuning to increase the accuracy of models.

1275First evidence of "trapped reentry" as dormant source of acute atrial fibrillation and fractionated atrial electrograms under sinus rhythm

Abstract Funding Acknowledgements This study was supported by the European Research Council (Starting grant 716509) to D.A. Pijnappels. Background Diseased atria are characterised by functional and structural heterogeneities (e.g. dense fibrotic regions), which add to abnormal impulse generation and propagation, like ectopy and block. These heterogeneities are thought to play a role in the origin of complex fractionated atrial electrograms (CFAEs) under sinus rhythm (SR) in atrial fibrillation (AF) patients, but also in the onset and perpetuation (e.g. reentry) of this disorder. The underlying mechanisms, however, remain incompletely understood. Purpose To test the hypothesis that dense local fibrotic regions could create an electrically isolated conduction pathway in which reentry can be established via ectopy and block to become "trapped" (giving rise to CFAEs under SR), only to be "released" under dynamic changes at a connecting isthmus (causing acute onset of AF). Methods The geometrical properties of such an electrically isolated pathway, under which reentry could be trapped and released, were explored in vitro using optogenetics by creating conduction blocks of any shape by means of light-gated depolarizing ion channels (CatCh) and patterned illumination. Insight from these studies was used for complementary computational investigation in virtual human atria to assess clinical translation and to provide deeper mechanistic insight. Results Optical mapping studies, in monolayers of CatCh-activated neonatal rat atrial cardiomyocytes, revealed that reentry could indeed be established and trapped by creating an electrically isolated pathway with a connecting isthmus causing source-sink mismatch. This proves that a tachyarrhythmia can exist locally with SR prevailing in the bulk of the monolayer. Next, it was confirmed under which conditions reentry could escape this pathway by widening of the isthmus (i.e. overcoming the source-sink mismatch), thereby converting this local dormant arrhythmic source into an active driver with global impact (i.e. acute monolayer-wide fibrillation). This novel phenomenon was shown in circuits &amp;lt;0.7cm², adding to their probability to exist in human atria. Computational 3D studies revealed that the conditions for "trapped reentry" and its release can indeed be realized in human atria. Unipolar epicardial pseudo-electrograms derived from these simulations showed CFAEs at the site of "trapped reentry" in coexistence with normal electrograms showing SR in the bulk of the atria. Upon release of the reentry through reduction of gap junctional coupling, acute onset of AF occurred, affecting the complete atria as evidenced by wave front and electrogram visualization. Conclusion This study reveals that trapped reentry, a previously unknown phenomenon, can explain the origin of two known ones: the observation of CFAEs under SR and acute onset of AF. Further exploration of the concept of "trapped reentry" may not only expand our understanding of AF initiation and perpetuation, but also termination, including ablation strategies by site-directed targeting.

Variability in electrophysiological properties and conducting obstacles controls re-entry risk in heterogeneous ischaemic tissue.

Ischaemia, in which inadequate blood supply compromises and eventually kills regions of cardiac tissue, can cause many types of arrhythmia, some life-threatening. A significant component of this is the effects of the resulting hypoxia, and concomitant hyperklaemia and acidosis, on the electrophysiological properties of myocytes. Clinical and experimental data have also shown that regions of structural heterogeneity (fibrosis, necrosis, fibro-fatty infiltration) can act as triggers for arrhythmias under acute ischaemic conditions. Mechanistic models have successfully captured these effects in silico. However, the relative significance of these separate facets of the condition, and how sensitive arrhythmic risk is to the extents of each, is far less explored. In this work, we use partitioned Gaussian process emulation and new metrics for source-sink mismatch that rely on simulations of bifurcating cardiac fibres to interrogate a model of heterogeneous ischaemic tissue. Re-entries were most sensitive to the level of hypoxia and the fraction of non-excitable tissue. In addition, our results reveal both protective and pro-arrhythmic effects of hyperklaemia, and present the levels of hyperklaemia, hypoxia and percentage of non-excitable tissue that pose the highest arrhythmic risks. This article is part of the theme issue 'Uncertainty quantification in cardiac and cardiovascular modelling and simulation'.

Engineered Cardiac Pacemaker Nodes Created by TBX18 Gene Transfer Overcome Source-Sink Mismatch.

Every heartbeat originates from a tiny tissue in the heart called the sinoatrial node (SAN). The SAN harbors only ≈10 000 cardiac pacemaker cells, initiating an electrical impulse that captures the entire heart, consisting of billions of cardiomyocytes for each cardiac contraction. How these rare cardiac pacemaker cells (the electrical source) can overcome the electrically hyperpolarizing and quiescent myocardium (the electrical sink) is incompletely understood. Due to the scarcity of native pacemaker cells, this concept of source–sink mismatch cannot be tested directly with live cardiac tissue constructs. By exploiting TBX18 induced pacemaker cells by somatic gene transfer, 3D cardiac pacemaker spheroids can be tissue‐engineered. The TBX18 induced pacemakers (sphTBX18) pace autonomously and drive the contraction of neighboring myocardium in vitro. TBX18 spheroids demonstrate the need for reduced electrical coupling and physical separation from the neighboring ventricular myocytes, successfully recapitulating a key design principle of the native SAN. β‐Adrenergic stimulation as well as electrical uncoupling significantly increase sphTBX18s' ability to pace‐and‐drive the neighboring myocardium. This model represents the first platform to test design principles of the SAN for mechanistic understanding and to better engineer biological pacemakers for therapeutic translation.

Microscopic Isthmuses and Fibrosis Within the Border Zone of Infarcted Hearts Promote Calcium-Mediated Ectopy and Conduction Block

Ventricular tachycardia (VT) secondary to myocardial infarction (MI) remain a major cause of sudden death in adults. Premature ventricular complexes (PVCs), the first initiating beats of a portion of these arrhythmias, arise from triggered activity in the infarct border zone (BZ). At the cellular scale, spontaneous calcium release (SCR) events are a known cause of triggered activity and have been reported in cells that survive MI. At the tissue scale, fibrosis has been shown to play an important role in creating the substrate for VT. However, the interplay between SCR-mediated triggered activity and fibrosis upon VT formation in infarcted hearts has not been fully investigated. Here, we conduct in-silico experiments to assess how macroscopic and microscopic anatomical properties of the BZ can create a substrate for SCR-mediated VT formation. To study this question, we employ a stochastic subcellular-scale model of SCR events and action potential to simulate different cardiac preparations. Within 2D sheet models with idealized infarct scars and BZ we show that the probability of PVCs is higher, 55%, in preparations with thin conducting isthmuses (0.2 mm) transcending the scar. In an anatomically-detailed model of the rabbit ventricles with a realistic representation of intramural scars, we show that the heart’s protective source-sink mismatch prevents ectopy. Furthermore, we demonstrate that fibrosis disrupts this antiarrhythmic mechanism making PVCs more likely. PVC probability is highest (≥ 25%) when fibrosis accounts for 60% and 90% of the BZ in the 2D sheet and the 3D anatomical model, respectively. Above these thresholds, PVC occurrence decreases because of: 1) the reduced number of myocytes in the BZ; 2) conduction block. Block is caused either by disconnection of BZ cells from the myocardium or due to source-sink mismatches at regions of rapid tissue expansion. Moreover, while outward propagation to healthy tissue may fail, PVCs traveling inward through the scar might encounter more favorable loading conditions. These PVCs may exit to the myocardium and reenter back at the region of block. Overall, our findings indicate that thin isthmuses and strands of myocytes interspersed with fibrosis can be arrhythmogenic. Ablation of these microscopic structures may prevent VT formation.

Source-Sink Mismatch Causing FunctionalConduction Block in Re-Entrant VentricularTachycardia.

Ventricular tachycardia (VT) caused by a re-entrant circuit is a life-threatening arrhythmia that at present cannot always be treated adequately. A realistic model of re-entry would be helpful to accurately guide catheter ablation for interruption of the circuit. In this review, models of electrical activation wavefront propagation during onset and maintenance of re-entrant VT are discussed. In particular, the relationship between activation mapping and maps of transition in infarct border zone thickness, which results in source-sink mismatch, is considered in detail and supplemented with additional data. Based on source-sink mismatch, the re-entry isthmus can be modeled from its boundary properties. Isthmus boundary segments with large transitions in infarct border zone thickness have large source-sink mismatch, and functional block forms there during VT. These alternate with segments having lesser thickness change and therefore lesser source-sink mismatch, which act as gaps, or entrance and exit points, to the isthmus during VT. Besides post-infarction substrates, the source-sink model is likely applicable to other types of volumetric changes in the myocardial conducting medium, such as when there is presence of fibrosis or dissociation of muscle fibers.