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Subthreshold delayed afterdepolarizations provide an important arrhythmogenic substrate in the border zone of infarcted hearts

Open AccessPublished:November 04, 2022DOI:https://doi.org/10.1016/j.hrthm.2022.10.026

      Graphical abstract

      Keywords

      Introduction

      Sudden cardiac arrest resulting from myocardial infarction (MI) is most often due to ventricular tachycardia (VT). In the infarcted heart, VT has been shown to originate at the periphery of the scar.
      • Stevenson W.G.
      Ventricular scars and ventricular tachycardia.
      Such tissue is often termed the infarct border zone (BZ) and is composed of a heterogeneous admixture of fibrosis and surviving cardiomyocytes.
      • Mendonca Costa C.
      • Plank G.
      • Rinaldi C.A.
      • Niederer S.A.
      • Bishop M.J.
      Modeling the electrophysiological properties of the infarct border zone.
      Extended regions of BZ tissue that penetrate through nonconducting necrotic core scar can give rise to anatomic isthmuses, which provide slow conducting reentrant pathways that can help sustain VT circuits.
      • Ciaccio E.J.
      • Anter E.
      • Coromilas J.
      • et al.
      Structure and function of the ventricular tachycardia isthmus.
      Significant technical challenges involved in measuring 3-dimensional electrical behavior at the tissue/organ level have largely prevented detailed preclinical and clinical analysis of the proarrhythmic behavior of the BZ tissue. Specifically, comprehensive understanding of exactly how the complex structural and electrophysiological (EP) remodeling in this region provides the so important, yet elusive, arrhythmic trigger remains lacking.
      VT is driven by the presence of triggers and substrate that promote initiation and sustenance of reentrant electrical wavefronts.
      • Berger M.D.
      • Waxman H.L.
      • Buxton A.E.
      • Marchlinski F.E.
      • Josephson M.E.
      Spontaneous compared with induced onset of sustained ventricular tachycardia.
      ,
      • Kléber A.G.
      • Rudy Y.
      Basic mechanisms of cardiac impulse propagation and associated arrhythmias.
      Several structural and EP remodeling processes associated with VT formation have been reported to occur in the BZ.
      • Mendonca Costa C.
      • Plank G.
      • Rinaldi C.A.
      • Niederer S.A.
      • Bishop M.J.
      Modeling the electrophysiological properties of the infarct border zone.
      Alterations such as abnormal repolarization can lead to prolongation of postrepolarization refractoriness, which is a known substrate for conduction block.
      • Coronel R.
      • Wilms-Schopman F.J.
      • Opthof T.
      • Janse M.J.
      Dispersion of repolarization and arrhythmogenesis.
      Reduced sodium (Na+) current (INa) and fibrosis have also been shown to provide a substrate, not only for block (by reducing excitability) but also for VT sustenance by slowing conduction and shortening the wavefront of electrical propagation.
      • Campos F.O.
      • Whitaker J.
      • Neji R.
      • et al.
      Factors promoting conduction slowing as substrates for block and reentry in infarcted hearts.
      In addition to substrates for conduction slowing and block, triggered activity has been reported in the BZ.
      • Amoni M.
      • Claus P.
      • Dries E.
      • et al.
      Discrete sites of frequent premature ventricular complexes cluster within the infarct border zone and coincide with high frequency of delayed afterdepolarizations under adrenergic stimulation.
      At the cellular level, triggered activity has been shown to be caused by delayed afterdepolarizations (DADs) linked to spontaneous calcium (Ca2+) release (SCR) events from the sarcoplasmic reticulum (SR).
      • Wasserstrom J.A.
      • Shiferaw Y.
      • Chen W.
      • et al.
      Variability in timing of spontaneous calcium release in the intact rat heart is determined by the time course of sarcoplasmic reticulum calcium load.
      SCRs activate the Na+-Ca2+exchanger (NCX), an inward current that leads to depolarization of the diastolic membrane potential (Vm). DADs can be divided into subthreshold or suprathreshold depending on whether the resulting depolarization is below or above the threshold for action potential (AP) initiation, respectively. The conditions under which DADs can summate to form premature ventricular complexes (PVCs) are still a matter of debate and have been a topic of research in our group and others.
      • Campos F.O.
      • Shiferaw Y.
      • Prassl A.J.
      • Boyle P.M.
      • Vigmond E.J.
      • Plank G.
      Stochastic spontaneous calcium release events trigger premature ventricular complexes by overcoming electrotonic load.
      • Campos F.O.
      • Shiferaw Y.
      • Vigmond E.J.
      • Plank G.
      Stochastic spontaneous calcium release events and sodium channelopathies promote ventricular arrhythmias.
      • Campos F.O.
      • Shiferaw Y.
      • Weber dos Santos R.
      • Plank G.
      • Bishop M.J.
      Microscopic isthmuses and fibrosis within the border zone of infarcted hearts promote calcium-mediated ectopy and conduction block.
      • Colman M.A.
      • Perez Alday E.A.
      • Holden A.V.
      • Benson A.P.
      Trigger vs. substrate: multi-dimensional modulation of QT-prolongation associated arrhythmic dynamics by a hERG channel activator.
      • Liu M.B.
      • de Lange E.
      • Garfinkel A.
      • Weiss J.N.
      • Qu Z.
      Delayed afterdepolarizations generate both triggers and a vulnerable substrate promoting reentry in cardiac tissue.
      At the tissue scale, DADs can only capture the local tissue and trigger propagating PVCs if the generated net ionic current is sufficient to overcome the local electrotonic load imposed by the surrounding tissue.
      • Xie Y.
      • Sato D.
      • Garfinkel A.
      • Qu Z.
      • Weiss J.N.
      So little source, so much sink: requirements for afterdepolarizations to propagate in tissue.
      ,
      • Myles R.C.
      • Wang L.
      • Kang C.
      • Bers D.M.
      • Ripplinger C.M.
      Local β-adrenergic stimulation overcomes source-sink mismatch to generate focal arrhythmia.
      In a computational study, we have demonstrated that this protective cardiac mechanism can be disrupted by fibrosis (which attenuates local electrotonic coupling), making DAD capture and PVCs more likely.
      • Campos F.O.
      • Shiferaw Y.
      • Weber dos Santos R.
      • Plank G.
      • Bishop M.J.
      Microscopic isthmuses and fibrosis within the border zone of infarcted hearts promote calcium-mediated ectopy and conduction block.
      Furthermore, we have shown that patchy fibrosis in the BZ can lead to unidirectional block due to source-sink mismatches at regions of rapid tissue expansion.
      • Campos F.O.
      • Shiferaw Y.
      • Weber dos Santos R.
      • Plank G.
      • Bishop M.J.
      Microscopic isthmuses and fibrosis within the border zone of infarcted hearts promote calcium-mediated ectopy and conduction block.
      ,
      • Connolly A.
      • Kelly A.
      • Campos F.O.
      • Myles R.
      • Smith G.
      • Bishop M.J.
      Ventricular endocardial tissue geometry affects stimulus threshold and effective refractory period.
      Less understood is the role played by subthreshold DADs in postinfarction VT initiation. Long-lasting subthreshold DADs have been shown to inactivate Na+ channels, leading to temporary conduction block
      • Liu M.B.
      • de Lange E.
      • Garfinkel A.
      • Weiss J.N.
      • Qu Z.
      Delayed afterdepolarizations generate both triggers and a vulnerable substrate promoting reentry in cardiac tissue.
      while not affecting overall activation wavelength as in the scenario of permanent changes in local repolarization. However, the role played by local infarct anatomy and altered intracellular coupling in facilitating this phenomenon is not well understood. The purpose of this study was to use in silico experiments to demonstrate a fundamental mechanism for arrhythmogenesis in the infarct BZ. Our hypothesis, as summarized in Figure 1, is that SCR-mediated subthreshold DADs occurring within the BZ can inactivate INa favoring conduction block in narrow isthmuses where electrotonic load is lessened by the nonconducting scar. This conduction block, occurring as it does at critical sites within the reentrant pathway, is responsible for directly initiating postinfarct VTs.
      Figure thumbnail gr1
      Figure 1Hypothesized mechanism for delayed afterdepolarization (DAD)-mediated conduction block within the isthmus. NCX = Na+-Ca2+exchanger; RyR = ryanodine receptor.

      Methods

      EP model and parameters

      Figure 2A shows the magnetic resonance imaging (MRI)-based porcine models of the left ventricular (LV) anatomy and scar morphology used in this study. Animal studies were performed at the Institut de Chirurgie Guidée par l’image, Strasbourg, France. The experimental protocol was approved by the national institutional animal care and ethics committee.
      • Whitaker J.
      • Neji R.
      • Kim S.
      • et al.
      Late gadolinium enhancement cardiovascular magnetic resonance assessment of substrate for ventricular tachycardia with hemodynamic compromise.
      Scar and BZ segmentation thresholds of 60% and 40% of the maximum pixel intensity in the late gadolinium enhancement MRI scans were used, respectively. Further details about model construction are given in our previous study.
      • Mendonca Costa C.
      • Gemmell P.
      • Elliott M.K.
      • et al.
      Determining anatomical and electrophysiological detail requirements for computational ventricular models of porcine myocardial infarction.
      Figure thumbnail gr2
      Figure 2Computational models showing the epicardial surface of the postinfarction porcine left ventricle (LV). A: Three-dimensional anatomy models. B: Pacing protocol. BZ = border zone.
      Electrical activity was represented by the monodomain model, solved using CARPentry-Pro (NumeriCor GmbH, Graz, Austria).
      • Neic A.
      • Campos F.O.
      • Prassl A.J.
      • et al.
      Efficient computation of electrograms and ECGs in human whole heart simulations using a reaction-eikonal model.
      Cardiac cellular dynamics were simulated using an experimentally based phenomenological model of SCR events coupled to the Mahajan-Shiferaw ventricular (MSH) AP model.
      • Chen W.
      • Aistrup G.
      • Wasserstrom J.A.
      • Shiferaw Y.
      A mathematical model of spontaneous calcium release in cardiac myocytes.
      Key parameters of the model were modified to increase its propensity for Ca2+-mediated DADs.
      • Campos F.O.
      • Shiferaw Y.
      • Prassl A.J.
      • Boyle P.M.
      • Vigmond E.J.
      • Plank G.
      Stochastic spontaneous calcium release events trigger premature ventricular complexes by overcoming electrotonic load.
      • Campos F.O.
      • Shiferaw Y.
      • Vigmond E.J.
      • Plank G.
      Stochastic spontaneous calcium release events and sodium channelopathies promote ventricular arrhythmias.
      • Campos F.O.
      • Shiferaw Y.
      • Weber dos Santos R.
      • Plank G.
      • Bishop M.J.
      Microscopic isthmuses and fibrosis within the border zone of infarcted hearts promote calcium-mediated ectopy and conduction block.
      • Colman M.A.
      • Perez Alday E.A.
      • Holden A.V.
      • Benson A.P.
      Trigger vs. substrate: multi-dimensional modulation of QT-prolongation associated arrhythmic dynamics by a hERG channel activator.
      ,
      • Chen W.
      • Aistrup G.
      • Wasserstrom J.A.
      • Shiferaw Y.
      A mathematical model of spontaneous calcium release in cardiac myocytes.
      In brief, Ca2+ overload was induced by increasing extracellular Ca2+ concentration, the NCX current was doubled, and the inward rectifier potassium current was decreased by 70%. Normal INa properties in the MSH model prevent subthreshold DADs to cause conduction block regardless of their amplitude. Thus, as performed in previous studies, the Na+ channel steady-state inactivation curve of the model was left-shifted by 5 mV to promote INa inactivation potentiating conduction failure.
      • Campos F.O.
      • Shiferaw Y.
      • Vigmond E.J.
      • Plank G.
      Stochastic spontaneous calcium release events and sodium channelopathies promote ventricular arrhythmias.
      ,
      • Liu M.B.
      • de Lange E.
      • Garfinkel A.
      • Weiss J.N.
      • Qu Z.
      Delayed afterdepolarizations generate both triggers and a vulnerable substrate promoting reentry in cardiac tissue.
      SCR events were inhibited in healthy myocardium to investigate DAD formation only in cells in the BZ.
      Anisotropic bulk conductivity values of 0.1361 S/m and 0.0176 S/m were assigned along and transverse to the fiber direction, respectively. Tissue conductivity in the BZ was adjusted by a scaling factor (1.0–0.25; steps of 0.25) to gauge the effects of gap junction uncoupling on DAD-mediated conduction block.

      Pacing protocol

      The MSH cell model was paced at a basic cycle length (BCL) of 500 ms for 100 cycles to stabilize. Single-cell model states at the end of the pacing protocol were stored and used as initial conditions for the LV model. Arrhythmia susceptibility was quantified by pacing the model for 3 S1 beats (BCL = 500 ms) from either apex or base (Figure 2B), followed by a 1500-ms pause, to see whether DADs would occur, followed by an S2 extrastimulus beat with coupling intervals (CIs) varying from 500 to 1000 ms. Due to the stochastic nature of the SCR-mediated DADs, 100 simulations were performed. Simulations with captured suprathreshold DADs (PVCs) were excluded to evaluate DADs only as substrate for conduction block rather than ectopy.

      Results

      Subthreshold DADs within the postinfarction heart

      Figure 3 shows the spatial distribution of Vm on the epicardial surface of the 3 LV models at the instant in time that DADs reached their highest amplitude inside the marked area. The endocardial DAD pattern (not shown) was similar to that of the epicardium. Note that for the same time instant after the paced beat, DADs with higher amplitudes were found to occur closer to the pacing site.
      Figure thumbnail gr3
      Figure 3Subthreshold delayed afterdepolarizations (DADs) following apical (top) and basal (bottom) pacing. Spatial distribution of Vm at the time DADs reach their highest amplitude within regions marked with a black circle. The scars were removed and the LVs clipped to aid visualization of the transmurality of the events.
      Figure 4 shows the maximum Vm elevation at all sites in the tissue caused by DADs over the entire duration of the pacing pause. DADs in cells within isthmus regions, where the presence of scar and fibrosis reduce cellular coupling and local electrotonic load, have a higher amplitude than DADs from regions surrounded by healthy, well-coupled myocardium. However, the direction of the wavefront had a minor effect on the max Vm elevation. Figure 4B illustrates subthreshold DADs from 2 different regions of the BZ of Pig 3. SCR events in cells from the isthmus were able to raise Vm to –55 mV (red trace) compared to –74 mV in the well-coupled region near the base. As shown in Figure 4C, DADs completely inactivated Na+ channels in the isthmus (red trace) and caused approximately 50% channel inactivation in well-coupled tissue (green trace).
      Figure thumbnail gr4
      Figure 4Delayed afterdepolarization (DAD) amplitude in the border zone of the left ventricular models. A: Maximum Vm elevation at all tissue regions caused by subthreshold DADs during the pacing pause. B: Time course of DADs from a well-coupled region (green trace) and from an isthmus within the scar (red trace) in Pig3. C: Na+ channel inactivation resulting from DADs shown in B.

      DAD-mediated block and reentry

      The pacing protocol described (Figure 2B) was used to investigate the occurrence of block and reentrant formation within the postinfarction models driven by subthreshold DADs. Figure 5 shows Vm maps of the S2 beat as well as the resulting sustained reentry in all 3 LV models. Conduction block depended on the specific S2 pacing location and subsequent conduction pathway. Particularly in Pig 3, VT was induced after an S2 beat (CI = 710 ms) had initially blocked at the isthmus mouth proximal to the stimulus site (t = 960 ms). Conduction block occurred in the isthmus as a direct result of the reduced excitability caused by the inactivation of the Na+ current (Figure 4C) by ongoing subthreshold DADs rather than prolonged AP duration. The wavefront then propagates around the scar, reentering the isthmus through the distal mouth, close to the apex leading to a sustained VT circuit.
      Figure thumbnail gr5
      Figure 5Delayed afterdepolarization (DAD)-mediated conduction block at the isthmus. Vm maps at different times (t = 0 corresponds to the time of the last S1 beat) showing DAD-mediated block of the S2 beat and reentry formation in the left ventricular models. Arrows indicate successful propagation; arrows with perpendicular line indicate conduction block.

      Arrhythmogenic potential of tissue uncoupling in the BZ

      Figures 6A and 6B show how reduced tissue conductivity affects the amplitude and spatial extent of DADs in Pig 3 model. The average Vm elevation due to DADs increases from about –72 mV to –69 mV when tissue conductivity is decreased from 1 (control) to 0.25 of the control values. However, the volume of tissue undergoing DADs correspondingly decreases with the decrease in tissue conductivity as uncoupling limits the dissipation of electrotonic currents from DAD sources.
      Figure thumbnail gr6
      Figure 6Effects of reduced tissue conductivity on spontaneous calcium (Ca2+) release (SCR)-mediated delayed afterdepolarizations (DADs) in Pig 3 model. A: Amplitude of DADs. B: Volume of tissue undergoing DADs. C: Time window for conduction block of the S2 beat.
      The arrhythmogenic link between tissue uncoupling and subthreshold DADs is shown in Figure 6C. In control conditions (ie, scaling factor 1.0), an S2 beat with CI = 700 ms still was able to propagate through the isthmus. However, S2 beats within 700 ms < CI < 900 ms resulted in unidirectional block as DADs rendered the entire isthmus area refractory. S2 beats with CI ≥900 ms resulted in successful propagation. This window of conduction block is illustrated in Figure 7. Reductions in tissue conductivity led to a widening of the S2 CI window in which block was observed. As shown in Figure 6C, applying a scaling factor of 0.25 to tissue conductivity shifted the beginning of the window for conduction block from 700 to 710 ms and prolonged it by 60 ms (710 ms <CI < 960 ms).
      Figure thumbnail gr7
      Figure 7Time window for conduction block of the S2 beat in Pig 3 model. Vm maps of S2 beats with different coupling intervals: 700 ms (propagation), 710 ms (block), and 900 ms (propagation).

      Discussion

      Remodeling in the infarct BZ is thought to play a key role in facilitating the genesis of VT, but the exact mechanism behind arrhythmia formation and maintenance is not comprehensively characterized. Capture of DADs at the tissue scale (PVC formation) has been shown to be implicated in the generation of focal arrhythmias in the intact heart. However, the heart’s protective source-sink mismatch related to electrotonic loading between well-coupled cells make these unlikely. Here, we hypothesized that DADs occurring in the BZ of infarct tissue in fact do not need to capture themselves to be arrhythmogenic. Instead, subthreshold DADs can still provide a substrate for unidirectional conduction block and subsequent reentry in regions where local myocyte coupling is disrupted by the complex fibrotic structure of the infarct.
      In silico experiments using high-resolution MRI-derived computational models have shown that narrow isthmuses within infarcted regions provide both the most likely and most critical sites of unidirectional block to facilitate VT onset by (1) reducing electrotonic loading as the depolarizing current is geometrically constrained by the surrounding scar, allowing DADs to inactivate the INa current, setting the stage for unidirectional conduction block; and (2) representing highly vulnerable areas for unidirectional block, being a crucial part of the reentrant circuit sustaining VT where conduction is “cablelike” or pseudo–1-dimensional. Furthermore, DADs did not change AP duration, making VT sustenance more likely as the cardiac wavelength is not altered, as in a scenario of long-lasting repolarization. Reduced tissue conductivity in the BZ enhanced DAD-mediated arrhythmogenicity by increasing the vulnerable window for conduction block.

      DAD-mediated conduction block

      VTs in postinfarction hearts are commonly sustained by anatomic isthmuses within regions of scar,
      • Ciaccio E.J.
      • Anter E.
      • Coromilas J.
      • et al.
      Structure and function of the ventricular tachycardia isthmus.
      which provide a reentrant pathway. In order to set up such a reentrant circuit, a prerequisite is a substrate that provides the initial unidirectional conduction block, usually within or at the mouth of the isthmus. In the context of ischemic heart disease, nonuniform anisotropy (slow conduction), abnormal repolarization, and impedance mismatch in the BZ are some of the proposed mechanisms of VT onset.
      • Ciaccio E.J.
      • Anter E.
      • Coromilas J.
      • et al.
      Structure and function of the ventricular tachycardia isthmus.
      Subthreshold DADs have been shown to cause conduction block by inactivating Na+ channels.
      • Liu M.B.
      • de Lange E.
      • Garfinkel A.
      • Weiss J.N.
      • Qu Z.
      Delayed afterdepolarizations generate both triggers and a vulnerable substrate promoting reentry in cardiac tissue.
      As shown in Figure 4, DADs are observed throughout the BZ, but INa inactivation was more pronounced in regions where local diastolic Vm was elevated to approximately –60 mV. Across all models, narrow isthmuses seemed to be where depolarization is raised the most, providing both mostly likely and most critical sites of unidirectional conduction block (Figure 5). However, the timing and location of conduction block and subsequent reentry, and, consequently, the window of conduction block shown in Figures 6 and 7, were still significantly influenced by (1) the specific pacing location of the S2 beat, as this dictates the time and incidence of the wavefront at the critical region; and (2) the properties of the tissue and local anatomic milieu determining the velocity/pathway the S2 takes to reach the vulnerable region.

      VT sustenance

      VT sustenance depends on the wavelength of the electrical impulse, which must be shorter than the anatomic pathlength formed by the conducting isthmus.
      • Kléber A.G.
      • Rudy Y.
      Basic mechanisms of cardiac impulse propagation and associated arrhythmias.
      The wavelength is given by the mathematical product of the conduction velocity (CV) and the effective refractory period (closely related to AP duration). Thus, a “successful” arrhythmogenic substrate must have electrophysiological alterations that are proarrhythmic to both initiation (ie, formation of unidirectional block at the isthmus mouth) and reentry sustenance (ie, reducing wavelength). Prolonged APD in the BZ, although making unidirectional block likely upon rapid pacing at the BZ/healthy myocardium interface, is not conducive to reentry sustenance as it also prolongs wavelength, making termination through head–tail interactions more likely. Structural remodeling (fibrosis/tissue uncoupling) as well as reduced INa have also been linked to VT formation as they slow CV (shortening wavelength) and increase the likelihood of unidirectional block.
      • Campos F.O.
      • Whitaker J.
      • Neji R.
      • et al.
      Factors promoting conduction slowing as substrates for block and reentry in infarcted hearts.
      As shown in Figures 4 and 5, subthreshold DADs can also cause the unidirectional block required for VT initiation at critical isthmus sites within the infarct while also making VT sustenance more likely by not impacting activation wavelength, as in the scenario of long-lasting repolarization.
      Incorporation of structural remodeling in our model by reducing tissue conductivity favored arrhythmogenesis by increasing the amplitude of subthreshold DADs (Figure 6A) enhancing INa inactivation, which in turn widened the vulnerable window for conduction block (Figure 6C). In this scenario, the reduced tissue coupling allows the local voltage near the site of DAD production to be driven higher, as local diffusive coupling is reduced. Furthermore, such reduced conductivity also slows CV, which also favors VT sustenance by shortening the wavelength.
      • Kléber A.G.
      • Rudy Y.
      Basic mechanisms of cardiac impulse propagation and associated arrhythmias.

      Clinical significance

      Increased occurrence of DADs in cells from the BZ and arrhythmia formation during increased adrenergic drive have been demonstrated in a recent in vivo study.
      • Amoni M.
      • Claus P.
      • Dries E.
      • et al.
      Discrete sites of frequent premature ventricular complexes cluster within the infarct border zone and coincide with high frequency of delayed afterdepolarizations under adrenergic stimulation.
      DADs have been attributed to SCR events that typically occur under Ca2+ overload.
      • Wasserstrom J.A.
      • Shiferaw Y.
      • Chen W.
      • et al.
      Variability in timing of spontaneous calcium release in the intact rat heart is determined by the time course of sarcoplasmic reticulum calcium load.
      ,
      • Myles R.C.
      • Wang L.
      • Kang C.
      • Bers D.M.
      • Ripplinger C.M.
      Local β-adrenergic stimulation overcomes source-sink mismatch to generate focal arrhythmia.
      Pharmacologic therapies aimed at severing the link between SCR and DADs could prevent arrhythmia formation and PVC burden. Although β-blockers are the first line of treatment by preventing adrenergic stimulation and Ca2+ loading, new compounds with more specific inhibition, such as stabilization of ryanodine receptors, may have potential benefits in arrhythmia/PVC prevention.
      The amplitude of DADs has been demonstrated to be highly sensitive to the timing variability of SCR events between cardiomyocyte.s9 At the tissue level, electrotonic coupling between cells will decrease the effective rise of Vm in regions of unsynchronized DADs. Thus, any drug capable of widening the time distribution of SCR events would reduce the probability of neighboring cells to undergo DADs. Desynchronized DADs are less likely not only to render tissue refractory, as shown here, but also to capture and propagate in the form of a PVC.
      • Campos F.O.
      • Shiferaw Y.
      • Prassl A.J.
      • Boyle P.M.
      • Vigmond E.J.
      • Plank G.
      Stochastic spontaneous calcium release events trigger premature ventricular complexes by overcoming electrotonic load.
      ,
      • Colman M.A.
      • Perez Alday E.A.
      • Holden A.V.
      • Benson A.P.
      Trigger vs. substrate: multi-dimensional modulation of QT-prolongation associated arrhythmic dynamics by a hERG channel activator.
      More recently, stabilizer cell gene therapy has been proposed as a strategy to prevent DADs by suppressing SCRs.
      • Liu M.B.
      • Priori S.G.
      • Qu Z.
      • Weiss J.N.
      Stabilizer cell gene therapy: a less-is-more strategy to prevent cardiac arrhythmias.
      Furthermore, as shown in Figure 6C, tissue uncoupling increased DAD amplitude, widening the time window for conduction block. Therefore, pharmacologic modulation of gap junctions to restore intercellular coupling as well as therapies aiming at reversing structural remodeling at the BZ would have the antiarrhythmic effects of narrowing down the vulnerable window and lengthening the wavelength by speeding up CV.
      Finally, identification of entry or exit sites of the isthmus is of great clinical significance as they provide an important target for catheter ablation therapy.
      • Verma A.
      • Marrouche N.F.
      • Schweikert R.A.
      • et al.
      Relationship between successful ablation sites and the scar border zone defined by substrate mapping for ventricular tachycardia post-myocardial infarction.
      • Anter E.
      • Tschabrunn C.M.
      • Buxton A.E.
      • Josephson M.E.
      High-resolution mapping of postinfarction reentrant ventricular tachycardia: electrophysiological characterization of the circuit.
      • Anter E.
      • Kleber A.G.
      • Rottmann M.
      • et al.
      Infarct-related ventricular tachycardia: redefining the electrophysiological substrate of the isthmus during sinus rhythm.
      • Martin R.
      • Maury P.
      • Bisceglia C.
      • et al.
      Characteristics of scar-related ventricular tachycardia circuits using ultra-high-density mapping: a multi-center study.
      • Aziz Z.
      • Shatz D.
      • Raiman M.
      • et al.
      Targeted ablation of ventricular tachycardia guided by wavefront discontinuities during sinus rhythm: a new functional substrate mapping strategy.
      • Orini M.
      • Seraphim A.
      • Graham A.
      • et al.
      Detailed assessment of low-voltage zones localization by cardiac MRI in patients with implantable devices.
      Our results suggest that very narrow regions of surviving tissue, where subthreshold DADs could render all tissue inexcitable, could be specific ablation targets that not only may eliminate the substrate for conduction block but also interrupt a reentrant pathway. Because DAD-mediated VT initiation was often co-located near the mouth of narrow isthmus, a substrate-based ablation strategy might be preferable.
      • Briceño D.F.
      • Romero J.
      • Villablanca P.A.
      • et al.
      Long-term outcomes of different ablation strategies for ventricular tachycardia in patients with structural heart disease: systematic review and meta-analysis.
      ,
      • Fernandez-Armenta J.
      • Soto-Iglesias D.
      • Silva E.
      • et al.
      Safety and outcomes of ventricular tachycardia substrate ablation during sinus rhythm: a prospective multicenter registry.
      However, mapping of stochastic DADs is challenging, requiring intricate placement of the catheter in space and the time to detect them. Furthermore, reliable detection of DAD signatures on electrograms might be challenging for current mapping systems with sufficient signal-to-noise. Adequate cardiac imaging and segmentation may be more suitable to identify the structural anatomy of isthmuses prone to DAD-mediated block.
      • Orini M.
      • Seraphim A.
      • Graham A.
      • et al.
      Detailed assessment of low-voltage zones localization by cardiac MRI in patients with implantable devices.
      Future investigations should focus on understanding and mapping anatomic parameters promoting DAD-mediated VT formation.

      Study limitations

      In this study, conduction block occurred within 700–900 ms after the last S1, which is longer than the BCL. This is because DADs in the MSH model are generated by stochastic SCRs with a functional dependence on the SR Ca2+ concentration, which was adjusted here to prevent PVC formation.
      • Campos F.O.
      • Shiferaw Y.
      • Prassl A.J.
      • Boyle P.M.
      • Vigmond E.J.
      • Plank G.
      Stochastic spontaneous calcium release events trigger premature ventricular complexes by overcoming electrotonic load.
      However, these values still are shorter than those reported in experiments.
      • Wasserstrom J.A.
      • Shiferaw Y.
      • Chen W.
      • et al.
      Variability in timing of spontaneous calcium release in the intact rat heart is determined by the time course of sarcoplasmic reticulum calcium load.
      Furthermore, although fast pacing has been shown to shorten the timing of SCRs,
      • Wasserstrom J.A.
      • Shiferaw Y.
      • Chen W.
      • et al.
      Variability in timing of spontaneous calcium release in the intact rat heart is determined by the time course of sarcoplasmic reticulum calcium load.
      this was not investigated here because we focused on the role played by local infarct anatomy. Future research into the effect of pacing cycle length on DAD formation and the role played by structural remodeling in reentry sustenance is needed. Finally, key parameters of the MSH model were modified to increase the probability of DADs because these are stochastic events, which are difficult to analyze without stressing the system.

      Conclusion

      The mechanisms behind initiation and maintenance of postinfarction VTs remain a matter of clinical interest. In this study we used in silico approaches to uncover a novel mechanism by which subthreshold DADs, when occurring in narrow isthmuses within the scar, can form a substrate for block and subsequent reentry. Simulation results showed that reduced electrotonic loading in those regions potentiates the ability of DADs to impair excitability by inactivating the INa current. Such substrate also makes VT sustenance more likely as the activation wavelength is not altered, as in a scenario of long-lasting repolarization. Moreover, tissue uncoupling, a hallmark of structural remodeling following MI, was shown to increase DAD amplitude, enhancing arrhythmogenic risk by increasing the time window of unidirectional block. This novel mechanistic insight represents a new perspective on arrhythmogenesis that cannot be investigated in current (pre)clinical settings due to technological constraints.

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