Local Gradients in Electrotonic Loading Modulate the Local Effective Refractory Period: Implications for Arrhythmogenesis in the Infarct Border Zone

Connolly, Adam; Trew, Mark L.; Smaill, Bruce H.; Plank, Gernot; Bishop, Martin J.

doi:10.1109/tbme.2015.2421296

Cited by 14 publications

(33 citation statements)

References 36 publications

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“…How the Cx43-dependent myofibroblast dynamism characterized in our study affects the formation of proarrhythmic substrates at the heterocellular coupling area should be investigated further. The irregularity of the interface between surviving cardiac muscle and the scar tissue of myocardial infarction is a well-characterized determinant and originator of re-entrant arrhythmias (60,61). Modeling studies have shown that microstructural variations in cardiac tissue facilitate the formation of isolated sites of wavefront breakthrough that may enable abnormal electrical activity; these small regions of heterogeneous diseased tissue can develop more widespread re-entrant activity (62,63).…”

Section: Discussionmentioning

confidence: 99%

Cardiomyocyte–myofibroblast contact dynamism is modulated by connexin‐43

et al. 2019

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Healthy cardiomyocytes are electrically coupled at the intercalated discs by gap junctions. In infarcted hearts, adverse gap‐junctional remodeling occurs in the border zone, where cardiomyocytes are chemically and electrically influenced by myofibroblasts. The physical movement of these contacts remains unquantified. Using scanning ion conductance microscopy, we show that intercellular contacts between cardiomyocytes and myofibroblasts are highly dynamic, mainly owing to the edge dynamics (lamellipodia) of the myofibroblasts. Decreasing the amount of functional connexin‐43 (Cx43) at the membrane through Cx43 silencing, suppression of Cx43 trafficking, or hypoxia‐induced Cx43 internalization attenuates heterocellular contact dynamism. However, we found decreased dynamism and stabilized membrane contacts when cellular coupling was strengthened using 4‐phenylbutyrate (4PB). Fluorescent‐dye transfer between cells showed that the extent of functional coupling between the 2 cell types correlated with contact dynamism. Intercellular calcein transfer from myofibroblasts to cardiomyocytes is reduced after myofibroblast‐specific Cx43 down‐regulation. Conversely, 4PB‐treated myofibroblasts increased their functional coupling to cardiomyocytes. Consistent with lamellipodia‐mediated contacts, latrunculin‐B decreases dynamism, lowers physical communication between heterocellular pairs, and reduces Cx43 intensity in contact regions. Our data show that heterocellular cardiomyocyte‐myofibroblast contacts exhibit high dynamism. Therefore, Cx43 is a potential target for prevention of aberrant cardiomyocyte coupling and myofibroblast proliferation in the infarct border zone.—Schultz, F., Swiatlowska, P., Alvarez‐Laviada, A., Sanchez‐Alonso, J. L., Song, Q., de Vries, A. A. F., Pijnappels, D. A., Ongstad, E., Braga, V. M. M., Entcheva, E., Gourdie, R. G., Miragoli, M., Gorelik, J. Cardiomyocyte–myofibroblast contact dynamism is modulated by connexin‐43. FASEB J. 33, 10453–10468 (2019). http://www.fasebj.org

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Section: Discussionmentioning

confidence: 99%

Cardiomyocyte–myofibroblast contact dynamism is modulated by connexin‐43

et al. 2019

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“…Such electrotonic effect can be seen in Figure 6. PVCs originated everywhere throughout the isthmus, but were found to lie away from both proximal and distal mouths (minimum focus-to-mouth distance was 2.61 mm for w isth = 0.2 mm) due to unfavored loading conditions in regions of abrupt tissue expansion [36,37]. As the size of the isthmus increases, the electrotonic load on cells comes closer to that of a well-coupled 2D cardiac tissue.…”

Section: The Role Of Electrotonic Loadmentioning

confidence: 99%

“…The cardiac safety factor for propagation has been shown to be minimum near regions of thin-to-thick tissue expansion [36], such as the mouth of the isthmus, where source current generated by the excited cells is insufficient to activate the downstream tissue [37]. Sink effects at the mouth of the isthmus can also be altered by elevations in V m resulting from subthreshold DADs [17].…”

Section: The Role Of Electrotonic Loadmentioning

confidence: 99%

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

et al. 2018

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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.

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“…We have recently demonstrated [5,6] that changes in local electrotonic loading (due to the presence of tissue boundaries, small cavities and rapid tissue expansions), can significantly affect the excitability of cardiac tissue, causing a corresponding spatial variation in local effective refractory period (ERP). Such spatial gradients in ERP were witnessed in absence of any significant changes in action potential duration (APD), and were shown to be responsible for causing uni-directional block and subsequent arrhythmia induction.…”

Section: Introductionmentioning

confidence: 99%

“…Such gradients are present both when the initial wavefront (prior to ERP calculation) occurs from healthy-to-BZ as well as from BZto-healthy tissue. In our previous studies [5,6], we have demonstrated how gradients in ERP (caused in these cases due to differences in electrotonic loading brought about by structural heterogeneity) can facilitate uni-directional conduction block following a focal ectopic beat applied close to the ERP of tissue experiencing a high gradient. We suggest that a similar mechanism may occur in this scenario.…”

mentioning

confidence: 98%

Modulation of Effective Refractory Period at the Infarct Border:Zone Provides a Mechanism for Focal Arrhythmogenesis

Connolly

Gawenda

Plank

et al. 2016

2016 Computing in Cardiology Conference (CinC)

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Border-zone (BZ) tissue, representing viable yet remodelled myocardium surrounding infarct scars, has been strongly correlated with arrhythmogenic risk postmyocardial infarction. How the electrophysiological remodelling in BZ tissue facilitates arrhythmogenesis, particularly of a focal origin, is currently unknown. In this study, we used computational models of human ventricular tissue to quantify spatial changes in action potential duration (APD) and effective refractory period (ERP) in the presence of electrophysiological BZ remodelling. Reductions in sodium channel conductivity to 35% increased ERP by > 30 ms relative to healthy tissue in absence of significant changes in APD due to a decrease in tissue excitability. When combined with remodelling of repolarising potassium currents, larger changes in ERP of > 60 ms occurred, due to concurrent increases in APD. Spatial plots of ERP along interfaces between healthy and BZ regions showed high spatial ERP gradients. Such heterogeneity may facilitate unidirectional block of nearby focal ectopic beats, providing an important focal arrhythmogenenic substrate.

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Local Gradients in Electrotonic Loading Modulate the Local Effective Refractory Period: Implications for Arrhythmogenesis in the Infarct Border Zone

Cited by 14 publications

References 36 publications

Cardiomyocyte–myofibroblast contact dynamism is modulated by connexin‐43

Cardiomyocyte–myofibroblast contact dynamism is modulated by connexin‐43

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

Modulation of Effective Refractory Period at the Infarct Border:Zone Provides a Mechanism for Focal Arrhythmogenesis

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