Different Mechanisms for Reentry in the Epicardial Border Zone of Healing Canine Infarcts: The Roles of Functional and Anatomical Conduction Block

Author(s):  
Adam E. Saltman ◽  
James Coromilas ◽  
Bernd Waldecker ◽  
Stephen M. Dillon ◽  
Andrew L. Wit
Keyword(s):  
EP Europace ◽  
2020 ◽  
Vol 22 (Supplement_1) ◽  
Author(s):  
F Campos ◽  
Y Shiferaw ◽  
G Plank ◽  
M J Bishop

Abstract Funding Acknowledgements National Institute for Health Research; British Heart Foundation; and The Wellcome Trust and Engineering and Physical Sciences Research Council. Background Delayed afterdepolarizations (DADs) due to spontaneous calcium (Ca) release (SCR) events from the sarcoplasmic reticulum have been implicated with a variety of arrhythmias. Such SCR events have also been reported in cells that survive in the infarct border zone (BZ). While the potential of Ca-mediated DADs to become suprathreshold and propagate in the form of ectopic beats has been well characterized, the role of subthreshold DADs in arrhythmia formation in the infarcted heart remains to be elucidated. Purpose To use computational modelling to investigate whether subthreshold Ca-mediated DADs may form a substrate for conduction block and reentry in the BZ. Our hypothesis is that subthreshold DADs can hinder local tissue excitability in critical infarct BZ regions by inactivating the fast sodium current (INa), leading to temporary unidirectional conduction block providing a trigger for arrhythmogenesis. Methods We developed an idealized infarct model of the left ventricle. The infarct region consisted of a non-conducting scar transcended by an isthmus of cells that survived myocardial infarction (border zone). These cells were made prone to Ca-mediated DADs described by a phenomenological model of SCR events. The model was pre-paced at the apex followed by a 1500ms-pacing pause to see whether DADs would emerge. An extra beat with a longer coupling interval (CI) was then applied. The following electrophysiological changes resulting from remodeling processes in the isthmus were simulated to assess their contribution to the arrhythmogenic potential of subthreshold DADs: INa loss-of-function due to a (2.5mV and 5mV) negative-shift in the steady-state channel inactivation; 50% reduction in tissue conductivity; and increased levels of fibrosis (up to 50%). Results On average, Ca-mediated DADs reached their maximum value 1065ms after the last paced beat (Fig. A). Despite this, in the default electrophysiological setup, simulations with extra beats with 1000ms > CI > 1100ms did not result in conduction block in any of the experiments. When repeated with combined changes of reduced tissue conductivity and fibrosis, subthreshold DADs were still unable to create a substrate for block. However, when combined with a 5mV-shift in INa inactivation, block at isthmus’ mouth proximal to the stimulus site was detected for extra beats 1010 ms ≥ CI ≥ 1070ms (see Fig. B). The cause of block was due to a subthreshold DAD occurring just prior to the arrival of the extra beat. All blocked beats degenerated into reentry. Conclusions Under most physiological conditions, subthreshold DADs are unlikely to provide a substrate for unidirectional block. However, under conditions of decreased excitability, subthreshold DADs can hinder tissue excitability in the infarcted region leading to conduction block and reentry. Abstract Figure. DAD-mediated conduction block in the BZ


2014 ◽  
Vol 7 (1) ◽  
pp. 152-163 ◽  
Author(s):  
Edward J. Ciaccio ◽  
Hiroshi Ashikaga ◽  
James Coromilas ◽  
Bruce Hopenfeld ◽  
Daniel O. Cervantes ◽  
...  

2010 ◽  
Vol 299 (5) ◽  
pp. H1588-H1597 ◽  
Author(s):  
Keith F. Decker ◽  
Yoram Rudy

The increased incidence of arrhythmia in the healing phase after infarction has been linked to remodeling in the epicardial border zone (EBZ). Ionic models of normal zone (NZ) and EBZ myocytes were incorporated into one-dimensional models of propagation to gain mechanistic insights into how ion channel remodeling affects action potential (AP) duration (APD) and refractoriness, vulnerability to conduction block, and conduction safety postinfarction. We found that EBZ tissue exhibited abnormal APD restitution. The remodeled Na+ current ( INa) and L-type Ca2+ current ( ICa,L) promoted increased effective refractory period and prolonged APD at a short diastolic interval. While postrepolarization refractoriness due to remodeled EBZ INa was the primary determinant of the vulnerable window for conduction block at the NZ-to-EBZ transition in response to premature S2 stimuli, altered EBZ restitution also promoted APD dispersion and increased the vulnerable window at fast S1 pacing rates. Abnormal EBZ APD restitution and refractoriness also led to abnormal periodic conduction block patterns for a range of fast S1 pacing rates. In addition, we found that INa remodeling decreased conduction safety in the EBZ but that inward rectifier K+ current remodeling partially offset this decrease. EBZ conduction was characterized by a weakened AP upstroke and short intercellular delays, which prevented ICa,L and transient outward K+ current remodeling from playing a role in EBZ conduction in uncoupled tissue. Simulations of a skeletal muscle Na+ channel SkM1- INa injection into the EBZ suggested that this recently proposed antiarrhythmic therapy has several desirable effects, including normalization of EBZ effective refractory period and APD restitution, elimination of vulnerability to conduction block, and normalization of conduction in tissue with reduced intercellular coupling.


2000 ◽  
Vol 278 (6) ◽  
pp. H2124-H2133 ◽  
Author(s):  
Masaaki Yashima ◽  
Toshihiko Ohara ◽  
Ji-Min Cao ◽  
Young-Hoon Kim ◽  
Michael C. Fishbein ◽  
...  

The vulnerability of the infarcted hearts to ventricular fibrillation (VF) was tested in in situ canine hearts during nicotine infusion. The activation pattern was mapped with 477 bipolar electrodes in open-chest anesthetized dogs ( n = 8) 5–6 wk after permanent occlusion of the left anterior descending coronary artery. Nicotine (129 ± 76 ng/ml) lengthened ( P < 0.01) the pacing cycle length at which VF was induced from 171 ± 8.9 to 210 ± 14.7 ms. Nicotine selectively amplified the magnitude of conduction time and monophasic action potential (MAP) amplitude and duration (MAPA and MAPD, respectively) alternans in the epicardial border zone (EBZ) but not in the normal zone. With critical reduction of the MAPA and MAPD in the EBZ, conduction block occurred across the long axis of the EBZ cells. Block led immediately to reentry formation in the EBZ with a mean period of 105 ± 10 ms, which, after one to two rotations, degenerated to VF. Nicotine widened the range of diastolic intervals over which the dynamic MAPD restitution curve had a slope >1. We conclude that nicotine facilitates conduction block, reentry, and VF in hearts with healed myocardial infarction by increasing the magnitude of depolarization and repolarization alternans consistent with the restitution hypothesis of vulnerability to VF.


2018 ◽  
Vol 6 ◽  
Author(s):  
Fernando O. Campos ◽  
Yohannes Shiferaw ◽  
Rodrigo Weber dos Santos ◽  
Gernot Plank ◽  
Martin J. Bishop
Keyword(s):  

2021 ◽  
Author(s):  
Brett Baggett ◽  
Kevin Murphy ◽  
Elif Sengun ◽  
Eric Mi ◽  
Yueming Cao ◽  
...  

Progressive tissue remodeling after myocardial infarction (MI) promotes cardiac arrhythmias. This process is well studied in young animals, but little is known about pro-arrhythmic changes in aged animals. Senescent cells accumulate with age and accelerate age-associated diseases. Senescent cells interfere with cardiac function and outcome post-MI with age, but studies have not been performed in large animals, and the mechanisms are unknown. Here, we investigated the role of senescence in regulating inflammation, fibrosis, and arrhythmogenesis in young and aged infarcted rabbits. Aged rabbits exhibited increased peri-procedural mortality and arrhythmogenic electrophysiological remodeling at the infarct border zone (IBZ) compared to young rabbits. Studies of the aged infarct zone revealed persistent myofibroblast senescence and increased inflammatory signaling over a twelve-week timecourse. Senescent IBZ myofibroblasts in aged rabbits appear to be coupled to myocytes, and our computational modeling showed that senescent myofibroblast-cardiomyocyte coupling prolongs action potential duration (APD) and facilitates conduction block permissive of arrhythmias. Aged infarcted human ventricles show levels of senescence consistent with aged rabbits, and senescent myofibroblasts also couple to IBZ myocytes. Our findings suggest that senolytic drugs may mitigate arrhythmias post-MI.


2020 ◽  
Vol 11 (1) ◽  
pp. 20190124 ◽  
Author(s):  
Hector Martinez-Navarro ◽  
Xin Zhou ◽  
Alfonso Bueno-Orovio ◽  
Blanca Rodriguez

Acute myocardial ischaemia caused by coronary artery disease is one of the main causes of sudden cardiac death. Even though sodium current blockers are used as anti-arrhythmic drugs, decreased sodium current availability, also caused by mutations, has been shown to increase arrhythmic risk in ischaemic patients. The mechanisms are still unclear. Our goal is to exploit perfect control and data transparency of over 300 high-performance computing simulations to investigate arrhythmia mechanisms in acute myocardial ischaemia with variable sodium current availability. The human anatomically based torso-biventricular electrophysiological model used includes representation of realistic ventricular anatomy and fibre architecture, as well as ionic to electrocardiographic properties. Simulations show that reduced sodium current availability increased arrhythmic risk in acute regional ischaemia due to both electrophysiological (increased dispersion of refractoriness across the ischaemic border zone) and anatomical factors (conduction block from the thin right ventricle to thick left ventricle). The asymmetric ventricular anatomy caused high arrhythmic risk specifically for ectopic stimuli originating from the right ventricle and ventricular base. Increased sodium current availability was ineffective in reducing arrhythmic risk for septo-basal ectopic excitation. Human-based multiscale modelling and simulations reveal key electrophysiological and anatomical factors determining arrhythmic risk in acute ischaemia with variable sodium current availability.


2021 ◽  
Vol 12 ◽  
Author(s):  
Eric Sung ◽  
Adityo Prakosa ◽  
Natalia A. Trayanova

Aims: Disease-induced repolarization heterogeneity in infarcted myocardium contributes to VT arrhythmogenesis but how apicobasal and transmural (AB-TM) repolarization gradients additionally affect post-infarct VT dynamics is unknown. The goal of this study is to assess how AB-TM repolarization gradients impact post-infarct VT dynamics using patient-specific heart models.Method: 3D late gadolinium-enhanced cardiac magnetic resonance images were acquired from seven post-infarct patients. Models representing the patient-specific scar and infarct border zone distributions were reconstructed without (baseline) and with repolarization gradients along both the AB-TM axes. AB only and TM only models were created to assess the effects of each ventricular gradient on VT dynamics. VTs were induced in all models via rapid pacing.Results: Ten baseline VTs were induced. VT inducibility in AB-TM models was not significantly different from baseline (p&gt;0.05). Reentry pathways in AB-TM models were different than baseline pathways due to alterations in the location of conduction block (p&lt;0.05). VT exit sites in AB-TM models were different than baseline VT exit sites (p&lt;0.05). VT inducibility of AB only and TM only models were not significantly different than that of baseline (p&gt;0.05) or AB-TM models (p&gt;0.05). Reentry pathways and VT exit sites in AB only and TM only models were different than in baseline (p&lt;0.05). Lastly, repolarization gradients uncovered multiple VT morphologies with different reentrant pathways and exit sites within the same structural, conducting channels.Conclusion: VT inducibility was not impacted by the addition of AB-TM repolarization gradients, but the VT reentrant pathway and exit sites were greatly affected due to modulation of conduction block. Thus, during ablation procedures, physiological and pharmacological factors that impact the ventricular repolarization gradient might need to be considered when targeting the VTs.


2019 ◽  
Vol 24 (6) ◽  
pp. 12-15
Author(s):  
Jay Blaisdell ◽  
James B. Talmage

Abstract Like the diagnosis-based impairment (DBI) method and the range-of-motion (ROM) method for rating permanent impairment, the approach for rating compression or entrapment neuropathy in the upper extremity (eg, carpal tunnel syndrome [CTS]) is a separate and distinct methodology in the AMA Guides to the Evaluation of Permanent Impairment (AMA Guides), Sixth Edition. Rating entrapment neuropathies is similar to the DBI method because the evaluator uses three grade modifiers (ie, test findings, functional history, and physical evaluation findings), but the way these modifiers are applied is different from that in the DBI method. Notably, the evaluator must have valid nerve conduction test results and cannot diagnose or rate nerve entrapment or compression without them; postoperative nerve conduction studies are not necessary for impairment rating purposes. The AMA Guides, Sixth Edition, uses criteria that match those established by the Normative Data Task Force and endorsed by the American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM); evaluators should be aware of updated definitions of normal from AANEM. It is possible that some patients may be diagnosed with carpal or cubital tunnel syndrome for treatment but will not qualify for that diagnosis for impairment rating; evaluating physicians must be familiar with electrodiagnostic test results to interpret them and determine if they confirm to the criteria for conduction delay, conduction block, or axon loss; if this is not the case, the evaluator may use the DBI method with the diagnosis of nonspecific pain.


Sign in / Sign up

Export Citation Format

Share Document