Electrophysiological and anatomical factors determine arrhythmic risk in acute myocardial ischaemia and its modulation by sodium current availability

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.

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P321Subthreshold delayed afterdepolarizations form a substrate for conduction block in the infarcted heart

EP Europace ◽

10.1093/europace/euaa162.349 ◽

2020 ◽

Vol 22 (Supplement_1) ◽

Author(s):

F Campos ◽

Y Shiferaw ◽

G Plank ◽

M J Bishop

Keyword(s):

Sodium Current ◽

Conduction Block ◽

Computational Modelling ◽

Border Zone ◽

Loss Of Function ◽

Physical Sciences ◽

Tissue Conductivity ◽

Infarcted Heart ◽

Coupling Interval ◽

Delayed Afterdepolarizations

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

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Images of a large fistulous communication between the right ventricle and left anterior descending coronary artery

Cardiology in the Young ◽

10.1017/s1047951119003305 ◽

2020 ◽

Vol 30 (2) ◽

pp. 271-272

Author(s):

Hayrullah Alp ◽

Ahmet M. Elmacı ◽

Mehmet Taşar

Keyword(s):

Heart Failure ◽

Coronary Artery ◽

Right Ventricle ◽

Right Ventricular ◽

Myocardial Ischaemia ◽

Heart Defects ◽

Asymptomatic Child ◽

Coronary Artery Fistulas ◽

The Right

AbstractCoronary artery fistulas are relatively rare congenital or iatrogenic heart defects that can present with or without symptoms. Symptomatic patients manifest as myocardial ischaemia, arrhythmia, or heart failure. We present a asymptomatic child with a large left anterior descending coronary artery to right ventricular fistula.

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Dysfunction of the Right Ventricle in Coronary Artery Disease

CHEST Journal ◽

10.1378/chest.66.3.230 ◽

1974 ◽

Vol 66 (3) ◽

pp. 230-235 ◽

Cited By ~ 25

Author(s):

David E. Wells ◽

Benjamin Befeler

Keyword(s):

Coronary Artery Disease ◽

Coronary Artery ◽

Right Ventricle ◽

Artery Disease ◽

The Right

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Detection of right-coronary-artery disease using stress thallium scintigraphy: Importance of considering the right ventricle

European Journal of Nuclear Medicine ◽

10.1007/bf00253297 ◽

1986 ◽

Vol 11 (9) ◽

pp. 336-340

Author(s):

R. H. Bahar ◽

I. M. Hassan ◽

M. M. Mohammed ◽

N. Hayat ◽

G. Ziada ◽

...

Keyword(s):

Coronary Artery Disease ◽

Coronary Artery ◽

Right Ventricle ◽

Right Coronary Artery ◽

Thallium Scintigraphy ◽

Artery Disease ◽

The Right

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Ventricular fibrillation with a 2:1 conduction block over the right ventricle in a Brugada syndrome patient

Kardiologia Polska ◽

10.5603/kp.2013.0242 ◽

2013 ◽

pp. 991-991

Author(s):

Marek Jastrzębski ◽

Piotr Kukla

Keyword(s):

Ventricular Fibrillation ◽

Right Ventricle ◽

Brugada Syndrome ◽

Conduction Block ◽

Syndrome Patient ◽

The Right

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A model for human action potential dynamics in vivo

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00557.2019 ◽

2020 ◽

Vol 318 (3) ◽

pp. H534-H546 ◽

Cited By ~ 1

Author(s):

Richard A. Gray ◽

Michael R. Franz

Keyword(s):

Action Potential ◽

Complex Dynamics ◽

Sodium Current ◽

Conduction Block ◽

Human Action ◽

Ionic Model ◽

Ethical Concerns ◽

Ventricular Tissue ◽

Current Availability

Computational modeling based on experimental data remains an important component in cardiac electrophysiological research, especially because clinical data such as human action potential (AP) dynamics are scarce or limited by practical or ethical concerns. Such modeling has been used to develop and test a variety of mechanistic hypotheses, with the majority of these studies involving the rate dependence of AP duration (APD) including APD restitution and conduction velocity (CV). However, there is very little information regarding the complex dynamics at the boundary of repolarization (or refractoriness) and reexcitability. Here, we developed a “minimal” ionic model of the human AP, based on in vivo human monophasic AP (MAP) recordings obtained during clinical programmed electrical stimulation (PES) to address the progressive decrease in AP take-off potential (TOP) and associated CV slowing seen during three tightly spaced extrastimuli. Recent voltage-clamp data demonstrating the effect of intracellular calcium on sodium current availability were incorporated and were required to reproduce large (>15 mV) elevations in take-off potential and progressive encroachment. Introducing clinically observed APD gradients into the model enabled us to replicate the dynamic response to PES in patients leading to conduction block and reentry formation for the positive, but not the negative, APD gradient. Finally, we modeled the dynamics of reentry and show that spiral waves follow a meandering trajectory with a period of ~180 ms. We conclude that our model reproduces a variety of electrophysiological behavior including the response to sequential premature stimuli and provides a basis for studies of the initiation of reentry in human ventricular tissue. NEW & NOTEWORTHY This work presents a new model of the action potential of the human which reproduces the complex dynamics during premature stimulation in patients.

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