Computational modeling of cardiac arrhythmias

Computational modeling of cardiac arrhytmia

Nele Vandersickel

Normal function of the heart

Normal function of the heart

Normal function of the heart

Normal rhythm 60 beats/min: determined by the SA node => 100.000 beats per day.

:delay of the signal

Normal function of the heart

  • Ischaemic heart disease: Ventricular arrhythmias remain the leading cause of death from coronary artery disease
  • Stroke can also be caused by cardiac arrhythmia: e.g. atrial fibrillation

Cardiac arrhythmia

Main questions

 

  • Mechanisms of the initiation of arrhythmia
     
  • Transition of arrhythmia (tachycardia) into more dangerous arrhythmia (fibrillation)
     
  • Control of arrhythmia, how to remove it from the heart

 

Computer modeling help with these questions!

Cardiac arrhythmia

1. Basic properties and computer modeling

1. Basic properties and computer modeling: single cell

The membrane: contains channels which can open and close

1. Basic properties and computer modeling: single cell

Nerst potential: 2 opposite forces:

  • diffusion
  • electrical force

You can find the equilibrium which gives you the Nerst potential

1. Basic properties and computer modeling: single cell

Nerst potential: 2 opposite forces:

  • diffusion
  • electrical force

You can find the equilibrium which gives you the Nerst potential

1. Basic properties and computer modeling: single cell

Most easy model: Hodgkin huxley (nerve cell)

1. Basic properties and computer modeling: single cell

Most easy model: Hodgkin huxley (nerve cell)

1. Basic properties and computer modeling: single cell

Most easy model: Hodgkin huxley (nerve cell)

1. Basic properties and computer modeling: single cell

The whole cell: many more channels

1. Basic properties and computer modeling: single cell

The whole cell: also internal dynamics

1. Basic properties and computer modeling: single cell

The whole cell: many more channels

1. Basic properties and computer modeling: single cell

The whole cell: many more channels

1. Basic properties and computer modeling: single cell

The whole cell: many more channels

All the channels can be modeled as:

1. Basic properties and computer modeling: single cell

The whole cell: many more channels

  • Only the most simple model (HH) can be solved analytically
     
  • All other models have to be solved numerically with the computer
     
  • At each timestep you can output any variable that you want: voltage, currents, concentration...

 

1. Basic properties and computer modeling: single cell

The whole cell: many more channels

  • There exist many different different models: for the ventricles 3 major models, more than 10 other models

 

  • The ORD model is being used to test the effect of drugs: ’Comprehensive in-vitro Pro-arrhythmia Assay (CiPA) initiative www.cipaproject.org. CiPA aims to replace the existing pro-arrhythmic safety testing and Thorough QT Study with a combination of ion channel screening, mathematical modelling, stem-cell derived myocyte experiments and more lightweight Phase I ECG monitoring’

1. Basic properties and computer modeling: single cell

Different cells are coupled

1. Basic properties and computer modeling: 2D modeling

  • conduction of a wavefront
  • refraction: during the wavefront: no new wave can be excited
  • resting state: new wave can arrive

Single cell

2D tissue

1. Basic properties and computer modeling: 2D modeling

Colliding waves annihilate

1. Basic properties and computer modeling: 2D modeling

Wave can rotate in a ring, rotation is possible if the length of a ring (L) is longer than the product of the refractory period and the velocity of the wave: L > Rv

1. Basic properties and computer modeling: 2D modeling

Wave can rotate around an obstacle/Wave can rotate around itself

Anatomical reentry

Functional reentry

Period of rotation is usually close to refractoriness time

1. Basic properties and computer modeling: 2D modeling

In a rabbit heart (Allessie 1973):

  • first to record it
  • not big enough preparation, called it a leading circle
  • wrong idea still exists up today

1. Basic properties and computer modeling: 2D modeling - experimental evidence

In a sheep and dog epicardial muscle (Davidenko, Jalife 1973):

--> First to record a real spiral wave

1. Basic properties and computer modeling: 2D modeling - experimental evidence

Cell cultures

(lab of L. Glass, neonatal rat cells)

1. Basic properties and computer modeling: 2D modeling - experimental evidence

Whole heart of guinea pig (lab of J. Jalife, 2002)

1. Basic properties and computer modeling: 2D modeling - experimental evidence

Many other systems also have spiral waves!

1. Basic properties and computer modeling: 2D modeling - experimental evidence

Many other systems also have spiral waves!

1. Basic properties and computer modeling: 2D modeling - experimental evidence

Many other systems also have spiral waves!

1. Basic properties and computer modeling: 2D modeling - experimental evidence

Cable equation

1. Basic properties and computer modeling: 2D modeling

Cable equation

1. Basic properties and computer modeling: 2D modeling

A spiral wave becomes a scroll wave: it can be open or closed

1. Basic properties and computer modeling: whole heart modelling

Whole heart simulation: mesh of the heart + fiber orientation

1. Basic properties and computer modeling: whole heart modelling

Spiral waves have many different names

1. anatomical reentry -> around obstacle

 

1. Basic properties and computer modeling: whole heart modelling

1. Basic properties and computer modeling: whole heart modelling

Spiral waves have many different names

1. anatomical reentry -> around obstacle

  

Spiral waves have many different names

1. anatomical reentry -> around obstacle

2. functional reentry -> around itself

2. Types of arrhythmia and treatment

Atrial fibrillation

Atrial tachycardia

Ventricular tachycardia

Ventricular fibrillation

Torsade de Pointes

2. Types of arrhythmia and treatment

2. Types of arrhythmia and treatmen: atrial tachycardia

  • In atria
  • Regular
  • Mechanism: anatomical reentry
  • No immediate risk of dying

Hypothesis 1: Persistant AF is maintained by rotors

Hypothesis 2: Multiple wavelets maintain AF

Hypothesis 3: Double layer hypothesis

Hypothesis 4: Mother rotor fibrillation

Hypothesis 5: Atrial fibrillation driven by micro-anatomic intramural re-entry

2. Types of arrhythmia and treatment: atrial fibrillation

  • In atria
  • Irregular
  • Mechanism: unknown
  • No immediate risk of dying. high risk of stroke

2. Types of arrhythmia and treatment: ventricular tachycardia

  • In ventricles
  • Regular
  • Mechanism: anatomical reentry in 3D
  • Risk of dying

2. Types of arrhythmia and treatment: ventricular fibrillation

  • In ventricles
  • Irregular
  • Mechanism: still no consensus
  • Dying within minutes

How to stop a reentry circuit?

Ablation: burning of tissue

2. Types of arrhythmia and treatment

3. More on Atrial Tachycardia

3. Atrial Tachycardia: a real case

Looks like typical case of flutter?

MV

LPV

RPV

3. Atrial Tachycardia: Anatomy of the left atrium: 3 natural holes

MV

3. Atrial Tachycardia: Anatomy of the left atrium: 3 natural holes

MV

LPV

RPV

SVC

TV

200 different simulations

Entrainment mapping

All possible virtual ablation lines: 600 simulation

3. Atrial Tachycardia: Simulations

3. Atrial Tachycardia -  3 possible patterns

3 Patterns

Complete rotation

Incomplete rotation

Parallel activation

Good entrainment

Bad entrainment

Bad entrainment

3. Atrial Tachycardia -  3 possible patterns

3 Patterns

Complete rotation

Incomplete rotation

Parallel activation

3. Atrial Tachycardia -  Ablation

Incomplete rotation becomes complete rotation, resulting in a slower AT

100% of simulations!

3. Atrial Tachycardia -  Index Theorem > 20 years old!

3. Atrial Tachycardia -  Index Theorem > 20 years old!

Complete rotation

Parallel activation

Incomplete rotation

Critical Boundary

Critical Boundary

Non-Critical Boundary

CB: Santucci et al. JACC EP 2023

CB:

CB:

NCB: 0

Incomplete rotation becomes complete rotation, resulting in a slower AT

Loops come in pairs of 2: currently second loop is always missed

3. Atrial Tachycardia -  Ablation: connect the critical boundaries!

3. Atrial Tachycardia -  Ablation: Clinical cases

200 simulation with 2 boundaries

Clinical cases

3. Atrial Tachycardia -  Ablation: Clinical cases

CB:

CB:

NCB: 0

Incomplete rotation becomes complete rotation, resulting in a slower AT

3. Atrial Tachycardia -  Ablation: Clinical cases

MV

LPV

RPV

3. Atrial Tachycardia: Scar creates additional holes

200 simulations with 4 boundaries

Clinical cases

3. Atrial Tachycardia: Scar creates additional holes

131 MRAT cases

3. Atrial Tachycardia: 131 clinical cases together!

3. Atrial Tachycardia: 20 detailed cases

20 detailed cases with slowing after ablation

Macro reentry

Localized reentry

Micro reentry

Focal

Rotor

Around anatomic obstacle, like valve or vessels.

Around non conducting area > 2-1.5cm, e.g. scar or functional block

  • Atypical Flutter    (LA involving valves or vessels)

  • Atypical Flutter   (RA involving valves or vessels)​

  • Typical Flutter (clockwise and counter clockwise)

  • WPW

  • Atypical Flutter    (LA with scar or previous ablation lines with gaps)​

  • AVNRT    (considering slow  and fast pathway)

Around non conducting area < 1cm, e.g. scar or functional block

  • Atypical Flutter    (LA with scar​)

  • Atypical Flutter   (RA crista terminalis region)

  • Ectopic AT

Spiral activation pattern with no scar in the core.

Focal activation from  one single spot with centrifugal activation pattern

CL tends to be longer >350ms due to larger path

CL range varies and CL can shift around 20-40 ms during arrhythmia due to slight path variations

CL tends to be shorter due to short path, whole CL is covered by signals found in a small area like e.g. 4cm2 often a combination of double potentials in the „middle“ and very long fractionated signals surrounding​

CL often not presented completely in one chamber

Focal activation patterns could also hint to epicardial entries – look for potential conducting structure like vein of Marshall, Bachmann´s etc. and exits that would fit a macro reentry with epicardial parts

We think non-existent in AT, especially as a stable configuration leading to a stable AT.

Maybe something close to a spiral pattern can exist in AF

  • AF

3. Atrial Tachycardia: Current Classification...

3. Atrial Tachycardia: Current Classification...

Macro reentry

Localized reentry

Micro reentry

Focal

Rotor

Around anatomic obstacle, like valve or vessels.

Around non conducting area > 2-1.5cm, e.g. scar or functional block

  • Atypical Flutter    (LA involving valves or vessels)

  • Atypical Flutter   (RA involving valves or vessels)​

  • Typical Flutter (clockwise and counter clockwise)

  • WPW

  • Atypical Flutter    (LA with scar or previous ablation lines with gaps)​

  • AVNRT    (considering slow  and fast pathway)

Around non conducting area < 1cm, e.g. scar or functional block

  • Atypical Flutter    (LA with scar​)

  • Atypical Flutter   (RA crista terminalis region)

  • Ectopic AT

Spiral activation pattern with no scar in the core.

Focal activation from  one single spot with centrifugal activation pattern

CL tends to be longer >350ms due to larger path

CL range varies and CL can shift around 20-40 ms during arrhythmia due to slight path variations

CL tends to be shorter due to short path, whole CL is covered by signals found in a small area like e.g. 4cm2 often a combination of double potentials in the „middle“ and very long fractionated signals surrounding​

CL often not presented completely in one chamber

Focal activation patterns could also hint to epicardial entries – look for potential conducting structure like vein of Marshall, Bachmann´s etc. and exits that would fit a macro reentry with epicardial parts

We think non-existent in AT, especially as a stable configuration leading to a stable AT.

Maybe something close to a spiral pattern can exist in AF

  • AF

All of this is replaced by our simple classification!

2nd Accepted paper

Atrial topology for a unified understanding of typical and atypical flutter

Mattias Duytschaever, Robin Van Den Abeele ... Annika Haas, Armin Luik, ... Sander Hendrickx, Nele Vandersickel

3. Real impact

2 papers almost finished: clinical, computational

Our work is going to be added to consensus paper on ablation of AT

3. Real impact

3. Atrial Tachycardia: a real case

3. Atrial Tachycardia: a real case

4. Study of spiral waves

Excitability important for creation of a spiral wave: properties of the single cell!

very low excitability

low excitability

INa

INa

4. Spiral waves: dynamics

low excitability

  • circular rotation
  • the period is longer to the refractory period
  • Substantial excitable gap

INa

4. Spiral waves: dynamics

high excitability

  • instantaneous rotation
  • the period is close to the refractory period
  • There is a small excitable gap

INa

4. Spiral waves: dynamics

very high excitability

INa

If wavefront cannot make a complete turn without interaction with the tail of the wave, there will be interaction and thus meandering.

long refractory tail

Ik

4. Spiral waves: dynamics

Stable spiral

Meandering spiral

4. Spiral waves: dynamics

Hypothesis:

different types of spirals give rise to different arrhythmias

4. Spiral waves: dynamics

4. Spiral waves: restitution curves

4. Spiral waves: restitution curves

4. Spiral waves: restitution curves

4. Spiral waves: restitution curves

4. Spiral waves: restitution curves and link to breakup of spiral wave

Very dangerous!!!!

Hypothesis:

different types of spirals give rise to different arrhythmias

4. Spiral waves: dynamics

Typical in aging heart: more myofibroblast = fibrotic tissue

4. Spiral waves: influence fibrosis

Spiral waves are attracted by fibrotic tissue

4. Spiral waves: influence fibrosis

Spiral waves are attracted by fibrotic tissue

4. Spiral waves: influence fibrosis

In clinic: spiral waves are often found close to fibrotic tissue

Currently, electrophysiologists are already ablating based on computer modeling

4. Spiral waves: influence fibrosis

5. Clinical research with computer models

Computer modeling is useful to understand arrhythmias, however, only one group in the world (Baltimore) uses modeling to actually treat patients. Still a long way to go...

Computer modeling can however also be used to test new techniques

5. Clinical research with computer models

2. Anatomical reentry

1. Rotors or functional reentry

3. Focal sources

5. Cardiac arrhythmias: 3 main different types of mechanisms

We developed a methodology to determine a sources automatically: we describe the electrical propagation in the heart as a directed network:

DG-mapping

5. Tool to analyze arrhythmia: DGM

Huge field of applications

Brain

Facebook

Search algorithm

Network theory

5. Tool to analyze arrhythmia: DGM

Network theory on the excitation of the heart: concept

5. Tool to analyze arrhythmia: DGM

Functional reentry

Anatomical reentry

5. Tool to analyze arrhythmia: DGM

Focal sources

5. Tool to analyze arrhythmia: DGM

DG-mapping on clinical AT cases

Optimization protocols

5. Tool to analyze arrhythmia: DGM

5. Tool to analyze arrhythmia: DGM

New version almost ready open source/source available with restrictions for commercial use

You can create your own pipeline!

www.dgmapping.com

5. Tool to analyze arrhythmia: DGM

www.dgmapping.com

Modeling can cover even more scales...

Conclusion: models can be extremely useful

Biomedical students: Computational modeling of cardiac arrhythmia

By Nele Vandersickel

Biomedical students: Computational modeling of cardiac arrhythmia

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