Computational modeling of cardiac arrhythmias
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
Cardiac arrhythmia
- 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 arrhythmias
- 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!
1. Basic properties and computer modeling
- Single cell
- 2D modeling
- Whole heart modeling
2. The study of spiral waves by computer modeling
- Dynamics of spiral waves in homogeneous media
- Breakup of a spiral
- 3D dynamics of filaments
- Influence of a spiral wave by a heterogeneity
- Influence of fibrosis on spiral waves
- EADs, spiral waves and ectopic activity
3. The real world: clinical research
1. Basic properties and computer modeling
- Single cell
- 2D modeling
- Whole heart modeling
2. The study of spiral waves by computer modeling
- Dynamics of spiral waves in homogeneous media
- Breakup of a spiral
- 3D dynamics of filaments
- Influence of a spiral wave by a heterogeneity
- Influence of fibrosis on spiral waves
- EADs, spiral waves and ectopic activity
3. The real world: clinical research
1. Basic properties and computer modeling
- Single cell
- 2D modeling
- Whole heart modeling
2. The study of spiral waves by computer modeling
- Dynamics of spiral waves in homogeneous media
- Breakup of a spiral
- 3D dynamics of filaments
- Influence of a spiral wave by a heterogeneity
- Influence of fibrosis on spiral waves
- EADs, spiral waves and ectopic activity
3. The real world: clinical research
Single cell
The membrane: contains channels which can open and close
Nerst potential: 2 opposite forces:
- diffusion
- electrical force
You can find the equilibrium which gives you the Nerst potential
Nerst potential: 2 opposite forces:
- diffusion
- electrical force
You can find the equilibrium which gives you the Nerst potential
Most easy model: Hodgkin huxley (nerve cell)
Most easy model: Hodgkin huxley (nerve cell)
Most easy model: Hodgkin huxley (nerve cell)
The whole cell: many more channels
The whole cell: also internal dynamics
The whole cell: many more channels
The whole cell: many more channels
The whole cell: many more channels
All the channels can be modeled as:
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...
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
- 2D modeling
- Whole heart modeling
2. The study of spiral waves by computer modeling
- Dynamics of spiral waves in homogeneous media
- Breakup of a spiral
- 3D dynamics of filaments
- Influence of a spiral wave by a heterogeneity
- Influence of fibrosis on spiral waves
- EADs, spiral waves and ectopic activity
3. The real world: clinical research
Different cells are coupled
- conduction of a wavefront
- refraction: during the wavefront: no new wave can be excited
- resting state: new wave can arrive
Single cell
2D tissue
Colliding waves annihilate
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
Wave can rotate around an obstacle/Wave can rotate around itself
Anatomical reentry
Functional reentry
Period of rotation is usually close to refractoriness time
Experimental evidence
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
Experimental evidence
In a sheep and dog epicardial muscle (Davidenko, Jalife 1973):
--> First to record a real spiral wave
Experimental evidence
Cell cultures (lab of L. Glass, neonatal rat cells)
Experimental evidence
Whole heart of guinea pig (lab of J. Jalife, 2002)
Many other systems also have spiral waves!
Many other systems also have spiral waves!
Many other systems also have spiral waves!
Cable equation
Cable equation
1. Basic properties and computer modeling
- Single cell
- 2D modeling
- Whole heart modeling
2. The study of spiral waves by computer modeling
- Dynamics of spiral waves in homogeneous media
- Breakup of a spiral
- 3D dynamics of filaments
- Influence of a spiral wave by a heterogeneity
- Influence of fibrosis on spiral waves
- EADs, spiral waves and ectopic activity
3. The real world: clinical research
A spiral wave becomes a scroll wave: it can be open or closed
Whole heart simulation: mesh of the heart + fiber orientation
Spiral waves have many different names
1. anatomical reentry -> around obstacle
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
How to stop a reentry circuit?
Ablation: burning of tissue
Atrial fibrillation
Atrial tachycardia
Ventricular tachycardia
Ventricular fibrillation
Torsade de Pointes
Atrial Tachycardia
MV
LPV
RPV
Anatomy of the left atrium: 3 natural holes
3 possible patterns
True loop
Suppressed loop
Fork
MV
LPV
RPV
3 possible patterns
True loop
Suppressed loop
Fork
Classification in case of three holes with at least one reentry
Ablation
Clinical example
MV
LPV
RPV
Scar creates additional holes
Classification in case of four holes with at least one reentry
Clinical example
Scar tissue at the anterior wall.
MV
LPV
RPV
1. Basic properties and computer modeling
- Single cell
- 2D modeling
- Whole heart modeling
2. The study of spiral waves by computer modeling
- Dynamics of spiral waves in homogeneous media
- Breakup of a spiral
- 3D dynamics of filaments
- Influence of a spiral wave by a heterogeneity
- Influence of fibrosis on spiral waves
- EADs, spiral waves and ectopic activity
3. The real world: clinical research
1. Basic properties and computer modeling
- Single cell
- 2D modeling
- Whole heart modeling
2. The study of spiral waves by computer modeling
- Dynamics of spiral waves in homogeneous media
- Breakup of a spiral
- 3D dynamics of filaments
- Influence of a spiral wave by a heterogeneity
- Influence of fibrosis on spiral waves
- EADs, spiral waves and ectopic activity
3. The real world: clinical research
Excitability important for creation of a spiral wave: properties of the single cell!
very low excitability
low excitability
INa
INa
low excitability
- circular rotation
- the period is longer to the refractory period
- Substantial excitable gap
INa
high excitability
- instantaneous rotation
- the period is close to the refractory period
- There is a small excitable gap
INa
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
Stable spiral
Meandering spiral
Hypothesis:
different types of spirals give rise to different arrhythmias
1. Basic properties and computer modeling
- Single cell
- 2D modeling
- Whole heart modeling
2. The study of spiral waves by computer modeling
- Dynamics of spiral waves in homogeneous media
- Breakup of a spiral
- 3D dynamics of filaments
- Influence of a spiral wave by a heterogeneity
- Influence of fibrosis on spiral waves
- EADs, spiral waves and ectopic activity
3. The real world: clinical research
Restitution curve
Restitution curve
Restitution curve
Restitution curve
Break-up of a spiral due to restitution
Atrial fibrillation
Atrial tachycardia
Ventricular tachycardia
Ventricular fibrillation
Torsade de Pointes
Very dangerous!!!!
Hypothesis:
different types of spirals give rise to different arrhythmias
1. Basic properties and computer modeling
- Single cell
- 2D modeling
- Whole heart modeling
2. The study of spiral waves by computer modeling
- Dynamics of spiral waves in homogeneous media
- Breakup of a spiral
- 3D dynamics of filaments
- Influence of a spiral wave by a heterogeneity
- Influence of fibrosis on spiral waves
- EADs, spiral waves and ectopic activity
3. The real world: clinical research
3D dynamics of filaments
There is a filament present!
3D dynamics of filaments
Example: filament with negative tension: possible mechanism of VF (Alonso, Panfilov)
1. Basic properties and computer modeling
- Single cell
- 2D modeling
- Whole heart modeling
2. The study of spiral waves by computer modeling
- Dynamics of spiral waves in homogeneous media
- Breakup of a spiral
- 3D dynamics of filaments
- Influence of a spiral wave by a heterogeneity
- Influence of fibrosis on spiral waves
- EADs, spiral waves and ectopic activity
3. The real world: clinical research
Steep APD gradient in the Mcell region of a non failing human heart
1. Basic properties and computer modeling
- Single cell
- 2D modeling
- Whole heart modeling
2. The study of spiral waves by computer modeling
- Dynamics of spiral waves in homogeneous media
- Breakup of a spiral
- 3D dynamics of filaments
- Influence of a spiral wave by a heterogeneity
- Influence of fibrosis on spiral waves
- EADs, spiral waves and ectopic activity
3. The real world: clinical research
Typical in aging heart: more myofibroblast = fibrotic tissue
Spiral waves are attracted by fibrotic tissue
Spiral waves are attracted by fibrotic tissue
In clinic: spiral waves are often found close to fibrotic tissue
Currently, electrophysiologists are already ablating based on computer modeling
1. Basic properties and computer modeling
- Single cell
- 2D modeling
- Whole heart modeling
2. The study of spiral waves by computer modeling
- Dynamics of spiral waves in homogeneous media
- Breakup of a spiral
- 3D dynamics of filaments
- Influence of a spiral wave by a heterogeneity
- Influence of fibrosis on spiral waves
- EADs, spiral waves and ectopic activity
3. The real world: clinical research
Single cells can have early afterdepolarizations when channels properties are changed
Regions of EAD sensitive cells can cause focal beats = extra beats
These extra beats can also cause spiral waves
Atrial fibrillation
Atrial tachycardia
Ventricular tachycardia
Ventricular fibrillation
Torsade de Pointes
Atrial Fibrillation
Atrial fibrillation
Hypothesis 1: Persistant AF is maintained by rotors
Hypothesis 2: Multiple wavelets maintain AF
Hypothesis 3: Double layer hypothesis
Hypothesis 4: Mother rotor fibrillation
Many of the clinical methods use phase mapping to determine rotational activity
Which one is correct?
Maybe there are many different types of AF?
Hypothesis 5: Atrial fibrillation driven by micro-anatomic intramural re-entry
1. Basic properties and computer modeling
- Single cell
- 2D modeling
- Whole heart modeling
2. The study of spiral waves by computer modeling
- Dynamics of spiral waves in homogeneous media
- Breakup of a spiral
- 3D dynamics of filaments
- Influence of a spiral wave by a heterogeneity
- Influence of fibrosis on spiral waves
- EADs, spiral waves and ectopic activity
3. The real world: clinical research
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
Cardiac arrhythmias: 3 main different types of mechanisms
2. Anatomical reentry
1. Rotors or functional reentry
3. Focal sources
Therefore, we developed a methodology to determine these sources automatically: we describe the electrical propagation in the heart as a directed network:
DG-mapping
Huge field of applications
Brain
Search algorithm
Network theory
Network theory on the excitation of the heart: concept
1. rotors or functional reentry
2. anatomical reentry
3. focal sources
DG-mapping on clinical AT cases
Optimization protocols
DG-mapping on clinical AT - DG GUI
DG-mapping can automatically find the mechanism of an AT without manual interpretation of the colormap of the atrium
-
Operator independent and in some cases better than the operator: DG-mapping removes intuition, is thus very robust
-
Can limit the amount of scar
-
Added value for complex cases
-
Can be used for training of fellows
-
faster: DG-mapping is instantaneous
-
no more entrainment mapping which is an extra technique usually performed
DG-mapping
Modeling can cover even more scales...
Biomedical students: Computational modeling of cardiac arrhythmia
By Nele Vandersickel
Biomedical students: Computational modeling of cardiac arrhythmia
- 899