Biophysical Mechanisms of Cardiac Arrhythmias due to Fibrosis and - - PowerPoint PPT Presentation

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Biophysical Mechanisms of Cardiac Arrhythmias due to Fibrosis and - - PowerPoint PPT Presentation

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Biophysical Mechanisms of Cardiac Arrhythmias due to Fibrosis and Other Pathological Conditions Ivan Kazbanov Ghent University Ghent, 2016 The Heart Biological machine designed for pumping blood. Source: Wikipedia ,

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Biophysical Mechanisms of Cardiac Arrhythmias due to Fibrosis and Other Pathological Conditions

Ivan Kazbanov

Ghent University

Ghent, 2016

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The Heart

Biological machine “designed” for pumping blood.

Source: Wikipedia, https://en.wikipedia.org/wiki/File:Latidos.gif Ivan Kazbanov (UGent) Arrythmias in Pathological Conditions 25/02/2016 2 / 70

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Blood Pumping

Delivers oxygen and nutritive materials to all organs Washes out toxic byproducts Arrest of the normal blood flow causes ischemia Brain cannot tolerate ischemia The heart is of vital importance The heart is hardly replaceable

Ivan Kazbanov (UGent) Arrythmias in Pathological Conditions 25/02/2016 3 / 70

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Work of the Heart

Heart performs its work in a periodic and coordinated fashion Coordination is done by propagation of a signal There are 4 main features of the heart for making it possible Excitability: response to stimulation by signal generation Automaticity: automatic generation of the signal Conductivity: propagation of the signal Contractility: converting the signal into mechanical work

Ivan Kazbanov (UGent) Arrythmias in Pathological Conditions 25/02/2016 4 / 70

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Work of the Heart

Signal is generated in the heart (automaticity) Signal propagates through the heart (excitability and conductivity) Signal is coupled to contraction (contractility) This ensures synchronized periodic work

Ivan Kazbanov (UGent) Arrythmias in Pathological Conditions 25/02/2016 5 / 70

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Conduction System of the Heart

Normal activation sequence

1 Sinus node 2 A-V node 3 His bundle and Purkinje

fibers

4 Ventricle muscle Source: Guyton, A. and Hall, J. E., Textbook of Medical Physiology, 12 ed. Elsevier Health Sciences, 2010. Ivan Kazbanov (UGent) Arrythmias in Pathological Conditions 25/02/2016 6 / 70

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Cardiac Arrhythmia

In certain cases, a disruption of the normal rhythm is plausible This is known as cardiac arrhythmia Cardiac arrhythmia can result in failure to perform blood pumping Which results in brain death Worse, such cardiac arrhythmias are sudden Sudden cardiac death is the major cause of death in the Western world

Ivan Kazbanov (UGent) Arrythmias in Pathological Conditions 25/02/2016 7 / 70

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Cardiac Arrhythmia The central question of cardiac physiology: How arrhythmias happen?

Ivan Kazbanov (UGent) Arrythmias in Pathological Conditions 25/02/2016 8 / 70

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Excitable Media: Forest Fire

Source: WorldView-3 Satellite Image, DigitalGlobe, http://www.satimagingcorp.com/gallery/worldview-3/ Ivan Kazbanov (UGent) Arrythmias in Pathological Conditions 25/02/2016 9 / 70

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Excitable Media

Consists of interconnected excitable elements An excitable element is an element that generates a large response on weak stimulation

Ivan Kazbanov (UGent) Arrythmias in Pathological Conditions 25/02/2016 10 / 70

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Excitable Element

Jack-in-the-Box: gentle simulation, high response

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Excitable Element: A Simpler Model

Standing domino: slight punch, falling down

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Excitable Medium: Interconnected Elements

Propagation of wave of falling No recovery

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Excitable Medium: Domino with Recovery

Wave in a loop

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More Realistic Example: Mexican Wave

Wave of audience in a football match

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Features of Excitable Media

Energy is stored within the medium System Energy reserve Jack-in-the-box Elastic energy of the spring Standing domino Gravitation Forest tree Chemical bonds Release (a part of) this energy on activation Interconnection of the elements Propagation of excitation wave Reentry formation if we have recovery

Ivan Kazbanov (UGent) Arrythmias in Pathological Conditions 25/02/2016 16 / 70

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Heart as an Excitable Medium

A structural element of the heart is the cardiac muscle cell: cardiomyocyte Cardiomyocyte has a membrane that separates it from the extracellular medium Cardiomyocyte maintains certain electric change and certain ionic concentrations, different from the extracellular medium The energy is stored within the gradients of ionic concentrations

Ivan Kazbanov (UGent) Arrythmias in Pathological Conditions 25/02/2016 17 / 70

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Cardiomyocyte as an Excitable Element

Ivan Kazbanov (UGent) Arrythmias in Pathological Conditions 25/02/2016 18 / 70

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Cardiac Tissue as an Excitable Medium

On stimulation, the ions flow through the membrane which results in change of the transmembrane electric field This is known as generation of the action potential The change of the transmemrane field is passed to a neighboring cardiomyocyte via intercellular connections

Ivan Kazbanov (UGent) Arrythmias in Pathological Conditions 25/02/2016 19 / 70

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The Action Potential

  • 80
  • 40

40 300 Transmembrane voltage, mV Time, ms Upstroke, INa Plateau, ICa and IK Recovery, IK

Ivan Kazbanov (UGent) Arrythmias in Pathological Conditions 25/02/2016 20 / 70

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Reentry in 2D: Spiral Waves

Ivan Kazbanov (UGent) Arrythmias in Pathological Conditions 25/02/2016 21 / 70

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Spiral Waves in Cardiac Tissue

Source: Lab of D. Pijnapples, Heart and Lungs Center, LUMC Ivan Kazbanov (UGent) Arrythmias in Pathological Conditions 25/02/2016 22 / 70

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Spiral Waves as Excitation Source

Spiral waves are persistent activity in the medium They rotate with a period that is close to the minimal possible activation period For cardiac tissue, a spiral wave can effectively be considered as an electrode stimulating the tissue with a high pace rate

Ivan Kazbanov (UGent) Arrythmias in Pathological Conditions 25/02/2016 23 / 70

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Spiral Waves and Arrhythmias

Ventricular tachicardia: fast synchronous activation originating from ventricles Ventricular fibrillation: fast chaotic activation of ventricles Atrial fibrillation: fast chaotic activation of artia

Ivan Kazbanov (UGent) Arrythmias in Pathological Conditions 25/02/2016 24 / 70

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Spiral Waves and Arrhythmias

Fast and persistent Ventricular tachicardia: spiral wave in ventricles Ventricular fibrillation: many spiral waves in ventricles Atrial fibrillation: many spiral waves in atria

Ivan Kazbanov (UGent) Arrythmias in Pathological Conditions 25/02/2016 25 / 70

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The Central Question: Reprise Since the spiral waves are the sources of arrhythmia, What leads to formation of the spiral waves?

Ivan Kazbanov (UGent) Arrythmias in Pathological Conditions 25/02/2016 26 / 70

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Known Mechanisms of Spiral Formation

Wavebreaks on obstacles or on heterogeneity Cross-field (S1S2) stimulation protocol Unidirectional wave block Dynamical instability in activation: restitution

Ivan Kazbanov (UGent) Arrythmias in Pathological Conditions 25/02/2016 27 / 70

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Pathological Conditions

Normally, none of those mechanisms can take place Pathological conditions can make it plausible Pathology is a result of adaptation failure There is often a positive feedback of arrhythmia on pathology

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The Central Question: Reprise 2 Since arrhythmia happen under pathological conditions, How pathological conditions affect formation and dynamics of arrhythmia sources—spiral waves? The aim of this work is to investigate this question for certain pathological conditions

Ivan Kazbanov (UGent) Arrythmias in Pathological Conditions 25/02/2016 29 / 70

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Methods: Mathematical Modeling

Model: an analogical system that shares the most interesting properties with the prototype Ideally the model should be simpler than the prototype, more general than the prototype, and should capture only the important features

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Hogdkin-Huxley Model

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Mathematical Modeling: TNNP

Cm ∂V ∂t = ∇ (D∇V ) −

  • Iion(V , · · · )

Ten Tusscher and Panfilov AJP Heart 2006, picture from cellml.org

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Chapter 2: Global Ischemia

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Ischemia

Shortage of blood supply which may be caused by different reasons: Atherosclerosis Thrombosis Hypoglycemia Hypotension

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Clinical data

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Clinical data

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Clinical data

Dominant frequency decreases which is followed by a rapid increase

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Clinical data

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Clinical data

Arrhythmia does not terminate during ischemia or reperfusion

Ivan Kazbanov (UGent) Arrythmias in Pathological Conditions 25/02/2016 36 / 70

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Ischemia Factors

Hyperkalemia: increasing of intracellular potassium concentration was modeled by elevating [K]o Acidosis: decreasing of pH was modeled by diminishing conductivity of INa and ICaL Hypoxia: decreasing of pO2 which leads to changing [ADP] to [ATP] ratio and thus activation of potassium ATP dependent channels was modeled by including an extra current to the model

Ivan Kazbanov (UGent) Arrythmias in Pathological Conditions 25/02/2016 37 / 70

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Restitution curves

160 200 240 280 320 360 200 400 600 800 1000 APD, ms Period, ms

Hyperkalemia

[K]o, mM 4 5 5.4 6 7 8 9 10 160 200 240 280 320 200 400 600 800 1000 Period, ms

Acidosis

INa and ICaL act., % 100 90 80 70 60 40 20 80 120 160 200 240 280 320 200 400 600 800 1000 Period, ms

Hypoxia

fATP, % 0.0 0.1 0.2 0.3 0.4 0.5

Ivan Kazbanov (UGent) Arrythmias in Pathological Conditions 25/02/2016 38 / 70

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3D Simulations Protocol

Clinical study Simulations

Ivan Kazbanov (UGent) Arrythmias in Pathological Conditions 25/02/2016 39 / 70

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Results: 3D Simulations

Hyperkalemia [K]o = 7 mM Acidosis GNa,CaL = 80% · G 0

Na,CaL

Hypoxia fATP = 0.1%

Ivan Kazbanov (UGent) Arrythmias in Pathological Conditions 25/02/2016 40 / 70

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Period of Fibrillation

Shows almost no dependency of acidosis

100 150 200 250 300 20 30 40 50 60 70 80 90 100 Period, ms INa and ICaL activation, %

Restitution curves

160 200 240 280 320 200 400 600 800 1000 APD, ms Period, ms INa and ICaL act., % 100 90 80 70 60 40 20

Ivan Kazbanov (UGent) Arrythmias in Pathological Conditions 25/02/2016 41 / 70

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Period of Fibrillation

Dependency on hypoxia and hyperkalemia

50 100 150 200 250 300 350 400 0.1 0.2 0.3 0.4 0.5 Period, ms IK(ATP) act., % [K]o, mM 5.4 6.0 7.0 8.0

Restitution curves

160 200 240 280 320 360 200 400 600 800 1000 APD, ms Period, ms [K]o, mM 4 5 5.4 6 7 8 9 10

Ivan Kazbanov (UGent) Arrythmias in Pathological Conditions 25/02/2016 42 / 70

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Period of Fibrillation

Dependency on hypoxia and hyperkalemia

50 100 150 200 250 300 350 400 0.1 0.2 0.3 0.4 0.5 Period, ms IK(ATP) act., % [K]o, mM 5.4 6.0 7.0 8.0

Restitution curves

80 120 160 200 240 280 320 200 400 600 800 1000 APD, ms Period, ms fATP, % 0.0 0.1 0.2 0.3 0.4 0.5

Ivan Kazbanov (UGent) Arrythmias in Pathological Conditions 25/02/2016 43 / 70

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Fitting Clinical Data

A: Normal conditions B: Both hypoxia and hyperkalemia C: Only hypoxia, potassium concentration is recovered

Ivan Kazbanov (UGent) Arrythmias in Pathological Conditions 25/02/2016 44 / 70

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Fitting Clinical Data

3 4 5 6 7 8 30 60 90 120 150 180 0.01 0.02 0.03 0.04 0.05 [K]o, mM fATP, % Time, s [K]o fATP Dom freq 3 4 5 6 7 8 30 60 90 120 150 180 0.005 0.01 [K]o, mM fATP, % Time, s [K]o fATP Dom freq

Ivan Kazbanov (UGent) Arrythmias in Pathological Conditions 25/02/2016 45 / 70

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Chapter 2: Conclusions

Acute ischemia reduces possibility of induction of arrhythmia by the dynamic restitution mechanism On the other hand acute ischemia significantly reduces possibility of termination of established arrhythmia arrhythmia The complexity of the activation pattern during fibrillation does not change in the course of ischemia and is determined by the initial conditions The increase of the activation period during ischemia is due to hyperkalemia, and the rapid decrease of the activation period during reperfusion is due to hypoxia Arrhythmias induced in clinics may substantially differ from arrhythmias that occur spontaneously

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Chapter 3: Heterogeneous Fibrosis

Ivan Kazbanov (UGent) Arrythmias in Pathological Conditions 25/02/2016 47 / 70

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Fibrosis

Fibrosis is characterized by formation of excess connective tissue and increased population of fibroblasts Fibrosis can be a consequence of would healing process or can be due to aging Some types of fibrosis are known to be arrhythmogenic due to the effect of fibrosis on wave propagation There are several experimental evidences that heterogeneous distribution of fibrosis has higher arrhythmogenic potential than uniform distribution

Ivan Kazbanov (UGent) Arrythmias in Pathological Conditions 25/02/2016 48 / 70

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Model

The medium is split into squares. In each square fibrosis is distributed uniformly. f : Average level of fibrosis in the medium σ:

  • Heterogeneity. How much one

square can differ from another

  • ne

l: Size of a square

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Reentry Formation

Burst pacing protocol

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Phase Diagram (σ–f )

Mean fibrosis (f), % Heterogeneity (σ), % 5 10 15 20 25 30 35 5 10 15 20 25 30 35 40 No reentry Reentry Outside of parameter domain

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Phase Diagram (σ–l)

5 10 15 20 25 30 35 10 15 20 25 30 35 40 Heterogeneity size (l), mm Heterogeneity (σ), % No reentry Reentry

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Activation Patterns

Regular, periodic activation patterns Mostly of the mother rotor type Ablation of the mother rotor terminates arrhythmia

Ivan Kazbanov (UGent) Arrythmias in Pathological Conditions 25/02/2016 53 / 70

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Activation Period

220 240 260 280 300 320 340 360 380 5 10 14 18 22 26 30 35 Activation period, ms Mean fibrosis (f), % Heterogeneity (σ) Uniform 6 % 12 % 18 % 24 % 30 %

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Activation Period

220 240 260 280 300 320 340 360 380 5 10 15 20 25 30 35 40 45 50 Activation period, ms Maximal fibrosis (f + σ/2), % Heterogeneity (σ) Uniform 6 % 12 % 18 % 24 % 30 %

Ivan Kazbanov (UGent) Arrythmias in Pathological Conditions 25/02/2016 55 / 70

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Chapter 3: Conclusions

Heterogeneity in fibrosis distribution increases the probability of the

  • nset of cardiac arrhythmias

Fibrillation of fibrotic tissue may be of the mother rotor and of multiple wavelet type The size of the tissue is the most important factor that determines the type of fibrillation The period of the activation patterns is determined by the regions with the highest degree of fibrosis

Ivan Kazbanov (UGent) Arrythmias in Pathological Conditions 25/02/2016 56 / 70

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Chapter 5: Attraction

Ivan Kazbanov (UGent) Arrythmias in Pathological Conditions 25/02/2016 57 / 70

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Attraction Radius

5 10 15 20 25 30 35 2 4 6 8 10 12 14 Time, s Distance from the scar border, cm Remodeling No remodeling Ivan Kazbanov (UGent) Arrythmias in Pathological Conditions 25/02/2016 58 / 70

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Attraction Factors

5 10 15 20 25 30 35 40 1 2 3 4 5 6 7 Fibrosis level, % Scar diameter, cm No Attraction Attraction Ivan Kazbanov (UGent) Arrythmias in Pathological Conditions 25/02/2016 59 / 70

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Attraction Factors

5 10 15 20 25 30 35 40 1 2 3 4 5 6 7 Fibrosis level, % Scar diameter, cm No Attraction Attraction

Small scar Low fibrosis High fibrosis

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Attraction Factors: Small Scar

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Attraction Factors: Low Fibrosis

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Attraction Factors: High Fibrosis

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Chapter 4: Patient-Specific Model

Ivan Kazbanov (UGent) Arrythmias in Pathological Conditions 25/02/2016 64 / 70

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Chapter 5: Clinical Evidences

150 200 250 300 350 400 1 2 3 4 5 6 Coupling interval, ms Time, s ECG Coupling interval Ivan Kazbanov (UGent) Arrythmias in Pathological Conditions 25/02/2016 65 / 70

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Clinical Evidences

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Chapter 5: Conclusions

Patches with a high degree of fibrosis can attract spiral waves This attraction is not due to a drift but due to a more complex restructuring of the activation pattern This attraction can explain the transition prom polymorphic to monomorphic ECG observed in clinics

Ivan Kazbanov (UGent) Arrythmias in Pathological Conditions 25/02/2016 67 / 70

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Concluding Remarks and Future Perspectives

Arrhythmias should be considered in connection with a given pathology The layout of fibrosis can determine the activation patterns Understanding how the layout affects activation patterns can help to develop effective ablation protocols for treating arrhythmias Mathematical modeling is a valuable source of insights for understanding potential mechanism of arrhythmias

Ivan Kazbanov (UGent) Arrythmias in Pathological Conditions 25/02/2016 68 / 70

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Not (Explicitly) Included in the Thesis

Published 6 more papers as a coauthor Developed software for analyzing the data for experiments on the cell cultures Developed an implementation for the TNNP model on graphics cards (speedup of 1.5 orders of magnitude)

Ivan Kazbanov (UGent) Arrythmias in Pathological Conditions 25/02/2016 69 / 70

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Thank you for your attention!

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