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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 ,

  1. Biophysical Mechanisms of Cardiac Arrhythmias due to Fibrosis and Other Pathological Conditions Ivan Kazbanov Ghent University Ghent, 2016

  2. 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

  3. 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

  4. 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

  5. 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

  6. 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

  7. 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

  8. Cardiac Arrhythmia The central question of cardiac physiology: How arrhythmias happen? Ivan Kazbanov (UGent) Arrythmias in Pathological Conditions 25/02/2016 8 / 70

  9. 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

  10. 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

  11. Excitable Element Jack-in-the-Box: gentle simulation, high response Ivan Kazbanov (UGent) Arrythmias in Pathological Conditions 25/02/2016 11 / 70

  12. Excitable Element: A Simpler Model Standing domino: slight punch, falling down Ivan Kazbanov (UGent) Arrythmias in Pathological Conditions 25/02/2016 12 / 70

  13. Excitable Medium: Interconnected Elements Propagation of wave of falling No recovery Ivan Kazbanov (UGent) Arrythmias in Pathological Conditions 25/02/2016 13 / 70

  14. Excitable Medium: Domino with Recovery Wave in a loop Ivan Kazbanov (UGent) Arrythmias in Pathological Conditions 25/02/2016 14 / 70

  15. More Realistic Example: Mexican Wave Wave of audience in a football match Ivan Kazbanov (UGent) Arrythmias in Pathological Conditions 25/02/2016 15 / 70

  16. 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

  17. 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

  18. Cardiomyocyte as an Excitable Element Ivan Kazbanov (UGent) Arrythmias in Pathological Conditions 25/02/2016 18 / 70

  19. 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

  20. The Action Potential 40 Plateau, I Ca and I K Transmembrane voltage, mV 0 Upstroke, I Na Recovery, I K -40 -80 0 300 Time, ms Ivan Kazbanov (UGent) Arrythmias in Pathological Conditions 25/02/2016 20 / 70

  21. Reentry in 2D: Spiral Waves Ivan Kazbanov (UGent) Arrythmias in Pathological Conditions 25/02/2016 21 / 70

  22. 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

  23. 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

  24. 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

  25. 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

  26. 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

  27. 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

  28. 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 Ivan Kazbanov (UGent) Arrythmias in Pathological Conditions 25/02/2016 28 / 70

  29. 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

  30. 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 Ivan Kazbanov (UGent) Arrythmias in Pathological Conditions 25/02/2016 30 / 70

  31. Hogdkin-Huxley Model Ivan Kazbanov (UGent) Arrythmias in Pathological Conditions 25/02/2016 31 / 70

  32. Mathematical Modeling: TNNP ∂ V � C m ∂ t = ∇ ( D ∇ V ) − I ion ( V , · · · ) Ten Tusscher and Panfilov AJP Heart 2006, picture from cellml.org Ivan Kazbanov (UGent) Arrythmias in Pathological Conditions 25/02/2016 32 / 70

  33. Chapter 2: Global Ischemia Ivan Kazbanov (UGent) Arrythmias in Pathological Conditions 25/02/2016 33 / 70

  34. Ischemia Shortage of blood supply which may be caused by different reasons: Atherosclerosis Thrombosis Hypoglycemia Hypotension Ivan Kazbanov (UGent) Arrythmias in Pathological Conditions 25/02/2016 34 / 70

  35. Clinical data Ivan Kazbanov (UGent) Arrythmias in Pathological Conditions 25/02/2016 35 / 70

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

  37. Clinical data Dominant frequency decreases which is followed by a rapid increase Ivan Kazbanov (UGent) Arrythmias in Pathological Conditions 25/02/2016 36 / 70

  38. Clinical data Ivan Kazbanov (UGent) Arrythmias in Pathological Conditions 25/02/2016 36 / 70

  39. 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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