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Osama Diab PowerPoint Presentation

Osama Diab

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Osama Diab

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  1. MECHANISMS OF ISCHEMIC VT Osama Diab

  2. + Voltage gated Na channels Inwardly rectifier K channels Voltage gated K channels L-Ca channels Na/K pump Cardiac Action Potential 2 Extracellular K+ 0 3 Ca++ K+ 3Na+ Na+ K+ 2K+

  3. Effect of Acute Ischemia on Na+ Dynamics Modulation of fast Na channels by the ischemic metabolite and free radicals leading to partial inhibition of Na+ upslope Low amplitude action potential

  4. Normal myocardium Transmural ischemic area Low amplitude action potential and current of injury Gradient Infarct LV cavity ECG

  5. Current of injury can depolarize subendocardial surviving Purkinje fibers Enhanced automaticity  PVCs and VT Infarct Purkinje Ventricular cavity Gets some O2 from V cavity and survive de Diego, C. et al. Circulation 2008;118:2330-2337

  6. AP amplitude during ischemia and reperfusion de Diego, C. et al. Circulation 2008;118:2330-2337

  7. Slow upslope of fast Na+ current Lysophosphatidylecholine (LPC) is an ischemic metabolite that has special affinity to Na+ channels, and free radicals Slow Na+ influx during phase 0

  8. Na+ Cell memb Free radicals LPC Na+ Cell memb Slow opening of Na+ channels  Slow conduction

  9. Normal Action Potential Propagation Na+ Normal myocardial conduction

  10. Slow upslope of phase 0 Na+ Slow conduction of the ischemic myocardium

  11. Reopening of Na+ channels after closure Lysophosphatidylecholine (LPC) causes reopening of Na+ channels after initial closure leading to afterdepolarizations EAD  PVCs, NSVT, VT Prolongation of ERP

  12. Na+ Cell memb Free radicals LPC Na+ Cell memb reopening after closure

  13. Increased Na-H exchange upon reperfusion Na+ Na+ Na+ Na+ Na+ Na+ Na+ Na+ Cell membrane Na-H pump H+ H+ H+ H+ H+ H+ H+ H+ H+ Intracellular acidosis Circulation Research. 1999;85:723-730

  14. Intracellular Na+ load Na++ load Am J Physiol. 1996 Aug;271(2 Pt 2):H790-7.

  15. _ + Voltage gated Na channels Voltage gated K channels L-Ca channels Effect of Acute Ischemia on K+ Dynamics Ca++ 2 Extracellular K+ 0 Increased extracellular K+ due Inhibition of Na+/K+ ATPase activity, internalization of Na+/K+ pumps and increased cellular permeability to K+ Increased activity of voltage gated K+ channels  rapid K+ efflux during phase 3 3 Ca++ K+ Na+ K+ Short action potential duration

  16. Decrease in APD during ischemia

  17. Effect of Acute Ischemia on Ca++ Dynamics Reduced Ca sequestration by SR Reversed Na-Ca exchange due to Na+ load Ca++ release from damaged SR Ca++ load, DADs

  18. Ca++ load during ischemia Ca++ load

  19. AP changes during acute ischemia

  20. Non specific cation channels Funny channels Ischemia  mechanical dysfunction  increased diastolic pressure  stretch Stretch stimulates NSC channels in myocardium and funny channels in Purkije cells  Na+ and Ca++ influx Enhanced automaticity of Purkinje cells Triggered activity of myocardium

  21. Ca++ If NSC ch HCN NSC and Funny channels activation due to diastolic stretch during ischemia Na+

  22. Automatic and triggered activity is more common in border zone, subendocardium (Purkinje) and reperfused zone Ischemic zone

  23. Gap Junction inhibition during ischemis Gap junctions are dynamic structures because connexons are able to open and close. Elevated intracellular calcium and low intracellular pH are established stimuli for rapid closing of connexons Gap junction inactivation: Cx43,45 (His-Purkinje specific) mutation: conduction deley Cx40 (atrial specific) mutation: causes atrial standstill

  24. Inactivated (dephosphorylated) gap junctions detected by immunofluorescence during ischemia with delayed recovery during reperfusion This accounts for the delayed recovery of CV after recovery of Na current and APD Beardslee MA, et al. Circ Res. 2000; 87: 656–662 de Diego, C. et al. Circulation 2008;118:2330-2337

  25. Normal Action Potential Propagation Na+ Normal Myocardium

  26. Gap junction inactivation during ischemia Na+ Ischemic myocardium (Slow conduction)

  27. Decrease in conduction velocity Ischemic zone is inexcitable after 5 min Recovery after reperfusion is delayed

  28. EP changes that favor enhanced automaticity and triggered activity Purkinje cells depolarization by injury current Activation of NSC channels and funny currents by mechanical stretch EAD due to Na channel reopenings (LPC) DAD due to Ca overload Carmeliet E. Cardiac ionic currents and acute ischemia: from channels to arrhythmias. Physiol Rev. 1999; 79: 917–1017

  29. EP changes that favor reentry Prolongation of ERP in the central zone due to reopening of Na channels Shortening of ERP in the borderzone (rapid recovery of Na channel function) Decrease in conduction velocity then loss of excitability in the central zone Heterogeneity between epicardium and endocardium (less EP changes in endocardium due to cavitary blood supply) Carmeliet E. Cardiac ionic currents and acute ischemia: from channels to arrhythmias. Physiol Rev. 1999; 79: 917–1017

  30. Reentry through the ischemic zone initiated by extrasystole at the border zone de Diego, C. et al. Circulation 2008;118:2330-2337

  31. Reentry (rotors) at the border of ischemic zone (with 2:1 block at the center of ischemic zone) de Diego, C. et al. Circulation 2008;118:2330-2337

  32. Reentry around ischemic inexcitable zone initiated by extrasystole at the border zone (short APD and DAD) de Diego, C. et al. Circulation 2008;118:2330-2337

  33. EP changes that favor ventricular arrhythmias during reperfusion Increased Na+ load due to activation of Na+/H+ exchange (requiring ATP) to remove accumulated intracellular H+ Increased Ca++ load due to increased Na+/Ca++ exchange following increased intracellular Na+ EADs and DADs Early recovery of Na+ channels than gap junctions  short ERP and persistent slow conduction  reentry Carmeliet E. Cardiac ionic currents and acute ischemia: from channels to arrhythmias. Physiol Rev. 1999; 79: 917–1017

  34. Reperfusion arrhythmias Recovery of tissue excitability before recovery of conduction delay (dephophorylated Cx43) Fibrillatory conduction of the reperfused zone Organization of fibrillatory conduction then normal conduction after recovery of gap junctions de Diego, C. et al. Circulation 2008;118:2330-2337

  35. Ischemia preconditioning attenuate Ventricular arrhythmias during ischemia and reperfusion * P < 0.05 and ** P < 0.01; n, no. of preparations. Zhu, J. et al. Am J Physiol Heart Circ Physiol 274: H66-H75 1998

  36. Post Infarction VT Components of VT reentry circuit 1- Area of conduction block: Scar area + MVA 2- Surviving myocardial strands within the scar (isthmus) 3- An outer loop of normal myocardioum 4- Entrance 5- Exit Viable Non viable

  37. Post Infarction VT Isthmus: diastolic potentials only. Entrance: early-diastolic electrograms. Exit: late-diastolic electrograms Scar/MVA: double potentials Outer loop: systolic electrograms

  38. Post Infarction VT Diastolic pathway: Entrance, isthmus, and exit Systolic pathway: Outer loop

  39. Electrophysiological characteristics of the diastolic pathway Slow conduction Occupies up to 80% of the VT cycle length Fractionated potentials during diastole Altered gap junctions ? Entrance and exit: Increased curvature of propagated waves

  40. Impedance mismatch at curvatures (Entrance and exits) Cabo C, Pertsov A, Baxter W, et al. Wavefront curvature as a cause of slow conduction and block in isolated cardiac muscle. Circ Res. 1994; 75: 1014–1028

  41. Single loop reentry 25% of postinfarction VT Circulation 2002;105;726-731

  42. Double loop reentry (figure of 8) 75% of postinfarction VT Circulation 2002;105;726-731

  43. Different VT morphologies

  44. Ablation Success rate up to 97% Scar/MVA Isthmus RA Scar Outer loop

  45. Thank You

  46. Decrease in wave length

  47. Changes in Ca current de Diego, C. et al. Circulation 2008;118:2330-2337

  48. Carmeliet E. Cardiac ionic currents and acute ischemia: from channels to arrhythmias. Physiol Rev. 1999; 79: 917–1017

  49. Ischemia preconditioning decreased transmural conduction block necessary for transmural reentry Zhu, J. et al. Am J Physiol Heart Circ Physiol 274: H66-H75 1998