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Osama Diab
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Na/K pump 3Na + 2K + Cardiac Action Potential K+K+ Voltage gated K channels K+K+ Inwardly rectifier K channels Na + Voltage gated Na channels 3 0 L-Ca channels Ca++ 2 Extracellular K + +
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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
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Gradient Normal myocardium Transmural ischemic area Infarct Low amplitude action potential and current of injury LV cavity ECG
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Infarct Ventricular cavity Purkinje Current of injury can depolarize subendocardial surviving Purkinje fibers Gets some O2 from V cavity and survive Enhanced automaticity PVCs and VT de Diego, C. et al. Circulation 2008;118:2330-2337
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AP amplitude during ischemia and reperfusion de Diego, C. et al. Circulation 2008;118:2330-2337
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Lysophosphatidylecholine (LPC) is an ischemic metabolite that has special affinity to Na+ channels, and free radicals Slow upslope of fast Na+ current Slow Na+ influx during phase 0
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Slow opening of Na+ channels Slow conduction Na + Cell memb Na + Cell memb Free radicals LPC
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Normal Action Potential Propagation Na + Normal myocardial conduction
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Slow upslope of phase 0 Na + Slow conduction of the ischemic myocardium
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Lysophosphatidylecholine (LPC) causes reopening of Na+ channels after initial closure leading to afterdepolarizations Reopening of Na+ channels after closure EAD PVCs, NSVT, VT Prolongation of ERP EAD PVCs, NSVT, VT Prolongation of ERP
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Na + Cell memb reopening after closure Na + Cell memb Free radicals LPC
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Na+ Na-H pump H+ Na+ H+ Intracellular acidosis Na+ H+ Increased Na-H exchange upon reperfusion Cell membrane Circulation Research. 1999;85:723-730
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Na ++ load Intracellular Na+ load Am J Physiol. 1996 Aug;271(2 Pt 2):H790-7.
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Effect of Acute Ischemia on K+ Dynamics 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 Short action potential duration K+K+ Voltage gated K channels K+K+ Na + Voltage gated Na channels 3 0 L-Ca channels Ca++ 2 Extracellular K + _ +
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Decrease in APD during ischemia
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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
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Ca ++ load Ca++ load during ischemia
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AP changes during acute ischemia
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Non specific cation channels Funny channels Non specific cation channels Funny channels Stretch stimulates NSC channels in myocardium and funny channels in Purkije cells Na+ and Ca++ influx Ischemia mechanical dysfunction increased diastolic pressure stretch Enhanced automaticity of Purkinje cells Triggered activity of myocardium
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IfIf Ca ++ HCN NSC ch NSC and Funny channels activation due to diastolic stretch during ischemia Na +
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Ischemic zone Automatic and triggered activity is more common in border zone, subendocardium (Purkinje) and reperfused zone
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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 inhibition during ischemis Gap junction inactivation: Cx43,45 (His-Purkinje specific) mutation: conduction deley Cx40 (atrial specific) mutation: causes atrial standstill
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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
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Normal Action Potential Propagation Na + Normal Myocardium
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Gap junction inactivation during ischemia Na + Ischemic myocardium (Slow conduction)
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Decrease in conduction velocity Ischemic zone is inexcitable after 5 min Recovery after reperfusion is delayed Decrease in conduction velocity Ischemic zone is inexcitable after 5 min Recovery after reperfusion is delayed
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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 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
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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) 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
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Reentry through the ischemic zone initiated by extrasystole at the border zone de Diego, C. et al. Circulation 2008;118:2330-2337
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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
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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
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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 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
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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
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Zhu, J. et al. Am J Physiol Heart Circ Physiol 274: H66-H75 1998 * P < 0.05 and ** P < 0.01; n, no. of preparations. Ischemia preconditioning attenuate Ventricular arrhythmias during ischemia and reperfusion
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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 Components of VT reentry circuit Non viable Viable
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Isthmus: diastolic potentials only. Entrance: early-diastolic electrograms. Exit: late-diastolic electrograms Scar/MVA: double potentials Outer loop: systolic electrograms
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Diastolic pathway: Entrance, isthmus, and exit Systolic pathway: Outer loop Diastolic pathway: Entrance, isthmus, and exit Systolic pathway: Outer loop
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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 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
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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
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Single loop reentry 25% of postinfarction VT Circulation 2002;105;726-731
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Double loop reentry (figure of 8) 75% of postinfarction VT Circulation 2002;105;726-731
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Different VT morphologies
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RA Ablation Success rate up to 97% Scar Outer loop Isthmus Scar/MVA
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Decrease in wave length
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Changes in Ca current de Diego, C. et al. Circulation 2008;118:2330-2337
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Carmeliet E. Cardiac ionic currents and acute ischemia: from channels to arrhythmias. Physiol Rev. 1999; 79: 917–1017
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Ischemia preconditioning decreased transmural conduction block necessary for transmural reentry Zhu, J. et al. Am J Physiol Heart Circ Physiol 274: H66-H75 1998
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Increased membrane permeability to K Decreased Na-K ATPase function Internalization of Na-K pumps Increased outward K currents
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