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Osama Diab
MECHANISMS OF ISCHEMIC VT
Na/K pump
3Na+
2K+
Cardiac Action Potential
K+Voltage gated K channels
K+
Inwardly rectifier K channels
Na+
Voltage gated Na channels
30L-Ca
channels
Ca++
2 Extracellular K+
+
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
Gradient
Normal myocardium
Transmural ischemic area
Infarct
Low amplitude action potential and current of injury
LV cavity
ECG
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
AP amplitude during ischemia and reperfusion
de Diego, C. et al. Circulation 2008;118:2330-2337
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
Slow opening of Na+ channels Slow conduction
Na+
Cell memb
Na+
Cell memb
Free radicalsLPC
Normal Action Potential Propagation
Na+
Normal myocardial conduction
Slow upslope of phase 0
Na+
Slow conduction of the ischemic myocardium
Lysophosphatidylecholine (LPC) causes reopening of Na+
channels after initial closure leading to afterdepolarizations
Reopening of Na+ channels after closure
EAD PVCs, NSVT, VTProlongation of ERP
Na+
Cell memb
reopening after closure
Na+
Cell memb
Free radicalsLPC
Na+
Na-H pump
H+
Na+Na+
Na+
H+H+
H+
H+
Intracellular acidosis
Na+
Na+
Na+Na+
H+H+ H+
H+
Increased Na-H exchange upon reperfusion
Cell membrane
Circulation Research. 1999;85:723-730
Na++ load
Intracellular Na+ load
Am J Physiol. 1996 Aug;271(2 Pt 2):H790-7.
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+Voltage gated K channels
K+
Na+
Voltage gated Na channels
30L-Ca
channels
Ca++
2Ca++
Extracellular K+
_
+
Decrease in APD during ischemia
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
Ca++ load
Ca++ load during ischemia
AP changes during acute ischemia
Non specific cation channelsFunny 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
IfCa++
HCN
NSC ch
NSC and Funny channels activation due to diastolic stretch during ischemia
NSC and Funny channels activation due to diastolic stretch during ischemia
Na+
Ischemic zone
Automatic and triggered activity is more common in border zone, subendocardium
(Purkinje) and reperfused zone
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
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: 656–662de Diego, C. et al. Circulation 2008;118:2330-2337
Normal Action Potential Propagation
Na+
Normal Myocardium
Gap junction inactivation during ischemia
Na+
Ischemic myocardium)Slow conduction(
Decrease in conduction velocityIschemic zone is inexcitable after 5 minRecovery after reperfusion is delayed
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
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)
EP changes that favor reentry
Carmeliet E. Cardiac ionic currents and acute ischemia: from channels to arrhythmias. Physiol Rev. 1999; 79: 917–1017
Reentry through the ischemic zone initiated by extrasystole at the border zone
de Diego, C. et al. Circulation 2008;118:2330-2337
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
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
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
EP changes that favor ventricular arrhythmias during reperfusion
Carmeliet E. Cardiac ionic currents and acute ischemia: from channels to arrhythmias. Physiol Rev. 1999; 79: 917–1017
Reperfusion arrhythmias
Recovery of tissue excitability before recovery of conduction delay (dephophorylated Cx43)
Fibrillatory conduction of the reperfused zoneOrganization of fibrillatory conduction then normal
conduction after recovery of gap junctions
de Diego, C. et al. Circulation 2008;118:2330-2337
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
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
Post Infarction VT
Non viable
Viable
Post Infarction VT
Isthmus: diastolic potentials only. Entrance: early-diastolic electrograms.Exit: late-diastolic electrogramsScar/MVA: double potentialsOuter loop: systolic electrograms
Post Infarction VT
Diastolic pathway: Entrance, isthmus, and exitSystolic pathway: Outer loop
Electrophysiological characteristics of the diastolic pathway
Slow conductionOccupies up to 80% of the VT cycle lengthFractionated potentials during diastole
Altered gap junctions? Entrance and exit: Increased curvature of propagated waves
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
Single loop reentry
25% of postinfarction VT
Circulation 2002;105;726-731
Double loop reentry (figure of 8)75% of postinfarction VT
Circulation 2002;105;726-731
Different VT morphologies
RA
Ablation
Success rate up to 97%
Scar
Outer loop
Isthmus
Scar/MVA
Thank You
Decrease in wave length
Changes in Ca current
de Diego, C. et al. Circulation 2008;118:2330-2337
Carmeliet E. Cardiac ionic currents and acute ischemia: from channels to arrhythmias. Physiol Rev. 1999; 79: 917–1017
Ischemia preconditioning decreased transmural conduction block necessary for transmural reentry
Zhu, J. et al. Am J Physiol Heart Circ Physiol 274: H66-H75 1998
Increased membrane permeability to KDecreased Na-K ATPase functionInternalization of Na-K pumps
Increased outward K currents
