Osama Diab. 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.

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