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MECHANISMS OF ISCHEMIC VT. Osama Diab. +. 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 +.

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Presentation Transcript
slide2

+

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+

slide3

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

slide4

Normal myocardium

Transmural ischemic area

Low amplitude action potential and current of injury

Gradient

Infarct

LV cavity

ECG

slide5

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

slide6

AP amplitude during ischemia and reperfusion

de Diego, C. et al. Circulation 2008;118:2330-2337

slide7

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

slide8

Na+

Cell memb

Free radicals

LPC

Na+

Cell memb

Slow opening of Na+ channels  Slow conduction

slide9

Normal Action Potential Propagation

Na+

Normal myocardial conduction

slide10

Slow upslope of phase 0

Na+

Slow conduction of the ischemic myocardium

slide11

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

slide12

Na+

Cell memb

Free radicals

LPC

Na+

Cell memb

reopening after closure

slide13

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

slide14

Intracellular Na+ load

Na++ load

Am J Physiol. 1996 Aug;271(2 Pt 2):H790-7.

slide15

_

+

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

slide17

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

slide20

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

slide21

Ca++

If

NSC ch

HCN

NSC and Funny channels activation due to diastolic stretch during ischemia

Na+

slide22

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

Ischemic zone

slide23

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

slide24

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

slide26

Gap junction inactivation during ischemia

Na+

Ischemic myocardium

(Slow conduction)

slide27

Decrease in conduction velocity

Ischemic zone is inexcitable after 5 min

Recovery after reperfusion is delayed

slide28

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

slide29

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

slide30

Reentry through the ischemic zone initiated by extrasystole at the border zone

de Diego, C. et al. Circulation 2008;118:2330-2337

slide31

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

slide32

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

slide33

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

slide34

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

slide35

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

slide36

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

slide37

Post Infarction VT

Isthmus: diastolic potentials only.

Entrance: early-diastolic electrograms.

Exit: late-diastolic electrograms

Scar/MVA: double potentials

Outer loop: systolic electrograms

slide38

Post Infarction VT

Diastolic pathway: Entrance, isthmus, and exit

Systolic pathway: Outer loop

slide39

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

slide40

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

slide41

Single loop reentry

25% of postinfarction VT

Circulation 2002;105;726-731

slide42

Double loop reentry (figure of 8)

75% of postinfarction VT

Circulation 2002;105;726-731

slide45

Ablation

Success rate up to 97%

Scar/MVA

Isthmus

RA

Scar

Outer loop

slide48

Changes in Ca current

de Diego, C. et al. Circulation 2008;118:2330-2337

slide49

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

slide50

Ischemia preconditioning decreased transmural conduction block necessary for transmural reentry

Zhu, J. et al. Am J Physiol Heart Circ Physiol 274: H66-H75 1998

slide51

Increased outward K currents

Increased membrane permeability to K

Decreased Na-K ATPase function

Internalization of Na-K pumps