EHRA EDUCATIONAL REVIEW AND PREPARATORY COURSE ON INVASIVE CARDIAC ELECTROPHYSIOLOGY

EUROPEAN HEART HOUSE, February 2011

Basic mechanisms of arrhythmogenesis and antiarrhythmia

Antonio Zaza Università Milano-Bicocca

ARRHYTHMIA MECHANISMS

Leading circle

REENTRY Spiral wave

RELEVANT PARAMETERS

? EADs

FOCAL ACTIVITY DADs

autom.

Excitable gap and circuit wavelength

EG >0 (circuit perpetuation)

WL = CV * RP (mm = mm/s * s)

obstacle size > WL

EG ≤ 0 circuit extinction EG = circuit length -WL

(mm = mm - mm)

obstacle size <WL

Feld et al, 2000

REFRACTORINESS MODULATION IN LEADING-CIRCLE REENTRY

Feld et al, 2000

REFRACTORINESS

TIME REQUIRED FOR

RECOVERY FROM INACTIVATION INa

REPOLARIZATION TIME (APD)

+INa RECOVERY KINETICS

I

APD (QT) modulation

repolarization velocity Inet

= net Ioutward + Iinward (+)

Ito

IKr

IKs

IK1

INaK

(-)

ICaL

INa

INCX

Genetic repolarization abnormalities

I = Ioutward + Iinward net

BrS. ()

IKs

IKr

IK1

Ito LQT8 (), SQT S. (), BrS. ()

LQT2, 6 (), SQT ()

LQT1, 4, 5 () INa

ICaL

LQT3 (), BrS. ()

LQT7 ()

INaK INCX

() = gain of function LQT7 = Andersen-Tawil S.LQT8 = Timothy S. () = loss of functionBrS. = Brugada S.

IKr block

INaL block

IKr block

IKr+ INaL block

Orth et al, CVR 2006

APD prolongation

cytosolic Ca2+

CaMKII activation

INaL enhancement

Vm (mV)

ERP RRP

0

REFRACTORINESS

Na+ channel

availability

C O I C

(1-PI)

Na+ channel

state

POST-REPOL. ERP RRP+DRUG

REFRACTORINESS

Vm (mV)

Na+ channel availability

block INa

0

QUESTION 1

Sodium current (INa) blockade may

affect:

1) conduction safety factor and velocity

2) action potential duration (or QT interval)

3)refractoriness

4) all of them

Wavebreak – Spiral wave formation

wb

myocyte monolayer, Cx43 ko - Nagakami et al, CVR 2008

Spiral wave reentry

I sink

low CV

high CV

THE PROPAGATION CIRCUIT

SOURCE LOAD

_ R RmmINa +

RGJ RGJ C C

m Cm m

VELOCITY length of tissue excited in unit time (cm/sec)

PROPAGATION PROPERTIES

SAFETY FACTOR source/load ratio

PROPAGATION VELOCITY AND SAFETY-FACTOR ROLE OF EXCITABILITY (Na channel availability)

from Shaw and Rudy 1997

SOURCE-LOAD MISMATCH

PURKINJE VENTRICLE

A

VENTRICLE PURKINJE

B

MYOCARDIAL ANISOTROPY 10

0 μm

100 μm

from Spach et al 1997

•Rtot = R1 + R2...+ Rn

PARAMETER L/T •n per unit length: 0.2•Rtot per unit length : 0.2 •θ ≈ √k/2Rtot ; 2.2

T L

Velocity: T < L

dVm/dt : T > L

SF : T > L

ANISOTROPY AND SAFETY FACTOR effect of front curvature

isotropic weakly anisotropic strongly anisotropic

source source source

load load load

PROPAGATION VELOCITY & SAFETY FACTOR

Spiral wave reentry

K+ channels Na+ channels

APD restitution and

rotor stability

Xie et al, Am J Phys 2002

QUESTION 2

PURKINJE VENTRICLE

In the situation shown, conduction of a

premature beat is likely to fail:

1. in left to right propagation

2. independently of direction of propagation

3. right to left propagation

SCAR

SCAR

action potential

Ca2+ current (ICaL)

EAD

ICaL react.

EAD mechanism and

promoting factors

Zeng & Rudy, Biophys J 1995

EAD facilitation by:

K+ ch loss of function Na+ ch gain of function (enhanced INaL) Ca2+ ch gain of function bradycardia

Rate-dependency of βAR-induced current

HIGH HR LOW HRSHORT AP LONG AP

outward

inward 0

0

prevents EADs

favours EADs

guinea-pig ventricular myocytes Iiso = isoproterenol-induced current

Roccheti et al, J Physiol 2006

DAD mechanism and promoting factors

SR

3Na+

Ca2+

NCX

RyR

T-tubule

RyR CaV1.2

Ca i (nM)

I m (pA)

Vm (m

V)

ms

DAD

ms

ms 0

0

0

SERCA Ca2+

RyR instability SR Ca2+ overload (catechols, HR) High cytosolic Ca2+ (heart failure) Altered RyR properties (phosphoryl, mutations)

EC coupling CE coupling

spontaneous excitation SR Ca release

SR Ca release contraction Na/Ca activation

(Iti)

contraction DADs

excitation

QUESTION 3

EADs are facilitated by:

1. loss of function of Na+ or K+ channels

2. gain of function of Na+ or Ca2+ channels

3. tachycardia and cell Ca2+ overload

4. all of them

1 sec200 ms

DD

Eth

Emax

50 mV

(depolarized Purkinje myocyte)

ABNORMAL AUTOMATICITY

(SA myocyte)

NORMAL AUTOMATICITY

block IK1

50 mV

AUTOMATICITY

Diastolic currents & membrane potential

IbCa IbNaDepolarizing INCX

ICaL(depol ventricle)

IK1 (ventricle) Hyperpolarizing IKACh (atrium and nodes)

IKs (nodes, depol ventricle)

Vm (mV)0

-75 mV -85

QUESTION 4

Increased sympathetic activity may

facilitate arrhythmias by:

1. focal activity (autom., EADs, DADs)

2. reentry

3. both

ARR. MECHANISM RELEVANT PARAMETERS

SUMMARY

Leading circle refractoriness

REENTRY

Spiral wave conduction, PSP stability (Na+ ch) (K+ ch)

EADs APD, repolarization reserve

FOCAL ACTIVITY DADs Ca2+ store stability

automaticity Ediast stability

DISCUSSION SLIDES

VENTRICULAR ACTION POTENTIAL and underlying currents

A

B

INWARD (depolarizing)

OUTWARD (repolarizing)

-100 -75 -50 -25 25 50

-600

-400

-200

200

400E

th

Erest

mV

pA

0

0

I inw

ard

I ou

twa

rd

Em

IK1

50 ms

50 pA

50 mV

stability of diastolic potential role of IK1

from Zaza et al 2000

ELECTRICAL ANISOTROPY atrium vs ventricle

anistropy ratio (θL/θT): ≈3 ≈10

(da Saffitz et al, Circ Res 1994)

FACTORS IN PROPAGATION

SOURCE

•net inward current density

•surface of excited membrane

•INa + ICa vs Ito •channel “availability”

•N of excited cells

COUPLING RESISTANCE

•gap junctional resistance •single GJ resistance •N of series junctions per unit length

•length of cytosolic path •intracellular (cytosolic) resistance

•extracellular (interstitial) resistance •width and density of interstitial space

LOAD

•resting outward current density

•surface of resting membrane

•IK1 density and availability

•N of cells electrically coupled to source

1-AR -AR

ADRENERGIC MODULATION OF CELL CALCIUM