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
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