Basic mechanisms of arrhythmogenesis and antiarrhythmia

Transcription

1 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

2 ARRHYTHMIA MECHANISMS Leading circle REENTRY Spiral wave EADs RELEVANT PARAMETERS? FOCAL ACTIVITY DADs autom.

3 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

4 REFRACTORINESS MODULATION IN LEADING-CIRCLE REENTRY Feld et al, 2000 Feld et al, 2000

5 REFRACTORINESS TIME REQUIRED FOR I Na RECOVERY FROM INACTIVATION REPOLARIZATION TIME (APD) + I Na RECOVERY KINETICS

6 APD (QT) modulation repolarization velocity I net I net = I outward + I inward (+) I to (-) I CaL I Kr I Ks I Na I K1 I NaK I NCX

7 Genetic repolarization abnormalities I = I outward + I inward net BrS. ( ) I to I CaL LQT8 ( ), SQT S. ( ), BrS. ( ) LQT2, 6 ( ), SQT ( ) I Kr LQT1, 4, 5 ( ) I Ks I Na LQT3 ( ), BrS. ( ) LQT7 ( ) I K1 I NaK I NCX LQT7 = Andersen-Tawil S. LQT8 = Timothy S. BrS. = Brugada S. ( ) = gain of function ( ) = loss of function

8 I Kr block I Kr block I NaL block I Kr + I NaL block Orth et al, CVR 2006 APD prolongation I NaL enhancement cytosolic Ca 2+ CaMKII activation

9 REFRACTORINESS ERP RRP V m (mv) 0 Na + channel availability (1-P I ) Na + channel state C O I C

10 POST-REPOL. REFRACTORINESS ERP RRP+DRUG V m (mv) 0 Na + channel availability I Na block

11 QUESTION 1

12 Sodium current (I Na ) blockade may affect: 1) conduction safety factor and velocity 2) action potential duration (or QT interval) 3)refractoriness 4) all of them

13 Wavebreak Spiral wave formation wb myocyte monolayer, Cx43 ko - Nagakami et al, CVR 2008

14 Spiral wave reentry high CV I sink low CV

15 THE PROPAGATION CIRCUIT SOURCE LOAD _ I Na + R m R m C R GJ R GJ C m C m m

16 PROPAGATION PROPERTIES VELOCITY length of tissue excited in unit time (cm/sec) SAFETY FACTOR source/load ratio

17 PROPAGATION VELOCITY AND SAFETY-FACTOR ROLE OF EXCITABILITY (Na channel availability) from Shaw and Rudy 1997

18 SOURCE-LOAD MISMATCH PURKINJE VENTRICLE A VENTRICLE PURKINJE B

19 MYOCARDIAL ANISOTROPY R tot = R1 + R2...+ Rn 100 μm PARAMETER L/T n per unit length: 0.2 R tot per unit length : 0.2 θ k/2r tot ; μm T L Velocity: T < L from Spach et al 1997 dv m /dt : T > L SF : T > L

20 ANISOTROPY AND SAFETY FACTOR effect of front curvature source source source load load load isotropic weakly anisotropic strongly anisotropic PROPAGATION VELOCITY & SAFETY FACTOR

21 Spiral wave reentry K + channels Na + channels

22 APD restitution and rotor stability Xie et al, Am J Phys 2002

23 QUESTION 2

24 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 PURKINJE SCAR VENTRICLE SCAR

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26 action potential EAD EAD mechanism and promoting factors EAD facilitation by: Ca 2+ current (I CaL ) K + ch loss of function Na + ch gain of function (enhanced I NaL ) Ca 2+ ch gain of function bradycardia I CaL react. Zeng & Rudy, Biophys J 1995

27 Rate-dependency of βar-induced current HIGH HR SHORT AP LOW HR LONG AP 0 0 outward inward prevents EADs favours EADs guinea-pig ventricular myocytes I iso = isoproterenol-induced current Roccheti et al, J Physiol 2006

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29 DAD mechanism and promoting factors Ca 2+ NCX 3Na + Ca i (nm) 0 ms SR RyR SERCA Ca2+ RyR CaV1.2 I m (pa) 0 ms V m (mv) 0 ms T-tubule DAD RyR instability SR Ca 2+ overload (catechols, HR) High cytosolic Ca 2+ (heart failure) Altered RyR properties ( phosphoryl, mutations)

30 EC coupling excitation CE coupling spontaneous SR Ca release SR Ca release contraction Na/Ca activation (I ti ) contraction DADs excitation

31 QUESTION 3

32 EADs are facilitated by: 1. loss of function of Na + or K + channels 2. gain of function of Na + or Ca 2+ channels 3. tachycardia and cell Ca 2+ overload 4. all of them

33 AUTOMATICITY NORMAL AUTOMATICITY (SA myocyte) 200 ms ABNORMAL AUTOMATICITY (depolarized Purkinje myocyte) 1 sec DD 50 mv 50 mv E max E th block I K1

34 Diastolic currents & membrane potential Depolarizing I bca I bna I NCX I CaL (depol ventricle) I K1 (ventricle) Hyperpolarizing I KACh (atrium and nodes) I Ks (nodes, depol ventricle) V m (mv) mv

35 QUESTION 4

36 Increased sympathetic activity may facilitate arrhythmias by: 1. focal activity ( autom., EADs, DADs) 2. reentry 3. both

37 SUMMARY ARR. MECHANISM Leading circle RELEVANT PARAMETERS refractoriness REENTRY Spiral wave conduction, PSP stability (Na + ch) (K + ch) EADs APD, repolarization reserve FOCAL ACTIVITY DADs Ca 2+ store stability automaticity E diast stability

38 DISCUSSION SLIDES

39 VENTRICULAR ACTION POTENTIAL and underlying currents A B INWARD (depolarizing) OUTWARD (repolarizing)

40 stability of diastolic potential role of I K1 E m E th pa mv E rest mv 200 I outward I inward 0 I K1 50 ms 50 pa from Zaza et al 2000

41 ELECTRICAL ANISOTROPY atrium vs ventricle anistropy ratio (θ L /θ T ): 3 10 (da Saffitz et al, Circ Res 1994)

42 FACTORS IN PROPAGATION SOURCE net inward current density surface of excited membrane I Na + I Ca vs I to channel availability N of excited cells COUPLING RESISTANCE gap junctional resistance intracellular (cytosolic) resistance extracellular (interstitial) resistance single GJ resistance N of series junctions per unit length length of cytosolic path width and density of interstitial space LOAD resting outward current density surface of resting membrane I K1 density and availability N of cells electrically coupled to source

43 ADRENERGIC MODULATION OF CELL CALCIUM -AR 1 -AR