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The Carmeliet-Coraboeuf-Weidmann Lecture - David Eisner

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  • 1. The Carmeliet-Coraboeuf-Weidmann Lecture Calcium signalling in the heart: From basic mechanisms to arrhythmias David Eisner
  • 2. Watch Video
  • 3. Watch Video
  • 4. •Introduction •SR Ca is a major regulator of the Ca transient size •How is SR Ca controlled? •Does modifying the RyR affect systolic Ca? •Leaky RyR and systolic function •The link between leaky RyRs and arrhythmias
  • 5. intracellular Ca Watch Video
  • 6. Ca cycling in the heart 3Na+ L-Ca channel NCX Ca2+ SR RyR SERCA phospholamban Ca2+ Ca2+ cytoplasmic Ca SR Ca ↑ po caffeine po in steady state influx = efflux po
  • 7. Measurement of Ca efflux and influx 0.8 Sarcolemmal Ca entry = exit 2+ [Ca ]i (µM) 0.0 Im (600 pA) L-type Ca current (Ca entry) Na-Ca exchange (Ca efflux) 25 pA 4 100 ms sarcolemmal Ca flux (µmol/L) 0 0.5 sec
  • 8. What controls the size of the Ca transient? 3Na+ L-Ca channel NCX Ca2+ SR RyR Ca2+ SERCA phospholamban Ca2+ Ca2+
  • 9. •Introduction •SR Ca is a major regulator of the Ca transient size •How is SR Ca controlled? •Does modifying the RyR affect systolic Ca? •Leaky RyR and systolic function •The link between leaky RyRs and arrhythmias
  • 10. Ca transient (SR Ca)3 0.8 Ca transient amplitude (µM) 0.0 0 25 50 SR Ca content (µmol/L) Trafford et al (2000). J. Physiol. 522, 259-270
  • 11. Consequences of steep relationship small changes of SR content inotropically significant Ca transient amplitude (µM) SR Ca content (µmol/L)
  • 12. Consequences of steep relationship small changes of SR content inotropically significant Must control SR Ca content precisely Ca transient amplitude (µM) SR Ca content (µmol/L)
  • 13. •Introduction •SR Ca is a major regulator of the Ca transient size •How is SR Ca controlled? •Does modifying the RyR affect systolic Ca? •Leaky RyR and systolic function •The link between leaky RyRs and arrhythmias
  • 14. How is SR content controlled? regulation of SERCA by phosphorylation of phospholamban (PKA & CaMKII) “autoregulation” – effects of SR release on sarcolemmal fluxes empty SR with caffeine: how does it refill?
  • 15. SR Ca content controls sarcolemmal fluxes (a) (a) (b) SR full SR empty 1 (b) 1 2+ [Ca ]i -1 (µmol.l ) 0 2+ [Ca ]i -1 (µmol.l ) Im (1.5 nA) 0 10 sec 1 sec systolic Ca systolic Ca inactivate L-type current & Ca influx Ca efflux on NCX influx efflux (a) ICa-L (1.25nA) (b) tail current (0.15nA) (a) (b) 50 ms 200 ms Trafford et al (1997) Circ Res 81, 477-484
  • 16. control of Ca entry and efflux by the systolic Ca transient controls SR Ca content: a simple feedback mechanism 3Na+ L-Ca channel NCX + - Ca2+ RyR Ca2+ SERCA Ca2+ Eisner et al (1998) Cardiovasc Res 38, 589-604 Eisner et al (2000) Circ Res 87, 1087-1094
  • 17. Relevance of feedback mechanism to HF 3Na+ L-Ca channel NCX + - Ca2+ RyR Ca2+ SERCA Ca2+ ↑NCX ↑ RyR po ↓ SR Ca ↓SERCA
  • 18. •Introduction •SR Ca is a major regulator of the Ca transient size •How is SR Ca controlled? •Does modifying the RyR affect systolic Ca? •Leaky RyR and systolic function •The link between leaky RyRs and arrhythmias
  • 19. Does systolic modulation of the RyR affect systolic Ca? phosphorylation ↑ RyR po contributes to inotropic effects of β-adrenergic stimulation? P RyR Ca2+ Ca2+ But does ↑ RyR po →↑ systolic Ca?
  • 20. 500 µM caffeine [Ca2+]i 1.5 RyR opening (uM) 0.0 12 sarcolemmal Ca flux efflux (µmol/L) = influx 0 efflux > influx [[[ SR Ca Ca transient efflux influx Increasing RyRSR Ca ↓ 110 opening does not SR Ca increase Ca content transient in the (µmol/L) 70 steady state 4 sec efflux = influx Ca efflux
  • 21. •Introduction •SR Ca is a major regulator of the Ca transient size •How is SR Ca controlled? •Does modifying the RyR affect systolic Ca? •Leaky RyR and systolic function •The link between leaky RyRs and arrhythmias
  • 22. Heart failure makes RyRs leaky Control Heart failure Open Closed What are the effects of leak on Ca cycling? Marx et al (2000) Cell 12, 365-376
  • 23. •Introduction •SR Ca is a major regulator of the Ca transient size •How is SR Ca controlled? •Does modifying the RyR affect systolic Ca? •Leaky RyR and systolic function •The link between leaky RyRs and arrhythmias
  • 24. Ca and arrhythmias Heart Failure Arrhythmias use positive inotropes to ↑SR & systolic Ca Why?
  • 25. Ca leak → diastolic Ca waves NCX 3 Na+ SR 3 Na+ Ca2+ Ca2+ RyR SERCA Ca2+ Ca2+ Ca2+ Watch video
  • 26. Ca waves occur above a threshold SR Ca content SR Ca content (µmol/L) Díaz et al (1997). J. Physiol. 501, 3-16
  • 27. wave Ca waves are arrhythmogenic Ca efflux on NCX depolarizing current DAD Ferrier et al (1973; Circ. Res. 38, 156-162)
  • 28. How do DADs produce arrhythmias? 1. Direct depolarization Ectopic beat 40 Em (mV) DAD -90 4.0 Ca (340/380 nm) Ca wave 2.4 500 ms
  • 29. How do DADs produce arrhythmias? 2. Increased APD heterogeneity 50 Vm (mV) -90 20 Ca (F/Fo) 470 ms 640 ms Ca wave 1 1s Ca wave systolic Ca release ICa APD Johnson……Volders (2013) Circ Res. 112:246-256.
  • 30. Ca waves arise from ↑ diastolic Ca leak from SR ↑SR Ca → ↑ Ca leak • Digitalis toxicity • Reperfusion arrhythmias • Inotropic agents ↑ RyR po ↑ Ca leak • Heart Failure • RyR mutations CPVT (catecholaminergic polymorphic ventricular tachycardia)
  • 31. CPVT Priori, S. G. et al. Circulation 2002;106:69-74 (catecholaminergic polymorphic ventricular tachycardia)  Why do leaky RyRs → arrhythmias?  How does β stimulation → arrhythmias?
  • 32. Two ways to produce Ca waves ↓ threshold 0 1 Wave probability normal SR Ca ↑SR Ca 0 0 50 100 SR Ca content (µmol/L) 150
  • 33. Lower SR threshold in RyR R4496C mouse 160 Ca wave threshold (µmol/L) +iso +iso WT R4496C 0 WT R4496C Kashimura et al (2010) Circ Res 107, 1483-1489
  • 34. SR Ca content is higher after β- stimulation 80 ** SR Ca threshold SR Ca content mol/L 0 iso β- stimulation acts by ↑ SR content (via ↑ SERCA) Venetucci, Trafford & Eisner (2007) Circ Res 100, 105-111
  • 35. Origin of Ca waves in CPVT RyR mutation ↓ threshold 0 1 β- stimulation Wave probability normal SR Ca ↑SR Ca 0 0 50 100 SR Ca content (µmol/L) 150
  • 36. Summary •Steep dependence of Ca release on SR content •Even a small decrease of SR Ca is important in HF •SR Ca controlled by effects of systolic Ca transient on NCX and L-type current • systolic Ca due to β-adrenergic stimulation not due to effect on RyR •Leaky RyR diastolic Ca •deranged RyR per se not arrhythmogenic •CPVT decreases threshold
  • 37. Acknowledgements Gina Galli David Greensmith Takeshi Kashimura Rajiv Sankaranarayanan Andrew Trafford Luigi Venetucci Carlo Napolitano Silvia Priori Dan Johnson Paul Volders
  • 38. 24 June 1983 2013
  • 39. Elisabetta Cerbai Paul Volders Godfrey Smith Felix Bonke Alex de Hemptinne Lennart Bouman Hilary Brown Barbara Casadei Guy Vassort Antonio Zaza Sylvain Richard Karin Sipido Alessandro Mugelli Ursula Ravens

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