The Carmeliet-Coraboeuf-Weidmann Lecture

Calcium signalling in the heart:
From basic mechanisms to arrhythmias
David Eisn...
Watch Video
Watch Video
•Introduction
•SR Ca is a major regulator of the Ca transient size
•How is SR Ca controlled?

•Does modifying the RyR affe...
intracellular Ca

Watch
Video
Ca cycling in the heart
3Na+

L-Ca
channel

NCX

Ca2+

SR
RyR

SERCA
phospholamban

Ca2+

Ca2+

cytoplasmic Ca
SR Ca ↑ po
...
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
...
What controls the size of the Ca transient?
3Na+

L-Ca
channel

NCX

Ca2+

SR
RyR

Ca2+

SERCA

phospholamban

Ca2+

Ca2+
•Introduction
•SR Ca is a major regulator of the Ca transient size
•How is SR Ca controlled?

•Does modifying the RyR affe...
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. ...
Consequences of steep relationship
small changes of SR content inotropically significant

Ca transient
amplitude
(µM)

SR...
Consequences of steep relationship
small changes of SR content inotropically significant
Must control SR Ca content prec...
•Introduction
•SR Ca is a major regulator of the Ca transient size
•How is SR Ca controlled?

•Does modifying the RyR affe...
How is SR content controlled?
regulation of SERCA by phosphorylation of
phospholamban (PKA & CaMKII)
“autoregulation” – ef...
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...
control of Ca entry and efflux by the systolic Ca transient
controls SR Ca content: a simple feedback mechanism
3Na+

L-Ca...
Relevance of feedback mechanism to HF
3Na+

L-Ca
channel

NCX

+
-

Ca2+
RyR
Ca2+

SERCA

Ca2+

↑NCX
↑ RyR po ↓ SR Ca
↓SER...
•Introduction
•SR Ca is a major regulator of the Ca transient size
•How is SR Ca controlled?

•Does modifying the RyR affe...
Does systolic modulation of the RyR affect systolic Ca?

phosphorylation ↑ RyR po
contributes to inotropic effects of
β-...
500 µM caffeine

[Ca2+]i

1.5
RyR opening

(uM)
0.0
12

sarcolemmal
Ca flux
efflux
(µmol/L) = influx
0

efflux > influx

[...
•Introduction
•SR Ca is a major regulator of the Ca transient size
•How is SR Ca controlled?

•Does modifying the RyR affe...
Heart failure makes RyRs leaky

Control

Heart failure

Open
Closed

What are the effects of leak on Ca cycling?

Marx et ...
•Introduction
•SR Ca is a major regulator of the Ca transient size
•How is SR Ca controlled?

•Does modifying the RyR affe...
Ca and arrhythmias
Heart Failure

Arrhythmias

use positive
inotropes to ↑SR
& systolic Ca

Why?
Ca leak → diastolic Ca waves
NCX
3 Na+
SR

3 Na+
Ca2+

Ca2+

RyR
SERCA

Ca2+

Ca2+

Ca2+

Watch video
Ca waves occur above a threshold SR Ca content

SR Ca content (µmol/L)
Díaz et al (1997). J. Physiol. 501, 3-16
wave

Ca waves are arrhythmogenic

Ca efflux on NCX
depolarizing current
DAD

Ferrier et al (1973; Circ. Res. 38, 156-162)
How do DADs produce arrhythmias?
1. Direct depolarization
Ectopic beat
40

Em (mV)

DAD
-90
4.0
Ca
(340/380 nm)

Ca wave

...
How do DADs produce arrhythmias?
2. Increased APD heterogeneity
50

Vm
(mV)
-90
20

Ca
(F/Fo)

470 ms

640 ms

Ca wave

1
...
Ca waves arise from ↑ diastolic Ca leak from SR
↑SR Ca → ↑ Ca leak
• Digitalis toxicity
• Reperfusion arrhythmias
• Inotr...
CPVT

Priori, S. G. et al. Circulation 2002;106:69-74

(catecholaminergic polymorphic ventricular tachycardia)

 Why do l...
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)...
Lower SR threshold in RyR R4496C mouse

160
Ca wave
threshold
(µmol/L)

+iso

+iso

WT

R4496C

0
WT

R4496C

Kashimura et...
SR Ca content is higher after β- stimulation
80

**
SR Ca threshold

SR Ca
content
mol/L

0

iso

β- stimulation acts by ↑...
Origin of Ca waves in CPVT
RyR mutation
↓ threshold

0

1

β- stimulation

Wave
probability

normal
SR Ca

↑SR Ca

0
0

50...
Summary

•Steep dependence of Ca release on SR
content
•Even a small decrease of SR Ca is important
in HF

•SR Ca controll...
Acknowledgements
Gina Galli
David Greensmith

Takeshi Kashimura
Rajiv Sankaranarayanan
Andrew Trafford
Luigi Venetucci

Ca...
24 June 1983
2013
Elisabetta Cerbai

Paul Volders

Godfrey Smith

Felix Bonke Alex de Hemptinne

Lennart Bouman

Hilary Brown
Barbara Casade...
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The Carmeliet-Coraboeuf-Weidmann Lecture - David Eisner

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The Carmeliet-Coraboeuf-Weidmann Lecture - David Eisner

  1. 1. The Carmeliet-Coraboeuf-Weidmann Lecture Calcium signalling in the heart: From basic mechanisms to arrhythmias David Eisner
  2. 2. Watch Video
  3. 3. Watch Video
  4. 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. 5. intracellular Ca Watch Video
  6. 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. 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. 8. What controls the size of the Ca transient? 3Na+ L-Ca channel NCX Ca2+ SR RyR Ca2+ SERCA phospholamban Ca2+ Ca2+
  9. 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. 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. 11. Consequences of steep relationship small changes of SR content inotropically significant Ca transient amplitude (µM) SR Ca content (µmol/L)
  12. 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. 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. 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. 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. 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. 17. Relevance of feedback mechanism to HF 3Na+ L-Ca channel NCX + - Ca2+ RyR Ca2+ SERCA Ca2+ ↑NCX ↑ RyR po ↓ SR Ca ↓SERCA
  18. 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. 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. 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. 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. 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. 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. 24. Ca and arrhythmias Heart Failure Arrhythmias use positive inotropes to ↑SR & systolic Ca Why?
  25. 25. Ca leak → diastolic Ca waves NCX 3 Na+ SR 3 Na+ Ca2+ Ca2+ RyR SERCA Ca2+ Ca2+ Ca2+ Watch video
  26. 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. 27. wave Ca waves are arrhythmogenic Ca efflux on NCX depolarizing current DAD Ferrier et al (1973; Circ. Res. 38, 156-162)
  28. 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. 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. 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. 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. 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. 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. 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. 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. 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. 37. Acknowledgements Gina Galli David Greensmith Takeshi Kashimura Rajiv Sankaranarayanan Andrew Trafford Luigi Venetucci Carlo Napolitano Silvia Priori Dan Johnson Paul Volders
  38. 38. 24 June 1983 2013
  39. 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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