the carmeliet-coraboeuf-weidmann lecture - david eisner
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The Carmeliet-Coraboeuf-Weidmann Lecture
Calcium signalling in the heart: From basic mechanisms to arrhythmias
David Eisner
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• 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
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Ca cycling in the heart
Ca2+
SRRyR
L-Cachannel
Ca2+
SERCACa2+
3Na+
NCX
phospholamban
in steady state
influx = efflux
cytoplasmic Ca po
SR Ca ↑ po
caffeine po
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L-type Ca current(Ca entry)
Na-Ca exchange(Ca efflux)
Measurement of Ca efflux and influx
Im(600 pA)
0.5 sec
0.0
[Ca2+]i(µM)
0.8
0
4
sarcolemmalCa flux
(µmol/L)
25 pA
100 ms
Sarcolemmal Ca entry = exit
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Ca2+
SRRyR
L-Cachannel
Ca2+
SERCA
Ca2+
3Na+
NCX
phospholamban
What controls the size of the Ca transient?
Ca2
+
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• 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
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SR Ca content (µmol/L)
0 25 500.0
0.8
0 25 50
Ca transientamplitude(µM)
0.0
0.8
Trafford et al (2000). J. Physiol. 522, 259-270
(SR Ca)3Ca transient
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Ca transientamplitude(µM)
SR Ca content (µmol/L)
Consequences of steep relationship
small changes of SR content inotropically significant
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Ca transientamplitude(µM)
SR Ca content (µmol/L)
Consequences of steep relationship
small changes of SR content inotropically significant
Must control SR Ca content precisely
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• 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
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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?
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(a)
(a)
1
[Ca2+]i(µmol.l-1)
0
10 sec
(a)
[Ca2+]i(µmol.l-1)
0
1
Im(1.5 nA)
(b)
1 sec
(b)ICa-L
(1.25nA)
50 ms
influx
tailcurrent
(0.15nA)
(b)
200 ms
efflux
Trafford et al (1997) Circ Res 81, 477-484
SR Ca content controls sarcolemmal fluxes
systolic Ca inactivate L-type current & Ca influx
systolic Ca Ca efflux on NCX
(a) (b)
SR empty SR full
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RyR
L-Cachannel
Ca2+
SERCA
Ca2+
3Na+
NCX
-
Ca2+
Eisner et al (1998) Cardiovasc Res 38, 589-604
Eisner et al (2000) Circ Res 87, 1087-1094
control of Ca entry and efflux by the systolic Ca transient
controls SR Ca content: a simple feedback mechanism
+
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RyR
L-Cachannel
Ca2+
SERCA
Ca2+
3Na+
NCX
-
Ca2+
Relevance of feedback mechanism to HF
+
↑NCX
↑ RyR po
↓SERCA
↓ SR Ca
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• 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
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RyR
Ca2+Ca2+
Does systolic modulation of the RyR affect systolic Ca?
P
phosphorylation ↑ RyR po contributes to inotropic effects of
β-adrenergic stimulation?
But does ↑ RyR po →↑ systolic Ca?
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[Ca2+]i
(uM)
SR Cacontent
(µmol/L)70
110
sarcolemmalCa flux
0
120.0
1.5
500 µM caffeine
efflux > influx
efflux = influx↓SR Ca
(µmol/L)
4 sec
efflux = influx
RyR opening
Ca transient
Ca efflux
SR Ca
efflux
influx
[[[
Increasing RyR opening does
not increase Ca transient in the
steady state
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• 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
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Closed
Open
Marx et al (2000) Cell 12, 365-376
Heart failure makes RyRs leaky
Heart failure Control
What are the effects of leak on Ca cycling?
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• 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
![Page 24: The Carmeliet-Coraboeuf-Weidmann Lecture - David Eisner](https://reader035.vdocuments.site/reader035/viewer/2022062617/54baaa024a79599e228b4709/html5/thumbnails/24.jpg)
Ca and arrhythmias
Why?
Heart Failure
use positive inotropes to
↑SR & systolic Ca
Arrhythmias
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Ca2+
Ca2+
3 Na+
Ca2+ Ca2+
SR
RyR
SERCA
Ca2+
3 Na+NCX
Ca leak → diastolic Ca waves
Watch video
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Díaz et al (1997). J. Physiol. 501, 3-16
SR Ca content (µmol/L)
Ca waves occur above a threshold SR Ca content
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Ferrier et al (1973; Circ. Res. 38, 156-162)
Ca efflux on NCX
DAD
Ca waves are arrhythmogenicwave
depolarizing current
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How do DADs produce arrhythmias?
1. Direct depolarization
Ca (340/380 nm)
2.4
4.0
Em (mV)
-90
40
500 ms
Ca wave
DAD
Ectopic beat
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2. Increased APD heterogeneity
How do DADs produce arrhythmias?
Johnson……Volders (2013) Circ Res. 112:246-256.
systolic Ca release ICa APD Ca wave
20
-90
50
Vm (mV)
Ca (F/Fo)
470 ms 640 ms
1 s
Ca wave
1
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• Digitalis toxicity• Reperfusion arrhythmias • Inotropic agents
↑SR Ca → ↑ Ca leak
↑ RyR po ↑ Ca leak
Ca waves arise from ↑ diastolic Ca leak from SR
• Heart Failure• RyR mutations CPVT (catecholaminergic
polymorphic ventricular tachycardia)
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CPVT
(catecholaminergic polymorphic ventricular tachycardia)
Priori, S. G. et al. Circulation 2002;106:69-74
Why do leaky RyRs → arrhythmias?
How does β stimulation → arrhythmias?
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Two ways to produce Ca waves
SR Ca content (µmol/L)0 50 150100
0
1
Waveprobability
0
normalSR Ca
↑SR Ca
↓ threshold
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WT WTR4496C R4496C
0
160
Ca wave threshold(µmol/L) +iso +iso
Lower SR threshold in RyR R4496C mouse
Kashimura et al (2010) Circ Res 107, 1483-1489
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SR Ca content is higher after β- stimulation
SR Cacontentmol/L
0
80
iso
**
SR Ca threshold
β- stimulation acts by ↑ SR content (via ↑ SERCA)
Venetucci, Trafford & Eisner (2007) Circ Res 100, 105-111
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Origin of Ca waves in CPVT
SR Ca content (µmol/L)0 50 150100
0
1
Waveprobability
0
normalSR Ca
↑SR Ca
↓ threshold
β- stimulation
RyR mutation
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• 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
Summary
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Gina Galli
David Greensmith
Takeshi Kashimura
Rajiv Sankaranarayanan
Andrew Trafford
Luigi Venetucci
Carlo Napolitano
Silvia Priori
Dan Johnson
Paul Volders
Acknowledgements
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198324 June 2013
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Felix BonkeLennart Bouman
Hilary Brown
Ursula RavensAlessandro MugelliKarin SipidoSylvain Richard
Antonio Zaza
Barbara Casadei
Elisabetta CerbaiPaul Volders Alex de Hemptinne
Guy Vassort
Godfrey Smith