Ca²+ - Dependent arrhythmia: role of RyR2 and mechanisms - Richard

49 Pages·2011·5.2 MB·English

Ca2+-dependent arrhythmia:
rôle of RyR2 and mechanisms
S. Richard
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Physiological conditions Pathology/ Drug therapy
Neurohormones
Circulating factors
Homeostasis Remodeling
Ion channels
Sinus rhythm Ventricularfibrillation
Normal circuit Re-entrant circuit
EAD
Normal [Ca2+] / E-C coupling [Ca2+] Inefficient [Ca2+] / E-C coupling
i
Ca-dependent
Arrhythmias
Spontaneous-control Self-sustainingand aggravatingprocesses
Healthy continuation -Phosphorylation/Nitrosylation
-Oxidativeprocess
-Remodelling(Gap junction, ion channel, tissue)…
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Ca2+-dependent Arrhythmias in cardiomyocytes
Diastolic Ca2+ Ca2+ entry E-C coupling
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Ca2+-dependent Arrhythmias in cardiomyocytes: EADs
Sustained Depolarization
Diastolic Ca2+ Ca2+ entry E-C coupling
sustained disorder
Arrhythmias
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AP repolarization is critical for EADs
Pathology, Drugs, …
Decrease in
Outward currents
Increase in (e.g I )
K…
Inward currents
(e.g I )
Na,Late
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Role of Ca2+ entry in EADs: proof of concept
Role for window Ca2+ current
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Modulation of I by Ca2+ release from the SR
(in hypertrophy)
CaL
Larger Window I : Central role during AP plateau
CaL
C O * modulated by SR Ca2+ release RyR2
* enhanced by -AR stimulation (increased Ca2+ release)
Voltage (mV)
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Ca2+-dependent inactivation of I and SR Ca2+ release
CaL
Ca2+ channel
Less SR Ca2+ release
Less Inactivation of I
CaL
More Ca2+ entry
(depolarisinginward current)
RyR2
Dynamic regulation of AP Duration
‘beat-to-beat basis’
(pacingrate)
Low rate
High rate
„Facilitation’
Ca2+ buffer (BAPTA)
SR Ca2+ depletion (thapsigargin)
RyR inhibition (Ryanodine)
Richard et al., 2006, Prog Biophys & Mol Biol.
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Pacing-dep. AP prolongation and EADs
(in HF; rodents)
Less SR Ca release during systole
1 5 8 weeks, PMI
EADs
large effect
EADs
1 0 mV
1 5
5
-76 mV
-77.5 mV
-80 mV
30 ms
5 s
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Ca2+-dependent Arrhythmias in cardiomyocytes: DADs
Diastolic Ca2+ E-C coupling
Ca2+ waves
I (NCX)
ti
Arrhythmias
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