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Alcohol Intoxication, Arrhythmias and Inward Rectifiers
4th Global Summit on Toxicology, Philadelphia (USA), 26. 8. 2015
Markéta BébarováDepartment of Physiology, Faculty of Medicine, Masaryk University,
Brno, Czech Republic
Proarrhythmogenic Effect of Alcohol Consumption
• supraventricular arrhythmias - atrial fibrillation (holiday heart sy)
http://chilternhillsheartclinic.com/content-images/image-chhc-IWpyt.jpg
• ventricular arrhythmias- ventricular extrasystoles - ventricular arrhythmias - torsades de pointes
http://img.medscape.com/pi/emed/ckb/emergency_medicine/756148-756734-760963-1575961.jpg
• prolongation of P wave, QRS complex, PR and QTc intervals
• direct effects on ionic channels and transporters
• indirect effects on the cardiac electrophysiology(e.g. changes of membrane phospholipids under ethanol, catecholamine release caused by ethanol and acetaldehyde, electrolyte dysbalance, pH changes)
Proarrhythmogenic Effect of Alcohol ConsumptionMechanisms
Ethanol
• depolarizing: INa and ICa (e.g. Habuchi et al. 1995, Bébarová et al. 2010)
• repolarizing: IKr (O´Leary 2002, Himmel 2007) and Ito (Bébarová et al. 2010)
inhibition of Na+/K+-ATPase (McCall and Ryan 1987)
ICa
IKr
inhibition of ionic currents:
Acetaldehyde ICa activation (Chen et al. 1999 and 2012)
• direct effects on ionic channels and transporters
• indirect effects on the cardiac electrophysiology(e.g. changes of membrane phospholipids under ethanol, catecholamine release caused by ethanol and acetaldehyde, electrolyte dysbalance, pH changes)
Proarrhythmogenic Effect of Alcohol ConsumptionMechanisms
Ethanol
• depolarizing: INa and ICa (e.g. Habuchi et al. 1995, Bébarová et al. 2010)
• repolarizing: IKr (O´Leary 2002, Himmel 2007) and Ito (Bébarová et al. 2010)
inhibition of Na+/K+-ATPase (McCall and Ryan 1987)
ICa
IKr
inhibition of ionic currents:
Acetaldehyde ICa activation (Chen et al. 1999 and 2012)
http://tmedweb.tulane.edu/tmedwiki/doku.php/intro_to_the_heart_cardiac_electrophysiology
IK(Ach)
Proarrhythmogenic Effect of Alcohol ConsumptionMechanisms
Cardiac inward rectifiers (both IK1 and IK(Ach)) are known to play an important role in arrhythmogenesis!(e.g. Dhamoon and Jalife 2005, Piao et al. 2007, Schimpf et al. 2008, Sekar et al. 2009, Wakili et al. 2011)
• IK1: Lazslo et al. (2009) statistically insignificant activation (by 25%)
• Kir2.1: Yakamura et al. (2001), Aryal et al. (2009) inhibition
• Kir3.1/3.4: Kobayashi et al. (2009), Yakamura et al. (2001), Aryal et al. (2009) significant activation
• IK(Ach): ?
Ethanol
Bébarová et al., J Physiol Pharmacol 2014;65(4):497-509
Proarrhythmogenic Effect of Alcohol ConsumptionMechanisms
Cardiac inward rectifiers (both IK1 and IK(Ach)) are known to play an important role in arrhythmogenesis!(e.g. Dhamoon and Jalife 2005, Piao et al. 2007, Schimpf et al. 2008, Sekar et al. 2009, Wakili et al. 2011)
Ethanol• IK1
rat ventricles
Proarrhythmogenic Effect of Alcohol ConsumptionMechanisms
Acetaldehyde• IK1: Chen et al. (1999) no effect on the inward component at 1 mM• IK(Ach): ?
Cardiac inward rectifiers (both IK1 and IK(Ach)) are known to play an important role in arrhythmogenesis!(e.g. Dhamoon and Jalife 2005, Piao et al. 2007, Schimpf et al. 2008, Sekar et al. 2009, Wakili et al. 2011)
Proarrhythmogenic Effect of Alcohol ConsumptionMechanisms
Acetaldehyde
Cardiac inward rectifiers (both IK1 and IK(Ach)) are known to play an important role in arrhythmogenesis!(e.g. Dhamoon and Jalife 2005, Piao et al. 2007, Schimpf et al. 2008, Sekar et al. 2009, Wakili et al. 2011)
• IK1
rat ventricles
Bébarová et al., Physiol Res 2015 (in press)
Proarrhythmogenic Effect of Alcohol ConsumptionMechanisms
• Atrial fibrillation is the most often arrhythmia related to alcohol consumption.
Cardiac inward rectifiers (both IK1 and IK(Ach)) are known to play an important role in arrhythmogenesis!(e.g. Dhamoon and Jalife 2005, Piao et al. 2007, Schimpf et al. 2008, Sekar et al. 2009, Wakili et al. 2011)
Aim of the study
Analysis of ethanol and acetaldehyde effects on atrial inward rectifiers, IK1 and IK(Ach)
• Data on atrial inward rectifiers are insufficient.
Methods
voltage clamp mode
Im
Um
Whole cell patch clamp technique
rat atrial cell CHO cells
Im
Um
current clamp mode
Results Ethanol & IK1
Concentration Dependence
0.1 1 10 100
80
100
120
140
160
Changes induced by 80 mM ethanol
Results Ethanol & Constitutively Active IK(Ach)
Changes induced by 20 mM ethanol
Concentration Dependence
Results Ethanol & Action Potential WaveformChanges induced by 20 mM ethanol in rat atrial cells
Rat Atrial Cell Modelling
Results Ethanol & Acetylcholine-induced IK(Ach)
Changes induced by 20 mM ethanol
activation inhibition
activation inhibition
Changes induced by 20 mM ethanol
Concentration Dependence
Results Ethanol & Acetylcholine-induced IK(Ach)
ConclusionsEthanol at clinically relevant concentrations caused:
1) minor, likely not relevant changes of the atrial IK1
2) significant increase of the atrial constitutively active component of IK(Ach)
- no interspecies differences including human channels
- may cause pro-arrhythmic heterogeneity of repolarization within the atrial tissue
- responsible for significant shortening of action potential, thus, of the refractory period (re-entry)
3) significant dual changes of the atrial acetylcholine-induced component of IK(Ach)
Thank you for your attention!
Supported by the grant project NT14301-3/2013 provided by the Ministery of Health of the Czech Republic.
Peter Matejovič
Zuzana Hořáková
Michal Pásek
Milena Šimurdová
Jiří Šimurda
Department of Physiology, Faculty of Medicine, Masaryk University, Brno, Czech Republic
Jan Hošek Department of Molecular Biology and Pharmaceutical Biotechnology, Faculty of Pharmacy, University of Veterinary and Pharmaceutical Sciences Brno, Czech Republic
Proarrhythmogenic Effect of Alcohol ConsumptionMechanisms
Heijman et al. (Circ Res 2014;114:1483-1499)
Proarrhythmogenic Effect of Alcohol ConsumptionMechanisms
http://tmedweb.tulane.edu/tmedwiki/doku.php/intro_to_the_heart_cardiac_electrophysiology
IK(Ach)
Results Ethanol & IK1
Changes induced by 80 mM ethanol
Effect on human Kir2.3 channels
Results Ethanol & Action Potential WaveformChanges induced by 20 mM ethanol in rat atrial cells
Rat Atrial Cell Modelling
Rat Atrial Cell Modelling
Results Ethanol & Action Potential WaveformChanges induced by 20 mM ethanol in rat atrial cells
Proarrhythmogenic Effect of Alcohol ConsumptionMechanisms
Cardiac inward rectifiers (both IK1 and IK(Ach)) are known to play an important role in arrhythmogenesis!
Ethanol• IK1
rat atria
020 mV
control 300 nM tertiapin-Q
20 ms
0
5
10
15
20
25
20 mM eth
APD
un
de
r te
rtia
pin
-Q (
%)
APD50
APD90
con
**
0
20 mM ethanol 20 mM ethanol
+ 300 nM tertiapin-Q
-75
-60
-45
-30
-15
020 mM eth
APD90
un
de
r a
cety
lch
olin
e (
%)
smaller APD90
under eth
bigger APD90
under eth
con
20 ms
control 3 M acetylcholine
0 20 mV 0
20 mM ethanol 20 mM ethanol
+ 3 M acetylcholine
Results Acetaldehyde & Ventricular IK1
Results Acetaldehyde & Ventricular IK1
Voltage Dependence Action Potential Waveform
• Ethanol i acetaldehyd vykazují v klinicky relevantních koncentracích reverzibilní vliv na proud IK1 v komorách.
Bébarová et al. (Acta Physiol 2010)
Závěry I – komorové srdeční buňky
• Ethanol – dvojí efekt na IK1, v nižších koncentracích než které ovlivňují jiné proudy
0,92‰
Ethanol & IK1 – model lidské komorové buňky