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1 ΚΟΛΠΙΚΗ ΜΑΡΜΑΡΥΓΗ!"#$%& (#" " $)#" &* +#! ",)%-.&%$)",, )% / 0.!) %1&,#%0%(#!% &2 %, ) 3 + " Dr. ΠΑΝΑΓΙΩΤΗΣ ΚΟΡΑΝΤΖΟΠΟΥΛΟΣ :! ;<=>=?@:! ;9AB7C7>5;: 2;D. #E ; DD5DE D

2 AF: Complex pathophysiology Camm AJ, et al. American Heart Journal Volume 164, Issue e1

3 J Clin Invest 2011

4 J Clin Invest 2011

5 ΨΑΧΝΟΝΤΑΣ ΓΙΑ ΤΟ ΙΔΑΝΙΚΟ ΑΝΤΙΑΡΡΥΘΜΙΚΟ.

6 ΦΑΡΜΑΚΑ ΣΤΗΝ ΚΟΛΠΙΚΗ ΜΑΡΜΑΡΥΓΗ Amiodarone Sotalol Class III Beta Blocker AADs New and old Class Ic Propafenone Flecainide New Class III agents Upstream therapies Novel drugs Dofetilide Connexin modulators VERNAKALANT DRONEDARONE 5-HT4 antagonist Na+/H+ inhibitor Multi-channel blockers Celivarone Na+/Ca2+ inhibitor INaL inhibitors RANOLAZINE

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9 Action Potential in the Atria and the Ventricles: Some K+ Ion Currents Are Present Only in the Atria1 Ito1 Atrial AP IKur It o IK ur IK r IK s IK 1 IK- Ach IK(AT P) IKr IKs IK1 IKATP IK- Ach Atrium Ito1 Ventricular AP IKr IKs It o IK r IK s IK 1 IK(AT P) IK1 IKATP Ventricle AP = action potential; Ito = transient outward current; IKur = ultrarapid delayed-rectifier potassium current; IKr = rapid delayed-rectifier potassium current; IKs = slow delayed-rectifier potassium current; IK1 = inward rectifier potassium current; IK-Ach = acetylcholine-regulated potassium current; IK(ATP) = ATP-sensitive potassium current. 1. Ravens U et al. Europace. 2008;10: Adapted with permission from Ravens U et al. Europace

10 Kv1.5 channels IK outward rectifying current IKur Ikur blockers: prolongation of APD and ERP without any effect on QT interval

11 First-in-human study Pavri BB, et al. MK-0448, a Specific Kv1.5 Inhibitor: Safety, Pharmacokinetics, An invasive electrophysiological and Pharmacodynamic trial Electrophysiology in healthy young in Experimental Animal Models and Humans, Circ Arrhythm Electrophysiol. 2012;5: male volunteers did not reveal any increase in atrial effective refractory period. However, it must be emphasized, that all electrophysiological testing was in a frequency range much below that of AF so that the question of whether or not IKur block is effective in pharmacological conversion of recent onset AF into SR and/or reducing AF burden by maintenance of SR remains unanswered.

12 IK,ACh (Kir 3.1/Kir 3.4 channels) Acetylcholine (ACh)-regulated potassium current (IK,ACh) They mediate AF induced by vagal stimulation via activation of muscarinic M2 receptors. Activation of IK,ACh hyperpolarizes the membrane and shortens atrial action potentials, thereby contributing to maintenance of AF by promoting reentry (reduced wavelength) and/or stabilizing rotors (negative membrane potential). Several antiarrhythmic agents including azimilide, dofetilide, dronedarone, ibutilide, sotalol are known to block IK,Ach Specific inhibitors: Tertiaptin-Q (TQ), carbachol Specific atrial inhibitor: NTC-801 No Human data

13 Effects of NTC-801 on VNS-induced AF (A) and aconitine-induced AF (B). Machida T et al. Circ Arrhythm Electrophysiol 2011;4: Copyright American Heart Association

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15 Vernakalant for Infusion: Efficacy Summary of Phase 3 Clinical Trials Cardioversion at 90 minutes (%) Median Time to Cardioversion in Responders (minutes) Vernakalant Placebo/Control Vernakalant ACT I Pivotal P< ACT III Pivotal P< ACT II Pivotal P< ACT IV NA NA 14 AVRO Pivotal (amiodarone) P< NA = not applicable. 1. Roy D et al. Circulation. 2008;117: Pratt CM et al. Am J Cardiol. 2010;106: Kowey PR et al. Circ Arrhythmia Electrophysiol. 2009;2: Stiell IG et al. Am Heart J. 2010;159: Camm AJ et al. J Am Coll Cardiol. 2011;57:

16 Novel targets

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18 Am J Cardiol;2011:108:673-6

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20 A+R 88% conversion rate / time to conversion 9.8±4.1 hours A 65% conversion rate / time to conversion 14.6±5.3 hours Am J Cardiol 2012;110:673-7.

21 25 pts with unsuccessful ECV 2gr Ranolazine, 2nd attempt h later 76% success rate Pacing and Clinical Electrophysiology Volume 35, Issue 3, pages , 9 JAN 2012 DOI: /j x

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23 Hypothesis Non-hypoxic cardiac preconditioning Moderate ROS levels enhance endogenous antioxidant response / Activation of Nrf2 transcription factor N-3 fatty acids increase myocardial ROS

24 Ø N-3 PUFAs 2gr/d 7 days before surgery until hospital discharge (1:2 EPA:DHA ratio) Vitamin C (1 g/d) plus vitamin E (400 IU/d) 2 days before surgery until hospital discharge 100 pts placebo, 32% POAF 103 pts supplemented, 9.7% POAF Rodrigo R, Korantzopoulos P, Cereceda M, et al. JACC 2013

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26 ΠΑΡΑΤΗΡΗΣΕΙΣ- ΣΥΜΠΕΡΑΣΜΑΤΑ Τα υποστρώµατα της ΚΜ είναι πολλά και διαφορετικά Ποτέ δεν υπάρχει αµιγώς ηλεκτροφυσιολογικό υπόστρωµα (eg. PAF without structyral heart disease / PV remodeling, PV-LA junction remodeling, Lone AF conduction abnormalities/low voltages/focal fibrosis-mri) - SECOND FACTOR Αναστροφή κολπικής αναδιαµόρφωσης σε ανθρώπους, ναι όσον αφορά ERP αλλά αργής και ατελής recovery of conduction Πολυπαραγοντική αντιµετώπιση Συνοσηρότητες Επεµβατική αντιµετώπιση Φάρµακα (κλασσικά ή µη κλασσικά αντιαρρυθµικά..)

27 Kirchhof P et al. Europace 2013;15: In clinical practice we are far from ideal