1. András Varró Department of Pharmacology and Pharmacotherapy University of Szeged, Hungary Albert Szent-Györgyi Medical Center 2006 CALCIUM HANDLING AND CARDIAC ARRHYTHMIAS

2. HEART FAILURE GENETIC (CPVT) DRUGS ATRIAL FIBRILLATION GAP JUNCTIONS

3. Ca 2+ SR Na + I Na Na HX H+H+ Na + NHE ATP 3Na + 2K + Na + pump K+K+ Myofilaments Ca 2+ Na CaX Na CaX 3Na + Ca 2+ NaCaX Forward Reverse 3Na + SL Ca 2+ pump ATP Mitochondria Ca 2+ PKA  -AR AC ATP cAMP PLB SERCA P ATP T-Tubule Ca 2+ I Ca PDE AMP RyR CARDIAC CELLULAR Ca 2+ HANDLING

4. Control Heart failure Control I Ks I Kr I to Control Heart failure CL 1000 ms Tsuji et al. Cardiovasc. Res. 2000. 48: 300-309 DECREASED REPOLARIZATION RESERVE IN HEART FAILURE I k1 Fadi G.Akar et al. Am J Physiol 288:2887-2896, 2005

5. W Xiong et al, Circ Res. 2005;97:207-209. UPREGULATION OF NCX IN HEART FAILURE Sipido et al. Circulation. 2000;102:2137-2144.

6. Ca 2+ DEPENDENT DOWNREGULATION OF I K1 J. Fauconnier et al. Cardiovasc Res 68 (2005) 204– 212 Rose et al. Am J Physiol 288: H2077–H2087, 2005. mRNA protein

7. M.Yano et al. Pharmacology & Therapeutics 107 (2005) 377 – 391 INCREASED Ca 2+ RELEASE FROM SR IN HEART FAILURE

8. ZA. Nagy, et al, British Journal of Pharmacology (2004) 143, 827–831 INHIBITION OF NCX ABOLISHES EAD AND DAD

9. Pogwizd et al. Circ Res. 2001;88: 1159-1167. ENHANCED DEPOLARIZATION EVOKED BY INTRACELLULAR Ca 2+ IN HEART FAILURE

10. Ca 2+ SR RyR Na + I Na Na HX H+H+ Na + NHE ATP 3Na + 2K + Na + pump Myofilaments Ca 2+ Na CaX Na CaX 3Na + Ca 2+ NaCaX Forward Reverse 3Na + SL Ca 2+ pump ATP Mitochondria Ca 2+ PKA  -AR AC ATP cAMP PLB SERCA P ATP T-Tubule Ca 2+ I Ca PDE AMP ARRHYTHMIA IN HEART FAILURE K+K+ I k1 K+K+ I Ks K+K+ I to K+K+ I Kr REPOLARIZATION RESERVE Cl - I Cl Na + IfIf DAD extra beat DAD Upregulated NCX Increased sympathetic tone EAD spont. extra beat

11. Lehnart et al. Circulation. 2004;109:r113–r119 Terentyev et al. Circ Res. 2005;96:651-658. ENHANCED Ca 2+ RELEASE DUE TO LEAKY SR

12. M.Yano et al. Pharmacology & Therapeutics 107 (2005) 377 – 391 ENHANCED Ca 2+ RELEASE DUE TO MUTATION OF THE SR RELEASE CHANNEL

13. Ca 2+ SR RyR Na + I Na Na HX H+H+ Na + NHE ATP 3Na + 2K + Na + pump Myofilaments Ca 2+ Na CaX Na CaX 3Na + Ca 2+ NaCaX Forward Reverse 3Na + SL Ca 2+ pump ATP Mitochondria Ca 2+ PKA  -AR AC ATP cAMP PLB SERCA P ATP T-Tubule Ca 2+ I Ca PDE AMP ARRHYTHMIA IN FPVT (Familial Polymorphic Ventricular Tachycardia) AND CPVT (Catecholaminergic Polymorphic Ventricular Tachycardia) K+K+ I k1 K+K+ I Ks K+K+ I to K+K+ I Kr REPOLARIZATION RESERVE Cl - I Cl Na + IfIf DAD extra beat DAD Upregulated NCX Increased sympathetic tone EAD ?

14. Ca 2+ SR RyR Na + I Na Na HX H+H+ Na + NHE ATP 3Na + 2K + Na + pump K+K+ Ca 2+ Na CaX Na CaX 3Na + Ca 2+ NaCaX Forward Reverse 3Na + SL Ca 2+ pump ATP Mitochondria Ca 2+ PKA  -AR AC ATP cAMP PLB SERCA P T-Tubule Ca 2+ I Ca PDE AMP DRUG INDUCED ARRHYTHMIAS DUE TO ALTERED Ca 2+ HANDLING Ca 2+ release activation McGarry and Williams Br.J. Pharmacol. 1993, 108: 1043-1050 Drug: Digoxin Actodigin Oubain FPL-64176 DAD extra beat DAD DIGOXIN 1nM

15. Ca 2+ SR RyR Na + I Na Na HX H+H+ Na + NHE ATP 3Na + 2K + Na + pump K+K+ Myofilaments Ca 2+ Na CaX Na CaX 3Na + Ca 2+ NaCaX Forward Reverse 3Na + SL Ca 2+ pump ATP PKA  -AR AC ATP cAMP PLB SERCA P ATP T-Tubule Ca 2+ I Ca PDE AMP DRUG INDUCED ARRHYTHMIAS DUE TO ALTERED Ca 2+ HANDLING Beta-adrenoceptor stimulation Drugs: dopamine dobutamine iv. norepinephrine denopamine iv. oral ? Tsien et al. J Mol Cell Cardiol 1986; 18:691-710 DAD extra beat DAD EAD

16. Ca 2+ SR RyR Na + I Na Na HX H+H+ Na + NHE ATP 3Na + 2K + Na + pump K+K+ Myofilaments Ca 2+ Na CaX Na CaX 3Na + Ca 2+ NaCaX Forward Reverse 3Na + SL Ca 2+ pump ATP PKA  -AR AC ATP cAMP PLB SERCA P ATP T-Tubule Ca 2+ I Ca PDE AMP DRUG INDUCED ARRHYTHMIAS DUE TO ALTERED Ca2+ HANDLING Ca 2+ channel activation Drug: Bay K 8644 Bay Y 5959 CGP 28-392 Hess et al. Nature 1984;311:538-44 DAD extra beat DAD EAD

17. Ca 2+ SR RyR Na + I Na Na HX H+H+ Na + NHE ATP 3Na + 2K + Na + pump K+K+ Myofilaments Ca 2+ Na CaX Na CaX 3Na + Ca 2+ NaCaX Forward Reverse 3Na + SL Ca 2+ pump ATP Mitochondria Ca 2+ PKA  -AR AC ATP cAMP PLB SERCA P ATP T-Tubule Ca 2+ I Ca PDE AMP DRUG INDUCED ARRHYTHMIAS DUE TO ALTERED Ca2+ HANDLING PDE inhibition Drugs: amrinone milrinone olprinone vesnarinone Varró and Papp, J. of Cardiovascular Pharmacology 1995; 26: S32-S44 DAD extra beat DAD

18. Shin-Ann Chen et al. PACE 2003; 26:1576-1582 MECHANISM OF ATRIAL FIBRILLATION DUE TO Ca 2+ OVERLOAD OF THE PULMONARY VEIN CELLS