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CALCIUM HANDLING AND CARDIAC ARRHYTHMIAS András Varró Department of Pharmacology and Pharmacotherapy University of Szeged, Hungary Albert Szent-Györgyi Medical Center 2006 CALCIUM HANDLING AND CARDIAC ARRHYTHMIAS HEART FAILURE GENETIC (CPVT) DRUGS ATRIAL FIBRILLATION GAP JUNCTIONS CARDIAC CELLULAR Ca2+ HANDLING NaCaX SL Ca2+ pump Forward Reverse 3Na+ Ca2+ Na CaX ATP b-AR AC Na CaX INa NHE Na+ Na+ Na HX Na+ pump 2K+ ATP cAMP ATP PKA PDE AMP Ca2+ 3Na+ H+ 3Na+ RyR P Ca2+ T-Tubule ICa Ca2+ SR PLB Ca2+ SERCA K+ ATP Ca2+ Ca2+ Mitochondria Myofilaments DECREASED REPOLARIZATION RESERVE IN HEART FAILURE Ik1 Fadi G.Akar et al. Am J Physiol 288:2887-2896, 2005 Control Control Ito IKs CL 1000 ms Heart failure Heart failure Heart failure Control Control IKr Heart failure Tsuji et al. Cardiovasc. Res. 2000. 48: 300-309 UPREGULATION OF NCX IN HEART FAILURE W Xiong et al, Circ Res. 2005;97:207-209. Sipido et al. Circulation. 2000;102:2137-2144. Ca2+ DEPENDENT DOWNREGULATION OF IK1 J. Fauconnier et al. Cardiovasc Res 68 (2005) 204– 212 mRNA protein J. Fauconnier et al. Cardiovasc Res 68 (2005) 204– 212 Rose et al. Am J Physiol 288: H2077–H2087, 2005. INCREASED Ca2+ RELEASE FROM SR IN HEART FAILURE M.Yano et al. Pharmacology & Therapeutics 107 (2005) 377 – 391 INHIBITION OF NCX ABOLISHES EAD AND DAD ZA. Nagy, et al, British Journal of Pharmacology (2004) 143, 827–831 ENHANCED DEPOLARIZATION EVOKED BY INTRACELLULAR Ca2+ IN HEART FAILURE Pogwizd et al. Circ Res. 2001;88: 1159-1167. ARRHYTHMIA IN HEART FAILURE Upregulated NCX Increased sympathetic tone ATP b-AR AC cAMP ATP PKA PDE AMP Na CaX Ca2+ Na CaX INa Na+ NHE Na+ pump Na+ 2K+ Na HX 3Na+ ATP H+ 3Na+ RyR P Ca2+ T-Tubule ICa Ca2+ SR Ik1 K+ IKs K+ Ito K+ IKr Cl- ICl I Na+ PLB Ca2+ SERCA ATP Ca2+ Ca2+ Mitochondria Myofilaments DAD extra beat DAD K+ EAD f spont. extra beat REPOLARIZATION RESERVE NaCaX SL Ca2+ pump Forward Reverse 3Na+ Ca2+ ENHANCED Ca2+ RELEASE DUE TO LEAKY SR Lehnart et al. Circulation. 2004;109:r113–r119 Terentyev et al. Circ Res. 2005;96:651-658. ENHANCED Ca2+ RELEASE DUE TO MUTATION OF THE SR RELEASE CHANNEL M.Yano et al. Pharmacology & Therapeutics 107 (2005) 377 – 391 ARRHYTHMIA IN FPVT (Familial Polymorphic Ventricular Tachycardia) AND CPVT (Catecholaminergic Polymorphic Ventricular Tachycardia) Upregulated NCX Increased sympathetic tone ATP b-AR AC cAMP ATP PKA PDE AMP Na CaX Ca2+ INa Na+ NHE Na+ pump Na+ Na CaX 2K+ Na HX ATP H+ 3Na+ 3Na+ RyR P Ca2+ T-Tubule ICa K+ Ik1 K+ IKs K+ Ito K+ IKr Cl- ICl If Na+ PLB Ca2+ Ca2+ SERCA SR ATP Ca2+ Ca2+ Mitochondria Myofilaments DAD extra beat DAD EAD ? REPOLARIZATION RESERVE NaCaX SL Ca2+ pump Forward Reverse 3Na+ Ca2+ DRUG INDUCED ARRHYTHMIAS DUE TO ALTERED Ca2+ HANDLING Ca2+ release activation NaCaX SL Ca2+ pump Forward Reverse 3Na+ Ca2+ Na CaX ATP b-AR AC Na CaX INa Na+ NHE Na+ pump Na+ Na HX 2K+ ATP cAMP ATP PKA PDE AMP Ca2+ 3Na+ H+ 3Na+ RyR P Ca2+ T-Tubule ICa Ca2+ SR PLB Ca2+ SERCA Ca2+ Drug: DAD Digoxin Actodigin Oubain FPL-64176 extra beat K+ Ca2+ Mitochondria DIGOXIN 1nM DAD McGarry and Williams Br.J. Pharmacol. 1993, 108: 1043-1050 DRUG INDUCED ARRHYTHMIAS DUE TO ALTERED Ca2+ HANDLING Beta-adrenoceptor stimulation NaCaX SL Ca2+ pump Forward Reverse 3Na+ Ca2+ Na CaX ATP b-AR AC Na CaX INa Na+ NHE Na+ pump Na+ Na HX 2K+ ATP cAMP ATP PKA PDE AMP Ca2+ 3Na+ H+ 3Na+ RyR P Ca2+ ICa Ca2+ T-Tubule SR PLB K+ SERCA ATP Ca2+ Ca2+ Myofilaments DAD Drugs: dopamine dobutamine iv. norepinephrine denopamine iv. oral ? EAD extra beat DAD Tsien et al. J Mol Cell Cardiol 1986; 18:691-710 DRUG INDUCED ARRHYTHMIAS DUE TO ALTERED Ca2+ HANDLING Ca2+ channel activation NaCaX SL Ca2+ pump Forward Reverse 3Na+ Ca2+ Na CaX ATP b-AR AC Na CaX INa Na+ NHE Na+ pump Na+ Na HX 2K+ ATP cAMP ATP PKA PDE AMP Ca2+ 3Na+ H+ 3Na+ RyR P Ca2+ ICa Ca2+ K+ SERCA SR T-Tubule PLB ATP Ca2+ Ca2+ Myofilaments Drug: Bay K 8644 Bay Y 5959 CGP 28-392 DAD EAD extra beat DAD Hess et al. Nature 1984;311:538-44 DRUG INDUCED ARRHYTHMIAS DUE TO ALTERED Ca2+ HANDLING PDE inhibition NaCaX SL Ca2+ pump Forward Reverse 3Na+ Ca2+ Na CaX ATP b-AR AC Na CaX INa Na+ NHE Na+ pump Na+ 2K+ Na HX ATP cAMP ATP PKA PDE AMP Ca2+ 3Na+ H+ 3Na+ RyR P Ca2+ T-Tubule ICa PLB Ca2+ Ca2+ SERCA SR ATP Ca2+ Ca2+ Mitochondria Myofilaments DAD Drugs: amrinone milrinone olprinone vesnarinone K+ extra beat DAD Varró and Papp, J. of Cardiovascular Pharmacology 1995; 26: S32-S44 MECHANISM OF ATRIAL FIBRILLATION DUE TO Ca2+ OVERLOAD OF THE PULMONARY VEIN CELLS Shin-Ann Chen et al. PACE 2003; 26:1576-1582
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