András Varró

Department of Pharmacology and PharmacotherapyUniversity of Szeged, Hungary

Albert Szent-Györgyi Medical Center2006

CALCIUM HANDLING AND CARDIAC ARRHYTHMIAS

CALCIUM HANDLING AND CARDIAC ARRHYTHMIAS

HEART FAILURE

GENETIC (CPVT)

DRUGS

ATRIAL FIBRILLATION

GAP JUNCTIONS

Ca2+

SR

Na+

INa

NaHX

H+

Na+

NHE

ATP

3Na+

2K+

Na+ pump

K+

Myofilaments

Ca2+

Ca2+

Ca2+

NaCaX

NaCaX

3Na+ Ca2+

NaCaXForward Reverse

3Na+

SL Ca2+

pump

ATP

Mitochondria

Ca2+

PKA

-ARAC

ATP

cAMP

PLB

SERCA

P

ATP

T-T

ub

ule

Ca2+

ICa

PDE

AMPR

yR

CARDIAC CELLULAR Ca2+ HANDLING

Control

Control Heart failure

Heart failure

Heart failureControl

IKs

IKr

Ito

Control

Heartfailure

CL 1000 ms

Tsuji et al. Cardiovasc. Res. 2000. 48: 300-309

DECREASED REPOLARIZATION RESERVE IN HEART FAILURE

Ik1

Fadi G.Akar et al. Am J Physiol 288:2887-2896, 2005

W Xiong et al, Circ Res. 2005;97:207-209.

UPREGULATION OF NCX IN HEART FAILURE

Sipido et al. Circulation. 2000;102:2137-2144.

Ca2+ DEPENDENT DOWNREGULATION OF IK1

J. Fauconnier et al. Cardiovasc Res 68 (2005) 204– 212

J. Fauconnier et al. Cardiovasc Res 68 (2005) 204– 212

Rose et al. Am J Physiol 288: H2077–H2087, 2005.

mRNA protein

M.Yano et al. Pharmacology & Therapeutics 107 (2005) 377 – 391

INCREASED Ca2+ RELEASE FROM SRIN HEART FAILURE

ZA. Nagy, et al, British Journal of Pharmacology (2004) 143, 827–831

INHIBITION OF NCX ABOLISHES EAD AND DAD

Pogwizd et al. Circ Res. 2001;88: 1159-1167.

ENHANCED DEPOLARIZATION EVOKED BY INTRACELLULAR Ca2+ IN HEART FAILURE

Ca2+

SR

Ry

R

Na+

INa

NaHX

H+

Na+

NHE

ATP

3Na+

2K+

Na+ pump

Myofilaments

Ca2+

Ca2+

Ca2+

NaCaX

NaCaX

3Na+ Ca2+

NaCaXForward Reverse

3Na+

SL Ca2+

pump

ATP

Mitochondria

Ca2+

PKA

-ARAC

ATP

cAMP

PLB

SERCA

P

ATP

T-T

ub

ule

Ca2+

ICa

PDE

AMP

ARRHYTHMIA IN HEART FAILURE

K+ Ik1

K+ IKs

K+ Ito

K+ IKr

RE

PO

LA

RIZ

AT

ION

RE

SE

RV

E

Cl- ICl

Na+

If

DAD

extra beat

DAD

Upregulated NCX

Increased sympathetic tone

EAD

spont.extra beat

Lehnart et al. Circulation. 2004;109:r113–r119Terentyev et al. Circ Res. 2005;96:651-658.

ENHANCED Ca2+ RELEASE DUE TO LEAKY SR

M.Yano et al. Pharmacology & Therapeutics 107 (2005) 377 – 391

ENHANCED Ca2+ RELEASE DUE TO MUTATIONOF THE SR RELEASE CHANNEL

Ca2+

SR

Ry

R

Na+

INa

NaHX

H+

Na+

NHE

ATP

3Na+

2K+

Na+ pump

Myofilaments

Ca2+

Ca2+

Ca2+

NaCaX

NaCaX

3Na+ Ca2+

NaCaXForward Reverse

3Na+

SL Ca2+

pump

ATP

Mitochondria

Ca2+

PKA

-ARAC

ATP

cAMP

PLB

SERCA

P

ATP

T-T

ub

ule

Ca2+

ICa

PDE

AMP

ARRHYTHMIA IN FPVT (Familial Polymorphic Ventricular Tachycardia) AND CPVT (Catecholaminergic Polymorphic

Ventricular Tachycardia)

K+ Ik1

K+ IKs

K+ Ito

K+ IKr

RE

PO

LA

RIZ

AT

ION

RE

SE

RV

E

Cl- ICl

Na+

If

DAD

extra beat

DAD

Upregulated NCX

Increased sympathetic tone

EAD ?

Ca2+

SR

Ry

R

Na+

INa

NaHX

H+

Na+

NHE

ATP

3Na+

2K+

Na+ pump

K+

Ca2+

Ca2+

Ca2+

NaCaX

NaCaX

3Na+ Ca2+

NaCaXForward Reverse

3Na+

SL Ca2+

pump

ATP

Mitochondria

Ca2+

PKA

-ARAC

ATP

cAMP

PLB

SERCA

P

T-T

ub

ule

Ca2+

ICa

PDE

AMP

DRUG INDUCED ARRHYTHMIAS DUE TO ALTERED Ca2+ HANDLING Ca2+ release activation

McGarry and Williams Br.J. Pharmacol. 1993, 108: 1043-1050

Drug:

DigoxinActodiginOubainFPL-64176

DAD

extra beat

DAD

DIGOXIN 1nM

Ca2+

SR

Ry

R

Na+

INa

NaHX

H+

Na+

NHE

ATP

3Na+

2K+

Na+ pump

K+

Myofilaments

Ca2+

Ca2+

Ca2+

NaCaX

NaCaX

3Na+ Ca2+

NaCaXForward Reverse

3Na+

SL Ca2+

pump

ATP

PKA

-ARAC

ATP

cAMP

PLB

SERCA

P

ATP

T-T

ub

ule

Ca2+

ICa

PDE

AMP

DRUG INDUCED ARRHYTHMIAS DUE TO ALTERED Ca2+ HANDLINGBeta-adrenoceptor stimulation

Drugs:

dopaminedobutamine iv.norepinephrinedenopamine iv. oral ?

Tsien et al. J Mol Cell Cardiol 1986; 18:691-710

DAD

extra beat

DAD EAD

Ca2+

SR

Ry

R

Na+

INa

NaHX

H+

Na+

NHE

ATP

3Na+

2K+

Na+ pump

K+

Myofilaments

Ca2+

Ca2+

Ca2+

NaCaX

NaCaX

3Na+ Ca2+

NaCaXForward Reverse

3Na+

SL Ca2+

pump

ATP

PKA

-ARAC

ATP

cAMP

PLB

SERCA

P

ATP

T-T

ub

ule

Ca2+

ICa

PDE

AMP

DRUG INDUCED ARRHYTHMIAS DUE TO ALTERED Ca2+ HANDLINGCa2+ channel activation

Drug:

Bay K 8644Bay Y 5959CGP 28-392

Hess et al. Nature 1984;311:538-44

DAD

extra beat

DAD EAD

Ca2+

SR

Ry

R

Na+

INa

NaHX

H+

Na+

NHE

ATP

3Na+

2K+

Na+ pump

K+

Myofilaments

Ca2+

Ca2+

Ca2+

NaCaX

NaCaX

3Na+ Ca2+

NaCaXForward Reverse

3Na+

SL Ca2+

pump

ATP

Mitochondria

Ca2+

PKA

-ARAC

ATP

cAMP

PLB

SERCA

P

ATP

T-T

ub

ule

Ca2+

ICa

PDE

AMP

DRUG INDUCED ARRHYTHMIAS DUE TO ALTERED Ca2+ HANDLINGPDE inhibition

Drugs:

amrinonemilrinoneolprinonevesnarinone

Varró and Papp, J. of Cardiovascular Pharmacology 1995; 26: S32-S44

DAD

extra beat

DAD

Shin-Ann Chen et al. PACE 2003; 26:1576-1582

MECHANISM OF ATRIAL FIBRILLATION DUE TO Ca2+ OVERLOAD OF THE PULMONARY VEIN

CELLS