INTRODUCTION: In the congenital long QT syndrome, inhomogeneously prolonged action potentials, bradycardia, and hypokalemia can cause afterdepolarizations and torsade de pointes. Other genetic factors may contribute to similar forms of ventricular tachycardias in hypertrophied or failing hearts, especially if the outward current I(Kr) is blocked pharmacologically. We sought to develop a mouse heart model for such arrhythmias in order to identify the proarrhythmic potential in transgenic animals. METHODS AND RESULTS: Hearts of adult wild-type (CD1) mice were isolated and the aorta was retrogradely perfused. Three monophasic action potentials and a volume-conducted ECG were simultaneously recorded. Sotalol (10(-5)M and 2 x 10(-5)M) prolonged action potential duration (APD) in a concentration-dependent and reverse frequency-dependent fashion (from 34 +/- 1 to 48 +/- 2 ms at 100 ms basic cycle length (BCL), from 38 +/- 2 to 54 +/- 3 ms at 180 ms BCL for APD90, p < 0.05). Sotalol did not alter the relation between refractoriness and APD (ERP/APD ratio = 0.76 - 0.93). AV nodal block caused ventricular bradycardia and doubled dispersion of APD (APD70max-min: 11 +/- 1 vs. 4 +/- 1 ms, APD90max-min: 12 +/- 1 vs. 5 +/- 1 ms, p < 0.05). If combined with hypokalemia, afterdepolarizations induced polymorphic ventricular tachycardias in 1 of 8 hearts at K(+) =3.0 mM and in 10 of 12 hearts at K(+) = 2.0 mM. Prior to polymorphic ventricular tachycardia, dispersion of APD further increased (APD70max-min: 17 +/- 3 ms; APD90max-min: 25 +/- 3 ms; p < 0.05). CONCLUSIONS: This isolated beating mouse heart model can be used to study drug-induced action potential prolongation and repolarization-related ventricular arrhythmias provoked by bradycardia and hypokalemia. It may be suitable to identify a genetic predisposition to ventricular arrhythmias that may only become apparent under such proarrhythmic conditions.
INTRODUCTION: In the congenital long QT syndrome, inhomogeneously prolonged action potentials, bradycardia, and hypokalemia can cause afterdepolarizations and torsade de pointes. Other genetic factors may contribute to similar forms of ventricular tachycardias in hypertrophied or failing hearts, especially if the outward current I(Kr) is blocked pharmacologically. We sought to develop a mouse heart model for such arrhythmias in order to identify the proarrhythmic potential in transgenic animals. METHODS AND RESULTS: Hearts of adult wild-type (CD1) mice were isolated and the aorta was retrogradely perfused. Three monophasic action potentials and a volume-conducted ECG were simultaneously recorded. Sotalol (10(-5)M and 2 x 10(-5)M) prolonged action potential duration (APD) in a concentration-dependent and reverse frequency-dependent fashion (from 34 +/- 1 to 48 +/- 2 ms at 100 ms basic cycle length (BCL), from 38 +/- 2 to 54 +/- 3 ms at 180 ms BCL for APD90, p < 0.05). Sotalol did not alter the relation between refractoriness and APD (ERP/APD ratio = 0.76 - 0.93). AV nodal block caused ventricular bradycardia and doubled dispersion of APD (APD70max-min: 11 +/- 1 vs. 4 +/- 1 ms, APD90max-min: 12 +/- 1 vs. 5 +/- 1 ms, p < 0.05). If combined with hypokalemia, afterdepolarizations induced polymorphic ventricular tachycardias in 1 of 8 hearts at K(+) =3.0 mM and in 10 of 12 hearts at K(+) = 2.0 mM. Prior to polymorphic ventricular tachycardia, dispersion of APD further increased (APD70max-min: 17 +/- 3 ms; APD90max-min: 25 +/- 3 ms; p < 0.05). CONCLUSIONS: This isolated beating mouse heart model can be used to study drug-induced action potential prolongation and repolarization-related ventricular arrhythmias provoked by bradycardia and hypokalemia. It may be suitable to identify a genetic predisposition to ventricular arrhythmias that may only become apparent under such proarrhythmic conditions.
Authors: Larissa Fabritz; Dierk Damke; Markus Emmerich; Susann G Kaufmann; Kathrin Theis; Andreas Blana; Lisa Fortmüller; Sandra Laakmann; Sven Hermann; Elena Aleynichenko; Johannes Steinfurt; Daniela Volkery; Burkhard Riemann; Uwe Kirchhefer; Michael R Franz; Günter Breithardt; Edward Carmeliet; Michael Schäfers; Sebastian K G Maier; Peter Carmeliet; Paulus Kirchhof Journal: Cardiovasc Res Date: 2010-01-28 Impact factor: 10.787
Authors: Attila S Farkas; Péter Makra; Norbert Csík; Szabolcs Orosz; Michael J Shattock; Ferenc Fülöp; Tamás Forster; Miklós Csanády; Julius Gy Papp; András Varró; András Farkas Journal: Br J Pharmacol Date: 2009-02-16 Impact factor: 8.739
Authors: Larissa Fabritz; Paulus Kirchhof; Lisa Fortmüller; John A Auchampach; Hideo A Baba; Günter Breithardt; Joachim Neumann; Peter Boknik; Wilhelm Schmitz Journal: Cardiovasc Res Date: 2004-06-01 Impact factor: 10.787
Authors: Mohammad Rajab; Hongwei Jin; Charles M Welzig; Alfred Albano; Mark Aronovitz; Yali Zhang; Ho-Jin Park; Mark S Link; Sami F Noujaim; Jonas B Galper Journal: Am J Physiol Heart Circ Physiol Date: 2013-10-25 Impact factor: 4.733