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Electropharmacological characterization of cardiac repolarization in German shepherd dogs with an inherited syndrome of sudden death: abnormal response to potassium channel blockers

Jocelyn Mérot, DVM, PhD^* , Vincent Probst, MSc^*, Michèle Debailleul, Uwe Gerlach, PhD, N. Sydney Moise, DVM, Hervé Le Marec, MD, PhD^* and Flavien Charpentier, PhD^*

^* INSERM U 533, Physiopathologie & Pharmacologie Cellulaires & Moléculaires, Nantes, France
Laboratoire de Médecine, Ecole Vétérinaire de Nantes, Nantes, France
the Department of Clinical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, New York, USA
Hchst Marion Roussel, Frankfurt, Germany

View larger version (23K): [in a new window]   Figure 1 Left panels. Effects of d,l-sotalol on (A) heart rate (HR), (B) PR interval duration (PR) and (C) QT interval duration (QT) in unaffected dogs (n = 9, solid circle) and affected dogs (n = 6, solid triangle). See protocol in Methods section. (B) #p < 0.05, that is, the two curves are parallel and significantly separated (two-way analysis of variance). (C) For better clarity, we plotted the sotalol-induced increase in QT interval. Values of the QT interval at t = 0 were 227 ± 5 ms in unaffected dogs and 219 ± 8 ms in affected dogs (NS vs. unaffected). *p < 0.05, that is, the effect of sotalol is greater in affected dogs (two-way analysis of variance performed on raw QT values). Right panels. Typical electrocardiogram recordings obtained in (D) in unaffected dog and (E) an affected dog under controlled conditions (top) and 15 min after the second injection of d,l-sotalol (bottom). Vertical bars, 20 mV; horizontal bars, 1 s. See text for further explanation. bpm = beats per min.

View larger version (19K): [in a new window]   Figure 2 (A) Typical superimposed endomyocardial action potentials recorded in an unaffected dog (left) and an affected dog (right) under control conditions at PCL = 1,000 ms and PCL = 8,000 ms. Vertical bar, 50 mV; horizontal bar, 100 ms. (B) Effects of PCL on APD at 30% (left) and 90% (right) of full repolarization (APD30 and APD90) of endomyocardial biopsies obtained from 17 unaffected dogs (n = 25 samples, open circle) and 12 affected dogs (n = 30 samples, open triangle) under control conditions. In both graphs, the two curves are significantly separated (two-way analysis of variance). APD = action potential duration; PCL = pacing cycle length.

View larger version (21K): [in a new window]   Figure 3 Effects on Purkinje fibers APD90 of an abrupt change in PCL from 300 to 1,000 ms (A) and from 1,000 to 300 ms (B), as illustrated above the graph (horizontal bar, 1 s). Action potential duration90 (Y-axis) is plotted versus time (X-axis), 0 corresponding to the change in PCL. Action potential duration90 values are expressed as the percentage of the steady-state value. For each sample, the APD90/time curve was fitted using a monoexponential function (see Methods section). Function parameters were averaged, and the resulting curves are shown in dotted lines for unaffected dogs and solid lines for affected ones. Corresponding equations are in (A) y = (255 + 73·exp[1-0.0194·x])/328·100 for unaffected dogs (n = 17) and y = (284 + 75·exp[1–0.0240·x])/359·100 for affected dogs (n = 11), in (B) y = (184 + 48·exp [–0.7130·x] + 34·[–0.0686·x])/195·100 for affected dogs (n = 10). Inserts: Average time-constants ( in A and ’ in B) in unaffected (white) and affected dogs (black). *p < 0.05 (Student t test). APD = action potential duration; PCL = pacing cycle length.

View larger version (24K): [in a new window]   Figure 4 Left panels. Increase in APD90 induced by d,l-sotalol 10–5 M (open symbols) and 10–4M (solid symbols) as a function of PCL in (A) endomyocardial biopsies of unaffected (n = 7; circle) and affected dogs (n = 8; triangle; #, n = 7) and (B) Purkinje fibers of unaffected (n = 6); circle) and affected dogs (n = 5; triangle). In the affected group, the number of experimental data decreased to 3 at PCL = 4,000 ms under sotalol 10–5 and 10–4 M and to 4 at PCL = 2,000 ms under sotalol 10–4 M because of the occurrence of early afterdepolarizations or triggered activity. Right panels. (C) Typical action potentials recorded in endomyocardial biopsies of an unaffected dogs (bottom) and an affected dog (top) under control conditions (C) and in presence of d,l-sotalol 10–5 M (10–5) and 10–4 M (10–4) at PCL = 1,000 ms. Vertical bar, 50 mV; horizontal bar, 100 ms. (D) Typical action potentials recorded from Purkinje fibers of an unaffected dog (bottom) and an affected dog (top) in the presence of d,l-sotalol 10–4 M at PCL = 8,000 ms. Vertical bar, 50 mV; horizontal bar, 2 s. APD = action potential duration; PCL = pacing cycle length.

View larger version (23K): [in a new window]   Figure 5 Left panels. Increase in APD90 induced by E-4031 10–7 M (open symbols) and 10–6 M (solid symbols) as a function of PCL in (A) endomyocardial biopsies of unaffected (n = 6; circle) and affected dogs (n = 7; triangle) and (B) Purkinje fibers of unaffected (n = 9; circle) and affected dogs (n = 5; triangle). At PCL = 4,000 ms, the number of experimental data decreased to 4 under E-4031 10–7 and 10–6 M in the unaffected group and to 4 under E-4031 10–7 M and 2 under 10–6 M in the affected group because of the occurrence of early afterdepolarizations or triggered activity. Right panels. Typical action potentials recorded in (C) endomyocardial biopsies and (D) Purkinje fibers of affected dogs (top) and unaffected dogs (bottom) under control conditions (C) and in the presence of E-4031 10–7 M (10–7 for Purkinje fibers only) and 10–6 M (10–6) at PCL = 1,000 ms. Vertical bar, 50 mV; horizontal bars, 100 ms in (C) and 200 ms in (D). APD = action potential duration; PCL = pacing cycle length.

View larger version (21K): [in a new window]   Figure 6 Left panels. Increase in APD90 induced by 293B 10–6 M (open symbols) and 10–5 M (solid symbols) as a function of PCL in (A) endomyocardial biopsies of unaffected (n = 6; circle) and affected dogs (n = 5; triangle) and (B) Purkinje fibers of unaffected (n = 9; circle) and affected dogs (n = 5; triangle). Right panels. Typical action potentials recorded in (C) endomyocardial biopsies and (D) Purkinje fibers of affected dogs (top) and unaffected dogs (bottom) under control conditions (C) and in the presence of 293B 10–5 M (10–5) at PCL = 1,000 ms. Vertical bar, 50 mV; horizontal bars, 100 ms in (C) and 200 ms in (D). APD = action potential duration; PCL = pacing cycle length.