901–41 Preliminary Mortality Results from the Survival with Oral D-Sotalol (SWORD) Trial

Waldo, Albert L.; Aj, Camm; Ruyter, Hanna de; Friedman, Peter L.; MacNeil, Daniel J.; Pitt, B.; Pratt, C.M.; Schwartz, Philip; Veltri, Enrico P.

doi:10.1016/0735-1097(95)91518-3

Cited by 51 publications

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“…A recent study on the effects of d-sotalol on mortality in patients with myocardial infarction was abruptly interrupted following a preliminary report indicating an increase in mortality in patients treated with dsotalol as compared to the control group (19). The lack of significant beta-blocking properties of dsotalol, as well as the proarrythmogenic effects owing to its reverse use-dependence effects on APD, preferential effects on M cells and Purkinje fibers, increased dispersion of repolarization, EAD-induced triggered activity in M cells and Purkinje fibers, and development of intramural reentry and torsade de pointes may contribute to the drug-induced proarrhythmogenic effects and increased mortality observed in the clinics.…”

Section: Physiologic and Clinical Implicationsmentioning

confidence: 96%

“…Early afterdepolarizations (EADs) have been described in Purkinje fibers exposed to high concentration of dsotalol (14); atypical polymorphic ventricular tachycardias known as torsade de pointes (15) were observed during sotalol infusion in conscious dogs made hypokalemic and bradycardic with permanent complete atrioventricular (AV) block (16) and in patients treated with oral sotalol (17,18). A recent clinical trial involving postmyocardial patients treated with d-sotalol (SWORD) had to be interrupted because of the higher mortality observed in the dsotalol group as compared to the control group ( 19).…”

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confidence: 96%

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d-Sotalol Induces Marked Action Potential Prolongation and Early Afterdepolarizations in M but Not Epicardial or Endocardial Cells of the Canine Ventricle

Sicouri

Moro

Elizari

1997

J Cardiovasc Pharmacol Ther

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BACKGROUND: Despite its class III antiarrhythmic actions, experimental and clinical studies have shown that d-sotalol can also be proarrhythmic; a recent clinical trial that evaluated d-sotalol in postmyocardial patients (SWORD) had to be prematurely interrupted because of the excess mortality in the treated group. Previous studies have demonstrated the existence of a marked heterogeneity across the ventricular wall; epicardial, endocardial, and M cells have been shown to display distinct electrophysiologic characteristics and pharmacologic behavior. The present study was designed to test the hypothesis that M cells are the primary target for the class III actions of d-sotalol in canine ventricular myocardium and may contribute to its proarrhythmic effects. METHODS AND RESULTS: We used standard microelectrode techniques to record transmembrane activity from endocardial, epicardial, midmyocardial, and transmural strips, isolated from the canine left ventricle. d-Sotalol (100 µM, 60 minutes of exposure, [K(+)]o = 4 mM) prolongs the action potential in the three cell types, but more so in M than epicardial or endocardial cells, especially at the slower rates. At a basic cycle length of 2000 ms, action potential duration after 90% repolarization increases from 199 +/- 20 to 247.5 +/- 28 ms in epicardium (n = 10), from 212 +/- 26 to 274 +/- 27 ms in endocardium (n = 11), and from 309 +/- 65 to 533 +/- 207 ms in M cells (n = 13). d-Sotalol produces a marked steepening of action potential duration-rate relationships of M cells and an upward shift of restitution of action potential duration curves, more accentuated in M cells. Early afterdepolarizations were observed at slow rates (basic cycle lengths > 1000 ms) in 7 of 13 M cell preparation s(54%) but not in endocardial or epicardial preparations. A sudden acceleration of the rate could also induce a transient prolongation of the action potential and early afterdepolarization activity. CONCLUSION: In canine ventricular tissues, d-sotalol manifests its class III effects preferentially in the M cells, leading to the development of early afterdepolarizations and a marked increase in transmural dispersion of repolarization. The data suggest an important role of M cells in the proarrhythmic effects of the drug.

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Section: Physiologic and Clinical Implicationsmentioning

confidence: 96%

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confidence: 96%

d-Sotalol Induces Marked Action Potential Prolongation and Early Afterdepolarizations in M but Not Epicardial or Endocardial Cells of the Canine Ventricle

Sicouri

Moro

Elizari

1997

J Cardiovasc Pharmacol Ther

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“…Vaughan Williams (1970) classified compounds which increase the duration of the cardiac action potential as Class III. The commonly used Class III agents, amiodarone and sotalol, can in certain cases be effective in suppressing life-threatening cardiac arrhythmias, despite the indications of a recent clinical trial that there is a decreased survival of post-infarction patients given sotalol compared with a placebo group (Waldo et al 1995). Both compounds block potassium currents but are non-selective in their action.…”

Section: Introductionmentioning

confidence: 99%

Inhibition by Compound II, a sotalol analogue, of delayed rectifier current (iK) in rabbit isolated sino-atrial node cells

Lei

Brown

1998

Naunyn-Schmiedeberg's Arch Pharmacol

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The effects of Compound II, a sotalol analogue, on spontaneous electrical activity and on three membrane currents (the delayed rectifier current, iK, the long-lasting inward calcium current, i(Ca,L) and hyperpolarization activated inward current, i(f)) were investigated in rabbit isolated sino-atrial node cells by whole cell clamp with amphotericin-permeabilised patches. A submaximal concentration of Compound II (50 nM) had a significant effect on the time and voltage dependent activation of iK and caused a positive shift of the iK activation curve. As well as blocking i(Kr), it caused some degree of block of i(Ks). Block of iK by Compound II was found to be concentration dependent with an IC50 of approximately 40 nM. 1 microM Compound II nearly completely blocked iK without significantly affecting the peak current or I/V relationships of i(Ca,L) or i(f). 50 nM Compound II caused a significant prolongation of APD100 and of cycle length. It also decreased diastolic depolarization rate without significantly affecting MDP and action potential amplitude. It is concluded that Compound II, a sotalol analogue, slows spontaneous activity of isolated rabbit SA node cells through a selective inhibition of iK.

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“…In view of the pessimism in general regarding prevention of VF in patients likely to develop it, whether as a consequence of ischaemia, infarction or reperfusion (Akhtar et al, 1990;Waldo et al, 1994), approaches to the understanding of arrhythmogenesis and its control that do not rely on a conventional electrophysiological model may be warranted (Curtis et al, 1993b). One such approach involves the concept of endogenous cardioprotective substances (Parratt, 1993).…”

Section: Introductionmentioning

confidence: 99%

An endogenous protectant effect of cardiac cyclic GMP against reperfusion‐induced ventricular fibrillation in the rat heart

Pabla

Bland-Ward

Moore

et al. 1995

British J Pharmacology

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1 After a period of myocardial ischaemia, reperfusion of the myocardium can elicit cardiac arrhythmias. Susceptibility to these arrhythmias declines with time, such that a preceding period of more than approximately 40 min ischaemia is associated with few reperfusion-induced arrhythmias. We have tested the hypothesis that this decline in susceptibility occurs, in part, because of protection by endogenous guanosine 3':5'-cyclic monophosphate (cyclic GMP). 2 Rat isolated hearts were subjected to 60 min left regional ischaemia followed by reperfusion (n = 10 per group). Methylene blue (20 gM), a soluble guanylate cyclase inhibitor, raised the incidence of reperfusion-induced ventricular fibrillation (VF) from 10% in control hearts to 80% (P<0.05). This effect of methylene blue was abolished by co-perfusion with zaprinast (100 juM), a phosphodiesterase inhibitor which, in the rat heart, is cyclic GMP-specific (specific for the type-V phosphodiesterase isozyme). 3 Methylene blue reduced cyclic GMP levels in the ischaemic, non-ischaemic and reperfused myocardium (P<0.05) to 50 +10, 52+12 and 70+7 fmolmg-1 tissue wet weight, respectively from control values of 143 + 38, 147 +43 and 156+15 fmol mg-'. Co-perfusion with zaprinast prevented this effect, and cyclic GMP levels were actually elevated (P< 0.05) to 366 + 102, 396 + 130 and 293+22 fmol mg -in ischaemic, non-ischaemic and reperfused myocardium, respectively. Zaprinast by itself also elevated cyclic GMP content. Cyclic AMP levels were not affected by zaprinast or methylene blue. 4 In conclusion, when endogenous cardiac cyclic GMP synthesis is reduced, susceptibility to reperfusion-induced VF after sustained ischaemia is substantially increased. The effect is prevented by inhibiting cyclic GMP degradation. Therefore cyclic GMP appears to be an endogenous intracellular cardioprotectant, and its actions may account for the low susceptibility to VF normally encountered in hearts reperfused after sustained ischaemia.

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901–41 Preliminary Mortality Results from the Survival with Oral D-Sotalol (SWORD) Trial

Cited by 51 publications

References 0 publications

d-Sotalol Induces Marked Action Potential Prolongation and Early Afterdepolarizations in M but Not Epicardial or Endocardial Cells of the Canine Ventricle

d-Sotalol Induces Marked Action Potential Prolongation and Early Afterdepolarizations in M but Not Epicardial or Endocardial Cells of the Canine Ventricle

Inhibition by Compound II, a sotalol analogue, of delayed rectifier current (iK) in rabbit isolated sino-atrial node cells

An endogenous protectant effect of cardiac cyclic GMP against reperfusion‐induced ventricular fibrillation in the rat heart

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