Sotalol hydrochloride (Betapace): a new antiarrhythmic drug

1993 ◽  
Vol 2 (5) ◽  
pp. 397-406
Author(s):  
CS Dunnington
Keyword(s):  
Side Effects ◽  
Antiarrhythmic Drug ◽  
Action Potential Duration ◽  
Antihypertensive Agent ◽  
Left Ventricular ◽  
Monophasic Action Potential ◽  
Class Iii ◽  
Cardiac Tissues ◽  
Supraventricular Tachyarrhythmias ◽  
Low Incidence

Sotalol hydrochloride (Betapace), recently released by the Food and Drug Administration for general use, is used to treat a variety of ventricular and supraventricular tachyarrhythmias. The drug's dominant action is the result of combined nonselective beta-adrenergic antagonism (Class II effect) and monophasic action potential duration prolongation in all cardiac tissues (Class III effect). It causes less left ventricular depression than propranolol and has a low incidence of toxicity. It is a useful addition to the antiarrhythmic drug armamentarium. This article reviews the drug's pharmacokinetic, pharmacodynamic and electrophysiologic properties, clinical uses and potential side effects. Reports on the drug's use as an antianginal and antihypertensive agent are also discussed.

Abstract 542: Chronic Doxorubicin Cardiotoxicity Assessed in Engineered Cardiac Tissues Generated in Biowire™ II Platform

2020 ◽  
Vol 127 (Suppl_1) ◽  
Author(s):  
Roozbeh Aschar-sobbi ◽  
Julia E Napolitano ◽  
Danielle R Bogdanowicz ◽  
Michael P Graziano
Keyword(s):  
Action Potential ◽  
Action Potential Duration ◽  
Cardiac Fibroblasts ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Resting Membrane Potential ◽  
Ventricular Ejection Fraction ◽  
Cardiac Tissues

The anthracycline doxorubicin is an effective anti-tumor agent widely used in both adults and children. One major adverse effect of doxorubicin therapy is dose-dependent cardiotoxicity, ranging from asymptomatic reduction in left ventricular ejection fraction to more serious, potentially fatal symptoms including arrythmias and congestive heart failure. The exact mechanism of doxorubicin-induced cardiotoxicity remains unknown. Recently, human induced pluripotent stem cells (hiPSC) have emerged as a potential tool to model cardiac toxicity, but their fetal-like phenotype raises concerns about the translatability of in vitro data to in vivo cardiotoxicity. To overcome this limitation, Biowire™ II platform was used to generate 3D engineered cardiac tissues (ECTs) from hiPSC-derived cardiomyocytes and human cardiac fibroblasts. Using long-term electrical stimulation, ECTs with a phenotype approaching that of adult human myocardium were obtained. The ECTs were then exposed to 1 μM doxorubicin for 8 days followed by 7 days of washout. Measurements of contractile force amplitude at 1 Hz stimulation showed a transient increase in force within 24 hours of doxorubicin exposure followed by decrease in force after 2 days. Intracellular recordings of action potential (AP) showed a decrease in maximum upstroke velocity (dV/dt), AP amplitude (APA), and resting membrane potential (RMP) after 8 days of doxorubicin treatment. In addition, action potential duration (APD) at 30% (APD30) repolarization was increased in doxorubicin-treated ECTs, whereas APD50 and APD90 were decreased. Following 7 days of washout, no difference in force or AP parameters was found between doxorubicin and vehicle-treated ECTs with the exception of APD50 and APD90 which remained abbreviated. A global untargeted analysis of the conditioned media from doxorubicin-treated ECTs identified 204 analytes and revealed an upregulation of redox homeostasis, differential fatty acid metabolism, altered glycolysis and TCA cycle metabolites, and decreased nucleoside metabolism compared to vehicle-treated ECTs. These results show that doxorubicin not only increases oxidative stress, but also irreversibly affects action potential duration which may predispose to cardiac arrhythmias.

Effect of abrupt changes in ventricular loading on repolarization induced by transient aortic occlusion in humans

1992 ◽  
Vol 263 (3) ◽  
pp. H816-H823 ◽  
Author(s):  
P. Taggart ◽  
P. Sutton ◽  
M. Lab ◽  
M. Runnalls ◽  
W. O'Brien ◽  
...  
Keyword(s):  
Action Potential ◽  
Action Potential Duration ◽  
Systolic Pressure ◽  
Left Ventricular ◽  
Aortic Occlusion ◽  
Monophasic Action Potential ◽  
Ectopic Beat ◽  
Abrupt Changes ◽  
Transient Aortic Occlusion ◽  
Acute Changes

We have investigated the influence of ventricular loading on repolarization from beat to beat in the human heart. Sixteen patients undergoing routine coronary artery surgery were studied. Left ventricular epicardial monophasic action potentials and local electrograms were recorded during acute changes in ventricular loading induced by transient aortic occlusion. Monophasic action potential duration shortened (P less than 0.0001) and returned to control values within one or two beats after release (P less than 0.0001). Values at 90% repolarization were 325 +/- 31 ms preocclusion, 311 +/- 29 ms during occlusion, 326 +/- 32 ms postocclusion. The Q-T interval of the local epicardial electrogram shortened during occlusion (P less than 0.001) and returned to control values after release (P greater than 0.0001): 396 +/- 44 ms preocclusion, 379 +/- 41 ms during occlusion, and, 399 +/- 42 ms postocclusion. A significant correlation was obtained between changes in peak systolic pressure and changes in monophasic action potential duration (R = 0.96; P less than 0.0001 at 90% repolarization). A significant correlation was also observed between changes in peak systolic pressure and the Q-T interval of the local electrogram (R = 0.91; P less than 0.0001). This study shows that abrupt changes in ventricular loading from one beat to the next induce significant changes in the timing of ventricular repolarization. These results may well be relevant to the initiation of arrhythmia by a single ventricular ectopic beat, particularly under pathological conditions.

Endothelin-1-induced elevations in purine metabolite concentrations — autoregulatory protection in the canine pericardium?

2002 ◽  
Vol 103 (s2002) ◽  
pp. 202S-205S ◽  
Author(s):  
Endre ZIMA ◽  
Violetta KÉKESI ◽  
Andrea NAGY ◽  
László LOSONCZI ◽  
Ildikó TOMA ◽  
...  
Keyword(s):  
Action Potential ◽  
Action Potential Duration ◽  
Left Ventricular ◽  
Pericardial Fluid ◽  
Monophasic Action Potential ◽  
Endothelin 1 ◽  
Purine Metabolites ◽  
Metabolite Concentrations ◽  
Purine Metabolite ◽  
Upstroke Velocity

Pericardial fluid accumulates the cardioprotective purine metabolites, as well as the endogenous vasoconstrictor agent endothelin-1 (ET-1). The aim of the present study was to characterize the pericardial concentrations of the purine metabolites adenosine, inosine and hypoxanthine before and after intrapericardial administration of ET-1 to the in situ heart. The closed pericardial sac of anaesthetized dogs (n = 9) was cannulated for ET-1 administration and for obtaining native pericardial fluid and control pericardial infusate samples (C1 and C2), as well as consecutive pericardial infusate samples (samples I, II and III) obtained 15min after intrapericardial administration of 150pmol/kg ET-1. In an additional five dogs, using the same protocol, ventricular epicardial and endocardial monophasic action potential recordings were performed to assess local ischaemic electrophysiological changes. Significant elevations of pericardial purine metabolite concentrations (measured by HPLC) were found in sample II compared with sample C2: adenosine, 4.5±1.7 compared with 0.5±0.1µM (P<0.05); inosine, 18.3±2.8 compared with 0.9±0.2µM (P<0.001); hypoxanthine, 38.1±8.0 compared with 13.4±2.6µM (P<0.01). Systemic blood pressure, left ventricular pressure and contractility, and systemic plasma levels of the purine metabolites remained unchanged during the ET-1 effect, while significant ECG ST elevations (STmax 0.68±0.01mV; P<0.001) were observed. In the five dogs analysed electrophysiologically, the left ventricular epicardial monophasic action potential duration and upstroke velocity decreased significantly at time point II compared with C2, while the endocardial monophasic action potential duration and upstroke velocity did not show ischaemia-related changes. The results suggest that intrapericardial administration of ET-1 induces subepicardial ischaemia, with parallel activation of coronary metabolic adaptive and cardiac self-protective mechanisms in the epimyocardial layer of the heart.

d-Sotalol: a new potent class III anti-arrhythmic agent

1985 ◽  
Vol 69 (5) ◽  
pp. 631-636 ◽  
Author(s):  
Peter Taggart ◽  
Peter Sutton ◽  
Robert Donaldson
Keyword(s):  
Bolus Injection ◽  
Dose Range ◽  
Parent Compound ◽  
Left Ventricular ◽  
Monophasic Action Potential ◽  
Ventricular Pacing ◽  
Class Iii ◽  
Heart Rates ◽  
Potential Map ◽  
Similar Class

1. We have compared the effect of a new drug d-sotalol which has minimal β-blocking action with the parent (β-blocking) compound dl-sotalol on monophasic action potential (MAP) duration in open-chested dogs. In seven experiments d-sotalol was administered in intravenous bolus doses of 1.5, 3 and 6 mg/kg given at 10 min intervals. In a further seven experiments dl-sotalol was administered using the same dosage regimen. 2. The animals were anaesthetized with chloralose and urethane. Atrioventricular block was created by injection of the bundle of His with 0.1 ml of 40% formalin in order to ensure capture by ventricular pacing. After prior β-blockade with propranolol (0.25 mg/kg), simultaneous epicardial and endocardial MAP were recorded at paced heart rates of 100 and 150 beats/min after each bolus injection. d-Sotalol and dl-sotalol showed similar prolongation of MAP duration (measured at 90% repolarization) in both endocardial and epicardial recording at both paced heart rates. 3. These results show that the dextro-isomer of sotalol possesses similar class III action to the parent compound and that this action is homogeneous with respect to left ventricular endocardium and epicardium at heart rates of 100 beats/min and 150 beats/min over a wide dose range. d-Sotalol may be a useful anti-arrhythmic agent in man.

Isoproterenol antagonizes drug-induced prolongation of action potential duration in humans

1993 ◽  
Vol 71 (10-11) ◽  
pp. 755-760 ◽  
Author(s):  
David Newman ◽  
Paul Dorian ◽  
Randi Feder-Elituv
Keyword(s):  
Steady State ◽  
Action Potential ◽  
Action Potential Duration ◽  
Refractory Period ◽  
Cycle Length ◽  
Monophasic Action Potential ◽  
Class Iii ◽  
State Action ◽  
Cycle Lengths ◽  
Prolongation Of Action Potential

The effects of an isoproterenol infusion on the duration of the human right ventricular endocardial monophasic action potential at 90% repolarization were recorded in the absence and in the presence of an antiarrhythmic drag regimen containing class III effects in two similar groups of patients. The drugs used were amiodarone (N = 3, 300 ± 50 mg), sotalol plus quinidine (N = 11, 156 ± 13 mg sotalol, 1688 ± 594 mg quinidine), and sotalol alone (N = 3, 300 ± 20 mg). All patients had underlying coronary disease but no evidence of inducible ischemia. In the absence of antiarrhythmic drug, isoproterenol did not significantly change the relationship of action potential duration at 90% repolarization to cycle length; there was a linear decrease in action potential duration by 19.8% between a paced cycle length of 600 and 300 ms. Isoproterenol did not significantly shorten the action potential duration at any cycle length. However, isoproterenol decreased the ventricular effective refractory period at 400 ms drive from 240 ± 5.0 to 225 ± 6.0 ms (p < 0.05) accompanied by no change in the ratio of refractory period to steady-state action potential duration. In the presence of class III drug effects, the action potential duration was increased by an average of 9.2% at all paced cycle lengths longer than 300 ms (p < 0.05). The ventricular refractory period was increased from 240 ± 5 to 269 ± 9.0 ms (p < 0.05 compared with baseline) with a concomitant increase in the ratio of refractory period to action potential duration from 96 ± 2 to 103 ± 2% (p < 0.05 compared with baseline). With infusion of isoproterenol in the presence of a class III containing regimen, the drug-prolonged action potential duration was shortened (p < 0.05) by an average of 8.1% at all cycle lengths longer than 300 ms. These results suggest that isoproterenol simulation of enhanced sympathetic tone can antagonize drug prolongation of action potential duration and that in the absence of drugs, the effects of isoproterenol on the steady-state action potential duration are modest. The clinical utility of class III agents may be augmented by the addition of concomitant β-blockade.Key words: action potential duration, antiarrhythmic drugs, isoproterenol.

Emerging Cardiac Resynchronisation Therapy Indications

2011 ◽  
Vol 7 (1) ◽  
pp. 29
Author(s):  
Charlotte Eitel ◽  
Gerhard Hindricks ◽  
Christopher Piorkowski ◽  
◽  
◽  
...  
Keyword(s):  
Heart Failure ◽  
Systolic Heart Failure ◽  
Cardiac Resynchronisation Therapy ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Current Evidence ◽  
Class Iii ◽  
Ventricular Ejection Fraction ◽  
Cardiac Resynchronisation ◽  
Resynchronisation Therapy

Cardiac resynchronisation therapy (CRT) is an efficacious and cost-effective therapy in patients with highly symptomatic systolic heart failure and delayed ventricular conduction. Current guidelines recommend CRT as a class I indication for patients with sinus rhythm, New York Heart Association (NYHA) functional class III or ambulatory class IV, a QRS duration ≥120ms, and left ventricular ejection fraction (LVEF) ≤35%, despite optimal pharmacological therapy. Recent trials resulted in an extension of current recommendations to patients with mild heart failure, patients with atrial fibrillation, and patients with an indication for permanent right ventricular pacing with the aim of morbidity reduction. The effectiveness of CRT in patients with narrow QRS, patients with end-stage heart failure and cardiogenic shock, and patients with an LVEF >35% still needs to be proved. This article reviews current evidence and clinical applications of CRT in heart failure and provides an outlook on future developments.

scholarly journals P-162 Transesophageal left ventricular pacing with different pacing mode in heart failure patients with NYHA class III

EP Europace ◽  
2003 ◽  
Vol 4 (Supplement_2) ◽  
pp. B105-B105
Author(s):  
M. Heinke ◽  
H. Kuhnert ◽  
R. Surber ◽  
G. Dannberg ◽  
H.R. Figulla ◽  
...  
Keyword(s):  
Heart Failure ◽  
Nyha Class ◽  
Left Ventricular ◽  
Ventricular Pacing ◽  
Class Iii ◽  
Heart Failure Patients ◽  
Pacing Mode ◽  
Left Ventricular Pacing
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