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PubMed1984

Sotalol, hypokalaemia, syncope, and torsade de pointes.

Thirteen patients developed syncope and a prolonged QTc interval while taking therapeutic doses of sotalol. Polymorphous ventricular tachycardia was observed in 12 patients, and criteria typical of torsade de pointes were present in 10. In 12 patients sotalol had been given with hydrochlorothiazide in a combined preparation, Sotazide, but with inadequate or no potassium supplementation. Serum potassium concentrations were reduced in eight patients. Four patients were taking other drugs known to prolong the QT interval, including disopyramide (three patients) and tricyclic antidepressants (two patients). The QT interval returned to normal in all patients after withdrawal of the drugs and correction of the hypokalaemia. Thus even in low dosage sotalol may be hazardous in the presence of hypokalaemia or when combined with drugs that also prolong the QT interval. The use of sotalol concurrently with potassium losing diuretics, such as the combined preparation Sotazide, may expose the patient to unnecessary risk and should be avoided unless the class III antiarrhythmic action of this unique beta adrenoreceptor blocking agent is also required.

Adult↗
PubMed1998

Bifid T waves induced by isoprenaline in a patient with Brugada syndrome.

A 41 year old man with incomplete right bundle branch block and persistent coved-type ST elevation in the right precordial leads during sinus rhythm had an episode of syncope while driving. He had never had syncope before and there was no family history of sudden cardiac death. Ventricular fibrillation was induced during electrophysiological study (EPS) by double extrastimuli applied to the right ventricle. Disopyramide was effective in preventing ventricular fibrillation during EPS. beta Adrenoceptor stimulation manifested bifid T waves and reduced ST segment elevation in right precordial leads. Simultaneously recorded monophasic action potential (MAP) duration at 90% repolarisation did not change in the right ventricular outflow tract, while it shortened in the left ventricular septum. These findings suggest that right precordial bifid T waves might result from relatively early repolarisation of the left ventricles. Moreover the gradient of action potential duration might explain the mechanism of ST segment abnormalities in a patient with Brugada syndrome.

Action Potentials↗
PubMed1998

Radiofrequency ablation of a fascicular tachycardia after orthotopic cardiac transplantation.

A 51 year old male received an orthotopic transplant because of end stage ischaemic heart disease. The donor was a healthy male teenager with no history of arrhythmias or other cardiac conditions. The patient presented with haemodynamically stable tachycardia and dyspnoea five weeks post-transplant. The ECG showed a regular tachycardia of 140 beats/min with a right bundle branch block morphology, left axis deviation, and a QRS duration of 135 ms. There were independent P waves, capture, and fusion beats confirming the diagnosis of ventricular tachycardia. Endomyocardial biopsy showed moderate focal rejection that was thought to be responsible for the arrhythmia. During the following six months the patient had recurrent tachyarrhythmias; on each occasion the ECG morphology was the same and there was no cellular rejection. The patient continued to have frequent hospital admissions with ventricular tachycardia requiring DC cardioversion despite the empirical use of amiodarone, sotalol, disopyramide, and procainamide. Eighteen months after transplantation the diagnosis of fascicular tachycardia was suspected by ECG morphology and supported by successful termination with intravenous verapamil. The arrhythmia was successfully managed by radiofrequency ablation. This patient shows that arrhythmias following transplantation are not always related to rejection, and that other potentially reversible causes should be considered, particularly when the ECG during arrhythmia conforms to a classic configuration.

Catheter Ablation↗
PubMed1987

Amiodarone-induced pulmonary toxicity mimicking metastatic lung disease.

A 65 year old man developed atrial arrhythmias secondary to a congestive cardiomyopathy which were resistant to quinidine and disopyramide. Amiodarone controlled the paroxysmal atrial tachycardia but 4 months after starting the drug he developed increasing dyspnoea and radiological changes highly suggestive of metastatic lung disease. Lung biopsy showed change of drug-induced pneumonitis and 4 months after stopping amiodarone his symptoms resolved and the chest X-ray had cleared. Amiodarone may cause pulmonary toxicity mimicking metastatic lung disease.

Aged↗
PubMed1994

Regulation of cholecystokinin secretion by ATP-sensitive potassium channels.

The relationship of potassium channel activity to the secretion of cholecystokinin (CCK) was evaluated in STC-1 cells, an intestinal CCK-secreting cell line. Patch-clamp and 86Rb efflux studies showed that an ATP-sensitive potassium channel was endogenously expressed in STC-1 cells. Furthermore, channels are present in sufficient number to significantly modulate whole cell potassium permeability after either channel activation or closure with diazoxide (100 microM) or disopyramide (200 microM), respectively. Inhibition of channel activity with glucose (5-20 mM) was found to depolarize the plasma membrane, increase cytosolic calcium levels, and stimulate CCK release. Glucose-mediated release of CCK, as well as the increase in cytosolic calcium, was inhibited by the calcium channel blocker diltiazem (10 microM). It is concluded that intestinal secretion of CCK may be tonically controlled by activity of basally active ATP-sensitive potassium channels, and after inhibition of channel activity, calcium-dependent CCK secretion is stimulated.

Adenosine Triphosphate↗
PubMed1999

Relation between activation sequence fluctuation and arrhythmogenicity in sodium-channel blockades.

To examine the correlation between activation sequence fluctuation and arrhythmogenicity, we investigated temporal changes in the activation sequence by measuring activation times [negative first derivative of voltage over time (-dV/dt) in QRS] from the entire heart in 18 dogs. The heart was paced by constant atrial stimulation. The character of the activation sequence fluctuation was established by a principal component analysis, in which the first principal component was defined as a stable component of the sequence and the second or third component as a fluctuated component. Steady state contained 2.2 +/- 0.6% (percent total principal component, mean +/- SD) of fluctuated components, which appeared in a beat-by-beat manner (activation sequence alternans). Activation sequence alternans was observed only during flecainide administration and not during lidocaine or disopyramide administration. Fluctuated components at a high dose of flecainide significantly increased (3.3 +/- 0.8%). Ventricular fibrillation ensued in all dogs (n = 6) exposed to flecainide after an increase in activation sequence alternans. In conclusion, flecainide evoked local activation sequence alternans. This phenomenon correlated with the occurrence of ventricular fibrillation.

Animals↗
PubMed1999

Pharmacotherapy of neurally mediated syncope.

A wide variety of pharmacological agents are currently used for prevention of recurrent neurally mediated syncope, especially the vasovagal faint. None, however, have unequivocally proven long-term effectiveness based on adequate randomized clinical trials. At the present time, beta-adrenergic receptor blockade, along with agents that increase central volume (eg, fludrocortisone, electrolyte-containing beverages), appear to be favored treatment options. The antiarrhythmic agent disopyramide and various serotonin reuptake blockers have also been reported to be beneficial. Finally, vasoconstrictor agents such as midodrine offer promise and remain the subject of clinical study. Ultimately, though, detailed study of the pathophysiology of these syncopal disorders and more aggressive pursuit of carefully designed placebo-controlled treatment studies are essential if pharmacological prevention of recurrent neurally mediated syncope is to be placed on a firm foundation.

Adrenergic beta-Antagonists↗
PubMed1999

Amiodarone protects cardiac myocytes against oxidative injury by its free radical scavenging action.

BACKGROUND: Oxidative stress plays an important role in the pathophysiology of ischemic heart disease and heart failure, and antioxidants might be beneficial in the treatment of these patients. This study was performed to determine the scavenging effects of amiodarone on oxygen free radicals and its protective effects against oxygen radical-mediated injury in cardiac myocytes. METHODS AND RESULTS: The formation of the radical spin adduct with hydroxy radical (.OH) in the presence of H(2)O(2) (10 mmol/L) and Fe(3+)-nitrilotriacetate (20 micromol/L) was monitored by electron paramagnetic resonance spectroscopy combined with a spin trapping agent, 5,5-dimethyl pyrroline-N-oxide (DMPO). Amiodarone decreased the intensity of the DMPO-OH signals in a dose-dependent manner (0.1 to 100 micromol/L), whereas other antiarrhythmia drugs such as disopyramide and atenolol had no such effects. Furthermore, amiodarone (10 micromol/L) protected intact adult canine cardiac myocytes against.OH-mediated myocyte injury, as assessed by the degree of morphological change from rod shape to the irreversible hypercontracture state during the exposure of cells to H(2)O(2) and Fe(3+) in vitro. CONCLUSIONS: Amiodarone can protect cardiac myocytes against oxidative stress-mediated injury by directly scavenging oxygen free radicals. Antioxidant action of amiodarone might potentially contribute to the beneficial effects of this drug in the treatment of patients with ischemic heart disease and congestive heart failure.

Amiodarone↗
PubMed1982

Aggravation and provocation of ventricular arrhythmias by antiarrhythmic drugs.

Antiarrhythmic drugs may aggravate or even induce ventricular arrhythmias. This type of adverse reaction is becoming more prevalent as the use of antiarrhythmic agents becomes more widespread. In a retrospective analysis of antiarrhythmic drug action, a worsening of arrhythmia was observed in 80 of 722 (11.1%) antiarrhythmic drug tests in 53 of 155 patients being treated for ventricular tachyarrhythmias. Aggravation of arrhythmias was defined by occurrence of a fourfold increase in the frequency of ventricular premature complexes, a 10-fold increase in repetitive forms, or the first emergence of sustained ventricular tachycardia coincident with time course of action of the particular drug under study. Such aggravation was noted with each of nine drugs tested: quinidine, procainamide, disopyramide, propranolol, metoprolol, aprindine, mexiletine, tocainide and pindolol. The frequency of this complication for a specific drug ranged from 5.9-15.8%. Blood drug concentrations were consistently in the therapeutic range. A study of the variability of ventricular arrhythmia during 48-hour Holter monitoring and exercise stress testing in no instance showed arrhythmia enhancement commensurate with that defining aggravation. Our data suggest that this potentially serious complication is not readily predictable and requires a systematic approach to antiarrhythmic drug testing before a patient is prescribed a long-range maintenance program.

Adolescent↗
PubMed1992

Hypolipidemic effect of type Ia antiarrhythmic agents in postinfarction patients.

BACKGROUND: Elevated levels of cholesterol and apoprotein B (apo B), the essential carrier protein for low density lipoprotein, are major lipid risk factors for premature coronary disease. Antiarrhythmic agents are frequently prescribed to patients with coronary heart disease and associated cardiac arrhythmias. As part of another study, we retrospectively investigated the effect of antiarrhythmic agents on blood lipids. METHODS AND RESULTS: The study population consisted of 1,567 postinfarction patients on whom we prospectively collected serial blood samples for lipid and apoprotein determinations and recorded the concomitant medications the patients were receiving at three follow-up time periods. The lipids, analyzed at a central core laboratory, included total cholesterol, triglycerides, high density lipoprotein cholesterol (HDL C), and apoproteins A-I (apo A-I), A-II (apo A-II), and apo B. The difference in the group mean lipid values for patients receiving and not receiving type Ia antiarrhythmic agents (quinidine, procainamide, and disopyramide) was evaluated by the two-sample t test, and multiple linear regression analyses were performed to adjust for relevant covariates. Patients using type Ia antiarrhythmic agents at the 30-month postinfarction contact (n = 76) had 8.6% lower cholesterol (p less than 0.003), 22.3% lower triglycerides (p less than 0.0002), 6.2% lower apo A-I (p = 0.02), 10.1% lower apo A-II (p less than 0.001), and 12.7% lower apo B (p less than 0.0001) levels than patients not on these medications (n = 1,491). These lower lipid levels were found after adjustment for age, sex, diabetes, smoking status, concomitant medications, and a variety of clinical factors relating to the severity of the coronary disease process. The HDL C levels were similar in those receiving and not receiving type Ia agents. CONCLUSIONS: Patients on type Ia antiarrhythmic agents had significantly and meaningfully lower cholesterol, triglyceride, apo A-II, and apo B levels than patients not receiving these agents. The mechanism of this hypolipidemic effect is undefined, but the mechanism may be related to an alteration by these agents of ionic membrane currents at the hepatocyte level.

Anti-Arrhythmia Agents↗
PubMed1995

ATP-sensitive K+ channels mediate alpha 2D-adrenergic receptor contraction of arteriolar smooth muscle and reversal of contraction by hypoxia.

Evidence in rat skeletal muscle suggests that local metabolic control of blood flow is facilitated by the reliance on alpha 2D-adrenergic receptors (ARs) for constriction of arterioles, together with the strong sensitivity of this constriction to inhibition by hypoxia. The present study examined the role of ATP-sensitive K+ (KATP) channels in the selective interaction between alpha 2D-ARs and hypoxia. Arterioles from rat cremaster muscle that possess both alpha 1D (alpha 1A/D)- and alpha 2D-AR subtypes were microcannulated, pressurized, and isolated in a tissue bath for measurement of changes in lumen diameter. Three studies first examined whether stimulation of alpha 2D- and alpha 1D-ARs involves inhibition of the KATP channel. Concentration-dependent constriction by the KATP antagonists glibenclamide (GLB, 0.01 to 10 mumol/L) and disopyramide (0.001 to 1 mmol/L) were abolished during alpha 2D stimulation but unaffected during alpha 1D stimulation. Activation of the KATP channel by cromakalim inhibited alpha 2D constriction with greater potency than alpha 1D (EC50, 7.0 +/- 0.2 versus 6.3 +/- 0.1). Finally, GLB (0.5 mumol/L) abolished dose-dependent alpha 2D constriction, whereas alpha 1D was unaffected. These data suggest that alpha 2D but not alpha 1D stimulation is "coupled" with closure of the KATP channel, leading to depolarization and contraction of vascular smooth muscle. In a second series, hypoxic (PO2, 6 mm Hg) inhibition of intrinsic smooth muscle tone was completely reversed by 0.1 mumol/L GLB, concentration-dependent GLB constriction was enhanced during hypoxia, and hypoxia reversed GLB constriction. These data confirm reports by others that hypoxia potentiates the activation of KATP channels, leading to hyperpolarization and relaxation. Finally, GLB constriction, which was abolished by concomitant alpha 2D stimulation, was completely restored by simultaneous activation of KATP channels with hypoxia. These findings suggest that the sensitivity of alpha 2D-AR constriction to inhibition by hypoxia arises through "antagonistic coupling" between these two stimuli, by which the alpha 2D-AR inhibits and hypoxia activates KATP channels.

Adenosine Triphosphate↗
PubMed1995

High- and low-affinity sites for [3H]dofetilide binding to guinea pig myocytes.

Dofetilide specifically blocks the rapid component of the delayed rectifier current (IKr) at nanomolar concentrations in a saturable manner, suggesting the presence of a receptor. We characterized two [3H]dofetilide binding sites to ventricular myocytes from adult guinea pigs by using a conventional filter assay. Scatchard analysis revealed two binding sites with different affinities: a high-affinity site (Kd, 2.8 +/- 0.3 x 10(-8) mol/L; Bmax, 76 +/- 15 fmol/10(6) myocytes) and a low-affinity site (Kd, 1.64 +/- 0.4 x 10(-6) mol/L; Bmax, 1620 +/- 260 fmol/10(6) myocytes) (n = 11). Kinetic studies showed that there were two dissociation rate constants for [3H]dofetilide (0.02 +/- 0.005 min-1 [high-affinity site] and 0.22 +/- 0.064 min-1 [low-affinity site], n = 4), although the observed association rate constant is equally well fit to a single- or two-site model. The ability of known IKr blockers to compete with [3H]dofetilide binding to both sites was assessed. E4031, clofilium, quinidine, and sotalol competed for binding at both sites. Disopyramide and NAPA only competed for a single binding site. The mean IC50 values for inhibition of binding to both the high- and low-affinity binding sites correlated with their concentrations required to inhibit IKr in electrophysiological studies. However, inhibition of [3H]dofetilide binding to the high-affinity site by class III antiarrhythmic drugs occurred at pharmacological concentrations, whereas suprapharmacological concentrations were required to inhibit binding to the low-affinity site.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Hemodynamic effects of continuous negative chest pressure ventilation in heart failure.

We have previously shown improved cardiac output (QT) with external continuous negative-pressure ventilation (CNPV) compared with continuous positive-pressure ventilation (CPPV) in dogs with low pressure pulmonary edema (1). The current study was done to determine if this effect was reversed in high pressure pulmonary edema. Seven supine, anesthetized dogs were fluid-loaded and treated with disopyramide (3.5 to 7.0 mg/kg) and propranolol (0.25 to 1.5 mg/kg). This produced a mean pulmonary wedge pressure (Ppaw) of 21.0 mm Hg on intermittent positive-pressure ventilation (IPPV). CPPV and CNPV were then alternated at 30-min intervals. Ventilators were matched for oxygen concentration, frequency, tidal volume (VT), and the increment in FRC (delta FRC) produced by a given positive (PEEP) or negative (NEEP) end-expiratory pressure. During 20 cm H2O of PEEP, QT values were significantly depressed from IPPV control values (2.13 +/- 0.2 versus 1.27 +/- 0.2 L/min, p less than 0.05) but not during CNPV with equivalent NEEP (1.66 +/- 0.2 L/min). Although arterial oxygen saturations were similar, mixed venous oxygen saturations were depressed by CPPV with PEEP of 15 and 20 cm H2O (67.9 +/- 3.8% during IPPV versus 54.1 +/- 4.9 and 51.9 +/- 5.8%, respectively, p less than 0.05 in both instances) but not during equivalent CNPV (59.9 +/- 4.3 and 58.7 +/- 4.5%). Despite potentially increased left ventricular afterload, external negative chest wall ventilation with NEEP does not appear to significantly depress QT compared with CPPV even when Ppaw is high and myocardial contractility is impaired.

Animals↗
PubMed1992

Head-upright tilt-table testing: a useful tool in the evaluation and management of recurrent vertigo of unknown origin associated with near-syncope or syncope.

Recurrent idiopathic vertigo associated with near-syncope and syncope is a common perplexing problem, some cases of which are considered autonomically mediated (vasovagal). Upright-tilt-table testing has emerged as a potential method to test for vasovagal episodes. This study evaluated the use of this technique in the evaluation and management of patients with recurrent idiopathic vertigo associated with near-syncope or syncope. Twenty-one patients with recurrent unexplained vertigo and syncope/near-syncope and 11 control subjects were evaluated by use of an upright-tilt-table test for 30 minutes, with or without a graded isoproterenol infusion (1 to 4 micrograms/min given intravenously), in an attempt to provoke hypotension, bradycardia, or both, which reproduced the patient's symptoms. The patients included 10 men and 11 women (mean age, 51 +/- 16 years). Eleven controls with no history of vertigo were also studied. Transcranial Doppler sonography was used to assess cerebral arteriolar blood flow during tilt. All tilt-positive patients were placed on therapy with either beta-blockers, disopyramide, or transdermal scopolamine, the effectiveness of which was determined with another tilt-table study. Symptoms occurred in seven patients (33%) during the baseline tilt and in eight patients (38%) during isoproterenol infusion (total positives, 71%). Transcranial Doppler sonography demonstrated a 225% +/- 192% increase in pulsatility index and a 70% +/- 29% increase in resistance index (indicative of cerebral arteriolar vasoconstriction) at the time of vertigo. No control subject experienced syncope during this test. Each tilt-positive patient eventually became tilt-negative with therapy, and over a mean follow-up period of 26 months, no further episodes have occurred.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMedDate not supplied

Uncharacteristic cutaneous reactions induced by quinidine.

Two patients who presented with unusual cutaneous reactions attributed to quinidine are described. One had a diffuse nonpruritic macular rash, and the other had a localized pruritus without cutaneous manifestations. Both resolved upon dechallenge with quinidine. Disopyramide phosphate was substituted for quinidine in both cases, without subsequent problems.

Drug Eruptions↗
PubMed1985

Flecainide: a new class Ic antidysrhythmic.

Flecainide acetate is a new orally active antidysrhythmic agent classified in the Ic category. Flecainide is effective in suppressing 88 to 100 percent of abnormal cardiac rhythms in the form of complex ventricular dysrhythmias, including couplets, ventricular tachycardia, reentrant junctional tachycardia, and Wolff-Parkinson-White syndrome. Flecainide appears to have a greater effect on conduction than on repolarization and only minimal effects on hemodynamic parameters. Flecainide is rapidly and completely absorbed after oral administration and has a 13-hour elimination half-life, allowing for twice-daily dosing regimens. Flecainide is generally well tolerated, with dizziness, blurred vision, nausea, and headache the most common side effects. Flecainide has been shown to be superior to quinidine and disopyramide in suppressing ventricular ectopic activity and may be considered a first-line oral agent for this indication. It is believe that flecainide has enough therapeutic advantages to be added to drug formularies.

Action Potentials↗
PubMedDate not supplied

Moricizine: a novel antiarrhythmic agent.

Moricizine is a phenothiazine derivative with Vaughan Williams class 1 antiarrhythmic properties. It undergoes extensive first-pass metabolism, has a bioavailability of 34-38 percent, and is 95 percent bound to plasma proteins. Moricizine is extensively metabolized and may have pharmacologically active metabolites. A recent clinical study has shown that moricizine is slightly less effective than encainide or flecainide in suppressing ventricular premature depolarizations. Compared with disopyramide and quinidine, moricizine was equally or more effective in suppressing ventricular premature depolarizations, couplets, and nonsustained ventricular tachycardia. Further studies are needed comparing moricizine with other class 1 agents in the treatment of life-threatening arrhythmias; available data suggest that moricizine is comparable with these agents in the treatment of ventricular tachycardias and fibrillation. Moricizine appears to have a low incidence of serious adverse effects compared with other antiarrhythmics. This combination of apparently similar efficacy with a decreased incidence of adverse effects makes moricizine a worthwhile addition to currently available antiarrhythmic agents.

Anti-Arrhythmia Agents↗
PubMed1996

Syncope: pathophysiology, diagnosis, and pharmacotherapy.

OBJECTIVE: To review the pathophysiology, diagnosis, and pharmacotherapy of syncope, with emphasis placed on neurocardiogenic syncope. DATA SOURCES: A MEDLINE search (1980-1995) using the term syncope and cross-referencing selected articles. STUDY SELECTION: Articles selected were those considered to assist in providing the reader with a basic introduction the pathophysiology, diagnosis, and pharmacotherapy of syncope, with emphasis placed on neurocardiogenic syncope. DATA SYNTHESIS: Syncope is a common disorder with many different etiologies. The patient's history and physical examination are extremely important in making the diagnosis. The recent availability of head-upright tilt testing and electrophysiologic studies of the myocardium have helped define the etiology in many patients in whom an etiology would not have been found in the past. When the cause of syncope has been diagnosed, the appropriate therapy to prevent future attacks will be defined in many instances. One form of syncope, known as neurocardiogenic syncope, can be difficult to treat. Recent trials have suggests the use of beta-blockers, fludrocortisone, disopyramide, or selective serotonin reuptake inhibitors may be helpful in some patients.

Adrenergic beta-Antagonists↗