Antiarrhythmic drug effects on premature beats are partly determined by prior cardiac activation frequency in perfused guinea-pig heart.

NEW FINDINGS: What is the central question of this study? Can antiarrhythmic drug effects on repolarization, conduction time and excitation wavelength in premature beats be determined by prior cardiac activation frequency? What is the main finding and its importance? In premature beats induced after a series of cardiac activations at a slow rate, antiarrhythmics prolong repolarization but evoke little or no conduction delay, thus increasing the excitation wavelength, which indicates an antiarrhythmic effect. Fast prior activation rate attenuates prolongation of repolarization, while amplifying the conduction delay induced by drugs, which translates into the reduced excitation wavelength, indicating proarrhythmia. These findings suggest that a sudden increase in heart rate can shape adverse pharmacological profiles in patients with ventricular ectopy. ABSTRACT: Antiarrhythmic drugs used to treat atrial fibrillation can occasionally induce ventricular tachyarrhythmia, which is typically precipitated by a premature ectopic beat through a mechanism related, in part, to the shortening of the excitation wavelength (EW). The arrhythmia is likely to occur when a drug induces a reduction, rather than an increase, in the EW of ectopic beats. In this study, I examined whether the arrhythmic drug profile is shaped by the increased cardiac activation rate before ectopic excitation. Ventricular monophasic action potential durations, conduction times and EW values were assessed during programmed stimulations applied at long (S1 -S1 [basic drive cycle length] = 550 ms) and short (S1 -S1  = 200 ms) cycle lengths in perfused guinea-pig hearts. The premature activations were induced with extrastimulus application immediately upon termination of the refractory period. With dofetilide, a class III antiarrhythmic agent, a prolongation in action potential duration and the resulting increase in the EW obtained at S1 -S1  = 550 ms were significantly attenuated at S1 -S1  = 200 ms, in both the regular (S1 ) and the premature (S2 ) beats. With class I antiarrhythmic agents (quinidine, procainamide and flecainide), fast S1 -S1 pacing was found to attenuate the drug-induced increase in action potential duration, while amplifying drug-induced conduction slowing, in both S1 and S2 beats. As a result, although the EW was increased (quinidine and procainamide) or not changed (flecainide) at the long S1 -S1 intervals, it was invariably reduced by these agents at the short S1 -S1 intervals. These findings indicate that the increased heart rate before ectopic activation shapes the arrhythmic profiles by facilitating drug-induced EW reduction.

Bigeminismo ventricular en relación con fluoxetina / Ventricular bigeminy in relation to fluoxetine

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Antiarrhythmic and antioxidant activity of novel pyrrolidin-2-one derivatives with adrenolytic properties.

A series of novel pyrrolidin-2-one derivatives (17 compounds) with adrenolytic properties was evaluated for antiarrhythmic, electrocardiographic and antioxidant activity. Some of them displayed antiarrhythmic activity in barium chloride-induced arrhythmia and in the rat coronary artery ligation-reperfusion model, and slightly decreased the heart rate, prolonged P-Q, Q-T intervals and QRS complex. Among them, compound EP-40 (1-[2-hydroxy-3-[4-[(2-hydroxyphenyl)piperazin-1-yl]propyl]pyrrolidin-2-one showed excellent antiarrhythmic activity. This compound had significantly antioxidant effect, too. The present results suggest that the antiarrhythmic effect of compound EP-40 is related to their adrenolytic and antioxidant properties. A biological activity prediction using the PASS software shows that compound EP-35 and EP-40 can be characterized by antiischemic activity; whereas, compound EP-68, EP-70, EP-71 could be good tachycardia agents.

[Urinary bladder tuberculosis and Bacillus Calmette-Guérin instillation: reduced efficacy of bisoprolol in hypertension]. / Tuberkulose durch Bacillus-Calmette-Guérin-Instillation bei Blasenkarzinom und Hypertonie: Verminderte Bisoprolol-Wirkung durch Rifampicin.

HISTORY AND ADMISSION FINDINGS: A 71-year-old patient with a superficial carcinoma of the urinary bladder and high risk of recurrence was treated with intravesical instillation of Bacillus Calmette-Guérin (BCG) after transurethral resection. As a complication of the catheterization during BCG-instillation therapy the patient suffered from tuberculosis. The patient received a tuberculosis triple-therapy including rifampicin 600 mg once daily, isoniazid 300 mg once daily and ethambutol 400 mg thrice daily. The existing arterial hypertension had successfully been controlled by 3.75 mg bisoprolol medication once daily for the last 15 years. An increase of blood pressure and cardiac arrhythmia were seen after combining the ß1-receptor blocker treatment with the triple-therapy. INVESTIGATIONS AND DIAGNOSIS: The blood pressure was 160/90 mm Hg. The heart rate reflected a value of 98 beats per minute. In the resting ECG monotopic ventricular extrasystoles could be diagnosed. TREATMENT AND COURSE: The dosage of bisoprolol was changed to 3.75 mg in the morning and additional 1.875 mg in the evening. Due to this increase of dosage the blood pressure could be controlled sufficiently. CONCLUSION: Rifampicin is one of the best known potent enzyme inducing drugs. It strongly induces the expression of cytochrome P450 3A4 in the liver. The enzyme induction enhance the hepatic bisoprolol metabolism, hence the metabolic clearance of the drug increased. The maximal plasma level of bisoprolol decrease and in our use the arterial hypertension could not be treated sufficiently. It is well known that half the dose of bisoprolol undergoes oxidative metabolism in the liver and the rest eliminated unchanged in the kidney. A dosage adjustment of bisoprolol is necessary if the clinical status of the patient requires treatment with the antituberculosis drug rifampicin.

Cardiotoxicity after massive amantadine overdose.

INTRODUCTION: Amantadine hydrochloride is an antiviral medication used as therapy for parkinsonism and as a cognitive enhancer. We report 2 cases of massive, acute ingestion of amantadine hydrochloride confirmed with serial serum levels. CASE REPORTS: A 47-year-old woman presented to the emergency department (ED) 30 minutes after ingesting 10 g of amantadine (150 mg/kg) by her report. Initial ECG revealed a sinus rhythm with rate of 93 bpm, and a QRS of 84 msec. While in the ED, the patient sustained a pulseless cardiac arrest and the monitor revealed ventricular tachycardia. She was successfully defibrillated. Postdefibrillation ECG showed a sinus rhythm (rate = 82 bpm), QRS of 236 msec, and QTc of 567 msec. The serum potassium was 1.0 mEq/L (1.0 mmol/L). The patient was given 300 ml (300 cc) 3% sodium chloride IV over 10 minutes. Ten minutes after completion of the hypertonic saline infusion, the patient's ECG abnormalities resolved and the QRS was 88 msec. Her potassium was repleted over the next 11 hours postpresentation, and she also received an IV bolus of 4 g of magnesium sulfate immediately after the cardiac arrest. No further hypotension, dysrhythmia, conduction delay, or ectopy was noted during the patient's hospital stay. The second case involved a 33-year-old female patient who presented 1 hour after ingesting 100 tablets of amantadine hydrochloride (100 mg/tab). Initial ECG revealed sinus tachycardia with a QRS of 113 msec, an R wave in lead aVR of 4-5 mm and a QTc of 526 msec. Her serum potassium was 3.0 mEq/L (3.0 mmol/L), her serum calcium was 9.4 mg/dl (2.35 mmol/L), and serum magnesium was 2.1 mg/dl (0.86 mmol/L) on labs drawn at initial presentation. The patient was intubated for airway protection, and her potassium was repleted and corrected over the next 9 hours. Her ECG abnormalities improved 8 hours after initial presentation and normalized at approximately 14 hours postingestion. The patient was discharged home 11 days after her ingestion. CONCLUSION: Acute amantadine toxicity manifests with life-threatening cardiotoxicity. Concurrent, often profound, hypokalemia may complicate the administration of sodium bicarbonate in the management of cardiac dysrhythmias.

5-fluorouracil increases the number and complexity of premature complexes in the heart: a prospective study using ambulatory ECG monitoring.

The cardiac toxicity of LV5FU2 (de Gramont) regimen which is a widely used chemotherapy regimen in gastrointestinal system cancers is not well defined. We aimed to evaluate the impact of this regimen on cardiac rhythm. Two Holter ECG recordings were obtained in all patients with gastrointestinal system cancers treated with LV5FU2 regimen as first-line chemotherapy (one before and the second during the first 24 h of chemotherapy). Records were reviewed for the heart rate, rhythm, atrial premature complexes (APC), ventricular premature complexes (VPC), grades according to Lown-Wolf grading system and ST segment changes. Holter ECG recordings were evaluated in 27 patients. In the baseline evaluation, neither clinical symptom nor ST segment changes were observed. During the treatment period, chest pain was observed in two patients without any cardiac enzyme and ST segment changes. Moreover, a decrease in mean heart rate, and an increase in the number and complexity of premature complexes secondary to treatment were observed. The mean heart rate, APC per hour and VPC per hour (+/-SD) before vs. during treatment were, respectively, 93.1+/-16.4 vs. 81.6+/-12.7 (p=0.001), 18.9+/-54.0 vs. 45.3+/-53.8 vs. (p=0.049) and 12.7+/-29.6 vs. 38.1+/-42.1 (p=0.002). LV5FU2 regimen leads to a decrease in mean heart rate and a significant increase in APC and VPC which may lead to serious arrhythmias. These effects must be better understood for a safer administration of this useful and widely used drug regimen.

Early and late arrhythmogenic effects of doxorubicin.

BACKGROUND: To determine the incidence of early and late arrhythmogenic effects of doxorubicin-containing chemotherapy regimens. PATIENTS AND METHODS: A prospective study including 29 patients who were treated with doxorubicin-containing regimens. Cardiac evaluation was based on 24-hour electrocardiographic monitorization (Holter), which was performed during the first cycle of doxorubicin-containing regimens, as well as after the last cycle of chemotherapy. RESULTS: The mean age of the patients was 45.8 +/- 15.1 (range 18-69). Holter records obtained during the first cycle of treatment revealed varying arrhythmias in 19 patients (65.5%) and in 18 (62.1%) patients after completion of therapy. One patient presented with syncope and both Mobitz Type 2 atrioventricular block and complete atrioventricular block were demonstrated. The patient subsequently underwent permanent pacemaker implantation. CONCLUSIONS: Doxorubicin may result in arrhythmias both in early and late periods of treatment. These arrhythmias are rarely life threatening.

Assessment of the proarrhythmic potential of the novel antiarrhythmic agent AZD7009 and dofetilide in experimental models of torsades de pointes.

BACKGROUND: This study examined the proarrhythmic potential of the novel antiarrhythmic agent AZD7009 and dofetilide. METHODS AND RESULTS: The electrophysiological and proarrhythmic effects of AZD7009 and dofetilide were assessed in the arterially perfused canine and rabbit left ventricular wedge preparation. The proarrhythmic potential of AZD7009, dofetilide, and azimilide was further assessed in the methoxamine-sensitized rabbit model of torsades de pointes (TdP) in vivo. AZD7009 lengthened the action potential duration (APD) and the QT interval in a bell-shaped manner (15.9 +/- 1.3% in canine wedge and 46.1 +/- 2.9% in rabbit wedge) occurring at 3 and 1 microM. In contrast, dofetilide did not show the bell-shaped concentration response and the QT interval was lengthened more extensively (27.7 +/- 1.6% and 100.8 +/- 10.0%). Furthermore, whereas dofetilide prolonged the midmyocardial and endocardial APD predominantly, resulting in an increased transmural dispersion of repolarization (TDR), AZD7009 prolonged the APD more homogenously in all cell layers. At 1 microM, AZD7009 produced phase 2 early afterdepolarizations (EADs) in 1/4 rabbit preparations but without ventricular R-on-T extrasystoles or TdP. In contrast, starting at 0.03 microM, dofetilide-induced EADs, R-on-T extrasystoles and TdP in 6/6, 5/6, and 4/6 preparations. Following intravenous infusion of AZD7009 (210 nmol/kg/minute), dofetilide (2 nmol/kg/minute) or azimilide (3.33 micromol/kg/minute), TdP was induced in 0/8, 5/8, and 5/8 rabbits (P = 0.026 vs AZD7009), respectively. In 5/5 rabbits, AZD7009 promptly suppressed TdP induced by dofetilide. CONCLUSIONS: In animal models of TdP, AZD7009 delays ventricular repolarization in a self-limited way associated with a low risk of repolarization-related proarrhythmia.

Increased short-term variability of repolarization predicts d-sotalol-induced torsades de pointes in dogs.

BACKGROUND: Identification of patients at risk for drug-induced torsades de pointes arrhythmia (TdP) is difficult. Increased temporal lability of repolarization has been suggested as being valuable to predict proarrhythmia. The predictive value of different repolarization parameters, including beat-to-beat variability of repolarization (BVR), was compared in this serial investigation in dogs with chronic AV block. METHODS AND RESULTS: In anesthetized dogs with electrically remodeled hearts, the dose-dependent difference in drug-induced TdP (d-sotalol, 2 and 4 mg/kg IV over 5 minutes, 25% and 75% TdP, respectively) could not be accounted for by prolongation of QT(c) (410+/-37 to 475+/-60 versus 415+/-47 to 484+/-52 ms, respectively). BVR was quantified by Poincare plots at baseline and immediately before onset of d-sotalol-induced extrasystolic activity. TdP occurrence was associated with an increase in short-term variability (STV) of the left ventricular monophasic action potential duration (3.5+/-1.5 to 5.5+/-1.6 versus 3.0+/-0.7 to 8.6+/-3.8 ms, respectively), which was reversible when TdP was abolished by I(K,ATP) activation. The absence of TdP despite QT(c) prolongation after chronic amiodarone treatment could also be explained by an unchanged STV. In experiments with isolated ventricular myocytes, STV increased after I(Kr) block and was highest in cells that subsequently showed early afterdepolarizations. CONCLUSIONS: Proarrhythmia is not related to differences in prolongation of repolarization but corresponds to BVR, here quantified as STV of the left ventricle. STV could be a new parameter to predict drug-induced TdP in patients.

Accidental ecstasy poisoning in a toddler.

A child of 14 months accidentally swallowed a portion of an Ecstasy pill. Forty minutes after ingestion, he started a generalized convulsion. He also presented hyperthermia (38 degrees C), hypertension, tachycardia (130 bpm), ventricular extrasystoles, tachypnea (50 rpm), and mydriasis. At the hospital 5 hours later, the urine levels of amphetamine/metamphetamine were >16 mg/L. He was treated with general support measures and benzodiazepines intravenously and admitted to the pediatric intensive care unit. During the first 12 hours, he continued with hypertension, tachycardia, and long periods of trigeminy, without hemodynamic repercussion. He was discharged fully recovered. Gas chromatography/mass spectrometry analysis (8 hours after ingestion) showed a serum level of 3,4 methylenedioximethylamphetamine (MDMA) of 0.591 mg/L. The 3 cases described in the literature have shown a good evolution of Ecstasy poisoning in toddlers and infants, despite an initial critical situation. Regarding adults, the toddler intoxication seems to present symptoms sooner (20 to 30 minutes), having as an initial manifestation convulsions. However, great care must be taken on accidental ingestion of these attractive design pills.

Cardiac effects of carbon monoxide and ambient particles in a rat model of myocardial infarction.

Ambient air pollution is a complex mixture of particulate matter (PM) and gaseous pollutants such as carbon monoxide (CO). The effect of exposure to CO, alone or in combination with ambient PM, on arrhythmia incidence is unclear. To evaluate these effects, left-ventricular myocardial infarction was induced in Sprague-Dawley rats by thermocoagulation. Diazepam-sedated rats were exposed (1 h) to either filtered air (n = 40), CO (35 ppm, n = 19), concentrated air particles (CAPs, median concentration = 350.5 microg/m(3), n = 53), or CAPs and CO (CAPs median concentration = 318.2 microg/m(3), n = 23), 12-18 h after surgery. Each exposure was immediately preceded and followed by a 1 h exposure to filtered air (pre-exposure and post-exposure periods, respectively). The CO target dose of 35 ppm is related to the 1 h U.S. National Ambient Air Quality Standard. Surface electrocardiograms were recorded and heart rate and arrhythmia incidence were quantified. CO exposure reduced ventricular premature beat (VPB) frequency by 60.4% (p = 0.012) during the exposure period compared to controls. This effect was modified by both infarct type and the number of pre-exposure VPBs, and was not mediated through changes in heart rate. Overall, CAPs exposure increased VPB frequency during the exposure period, but this effect did not reach statistical significance. This effect was modified by the number of pre-exposure VPBs. Overall, neither CAPs nor CO had any effect on heart rate, but CAPs increased heart rate in specific subgroups. No significant interactions were observed between the effects of CO and CAPs. In this animal model, the responses to CO and CAPs are distinctly different.

Ambulatory electrocardiographic evaluation of the heart in patients treated by megachemotherapy and bone marrow transplantation.

The aim of the study was evaluation of the frequency of conduction defects and cardiac arrhythmias before and one month (once a week) after bone marrow transplantation (BMT). It was evaluated by 24-hour electrocardiography based on the Holter's method. There were 50 patients (mean age 29.0 years) examined who were treated with megachemotherapy based on BuCy2, BuCy4 (busulphan and cyclophosphamide), BEAM (carmustine, etoposide, cytarabine, melphalan) and dexaBEAM (dexa-dexamethason) programs before BMT. No heart conduction defects occurred. The mean heart rate increased after BMT. Tachycardia (> 100/min) was observed in 92.5-98.1% of patients and bradycardia (< 60/min) in 41.6-68.0% patients. In 6% of patients bradycardia below 40/min occurred. The heart rate was increased in patients who previously used anthracycline antibiotics, had anaemia or fever, and in patients after autologous BMT (p < 0.05). The complex ventricular extrasystoles were detected in 20% of patients before megachemotherapy. They were more frequently observed in patients with hypokalemia (p < 0.05). After therapy these extrasystoles were observed in a total of 24% patients. There was a statistically significant correlation between this kind of extrasystole and age. The extrasystoles developed mainly in young men. In 10% they occurred de novo and also mainly in men. The heart failure (III degrees, IV degrees according to NYHA) occurred in 14% of patients and death caused by heart (or multiorgan) damage in 18%. Older patients and those who had higher mean heart rate during the first month after BMT were dying more frequently (p < 0.05).

NO-ergic mechanisms are implicated in a disturbed cardiac rhythm after systemic application of lipopolysaccharide E. coli to rats.

In acute experiments on nembutal-urethan-anaesthetized rats, a slow infusion of subseptic dose of lipopolysaccharide (LPS) Escherichia coli (1 mg/ml) via the right jugular vein immediately led to bradycardia and extrasystoles. Preliminary administration of 20 mg/kg N(G)-nitro-L-arginine methyl ester (L-NAME) or 30 mg/kg aminoguanidine hydrochloride prevented the LPS-induced extrasystoles but did not affect the pattern of bradycardia. We conclude that nitric oxide (NO)-ergic mechanisms are involved in provoking electrical instability of the heart in conditions of endotoxemia.

Opening of K(ATP) channel attenuates the increase in QT dispersion produced by the first balloon inflation during coronary angioplasty.

Increased QT dispersion predicts the occurrence of lethal ventricular arrhythmias complicating percutaneous transluminal coronary angioplasty (PTCA). Moreover, these arrhythmias occur more frequently at the first balloon inflation. Activation of the K(ATP) channel may influence QT dispersion and ventricular arrhythmias during coronary angioplasty, so 40 consecutive patients with stable angina were randomized to receive 3 mg/h of nicorandil infusion or placebo and QT dispersion and the incidence of ventricular ectopy were investigated before and throughout PTCA. There were no significant differences in QT dispersion at baseline between the nicorandil group (42+/-8 ms) and placebo (42+/-12ms). At the first balloon inflation, the QT dispersion in the nicorandil group (51+/-13 ms) was significantly less than that observed with placebo (76+/-16ms, p<0.001). However, the QT dispersion at the second inflation was similar in both groups (nicorandil: 45+/-12ms; placebo: 52+/-14ms). Ventricular ectopy was observed in 1 patient receiving nicorandil and 5 patients in the placebo group during the first inflation, and none in the nicorandil and 1 patient in the placebo group during the second balloon inflation. Activation of the K(ATP) channel may inhibit the development of ventricular arrhythmias during PTCA, particularly at the first balloon inflation.

Preventive effect of rilmenidine on the occurrence of neurogenic ventricular arrhythmias in rabbits.

BACKGROUND: Centrally acting antihypertensive drugs bearing an imidazoline or a related chemical structure inhibit sympathetic nervous output to the heart and vascular beds, and enhance parasympathetic tone. Cardiac ischaemia and ventricular arrhythmias that can result from hypertension are likely to benefit from such effects. OBJECTIVE: To investigate the effects of rilmenidine, an oxazoline with antihypertensive properties, in a model of neurogenically induced ischaemic ventricular arrhythmias. METHODS AND RESULTS: Bicuculline, a alpha-aminobutyric acid (GABA(A)) receptor antagonist, was administered intracisternally in pentobarbitone anaesthetized rabbits; 10 microg/kg intracisternal bicuculline induced polymorphic ventricular ectopic beats and ventricular tachycardia, while blood pressure increased by about 50-60% and heart rate in sinus rhythm decreased by about 20%. Rilmenidine pretreatment (10 min), either administered intravenously (0.01, 0.1, 1 mg/kg) or intracisternally (3, 10, 30 microg/kg), dose-dependently prevented the occurrence of bicuculline-induced arrhythmias and, because of a lower baseline, the blood pressure values reached were less when compared with controls. Intracisternal idazoxan (15 microg/kg) had no significant antiarrhythmic effect but antagonized, in part, the haemodynamic and antiarrhythmic effects of rilmenidine (1 mg/kg intravenously; 30 microg/kg intracisternally). CONCLUSION: The antiarrhythmic effects observed with rilmenidine are mainly mediated by blunting the bicuculline-induced increase in the sympathetic nervous output to the heart and the vascular beds. These effects of rilmenidine are likely to originate from action on the central as well as on the peripheral nervous systems. Direct coronary or cardiac effects might also play a role, in particular at low non-hypotensive intravenous doses.

RITED (Registro Italiano Test Eco-Dobutamina): side effects and complications of echo-dobutamine stress test in 3041 examinations.

AIM: The aim of the study was to report the incidence and clinical meaning of side-effects caused by echo-dobutamine testing in a large population and to evaluate any possible correlation between dobutamine dose and side-effects. METHODS: The study population consisted of 3041 patients enrolled from January 1994 to August 1995 at 63 centers participating in the Italian Register of Echo-Dobutamine Testing (Registro Italiano Test Eco-Dobutamina, RITED). The four major indications were myocardial infarction older than one month (40.4%), recent myocardial infarction (22.7%), coronary artery disease without a history of myocardial infarction (10.8%) and suspected coronary artery disease (19.3%). Dobutamine was administered in a peripheral vein at 5, 10, 20, 30, 40 micrograms/kg/minute + atropine 1 mg in four divided doses of 0.25 mg/minute. RESULTS: Severe complications were asystole, which went as high as 6" in one patient, and ventricular fibrillation in two patients. The clinical side-effects were headache (2.5%), hypotension (2.2%), nausea (1.7%), bradycardia (1.4%), palpitations (0.5%), tremors (0.3%), dyspnea (0.2%), paresthesia (0.2%) and hypertension (0.2%). Atrial arrhythmia was recorded in 10.6% of patients, while ventricular arrhythmia was recorded in 26.5%. The percentage of supraventricular and ventricular repetitive arrhythmia did not increase with dosage. The cumulative incidence of supraventricular and ventricular repetitive arrhythmia, considered as an interruption criteria, was 6.6% and 5.9%, respectively. CONCLUSIONS: Echo-dobutamine stress test seems to be a very safe and reliable test for unmasking myocardial ischemia or viability in known or suspected coronary artery disease. It has been shown to be widely applicable in clinical practice for outpatients as well, as long as a protected environment is available.