Adverse effects of low dose amiodarone: a meta-analysis.

OBJECTIVES: We sought to assess the odds of experiencing adverse effects with low dose amiodarone therapy compared with placebo. BACKGROUND: An estimate of the likelihood of experiencing amiodarone-related adverse effects with exposure to low daily doses of the drug is lacking in the published reports, and little information is available on adverse effect event rates in control groups not receiving the drug. METHODS: Data from four published trials involving 1,465 patients were included in a meta-analysis design. The criteria for inclusion were 1) double-blind, placebo-controlled design; 2) absence of a crossover design between patient groups; 3) mean follow-up of at least 12 months; 4) maintenance amiodarone dose < or = 400 mg/day; and 5) presence of an explicit description of adverse effects. Data were pooled after testing for homogeneity of treatment effects across trials, and summary odds ratios were calculated by the Peto-modified Mantel-Haenszel method for each adverse effect. RESULTS: The mean amiodarone dose per day ranged from 152 to 330 mg; 738 patients were randomized to receive amiodarone and 727 placebo. Exposure to amiodarone in this dose range, for a minimal duration of 12 months, resulted in odds similar to those of placebo for hepatic and gastrointestinal adverse effects, but in significantly higher odds than those of placebo (p < 0.05) for experiencing thyroid (odds ratio [OR] 4.2, 95% confidence interval [CI] 2.0 to 8.7), neurologic (OR 2.0, 95% CI 1.1 to 3.7), skin (OR 2.5, 95% CI 1.1 to 6.2), ocular (OR 3.4, 95% CI 1.2 to 9.6) and bradycardic (OR 2.2, 95% CI 1.1 to 4.3) adverse effects. A trend toward increased odds of pulmonary toxicity was noted (OR 2.0, 95% CI 0.9 to 5.3), but this did not reach statistical significance (p = 0.07). The unadjusted total incidence of drug discontinuation was 22.9% in the amiodarone group and 15.4% in the placebo group. The odds of discontinuing the drug in the amiodarone group was approximately 1.5 times that of the placebo group (OR 1.52, 95% CI 1.2 to 1.9) (p = 0.003). CONCLUSIONS: Compared with placebo, there is a higher likelihood of experiencing several amiodarone-related adverse effects with exposure to low daily doses of the drug. Thus, although low dose amiodarone may be well tolerated, it is not free of adverse effects.

Predictors of inducible sustained ventricular tachyarrhythmias in patients with coronary artery disease.

To determine predictors of inducible sustained ventricular tachycardia or fibrillation by programmed electrical stimulation in patients with coronary artery disease and ventricular tachyarrhythmias, 14 clinical and angiographic variables were analyzed in 60 consecutive patients. All patients had angiographically documented coronary artery disease and symptomatic ventricular arrhythmias (sustained ventricular tachycardia in 21, ventricular fibrillation in 21 and nonsustained ventricular tachycardia in 18). Baseline programmed electrical stimulation while the patient was not taking antiarrhythmic drugs was performed with use of single, double and triple extrastimuli and burst pacing from two right ventricular sites. The variables analyzed were presenting arrhythmia; presence, frequency and complexity of ventricular ectopic activity on baseline 24 h electrocardiographic (Holter) monitoring; greater than or equal to 70% narrowing in either the left anterior descending, proximal left anterior descending, right coronary or circumflex coronary artery (independently assessed); single, double or triple vessel coronary disease; anterior, apical or inferior wall motion abnormalities; segmental dyskinesia and ejection fraction. Thirty-seven patients (62%) had inducible sustained ventricular tachycardia (rate greater than 100 beats/min, duration greater than 30 s or requiring cardioversion) and two patients (3%) had ventricular fibrillation induced. Eleven patients (18%) had nonsustained ventricular tachycardia (duration greater than or equal to 3 beats, less than 30 s) induced and 10 patients (17%) had no inducible arrhythmia (duration less than 3 beats). Multivariate stepwise logistic regression analysis identified three independent variables predictive of inducible sustained ventricular arrhythmias: sustained ventricular tachycardia as the presenting arrhythmia (p = 0.004), proximal left anterior descending artery lesion (p = 0.002) and anterior wall motion abnormality (p = 0.005).(ABSTRACT TRUNCATED AT 250 WORDS)

Torsade de pointes with an antihistamine metabolite: potassium channel blockade with desmethylastemizole.

OBJECTIVES: Proarrhythmic effects have been observed with the selective histamine1 (H1) receptor antagonist drug astemizole, a widely prescribed antihistamine. The metabolites of astemizole and those of other antihistamine compounds have not been implicated as causative agents of cardiac arrhythmias. The purpose of this study was to examine whether desmethylastemizole, the principal metabolite of astemizole, blocks delayed rectifier potassium (K+) channels. BACKGROUND: QT interval prolongation and torsade de pointes are associated with astemizole intake and have been ascribed to block the repolarizing K+ currents, specifically the rapidly activating component of the delayed rectifier iKr. Astemizole undergoes extensive first-pass metabolism, and its dominant metabolite, desmethylastemizole, has a markedly prolonged elimination time. We report the clinical observation of QT prolongation and torsade de pointes in a patient with undetectable serum concentrations of astemizole (< 0.5 ng/ml) and "therapeutic" concentrations of desmethylastemizole (up to 7.7 ng/ml or 17.3 nmol/liter). METHODS: The perforated patch clamp recording technique was used to study the effects of desmethylastemizole (20 nmol/liter) on action potentials and iKr in isolated rabbit ventricular myocytes. RESULTS: Desmethylastemizole produced action potential prolongation and the induction of plateau early afterdepolarizations. Under voltage clamp conditions, desmethylastemizole suppressed iKr amplitude by approximately 65%. The drug E-4031 (100 nmol/liter), which selectively blocks iKr, had a similar effect on current amplitude. CONCLUSIONS: Desmethylastemizole, the major astemizole metabolite, blocks the repolarizing K+ current iKr with high affinity. The clinical observation of QT prolongation and torsade de pointes found with astemizole intake may principally be caused by the proarrhythmic effects of its metabolite desmethylastemizole.

Prospective, randomized comparison of conventional and high dose loading regimens of amiodarone in the treatment of ventricular tachycardia.

OBJECTIVES: The purpose of this prospective randomized study was to compare the electrophysiologic effects of conventional and high dose loading regimens of amiodarone in patients with sustained ventricular tachycardia. BACKGROUND: Uncontrolled studies in which patients have been treated with an oral loading dose of 2 to 4 g/day of amiodarone have suggested that, compared with a conventional loading dose, this dosing regimen results in more rapid control of spontaneous ventricular tachycardia and ventricular tachycardia induced by programmed stimulation. METHODS: Patients in whom sustained monomorphic ventricular tachycardia was inducible by programmed stimulation and who were refractory to class I antiarrhythmic medications were randomly assigned to receive either a conventional (n = 15) or a high (n = 17) loading dose of amiodarone. The conventional dose consisted of 600 mg twice a day for 10 days. The high dose regimen consisted of 50 mg/kg body weight per day on days 1 to 3, 30 mg/kg per day on days 4 and 5 and 600 mg twice a day on days 6 to 10. An electrophysiologic test was performed in the baseline state and after 3 and 10 days of therapy. An adequate response to amiodarone was defined as the inability to induce ventricular tachycardia or the ability to induce only relatively slow (cycle length > or = 350 ms) hemodynamically stable ventricular tachycardia. RESULTS: After 3 days of therapy, 2 of 14 patients who received the conventional loading dose and 6 of 15 patients who received the high dose loading regimen had an adequate response to amiodarone (p = 0.08). After 10 days of therapy, four patients in each group had an adequate response to amiodarone (p = NS). Three patients who received the high dose and one patient who received the conventional dose of amiodarone had an adequate response after 3 days of therapy but not after 10 days of therapy. There were significant increases in the sinus cycle length, atrioventricular block cycle length, ventricular effective refractory period and ventricular tachycardia cycle length after 3 and 10 days of therapy compared with baseline values regardless of the dosing regimen. The extent of the effects of amiodarone on these variables after 3 and 10 days of therapy was similar with both dosing regimens. CONCLUSIONS: The therapeutic and electrophysiologic effects of conventional and high dose loading regimens of amiodarone do not differ significantly after 3 or 10 days of therapy. High oral loading doses of amiodarone do not offer any significant clinical advantage over a conventional loading dose of amiodarone for controlling ventricular tachycardia induced by programmed stimulation.

Recognition and catheter ablation of subepicardial accessory pathways.

OBJECTIVES: The purpose of this study was to characterize left-sided accessory pathways that traverse the atrioventricular (AV) groove subepicardially and to describe results of radiofrequency catheter ablation within the coronary sinus in the patients studied. BACKGROUND: Radiofrequency catheter ablation has proved to be a safe and effective method for treatment of accessory pathways; however, subepicardial accessory pathways may account for some of the failures encountered during endocardial ablation. METHODS: The study group comprised 51 consecutive patients with a left-sided accessory pathway who were undergoing radio-frequency catheter ablation. Initially, the ablation catheter was introduced into a femoral artery and positioned on the ventricular aspect of the mitral annulus. If this endocardial approach was unsuccessful, the ablation catheter was introduced into the coronary sinus and energy applied at sites with shorter activation times than those recorded from the endocardium. RESULTS: Five (10%) of 51 patients with a left-sided accessory pathway could not have accessory pathway conduction interrupted with a median of 18 endocardial radiofrequency energy applications. Accessory pathway potentials were less frequent during endocardial mapping in these 5 patients than in the 46 patients whose accessory pathway was successfully ablated from the endocardial surface. All five of these patients later had successful ablation using one or two applications of radiofrequency energy from within the coronary sinus. Effective target site electrograms in the coronary sinus were characterized by an accessory pathway potential that was larger than the corresponding atrial or ventricular electrogram. There were no complications or recurrences after ablation within the coronary sinus. CONCLUSIONS: Some left-sided accessory pathways may be difficult to ablate from the endocardial surface because they traverse the AV groove subepicardially. The absence of an accessory pathway potential during endocardial mapping in combination with a relatively large accessory pathway potential within the coronary sinus may be a useful marker of a subepicardial pathway. In this select group of patients, radiofrequency catheter ablation from within the coronary sinus appears to enhance efficacy.

Randomized comparison of anatomic and electrogram mapping approaches to ablation of the slow pathway of atrioventricular node reentrant tachycardia.

OBJECTIVES: The purpose of this study was to prospectively compare in random fashion an anatomic and an electrogram mapping approach for ablation of the slow pathway of atrioventricular (AV) node reentrant tachycardia. BACKGROUND: Ablation of the slow pathway in patients with AV node reentrant tachycardia can be performed by using either an anatomic or an electrogram mapping approach to identify target sites for ablation. These two approaches have never been compared prospectively. METHODS: Fifty consecutive patients with typical AV node reentrant tachycardia were randomly assigned to undergo either an anatomic or an electrogram mapping approach for ablation of the slow AV node pathway. In 25 patients randomly assigned to the anatomic approach, sequential radiofrequency energy applications were delivered along the tricuspid annulus from the level of the coronary sinus ostium to the His bundle position. In 25 patients assigned to the electrogram mapping approach, target sites along the posteromedial tricuspid annulus near the coronary sinus ostium were sought where there was a multicomponent atrial electrogram or evidence of a possible slow pathway potential. If the initial approach was ineffective after 12 radiofrequency energy applications, the alternative approach was then used. RESULTS: The anatomic approach was effective in 21 (84%) of 25 patients, and the electrogram mapping approach was effective in all 25 patients (100%) randomly assigned to this technique (p = 0.1). The four patients with an ineffective anatomic approach had a successful outcome with the electrogram mapping approach. On the basis of intention to treat analysis, there were no significant differences between the electrogram mapping approach and the anatomic approach with respect to the time required for ablation (28 +/- 21 and 31 +/- 31 min, respectively, mean +/- SD, p = 0.7) duration of fluoroscopic exposure (27 +/- 20 and 27 +/- 18 min, respectively, p = 0.9) or mean number of radiofrequency applications delivered (6.3 +/- 3.9 vs. 7.2 +/- 8.0, p = 0.6). With both the anatomic and electrogram mapping approaches, the atrial electrogram duration and number of peaks in the atrial electrogram were significantly greater at successful target sites than at unsuccessful target sites. CONCLUSIONS: The anatomic and electrogram mapping approaches for ablation of the slow AV nodal pathway are comparable in efficacy and duration. If the anatomic approach is initially attempted and fails, the electrogram mapping approach may be successful at sites outside the areas targeted in the anatomic approach. With both the anatomic and electrogram mapping approaches, there are significant differences in the atrial electrogram configuration between successful and unsuccessful target sites.

A randomized comparison of the right- and left-sided approaches to ablation of the atrioventricular junction.

Radiofrequency ablation of the atrioventricular (AV) junction may be performed using either a right- or left-sided approach. This study prospectively compared the left-sided approach with persistent attempts from the right side in patients in whom initial radiofrequency applications on the right side were unsuccessful. Twenty-one of 54 patients did not have complete AV block induced after 3 right-sided radiofrequency applications. These 21 patients were randomly assigned to undergo either the left-sided approach (n = 10) or to undergo additional attempts from the right side (n = 11). The right-sided approach was performed by positioning the ablation catheter to record the largest possible atrial and His bundle electrograms. The left-sided approach was performed by positioning the ablation catheter along the left ventricular septum, where a His bundle potential was recorded. If either approach was not successful after an additional 17 radiofrequency applications, the alternative approach was then used. The AV junction was successfully ablated in all 10 patients randomized to the left-sided approach, but in only 6 of 11 patients randomized to persistent right-sided attempts (p < 0.05). The 5 patients in whom the AV junction was not successfully ablated using the right-sided approach underwent the left-sided approach and had a successful outcome after a mean of 1.2 +/- 0.4 radiofrequency applications. The left-sided approach required significantly fewer radiofrequency applications after randomization than the right-sided approach (3 +/- 3.4 vs 11 +/- 7.6, p < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Guidelines for predicting lesion size at common endocardial locations during radio-frequency ablation.

We used the finite element method to study the effect of radio-frequency (RF) catheter ablation on tissue heating and lesion formation at different intracardiac sites exposed to different regional blood velocities. We examined the effect of application of RF current in temperature- and power-controlled mode above and beneath the mitral valve annulus where the regional blood velocities are high and low respectively. We found that for temperature-controlled ablation, more power was delivered to maintain the preset tip temperature at sites of high local blood velocity than at sites of low local blood velocity. This induced more tissue heating and larger lesion volumes than ablations at low velocity regions. In contrast, for power-controlled ablation, tissue heating was less at sites of high compared with low local blood velocity for the same RF power setting. This resulted in smaller lesion volumes at sites of low local velocity. Our numerical analyzes showed that during temperature-controlled ablation at 60 degrees C, the lesion volumes at sites above and underneath the mitral valve were comparable when the duration of RF current application was 10 s. When the duration of RF application was extended to 60 s and 120 s, lesion volumes were 33.3% and 49.4% larger above the mitral valve than underneath the mitral valve. Also, with temperature-controlled ablation, tip temperature settings of 70 degrees C or greater were associated with a risk of tissue overheating during long ablations at high local blood velocity sites. In power-controlled ablation (20 W), the lesion volume formed underneath the mitral valve was 165.7% larger than the lesion volume above the mitral valve after 10 s of ablation. We summarized the guidelines for energy application at low and high flow regions.

Finite element analyses of uniform current density electrodes for radio-frequency cardiac ablation.

The high current density at the edge of a metal electrode causes hot spots, which can lead to charring or blood coagulation formation during radio-frequency (RF) cardiac ablation. We used finite element analysis to predict the current density distribution created by several electrode designs for RF ablation. The numerical results demonstrated that there were hot spots at the edge of the conventional tip electrode and the insulating catheter. By modifying the shape of the edge of the 5-mm tip electrode, we could significantly reduce the high current density at the electrode-insulator interface. We also studied the current density distribution produced by a cylindrically shaped electrode. We modified the shape of a cylindrical electrode by recessing the edge and filled in a coating material so that the overall structure was still cylindrical. We analyzed the effects of depth of recess and the electrical conductivity of the added material. The results show that more uniform current density can be accomplished by recessing the electrode, adding a curvature to the electrode, and by coating the electrode with a resistive material.

Dependence of apparent resistance of four-electrode probes on insertion depth.

The apparent resistance of a finite-thickness layer measured with a four-electrode plunge probe depends on the electrode insertion depth, electrode spacing, and layer thickness, as well as the resistivity ratio of an underlying layer. A physical model consisting of air, a saline solution layer, and an agar layer simulates the real situation of resistivity measurement. The saline layer represents the finite-thickness layer whose resistivity is to be measured by a plunge electrode probe, and the agar layer represents an underlying perturbing layer. A micropositioner controls the insertion depth of the four electrodes into the saline solution. With the apparent resistance measured on a semi-infinite-thickness layer of saline solution as standard, measurement results show decreasing apparent resistance and increasing error with increasing electrode insertion depth. This information is important for correct measurement of myocardial resistivity in vivo and in vitro.

Temperature measurement within myocardium during in vitro RF catheter ablation.

While most commercial ablation units and research systems can provide catheter tip temperature during ablation, they do not provide information about the temperature change inside the myocardium, which determines the lesion size. We present the details of a flow simulation and temperature measurement system, which allows the monitoring of the temperature change inside the myocardium during in vitro radio frequency (RF) cardiac catheter ablation at different blood flow rates to which the catheter site may be exposed. We set up a circulation system that simulated different blood flow rates of 0 to 5 L/min at 37 degrees C. We continuously measured the temperature at the catheter tip using the built-in thermistor and inside the myocardium using a three-thermocouple probe. The system provides a means for further study of the temperature inside myocardium during RF catheter ablation under different flow conditions and at different penetration depths.

Flow effect on lesion formation in RF cardiac catheter ablation.

This study investigated the flow effect on the lesion formation during radio-frequency cardiac catheter ablation in temperature-controlled mode. The blood flow in heart chambers carries heat away from the endocardium by convection. This cooling effect requires more power from the ablation generator and causes a larger lesion. We set up a flow system to simulate the flow inside the heart chamber. We performed in vitro ablation on bovine myocardium with three different flow rates (0 L/min, 1 L/min and 3 L/min) and two target temperatures (60 degrees C and 80 degrees C). During ablation, we also recorded the temperatures inside the myocardium with a three-thermocouple temperature probe. The results show that lesion dimensions (maximum depth, maximum width and lesion volume) are larger in high flow rates (p<0.01). Also, the temperature recordings show that the tissue temperature rises faster and reaches a higher temperature under higher flow rate.

A new catheter design using needle electrode for subendocardial RF ablation of ventricular muscles: finite element analysis and in vitro experiments.

Radio-frequency (RF) cardiac ablation has been very successful for treating arrhythmias related with atrioventricular junction and accessory pathways with successful cure rates of more than 90%. Even though ventricular tachycardia (VT) is a more serious problem, it is known to be rather difficult to cure VT using RF ablation. In order to apply RF ablation to VT, we usually need to create a deeper and wider lesion. Conventional RF ablation electrodes often fail to produce such a lesion. We propose a catheter-electrode design including one or more needle electrodes with a diameter of 0.5-1.0 mm and length of 2.0-10 mm to create a lesion large enough to treat VT. One temperature sensor could be placed at the middle of the needle electrode for temperature-controlled RF ablation. From finite element analyses and in vitro experiments, we found that the depth of a lesion is 1-2 mm deeper than the insertion depth of the needle and the width increases as we increase the diameter of the needle and the time duration. We showed that a single needle electrode can produce a lesion with about 10-mm width and any required depth. If a wider lesion is required, more than one needle with suggested structures can be used. Or, repeated RF ablations around a certain area using one needle could produce a cluster of lesions. In some cases, a catheter with both conventional electrode and needle electrode at its tip may be beneficial to take advantage of both types of electrode.

Thermal--electrical finite element modelling for radio frequency cardiac ablation: effects of changes in myocardial properties.

Finite element (FE) analysis has been utilised as a numerical tool to determine the temperature distribution in studies of radio frequency (RF) cardiac ablation. However, none of the previous FE analyses clarified such computational aspects as software requirements, computation time or convergence test. In addition, myocardial properties included in the previous models vary greatly. A process of FE modelling of a system that included blood, myocardium, and an ablation catheter with a thermistor embedded at the tip is described. The bio-heat equation is solved to determine the temperature distribution in myocardium using a commercial software application (ABAQUS). A Cauchy convergence test (epsilon = 0.1 degree C) was performed and it is concluded that the optimal number of elements for the proposed system is 24610. The effects of changes in myocardial properties (+/- 50% electric conductivity, +100%/-50% thermal conductivity, and +100%/-50% specific heat capacity) in both power-controlled (PCRFA) and temperature-controlled RF ablation (TCRFA) were studied. Changes in myocardial properties affect the results of the FE analyses of PCRFA more than those of TCRFA, and the maximum changes in lesion volumes were -58.6% (-50% electric conductivity), -60.7% (+100% thermal conductivity), and +43.2% (-50% specific heat).

Sudden cardiac death in a patient taking an over-the-counter diet pill.

The case of an otherwise healthy woman with a history of palpitations who survived sudden cardiac death from a ventricular arrhythmia is presented. Her only medications at the time of the event were alprazolan prn and over-the-counter diet pills. The relation between ventricular arrhythmias and over-the-counter diet pills is explored. Basic electrophysiologic principles are discussed as well as an overview for the work-up and long term management of sudden cardiac death.

Theophylline produces an adverse effect on myocardial lactate metabolism at a therapeutic serum concentration: an effect blocked by verapamil.

To assess the actions of theophylline on coronary blood flow and myocardial energetics, 1 mg/kg/min of this methylxanthine was infused i.v. in the dog for 15 min, producing an average concentration of 18 +/- 3 micrograms/ml. Heart rate increased by 20 +/- 7 min-1, P less than .05, but left ventricular (LV) systolic and end-diastolic pressures, cardiac output and LV peak dp/dt did not change. Although coronary vascular resistance decreased by 0.26 +/- 0.08 mm Hg/ml/min, P less than .05, coronary flow and myocardial oxygen consumption and extraction did not change. Myocardial lactate extraction decreased, from 22 +/- 2 to 1 +/- 5%, P less than .05. The decrement in lactate extraction was not related to heart rate, but to the change in LV peak dp/dt, r = 0.74, P less than .05. Furthermore, with verapamil, 0.2 mg/kg, pretreatment, and 0.2 mg/kg, during the theophylline infusion, reduction in lactate extraction was blocked and LV peak dp/dt increased by 843 +/- 311 mm Hg/sec, P less than .05. Thus, at therapeutic concentrations, theophylline reduces myocardial lactate extraction, an effect that is associated with the absence of the expected inotropic actions of theophylline. However, when verapamil is administered with theophylline, a reduction of myocardial extraction does not occur and myocardial inotropy is enhanced.

Replacing abdominally implanted defibrillators: effect of procedure setting on cost.

Although most ICDs are currently placed using a pectoral approach, there exists a large population of patients with abdominally implanted ICDs who will require device replacement due to a depleted battery. The purpose of this study was to compare the cost, convalescence, and complication rate of replacing abdominally implanted ICDs in the OR versus the EP laboratory. Between August 1993 and September 1994, we prospectively enlisted nine consecutive patients who presented for their second ICD generator replacement and who had a prior generator replacement in the OR 3-4 years earlier. The mean age of the patients was 63 +/- 17 years and their mean ejection fraction was 37% +/- 15%. ICD replacement was performed in the EP laboratory and consisted of explanting the old device, electronic interrogation of the lead system, and confirmation of defibrillation thresholds prior to implanting a new device. Local anesthesia was provided by lidocaine infiltration and sedation was achieved with intravenous (i.v.) midazolam and fentanyl. Following the procedure, the patients were returned to an outpatient monitored setting for 4 hours and were then discharged. Comparisons of the health care charges for the same procedure performed in the two different settings revealed a significant reduction in physician fees (from $3,621 +/- $556 to $2,179 +/- $577, P < 0.05), in hospital charges (from $5,811 +/- $1,102 to $2,306 +/- 696, P < 0.05), and in total charges (from $9,431 +/- $1,375 to $4,541 +/- $1,010, P < 0.05), exclusive of ICD cost, when the procedure was performed on an outpatient basis in the EP laboratory. Inpatient days averaged 3.0 +/- 0.3 when the procedure was performed in the OR. On long-term follow-up there were no complications following abdominal ICD generator replacement in the OR (mean follow-up, 39 +/- 2 months) or in the EP laboratory (mean follow-up, 42 +/- 4 months). Thus, ICD replacements in the EP laboratory cost less than in the OR due to significantly lower physician fees, hospital charges, and a shorter postprocedural convalescence.

Effect of hypercapnic acidemia on anisotropic propagation in the canine ventricle.

BACKGROUND: Impulse propagation in the ventricle depends on both sodium channel availability and cell-to-cell coupling through gap junctions. Sodium channel block has been shown to depress conduction velocity (theta) more longitudinal (LONG) to than transverse (TRANS) to fiber orientation. Because exposure to CO2 produces intracellular acidosis and decreased gap junction conductance in vitro, we tested the hypothesis that increased PCO2 would result in preferential depression of transverse conduction in vivo. METHODS AND RESULTS: In anesthetized dogs, when atrial pH was reduced to 6.70 +/- 0.04 by increasing the fraction of inhaled CO2 to 40%, theta TRANS fell from 0.23 +/- 0.04 to 0.19 +/- 0.02 m/s (-16 +/- 8%, P < .03), while theta LONG was unchanged (-3 +/- 7%, P = NS). In contrast, with the same degree of acidemia produced by HCl infusion, only theta LONG fell (-8 +/- 7%), coincident with a rise in serum K+. CONCLUSIONS: The observed effect of CO2 on propagation in the intact heart is consistent with its previously described in vitro actions to uncouple cell-to-cell communication and may provide a model to study the role of cell-to-cell coupling in normal and abnormal propagation.

Block of HERG potassium channels by the antihistamine astemizole and its metabolites desmethylastemizole and norastemizole.

INTRODUCTION: The selective H1-receptor antagonist astemizole (Hismanal) causes acquired long QT syndrome. Astemizole blocks the rapidly activating delayed rectifier K+ current I(Kr) and the human ether-a go-go-related gene (HERG) K+ channels that underlie it. Astemizole also is rapidly metabolized. The principal metabolite is desmethylastemizole, which retains H1-receptor antagonist properties, has a long elimination time of 9 to 13 days, and its steady-state serum concentration exceeds that of astemizole by more than 30-fold. A second metabolite is norastemizole, which appears in serum in low concentrations following astemizole ingestion and has undergone development as a new antihistamine drug. Our objective in the present work was to study the effects of desmethylastemizole, norastemizole, and astemizole on HERG K+ channels. METHODS AND RESULTS: HERG channels were expressed in a mammalian (HEK 293) cell line and studied using the patch clamp technique. Desmethylastemizole and astemizole blocked HERG current with similar concentration dependence (half-maximal block of 1.0 and 0.9 nM, respectively) and block was use dependent. Norastemizole also blocked HERG current; however, block was incomplete and required higher drug concentrations (half-maximal block of 27.7 nM). CONCLUSIONS: Desmethylastemizole and astemizole cause equipotent block of HERG channels, and these are among the most potent HERG channel antagonists yet studied. Because desmethylastemizole becomes the dominant compound in serum, these findings support the postulate that it becomes the principal cause of long QT syndrome observed in patients following astemizole ingestion. Norastemizole block of HERG channels is weaker; thus, the risk of producing ventricular arrhythmias may be lower. These findings underscore the potential roles of some H1-receptor antagonist metabolites as K+ channel antagonists.