Sung Chun

The Role of Intravenous Amiodarone in the Management of Cardiac Arrhythmias

Therapy for arrhythmias involves analysis of the proarrhythmic and adverse side effects and the desired antiarrhythmic effects of a medication. In the past decade, data on the increased mortality rate noted with conventional antiarrhythmic drug therapy have prompted the reexamination of available therapies and investigation into new pharmaceutical agents [1]. Amiodarone, in contrast to other available antiarrhythmic agents, has been reported to be safe and effective in various clinical settings without an associated increase in mortality rate [2]. This drug, initially developed for use as an antianginal agent, has been used orally to suppress many types of supraventricular and ventricular arrhythmias. Although it was initially reserved for treatment of life-threatening ventricular arrhythmias refractory to other antiarrhythmic drugs, oral amiodarone is being used more often as a first-line agent for supraventricular and ventricular arrhythmias. Oral amiodarone was recently extensively reviewed by Podrid [2]. In the United States, intravenous amiodarone has been approved by the U.S. Food and Drug Administration for the treatment and prophylaxis of recurrent ventricular fibrillation or hemodynamically unstable ventricular tachycardia in patients in whom other therapy is unsuccessful [3]. Much interest has been generated about the use of intravenous amiodarone for the treatment of life-threatening arrhythmias because of amiodarones rapid onset of action and beneficial electropharmacologic and hemodynamic profile [4]. In this article, we review the electropharmacology, pharmacokinetics, and side effects of intravenous amiodarone and define the role of amiodarone in the treatment of various types of arrhythmias. Methods We searched the MEDLINE database for English-language material, including reports of clinical trials and in vivo studies, review articles, and abstracts presented at national symposia, that was published between 1985 and 1996. We also examined bibliographies of textbooks and articles. Studies that reported on the efficacy, toxicity, and hemodynamic dynamic profile of intravenous amiodarone and studies that examined the pharmacologic behavior of intravenous amiodarone in laboratory models were reviewed. We assessed study design and quality and relevant data on the efficacy of suppression and treatment of arrhythmias with oral and intravenous amiodarone therapy, the reported mechanisms of antiarrhythmic effect, and the hemodynamic changes seen with therapy. Data Synthesis Electropharmacology Amiodarone is now used as an extremely potent antiarrhythmic drug. Although traditionally classified as a class III antiarrhythmic agent, oral amiodarone is now known to exert the entire spectrum of antiarrhythmic effects (Table 1) [2, 5]. It also has an antithyroid effect that may contribute to its antiarrhythmic potency [6]. Intravenous amiodarone shares many electrophysiologic properties with the oral form, but there are several important differences. Table 1. Electropharmacologic Effects of Amiodarone* In animal and human studies, intravenous amiodarone caused electrophysiologic changes in atrioventricular nodal tissue similar to those caused by oral therapy; with both forms of the drug, atrioventricular nodal refractoriness and the intranodal conduction interval are increased [5, 7-11]. These changes are thought to be mediated by the drugs calcium-channel-blocking action [8] and by its noncompetitive antiadrenergic effect, whereby the total number of -adrenoreceptors is decreased rather than truly blocked [6, 12-15]. On the other hand, intravenous amiodarone seems to be less thorough than oral amiodarone in its electrophysiologic action against other myocardial tissues. Its effects on the effective refractory periods of atrial, ventricular, and His-Purkinje tissue and the accessory pathways are minimal, and it does not prolong the H-V interval (His bundle-to-ventricular conduction interval), the QRS interval, or the QTc duration [5, 7, 9, 10, 16]. One hypothesis for this difference is that the exertion of amiodarones notable electrophysiologic effects requires long-term administration, which allows greater penetration of the drug and its active metabolite into these tissues. Oral amiodarone depresses sinoatrial node automaticity by decreasing phase 4 depolarization in the sinoatrial node and reducing the pacemaker potential amplitude [17], thereby slowing the heart rate. This bradycardiac effect of intravenous amiodarone is counteracted by the drugs vasodilatory action, which triggers a sympathetic response and minimizes the net decrease in heart rate [2, 5, 9-11, 18]. Intravenous amiodarone lacks two important antiarrhythmic mechanisms that are seen with the oral form of the drug. First, it has minimal antithryoid action [19]. Second, its active metabolite, N-desethylamiodarone, which has significant antiarrhythmic potency, is not accumulated in serum or tissue sufficiently to generate any remarkable antiarrhythmic action [7]. The antiarrhythmic property of intravenous amiodarone is potentiated by this forms ability to exert three electrophysiologic actions faster than the oral form. First, intravenous amiodarone substantially inhibits inactivated sodium channels, especially those with shorter cycle lengths (use-dependency phenomenon) [11, 17, 20, 21]. This suggests that the intravenous forms short-term antiarrhythmic action should be greater during rapid tachyarrhythmias. In a canine model, this action on the sodium channel was shown to be more pronounced in ischemic myocardial tissues than in normal tissues [20]. Second, a study using isolated rat hearts showed that intravenous amiodarone significantly decreased the frequency of ventricular fibrillation. This decrease was associated with a substantial reduction in intracellular calcium concentration, suggesting that intravenous amiodarones effect on cellular calcium homeostasis plays an important role in its antiarrhythmic action [22]. Third, indirect evidence in a rat heart model showed that intravenous amiodarone has a more potent and faster antiadrenergic action than does oral amiodarone [23]. Pharmacokinetics Many of the unique pharmacokinetic properties of amiodarone are related to the drugs high lipophilicity. As a result of this quality, the drug tends to accumulate in most tissues, especially fatty tissue and liver [14]. Unlike the low bioavailability (35% to 65%) achieved with oral amiodarone, intravenous amiodarone is 100% bioavailable; thus, use of the intravenous form results in substantially higher plasma concentrations than does use of the oral form. These peak concentrations occur more rapidly with the intravenous form because absorption is not required [14]. Peak serum concentrations after single 15-minute intravenous infusions of 5 mg/kg of body weight range from 5 to 41 mg/L [4]. Amiodarones calculated volume of distribution exceeds 5000 L. This large volume occurs because amiodarone and its major metabolite, N-desethylamiodarone, are taken up from plasma and concentrated (as much as 1000-fold) in erythrocyte membranes and peripheral tissue, especially tissues with a high fat content. In fact, it has been hypothesized that amiodarone exerts at least some of its pharmacologic effects by concentrating in lipid-rich cell membranes and pertubing the milieu around ion channels rather than by modulating ion flow through channels [14]. Intravenous amiodarone is rapidly distributed. Tissue distribution accounts for most of the decline in plasma concentration. Concentrations can decline to 10% of peak values within 30 to 45 minutes after completion of infusion [4, 24]. These distribution characteristics explain why plasma concentrations of the drug do not correlate well with observable clinical effect. Finally, amiodarone is highly protein bound (approximately 98% of the compound). As a result, neither amiodarone nor N-desethylamiodarone appear in dialysis fluid, a fact that has important implications for the treatment of amiodarone toxicity [14]. Amiodarone is biotransformed in the liver to N-desethylamiodarone. This metabolite has been reported to be equipotent as a sodium-channel blocker and less potent as a calcium-channel blocker compared with the parent compound. N-desethylamiodarone can be detected in plasma shortly after large oral doses of amiodarone but not after intravenous doses [14]. Amiodarone is eliminated primarily by hepatic metabolism and biliary excretion. Urinary excretion of amiodarone or N-desethylamiodarone is negligible [14]. No dosage adjustments seem to be needed in patients with renal or hepatic insufficiency or left ventricular dysfunction [3]. Clinical Applications Supraventricular Arrhythmias Atrial fibrillation and atrial flutter. The oral form of amiodarone has been used to convert atrial fibrillation and atrial flutter to normal sinus rhythm and to maintain normal sinus rhythm after conversion. Success rates for conversion and maintenance of normal sinus rhythm range from 53% to 87% (Table 2). Table 2. Oral and Intravenous Amiodarone for Atrial Fibrillation and Atrial Flutter* The efficacy of intravenous amiodarone in converting atrial fibrillation to sinus rhythm in an acute setting seems to be controversial, although most studies suggest that efficacy is modest at best. Kerin and Zehender and their colleagues [35, 42] independently compared intravenous amiodarone and quinidine for the conversion of chronic atrial fibrillation to sinus rhythm. Kerin and coworkers [35] found that both treatments were equally effective: Rates of conversion to sinus rhythm were 44% for intravenous amiodarone and 47% for quinidine and digoxin. Zehender and colleagues [42] found similar results; Conversion rates were 55% with quinidine and verapamil and 60% with intravenous amiodarone. In comparing intravenous procainamide with intravenous amiodarone, Chapman and associates [41] examined 21 patients with atrial tachyarrhythmi

Exercise-induced ventricular arrhythmias and cardiovascular death.

Background: Exercise‐induced ventricular arrhythmias (EIVA) are frequently observed during exercise testing. However, the clinical guidelines do not specify their significance and so we examined this issue in our population.

Microwave Catheter Ablation Using a Clinical Prototype System with a Lateral Firing Antenna Design

Microwave has been considered a potentially more effective and more versatile form of energy than radiofrequency. Its feasibility has been tested using various prototype systems and catheter designs. This study assessed the safety and efficacy of a clinically‐suitable prototype microwave power supply and catheter system with a lateral‐firing antenna design for atrioventricular (AV) junction ahlation in canines and to correlate with tissue histopathology. The system consisted of a deflectable catheter with a 6‐mm antenna and a thermocouple; and a 2.45‐CHz frequency generator with power, time, and temperature controls. AV junction ablations were performed using 75 W energy for up to 60 seconds. Effective heating was confirmed hy a rise in catheter temperature to 69.3 ± 8.8°C. Complete AV nodal block was accomplished in all canines after an average of 4.1 ± 2.3 applications at 66.8 ± 7.7°C, and persisted after 28 days in all chronic animals. Lesions were consistent with thermal necrosis, were hemispherical to semi linear in shape and have distinct borders. Acute lesions were 3.4 ± 1.5 mm wide, 4.8 ±2.1 long, and 2.0 ± 0.9 deep. Chronic lesions showed typical healing and were smaller in size. Ablations did not cause any transvalvular, vascular or other cardiac structural damage, and no coagulum formation was noted on the antenna or catheter tip. Microwave AV junction ablation using this clinical prototype system specifically designed for it was safe and effective. Lesions depth was limited to 5 mm with 60‐second heating while its shape corresponded to the antennas length. Microwave energy may provide greater versatility for producing discrete or linear ablation.

Prognostic value of exercise tests in male veterans with chronic coronary artery disease.

PURPOSE The authors evaluate the prognostic value of treadmill testing in a large consecutive series of patients with chronic coronary artery disease. Exercise testing is widely performed, but analyses of the prognostic value of test results have largely concentrated on patients referred for the diagnosis of coronary artery disease, patients after an acute coronary event or procedure, or patients with congestive heart failure. METHODS All patients referred for evaluation at two university-affiliated Veterans Affairs Medical Centers who underwent exercise treadmill tests for clinical indications between 1987 and 2000 were determined to be dead or alive using the Social Security Death Index after a mean 5.8-year follow-up. Patients without established heart disease and those with congestive heart failure were excluded, leaving the target population of those with a history myocardial infarction or coronary intervention. Clinical and exercise test variables were collected prospectively according to standard definitions; testing and data management were performed in a standardized fashion using a computer-assisted protocol. All-cause mortality was used as the endpoint for follow-up. Standard survival analysis was performed including Kaplan Meier curves and the Cox Hazard Model. RESULTS Of the 1,473 patients with coronary artery disease who had exercise testing, 273 (19%) patients had a revascularization procedure (Revascularization group); 813 (55%) had a history of myocardial infarction, diagnostic Q waves (MI group), or both; and 387 (26%) had a history of myocardial infarction or Q wave and revascularization (Combined group). Mean age of the patients was 61.8 +/- 9 years. A total of 401 deaths occurred during a mean follow-up of 5.8 years with an annual mortality rate of 4.5%. Only two variables, age and maximal exercise capacity, were independently and statistically associated with time to death in all three groups and were the strongest predictors of all cause mortality. CONCLUSION A simple score based on METs, age, and history of myocardial infarction or diagnostic Q waves can stratify prognosis in patients with chronic coronary artery disease. The score enabled the identification of a group at low risk (32% of the cohort) with an annual mortality rate of 2%, a group at intermediate risk (42% of the cohort) with an annual mortality rate of about 4%, and a group at high risk (26% of the cohort) with an average annual mortality rate of approximately 7%.

Unidirectional Conduction Block at Cavotricuspid Isthmus Created by Radiofrequency Catheter Ablation in Patients With Typical Atrial Flutter

Unidirectional Block at Cavotricuspid Isthmus. Introduction: Although unidirectional conduction block at the cavotricuspid isthmus can be created by radiofrequency ablation for atrial flutter, its underlying mechanism has not been elucidated.

Limited predictive value of inducible sustained ventricular tachycardia for future occurrence of spontaneous ventricular tachycardia in patients with coronary artery disease and relatively preserved cardiac function.

To evaluate the significance of inducible sustained ventricular tachycardia (VT) in patients with coronary artery disease and relatively preserved cardiac function, 33 patients who met the following criteria were studied; documented nonsustained VT but no history of life-threatening arrhythmia, inducible sustained VT at electrophysiologic study, and implantation of a cardioverter-defibrillator. Eighteen patients developed clinical sustained VT within 2 years. By univariate analysis, left ventricular ejection fraction (EF) and the cycle length of induced VT were associated with clinical VT occurrence. By multivariate analysis, however, EF was the only independent predictor. Among 23 patients with EF <or=40%, 16 patients developed clinical sustained VT compared to 2 of 10 patients with EF >40% (P <.01). In coronary artery disease patients with relatively preserved EF, the incidence of clinical VT is considerably low even though sustained VT is inducible. Inducible VT is therefore not appropriate for risk stratification in this patient population.

Clinical Implications of Technological Advances in Screening for Atrial Fibrillation

The incidence of atrial fibrillation (AF) continues to increase worldwide as people live longer. AF is the leading cause of stroke among patients older than 75 years and is responsible for at least 15% of all strokes. Industry has responded to this problem with a plethora of monitoring devices. These include single lead ECG adhesive sensors, implantable loop recorders, smartphone attachments and wearables. This review will concentrate on clinical studies using these technologies. There are wearables including watches and watch-like devices that will be mentioned but these have not been validated for clinical use. This review will begin with a background regarding screening for AF and at the end present findings from Cardiac Implantable devices that could influence use of the new mobile health technologies.

874-5 Optimal prognostication from the 12-lead ECG: Spatial angle between the QRS and T wave complexes

Background: Microvolt level T-wave alternans (MTWA) is increasingly used for arrhythmia risk stratification in patients prone to malignant ventricular tachyarrhythmias and sudden cardiac death. Antiadrenergic therapy by means of beta blocker (BB) administration may influence MTWA assessment using exercise testing, mainly because patients may not achieve a sufficient increase in heart rate. However the effects of BB on MTWA assessment have not been prospectively studied. Methods. Consecutive patients scheduled for ICD implantation underwent noninvasive MTWA assessment using bicycle exercise testing (spectral method; CH2000, Cambridge Heart Inc) on and off BB treatment in random order. Antiadrenergic therapy was withheld for at least 5 half lifes prior to the test off BB. Results of MTWA tests were compared using Fisher’s exact test. Separate analysis was performed in a subgroup of patients who were on chronic amiodarone treatment. Results: Sixty-six patients were included in the protocol. Of these, 17 were treated with amiodarone. Patients on BB had a resting heart rate of 71+10 bpm compared to 79+10 bpm of BB (p<0.05). The maximal exercise heart rate averaged 102+13 bpm to 107+13 bpm of BB (p<0.05). Whereas 13 pts (27%) tested MTWA positive on BB, the positivity rate was 47% (23 pts) off the drug (p=0.05).The prevalence of an indeterminate test result decreased from 41% to 24% (p=0.09). In the subgroup of patients with amiodarone, no patient tested MTWA positive, irrespective of the status of BB therapy. The proportion of indeterminate tests was 88% on and 82% off BB therapy exclusively due to chronotropic incompetence during testing. Conclusion: MTWA assessment is facilitated by withholding BB prior to testing by reducing the prevalence of indeterminate tests as a consequence of insufficient heart rate increase. Chronic amiodarone therapy results in chronotropic incompetence in almost all patients which precludes exercise-based MTWA assessment.

Importance of Using Standard Rather Than Torso Surface Electrocardiographic Leads for Pacemapping at the Right Ventricular Outflow Tract

MATSUSHITA, T., et al.: Importance of Using Standard Rather Than Torso Surface Electrocardiographic Leads for Pacemapping at the Right Ventricular Outflow Tract. Although pacemapping has been used to localize the origin of ventricular tachycardia, the effect of changes in the position of ECG electrodes during ventricular pacing remains unknown. To clarify the relationship between the position of ECG limb electrodes and QRS configuration during pacemapping at the right ventricular outflow tract (RVOT), RVOT pacing was performed on 12 patients at eight pacing sites located in the anterior, septal, lateral, and posterior portions each in the high and low RVOT. Standard and torso ECGs were recorded simultaneously during each pacing protocol, and the QRS axis and amplitude were compared between the two ECGs. Differences between sites in the horizontal plane and in the longitudinal direction were also compared. The QRS axis on the torso ECG was significantly more rightward than that on the standard ECG at all eight pacing sites (72.1 ± 17.4 vs 64.0 ± 21.9 degrees). The magnitude of differences in the QRS axis and amplitude between the anterior and other sites at the same height was significantly greater in the standard ECG in all locations and in 7 of 18 comparable leads, respectively. The magnitude of differences between high and low sites was significantly greater in the standard ECG in three of four locations and in 5 of 12 comparable leads, respectively. In conclusion, the torso ECG is less sensitive to changes in pacing site at the RVOT than the standard ECG. The torso ECG is, therefore, not proper for pacemapping in attempts to ablate ventricular tachycardia arising from the RVOT.