胺碘酮在心房颤动治疗中的研究进展

近年来,对心房颤动治疗方法的探讨已成为医学界研究的焦点问题并取得了很大进展,同时胺碘酮在心房颤动治疗中的地位也有所改变。目前胺碘酮在心房颤动中的地位如何,怎样合理地应用胺碘酮?现就这些问题作一综述。     

Amiodarone for the Restoration of Sinus Rhythm in Patients with Atrial Fibrillation

Although the use of amiodarone for the treatment of atrial fibrillation has increased, reports of its use for the restoration of sinus rhythm have been conflicting. In a recent prospective, randomized, single-blind, placebo controlled study, we examined the efficacy and safety of amiodarone as initial treatment to restore sinus rhythm in patients with atrial fibrillation of varying duration. We studied 335 patients (169 men, 166 women), aged 27-78 years (mean age 65 +/- 10 years), with symptomatic atrial fibrillation, who presented to the emergency room or to our clinic. Patients randomized to amiodarone ( n = 173) received 300 mg intravenously over 1 hour followed by 20 mg/kg over 24 hours. Oral administration was initiated simultaneously at 600 mg/day in 3 divided doses for one week followed by 400 mg/day, in two doses, for three weeks. Amiodarone was almost twice as likely as placebo to restore sinus rhythm (85% vs. 43%, p < 0.0001). Larger left atrial size and longer duration of atrial fibrillation decreased amiodarone's effectiveness. These factors were also associated with longer duration of treatment before conversion to sinus rhythm. We observed relatively few and only minor complications despite relatively high doses of amiodarone administered to achieve high serum concentrations. In conclusion, our findings indicate that amiodarone is an effective and safe antiarrhythmic drug even when administered in large doses. It may be used for the restoration of sinus rhythm when rapid cardioversion is not needed.     

Persistent Atrial Flutter in Patients Treated for Atrial Fibrillation with Amiodarone and Propafenone:

INTRODUCTION: Antiarrhythmic drugs have been reported to promote the conversion of atrial fibrillation to atrial flutter in patients with paroxysmal atrial fibrillation. However, information about the electrophysiologic mechanism and response to radiofrequency ablation of these drug-induced atrial flutters is limited. Furthermore, the determinants of the development of persistent atrial flutter in patients treated for atrial fibrillation with antiarrhythmic drugs are still unknown. METHODS AND RESULTS: Among the 136 patients treated for atrial fibrillation with amiodarone (n = 96) or propafenone (n = 40), 15 (11%, mean age 65.5 +/- 12.3 years) were identified to have subsequent development of persistent atrial flutter based on surface ECG characteristics during antiarrhythmic drug treatment. The mean interval between the beginning of drug treatment and the onset of atrial flutter was 5.0 +/- 5.5 months. Intracardiac mapping and entrainment studies revealed that 11 patients had counterclockwise typical atrial flutter, and 4 had clockwise typical atrial flutter. All 15 patients underwent successful ablation with creation of complete bidirectional isthmus conduction block. After a mean follow-up of 12.3 +/- 4.2 months, 14 (93%) of 15 patients who underwent successful ablation and continued taking antiarrhythmic drugs have remained in sinus rhythm. Univariate analysis of clinical variables demonstrated that only atrial enlargement was significantly related to the occurrence of persistent atrial flutter. CONCLUSION: In patients with atrial fibrillation, persistent typical atrial flutter might occur during antiarrhythmic drug treatment, and atrial enlargement was a risk factor for the development of such an arrhythmia. Radiofrequency ablation and continuation of pharmacologic therapy offered a safe and effective means of achieving and maintaining sinus rhythm.     

Antiarrhythmic Drug Therapy in the Management of Atrial Fibrillation

Antiarrhythmic Drugs for AF. Antiarrhythmic drugs have been used for the acute conversion of atrial fibrillation to sinus rhythm, as well as for the long-term maintenance of sinus rhythm. In recent years, concerns regarding antiarrhythmic drug efficacy as well as safety have prompted a re-examination of the indications for antiarrhythmic therapy in patients with atrial fibrillation. This review will focus on the safety and efficacy of antiarrhythmic therapy in the acute and chronic management of patients with atrial fibrillation.     

Evaluation of Atrial Refractoriness and Atrial Fibrillation Inducibility Immediately after Internal Cardioversion in Patients with Chronic Persistent Atrial Fibrillation

Summary. Objective: To prospectively evaluate right atrial refractoriness and sustained atrial fibrillation (AF) inducibility at programmed electrical stimulation in two groups of patient: a series of patients with chronic persistent AF, studied immediately after successful low energy internal atrial cardioversion, and a group of control patients without history of supraventricular arrhythmias.Patients: Nineteen patients with chronic persistent AF (mean AF duration 11 ± 10 months, range 2–61 months) submitted to successful internal low energy atrial cardioversion in fully conscious state and 11 control patients without history of supraventricular arrhythmias.Methods: An electrophysiological evaluation was performed to measure atrial refractoriness and AF inducibility, by delivering single atrial extrastimuli in high right atrium, at decremental coupling, during spontaneous sinus rhythm and after 8 beats at 600, 500, 400 and 330 ms cycle length. If sustained AF was induced the protocol was terminated.Results: During programmed atrial stimulation sustained AF was induced in 8 out 19 (42%) of the AF patients but in none of the control group. Atrial effective refractory period was significantly shorter in AF patients compared to controls both at basic cycle length, at 600 ms, 500 ms and 400 ms cycle length, meanwhile no statistically significant differences were found at 330 ms cycle length. An altered relationship between atrial effective refractory period and cycle length was found in AF patients compared to controls: the slope of linear correlation slope was significantly lower in AF group than in controls (0.04 ± 0.07 vs 0.17 ± 0.10, p < 0.002).Conclusions: Marked abnormalities of atrial refractoriness and of its heart rate relationship are observed after internal cardioversion of chronic persistent AF in humans and these abnormalities are associated with an high vulnerability to AF. These observations may explain the high risk of AF recurrences in the early phases following successful cardioversion. In this scenario antiarrhythmic drug therapy seems to be mandatory for reducing arrhythmia relapses.     

Intravenous Amiodarone Decreases the Duration of Atrial Fibrillation Associated with Acute Myocardial Infarction

Purpose: Atrial fibrillation (AF) is a fairly common complication of acute myocardial infarction (AMI). The aim of this study was to examine the safety and efficacy of intravenous amiodarone in converting AF associated with AMI. Methods: Seventy patients with AMI complicated with AF were prospectively divided into 3 groups: a) In group D (n = 26), 0.75 mg digoxin was administered intravenously and thereafter as needed, b) In group AM (n = 16), 300 mg of amiodarone was infused over 2 hours followed by 44 mg/hour for up to 60 hours or until sinus rhythm was restored, c) In group D + AM (n = 28), 0.75 mg of digoxin was administered (as in group D) for the initial 2 hours followed by amiodarone infusion as in group AM. Results: Sinus rhythm was restored: a) by the end of the 2nd hour in 9/26 patients from group D, 4/16 from group AM, and 10/28 from group D + AM (p = NS), b) by the end of the 96th hour, in 18/26 patients from group D, and in all patients from group AM and groupd D + AM. The corresponding duration of AF was 51 ± 34 hours, 17 ± 15 hours and 9 ± 13 hours, respectively (F = 15.4, p < 0.001). AF recurred in 9/26, 5/16 and 1/28 patients of groups D, AM and D + AM, respectively (p = 0.026). The required dosage of amiodarone was lower in the D + AM group than in the AM group (603 ± 563 mg versus 1058 ± 680 mg, p = 0.037). Conclusions: Intravenous amiodarone was well tolerated in patients with AMI complicated by AF and was effective in decreasing the duration of AF. However, the combination of amiodarone and digoxin was superior to amiodarone alone in restoring sinus rhythm faster, maintaining sinus rhythm longer, and allowing the use of a lower cumulative amount of amiodarone.     

Amiodarone Instilled Into the Canine Pericardial Sac Migrates Transmurally to Produce Electrophysiologic Effects and Suppress Atrial Fibrillation

Pericardial Sac as Amiodarone Reservoir. Introduction : We investigated whether amiodarone delivered into the pericardial sac exerted an effect on atrial and ventricular refractoriness, impulse generation, and conduction and on induced atrial fibrillation.
Methods and Results : All animals were anesthetized with α-chloralose. After a sternotomy, the pericardium was opened and cradled to produce a "container" of approximately 75 mL. Part 1 experimental animals received amiodarone, 0.5, 1.0, or 5.0 mg/mL, dissolved in 3 mL polysorbate 80 and 5% dextrose in water (D5W) instilled into their pericardial sac for 3-hour intervals. Part II experimental animals received either 1.0 or 5.0 mg/mL of amiodarone. Control dogs received a pericardial solution of 3 mL polysorhate 80 in D5W. Pre- and postinstillation electrophysiologic studies were performed. In part I, the increase in sinus cycle length, 1:1 AV conduction, and effective refractory period (ERP) of atrium, right ventricular (RV) and left ventricular epicardium, and RV endocardium were significantly greater in animals receiving amiodarone compared with controls. Amiodarone concentrations in the tissue samples were highest in the superficial sites of the atria, sinoatrial node, and ventricular epicardial samples and lowest in the interventricular septum. Only trace concentrations of amiodarone and no desethylamiodarone were found in the blood samples. In part II, atrial ERP significantly increased in the animals receiving amiodarone, and the number of episodes of sustained atrial fibrillation that could he induced decreased.
Conclusions : Amiodarone instilled into the pericardial sac migrates transmurally to produce significant electrophysiologic effects at superficial sites and appears to suppress electrically induced atrial fibrillation.     

Pharmacological Cardioversion of Recent Onset Atrial Fibrillation with Intravenous Amiodarone in Patients Receiving Long-Term Amiodarone Therapy: Is It Reasonable?

In clinical practice the use of intravenous amiodarone has been proposed for the conversion of recurrent atrial fibrillation in patients already under chronic treatment with the same drug. Given that intravenous amiodarone exhibits different electrophysiological properties than when the drug is taken orally over a long period, this approach seems reasonable, but its effectiveness and safety have not been investigated systematically before.Of 45 patients under chronic treatment with amiodarone for the maintenance of sinus rhythm who had atrial fibrillation of recent onset, 23 were given intravenous loading of the same drug for 24 hours and 22 received placebo. Nine patients underwent an electrophysiological study several months after the successful restoration of sinus rhythm, before and after another intravenous loading dose of amiodarone, in order to examine the possible electrophysiological changes.In the amiodarone group 20 patients were successfully converted to sinus rhythm, compared to 13 of the placebo group (p < 0.05). No serious side effects of the intravenous administration were observed. Prolongation of refractoriness was seen in all 9 patients who underwent electrohysiological study after intravenous loading, without any effect on repolarization, atrioventricular conduction or sinus node function.In conclusion an intravenous loading dose of amiodarone exerts an additional electrophysiological effect in patients already under chronic treatment with the same drug. Such a combined therapy could be used with a high efficacy and safety for the conversion of recent onset atrial fibrillation in patients who are receiving long-term amiodarone therapy.     

Effects of Combination Therapy of Amiodarone and Bisoprolol in Patients With Paroxysmal Atrial Fibrillation

To examine the long-term efficacy of combination therapy of amiodarone and bisoprolol in patients with paroxysmal atrial fibrillation （P-AF）. Methods Eighty-eight patients with P-AF were divided into two groups ： 44 patients treated with bisoprolol and amiodarone were enrolled in group A; 44 patients treated with amiodarone alone were enrolled in group B. Survival rates, rates of conversing to permanent atrial fibrillation （AF）, subjective symptom improvement rates and secondary bradyarrhythmia rates of the two groups were measured and analyzed. Results At 12 and 24 months, the survival rates for patients free from atrial fibrillation recurrence were 75 % and 59. 1% in group A, and 54.5 % and 36. 4 % in group B （P 〈 0. 05, group A vs. group B）. The percentage of patients with conversion to permanent AF was 6.8 % in group A and 25 % in group B （ P 〈 0. 05, group A vs. group B）. In group A, 36 patients （81.8 % ） experienced subjective symptom improvement and only 24 patients （54. 5 % ） in group B （P 〈 0. 01, group A vs. group B）. Whereas there was no significant difference in patients with secondary bradyarrhythmia （ P 〉 0. 05, group A vs. group B）. Conclusions In patients with P-AF, bisoprolol appears to enhance the efficacy of amiodarone therapy in maintaining sinus rhythm and improving subjective symptoms. （ S Chin J Cardiol 2009：10（1 ） ： 26 -30）     

Mechanisms of Termination of Atrial Fibrillation by Class I Antiarrhythmic Drugs:

Sodium channel blocking drugs (Class I antiarrhythmic agents) have been used for the termination of atrial fibrillation (AF) and for sinus rhythm maintenance for almost 100 years. Despite this long history, the mechanisms that underlie their efficacy in AF remain poorly understood. Classic notions about the determinants of cardiac reentry, as embodied in leading circle theory, and of AF, as reflected in the multiple wavelet hypothesis, suggest that cardiac conduction slowing should promote, rather than prevent, AF. This article reviews the evidence (both clinical and experimental) for the efficacy and mechanisms of action of Class I antiarrhythmic agents in AF. Application of mathematical models of AF to the evaluation of Class I mechanisms is discussed, and recent insights into the latter are presented. A better understanding of the ways in which Na⁺ channel blockers affect AF will be useful, not only for new antiarrhythmic drug development but also for gaining insight into the mechanisms of the arrhythmia. (J Cardiovasc Electrophysiol, Vol. 14, pp. S133-S139, October 2003, Suppl.)     

Hybrid Pharmacologic and Ablative Therapy: A Novel and Effective Approach for the Management of Atrial Fibrillation

Hybrid Therapy for Atrial Fibrillation. Introduction: Maintenance of sinus rhythm in patients with recurrent atrial fibrillation is often difficult to achieve with pharmacologic therapy. Complex catheter ablative procedures are being developed, but efficacy and safety issues remain to be clarified. We hypothesized that combined pharmacologic and simple ablative therapies in a targeted subset of patients will improve success in the treatment of atrial fibrillation. Methods and Results: We identified 13 patients (mean age 61.5 ± 16.2 years) with atrial fibrillation who converted to electrocardiographic atrial flutter during antiarrhythmic drug treatment. Surface ECG suggested “typical” atrial flutter in 11 patients and “atypical” atrial flutter in 2. Intracardiac mapping and entrainment studies revealed 9 patients had counter-clockwise isthmus-dependent atrial flutter, and the remaining 4 had complex activation patterns, suggesting the presence of multiple wavefronts. All 9 patients with typical atrial flutter underwent successful ablation. None of the 4 patients with complex activation patterns had successful ablation. Patients were followed for recurrences of atrial arrhythmias via clinic visits, record review, and interviews. In patients who underwent successful ablation and continued on antiarrhythmic drugs, 88.9% remain in sinus rhythm after a mean follow-up of 14.3 ± 6.9 months (range 1 to 28). Conclusion: In patients who experience conversion of atrial fibrillation to atrial flutter during antiarrhythmic drug treatment, ablation and continuation of pharmacologic therapy is a safe and effective means of achieving and maintaining sinus rhythm.     

心房颤动的药物治疗进展

心房颤动是临床上最常见的心律失常类型,患病率随年龄增长而增加,药物是心房颤动治疗的首选,由于传统抗心律失常药物潜在的致心律失常作用及心脏外的不良反应,故而在心房颤动的治疗中受限。近年一些新药的研制给心房颤动的治疗带来了新的希望,也为临床医生提供了更多的选择。现就心房颤动药物治疗进展做一综述。     

Atrial Mechanical Function Before and After Electrical or Amiodarone Cardioversion in Atrial Fibrillation: Assessment by Transesophageal Echocardiography and Pulsed Doppler

In some patients with atrial fibrillation (AF), it has been suggested that left atrial mechanical dysfunction can develop after successful electrical cardioversion, justifying postcardioversion anticoagulant treatment. The purpose of this study was to investigate differences in left atrial appendage peak flow velocities and the incidence of left atrial spontaneous echo contrast in patients with AF before and after electrical cardioversion or intravenous amiodarone, studied using transesophageal echocardiography (TEE) and pulsed Doppler. We performed a control TEE in 7 patients in the electrical group and 6 in the amiodarone group, with no significant clinical differences between both groups. A second TEE was performed immediately in the 7 patients with successful electrical cardioversion. The peak flow velocities in the appendage before and after the procedure were: filling 43.3 ± 22 vs 27.7 ± 28 cm/sec (P = 0.01) and emptying 35.5 ± 22 vs 23.6 ± 17 cm/sec (P = 0.01), respectively. The spontaneous echo contrast increased in 4 of the 7 patients. In 4 patients of the amiodarone group, the peak flow velocities in the appendage during AF and within the first 24 hours after restoration of sinus rhythm were: filling 37.4 ± 12 vs 37.8 ± 18 cm/sec and emptying 36.4 ± 18 vs 35.9 ± 18 cm/sec, respectively (P = NS). There was no change in spontaneous echo contrast. In conclusion, patients with AF reverted to sinus rhythm using amiodarone did not show changes in left atrial mechanical function; however, patients with electrical cardioversion showed mechanical dysfunction. Further investigations on the effects of amiodarone and other drugs on the mechanical function of the atria are needed to determine if patients reverted pharmacologically require antico-agulation post reversion.     

The Future of Atrial Fibrillation Therapy

Today management of atrial fibrillation (AF) centers on restoration and maintenance of normal sinus rhythm or control of the ventricular rate response to AF. Current guidelines state that rhythm and rate control strategies should be considered therapeutically equivalent, but recognize that no "one size fits all," an approach consistent with growing recognition of the heterogeneity of AF. As data from the Sotalol Amiodarone Atrial Fibrillation Efficacy Trial clearly demonstrate, conventional antiarrhythmics have a role in highly symptomatic AF accompanied by decreased quality of life. However, for many AF patients such drugs lack efficacy, have potentially serious side effects, and are poorly tolerated. In parallel with the development of more effective and safer antiarrhythmics, nontraditional approaches to prevention and treatment of AF are being explored. Treatments not considered "antiarrhythmic" that may prevent or forestall AF include aggressive antihypertensive therapy with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, and some, but not all, beta-blockers and calcium channel antagonists, especially when used as adjunctive therapy. Other approaches include statins, steroids, and fish oil to reduce atrial fibrosis and inflammation, and pacemakers to prevent bradycardia-mediated AF and as a pacing preventive strategy in selected patients. Ablative techniques with potential to cure AF are gaining popularity, but are not yet simple, straightforward, and risk-free procedures. In the future, treatment of AF will progress beyond today's focus on AF as a purely electrocardiographic disease toward a patient and context-specific management strategy involving multiple treatment modalities.     

Pharmacotherapy of Atrial Fibrillation

Atrial fibrillation is a common medical problem that has a wide clinical spectrum ranging from a benign condition, such as “lone” atrial fibrillation, to a life-threatening arrhythmia, when there is an accessory pathway. There is a striking contrast between the frequency of atrial fibrillation and the absence of well-defined, scientifically based medical management. At least four considerations guide the pharmacological treatment of patients with atrial fibrillation: (1) restoration of sinus rhythm; (2) acute and long-term control of the ventricular rate; (3) maintenance of sinus rhythm; and (4) anticoagulation. Pharmacological cardioversion is best achieved with intravenous flecainide, intravenous propafenone, or intravenous ibutilide. During episodes of atrial fibrillation, the drugs of first choice for control of the ventricular rate are calcium antagonists and beta-blockers. Digitalis is helpful in elderly patients and in cases with congestive heart failure. Maintenance of sinus rhythm is a complex task, owing to the proarrhythmic potential of antiarrhythmic drugs, and the treatment should be tailored to the individual patient's needs. No one drug is clearly better than another. As for amiodarone, its benefit/risk ratio remains to be evaluated prospectively. Usually, most of the patients benefit from serial electrical cardioversion, with the longest possible interval between cardioversion sessions being sought. The question about whether the aim of the treatment of atrial fibrillation should be to control the ventricular rate or to restore sinus rhythm will be answered by ongoing trials. The effectiveness of low-dose anticoagulation in preventing stroke in patients with nonrheumatic atrial fibrillation has been validated by seven separate studies. Anticoagulation with warfarin should be monitored carefully in order to achieve an International Normalized Ratio (INR) of between 2.0 and 3.0. This targeted INR decreases the embolic rate and eliminates the risk of intracranial bleeding. The role of aspirin alone in decreasing the risk of stroke remains to be established. Pharmacological management of patients with atrial fibrillation has to be improved, by better risk stratification and the development of new drugs with an optimal benefit/risk ratio. Ongoing trials are expected to provide important guidelines, corresponding to the needs of the many different types of patients with atrial fibrillation.     

Atrial Ectopics Prior to Atrial Fibrillation Onset

Background: This study examined the possible role of atrial ectopics and short runs of atrial tachycardia in the initiation of episodes of paroxysmal atrial fibrillation (PAF). Methods: Holter recordings from patients participating in pharmacotherapy trials for the prevention of PAF were examined. Treatment comprised placebo, digoxin, disopyramide, or atenolol. The frequency of atrial ectopic beats during each 30 seconds over the 5 minutes prior to PAF and whether this was also associated with atrial tachycardia (3 or more ectopics in succession) was calculated. Results: The mean number of ectopics was 4.1 in the final minute, but patients receiving disopyramide or atenolol had significantly more ectopics than those on placebo (P > 0.05 for both). Those on digoxin had a similar number of ectopics to placebo patients. There was no relationship between heart rate at PAF onset and ectopic frequency, nor any association between the presence of one or more episodes of atrial tachycardia and ectopic frequency. Conclusion: Atrial ectopics increase in frequency prior to PAF onset, and this study suggests that antiarrhythmic therapy may increase the number of ectopics required to initiate PAF.     

Parenteral Antiarrhythmic Drug Therapy in Ventricular Tachycardia/Ventricular Fibrillation: Evolving Role of Class III Agents—Focus on Amiodarone

Intravenous Amiodarone. More effective intravenous antiarrhythmic agents are required for treatment of patients with refractory malignant ventricular arrhythmias. More recently, a great deal of interest has been focused on use of intravenous amiodarone for these patients. Uncontrolled early studies showed that intravenous amiodarone was effective in 42% to 81% of treated patients. Recent large cooperative trials have documented the efficacy of intravenous amiodarone in these patients and have shown an efficacy comparable to bretylium in patients with refractory sustained ventricular tachycardia or fibrillation.     

Chronic Atrial Fibrillation

ABSTRACT One hundred consecutive patients admitted in 1980–82 for direct current conversion of chronic atrial fibrillation (AF) were followed. The first attempt to convert was made without the institution of class I antiarrhythmics. If AF relapsed, patients were selected for further conversions, in connection with which quinidine or disopyramide treatment was instituted. The proportion of patients maintaining sinus rhythm (SR) one and two years after the first conversion was 23% and 16%, after the second conversion 40% and 33% and after any number of conversions [1–12] 54% and 41%. Fifty-three per cent of the patients were symptomless before at least one conversion. Of the patients maintaining SR two years after conversion, 46% did not receive antiarrhythmic therapy. More than two conversions should be exceptional since symptoms of AF are often absent and the additional effect of further conversions is minor. A first attempt to convert without antiarrhythmics identifies a substantial proportion of patients maintaining SR without any prophylactic antiarrhythmic therapy.