Journal of Cardiovascular Pharmacology and Therapeutics

Atrial fibrillation is the most common cardiac arrhythmia in clinical practice, and its management remains challenging. A solid understanding of the scientific basis for atrial fibrillation therapy requires insight into the mechanisms underlying the arrhythmia, about which an enormous amount has been learned over the past 10 years. The basic information presently available about atrial fibrillation mechanisms is reviewed. The particular properties of normal atrial electrophysiology are discussed, including salient ionic determinants of the atrial action potential and key anatomic features. Reviewed are three crucial arrhythmia mechanisms long held to be involved in atrial fibrillation: 1) rapid ectopic activity, 2) single-circuit reentry with fibrillatory conduction, and 3) multiple-circuit reentry. The determinants of each and the evidence for their involvement in clinical and/or experimental atrial fibrillation are noted. The physiological consequences, various contributing mechanisms, and clinical implications of the role of atrial-tachycardia remodeling are analyzed. Atrial-tachycardia remodeling links the potential mechanisms of atrial fibrillation, since atrial fibrillation beginning by any mechanism is likely to cause tachycardia-remodeling and thus promote the maintenance of atrial fibrillation by multiple-circuit reentry. Atrial structural remodeling is discussed as a paradigm of atrial fibrillation in which the classic features required for reentry (reduced refractory period and reentrant wavelength) may be lacking. Finally, the importance of recent insights into potential genetic determinants of atrial fibrillation is reviewed. The classic understanding of atrial fibrillation pathophysiology saw the different possible mechanisms as being alternative and opposing hypotheses. We now consider the multiple potential mechanisms as contributing to the pathophysiology of the arrhythmia to a different extent in different clinical settings and interacting with each other in a dynamic way at various stages of the natural history in many patients. It is hoped that this improved mechanistic understanding will lead to the development of improved therapeutic options.

Atrial fibrillation is now the most common cardiac arrhythmia for which a patient is hospitalized. Clinically, it presents in a form that is paroxysmal, persistent, or permanent and may be symptomatic or asymptomatic, occurring in the setting of either no cardiac disease (“lone atrial fibrillation”) or, most often, in association with an underlying disease. Atrial fibrillation is associated with a 2-fold increase in mortality and, in the United States alone, causes over 75,000 cases of stroke per year. The annual prevalence of stroke is 5% to 7%, but the use of adequate anticoagulation can reduce this to less than 1%. Atrial fibrillation is a disorder of the elderly, with almost equal prevalence in men and women. In the United States, 80% of atrial fibrillation occurs in patients over the age of 65 years, and its prevalence tracks that of heart failure, which may be the cause, as well as the result, of the arrhythmia. Both conditions are increasing in epidemic proportions in the aging population. The most common causes of atrial fibrillation are hypertensive heart disease, coronary artery disease, and heart failure with a miscellany of lesser conditions, with about 10% lacking structural heart disease. Unlike other supraventricular arrhythmias, cure by the use of catheter ablation and surgical techniques has not been a reality except in a relatively small number of cases. However, restoration and maintenance of sinus rhythm remain the initial goal of therapy for most patients. Pharmacologic approaches remain the mainstay of therapy for rate control and anticoagulation as well as for maintenance of sinus rhythm following pharmacological or electrical conversion. The changing epidemiology of atrial fibrillation is highlighted, with the focus on its conversion by the use of newer and novel antifibrillatory agents relative to the mechanisms of the arrhythmia, to restore the stability of sinus rhythm.

The precise mechanisms of clinical effect of antiarrhythmic agents and the ideal “molecular targets” against arrhythmias, in particular atrial fibrillation, are poorly understood. Current antiarrhythmic drug development, particularly for drugs expected to be active against atrial fibrillation, has focused on drugs with multiple ionic mechanisms of action, in particular on those that block multiple potassium channels. Investigation of antiarrhythmic agents is complicated by the diversity of animal-disease models studied, by the potential multiple mechanisms of arrhythmias, and by the incompletely understood relationships between risks and benefits of antiarrhythmic drug therapy. Furthermore, rhythm control strategies in large groups of patients with atrial fibrillation have failed to show substantial clinical benefit. Nevertheless, drugs that block multiple potassium channels and appear to have relatively little organ toxicity, such as tedisamil, may represent an important new avenue in the therapeutic approach to highly symptomatic arrhythmias such as atrial fibrillation.

Atrial fibrillation has recently come into clinical and research focus. In particular, ventricular rate control has been carefully compared with atrial rhythm control. Additionally, the recent discovery of atrial stunning has initiated clinical and research interest in atrial remodeling. Atrial fibrillation is more likely to occur when the atria are damaged by increased fibrosis. The ideal way to prevent atrial fibrillation and the risk of repetition is by tackling the root causes, such as ischemic heart disease, heart failure, and left ventricular hypertrophy. Tedisamil is an unusual antifibrillatory compound that has a novel mechanism of action by inhibiting the transient outward current (Ito) and the repolarizing potassium currents in the sinoatrial node. Tedisamil works acutely against atrial fibrillation. Importantly, atrial fibrillation is often caused by or related to cardiac ischemia, and conversely, ischemia is caused by the increased oxygen demand of atrial fibrillation. Hence, the double properties of tedisamil as a drug that both inhibits atrial fibrillation and acts in an anti-ischemic mode are an attractive basis for future clinical research.

Pharmacologic treatment remains the mainstay of therapy in patients with atrial fibrillation for the maintenance of normal sinus rhythm. Initial therapy of atrial fibrillation is often directed toward the maintenance of sinus rhythm by means of cardioversion and the use of antiarrhythmic drugs. Heart rate control is often only pursued when rhythm control fails. Four randomized controlled trials have carefully evaluated the yield of these two treatment strategies as the initial approach to patients with paroxysmal or persistent atrial fibrillation. In essence, all four trials demonstrated that an initial strategy of rate control is equally effective compared to the rhythm control approach in terms of clinically important outcome measures including mortality, stroke prevention, or quality of life. Accordingly, rate control can be considered as an initial approach to therapy in patients with paroxysmal or persistent atrial fibrillation. The four randomized trials clearly demonstrate that continuous anticoagulation is mandatory in all patients with atrial fibrillation and risk factors for stroke, irrespective of the initial therapeutic approach of rhythm or rate control.