Arrhythmias are common clinical problems. Atrial fibrillation (AF) affects 2-5 million Americans, is a common cause of cardiovascular morbidity including hospitalization, heart failure, and stroke, and is associated with increased mortality [1]. Sudden cardiac death (SCD) due to very rapid ventricular arrhythmias (ventricular tachycardia, VT, and ventricular fibrillation, VF) is the commonest cause of death among American adults, accounting for 250,000-500,000 cases annually, 10-20% of all adult death [2]. This review will outline the challenges and opportunities presented in applying contemporary genetic analyses to understanding variability in drug response in this area. Relevant clinical features are first discussed, followed by a description of challenges in the field and current status.
Atrial fibrillationMost patients with AF have concomitant structural abnormalities of the heart such as left ventricular hypertrophy. In a minority, AF occurs in the absence of such abnormalities, and is termed "lone AF". A family history of AF is common in affected individuals, and is even more common in those with lone AF [3,4]. Other studies associate indices of oxidant stress [5] or renin-angiotensin activation [6][7][8] with the arrhythmia. One setting in which AF is especially common is in patients who have undergone cardiac surgery, where the incidence can be as high as 25% in the week after the procedure. In this setting, inflammatory pathways have been implicated [9,10].Clinical presentations in AF are highly heterogeneous. AF results in loss of coordinated atrial activity, and irregular and often rapid ventricular response rates due to conduction of atrial fibrillatory activity through the atrioventricular node. Therapies are thus designed to prevent the arrhythmia and maintain normal atrial activity ("rhythm control") or to slow conduction through the AV node, thereby slowing the ventricular response rate ("rate control"). It is intuitively obvious that a strategy to prevent the arrhythmia and maintain normal cardiac electrical activity should be superior to one designed to ignore the arrhythmia but treat its symptoms; nevertheless, randomized trials comparing rhythm control to rate control have shown, if anything, slight superiority of the rate control strategy [11]. One reasonable explanation for this apparent paradox is that the drugs used for rhythm control are not uniformly effective, and do carry serious cardiac and non-cardiac risks of their own.In patients who are highly symptomatic with the arrhythmia, a rate control strategy is often ineffective. In such individuals non-pharmacologic, catheter-based ablative therapies are now being developed to identify specific regions within the atria -notably extensions of the left atrial myocardium into pulmonary veins -that drive fibrillatory activity. These approaches are meeting with increasing, although currently incomplete, success [12,13].
