Arrhythmia Pharmacogenomics: Methodological Considerations

Abstract

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].

Standard Antiarrhythmic Drugs

“…29 Proarrhythmia is defined as the generation of new or worsened arrhythmias with drug therapy, but it might not be readily apparent that a drug is, in fact, responsible for an arrhythmia exacerbation. The recognition that drugs designed to suppress arrhythmias can, in some patients, actually increase arrhythmias or provoke new ones is probably the most important factor governing the selection and use of antiarrhythmic drugs.…”

“…This phenomenon has been referred to as "reduced repolarization reserve" 16,34 (Figure 111-3) and suggests that multiple often redundant mechanisms maintain normal repolarization, so that minor alterations in function might not be obvious at baseline. 29 Some of the ion channel variants appear to represent relatively straightforward examples of subclinical LQTS that is then exposed by drug administration. Other risk factors for torsades de pointes appear pharmacodynamic in nature: female sex, advanced heart disease or left ventricular hypertrophy, bradyarrhythmias, hypokalemia, and The concept of reduced repolarization reserve.…”

Cardiovascular pharmacogenetics

“…The D allele which is associated with higher angiotensin II levels has been shown to cause a blunted response to anti-arrhythmic drug therapy: subjects with DD/ID genotypes (71%) were more likely to have recurrent AF during therapy (Roden et al, 2009). Furthermore, in a single-locus analysis to identify susceptibility genes of non-familial structural AF, the ACE gene insertion/deletion polymorphism M235T, G-6A and G-217A were all significantly associated with AF with significantly higher allelic frequencies in cases than in controls (Tsai et al, 2008;Tsai et al, 2004;Xiao et al, 2010).…”

Implications for Educating the Next Generation of Nurses on Genetics and Genomics in the 21st Century

“…One's genotype can also guide decisions about risk management strategies for inherited conditions. For example, arrhythmogenic right ventricular cardiomyopathy (ARVC) and congenital long QT (LQT) syndrome cause sudden death due to altered electrical conductivity of the heart muscle (Roden, Kannankeril & Darbar, 2009). Genetic tests for mutations associated with ARVC and LQT are available, and persons found to be at risk can be treated prophylactically with antiarrhythmics, beta‐blockers, angiotensin‐converting enzyme inhibitors, or other medications.…”