Correspondence *Division of Cardiac and Vascular Sciences, St George's University of London, Cranmer Terrace, London SW17 0RE, UK

Email jcamm@sgul.ac.uk

Introduction

Lifetime risk for development of atrial fibrillation (AF) is 1 in 4 for men and women aged 40 years or older.^{1, 2} A recent study from the Mayo Clinic, Rochester, MN, analyzed the Poisson estimates of the increase in AF in Olmsted County, MN, between 1980 and 2000.³ According to this study, 12.1 million adults will have AF by 2050, assuming there is no further increase in age-adjusted AF incidence beyond 2000, and this figure could reach 15.9 million if the incidence of AF continues to rise.³ Even these projections could, however, underestimate the prevalence of unrecognized or silent AF.⁴

Frequently associated with costly complications such as thromboembolic stroke and heart failure, AF presently consumes approximately 1% of respective health-care budgets in the UK, France and the US.⁵ Despite advances in pharmacological and nonpharmacological approaches to the prevention of recurrent AF and thromboembolic complications, primary prevention of AF with 'upstream' therapy and risk factor modification is likely to produce a greater benefit in the general population than specific interventions.

Evidence to support the antiarrhythmic effects of drugs not traditionally used as antiarrhythmic agents is accumulating. Inflammation, oxidative injury, atrial myocyte metabolism, remodeling of the extracellular matrix, and fibrosis, are potential novel therapeutic targets. Angiotensin-converting-enzyme (ACE) inhibitors, angiotensin-receptor blockers (ARBs), -blockers, statins and n-3 polyunsaturated fatty acids (PUFAs) all have antiarrhythmic potential, in addition to any treatment effect they have on the underlying disease. These observations open the possibility of exploiting these agents for the prevention or delay of atrial remodeling in patients with AF, even when there is no routine indication for such therapy. Here, we explore the possible roles statins and PUFAs may have in the prevention of AF and their potential beneficial effects on adverse remodeling seen in patients with AF.

Remodeling in atrial fibrillation

AF results from a complex pathophysiological process that promotes triggers of the arrhythmia and prompts formation of the electrophysiological substrate that supports this condition. The electrical properties of the atria are adjusted by sustained AF, such that the atria become more susceptible to the initiation and maintenance of the arrhythmia—a process known as atrial remodeling (Figure 1).⁶ Electrical activation in sustained AF occurs as multiple wavelets separated by lines of conduction block, generating irregular re-entrant activity. Conduction block can occur because of fixed anatomical obstacles, myocardial regions with inherently different electrophysiological properties, the presence of acquired structural barriers such as scars and incisions, functional obstructions caused by patchy fibrosis, stretch-induced longitudinal dissociation, or areas of myocardium being at different stages of recovery and excitability. Spatial orientation of atrial myocytes, structural changes (e.g. increased cellular volume and sarcomere misalignment), and gap junction properties have an essential role in AF pathophysiology. Hence, any process that induces changes in atrial geometry and the uniformity of atrial electrophysiology could contribute to arrhythmogenesis.

Figure 1 Pathophysiological processes associated with atrial remodeling that could be targets potentially modifiable by statins and n-3 polyunsaturated fatty acids, and summary of the evidence of their clinical use in the prevention of atrial fibrillation.

Abbreviations: eNOS, endothelial nitric oxide synthase; MMP, matrix metalloproteinases; PPAR, peroxisome proliferator-activated receptor; PUFA, n-3 polyunsaturated fatty acid.

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When associated with persistent rapid atrial rates, atrial stretch and ischemia lead to atrial myopathy.⁶ Increased cellular volume, sarcomere misalignment, sustained proteolysis, loss of contractile elements, and accumulation of glycogen are all evident in myopathic myocytes. The metabolism of atrial myocytes also changes during AF, shifting to a more fetal phenotype, so-called 'dedifferentiation'. Further changes involve gap junction remodeling, with reductions in the expression of connexin-40 and connexin-43.

Stretch-activated channels convert mechanical gradients caused by stress to electrical gradients. Activation of these channels also enhances calcium binding to cellular myofilaments, generating calcium currents, which produce afterdepolarizations and increase automaticity.⁷ In a sheep heart model of stretch-related AF, an acute increase in intra-atrial pressure was associated with an inrease in the rate and organization of waves emanating from the pulmonary veins, indicating that stretch is a key factor underlying AF development.⁸ In concordance with this observation, blockade of stretch-activated channels by gadolinium or a peptide isolated from the venom of the Chilean tarantula Grammostola spatulata (Gs-MTx4) impeded initiation and maintenance of electrically induced AF and suppressed the occurrence of spontaneous arrhythmia.^{9, 10}

Atrial stretch increases local synthesis of angiotensin II. The density of angiotensin II receptors in the atria is generally greater than in the ventricles, rendering the atria more vulnerable to the effects of angiotensin. Stimulation of angiotensin II type 1 receptors initiates a cascade of processes that result in myocyte hypertrophy, fibroblast proliferation, accumulation of collagen and apoptosis.¹¹ In addition, angiotensin II modifies atrial electrophysiology by indirect effects on ion channels, by increasing calcium influx, promoting inflammation, and possibly also causing gap junctional remodeling, which in turn impairs cell-to-cell coupling.

Mechanisms of atrial fibrillation

Antiarrhythmic effects of statins

Statins have pleiotropic effects beyond improving lipid abnormalities, stabilizing the atherosclerotic plaque, and treating underlying heart disease, and it is these other effects that can prevent AF (Figure 1 and Box 1). Statins have strong anti-inflammatory and anti-oxidant actions. They inhibit leukocyte–endothelium interaction by downregulating endothelial cell adhesion molecules, such as P-selectin and intracellular adhesion molecule 1, and attenuate leukocyte infiltration, thus curtailing tissue damage. Statins antagonize oxidant pathways involved in atrial remodeling by augmenting catalase and glutathione peroxidase activity. Oxidized LDLs are known to upregulate angiotensin II type 1 receptors. By reducing oxidative stress and LDL concentration, statins might counteract the arrhythmogenic effects of angiotensin II. Statins might also alter the lipid portions of the membrane through which the transmembrane segments of ion channels penetrate, thereby affecting ion channel conductance.

By increasing NO synthesis in the endothelium, statins protect atrial myocytes during ischemia associated with rapid atrial rates, and can also reduce the expression of a variety of MMPs—effects implicated in atherosclerotic plaque stabilization that could also have an important role in the extracellular matrix remodeling associated with AF. Evidence from patients undergoing elective CABG surgery indicates that statin use is associated with a reduced incidence of postoperative AF, which is paralleled by changes in the TIMP-1–MMP-1 balance.⁴⁷ Spatial and temporal relationships between the MMP system and AF are complex, however, and there are no experimental data to indicate whether the inhibiting effects of statins on MMPs are protective in those with AF.

Clinical evidence

Small observational studies and retrospective analyses have provided most of the clinical evidence for the efficacy of statins in preventing AF (Table 1).^{47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66} AF following cardiac surgery represents an excellent model for studying the effects of agents that target the inflammatory mechanisms of AF. The incidence of postoperative AF is high, with the condition usually developing within 3 days of intervention. In an observational study of 234 patients, Marin et al. reported that statin use significantly reduced AF risk after CABG surgery by 48%, and following analysis of MMP-1 and TIMP-1 plasma levels, suggested that this effect could be attributable to the modulating effect of statins on matrix remodeling.⁴⁷

Table 1 Clinical studies of statins for the prevention of atrial fibrillation.

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The putative antiarrhythmic properties of atorvastatin were demonstrated in the Atorvastatin for Reduction of Myocardial Dysrhythmia after Cardiac Surgery (ARMYDA-3) trial.⁴⁸ This randomized, prospective study of 200 patients showed that pretreatment with 40 mg atorvastatin daily, starting 7 days before the operation, was associated with a significant reduction in the incidence of in-hospital AF (35% in the atorvastatin group vs 57% in the placebo group; relative risk reduction 61%). Despite being the first 'proof of concept' study, ARMYDA-3 was conducted in a highly specific patient population in which inflammation and oxidative stress—the key targets for statin therapy—were key in the development of AF. Furthermore, although not statistically significant, there were differences between the placebo and atorvastatin arms—fewer patients in the placebo arm received -blockers and more underwent valve surgery thus increasing the risk of AF in this arm. In many patients, postoperative AF is a 'one-off' event with a low risk of recurrence and is, therefore, easily prevented. For these reasons, the ARMYDA-3 findings cannot be readily extrapolated to other patient populations with AF.

Retrospective analyses of data from two observational, nonsurgical studies have demonstrated that statin therapy lowered both the incidence of new-onset AF (18 cases vs 37 per 1,000 person-years)⁴⁹ and AF onset after electrical cardioversion reduced the recurrence rate by 70%.⁵⁰ In ADVANCENT^(SM)—a registry of 25,268 patients with left ventricular dysfunction—lipid-lowering therapy reduced the occurrence of AF by 34% (95% CI 29–39%), regardless of lipid status at baseline.⁵¹ The effect of statins was greater than that of -blockers, ACE inhibitors or ARBs. Post hoc analysis of data from the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) mirrored these findings.⁵² Statin use was independently associated with a highly significant 28% reduction in relative risk of AF and was as potent a predictor of reduced AF incidence as amiodarone use, and a stronger predictor than any other medication assessed, such as ACE inhibitors. Approximately 30% of patients analyzed had nonischemic cardiomyopathy; whether this subgroup benefited from statin therapy is unknown. In a single-blind study of patients without coronary artery disease, 20–40 mg atorvastatin daily for 6 months abolished AF paroxysms in 65% of patients, compared with only 10% in the placebo group. The reduction in the occurrence of AF with atorvastatin was paralleled by a decrease in CRP levels.¹⁷ These findings should, however, be treated with caution; a 6-month follow-up period is insufficient to demonstrate any clinically meaningful effect on paroxysmal AF given the unpredictable nature of this condition. Furthermore, there was significant variation in the frequency of paroxysms recorded before study start, and asymptomatic AF could have lead to underestimation of AF incidence.

Treatment duration and dose could influence the ability of statins to prevent the formation of AF substrate. A prospective randomized study of 114 patients with persistent AF showed that pretreatment with 40 mg pravastatin for 3 weeks before electrical cardioversion, and continued for 6 weeks afterwards, had no effect on AF recurrence.⁵³ In the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) substudy, a trend towards improved AF resolution was observed in the 80 mg atorvastatin arm compared with placebo; however, the 16-week statin course was probably too short to demonstrate any significant effect on the occurrence of AF.⁵⁴ Interestingly, analysis of nearly 10,000 patients with heart failure who were prescribed statins found that AF was less common in those who received the highest doses than in those who received lower doses; AF incidence was lowest in those who were treated with high-dose atorvastatin.⁶²

These observations triggered several well-designed prospective trials instigated to assess the antiarrhythmic value of statins in the absence of formal indications such as hyperlipidemia or underlying heart disease. The Atorvastatin Therapy for the Prevention of Atrial Fibrillation (SToP-AF) study is an ongoing randomized, double-blind, placebo-controlled trial assessing the effects of 80 mg atorvastatin on AF incidence after cardioversion during 1 year of follow-up. The ability of intervention to decrease markers of oxidative stress at 30 days will also be assessed.

Antiarrhythmic effects of N-3 polyunsaturated fatty acids

Several mechanisms have been implicated in the antiarrhythmic action of n-3 PUFAs (Figure 1 and Box 1). Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are found in varying proportions in PUFAs extracted from fish oil. The presence of PUFAs in cell membranes has membrane-stabilizing and anti-inflammatory effects, can prevent stretch-induced shortening of atrial refractoriness and reduces membrane fluorescence anisotropy by increasing membrane fluidity.⁶³ PUFAs are also involved in the modulation of a number of ion channels.⁶⁴

Clinical evidence

The antiarrhythmic potential of PUFAs has been demonstrated in a randomized controlled trial of patients with postoperative AF. Pretreatment of 160 patients with fish oil capsules containing 850–882 mg EPA and DHA in a ratio of 1:2, for 5 days before CABG surgery reduced the occurrence of postoperative AF (15% in the PUFA group vs 33% in the placebo group; a relative risk reduction of 65%).⁷⁰ Data from epidemiological studies, however, are highly controversial (Table 2). Although the CHS, which enrolled 4,815 individuals older than 65 years, reported a significant 31% reduction in AF risk with greater intake of PUFAs from fish (i.e. 5 portions or more per week),⁷¹ other large, population-based studies have failed to reproduce these results (Figure 2).^{72, 73, 74} In fact, the Danish Diet, Cancer, and Health Study of 47,949 adults,⁷² and the US-based Physicians' Health Study of 17,679 men,⁷³ actually reported a trend toward increased risk of developing AF in those with greater fish intake.

Figure 2 Risk of atrial fibrillation in the highest versus lowest fish-consumption groups, as reported in several population-based studies.

Abbreviation: CHS, Cardiovascular Health Study.

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Table 2 Incidence of atrial fibrillation in population-based studies of n-3 polyunsaturated fatty acids.

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Of interest, even in the positive CHS report, a lower AF incidence was associated with consumption of broiled or baked fish but not fried fish or fish sandwiches, indicating that the preparation method might also influence risk.⁷¹ Frying, for example, can greatly alter the nutrient composition, increasing the content of n-6 and trans fatty acids, and oxidation species. Studies that demonstrated no benefit of PUFAs on AF generally enrolled younger patients than studies showing benefit; the mean age in these 'no benefit' studies was 56 years⁷² and 60 years⁷³ as opposed to 73 years in the CHS study.⁷¹ The overall incidence of AF was also substantially lower in the 'no benefit' studies (1.2% and 7%, respectively) than in the CHS study (20%). Other factors, such as underestimation of AF incidence, socioeconomic and lifestyle differences, dietary changes during follow-up, and incidental differences in underlying heart disease, all could have contributed to the variations seen in outcomes. In a placebo-controlled, triple-blind study that enrolled 108 patients with persistent AF, treatment with PUFAs started 4 weeks before cardioversion had no effect on the recurrence rate during 1 year of follow-up.⁷⁵ Similarly, three prospective randomized studies in patients with implantable cardioverter-defibrillators failed to demonstrate any significant beneficial effect of EPA/DHA supplementation on ventricular tachyarrhythmias.⁷⁶ Several randomized controlled studies are ongoing that will look at the effects of PUFAs in paroxysmal AF and after electrical cardioversion.

Clinical recommendations

The preventive effect of statins and PUFAs on AF should be considered in the context of other therapies with proven antiarrhythmic effects, such as -blockers, and therapies with emerging antiarrhythmic potential, such as ACE inhibitors, ARBs, aldosterone antagonists and anti-inflammatory agents.

Although the results of several retrospective analyses and small studies have been controversial, the overall trend highlights the potential benefit of statins in patients with AF. Not surprisingly, the impact of statin therapy on AF burden is particularly recognizable in AF associated with heart surgery, in which inflammation and oxidative stress demonstrate strong mechanistic links to arrhythmogenesis. Even in this clinical setting, however, more studies in larger and well-balanced populations are required before strong clinical recommendations are formed. Evidence of the incremental benefit of statins in general AF populations treated with optimal medical therapy (-blockers, ACE inhibitors and ARBs) is much more elusive and the conclusion balances between trends observed in small studies and mere assumptions. Statins have a proven and considerable impact on morbidity and mortality both in patients with risk factors and patients with cardiovascular pathologies, but there are no data to support their effect on AF or their use outside licensed indications (e.g. lone AF).

Evidence in favor of therapy with PUFAs to prevent arrhythmias is even less robust. Epidemiological studies have shown no advantage of increased fish intake on AF incidence, and three prospective randomized studies have failed to demonstrate the antiarrhythmic effect of EPA and DHA supplementation in patients with implantable cardioverter-defibrillators; some trials have even hinted at their potential proarrhythmic effect. We do not, therefore, support the use of PUFAs in the prevention of AF recurrence. Elucidating the incremental benefit of PUFAs on AF after heart surgery in patients treated with proven therapies, such as -blockers and amiodarone, would require a larger, adequately designed study.

Conclusions

By 2050 AF will be present in 2% of the general population and in a far higher proportion of elderly patients. Although many new antiarrhythmic drugs are under evaluation, only a few have proven sufficiently safe and effective to have reached the final stage of development. Nonpharmacological therapies for AF, such as catheter-based ablation techniques, have evolved rapidly and their widespread uptake has been fueled by several studies that have reported substantial advantage over antiarrhythmic drugs. Catheter ablation is not yet a well-proven therapeutic option for broader AF populations, however, and its long-term effects and impact on all-cause mortality are unknown. Even if new drugs, devices, or catheter-based approaches do prove superior to current therapies, their benefits must be substantial (i.e. they must be highly efficacious, safe and convenient) in order to off-set their inevitably increased cost.

Preventative therapy with agents targeting specific AF mechanisms, such as statin or PUFA-mediated prevention of remodeling, and inflammation and oxidative injury, offer comparatively cheap and potentially valuable, novel therapeutic strategies that can be widely applied. Despite exciting results from animal experiments and promising outcomes from observational studies and post hoc analyses, however, evidence of clinical benefit with statins and PUFAs is not sufficient to warrant a change in clinical practice for the time being.

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Subject areas under which this article appears: Arrhythmias | Intervention