QJM Advance Access originally published online on August 24, 2008
QJM 2008 101(11):845-861; doi:10.1093/qjmed/hcn101
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The impact of statin use on atrial fibrillation
From the 1Department of Cardiology, Hospital General Universitario, Alicante, 2Department of Cardiology, Hospital Universitario Virgen de la Arrixaca, Murcia, 3Centro Regional de Hemodonación, University of Murcia, Spain and 4Haemostasis, Thrombosis and Vascular Biology Unit, University Department of Medicine, City Hospital, Birmingham, UK
Address correspondence to Prof. G.Y.H. Lip, University Department of Medicine, City Hospital, Birmingham B18 7QH, UK.
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Summary |
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 Top Summary IntroductionSearch strategyUnderlying mechanisms in AF:...The role of inflammation...The pleiotropic effects of...ConclusionReferences |
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The aim of the present systematic review is to present an overview of the evidence linking atrial fibrillation (AF), inflammation and oxidative stress, with emphasis on the potential of statins to decrease the incidence of different types of AF, including new-onset AF, after electrical cardioversion (EC) and after cardiac surgery. Observational and clinical trials have studied the impact of statin therapy on new-onset, post-EC or postoperative AF. Data from different observational trials have shown that treatment with statins significantly reduces the incidence of new-onset AF in the primary and secondary prevention. The data are insufficient to recommend the use of statins before EC. Finally, perioperative statin therapy may represent an important non-antiarrhythmic adjunctive therapeutic strategy for the prevention of postoperative AF.
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Introduction |
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TopSummaryIntroductionSearch strategyUnderlying mechanisms in AF:...The role of inflammation...The pleiotropic effects of...ConclusionReferences |
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Atrial fibrillation (AF) is the most commonly sustained arrhythmia in daily clinical practice, affecting
0.9% of the population,1 and is associated with an increased mortality and morbidity from stroke and thromboembolism, heart failure and impaired quality of life.2 Attention has therefore been directed towards understanding the underlying pathophysiology of this condition, to provide novel insights into improving the therapeutic management of this condition. Whilst many patients with AF show some degree of atrial enlargement, elevation in atrial pressure, infiltration and/or inflammation of the atria, a substantial proportion of patients with AF have no detectable heart disease (lone AF).3,4 The mechanisms and role of remodelling and triggers in AF pathogenesis have attracted much interest. Remodelling can result from cardiac disease, cardiac arrhythmias or biologic processes such as senescence. Indeed, AF occurs because of a complex interaction between an arrhythmogenic substrate, trigger factors and the autonomic nervous system.5 AF induces electrophysiological changes in the atria causing a perpetuation of the arrhythmia (the so-called ‘electrical remodelling’) and also structural and ultrastructural changes in atrial tissue (structural remodelling).4,5
There are also emerging data to support a significant association between inflammation, oxidative stress and the development, recurrence and perpetuation of AF. For example, AF remains the most common complication of cardiac surgery and several studies suggest that AF may be induced by structural changes in the atria that are promoted by the active inflammatory process after this procedure.6–8 Thus, drugs that modulate oxidative stress and have anti-inflammatory action—such as glucocorticoids, angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (ACE-I/ARBs), oral vitamin C and non-esteroidal anti-inflammatory drugs—have been evaluated for favourable effects on the prevention on AF development and recurrence.9 Specifically, the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) may have multiple pleiotropic effects, including anti-inflammatory activity, and increasing data support a reduction in the development of AF by statin use6–9 and some reviews on the role of statins on arrhythmias have recently been published.10–12
The aim of the present review was to present an overview of the evidence linking AF and inflammation, with emphasis on the potential of statins to decrease the incidence of different types of AF, including new-onset, post-cardioversion and postoperative AF.
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Search strategy |
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TopSummaryIntroductionSearch strategyUnderlying mechanisms in AF:...The role of inflammation...The pleiotropic effects of...ConclusionReferences |
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We performed a comprehensive literature search by using electronic bibliographic databases (i.e. MEDLINE and Cochrane databases) up to February 2007 using the following keywords: atrial fibrillation, treatment, inflammation, high-sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6), statins, atorvastatine, simvastatine, postoperative, fibrosis, apoptosis, metalloproteinases, connexins, electrophysiology, atrial remodelling, mechanism, pleiotropic effects, electrical cardioversion (EC), ablation, postoperative, cardiac surgery, coronary artery bypass grafting (CABG). Bibliographies of all selected articles and review articles were reviewed for other relevant articles. Finally, the supplements of major journals were hand-searched to identify relevant abstracts that had not been published as peer-reviewed articles. When necessary, study authors were contacted to obtain further data. We included articles that were relevant to the topic of this review.
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Underlying mechanisms in AF: an overview |
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TopSummaryIntroductionSearch strategyUnderlying mechanisms in AF:...The role of inflammation...The pleiotropic effects of...ConclusionReferences |
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The pathophysiology of AF is highly complex and we must take the normal age-related changes into account in any interpretation of atrial histology, given the relation between AF and advanced age, associated heart disease, obesity, hypertension or diabetes.13–15 The available data support two main theories as mechanisms of AF: a multiple-circuit re-entry hypothesis, which has been the dominant theory for many years and the focal origin theory, which is strongly supported during the last years. These two mechanisms are not mutually exclusive and may coexist sometimes.16 Undoubtedly the most common form of AF is that associated with structural heart disease. The longer the AF persists, the more difficult it is to restore sinus rhythm and to prevent recurrence and clearly, time is a factor for perpetuation.
The persistence of AF may lead to changes in atrial function and structure, a process known as atrial remodelling. Two principal forms of remodelling have been described, at least in animal models of AF: (i) tachycardia-induced electrical remodelling, which alters cellular electrical properties and (ii) structural remodelling, which alters atrial tissue architecture.17,18
Electrical remodelling
AF alters atrial electrophysiology in a way that favours AF initiation and maintenance, a phenomenon called electrical remodelling. This perpetuation of AF has been described from experimental studies as ‘AF begets AF’.19 Characteristic electrophysiologic features of AF-induced remodelling are decreased atrial effective refractory period (ERP) and a reduction in physiological ERP rate adaptation. This ERP decrease reduces the wavelength and thus atrial tachycardia remodelling produces a substrate favourable for AF perpetuation.16 Decreased calcium current reduces action potential duration, reducing the atrial ERP and the wavelength, favouring multiple circuit re-entry and the promotion of AF.20,21
Structural remodelling
AF induces structural and ultrastructural changes in atrial tissue. Structural remodelling occurs in parallel with the precedent electrical changes, at least in animal experimental models of AF. Nonetheless, data on human atrial structural remodelling are limited and difficult to distinguish from the many degenerative changes related to aging and associated heart disease.15
Fibrosis is an important component of the pathophysiology of AF, especially when the arrhythmia is associated with heart failure. Advanced interstitial fibrosis in human AF would predict an impairment of atrial conduction at the microscopic level and may render the atrial myocardium discontinuous, resulting in a branching structure.22–24 The extracellular matrix is a dynamic structure, with continuous changes in the amount and proportions of its structural proteins that include different types of collagen, elastin, proteoglycans and glycoproteins.25 Different enzymes such as the matrix metalloproteinase (MMP) family help with the degradation of extracellular components.26,27 Unsurprisingly, the presence of AF results in a differential upregulation of different MMPs and a downregulation in the tissue inhibitors of metalloproteinases (TIMPs), as an evidence of impaired matrix degradation.28,29
Other factors potentially involved in the induction or maintenance of AF include inflammation, oxidative stress, endothelial/endocardial dysfunction, ischaemia and autonomic nervous system activity. In experimental models, AF induced by rapid atrial pacing is associated with a marked decrease in endocardial nitric oxide bioavailability and endothelial NO synthase expression in the left atria.11 On the other hand, the initiation and maintenance of AF can also be related to increased atrial expression of components of the renin–angiotensin system. In animals, for example, blockade of the renin–angiotensin system has been reported not only to prevent left atrial dilation, cell death and atrial fibrosis, but also to slow conduction velocity. The association between AF and renin–angiotensin system is strongly supported by other clinical data suggesting that inhibition of the system may decrease the incidence of new-onset AF.11,30 Finally, experimental data suggest that atrial ischaemia may create a substrate for AF maintenance31 and increased sympathetic or parasympathetic tone has also been implicated in the initiation of AF.32,33
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The role of inflammation and oxidative stress in AF |
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TopSummaryIntroductionSearch strategyUnderlying mechanisms in AF:...The role of inflammation...The pleiotropic effects of...ConclusionReferences |
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Accumulating data suggest that inflammation as well as abnormal oxidative stress is a pathophysiological feature involved in the development, recurrence and persistence of AF. These conditions are associated with enhanced myocardial tissue inflammation and atrial remodelling that may serve as a substrate for the development of AF.6,7,34–36 There is also solid evidence to suggest that in several pathophysiological conditions, inflammation augments oxidative stress and vice versa. It is therefore tempting to speculate that oxidative stress and inflammation interrelate at some level facilitating atrial remodelling.35,36
The link between inflammation and AF
The available data have suggested a significant association between inflammation and the development, recurrence and perpetuation of AF.7,8 This association can be extracted from the frequent relation between inflammatory conditions of the heart, such as myocarditis or pericarditis and AF.37,38 Histologic studies have demonstrated that inflammatory infiltrates are present in biopsies from patients with lone AF but absent in control subjects. Frustaci et al.23 demonstrated in atrial biopsies, a high prevalence of inflammatory infiltrates, myocyte necrosis and fibrosis, linking atrial remodelling to inflammation.
On the other hand, there is increasing evidence that inflammation plays a pivotal role in atherosclerotic heart disease39 and increased CRP is an important predictor of vascular events in cardiovascular disease (stroke, peripheral vascular disease, sudden cardiac death, AF, plaque rupture and recurrent ischaemia and myocardial infarction).40,41 Bruins et al.42 were the first to propose the inflammation-AF hypothesis, following their observations of an increased frequency of AF after CABG, in relation with the peak elevation of CRP levels. Patients with AF also have been reported to have increased hs-CRP levels compared with controls in sinus rhythm,43–45 being higher in persistent AF than in paroxysmal46 and may also predict patients at increased risk for future development of the arrhythmia.47,48 Furthermore, measurement of hs-CRP prior to cardioversion may help in the stratification of patients in terms of the risk of recurrence of AF after cardioversion.49 The precise mechanism for the increased circulating hs-CRP in AF is uncertain, but might reflect active participation of CRP in the local inflammatory response within the atrial myocardium.6,7 Other inflammatory cytokines as IL-6 are also increased in patients with AF,50–52 but may be more related to associated co-morbidities rather than AF per se.51
The obvious important question that remains is the one of the ‘chicken and egg phenomenon’. Does inflammation occur as a response to the onset of AF or is it itself an initiating event in the development of AF?7,8,53 It is also possible that the two mechanisms are interconnected. Rapid atrial activation can induce apoptosis of atrial cardiomyocytes and this damage can lead to a low inflammatory response, with the consequent elevation of CRP levels and be part of a structural remodelling leading to the persistence of AF.54 On the other hand, the presence of systemic inflammation with increased CRP levels may predispose patients to developing AF. The fact that elevation was more pronounced in patients with persistent AF than in those with paroxysmal AF led Chung et al.46 to propose that the role of inflammation in AF may be more pathogenetic in promoting persistence rather than initiation of AF. CRP may localize in atrial tissue possibly binding to the membranes of myocardial cells in inflamed tissues, and it has been suggested that this acute-phase protein promotes local complement activation and, hence, tissue damage. The latter may predispose patients with triggering atrial foci to the development of AF.55
Importantly, high plasma IL-6 levels in patients with AF were reported to be an independent predictor of stroke and the composite end point of stroke or death,56 and more recently raised CRP levels were positively correlated to stroke risk and related to stroke risk factors, vascular events and mortality,57 suggesting that inflammation in AF may predict a poor prognosis. Interestingly, the observation that CRP is predictive of all-cause mortality rather than stroke per se reflects the relationship of CRP to associated vascular disease and co-morbidities in AF, rather than AF and thrombogenesis per se.57
The renin–angiotensin system seems to have a key role in this process, since AF leads to altered angiotensin II receptor expression and, conversely, blockade of the system decreases inflammatory processes.30 Angiotensin II receptor blockade significantly reduces multiple markers of inflammation (CRP, TNF-
, IL-6) in hypertensive patients.58 Thus, the beneficial anti-arrhythmic effects of ACE-I/ARBs could be attributed, at least in part, to their anti-inflammatory action.
On the other hand, one study with corticosteroids also suggested the possibility that CRP-lowering therapy may reduce the recurrence of AF, supporting the potential utility of anti-inflammatory therapy in the prevention of AF.59
On the basis of these observations, inflammation is probably an integral part of both the initiation and the perpetuation of AF. Although these available data have suggested a significant association between inflammation and the development, recurrence and perpetuation of AF, further data from prospective and interventional studies are mandatory to well establish this association.
The link between oxidative stress and AF
Oxidative stress has also been implicated in the pathogenesis of AF in animal models and humans.54,60,61 Mihm et al.54 were the first to investigate the energetic status of myofibrils and the oxidative modification of proteins in right atrial appendage biopsies of patients with chronic AF subjected to Maze operation. In the atrial myocardium of chronic AF patients, there is also evidence of oxidative damage that has impact on the energetic, electrophysiological and mechanical properties of atrial myocytes, probably contributing to atrial remodelling. Indeed, atrial tachy-pacing in a dog model provokes an increase in protein nitration associated with a decrease in tissue levels of vitamin C; and these oxidative modifications lead to a decrease in the ERP and atrial electrical remodelling.62 Interestingly, supplementation with ascorbate attenuated the pacing-induced atrial ERP shortening and the accumulation of peroxynitrite.62 When given before and for 5 days following cardiac by-pass surgery, ascorbate also reduced the incidence of postoperative AF.62
On the other hand, Dudley et al.61 demonstrated that AF induced by rapid atrial pacing in pigs is characterised by increased nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity, which is a major source of myocardial superoxide production. Moreover NADPH-dependent superoxide production is increased in the fibrillating human atria, which suggests that reactive oxygen species may play an important role in atrial oxidative injury, as well as the electrical and structural remodelling of the atria.63 The NADPH oxidase-derived ROS might have several pathologic effects in the atrial myocardium, including oxidative degradation of endocardial NO, local activation of coagulation cascade components and prothrombotic molecules such as PAI-1 and tissue factor, thus facilitating thrombus formation, induction of fibrosis, inflammatory responses and alteration of ion channel function.54,61,63
Rac1 GTPase has been shown to participate in signalling pathways for the activation of the NADPH oxidase complex and analysis of human left atria myocardium reveals that Rac1 GTPase and NADPH oxidase activity are up-regulated in patients with AF compared with patients in sinus rhythm.64 At the gene level, Kim et al.65 examined the gene transcriptional profiles in the human atria tissue from patients with permanent AF who underwent the Maze surgical procedure, and showed a balance towards a ‘pro-oxidative’ gene expression state.65 In other study, the degree of mitochondrial DNA damage in patients with AF was greater than that of control patients who were in sinus rhythm.66 More recently, Neuman et al.67 found that oxidative stress markers differed between patients with and those without persistent or permanent AF. All measures of oxidative stress were significantly increased in AF patients compared with controls.
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The pleiotropic effects of statins |
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TopSummaryIntroductionSearch strategyUnderlying mechanisms in AF:...The role of inflammation...The pleiotropic effects of...ConclusionReferences |
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Statins were developed and tested clinically on the basis of their capacity to suppress cholesterol biosynthesis and thereby modify an important vascular risk factor.68,69 As statins became more widely used, their effects beyond lipid lowering began to emerge. These so-called ‘pleiotropic’ actions affect almost the entire process of atherogenesis, from initial endothelial injury to the moment of plaque rupture and thrombosis.
There are a number of potential mechanisms by which lipid-lowering drug therapy could reduce the incidence of AF. The anti-inflammatory actions of statins may favourably affect atrial remodelling in AF. Activation of endothelial cells, by cytokines or other inflammatory mediators, is one of the incipient events in atherogenesis and it induces increased expression of binding molecules, which in turn facilitates the cellular attachment and migration of leukocytes and monocytes into the vascular wall.70 Statins diminish the expression and function of inflammatory mediators such as IL-6, TNF-, CRP, cyclooxygenase 2 and serum amyloid A71,72 and also reduce the surface expression of binding molecules.73 The use of statins in canine sterile pericarditis model74 and in patients with paroxysmal AF75 has been shown to be associated with a reduced incidence of AF and with significant lower CRP levels. These associations have also been found in patients who maintain sinus rhythm after EC.76 In other studies, the favourable effect of statins was not associated with amelioration of markers of inflammation.77–79
Other mechanisms, such as antioxidant effects, might contribute to the clinical benefit of statins. By depleting cholesterol intermediates, statins down-regulate Rac-1 GTPase activity by reducing isoprenylation and the membrane translocation of the small G-protein Rac1, a necessary step in the activation of various NAD(P)H oxidases, which constitute the major sources of reactive oxygen species in the cardiovascular system.80 Specifically, in right atrial myocardium from patients undergoing elective coronary artery by-pass surgery who were prospectively treated with statins, Rac-1 GTPase activity was significantly decreased compared to patients without statin use.81 In animal models, inhibition of Rac1 activity by statin treatment was associated with a 50% reduction of the incidence of AF.64
On the other hand, there are several data that suggest a strong association between atherosclerotic disease and AF.4 Statins have plaque-stabilising properties mediated through a combined reduction in lipids, macrophages and MMPs.82,83 Macrophages in particular are involved in all phases of atherosclerosis and some studies in animals have demonstrated that statins can suppress the growth of macrophages that express proteolytic enzymes such as MMPs and thrombogenic factors such as tissue factor.84 Other important pleiotropic effect of statins include the increasing of the bioactivity of endothelial-derived oxide (NO), either indirectly by its effect on lipoprotein levels and protection of low-density lipoprotein cholesterol (LDL-c) from oxidation, or directly by effects on NO synthesis and release, and endothelial-NO inhibits several components of the atherogenic process.85,86 Statins may also have an antiarrhythmic effect through these actions on atherosclerotic vascular disease.
Left ventricular hypertrophy is one of the aetiologic mechanisms for AF and epidemiological studies found that hypercholesterolemia is associated with left ventricular hypertrophy.87 In experimental models, statins can prevent myocardial hypertrophy.88,89 In hyperlipidaemic patients, pravastatin reduces left ventricular mass, and the left ventricular regression correlates with the magnitude of inhibition of free radical formation assessed by the isoprenoid formation.90 Treatment with statins also has a beneficial effect on autonomic function, as reflected by improvement in heart rate indices.91,92 Endothelial-dependent blood flow improvement in coronary vasculature may be a possible explanation.92
More recent evidence has demonstrated that statins could exert some direct effects on transmembrane ion fluxes, by reducing cholesterol content in cardiac membranes and even interacting directly with the channel proteins that may directly affect the electrophysiological properties of atrial muscle.93 In the human atria, a balance between the L-type calcium current (ICa) and several outward K+ currents determines the action potential duration and refractoriness.94,95 Data in animal models demonstrates that statins may modulate these ionic currents.93,96,97
Finally, there is also evidence suggesting an interaction between dyslipidaemia and the renin–angiotensin system. Raised LDL-c may increase Ang II sensitivity,98,99 and downregulation of the renin–angiotensin system by statins could be a mechanism explaining an antiarrhythmic effect.
Statins and AF: clinical and experimental evidence
Several studies have examined the role of anti-inflammatory therapies in the setting of AF. Firstly, ACE-I, such as trandolapril or enalapril100 and β-blocking agents which have antioxidant properties (e.g. carvedilol)101 have shown a reduction in the incidence of new-onset AF. Oral glucocorticoids, non-steroidal anti-inflammatory medications, long chain 
-3 fatty acids (PUFA) or fish oils have showed some favourable effects in AF.59,102,103 In addition, data from different trials have shown that treatment with statins significantly reduces the incidence of new-onset AF.
Preliminary animal data (Table 1) also suggest a protective effect of statins on AF risk. In the canine sterile pericarditis model74 and in the atrial rapid-pacing canine model79 of AF, and recently in the ventricular tachy-pacing canine model,104 treatment with statins (atorvastatin 2 mg/kg/day, simvastatin 80 mg/day and simvastatin 20 or 80 mg/day respectively) results in decreased inducibility and sustainability of the arrhythmia.
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Data from human studies remain limited by their sample size and by the characteristics of the patients enrolled. The studies evaluated different types of AF, including new-onset or recurrent (Table 2), post-cardioversion (Table 3) and postoperative (Table 4). One of the first studies was performed by Young-Xu et al.105 as an observational study in a cohort of 449 patients with coronary artery disease (CAD) and preserved left ventricular ejection fraction (LVEF) at high risk of AF. They observed a significant reduced risk of developing AF if patients were treated with statins over an average follow-up of 5 years (9% vs. 15%, crude odds ratio 0.48; 95% CI 0.28–0.83, P = 0.01). They also observed that this association remained significant after adjustment for potential confounders (age, hypertension, left ventricular systolic function, heart failure, acute ischaemic events and baseline cholesterol and changes in its levels).
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In the recent years, two additional studies have investigated the impact of statin therapy on AF in the setting of left ventricular dysfunction. The first106 sought to determine the impact of the use of statins on AF or atrial flutter in 2521 patients enrolled in the sudden cardiac death heart failure trial (SCD-HeFT), a randomized trial looking at the mortality benefit of an implantable defibrillator or amiodarone vs. placebo in patients with a functional class II–III heart failure and LVEF
35%. Statin use was reported in 1187 patients (47%) at last follow-up, and AF or atrial flutter in 434 patients (17%) in a median follow-up of 45.5 months. This suggested that statin use was associated with a 28% relative risk significant reduction in the incidence of these arrhythmias in chronic moderate heart failure (adjusted HR 0.72; CI 0.58–0.91, P = 0.006), and statin use appeared as potent predictor of reduced AF or atrial flutter as amiodarone, and stronger than any other medication assessed (β-blocker, spironolactone, ACE-I). In the second study,107 25 268 patients enrolled in a multicentre registry from 106 centres in the United States, with reduced LVEF 40% (ADVANCENT registry) were included, with a median follow-up of 45.5 months. This showed that the use of lipid-lowering drugs was associated with a significant reduction in the odds of AF (OR 0.69, 95% CI 0.64–0.74). These registries did not capture the specific lipid-lowering drug prescribed for each patient. Recently, an observational study has been published assessing the impact of statin use on preventing AF in patients with coronary heart disease and a subgroup with heart failure.108 During an average follow-up of 4.8 years, 13 783 patients with coronary heart disease were included in the analysis where 39% received a prescription for statin and 61% did not. These investigators found that receiving statin treatment for any length of time was no associated with AF (HR 1.00, 95% CI 0.88–1.14, P = 0.99), but in the subgroup of patients with heart disease, recent statin treatment was associated with a 43% reduction in AF incidence (HR 0.57, 95% CI 0.33–1.00, P = 0.04). This finding was consistent with the results of the studies described before and shows that statin therapy was associated with lower prevalence of AF in patients with heart failure. In contrast with the results published by Young-Xu et al.,105 they did not find any effect in a large cohort of patients with coronary heart disease. Perhaps the small sample size and inadequate adjustment for baseline characteristics, particularly the differences in medical regimen, was a limitation of the study published by Young-Xu et al. These deficiencies have been addressed in a study published by Adabag et al.108 with a larger sample size and by balancing the statin-treated and untreated groups with respect to baseline characteristics, co-morbid conditions and medication by using propensity scores.
Finally, Merckx et al.109 studied the role of statins in preventing AF in patients with left ventricular hypertrophy (LVH: wall thickness 
10 mm) and left atrial dilation (LA 40 mm), but with a preserved LVEF. From an echocardiographic database of 9255 patients, they selected 667 patients in sinus rhythm with increased risk for the development of AF. During a mean follow-up of 6.5 years, there was a significant reduction in the incidence of AF in the statin therapy group, 7.3% vs. 11.6% (OR 0.33, P < 0.001).
It is worth re-emphasizing that many of these studies were not randomized double-blinded clinical trials and have some limitations. First, health information was ascertained from different databases and the possibility of misclassification of AF episodes cannot be excluded. Second, these studies are limited by its observational design. As a result, they could not adjust for unknown potential confounders. Third, as a result of the cross-sectional nature, it is difficult to ascertain the temporal relationship between statin use and development of AF. Finally, patients in these studies were treated with different statins, variable doses and duration not well-defined.
Considering these limitations, the available data support statin use in patients with heart failure to prevent AF. There are opposing results about the use for this purpose in patients with CAD without cardiac heart failure. Therefore, caution should be recommended in extrapolating these findings and future large randomized placebo-controlled clinical trials should be conducted to evaluate the impact of the use of statins on preventing AF in these settings.
Statins and prevention of AF after cardioversion or ablation
Available data demonstrate that high levels of CRP are associated with an increased risk of recurrence of AF after cardioversion, supporting the overall concept of systemic inflammation as an important etiologic mechanism in the pathogenesis of AF.110 Nevertheless, controversial results have been published concerning the protective role of statins after pharmacological or electrical cardioversion (EC) (Table 3). Some investigators found a significant decrease in arrhythmia recurrence with statins, whilst others did not. Adrenergic stimulation may also contribute to calcium overload and AF recurrence111 and statins have also been reported to beneficially affect disordered autonomic control of cardiovascular function. On the other hand, statins have shown an antiarrhythmic effect in patients with CAD and cardioverter defibrillators.112
The number of published studies concerning the protective role of statins after cardioversion are still small, with relatively small sample sizes and controversial results. The first study was published by Siu et al.,113 as a retrospective and small (n = 62) study. They concluded that the use of statins (simvastatin 20 ± 13 mg or atorvastatin10 ± 3 mg) during a mean of 32 ± 6 weeks prior to EC and for duration of follow-up (44 ± 1 months), in patients with lone AF >3 months, was associated with a 77% relative risk reduction in AF recurrence (RR 0.31, 95% CI 0.103–0.905, P = 0.032). The first prospective randomized study114 only had a total of 48 patients with persistent AF (>48 h) enrolled, where atorvastatin 10 mg/day was given 48 h before EC and during the 3 months of follow-up. Atorvastatin was associated with a significant reduction in the risk of developing AF after adjustment for the predictors of AF recurrence (RR 0.19, 95% CI 0.052–0.072, P = 0.01).
Another study of electrical and pharmacological cardioversion115 enrolled 851 patients with AF and essential hypertension without evidence of any other concomitant cardiac disease. Statin therapy given after cardioversion was associated with a lower risk of AF recurrence in 1 year after successful electrical or pharmacological cardioversion among hypertensive patients (OR 0.72; 95% CI 0.54–0.97, P = 0.034).
In contrast to these findings, Tveit et al.116 conducted a randomized study in 114 patients with AF >48 h, but did not find any reduction in the number of patients converting to sinus rhythm before EC, immediate EC success, or the recurrence of AF after EC in patients treated with pravastatin 40 mg/day once daily for 3 weeks before and 6 weeks after EC. Similarly, García-Fernández et al.76 tested the effect of atorvastatin 80 mg/day or control pre-EC and maintained until recurrence of AF or 3 months of follow-up, and no differences were found between the two groups (P = 0.275). Additionally, markers of inflammation and tissue remodelling were measured (CRP, MMP-2 and TIMP-1) before and after EC, without any difference in the levels between the two groups. Finally, a recent observational study about statins and cardioversion has been published by Humphries et al.117 Patients in the Canadian Registry of Atrial Fibrillation were followed if they had a successful cardioversion (electrical or pharmacological) at the time of their first episode of AF, and they were classified as on statins if they were taking any statin (simvastatin, atorvastatin, lovastatin and pravastatin) at either the time of diagnosis or at discharge from the baseline visit. The final cohort size was 625 patients and by 1 year of follow-up, there was no association with changes in AF recurrence [adjusted OR 0.51 (95% CI 0.26–1.00)]. On the other hand, statin use was associated with a significant 74% reduction in the odds of recurrent AF in patients also taking β-blockers, independent of the presence of CAD, suggesting that there may be a role for statins in addition to these drugs in patients with established AF. Humphries et al.117 suggest that the interaction between β-blockers and statins could be an ‘apparent’ interaction owing to clinical differences in the β-blocker-treated and not-treated patients.
The role of statins in patients with permanent pacemaker was evaluated by Amit et al.118 in a cohort of 264 patients, where treatment with a statin was associated with a reduced incidence of subsequent AF. Richter et al.119 reported a retrospective study on the influence of different statins on AF-free survival after AF ablation. They found an acute upregulation of CRP and fibrinogen levels as well as the leukocyte count was associated with ablation, with no relation with the previous statin treatment. The use of statins started >3 months before ablation and continued during 12.7 months of median follow-up, did not significantly improve outcome of AF ablation (hazard ratio 1.06; P = 0.79). However, the study cohort consisted of patients with long history of drug refractory AF and thus could constitute a collective with a rather advanced stage of the disease, where statins could not be as useful as in the early phase of AF development.
Thus, there are controversial data to support the potential utility of statins in the prevention of AF recurrence after successful EC or ablation. Firstly, some are mainly derived from retrospective studies. Secondly, these conflicting data may in part be related to profound differences in study populations such as differences in AF history and predisposing diseases. Furthermore, there was a great variation in study protocols (sample size, follow-up duration, duration of treatment and method to assess occurrence of AF). Moreover, many patients received intermediate statin dosages and the use of higher dosages would have yielded different results. On the other hand, the duration of statin treatment and follow-up could have been too short to show an effect, because lengthy processes such as fibrosis and atrial remodelling are involved in AF. Finally, the anti-inflammatory properties of statins might vary among the available substances and might also account for these inconsistent results.
Statins and prevention of postoperative AF after cardiac surgery
Postoperative AF is one of the most frequent complications of cardiac surgery, and an important predictor of patient morbidity, prolonged hospitalisation and increased hospital costs. The arrhythmia typically occurs on the second or third postoperative days with 70% of events occurring within the first 4 postoperative days.120 AF is associated with a higher incidence of early complications such as stroke or congestive heart failure, cerebrovascular accidents, renal dysfunction, infections and neurocognitive impairment.121 In the postoperative heart, multiple factors may potentially predispose the patient to AF through alterations in refractoriness and local re-entry.122 Recently, inflammatory mechanisms have attracted interest, given that activation of the complement system and release of proinflammatory cytokines occur after cardiac surgery (Table 4). For example, IL-6 levels peak after 6 h after cardiac surgery and CRP and complement-CRP complexes increases with a peak on the second or third postoperative day, coinciding with the peak of atrial arrhythmias.39,123–125 Subsequent data have shown an association between the use of statins and attenuated inflammatory responses after CABG.126,127 The incidence of cardiovascular events in the first 6 months after surgery, including death from cardiac causes, non-fatal acute MI, ischaemic stroke and unstable angina, can also be reduced with perioperative use of atorvastatin in patients who must undergo vascular surgery.128
The use of statins has been related to a 3-fold decrease in the odds of AF after non-cardiac thoracic surgery77 and their benefit in CABG is supported by some observational studies.129–131 However, Dotani et al.129 were the first to report a significant association between preoperative statin therapy (average duration 3 days) and reduced incidence of post-CABG arrhythmias, including AF at 60 days and one year later (OR 0.23, 95% CI 0.08–0.65; P = 0.006). Dosages of atorvastatin, simvastatin, lovastatin, pravastatin and fluvastatin were 10–20 mg/day and statin therapy was remained during follow-up visits. Similarly, Ozaydin et al.130 and Auer et al.132 found similar results. Ozaydin et al., in a population of 362 patients, monitored during 1 week of hospitalisation, where postoperative AF was less frequent and its duration was shorter in statin group compared with non-statin group, being associated with a significantly reduced risk of developing postoperative AF (RR 0.47; 95% CI 0.25–0.9, P = 0.02). Mean time between initiation of statin (atorvastatin, simvastatin, pravastatin or fluvastatin) and CABG was 2.7 ± 5 months and mean dose of statin was 27 ± 15 mg).
On the other hand, Auer et al.132 reported a prospective study including 253 patients from the study of prevention of postoperative atrial fibrillation (SPPAF) trial, a significantly higher risk of AF in patients without statin therapy compared to statin users (45.9% vs. 32.8%; P < 0.05). In this case, the dosages and time of statin treatment are unknown.
Till date, there are also observational data129–132 that patients taking statins may have a lower incidence of AF or other cardiac arrhythmias after CABG. Marín et al.131 evaluated in 234 patients if the administration of statins during a median of 31 days before and after surgery was associated with a decrease in the development of AF after CABG. They also measured plasma levels of MMP-1, TIMP-1 and N-terminal pro-brain natriuretic peptide at baseline, 24 h after surgery. In multivariate analysis, statin use was related to a significant decrease in AF (OR 0.52; 95% CI 0.28–0.95, P = 0.038) and with increased TIMP-1 levels and TIMP-1/MMP-1 ratio. Thus, patients in many studies were treated with different statins, variable doses and different duration.
The only randomized prospective double-blinded placebo-controlled study was published by Patti et al.78 who evaluated whether administration of atorvastatin 40 mg/day, started 1 week before cardiac surgery with cardiopulmonary bypass and continued in the postoperative period, prevented postoperative AF in a total of 200 randomized patients. The use of statins was related with a significant reduction on the risk of AF (OR 0.39, 95% CI 0.18–0.85, P = 0.017). CRP levels were monitored every 24 h following procedure until discharge and peak CRP levels were higher in AF patients.
The low cost and low risk of statin therapy may support the routine early initiation of atorvastatin treatment in moderate-risk patients with no history of AF undergoing elective cardiac surgery with CABG who were not receiving previous therapy with statins. It is possible that the benefit may be even greater in ‘higher-risk’ surgical patients. In addition, the improved outcome requires further data in patients undergoing off-pump cardiac surgery. Finally, a lack of detection of self-limiting episodes of paroxysmal AF after discharge from the intensive care unit cannot be excluded in these studies.78
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TopSummaryIntroductionSearch strategyUnderlying mechanisms in AF:...The role of inflammation...The pleiotropic effects of...ConclusionReferences |
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There is increasing evidence to support the influence of inflammation in the pathogenesis of AF. Atrial biopsies from patients with AF have also confirmed the presence of inflammation. Recent studies suggest statins may have multiple pleiotropic effects including antioxidant and anti-inflammatory activity. Observational and clinical trials have studied the impact of statin therapy on new-onset, after cardioversion (pharmacological or electrical) or postoperative AF. Observational studies have shown that treatment with statins significantly reduces the incidence of new-onset or recurrent AF in the primary and secondary prevention, therefore, caution should be recommended in extrapolating these findings. On the other hand, the number of studies investigating the role of statins after cardioversion is small with controversial results and is insufficient to recommend the use of statins before and after cardioversion. Finally, statins have been related to a decrease in the risk of developing AF after non-cardiac thoracic surgery. In cardiac surgery, one controlled randomized study supports the routine early initiation of atorvastatin treatment in moderate-risk patients with no history of AF undergoing elective cardiac surgery with CABG who was not receiving previous therapy with statins. Future large randomized placebo-controlled clinical trials should be conducted to evaluate the impact of the use of statins on preventing AF.
Conflict of interest: None declared.
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