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Cardiovascular Research 2007 75(1):10-20; doi:10.1016/j.cardiores.2007.02.029
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Copyright © 2007, European Society of Cardiology

Do statins have an antiarrhythmic activity?

M.S. Kostapanosa, E.N. Liberopoulosa, J.A. Goudevenosb, D.P. Mikhailidisc and M.S. Elisafa,*

aDepartment of Internal Medicine, School of Medicine, University of Ioannina, 451 10 Ioannina, Greece
bDepartment of Cardiology, School of Medicine, University of Ioannina, Ioannina, Greece
cDepartment of Clinical Biochemistry, Royal Free Hospital University College Medical School, University of London, London, UK

* Corresponding author. Tel.: +30 26510 97509; fax: +30 26510 97016. egepi{at}cc.uoi.gr

Received 30 December 2006; revised 17 February 2007; accepted 26 February 2007


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Statins and ventricular...
 4. Statins and atrial...
 5. Concluding remarks
 6. Declaration of interest
 References
 
Sudden cardiac death, which is mainly associated with the presence of life-threatening ventricular arrhythmias, is a common ‘killer’ among patients with coronary artery disease. Moreover, atrial fibrillation is the most common arrhythmia encountered in the clinical practice. The beneficial effect of statins on cardiovascular morbidity and mortality is well-established, while the exact role of this class of drugs against arrhythmias remains unclear.

This review discusses the effect of statin treatment on arrhythmias that are commonly seen in the clinical setting. The underlying pathophysiological mechanisms are also overviewed. Compelling evidence from the majority of the studies reviewed shows that statins exhibit a protective effect against the occurrence of ventricular arrhythmias and atrial fibrillation.

KEYWORDS Statins; Arrhythmias (mechanisms); Sudden death


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Statins and ventricular...
 4. Statins and atrial...
 5. Concluding remarks
 6. Declaration of interest
 References
 
Sudden cardiac death is one of the most frequent causes of death in industrialized countries, exceeding 300,000 events per year in the United States, or about 20% of all deaths annually. In 60–80% of cases sudden cardiac death occurs in the setting of coronary artery disease (CAD) [1]. Ventricular arrhythmias (VA) [i.e. ventricular tachycardia and ventricular fibrillation] are common causes of sudden cardiac death [2]. Moreover, atrial fibrillation (AF) is the most common arrhythmia encountered in clinical practice, accounting for approximately one third of hospitalizations for cardiac rhythm disturbances [3]. An estimated of 2.3 million people in North America and 4.5 million people in the European Union have paroxysmal or persistent AF [3]. There is evidence suggesting that hypertension, diabetes mellitus, obesity and the metabolic syndrome may be risk factors for AF [4]. Thus, AF, especially in older and hypertensive patients, might be part of the atherosclerosis spectrum [4].

Statins are the cornerstone in the management of dyslipidemia [5]. Clinical trials demonstrated that statin therapy is associated with a significant reduction in cardiovascular morbidity and mortality when used for either the primary or the secondary prevention [6–9]. These favorable results are not entirely explained by lipid modulation itself [6]. Besides their lipid-lowering capacity, statins exhibit a variety of favorable anti-atherogenic (anti-inflammatory, anti-proliferative, anti-oxidative and anticoagulation) actions [10–14].

Large randomized trials suggested that statin therapy may result in a sudden cardiac death reduction in patients with CAD [6,8]. This led to the hypothesis that part of the mortality benefit may lay beyond the anti-atherogenic effects of statins on coronary arteries and could be related to potential antiarrhythmic properties of such drugs against VA [15,16]. Moreover, despite the well-known anti-atherogenic actions, it is not clear whether statins exhibit an antiarrhythmic effect against AF.

In this review we discuss the effect of statin treatment on the incidence of the most common arrhythmias as well as on conditions that predispose to the development of these arrhythmias.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Statins and ventricular...
 4. Statins and atrial...
 5. Concluding remarks
 6. Declaration of interest
 References
 
MEDLINE (up to December 2006) was used to access the literature. Search terms included ‘arrhythmias’, ‘ventricular arrhythmias’, ‘atrial fibrillation’ and ‘statins’. Furthermore, a manual search of major randomized clinical trials with statins was conducted. Additionally, the reference lists from original papers and review articles as well as major randomized clinical trials with statins were scrutinized. We included articles that were relevant to the topic of this review.


   3. Statins and ventricular arrhythmias
Top
 Abstract
 1. Introduction
 2. Methods
 3. Statins and ventricular...
4. Statins and atrial...
 5. Concluding remarks
 6. Declaration of interest
 References
 
3.1 Pathophysiological implications
Sudden cardiac death can be caused by VA due to acute myocardial ischemia or re-entrant arrhythmias in the setting of myocardial scar tissue [17]. In the presence of scar tissue, episodes of myocardial ischemia and changes in autonomic tone can create conditions that make the recurrence of VA possible [18,19]. Clinical and autopsy studies have shown an association between elevated cholesterol levels and sudden cardiac death [20], although a recent study showed that patients with acute myocardial infarction and primary ventricular fibrillation had less hypercholesterolemia compared to matched myocardial infarction patients that did not exhibit primary ventricular fibrillation [21].

It has been postulated that statins have lipid-independent effects that could indirectly regulate circumstances that are responsible for the development of VA in patients with CAD (Fig. 1A). Specifically, statins are known to prevent progression or even promote regression of atherosclerotic plaques [22,23]. Furthermore, the anti-inflammatory and anti-proliferative effects of statins are well-established [11,12,24]. Additionally, statins may have beneficial effects on the coronary arterial tone by regulating the nitric oxide (NO)-mediated endothelial function through a statin-induced increase in the endothelial NO production and bioavailability [13,14]. Moreover, statins may contribute significantly to the plaque stabilization in high-risk atherosclerotic lesions by modifying their lipid content [10,25]. These effects improve myocardial perfusion, ameliorate myocardial ischemia-reperfusion injury during an acute coronary syndrome [26] and reduce the risk of plaque rupture, thereby preventing the ischemia-induced electrophysiological effects that predispose to VA [27]. Moreover, statin therapy may affect ventricular conduction and excitability by modulating the fatty acid composition and physiochemical properties of the sarcolemma that result in alterations in transmembrane ion channel properties [28]. It is also known that statin administration may reduce ischemia-induced oxidative stress that leads to sarcoplasmic injury and intracellular calcium overload, conditions known to contribute to the development of VA [29].


Figure 1
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  		Fig. 1 Possible mechanisms of antiarrhythmic effects of statins. A) Against ventricular arrhythmias. B) Against atrial fibrillation.

 
There are certain electrophysiological conditions recognized to predispose to VA. Specifically, decreased heart rate variability is associated with decreased parasympathetic tone and has been shown to be a good predictor of arrhythmic events and sudden cardiac death [30,31]. Statins are suggested to have beneficial effects on heart rate variability. Specifically, Pehlivanidis et al. [32] suggested that 2-year atorvastatin administration in dyslipidemic patients with or without CAD significantly increased heart rate variability independently of its lipid-lowering capacity. Of note, this was a small not randomized and not placebo-controlled study. Similar results were obtained in patients with heart failure following atorvastatin treatment [33] (also see below). There are also experimental data to support the clinical study results. Specifically, rosuvastatin increased heart rate variability in an animal model prone to atherosclerosis [34]. This increase was correlated with a statin-induced NO-dependent improvement in endothelial function [34]. Additionally, simvastatin had a beneficial effect on autonomic tone, as it increased the heart rate variability in an animal model [35]. In contrast, Riahi et al. [36] failed to confirm such observations in patients with CAD and implantable cardioverter defibrillator (ICD) implants during a 12-month follow-up (for study limitations see below).

Increased QT variability as well as QTc interval prolongation have been associated with heterogeneity in ventricular repolarization and changes in autonomic nervous tone that predispose to the development of VA and sudden cardiac death [33,37,38]. Short-term (3 months) atorvastatin therapy decreased QT variability and shortened QTc intervals in patients with advanced heart failure [33]. In this study, patients with total cholesterol levels less than 175 mg/dL were excluded, the follow-up was short and no dose titration of atorvastatin was performed [33]. In agreement, treatment with fluvastatin for 12 months led to a decreased variability of QT dispersion in another small study [39].

Ventricular late potentials are low amplitude waveforms that correspond to fragmented activation of ventricular tissue and are considered to originate from areas of slow and inhomogenous conduction within the diseased myocardium [40]. They are also thought to represent delayed activation of damaged myocardium that serves as an anatomical substrate for repeated VA [40]. It has been shown that early pravastatin administration following thrombolytic therapy after an acute myocardial infarction led to a significant decrease in the incidence of ventricular late potentials [41]. This was accompanied by a reduction in the in-hospital 10-day incidence of VA [41].

Of interest, pravastatin therapy decreased cardiomyocyte hypertrophy following a myocardial infarction in an animal model of normolipidemic rats [42]. Cardiomyocyte hypertrophy contributes to ventricular remodeling that predispose to life-threatening VA following myocardial infarction [43]. This drug effect was associated with a decreased endothelin-1 secretion from cardiac myocytes [42]. Endothelin-1 acts as a key autocrine/paracrine mediator to trigger the hypertrophic signaling pathways in myocardium associated with the development of VA [44].

3.2 Clinical and experimental evidence
The outcomes of life-threatening arrhythmias as well as of cardiac arrest with resuscitation were evaluated in many large-scale randomized trials that assessed the effect of statins on cardiovascular morbidity and mortality in patients at high risk (Table 1). Some studies did not show a beneficial effect of statins on life-threatening arrhythmias despite the overall positive effect of statin treatment on cardiovascular mortality. Specifically, the Anglo-Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm (ASCOT-LLA) [7] demonstrated that atorvastatin 10 mg/day resulted in a non-significant greater incidence of life-threatening arrhythmias as compared with placebo [10 vs 3, hazard ratio 3.31 (0.91–12.01), p=0.054] in high risk hypertensive patients. Furthermore, the Incremental Decrease in End Points Through Aggressive Lipid Lowering (IDEAL) Study [45] showed that patients with a history of acute myocardial infarction who were on high-dose atorvastatin therapy (80 mg/day) exhibited a similar incidence of cardiac arrest with resuscitation compared with those on usual dose of simvastatin treatment (20 mg/day) (10 vs 7 cases, respectively). In agreement, there was no difference between aggressive atorvastatin treatment (80 mg/day) and usual dose atorvastatin therapy (10 mg/day) in the incidence of resuscitated cardiac arrest [25 vs 26 cases, hazard ratio 0.96 (0.56–5.67), p=0.89] in patients with known CAD and low density lipoprotein cholesterol (LDL-C) levels below 130 mg/dL who participated in the Treating to New Targets (TNT) Study [46]. Moreover, the results of the Aggressive Lipid-Lowering Initiation Abates New Cardiac Events (ALLIANCE) study highlighted no significant difference between aggressive lipid-lowering therapy based on atorvastatin (titrated up to 80 mg/day in order to achieve LDL-C goals below 130 mg/dL) and usual care lipid-lowering therapy in the incidence of the same end point [2 vs 5 cases, hazard ratio 0.37 (0.07–1.89), p=0.229] [47]. Additionally, atorvastatin 80 mg/day led to no significant difference in the incidence of resuscitated cardiac arrest as compared to placebo [8 vs 10 cases, hazard ratio 0.82 (0.33–2.06), p=NS] in patients with unstable angina and non-Q wave myocardial infarction followed-up for 16 weeks in the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) Study [48]. Moreover, among other endpoints, the Collaborative Atorvastatin Diabetes Study (CARDS) [49] evaluated the effect of atorvastatin on the incidence of resuscitated cardiac arrest in diabetic patients with moderately elevated LDL-C compared with placebo. No case of cardiac arrest was observed either in the atorvastatin or the placebo group [49]. Also, the Scandinavian Simvastatin Survival Study (4S) [6], in which simvastatin was compared with placebo in patients with established CAD, demonstrated just one case of resuscitated cardiac arrest in the simvastatin group, while there was no such case in the placebo group. It is obvious that the too small number of patients who presented with life-threatening arrhythmias in the above studies does not allow reliable conclusions regarding the effect of statins on the incidence of arrhythmias leading to cardiac arrest. Moreover, 2 of these studies (IDEAL and TNT) compared different statins or different doses of the same statin, respectively. The effect of statins on cardiac arrhythmias may not be specific statin- or statin dose-related.


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  		Table 1 Clinical evidence for the effect of statins on the incidence of ventricular arrhythmias

 
In contrast, there is increasing evidence on possible beneficial effects of statins on the development of VA in patients who suffered an acute myocardial infarction [50,51], those who underwent revascularization procedures [41,52] or in subjects with CAD and ICD implants [15,36,53–55].

Early statin therapy after an acute myocardial infarction has been suggested to decrease the incidence of various arrhythmias and mostly of VA that are associated with increased rates of post-infarction mortality [50,51]. Specifically, Fonarow et al. [50] retrospectively demonstrated that early statin administration (within 24 h) following an acute myocardial infarction led to a significant decrease (p<0.001) in the incidence of ventricular tachycardia/ventricular fibrillation in a population of 126,128 hospitalized patients. Additionally, there is evidence from an observational study suggesting that early withdrawal of statin therapy (within the first 24 h) after hospital admission due to a non-ST-segment elevation myocardial infarction was associated with higher rates of post-infarction VA [51]. Both studies proposed a potential protective role of early statin therapy towards the dangerous VA that follow an acute myocardial infarction and are known to increase cardiovascular mortality. This may represent a mechanism by which statins reduce mortality when administered early following an acute coronary syndrome [26].

Other studies suggested that pretreatment with statins may have a beneficial effect on the incidence of VA after revascularization procedures, such as coronary bypass artery grafting or thrombolytic therapy [52,54]. Specifically, Dotani et al. [52] retrospectively recorded the post-operative incidence of various arrhythmias (i.e. AF, atrial flutter and VA) in 2 groups of patients who underwent a coronary artery bypass grafting: the first group was on preoperative statin therapy, while the second group was not (controls). A significantly lower incidence of arrhythmias 60 days as well as 1 year after the operation was observed in the statin group as compared with controls [hazard ratio 0.23 (0.08–0.65), p<0.01] [52].

Moreover, in a small study (n=72) pravastatin administration concomitantly with thrombolytic therapy in acute myocardial infarction was associated with a lower post-infarction incidence of VA compared with thrombolysis but no statin therapy (controls) (27% in the pravastatin group vs 63% in the control group, p=0.02) [41]. In addition, pretreatment with statins resulted in a significant decrease in post-operative mortality, but had no effect on the post-operative incidence of cardiac arrhythmias in a retrospective analysis of 1663 patients who underwent coronary artery bypass grafting [56].

These results are supported by experimental studies conducted in animal models [57,58]. Lazar et al. [57] demonstrated that pretreatment with atorvastatin led to significantly fewer cardioversions due to VA compared with placebo after revascularization following myocardial infarction in pigs. Interestingly, this effect seemed to be independent of the lipid-lowering effect of atorvastatin as no significant differences in the lipid profile were observed between the statin and the placebo group [57]. In addition, Chen et al. [58] suggested that chronic administration of pravastatin was associated with lower incidence of the ischemia-induced VT as well as of the reperfusion-induced lethal ventricular fibrillation compared with no statin administration in a rat arrhythmia model of coronary artery ischemia/reperfusion. Again this effect was independent of cholesterol lowering [58].

Several studies were conducted to assess the effect of statins on the recurrence of VA in patients with ICD implants. De Sutter et al. [15] suggested that lipid-lowering treatment (i.e. statins and fibrates) was independently associated with a decreased risk for VA recurrences after an ICD implantation in a small observational study including 78 patients. Larger prospective trials confirmed this observation. Mitchell et al. [59] demonstrated that early and consistent lipid-lowering therapy (i.e. statins, fibric acid derivatives and bile acid resins) after the implantation of an ICD in patients with CAD reduced the risk for VA recurrence by 60% in the Analysis of the Antiarrhythmic Versus Implantable Defibrillators (AVID) trial. The major limitation of this trial was the non-random allocation of patients to receive lipid-lowering therapy [59]. Chiu et al. [53] assessed the effect of statin treatment compared with non-statin therapy (controls) on the incidence of first recurrent VA requiring an ICD intervention in 281 patients with CAD. In a mean follow-up of 10.2 months, statin administration was associated with a significantly lower incidence of the primary end point (30% in the statin group compared to 50% in the control group, p=0.0007) [53]. The main limitation of this study was its observational, retrospective and non-randomized nature [53]. Recently, the Multicenter Automatic Defibrillator Implantation Trial-II (MADIT-II) suggested a time-dependent beneficial effect of statin therapy on the incidence of ICD intervention for a first VA or cardiac death in 654 patients with CAD treated with an ICD [54]. Specifically, patients who received statin treatment for over 90% of the mean 17-month follow-up were at lower risk for cardiac death or VA compared with those who received statins for less than 10% of the follow-up (p<0.01) [54]. This study was also observational and non-randomized. Moreover, De Sutter et al. [the Cholesterol Lowering and Arrhythmias Recurrences after Internal Defibrillator Implantation (CLARIDI) study] [55] recently concluded that aggressive treatment with atorvastatin (80 mg daily) in patients with CAD and implanted ICD resulted in fewer VA requiring ICD treatment compared with placebo over 1 year of follow-up (hazard ratio 0.47; 0.22–0.98, p=0.04). In line, Goldberger et al. demonstrated that statin therapy was associated with decreased risk for death due to life-threatening arrhythmias (hazard ratio 0.22; 0.09–0.55, p=0.001) as compared to non-statin therapy in 458 patients with non-ischemic dilated cardiomyopathy treated with an ICD in the DEFIbrillators in Non-Ischemic Cardiomyopathy Treatment Evaluation (DEFINITE) study [60]. This beneficial effect of statins remained significant (hazard ratio 0.23; 0.09–0.58, p=0.002) after adjustment for multiple covariates [60]. On the other hand, Riahi et al. [36] demonstrated no differential effect of statin comparing to no statin treatment concerning the incidence of VA in patients with CAD treated with an ICD during a 12-month follow-up period. However, this was an observational study including a small number of patients, in which Holter monitoring and heart rate variability data were based on a single measurement during the follow-up [36]. It should be mentioned that all studies in patients with ICD demonstrated an effect of statins on the recurrence (not the occurrence) of VA.

Compelling evidence from the majority of the above studies now shows that statins reduce the incidence of VA. In this context, the recent guidelines of the American College of Cardiology (ACC)/American Heart Association (AHA)/European Society of Cardiology (ESC) for the management of VA recommend that statin therapy could be beneficial in patients with CAD to reduce the risk of vascular events, possibly VA, and sudden cardiac death [1].


   4. Statins and atrial fibrillation
Top
 Abstract
 1. Introduction
 2. Methods
 3. Statins and ventricular...
 4. Statins and atrial...
5. Concluding remarks
 6. Declaration of interest
 References
 
4.1 Pathophysiological implications
Accumulating data suggest that inflammation as well as oxidative stress is involved in the development, recurrence and persistence of AF [61–64]. These conditions are associated with enhanced myocardial tissue inflammation and atrial remodeling that may serve as a substrate for the development of AF [61,65]. Furthermore, elevated C-reactive protein (CRP) levels have been proposed to be independently associated with the presence of AF as well as with increased risk for the development or recurrence of AF [66]. The capacity of statins to reduce inflammation, CRP levels and oxidative stress is well-established [67–69]. These effects may explain a potential beneficial effect of this class of drugs against AF.

There is evidence suggesting an association between AF and enhanced renin angiotensin system activity. Specifically, angiotensin II exhibits a growth-enhancing effect on cardiac myocytes as well as on vascular smooth muscle cells and fibroblasts, thus resulting in the remodeling and fibrosis of the atria that could serve as a potential arrhythmogenic substrate for the development of AF [70]. Furthermore, it has been suggested that angiotensin II may cause intracellular calcium overload, resulting in conduction heterogeneity that could facilitate the development of AF [71]. Additionally, increased expression of the angiotensin converting enzyme in the atrial tissue has been observed in patients with AF [72]. An angiotensin converting enzyme-induced atrial cell death and fibrosis could explain this observation [73]. Also, this association is strongly supported by clinical data suggesting that inhibition of the renin angiotensin system may decrease the incidence of new-onset AF [74]. There is also evidence suggesting an interaction between dyslipidemia and the renin angiotensin system activity [73]. For example, oxidized LDL may upregulate angiotensin II type 1 receptors [73,75]. Statins are known to decrease both cholesterol levels [5] and oxidative stress [68], thus down-regulating the renin angiotensin system. This could be a mechanism explaining a potential antiarrhythmic effect of this class of drugs against AF [73].

Several risk factors for atherogenesis, such as age, gender, obesity, metabolic syndrome and hypertension have been associated with increased risk for the development of AF, suggesting a strong association between AF and atherosclerotic vascular disease [4]. Additionally, dyslipidemia often coexists with these risk factors [76]. However, it remains to be established whether dyslipidemia contributes to the development of AF. Statins are known to improve lipid abnormalities and have anti-atherogenic properties. Specifically, statins improve NO-dependent endothelial function [13,14], reduce oxidative stress [24], stabilize high-risk atherosclerotic lesions [10,25], and have anti-inflammatory [11,12] as well as anti-proliferative effects [11,12]. Given the association between AF and atherosclerotic disease, one could hypothesize that statins may have a protective role against AF development through their anti-atherogenic properties (Fig. 1B).

Moreover, it has been suggested that statins may have a protective role against AF in post-operative patients by a statin-induced autonomous nervous system modulation against the enhanced post-operative sympathetic activity [77], which increases the susceptibility to AF [78]. This could represent an alternative antiarrhythmic mechanism of statins against AF in such patients.

4.2 Clinical and experimental evidence
Several clinical and experimental studies assessed the role of statins against AF. Specifically, observational studies provided evidence supporting a protective role of statins against AF. Young-Xu et al. [79] demonstrated that statin therapy was associated with reduced incidence of AF [odds ratio 0.48 (0.28–0.83)] in 449 patients with chronic stable CAD who were followed for an average of 5 years. This benefit was independent of cholesterol lowering, whereas there was a dose–response relation between length of statin therapy and reduction of AF [79]. Additionally, statin-induced reduction in the incidence of AF remained significant after adjustment for many confounding factors [79]. Of course, this was a not randomized and double-blinded study [79]. In addition, Siu et al. [80] retrospectively postulated that patients with persistent AF lasting 3 months or more who received statin therapy exhibited lower AF recurrence rates after a successful electrical cardioversion compared with those not on statins (controls) (40% in the statin group vs 84% in the control group, p=0.007) during a mean follow-up of 44 months. This benefit was significant in multivariate Cox regression analysis [relative risk 0.31, (0.103–0.905), p=0.032] (Table 2) [80].


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  		Table 2 Clinical evidence on the effect of statin therapy on the incidence of atrial fibrillation

 
However, a beneficial effect was not confirmed with the use of pravastatin in a prospective randomized study conducted in a similar cohort of 114 patients with persistent AF [81]. These patients were randomly assigned either to pravastatin 40 mg/day or to no statin therapy (controls). Similar rates of AF recurrences 6 weeks after electrical cardioversion were observed in the 2 groups (35% in the pravastatin vs 33% in the control group) [81]. This was an open label study, in which there might have been selection bias. Specifically, patients with coronary heart disease may have been under-represented since patients already on statin treatment were excluded. Also, the duration of statin treatment might have been too short to have an effect on atrial remodeling [81]. On the other hand, in a prospective study 48 patients with persistent AF (lasting more than 48 h) were randomized either to atorvastatin 10 mg/day or to no atorvastatin therapy (controls) initiated 48 h before electrical cardioversion [82]. The end point was AF recurrence incidence during the 3-month follow-up. Atorvastatin was associated with a significantly reduced risk of developing AF [relative risk 0.23 (0.064–0.82), p=0.024] [82]. This benefit remained significant after adjustment for many confounding factors. This study included a small sample size, it was not placebo-controlled and double-blinded, and the duration was too short to have any effect on atrial remodeling.

Recently, statin therapy was associated with decreased post-operative incidence of AF in patients who underwent either non–cardiac thoracic surgery [(odds ratio 0.26 (0.08 to 0.82)] in a well-designed study [83] or coronary artery bypass grafting [odds ratio 0.52 (0.28 to 0.96)] [84]. Additionally, the Atorvastatin for Reduction of Post-operative Atrial Fibrillation in Patients Undergoing Cardiac Surgery (ARMYDA-3) Study [85] demonstrated that atorvastatin 40 mg/day when administered 1 week before elective cardiac surgery with cardiopulmonary bypass in 200 patients significantly decreased the incidence of post-operative AF as compared to placebo (35% in the atorvastatin group vs 57% in the placebo group) [odds ratio 0.39 (0.18–0.85), p=0.017]. ARMYDA-3 was a well-designed study without having major limitations. Ozaydin et al. [86] recently demonstrated in an observational study that preoperative statin therapy before bypass surgery was associated with a lower incidence (p=0.03) and shorter duration (p=0.0001) of post-operative AF as compared to non-statin therapy in 362 patients who underwent bypass surgery.

Three well-designed randomized studies demonstrated a protective role of statin administration against AF. Atorvastatin treatment led to less episodes of paroxysmal AF in 80 patients with proven paroxysmal AF during daily life compared with placebo [0 episodes in the atorvastatin group vs 12 episodes in the placebo group, p=0.001] during a 6-month follow-up [87]. Of interest, in this study logistic regression analysis showed that assignment to treatment was the most significant predictor of improvement in paroxysmal AF [odds ratio 13.5 (2.8–46.7), p=0.001] [87]. Additionally, atorvastatin resulted in a greater proportion of patients with total resolution of paroxysmal AF compared with placebo (65% in the atorvastatin group vs 10% in the placebo group, p<0.001) [87]. In another study conducted in patients with a permanent pacemaker there was a non-significant trend towards a protective effect of statins against AF (hazard ratio 0.59, 0.31–1.12) (for over a 3-year period) [88].

Experimental studies conducted in animal models also provided evidence concerning the role of statins on the prevention of AF. Kumagai et al. [89] assessed the effect of atorvastatin on the maintenance of AF in a canine sterile pericarditis model. A total of 20 dogs were randomized to receive atorvastatin (2 mg/kg/day) 1 week before the initiation of the study or not (controls) [89]. Before and 2 days after the operation that induced sterile pericarditis, induced AF duration, atrial effective refractory period, intra-atrial conduction time as well as CRP levels were determined. A significant lower induced AF duration, CRP levels as well as longer atrial effective refractory period and shorter intra-atrial conduction time were observed in the atorvastatin group compared with controls [89]. In addition, pathological examination demonstrated that atorvastatin therapy was associated with significant regression of myocardial inflammation and fibrosis [89]. These findings suggest an antiarrhythmic effect of atorvastatin against AF, which is associated with its anti-inflammatory activity. In addition, simvastatin was found to attenuate AF promotion by atrial-tachycardia remodeling in dogs [90]. This effect of simvastatin was associated with its capacity to attenuate tachypacing-induced downregulation of L-type Ca2+-channel {alpha}-subunit expression [90], which is associated with electrophysiological changes caused by atrial remodeling [91].

Most of the presented studies show that statins reduce the incidence of VF. In this context, the recent guidelines of ACC/AHA/ESC for the management of AF report that although inadequately explored yet, the use of statins is suggested to protect against AF [3].


   5. Concluding remarks
Top
 Abstract
 1. Introduction
 2. Methods
 3. Statins and ventricular...
 4. Statins and atrial...
 5. Concluding remarks
6. Declaration of interest
 References
 
There is increasing literature concerning the effect of statins on arrhythmias commonly observed in the clinical setting. Clinical and experimental data mostly come from retrospective and observational studies including inhomogeneous populations, whereas there is only a limited number of well-designed prospective, randomized, placebo-controlled trials. Nevertheless, most clinical evidence from all these studies supports a potential protective role of statins against arrhythmia development. Additionally, clinical data suggest that these antiarrhythmic properties of statins may, at least in part, account for the statin-induced decrease in cardiovascular morbidity and mortality. Of interest, in many studies the antiarrhythmic effect of statins was independent of their lipid-lowering capacity, while it was highly correlated with several pleiotropic actions of this class of drugs. The ability of statins to regulate NO-dependent endothelial function, decrease inflammation and oxidative stress, prevent high-risk plaque rupture as well as ischemia/reperfusion myocardial injury and attenuate atrial and ventricular remodeling could represent possible mechanisms to explain a potential antiarrhythmic action. Also, direct mechanisms were proposed to explain this effect, such as a statin-induced regulation of the autonomic tone as well as a modulation of repolarization disturbances.

Statins seem to have beneficial effect against arrhythmias. However, large-scale, prospective, randomized clinical trials for the assessment of the statin effect on the incidence of arrhythmias are urgently needed to establish if statin treatment is a novel therapeutic option in the management of cardiac arrhythmias.


   6. Declaration of interest
Top
 Abstract
 1. Introduction
 2. Methods
 3. Statins and ventricular...
 4. Statins and atrial...
 5. Concluding remarks
 6. Declaration of interest
References
 
This review was written independently; no company or institution supported it financially. Some of the authors have given talks, attended conferences and participated in trials and advisory boards sponsored by various pharmaceutical companies.

Time for primary review 14 days


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Statins and ventricular...
 4. Statins and atrial...
 5. Concluding remarks
 6. Declaration of interest
 References
 

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L. Fauchier, B. Pierre, A. de Labriolle, C. Grimard, N. Zannad, and D. Babuty
Antiarrhythmic Effect of Statin Therapy and Atrial Fibrillation: A Meta-Analysis of Randomized Controlled Trials
J. Am. Coll. Cardiol., February 26, 2008; 51(8): 828 - 835.
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