doi: 10.1161/CIRCULATIONAHA.107.760892
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(Circulation. 2008;118:1285-1293.)
© 2008 American Heart Association, Inc.
Contemporary Reviews in Cardiovascular Medicine |
Prevention of Atrial Fibrillation With 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibitors
From the Klinik für Innere Medizin III, Kardiologie, Angiologie und Internistische Intensivmedizin; Universitätsklinikum des Saarlandes, Homburg/Saar, Germany.
Correspondence to Oliver Adam, MD, Klinik für Innere Medizin III, Kardiologie, Angiologie und Internistische Intensivmedizin, Universitätsklinikum des Saarlandes, 66424 Homburg/Saar, Germany. E-mail o.adam{at}freenet.de
Key Words: atrial fibrillation • statins • prevention • inflammation • oxidative stress • review
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Introduction |
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 Top Introduction MethodsPotential Mechanisms of Rapid...Molecular Mechanisms of Statins...Clinical Evidence for Prevention...ConclusionReferences |
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A trial fibrillation (AF) is the most common arrhythmia. The prevalence of AF is estimated at 0.4 to 1% of the general population, increasing with age to >8% in those over 80 years of age.1–6 AF is also the most frequent complication after cardiac surgery, with an incidence of
30% after coronary artery bypass grafting7 and up to 60% after valve replacement.8 AF is complicated by an increased risk of stroke and increased mortality.9 Postoperative AF is also associated with a longer hospital stay and causes significant additional costs.8,10–19 Anticoagulation, rate control, and rhythm control strategies are treatment options of AF. Theoretically, establishment and maintenance of sinus rhythm would be hemodynamically beneficial and should reduce symptoms, morbidity, and mortality. However, large studies could not demonstrate that rhythm control is superior to rate control.20,21 Therefore, strategies to prevent AF (eg, in patients undergoing cardiac surgery) are needed. Here, we review recent mechanistic and clinical evidence suggesting an additional preventive strategy for patients at risk for AF and patients after thoracic and cardiac surgery, namely, treatment with 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins). We discuss recent data suggesting that in addition to cholesterol lowering, statins exert antiarrhythmic effects by improving endothelial nitric oxide (NO) availability and reducing inflammation, oxidative stress, and neurohormonal activation.
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Methods |
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TopIntroductionMethodsPotential Mechanisms of Rapid...Molecular Mechanisms of Statins...Clinical Evidence for Prevention...ConclusionReferences |
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A systematic literature search was conducted to identify studies evaluating pharmacological strategies to prevent AF published between 1966 and November 2007. The search technique included computerized Medline searches that used the combination of the search term "atrial fibrillation" with "prevention," "treatment," "surgery," "mice," "drugs," "statins," "HMG-CoA reductase," "adrenergic beta antagonists," "angiotensin," "calcium-channel blockers," and "antiarrhythmic agents." Additional studies were identified by reviewing the bibliographies of published reports and the authors’ knowledge of the current literature.
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Potential Mechanisms of Rapid Cholesterol-Independent Effects of Statins |
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TopIntroductionMethodsPotential Mechanisms of Rapid...Molecular Mechanisms of Statins...Clinical Evidence for Prevention...ConclusionReferences |
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HMG CoA reductase inhibitors (statins) have been shown to be effective lipid-lowering agents and are able to significantly reduce cardiovascular mortality and morbidity in patients at risk for cardiovascular disease. Recent clinical and experimental data suggest that the benefit of statins may extend beyond their hepatic effects on serum cholesterol levels.22 Evidence exists for direct effects of statins on endothelial and myocardial function, oxidative stress, plaque stability, inflammation, thrombosis, and stroke (Figure).23
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An important mechanism underlying cholesterol-independent effects relates to the inhibition of isoprenoid intermediates of the cholesterol synthesis pathway. Statins work by reversibly inhibiting HMG-CoA reductase through side chains that bind to the enzyme’s active site and block the substrate-product transition state of the enzyme. Statins thereby competitively inhibit the synthesis of L mevalonic acid, the immediate product of HMG-CoA reductase. At the same time, statins prevent the synthesis of other important isoprenoid intermediates of the cholesterol biosynthetic pathway, such as farnesylpyrophosphate and geranylgeranylpyrophosphate.23,24 These intermediates serve as important lipid attachments for the posttranslational modification of a variety of proteins, including the family of small GTP-binding proteins, such as Ras, RhoA or Rac1. Thus, protein isoprenylation permits the covalent attachment, subcellular localization, and intracellular trafficking of membrane-associated proteins. Both Ras and Rho are small GTP-binding proteins that cycle between the inactive GDP-bound state and active GTP-bound state.23 Because the Rho family members are major targets of geranylgeranylation, inhibition of Rho is a likely mechanism mediating some of the cholesterol-independent cardiovascular effects. The Rho family serve as regulators of cell shape, motility, secretion, proliferation, and gene expression. Indeed, experimental evidence suggests that inhibition of Rho isoprenylation mediates many of the cholesterol-independent effects of statins in a variety of cell types.23
Improvement of Endothelial Function
Improvement of NO-dependent endothelial function is one of the clinical hallmarks of statin treatment and can be observed very rapidly (eg, treatment with statins has been shown to improve coronary endothelial function within one day, significantly before serum cholesterol starts to fall).23,25 Statins increase endothelial NO production by stimulating and upregulating endothelial NO synthase (eNOS).26 Statins also increase the expression of tissue-type plasminogen activator and inhibit the expression of endothelin-1, a potent vasoconstrictor and mitogen. On the molecular level, the small G protein RhoA has been identified as a negative regulator of eNOS mRNA stability. Statins prolong eNOS mRNA half-life by inhibiting the isoprenoid-dependent activation of RhoA. Additional important effects of statin treatment on eNOS function include the activation of protein kinase Akt,27 inhibition of calveolin,26 and activation of the phosphatidylinositol 3-kinase/protein kinase Akt (PI3K/Akt) pathway.27,28
Antioxidative Effects
The small GTPase Rac1 regulates NADPH oxidase activity and is critical for generating oxidative stress and producing cardiac left ventricular hypertrophy.29–31 Statins downregulate Rac1-GTPase activity by reducing isoprenylation and translocation of Rac1 to the cell membrane.30–32 Inhibition of Rac1 by statins decreases NADPH oxidase-related reactive oxygen species production in cardiac myocytes and reduces cardiac hypertrophy.30,31,33,34 In addition, statins exert antioxidative effects through upregulation of endothelial NO.26
Antiinflammatory Effects
Recent studies suggest that statins possess antiinflammatory properties by their ability to reduce the number of inflammatory cells and inhibit adhesion molecules.23 Some of these effects can be explained by upregulation of endothelial NO and inhibition of superoxide release.23,26 The activation of T-lymphocytes and the control of the immune response is mediated by the major histocompatibility complex class II (MHC-II). Statins are able to inhibit the inducible MHC-II expression on endothelial cells and monocyte-macrophages via inhibition of the promoter IV of the major histocompatibility class II transactivator (CIITA) and thereby repress MHC-II–mediated T-cell activation.35 In addition, statins have been shown to decrease CD40 expression and CD40-related activation of vascular cells,36 as well as to reduce tumor necrosis factor 
and interferon 
in stimulated t-lymphocytes.37
Modification of Neurohormonal Activation by Statins
Importantly, statins are able to decrease angiotensin type 1 receptors both in vitro and in vivo and to enhance the efficacy of angiotensin receptor blockers.30,32,38 In addition to inhibiting AT1-signaling, statins desensitize cultured cardiac myocytes to β-adrenergic stimulation by a mechanism that involves reduced isoprenylation of G and subsequent reductions in the cellular content of G.39 Statins inhibit β-adrenergic receptor-stimulated apoptosis in adult rat ventricular myocytes, potentially via a Rac1-dependent mechanism.40
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Molecular Mechanisms of Statins in Preventing AF |
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TopIntroductionMethodsPotential Mechanisms of Rapid...Molecular Mechanisms of Statins...Clinical Evidence for Prevention...ConclusionReferences |
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The potential mechanisms through which statins prevent AF in basic studies are summarized in Table 1.
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Endothelial NO and AF
Patients with impaired left ventricular function are characterized by impairment of endothelium-dependent vasodilatation.23,47,48 Interestingly, several lines of recent evidence suggest that AF is associated with impairment in endothelial function even in the absence of heart failure or hypertension.49–53 Recent data show that decrease in endocardial NOS expression and atrial NO bioavailability directly contributes to the pathogenesis in AF.54,55 Statin treatment improves endothelial function in experimental models for heart failure, an effect that may be especially important in the context of ischemia-reperfusion injury.23,48,56–59 Atrial ischemia can produce a substrate for AF. Thus, improved eNOS expression and function, leading to a better myocardial perfusion and improved substrate utilization, might prevent AF in atria at risk.
Inflammation and AF
Experimental and clinical observations suggest that inflammation contributes to the development and maintenance of AF. A well-characterized clinical marker of inflammation is C-reactive protein (CRP), an acute-phase reactant that is produced by the liver and reflects low-grade systemic inflammation. Once CRP becomes bound, it activates complement. Furthermore, CRP has been shown to induce plasminogen activator inhibitor-1 expression, increase the expression of cellular adhesion molecules, and decrease eNOS expression, leading to propensity for thrombosis, inflammation, and endothelial dysfunction. CRP release is driven by the proinflammatory cytokines interleukin-1, tumor necrosis factor-, and interleuken-6.60 Targeted overexpression of tumor necrosis factor- in mouse hearts leads to downregulation of connexin 40 with increased prevalence of atrial arrhythmias.61 Another mouse model of tumor necrosis factor- overexpression in the heart showed biventricular dilatation with decreased ejection fraction, and abnormal systolic and diastolic Ca2+ handling, increased collagen deposition and atrial arrhythmias associated with decreased survival.62 In a model of canine sterile pericarditis,63 AF can be induced and peaks on the second postoperative day.42 In this model, elevated CRP was associated with sustained AF, suggesting that electrophysiological changes resulting from inflammation may perpetuate AF.
In patients, elevated levels of CRP are positively associated with the incidence of AF.64,65 A case-control study showed that CRP levels were higher in patients with atrial arrhythmias than in those without rhythm disturbances, and patients with persistent AF are characterized by higher CRP levels than patients with paroxysmal AF.65 Anderson et al found that high levels of CRP independently predicted an increased risk for AF among a large, prospectively studied patient cohort.64 Similarly, the Cardiovascular Health Study showed that high CRP levels are predictive of the risk for future development of AF.66 On the other hand, in patients with AF, low CRP levels are associated with successful cardioversion.67 Small studies suggest that antiinflammatory treatment strategies may reduce the risk of AF in selected patients.67,68 Inflammation induced by pericardiotomy or pericarditis and high postoperative CRP levels predict an increased likelihood of postoperative AF.65,69,70 Activation of the complement system and release of proinflammatory cytokines occur during and after cardiac surgery. CRP levels peak on the second day after surgery,71 and postoperative AF after cardiac operations typically develops within the first 72 postoperative hours.65,72 Taken together, these findings support the hypothesis that both systemic and cardiac inflammation enhances the risk of developing AF.
Several large trials showed that statin therapy effectively and rapidly lowers hs-CRP levels both in hyper- and normocholesterolemic patients and indicated that statins are effective in decreasing systemic inflammation.73,74 In addition to lowering hs-CRP, statins reduce the production of proinflammatory cytokines, which may be of special interest in the prevention of AF. Examples are tumor necrosis factor , interleukin-1, and interleukin-6, all of which have been demonstrated to be downregulated by statin application in animal models and in patients.23,48,75 Indeed, in the model of sterile pericarditis, treatment with statin lowered CRP level, shortened intra-atrial conduction time and AF duration, and increased atrial effective refractory period compared with control group.42 In summary, antiinflammatory effects of statin treatment could significantly contribute to the prevention of AF.
Oxidative Stress and AF
Increased atrial oxidative stress may play an important role in inducing and maintaining AF.54,76,77 Right human atrial appendages of patients with AF undergoing the maze procedure exhibit higher levels of the oxidative markers 3-nitrotyrosine and protein carbonyls compared with patients with sinus rhythm undergoing cardiac surgery.76 Myofibrillar creatine kinase, a controller of myocyte contractility sensitive to oxidative injury, was reduced in AF patients, potentially contributing to altered myofibrillar energetics and contractile dysfunction.76 In chronically instrumented dogs with AF induced by rapid atrial pacing, ascorbate, an antioxidant and peroxynitrite decomposition catalyst, attenuated peroxynitrite formation and electrical remodeling.78
In the left ventricle, myocardial oxidative stress is mediated, in part, by increased activity of the superoxide producing NADPH oxidase. The small GTPase Rac1 regulates NADPH oxidase activity and is critical for generating oxidative stress and producing cardiac left ventricular hypertrophy.29–31,79 AF induced by rapid atrial pacing in pigs is characterized by increased NAD(P)H oxidase activity and superoxide production in the left atrium.80 Kim et al showed that in isolated atrial myocytes from human right atrial appendages, NADPH oxidase is the main source of atrial superoxide production.55 NADPH-stimulated superoxide release was higher in patients with AF. NO synthase contributed to atrial superoxide production in fibrillating atria, suggesting that increased oxidative stress may lead to NOS "uncoupling." These findings indicate that NADPH oxidase significantly contributes to superoxide production in AF.55 Indeed, left atrial tissue of patients with AF is characterized by upregulation of Rac1-GTPase and the superoxide-producing NADPH oxidase compared with patients with sinus rhythm.46
In mice with cardiac-specific overexpression of Rac1 under the control of the MHC promoter (RacET), we observed AF with aging, which was associated with an increased NADPH oxidase activity.46 Oral treatment of the Rac1-overexpressing mice with statins inhibited Rac1, thereby lowering NADPH-oxidase activity and markedly reducing the incidence of AF.46 Interestingly, prospective short-term oral statin treatment of patients with ischemic heart disease is able to downregulate Rac1 activation and NADPH oxidase activity in the right atrium, suggesting that relevant antioxidative atrial effects of statins may occur in humans.34
NADPH oxidase–derived reactive oxygen species may have several pathological effects in the atrial myocardium, including oxidative degradation of endocardial NO, local activation of coagulation cascade components and prothrombotic molecules such as plasminogen activator inhibitor-1 and tissue factor, induction of fibrosis, inflammatory responses, and alteration of ion channel function.42,54,55,76,80–84 In addition to the contribution to initiation and perpetuation of AF, production of reactive oxygen species increases the risk of thrombus formation in the left atrium.
Neurohumoral Activation and AF
Neurohormonal activation increases the risk of AF. Inhibition of the renin-angiotensin-aldosteron system by angiotensin-converting enzyme inhibitors and angiotensin receptor blockers have been shown to prevent atrial fibrosis and the promotion of fibrillation.77,85–90 Retrospective analyses of several clinical trials confirmed benefits of these drugs in prevention of new-onset and recurrent AF, especially in patients with heart failure.85,91–94 However, large prospective studies are needed to better define the value of renin-angiotensin-aldosteron inhibition.94,95 Several lines of evidence suggest that statins may reduce neurohormonal activation. The combination of AT1-receptor blockers with statins may improve their anti-oxidative, antiinflammatory and anti-fibrotic potential, however the effects of this combination on AF has not been tested.96 Furthermore, statin treatment decreased sympathetic activation and thereby attenuates promotion of AF by atrial tachycardia in dogs.45,97
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Clinical Evidence for Prevention of AF by Statins |
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TopIntroductionMethodsPotential Mechanisms of Rapid...Molecular Mechanisms of Statins...Clinical Evidence for Prevention...ConclusionReferences |
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The clinical studies on the effects of statins on AF are summarized in Table 2. Retrospective studies, large observational and smaller prospective trials observe a benefit of statin treatment for patients undergoing electrical cardioversion,99–101,107 for patients with postoperative AF,70,102,103 patients with paroxysmal AF,67 and individuals with AF and coronary artery disease,104 as well as those with AF and left ventricular dysfunction.106 The effects appear to remain significant after adjustment for potentially confounding factors including age, hypertension, left ventricular systolic function, congestive heart failure, acute ischemic events, and baseline cholesterol. However, many studies are limited by their observational design and relatively small patient numbers. The detailed limitations are listed in Table 2. Therefore, important evidence is provided by the recent ARMYDA-3 (Atorvastatin for Reduction of Myocardial Dysrhythmia After cardiac surgery) study, a randomized, prospective, placebo-controlled, double-blind trial that investigated the effect of statin therapy on the prevalence of postoperative AF in 200 patients undergoing cardiac surgery without history of AF.70 Treatment with atorvastatin 40 mg/d started 1 week before surgery was associated with a 61% reduction in risk of postoperative AF (AF occurrence: 35% atorvastatin group versus 57% placebo, P=0.003). Subgroup analyses showed that atorvastatin treatment resulted in a lower risk of AF in patients irrespective of age, sex, presence of diabetes mellitus, hypertension, and chronic obstructive pulmonary disease.70 The hospital stay was 0.6 days longer in the placebo versus the atorvastatin arm. The number needed to treat to prevent 1 episode of AF was 4.5, and 8 to avoid a postoperative length of stay >7 days.70 Taken together, these clinical data suggest that statins are potent drugs for the prevention of postoperative AF.
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Evidence exists for the relevance of the mechanistic preclinical observations on statins and AF in humans. For example, several studies demonstrate that the effects of statins on AF are associated with reduction of inflammatory markers and oxidative stress. Ozaydin et al100 showed that statin treatment decreased CRP levels 48 hours after electrical cardioversion, a decrease that was associated with inhibition of AF recurrence. Dernellis et al67 reported a reduction of CRP levels in patients with paroxysmal AF after statin treatment that was associated with a significant risk reduction for paroxysmal AF. Similarly, a multivariable analysis of ARMYDA-3 showed that postoperative C-reactive protein levels above the median were associated with a higher risk of AF (odds ratio 2.0, P=0.01).70 Marin et al found in 234 consecutive patients who underwent coronary artery bypass grafting that statin use was associated with decreased AF and increased levels of tissue inhibitor matrix metalloproteinase-1.103 Atrial myocardium from patients with AF is characterized by increased oxidative stress,46 and oral statin treatment reduces Rac1-dependent NADPH-oxidase activity and superoxide production in the atria.34 Interestingly, some of the clinical studies did not find a correlation of lipid-lowering with the reduction of AF,104 similar to the animal studies that observed cholesterol-independent anti-AF effects of statins.
Open Questions and Next Steps
An important question relates to the identification of specific patient subpopulations that may benefit from statins. The prospective ARMYDA-3 study observed the treatment benefit from statins primarily in patients with cardiac surgery and in those with normal-sized left atrium.70 Patients with coronary artery disease and patients undergoing coronary artery bypass grafting appear to benefit especially from statins with regard to the prevention of AF,102–104 whereas patients with permanent AF of long duration and patients with left atrial enlargement may not respond.70,99 The combination of statins with β-blockers is considered to be more potent in preventing AF than statin treatment alone.70,101 In ARMYDA-3, Patients randomized to atorvastatin who were taking β-blockers showed a 90% risk reduction in postoperative AF (odds ratio 0.10, 95% confidence interval 0.02 to 0.25, P<0.0001). However, further studies are needed to better define the patient groups that are likely to benefit the most. In addition, the time course and the duration of the prevention of AF by statins need further characterization. Because some of the effects may occur independently of or in addition to cholesterol lowering, the dose of statin required is not clear. Another issue is the evidence suggesting that an abrupt discontinuation of statin medication may exert negative effects in patients with acute coronary syndromes or stroke whereas in stable vascular patients discontinuation may be safe. Withdrawal of statin treatment confers overshoot activation of small G-proteins Rho and Rac, causing production of reactive oxygen species and suppression of NO bioavailability (for review see Endres and Laufs108). Therefore, the question arises whether patients with risk factors for AF who are treated long term with a statin may be at increased risk when statins are stopped (eg, during surgery). In view of the evidence that statins have half-lives between 2 and 27 hours, that withholding statin medication for only 24 hours was shown to increase in-hospital mortality in patients with acute coronary syndromes, and that short-term statin treatment protects from perioperative AF, patients at high risk for AF should probably not discontinue statin use in high-risk situations and may even benefit from an intravenous statin formulation during surgery or intensive care.70,108
However, prospective clinical trials are necessary to answer these open questions. Specifically, the role of statins in the prevention of AF in patients with coronary artery disease, congestive heart failure, valvular heart disease, and perioperative and lone AF needs to be tested to understand which patients will and which will not benefit from statins. Furthermore, basic research is required to identify the mediators of statin effects, especially with regard to the structural and electrical changes during the development and stabilization of AF.
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Conclusion |
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TopIntroductionMethodsPotential Mechanisms of Rapid...Molecular Mechanisms of Statins...Clinical Evidence for Prevention...ConclusionReferences |
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AF is associated with impairment of endothelial function, inflammation, and oxidative stress. Because statins can improve endothelial NO production, have antiinflammatory effects, and reduce oxidative stress, these drugs may prevent the establishment of a substrate for AF. Experimental evidence and emerging clinical data show that treatment with statin drugs may represent a new and safe strategy to prevent AF in patients at risk. In contrast to antiarrhythmic drugs directly acting on ion channels, statins might not only prevent AF but also reduce morbidity and mortality.
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Acknowledgments |
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Sources of Funding
This work was supported by the Deutsche Forschungsgemeinschaft (Drs Laufs, Neuberger, and Böhm; Klinische Forschergruppe; KFO 196) and the Universität des Saarlandes (Homburger Forschungsförderungsprogramm; Drs Adam, Neuberger, Böhm, and Laufs).
Disclosures
None.
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