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Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Inflammation in the pathogenesis of atrial fibrillation
  5. Anti-inflammatory treatment in atrial fibrillation
  6. Concluding remarks
  7. References

Atrial fibrillation is highly prevalent, and affected patients are at an increased risk of a number of complications, including heart failure and thrombo-embolism. Over the past years, there has been increasing interest in the role of inflammatory processes in atrial fibrillation, from the first occurrence of the arrhythmia to dreaded complications such as strokes or peripheral emboli. As the standard drug combination which aims at rate control and anticoagulation only offers partial protection against complications, newer agents are needed to optimize treatment. In this paper, we review recent knowledge regarding the impact of inflammation on the occurrence, recurrence, perpetuation and complications of the arrhythmia, as well as the role of anti-inflammatory therapies in the treatment for the disease.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Inflammation in the pathogenesis of atrial fibrillation
  5. Anti-inflammatory treatment in atrial fibrillation
  6. Concluding remarks
  7. References

Atrial fibrillation (AF) is associated with significant morbidity and mortality [1]. It is the most common of all persistent cardiac arrhythmias, and even with optimal treatment, patients are at an increased risk of strokes and peripheral embolism, of heart failure and of neurocognitive decline. Traditional medical treatment includes rhythm control or rate control [2], and in higher-risk patients also oral anticoagulation to prevent thrombo-embolism [1]. Recently, pulmonary vein isolation and ablation have been documented as an effective strategy in selected groups of patients [3-8]. Although usually paroxysmal in the beginning, a majority of patients will experience recurrence or chronification. Data from a Canadian Registry show that 5 years after having experienced their first episode of AF, 25% of the patients will have chronic AF and another 40% will have had recurrence of paroxysmal AF [9].

A number of risk factors for development of AF have been identified; the pathogenesis is not fully understood and is probably multifactorial. Development of AF is a self-perpetuating process involving various degrees of volume and/or pressure overload in the heart, remodelling, hormonal (thyroxin, adrenalin) and toxic (alcohol) factors, fibrosis, oxidative stress and inflammation (Fig. 1). The different factors probably contribute differently depending on the main underlying cause of the AF, for example hypertension, valvular disease, recent cardiac surgery or others.

image

Figure 1. Interplay between factors involved in the occurrence, recurrence and perpetuation of atrial fibrillation.

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The notion that AF is closely associated with inflammation is originally a result of the clinical observation that cardiac inflammatory disorders such as myo- and pericarditis and post-periocardiotomy syndrome frequently are accompanied by AF [10]. Thus, inflammatory processes have been shown to be involved both before the first occurrence [11] and in the risk of recurrence of AF [12]. In addition, in the special setting of AF after cardiac surgery, inflammation also plays a central role [13]. Finally, inflammation appears to be a key player in the development of thrombo-embolic complications due to AF [14]. In this paper, we review recent studies demonstrating the importance of inflammation in the development, recurrence and perpetuation of AF, as well as clinical trials in which the effect of anti-inflammatory agents on AF has been examined.

Inflammation in the pathogenesis of atrial fibrillation

  1. Top of page
  2. Abstract
  3. Introduction
  4. Inflammation in the pathogenesis of atrial fibrillation
  5. Anti-inflammatory treatment in atrial fibrillation
  6. Concluding remarks
  7. References

Animal studies and their limitations

Several risk factors for the development of AF are acknowledged. Some of these, such as hypertension, diabetes, congestive heart failure and valvular heart disease, involve inflammatory processes to varying degrees. Knowledge regarding the importance of inflammation in AF derives from animal studies, epidemiological studies, cohort studies and intervention trials. Methods of investigation include both analysis of local and peripheral serological markers and atrial biopsies.

Several animal models have been designed to study the processes involved in AF. There are differences between the various models which are important to consider when extrapolating the results to humans. The models include hypertension [15], congestive heart failure [16], mitral regurgitation [17] and rapid atrial pacing [18]. With respect to development of pathology, for example atrial fibrosis, there are large differences between the models, indicating a multifactorial cause of AF in these experimental models, limiting the extrapolation to humans. As an example of the discrepancy between studies in animal and humans, an Australian study with sheep showed that increasing weight/obesity was associated with an increase in inflammatory markers, electrophysiological changes in the atrium and increased risk of AF [19], whereas in a human study from Greece, body mass index was not a risk factor for recurrence after AF ablation [20].

Inflammatory markers in humans with AF

Several trials have demonstrated that the levels of both interleukin (IL)-6 and C-reactive protein (CRP) correlate with the presence or development of AF [11, 21-23], as well as the risk of recurrence after direct current conversion [12, 24-26]. However, some studies fail to demonstrate such a correlation [27, 28]. In the study by Marcus and co-workers, there were no differences in CRP and IL-6 between patients scheduled for AF ablation and a control group. However, if blood was drawn at the time of an AF episode, plasma levels of both CRP and IL-6 were significantly higher than at baseline [28]. Several possible explanations for these discrepancies exist, such as lack of power in certain trials, limits of detection for the different serological assays and differences between patient groups with regard to risk factors and type of AF.

It may be that inflammatory processes are of different importance depending on whether hypertension, valvular disease, heart failure or other factors dominate as risk factors. Interestingly, Li and co-workers recently showed that development of AF in hypertensive patients was associated with certain IL-6 polymorphisms, indicating that IL-6 may not have the same functional importance in all individuals [29]. It may also be that elevation of a combination of inflammatory markers is required to predict increased risk of AF, as demonstrated for complement factors C3, C4 and CRP in a study by Dernellis and co-workers [30]. The lack of association between AF and individual complement components in this study was later confirmed in a population-based study from Sweden where baseline levels of C3 and C4 did not correlate with development of AF (>6000 men with a mean follow-up of 25 years). However, when combining levels of complement factors with levels of the inflammation-sensitive plasma proteins fibrinogen, haptoglobin, ceruloplasmin, α1-antitrypsin and orosomucoid, there was an increasing risk of development of AF with an increasing number of inflammatory markers in the upper quartile [31].

In addition to CRP and IL-6, a number of other inflammatory markers have been associated with development of AF, such as CCL-2 (MCP-1) [21], YKL-40 [32], CXCL8 (IL-8) and TNF [33]. AF is also associated with the level of advanced glycation end products – independently of diabetes [34]. Other markers have been associated with the risk of recurrence after direct current conversion, such as MPO [35] and serum amyloid A [24], and after pulmonary vein ablation, such as heat-shock protein 27S [36]. YKL-40 is of special interest as this inflammatory mediator is produced in neutrophils and macrophages at the site of inflammation [37-39], and not in the liver like CRP and IL-6. Thus, increased levels in AF may indicate local inflammation in the myocardium, although population studies of plasma levels [32] cannot determine the cellular origin of the protein.

Even if the main focus in linking AF to inflammation has been on analyses of soluble markers, it has also been demonstrated that AF patients have increased expression of monocyte Toll-like receptor (TLR) 2 [22] as well as signs of T cell activation [40] when compared with controls. TLR2 has a number of endogenous (e.g. oxidized low density lipoproteins, serum amyloid A, heat-shock proteins 60 and 70 and antiphospholipid antibodies) as well as exogenous (e.g. zymosan, lipoteichoic acid, peptidoglycans, atypical lipopolysaccharide and viral envelope glycoproteins) ligands [41], but the ligands involved in patients with AF is not known.

Metabolism, adipose tissue and link to heart surgery

The inflammatory properties and importance of adipose tissue is gaining increasing interest, especially in the setting of obesity and the metabolic syndrome [42]. In the case of AF, the impact of local adipose tissue in the pathogenesis should not be neglected. Lin and co-workers recently showed that epicardial adipocytes modulate electrophysiological properties of atrial myocytes, leading to increased risk of AF [43]. Similar results have been reported by others [44]. From this, it appears that local processes also are involved in the development of AF, but an association between systemic serum levels of resistin, involved in insulin resistance and increased in obesity, and AF has also been demonstrated [45], supporting a systemic relation as well. Gungor and co-workers found that post-operative, but not preoperative levels of resistin can predict the risk of developing post-operative AF in patients after coronary artery bypass grafting (CABG) [46]. Kourliourus and co-workers have shown that data from proteomic studies of tissue from the left atrium at the time of CABG can predict the development of post-operative AF [47]. Kaireviciute and co-workers have presented similar data where the level of tissue expression of von Willebrand factor in the left atrial appendage at the time of CABG predicts post-operative AF [13]. Thus, even for those developing AF as a complication to heart surgery, there seem to be predisposing myocardial changes present before the surgical procedure.

Clinical–epidemiological data

Epidemiological research linking AF to inflammatory processes, and not only to inflammatory markers, includes a Danish study demonstrating that development of AF was associated with the presence of psoriasis, and even to the severity of the disease [48]. The same relationship was recently established in rheumatoid arthritis by the same group [49]. Other trials have found associations between AF and coeliac disease [50] and herpes simplex virus infection [51].

Development of post-operative AF may be related to structural remodelling and perhaps also impaired cardiac autophagy [52]. Ling and co-workers have demonstrated that AF patients have signs of diffuse fibrosis in the left ventricle and hypothesize that this is a result of a common, underlying process [53]. However, Frustaci and co-workers found that in a group of patients with lone fibrillation (no known risk factors or underlying disease), a majority of atrial but not ventricular biopsies had inflammatory changes, including fibrosis [54]. Such remodelling and fibrosis could lead to local synthesis and release of inflammatory mediators, for example YKL-40 and IL-6, as has been shown in ischaemia [55]. There are, however, data questioning the notion that the inflammatory process in AF is being mainly of local origin, but in contrast supporting a systemic contribution. Scridon and co-workers found similar levels of a number of inflammatory markers in systemic blood as well as blood from the left atrium, the coronary sinus and the pulmonary veins in a group of patients with either paroxysmal AF, persistent AF or the Wollf-Parkinson-White syndrome. Thus, from this trial, it appears that the inflammatory markers tested were of peripheral/systemic and not cardiac origin [56]. This is supported by others also [57].

Inflammation and thrombosis

The demonstration of higher levels of pro-inflammatory mediators in patients with spontaneous contrast during echocardiographic examination links inflammation to thrombosis [58]. Such spontaneous echo contrast generally occurs in heart cavities with low flow velocity and perhaps turbulent flow and – unless treated with anticoagulation – is considered to be a sign of increased thrombo-embolic risk. It has been demonstrated that the occurrence of spontaneous contrast not only depends on slow flow, but is also related to the haematocrit level and the level of inflammatory proteins such as fibrinogen [59]. It is possible that in the near future, biomarkers including inflammatory mediators may be part of risk stratification in AF, CRP and IL-6 being the most promising ones at the moment [14, 60, 61].

The demonstrated link between higher systemic levels of inflammatory mediators and the occurrence of thrombosis is in agreement with the finding that inflammation increases blood viscosity [62-64]. Increased blood viscosity again is linked to an increased risk of thrombosis due to the higher aggregation between the blood cells [65]. Viscosity itself is maybe the factor which links the occurrence of AF to inflammation. In the Hagen–Poiseuille equation, resistance (R) of blood flow is determined by both a vascular and a viscous component: R = 8ηL/π.r4, in which r = vessel radius, L = vessel length and η = blood viscosity [62, 66]. If blood viscosity increases due to the presence of more ‘sticky’ inflammatory proteins, the flow resistance for the atria, as well as for the ventricles, will increase. This in turn will lead to increased filling pressures in atria and ventricles, consequently triggering AF.

A support for this role of blood viscosity as physical determinant of the occurrence of AF due to systemic inflammation may be that statins might have their positive effect on the occurrence of AF by their viscosity-lowering effect through the reduction of inflammation [67]. Furthermore, it has been demonstrated that blood transfusion after cardiac surgery is also related to the occurrence of post-operative AF [68]; an increase in haematocrit will substantially increase blood viscosity [69].

Previously considered to be a rather inert subcellular fragment taking part only in haemostasis, platelets are now recognized to have key roles also in inflammatory processes [70, 71]. Several recent trials have established a link between the risk of AF and specific platelet markers. In one study, preoperative mean platelet volume (MPV) correlated with the risk of developing post-operative AF after coronary artery bypass grafting [72], and patients with chronic AF have increased MPV when compared with controls [73]. Increasing volume is a sign of platelet activation, and Ha and co-workers showed that in AF patients, MPV could predict the risk of stroke development [74]. Whether increased MPV contributes to the development of or is a consequence of AF remains to be determined, but that AF activates platelets has been shown in an interesting study by Akar and co-workers in patients undergoing radiofrequency ablation for AF [75]. They found that platelets harvested from the coronary sinus during AF expressed higher levels of P-selectin as compared to platelets from systemic blood. Furthermore, this difference was not present in patients who were paced at a high atrial rate but who maintained a regular atrial rhythm. Thus, there seemed to be local, intracardiac activation of the platelets as a response to the arrhythmia. Aspirin does not affect MPV in patients with paroxysmal AF [76], in line with the poor effect of aspirin on thrombo-embolic risk in these patients.

Transfusion

Transfusion of blood products can induce inflammatory reactions, including life-threatening ones. Although serious adverse events are seldom, minor and subclinical reactions probably occur frequently. In an in vitro endothelial model, Urner and co-workers showed that different blood products had different ability to induce inflammatory responses [77]. Whether these findings can be transferred to a clinical setting is uncertain, but several studies have documented that transfusion of red cells – at least in the setting of CABG – increases the risk of AF [78-80]. Thus, in patients at high risk of developing AF, precautions should be taken if blood transfusion is required.

The hen and the egg

Although much research has focused on the possible pro-arrhythmic effect of inflammation, there is also evidence that the inflammatory process at least in part is a result of the arrhythmia. For instance, Rotter and co-workers found a decline in CRP after successful ablation of AF [81]. This was later confirmed by Marcus and co-workers in a study on ablation of atrial flutter [57]. In this study, there were several other interesting observations such as higher baseline values of CRP and IL-6 in atrial flutter patients compared with patients with supraventricular tachycardias as well as higher levels of inflammatory markers in systemic blood compared with blood from coronary sinus, indicating peripheral rather than cardiac origin of the mediators.

Anti-inflammatory treatment in atrial fibrillation

  1. Top of page
  2. Abstract
  3. Introduction
  4. Inflammation in the pathogenesis of atrial fibrillation
  5. Anti-inflammatory treatment in atrial fibrillation
  6. Concluding remarks
  7. References

Statins – a link to inflammation

Prevention and treatment of AF with non-anti-arrhythmic drugs have been demonstrated in numerous clinical studies and large trials [1]. The pleiotropic effects of the cholesterol-lowering statin drugs (HMG coenzyme A reductase inhibitors) have been extensively studied, and the efficacy in primary prevention of AF now seems well documented. Both patients at risk of [23] and with established coronary artery disease [82] and high-risk patients with low ejection fraction [83] have reduced risk of developing AF if treated with statins. This has been confirmed in a meta-analysis looking at results from several of the large statin trials [84]. Interestingly, a recent study indicates that the protective effect of statins is more pronounced in patients with higher risk for thrombo-embolic complications [85].

Patients on long-term statin therapy have reduced risk of post-operative AF, both after non-cardiac thoracic surgery [86] and after coronary artery bypass graft [87]. Even short-term (14 days) treatment with atorvastatin before surgery can prevent the occurence of AF after CABG [88]. When it comes to direct current conversion, however, there is conflicting evidence regarding the beneficial effects of statins, both with respects to immediate and long-term success rate [89-91]. One possible explanation is that although different statins have similar effects with regard to cholesterol lowering, pleiotropic properties may differ. Thus, according to current guidelines, statins are not recommended for treatment of AF [1]. Another possibility is that the various trials have included patients with AF of different aetiology and that the inflammatory ‘burden’ varies among those patients. In support of such a notion is the observation in one trial where the likelihood of effective conversion by the anti-arrhythmic drug amiodarone was reduced when increasing levels of IL-2 were present [92]. Finally, there is increasing evidence that first-time AF and recurrent AF are quite dissimilar with regard to degrees of local fibrosis, inflammation, oxidative stress, etc. Thus, expecting a drug to have identical effects in both settings may be unrealistic.

Other anti-inflammatory drugs

In addition to statins, several other drugs with anti-inflammatory properties have been shown to affect the occurrence of AF after heart surgery, such as colchicine [93], omega-3 fatty acids [94] and ascorbic acid [95]. Ascorbic acid can also reduce the rate of recurrence after electric cardioversion [96]. Although omega-3 fatty acids could reduce post-CABG AF, they were unable to prevent recurrences in paroxysmal AF [97] and after direct current conversion [98]. Again, such results probably underline the differences between the various types of AF.

Several clinical trials with inhibitors of angiotensin-converting enzyme and angiotensin-II receptor blockers have shown that these drugs reduce the risk of developing AF and that this effect is independent of the blood pressure lowering effect of the drugs. This was best demonstrated in the LIFE-trial [99]. Trials where such drugs have been used in secondary prevention are, however, less encouraging.

Thiazolidinediones (PPAR-agonists) are a novel group of anti-diabetic drugs intended for selected patients with diabetes mellitus type II. The drugs have anti-inflammatory properties and can reduce the risk of developing AF in diabetics [100].

For the drugs mentioned, the anti-inflammatory properties may be considered as ‘side effects’. Corticosteroids, however, are administered with the purpose of modifying an inflammatory reaction, and steroids are well documented to reduce AF after CABG [101] as well as to reduce the rate of recurrence after successful cardioversion [102]. Although a Cochrane review states that steroids reduce post-operative AF after CABG [103], such therapy is currently not included in treatment guidelines [1].

Beneficial non-anti-arrhythmic effects of anti-inflammatory treatment in AF

Over the past few years, evidence has accumulated to prove a close connection between inflammation and thrombosis [104-106].

As thrombo-embolic events are the most common, as well the most feared complications of AF, any treatment that could affect both these factors as well as the arrhythmia itself would be highly desired.

Even in the absence of overt strokes, AF patients have increased cognitive decline compared with individuals in sinus rhythm [107-111]. Such cognitive impairment is associated with localized cerebral atrophy, both in the hippocampus [110] and in the temporal lobe [112]. We and others have recently shown that anti-inflammatory treatment with powerful lipid-lowering drugs (e.g. a combination of statin and ezetimibe) can reduce the ‘inflammatory load’ in such patients [112, 113] (K.T. Lappegård, M. Pop-Purceleanu, Waander van Heerde, Joe Sexton, I. Tendolkar, Gheorghe A. M. Pop, submitted). Such a reduction correlates with a reduced pro-thrombotic tendency [113] and also with a reduction in cognitive decline and temporal lobe atrophy [112] (K.T. Lappegård, M. Pop-Purceleanu, Waander van Heerde, Joe Sexton, I. Tendolkar, Gheorghe A. M. Pop, submitted) These findings deserve confirmation in larger trials.

Concluding remarks

  1. Top of page
  2. Abstract
  3. Introduction
  4. Inflammation in the pathogenesis of atrial fibrillation
  5. Anti-inflammatory treatment in atrial fibrillation
  6. Concluding remarks
  7. References

Due to its large impact on human health, AF has been the subject of intensive research over the past decades. Lately, there has been increasing interest in addressing the causal factors involved in the pathogenesis underlying the arrhythmia such as local and systemic inflammation, and not just searching for more effective anti-arrhythmic drugs. It should be noted, however, that several drugs with anti-inflammatory properties such as statins, polyunsaturated fatty acids, angiotensin-converting enzyme inhibitors and angiotensin receptor blocking agents have performed differently when comparing the efficacy of primary versus secondary prevention. Therefore, results from primary prevention trials cannot be readily extrapolated to a setting of secondary prevention. Finally, new therapies should not focus exclusively on prevention of the arrhythmia, but also on its complications in general and cognitive decline in particular.

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  1. Top of page
  2. Abstract
  3. Introduction
  4. Inflammation in the pathogenesis of atrial fibrillation
  5. Anti-inflammatory treatment in atrial fibrillation
  6. Concluding remarks
  7. References
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