Thông tâm nhĩ có phải là rối loạn điều hòa không? cập nhật năm 2005

Xem lại Tạp chí Tim mạch Châu Âu (2006) 27, 136–149 doi: 10.1093 / eurheartj / ehi645 Thông tâm nhĩ có phải là rối loạn điều hòa không? Christopher J Boos1, Richard A Anderson2 và Gregory Y.H Lip1 * Đơn vị sinh học huyết khối, huyết khối và mạch máu, Khoa Y Đại học, Bệnh viện Thành phố, Birmingham B18 7QH, Vương quốc Anh; và Bệnh viện Đại học Wales, Heath Park, Cardiff CF14 4XN, Vương quốc Anh Nhận ngày 18 tháng 5 năm 2005; sửa đổi ngày 28 tháng 7 năm 2005; chấp nhận ngày 20 tháng 10 năm 2005; xuất bản trực tuyến trước khi in tháng 11 năm 2005 Atrial fi brillation; Trong fl ammation; Angiotensin II; Phòng ngừa; Các liệu pháp mới lạ Có bằng chứng ngày càng gia tăng để chứng minh cho sự tồn tại của tình trạng tắc nghẽn trong cơ chế bệnh sinh của quá trình thông liên nhĩ (AF) Thật vậy, AF có liên quan đến sự gia tăng mức độ đã biết trong các dấu ấn cơ động, ngay cả sau khi điều chỉnh các yếu tố gây nhiễu Hệ thống renin – angiotensin – aldosterone (RAAS) dường như đóng một vai trò quan trọng trong quá trình này Sinh thiết nhĩ từ bệnh nhân AF cũng đã xác định được sự hiện diện của AF Trong tổng quan này, có bằng chứng sơ bộ hỗ trợ một số liệu pháp điều trị bằng thuốc có khả năng làm giảm gánh nặng lâm sàng của AF Trong tổng quan này, chúng tôi trình bày tổng quan về các bằng chứng chứng minh mối liên hệ giữa cơ năng và AF, và một số liệu pháp điều trị bằng thuốc, chẳng hạn như thuốc ức chế men chuyển, thuốc chẹn thụ thể angiotensin II, steroid, dầu fi sh và vitamin C, có thể hiệu quả trong phòng ngừa AF bằng cách điều chỉnh trong các con đường điều chỉnh Giới thiệu Rung nhĩ (AF) đại diện cho một vấn đề lâm sàng thực sự trong thực hành hàng ngày AF tice là rối loạn nhịp tim kéo dài phổ biến nhất gặp phải trong thực hành lâm sàng, ảnh hưởng đến khoảng 0,9% dân số.1–3 Tỷ lệ AF phổ biến phụ thuộc nhiều vào tuổi, ảnh hưởng đến khoảng 1% người 65 tuổi và 5% người lớn tuổi. hơn 65 tuổi.4 AF cũng có liên quan đến sự gia tăng nguy cơ tử vong tương đối — dao động từ 1,3 đến 2,34, không phụ thuộc vào các yếu tố nguy cơ khác5,6 — cũng như gia tăng tỷ lệ mắc bệnh và ảnh hưởng xấu đến chất lượng cuộc sống.7 Đặc biệt, những bệnh nhân đột quỵ trong tình trạng AF có kết cục xấu hơn đáng kể, rõ ràng là tỷ lệ tử vong, bệnh tật và thời gian nằm viện lâu hơn so với những bệnh nhân bị đột quỵ khi không có AF.8,9 Ngay cả những bệnh nhân kịch phát (tự chấm dứt) và AF dai dẳng (kéo dài hơn ngày hoặc cần chuyển động tim) có nguy cơ đột quỵ tương tự như bệnh nhân AF vĩnh viễn.10 Ở dân số phương Tây, số ca nhập viện do AF đã tăng gấp 2-3 lần trong năm gần đây s.11 Điều này phần lớn được giải thích là do sự xuất hiện của dân số già, tỷ lệ AF chiếm ưu thế ở người già và khả năng sống sót của bệnh nhân mắc bệnh tim mạch (CVD) được cải thiện .12 Thật vậy, tỷ lệ AF được điều chỉnh theo tuổi ở bệnh nhân đột quỵ do thiếu máu cục bộ đã tăng hơn 40% trong vòng 30 năm qua.13 Vì vậy, ngày càng có nhu cầu về các chiến lược phòng ngừa AF chính và phụ được cải thiện để giảm gánh nặng sức khỏe to lớn tiềm tàng này. Thật không may, các chiến lược kiểm soát nhịp hiện tại không phải là Dữ liệu lý tưởng từ fi ve nghiên cứu so sánh giữa chiến lược kiểm soát nhịp chính và kiểm soát nhịp cho bệnh nhân * Tác giả tương ứng Tel: ỵ44 121 507 5080; fax: ỵ44 121 554 4083 Địa chỉ e-mail: gyhlip@bham.ac.uk với tiền sử AF không cho thấy sự vượt trội đáng kể của việc kiểm soát nhịp điệu.14–18 Trên thực tế, những nghiên cứu này chỉ nhấn mạnh đến hạn chế của cacy và độ cao - Hiệu quả của các thuốc chống loạn nhịp tim hiện có.19 Khi so sánh với chiến lược kiểm soát nhịp chính, việc kiểm soát nhịp cũng đắt hơn và dẫn đến tăng tỷ lệ nhập viện (chủ yếu là do tim mạch) với xu hướng tăng tỷ lệ tử vong, nhưng không phủ nhận nhu cầu chống đông lâu dài.20,21 Mặc dù kiểm soát nhịp có thể là mong muốn ở một số bệnh nhân, nhưng các chiến lược kiểm soát nhịp hiện có là chưa tối ưu và rõ ràng là chưa được đáp ứng về các chiến lược kiểm soát nhịp thay thế, an toàn hơn và hiệu quả hơn. bằng chứng về mối liên hệ với một loạt các tình trạng tim mạch, chẳng hạn như bệnh mạch vành (CAD), kháng insulin và đái tháo đường, và tăng huyết áp. 22-26. Ngoài ra, có đang nổi lên dữ liệu để hỗ trợ mối liên hệ giữa in-ammation và AF.27,28. Điều này đã tạo ra những cơ hội tiềm năng thú vị để nhắm mục tiêu trong các quy trình điều hòa để ngăn ngừa AF. với việc sử dụng các tác nhân mới có thể hỗ trợ quá trình điều trị trong AF Mục đích của bài báo này là trình bày tổng quan về các bằng chứng liên kết trong quá trình điều trị với AF và thứ hai, làm nổi bật một số tác nhân dược lý có tiềm năng thực sự để giảm gánh nặng lâm sàng của AF bằng cách điều chỉnh trong các con đường bổ sung Chiến lược tìm kiếm Chúng tôi đã thực hiện tìm kiếm tài liệu toàn diện bằng cách sử dụng cơ sở dữ liệu thư mục điện tử (ví dụ: MEDLINE, EMBASE, DARE và COCHRANE DATABASE) u

Review European Heart Journal (2006) 27, 136–149 doi:10.1093/eurheartj/ehi645 Is atrial fibrillation an inflammatory disorder? Christopher J Boos1, Richard A Anderson2, and Gregory Y.H Lip1* Haemostasis, Thrombosis and Vascular Biology Unit, University Department of Medicine, City Hospital, Birmingham B18 7QH, UK; and University Hospital of Wales, Heath Park, Cardiff CF14 4XN, UK Received 18 May 2005; revised 28 July 2005; accepted 20 October 2005; online publish-ahead-of-print November 2005 Atrial fibrillation; Inflammation; Angiotensin II; Prevention; Novel therapies There is mounting evidence to support the influence of inflammation in the pathogenesis of atrial fibrillation (AF) Indeed, AF is associated with increased levels of known inflammatory markers, even after adjustment for confounding factors The renin–angiotensin–aldosterone system (RAAS) appears to play a key role in this process Atrial biopsies from patients with AF have also confirmed the presence of inflammation Furthermore, there is preliminary evidence to support a number of drug therapies that have the potential to reduce the clinical burden of AF In this review, we present an overview of the evidence supporting a link between inflammation and AF, and some of the drug therapies, such as the angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, steroids, fish oils, and vitamin C, that might be efficacious in the prevention of AF by modulating inflammatory pathways Introduction Atrial fibrillation (AF) represents a genuine clinical problem in everyday practice AF is the most common sustained arrhythmia encountered in clinical practice, affecting approximately 0.9% of the population.1–3 The prevalence of AF is strongly age-dependent, affecting approximately 1% of persons aged 65 years and 5% of individuals older than 65 years.4 AF is also associated with an increase in the relative risk of mortality—ranging from 1.3 to 2.34, independent of other risk factors5,6—as well as an increasing morbidity and adversely affects quality of life.7 In particular, patients who present with stroke in AF have a considerably worse outcome, defined by a higher mortality, morbidity, and longer hospital stays compared with patients who have a stroke in the absence of AF.8,9 Even patients with paroxysmal (self-terminating) and persistent AF (lasting more than days or requiring cardioversion) have a risk of stroke that is similar to patients with permanent AF.10 In Western populations, hospitalizations for AF have increased by two- to three-fold in recent years.11 This is largely explained by the advent of an ageing population, the predominance of AF among the elderly, and improved survival of patients with cardiovascular disease (CVD).12 Indeed, the age-adjusted prevalence of AF among patients with ischaemic stroke has already risen by greater than 40% over the last 30 years.13 So, there is a growing need for improved primary and secondary AF prevention strategies to reduce this potentially enormous health burden Unfortunately, current rhythm control strategies are far from ideal Data from five comparative studies of a primary rate control vs rhythm control strategy for patients *Corresponding author Tel: ỵ44 121 507 5080; fax: ỵ44 121 554 4083 E-mail address: g.y.h.lip@bham.ac.uk with a history of AF failed to show a significant superiority of rhythm control.14–18 In fact, these studies merely emphasized the limited efficacy and high side-effect profile of the currently available anti-arrhythmic drugs.19 When compared with a primary rate control strategy, rhythm control is also more expensive and leads to increased hospitalization (mainly for cardioversion) with a trend to increased mortality, without negating the need for long-term anticoagulation.20,21 Although rhythm control may be desirable in some patients, currently available rhythm control strategies are suboptimal and there is clearly an unmet need for alternative, safer, and more effective rhythm control strategies There is now an increasing body of evidence linking inflammation to a broad spectrum of cardiovascular conditions, such as coronary artery disease (CAD), insulin resistance and diabetes mellitus, and hypertension.22–26 In addition, there is emerging data to support the association between inflammation and AF.27,28 This has created exciting potential opportunities to target inflammatory processes for the prevention of AF This has lead to a paradigm shift from a more ‘electrical’ to something more ‘structural’, with the use of novel agents that can influence the inflammatory processes in AF The aim of this article is to present an overview of the evidence linking inflammation to AF and, secondly, to highlight several pharmacological agents that have genuine potential to reduce the clinical burden of AF by modulating inflammatory pathways Search strategy We performed a comprehensive literature search by using electronic bibliographic databases (i.e MEDLINE, EMBASE, DARE, and COCHRANE DATABASE) using the following keywords: atrial fibrillation, inflammation, vascular markers, & The European Society of Cardiology 2005 All rights reserved For Permissions, please e-mail: journals.permissions@oxfordjournals.org Downloaded from http://eurheartj.oxfordjournals.org/ at St Petersburg State University on November 27, 2013 KEYWORDS Is AF an inflammatory disorder? prevention, C-reactive protein (CRP), interleukins, angiotensin II, etc We also scanned www.theheart.org and reference lists from included articles and hand searching abstracts from national and international cardiovascular meetings 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 Where necessary, study authors were contacted to obtain further data Pathophysiology of AF—a brief overview Link between inflammation and AF Historical evidence to support an association between AF and inflammation can be extracted from the frequent association of AF with inflammatory conditions of the heart, such as myocarditis and pericarditis.41,42 Bruins et al.43 were the first to propose the inflammation-AF hypothesis, following their observations of an increased frequency of AF after coronary artery bypass surgery They noted that the peak incidence of AF occurred on the second and third post-operative days, which coincided with the peak elevation of CRP levels In an intriguing study by Maixent et al.,44 the authors demonstrated the presence of circulating autoantibodies against myosin heavy chain in a significant percentage of patients with idiopathic paroxysmal AF raising the possibility of an inflammatory autoimmune process in some patients with paroxysmal AF Histology Histological evidence to support the association between inflammation and AF has been derived from several sources (Table 1).45–49 Results of atrial biopsies taken from patients in AF compared with controls have demonstrated evidence of inflammatory infiltrates and oxidative damage within the atrial tissue (see Table 1) In one of these studies, abnormal atrial histology was uniformly found in multiple biopsy specimens of 12 patients with lone AF, compared with normal histology in all of the controls, with 66% of the AF group showing evidence of occult myocarditis.49 This would strongly support the view that inflammation acts as an initiator rather than as a consequence of AF in this patient group Inflammatory markers There have been numerous clinical studies that have investigated the relationship between inflammation (using known serum or plasma vascular inflammatory markers) and AF (Table 2).50–65 The vascular markers that have been most frequently studied are high-sensitivity C-reactive protein (hs-CRP) and interleukin (IL)-6 hs-CRP has evolved as the most robust and reproducible marker of vascular inflammation.66 CRP is a circulating acute-phase reactant named initially for its capacity to bind to the c-polysaccharide of streptococcus pneumoniae, and has been considered as the prototypic downstream marker of inflammation.67 CRP is synthesized primarily by the liver in response to IL-6 and IL-1.68 Of note, there is a consistent and significant association (in all populations) between baseline hs-CRP levels and risk of future cardiovascular events (stroke, peripheral vascular disease, sudden cardiac death, AF, plaque rupture and recurrent ischaemia, and myocardial infarction).69–71 Levels of hs-CRP have been noted to be higher among patients with AF compared with controls in sinus rhythm (see Table 1).57,60–65 Also, persistent AF patients have higher hs-CRP levels than paroxysmal AF patients, and both have higher levels than controls.65 In one study, the combination of microalbuminuria and an elevated hs-CRP increased the risk of subsequent AF development by up to four-fold.54 Furthermore, a longer duration of AF is associated with higher hs-CRP levels and larger left atrial dimensions, supporting a link between the burden of AF, inflammation, and structural remodelling.56 In both crosssectional and longitudinal studies, hs-CRP has remained a consistent and significant predictor of early AF relapse after successful cardioversion, even after adjustment for risk factors for AF, such as hypertension and CAD.51,53,58,59,62,64 hs-CRP has also been shown to be predictive of subsequent future development of new cases of AF among a large cohort of patients in sinus rhythm.63 The precise mechanism for the increased circulating hsCRP in AF is uncertain, but might reflect active participation of CRP in the local inflammatory response within the atrial myocardium In patients with AF, CRP may localize in Downloaded from http://eurheartj.oxfordjournals.org/ at St Petersburg State University on November 27, 2013 The pathophysiology of AF is highly complex It is now recognized that the development of AF leads to functional changes within the atria that perpetuate the arrhythmia (‘AF begets AF’), by a process known as electrical remodelling.29 The key features of electrical remodelling are shortening of the atrial refractory period, the loss of rate adaptation, and prolongation of atrial conductivity.30,31 There is also accumulation of calcium within atrial myocytes, leading to a reduction of the inward L-type Ca2ỵ current, which in turn contributes to the shortening of the atrial effective refractory period and the promotion and maintenance of multiple wavelet-re-entry circuits.32,33 Structural remodelling of the atria occurs in parallel with the changes of electrical remodelling described earlier The structural changes that define this structural remodelling include left atrial dilatation and increasing atrial fibrosis.33 Key to this fibrotic process is the deposition of increased amounts of connective tissue between individual cells and with the deposition of large amounts of collagen and fibronectin.34 This leads to separation of myocytes from one another and subsequent impairment of atrial conduction at the microscopic level35,36 and culminates in alterations in the biophysical properties of atrial tissue, allowing the initiation and perpetuation of AF.37 It is now known that the pulmonary veins have a crucial role as one of the key trigger sites for the onset of AF.38 The exact stimulus for this focal triggering is unknown at this point, however, inflammation may provide one explanation Indeed, inflammation could also act as an ongoing catalyst to the remodelling process Of note, electrical remodelling commences within only a few hours of AF onset and accounts for the increasing difficulty of successful cardioversion after the first 24 h of AF, whereas reverse remodelling after successful restoration of sinus rhythm appears to occur much more slowly.39,40 Again, these observations suggest that the processes involved are likely to be more than simply electrical 137 138 C.J Boos et al Table Histological evidence to support the association between inflammation and AF Year Active group Control group Key findings Nakamura et al 45 2003 Seven patients with cardiogenic thromboembolism and non-valvular AF (five undergoing surgical thrombectomy and two were post-mortem samples) Four controls without cardiac disease or AF (all post-mortem samples) Inflammatory cells infiltrated the left atrial endocardium (with high tissue factor expression) in all seven patients with non-valvular AF consistent with myocarditis vs no evidence of significant inflammation in the control group Verheule et al 46 2003 19 dogs with severe chronic mitral regurgitation in sinus rhythm exposed to burst atrial pacing 13 healthy control dogs in sinus rhythm exposed to burst atrial pacing Sustained AF was induced in 10 of 19 dogs with mitral regurgitation but in none of the 13 controls; transmural tissue sections from the left atrium in the mitral regurgitation dogs revealed infiltrates of inflammatory cells indicative of chronic inflammation not seen in the control group Mihm et al 47 2001 Right atrial appendage biopsies from seven permanent AF patients undergoing Maze procedure Seven patients in normal sinus rhythm with either coronary disease or end-stage heart failure Evidence of significant oxidative stress in the patients with AF compared with the control group Kamiyama48 1998 Five white rabbits exposed to right atrial pacing and AF induction Five white rabbits subjected to sham operation without atrial stimulation Left atrial appendage endothelial cells and leukocytes showed positive staining for ICAM-1 and P-selectin in atrial paced rabbits compared with controls; leukocytes were adherent in the atrially paced group Frustaci et al 49 1997 Endomyocardial biopsies of the right atrium in 12 patients with refractory paroxysmal lone AF Endomyocardial right atrial biopsies from 11 patients with Wolff–Parkinson– White Syndrome All control biopsies were normal, however, all lone AF biopsies showed abnormalities with 6/12 showing evidence of active inflammatory infiltrates atrial tissue, possibly binding to the membranes of myocardial cells in inflamed tissues and activating complement, leading to tissue damage.72,73 In human coronary disease models (where inflammation has been clearly linked to thrombosis), deposits of CRP have also been demonstrated on immunohistochemical staining, in the vascular wall of active atherosclerotic plaques, where it is co-localized with the terminal complement complex.22 IL-6 is a pleiotropic cytokine that has diverse physiological roles, including mediation of both pro-inflammatory responses and cyto-protective functions.74 This cytokine is produced by T-cells, macrophages, and endothelial cells and physiologically it stimulates the synthesis of several acute-phase reaction proteins, such as CRP, serum amyloid-A, and fibrinogen, and counter-regulates tumour necrosis factor (TNF)-a and IL-1b.75 It would thus seem logical to assume that IL-6 levels would be raised in patients with AF compared with healthy controls There have been five studies that have investigated the relationship between IL-6 and AF (see Table 2).55,57,60–62 Four of these studies found increased levels of IL-6 in patients with AF compared with healthy controls55,57,60,61 with one failing to find any association.62 Supportive data from genetic studies have revealed that a common polymorphism Val34Leu in the clotting factor XIII-A was independently associated with increased IL-6 levels, leading to more rapid activation of factor XIII and consequently greater cross-linking of fibrin monomers and increased clot resistance.76 These events may potentially increase the prothrombotic state in affected AF patients, perhaps by modulating the inflammatory state Furthermore, a 174G/C polymorphism of the promoter of the IL-6 gene appears to influence the development of post-operative (coronary artery bypass surgery) AF, again supporting the role of inflammation in the development of post-operative AF.77 TNF-a is a 185 amino acid glycoprotein peptide hormone that is synthesized mainly by monocytes and macrophages.78,79 This hormone plays a significant role in the initial activation of the immune system Its release is stimulated by several factors, including IL-1b and bacterial endotoxin.80 Intra-arterial TNF-a causes an acute local vascular inflammation that is associated with impaired endothelium-dependent relaxation.81 So far, there has been only one study that has looked into the possible association between TNF-a and AF.53 This was a very small study and did not adjust for confounding factors; however, it did demonstrate increased levels of TNF-a in patients with AF compared with healthy controls in sinus rhythm.60 Finally, there appears to be a relationship between elevated white blood cell count as a marker of inflammation and the development of AF after cardiac surgery in 181 consecutive patients undergoing coronary bypass or cardiac valve surgery (AF), even after multivariate analyses.82 In summary, there appears to be consistent links between inflammatory markers, whether assessed by serum or plasma indices or white cell count, and AF Further data from prospective and interventional studies would inform us on whether these links are merely associations or causal in the complex pathophysiology of AF Downloaded from http://eurheartj.oxfordjournals.org/ at St Petersburg State University on November 27, 2013 Author Is AF an inflammatory disorder? Table Key studies investigating the association of plasma inflammatory markers and AF Author Year Type of AF Markers studied Control group (n) Korantzopoulos et al 50 2005 Persistent AF Fibrinogen, CRP, WBC NA Korantzopoulos et al 51 2005 Persistent CRP, fibrinogen Acevedo et al 52 2005 Newly diagnosed AF Watanabe et al 53 2005 Asselbergs et al 54 Active group (n) Adjusted for Key findings 30 Nil NA 44 Nil CRP and TAT NA 130 No difference in baseline values of inflammatory indices between patients who remain in sinus rhythm and amongst those who relapsed into AF CRP and fibrinogen levels were higher in patients who relapsed into AF compared to patients who maintained sinus rhythm (P ¼ 0.017) Both CRP and TAT levels were significantly elevated in AF patients versus controls Persistent symptomatic AF CRP NA 106 2005 All CRP 7471 Roldan et al 55 2005 Permanent 74 191 Watanabe et al 56 2005 Paroxysmal Plasma IL-6 and F1 ỵ CRP 50 50 Psychari et al 57 2005 Persistent and permanent CRP, IL-6 46 90 75 Age, anti-arrhythmic drugs, TAT levels, left atrium diameter, and left ventricular systolic dysfunction CAD, smoking, and DM Nil Age, sex, DM, HBP, CAD, HF, stroke/embolism Left ventricular mass, left ventricular end-systolic dimension, left atrial dimension Age, gender, CAD, DM, smoking, inflammatory markers, HBP, left atrial dimension, LVEF Pre-cardioversion hs-CRP level determined prior to cardioversion represents an independent predictor of both successful cardioversion for AF and the maintenance of sinus rhythm after conversion Elevated CRP and microalbuminuria associated with AF and the combination is associated with a four-fold increase of AF Increased IL-6 and F1 and compared with controls CRP in PAF greater than controls in sinus rhythm; also longer AF duration associated with CRP elevation and atrial structural remodelling, as approximated by larger left atrial CRP and IL-6 greater in AF than in controls Continued 139 Downloaded from http://eurheartj.oxfordjournals.org/ at St Petersburg State University on November 27, 2013 2004 Persistent AF CRP NA 130 Sex, CAD, hypertension, smoking, DM, AF duration, left atrial dimension, left ventricle ejection fraction Age, gender, DM, HBP, BMI, lipids, smoking status, family history, CAD, renal function Nil Anderson et al 59 2004 All types CRP 2449 347 Sata et al 60 2004 Paroxysmal CRP, IL-6, TNF-a 15 11 Conway et al 61 2004 Permanent 106 41 HBP, DM, previous stroke, HF, CAD, anti-thrombotic therapy Conway et al 62 2004 Persistent 41 54 Age, anti-arrhythmic therapy Aviles et al 63 2003 All types IL-6, CRP, TF, P-selectin, and plasma viscosity hs-CRP, IL-6, vWF, sP-selectin, fibrinogen hs-CRP 5491 315 Dernellis and Panaretou64 2001 Paroxysmal hs-CRP 50 50 Age, gender, BMI, CAD, HBP, cerebrovascular disease, HF, DM, Left atrial dimension Chung et al 65 2001 Paroxysmal and persistent lone AF hs-CRP 71 125 Age, gender, HF, CAD, history of cerebrovascular disease, valvular heart disease, and HBP CRP level determined prior to cardioversion is an independent predictor of both successful cardioversion for AF and the maintenance of SR after conversion 140 Dernellis et al 58 CRP independently predicted an increased risk of AF CRP and IL-6 levels higher in AF patients than healthy control; cardioversion to sinus rhythm failed to significantly reduced the CRP levels Compared with controls, AF patients had higher levels of IL-6, CRP, TF, and plasma viscosity on unadjusted analysis, but only TF was associated with AF on adjusted analysis hs-CRP AF HC; hs-CRP predictive of initial, but not long-term cardioversion success CRP is associated with the presence of and future risk of AF development Increased CRP in AF compared with controls, CRP is a potent determinant of successful cardioversion of PAF in sinus rhythm CRP persistent AF PAF controls WBC, white cell count; HBP, high blood pressure; DM, diabetes mellitus; TAT, thrombin-antithrombin complex; LVH, left ventricular hypertrophy; HF, heart failure; BMI, body mass index; vWF, von Willebrand factor; PAF, paroxysmal AF C.J Boos et al Downloaded from http://eurheartj.oxfordjournals.org/ at St Petersburg State University on November 27, 2013 Is AF an inflammatory disorder? Renin–angiotensin–aldosterone system, inflammation, and AF linking polymorphisms in the rennin–angiotensin system (RAS) gene with an increase risk of subsequent AF development, further supporting the role of the RAAS in the development of AF.111–113 Link between inflammation and thrombosis in AF AF confers a hypercoagulable state, even in the absence of underlying heart disease Abnormalities of haemostasis, fibrinolysis, endothelium, and platelets have all been described in AF, which may increase the risk of stroke and thromboembolism.61,114–117 Although there appears to be a link between inflammation and AF, one of the key questions is whether the observed inflammation in AF increases the risk of thromboembolism as has been demonstrated for atherosclerotic models Conway et al.118 were the first to confirm this putative link between inflammation and complications of AF In a small pilot study, they showed that elevated IL-6 levels were an independent predictor of the composite of stroke or death among a cohort of 77 high-risk AF patients This observation was complemented by data from Thambidorai et al.,119 which showed that trans-oesophageal risk factors for stroke were greater for patients with elevated hs-CRP compared those with normal levels among 104 patients with AF Hence, there appears to be an established link between inflammation, AF, and thrombosis Preventing AF by modulating the inflammatory state Modulation of the RAS We have, so far, illustrated the emerging evidence supporting a role for the RAAS in the pathogenesis of AF, via inflammation Both ACE-inhibitors and ARBs appear to have significant anti-inflammatory actions.98 For example, inhibition of the RAAS has been shown to reduce the number of macrophages, T-lymphocytes, and HLA-DRỵ inammatory cells in atheromatous plaques, strongly supporting its antiinflammatory properties.120 Inhibition of the RAAS has also been shown to suppress reactive oxygen species (ROS) generation in leukocytes, NF-kB binding activity in mononuclear cells, and reduce plasma levels of hs-CRP, TNF-a, MCP-1, ICAM-1, and VCAM-1.121–125 The angiotensin II-dependent induction of atrial fibrosis would suggest that ACE-inhibitors or ARBs might be beneficial in patients prone to AF Indeed, experiments have shown that inhibition of atrial angiotensin II-dependent effects reduces the amount of phosphorylated extracellular signal-regulated protein kinase, the degree of atrial fibrosis, and thereby the inducibility of AF with ACE-inhibitors and ARBs being similarly effective.126,127 There have been a large number of studies that have analysed the relationship between RAAS inhibition and AF, but its detailed treatise is beyond the scope of this article.84,85 Unfortunately, this data have been mainly derived from small retrospective observational studies, with the vast majority failing to adjust for potential confounders However, in a recent large meta-analysis (56 308 patients) incorporating 11 of the 12 randomized trials (see Table 3) using either ACE-inhibitors or ARBs for the Downloaded from http://eurheartj.oxfordjournals.org/ at St Petersburg State University on November 27, 2013 Angiotensin-converting enzyme (ACE) converts angiotensin I to angiotensin II Angiotensin II mediates its action via the counter-regulatory angiotensin II receptors AT1 and AT2 Activation of the renin–angiotensin–aldosterone system (RAAS) plays a central role in the development of CVD.83 Blockage of the RAAS by either ACE-inhibitors or angiotensin II receptor blockers (ARBs) have been shown to improve endothelial function and reduce both morbidity and mortality.83 Angiotensin II is a regulatory hormone with a key role in blood pressure control, by stimulating vascular smooth muscle constriction, aldosterone release from the adrenal cortex, and sodium re-absorption from the renal tubule A detailed treatise of the mechanisms linking the RAAS, in particular, ACE and angiotensin II, to electrophysiological and structural remodelling in AF is beyond the scope of this review and has been discussed in detail elsewhere.84,85 Experimental studies have revealed that angiotensin II possesses several pro-inflammatory properties.86 Nuclear factor-kappaB (NF-kB) appears to be the key mediatory factor in this inflammatory cascade stimulating the upregulation of genes encoding host of known inflammatory mediators 87,88 Ang II has been shown to increase the production of pro-inflammatory cytokines [e.g IL-6, IL-8, TNF-a, and gamma interferon (IFN-g)], adhesion molecules (such as vascular cell adhesion molecule [VCAM]-1 on endothelial cells and intracellular adhesion molecule [ICAM]-1), chemoattractant protein (MCP)-1 (further increasing monocyte recruitment), and selectins (such as P-selectin and s-selectin, leading to leukocyte tethering and rolling).89–99 Furthermore, angiotensin II provokes rapid neutrophil recruitment via the release of known chemokines, such as cytokine-induced neutrophil chemoattractant (CINC), macrophage inflammatory protein (MIP)-2, osteopontin, and regulated on activation, normal T expressed and secreted (RANTES).99 Increasing evidence would support the concept of reciprocal ‘cross-talk’ relationship between angiotensin II and inflammation Not only does angiotensin II cause inflammation, but the converse is also true with inflammation itself acting as a stimulus for increased angiotensin II production.80 For example, both hs-CRP and TNF-a have been shown to upregulate angiotensin type receptors in human vascular smooth and cardiac fibroblasts, respectively.100,101 Also, angiotensin II receptors are known to be present on mononuclear cells and the vascular endothelium.102 Of note, human atrial tissue also expresses receptors for angiotensin II Furthermore, angiotensin II is not only formed within the systemic circulation, but also within tissues (such as the endothelial wall) as tissue ACE.103,104 Indeed, human atrial tissue locally expresses ACE, with the capacity for local production of angiotensin III.105–107 There is histological evidence to confirm that AF (both persistent and paroxysmal) leads to altered angiotensin II receptor expression.108,109 In a key paper, Cardin et al.110 were able to link increased atrial expression of angiotensin II receptors with increased atrial cell death and leukocyte infiltration supporting a potential link between the RAAS, inflammation, and AF Furthermore, there is now evidence 141 142 Table Summary of randomized trials of ACE-inhibitors and angiotensin II receptor blockers in the prevention of AF Author Trial type Patient population Trial design Treatment group (n) Control group (n) Key findings Val-HeFT129 2005 In sinus rhythm with HF 2205 2190 Lower rate of AF development in valsartan group (113/2205, 5.12%) compared with placebo (174/2190, 7.95%; P ¼ 0.0002) LIFE130 2005 Hypertensive patients with LVH and in SR Valsartan vs placebo on top of treatment with ACE-inhibitor Losartan vs atenolol 4298 4182 Madrid et al 131 2004 30 2004 Amiodarone + irbesartan (two doses) Candesartan vs placebo 60 CHARM132 2769 2749 Ueng et al 133 2003 Persistent lone AF and cardioversion Heart failure and sinus rhythm Persistent AF and cardioversion Significantly less new-onset AF and associated stroke among losartan-compared with atenolol-based antihypertensive treatment despite similar blood pressure reduction Irbesartan plus amiodarone significantly decreased the rate of AF recurrences in dose with a dose-dependent effect Significant reduction in AF among candesartan-treated patients 70 75 SOLVD134 2003 Enalapril vs placebo 186 188 Madrid et al 135 2002 79 75 GISSI-3136 2002 Lisinopril vs placebo 8865 8846 STOP-2137 1999 Enalapril/lisinopril vs diuretic + b-blocker 2205 4409 TRACE138 1999 Trandolapril vs placebo 790 787 CAPP139 1999 Sinus rhythm with left ventricular dysfunction Persistent AF and cardioversion In sinus rhythm following myocardial infarction Elderly hypertensives (SBP  180 mmHg + DBP  100 mmHg) Post-myocardial infarction Hypertension (DBP 100 mmHg) 5492 5493 Van Den Berg140 1995 18 Congestive failure and chronic AF Amiodarone + enalapril Amiodarone + irbesartan Captopril vs conventional treatment (diuretics + b-blockers) Lisinopril vs placebo Enalapril increased the chance of remaining in sinus rhythm at weeks (84.3 vs 61.3%, P ¼ 0.002) and at the median follow-up period of 270 days (74.3 vs 57.3%, P ¼ 0.021) Significantly lower rate of AF development in the enalapril (5.4%) vs placebo group (24%, P , 0.0001) Amiodarone ỵ irbesartan lower rate of AF recurrence than amiodarone alone No significant reduction in AF among ACE-inhibitor compared with placebo at weeks post-myocardial infarction Trend to higher rate of AF development with use of ACE-inhibitors compared with conventional treatment Significantly lower rate of AF development with ACE-inhibitor (2.8%) vs placebo (5.3%, P ¼ 0.01) Trend to reduced AF occurrence with captopril compared with conventional group Trend to reduced AF among lisinopril-treated patients C.J Boos et al AF, atrial fibrillation; HF, heart failure; ACE-inhibitors, angiotensin-converting enzyme inhibitor; Val-HeFT, Valsartan Heart Failure Trial; LIFE, Losartan Intervention for Endpoint reduction study; CHARM, Candesartan in Heart Failure-Assessment of Reduction in Mortality and Morbidity Program Investigators; SOLVD, Studies of Left Ventricular Dysfunction; GISSI-3, Third Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto (GISSI)-Prevenzione Trial; STOP-2, Swedish Trial of Old people with Hypertension; TRACE, TRAndopril Cardiac Evaluation study; CAPPP, the Captopril Prevention Project; SBP, systolic blood pressure; DBP, diastolic blood pressure Downloaded from http://eurheartj.oxfordjournals.org/ at St Petersburg State University on November 27, 2013 143 2004 2004 2003 2003 Merckx et al 164 Tveit et al 165 Young-Xu et al 166 Siu et al 167 HBP, high blood pressure; HF, heart failure Simvastatin and atorvastatin 10 52 Age, HBP, HF, alcohol, CAD, cholesterol Nil 186 263 All types Nil 57 57 Pravastatin CAD, age 25 000 patients in sinus rhythm 218 449 All types 2005 Hanna et al 163 Patients with reduced ejection fraction, at high risk of subsequent AF Patients in sinus rhythm but identified at high risk of AF development (left atrial dilatation 40 mm and left ventricular hypertrophy wall thickness 10 mm) Persistent AF 48 h, scheduled for electrical cardioversion Adult patients in sinus rhythm with coronary artery disease CAD in sinus rhythm at high risk of AF Retrospective post-electrical cardioversion study for patients with lone AF months duration All types Key findings Adjusted for Control group (n) Treatment group (n) Statin Study design Year Author Statins, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, remain the most powerful and effective lipidlowering drugs A series of landmark clinical trials have established statins as effective agents in the primary and secondary prevention of coronary disease.143–151 It has become increasingly apparent that the benefits of statins extend to mechanisms beyond their cholesterol-reducing effects These ‘pleiotropic’ (multiple) effects include improved endothelial function with increased nitric oxide bioavailability, anti-thrombotic effects, enhanced stability of the atherosclerotic plaque, and decreased oxidative stress and vascular inflammation.152–155 There is now compelling evidence that statin therapy may attenuate the effect of inflammation on risk of cardiovascular events among a broad spectrum of patients with CVD.156–162 It would, thus seem, intuitive to suppose that if AF is indeed linked to inflammation then statins would offer a potentially preventative role in AF There have been five studies so far that have analysed the efficacy of statins in the prevention of AF (Table 4).163–167 Four of these studies showed favourable effects of statins to reduce the incidence of AF, with only one study reporting negative results (see Table 3) Unfortunately, again, these Table An illustration of the trials involving statins for the prevention of AF Statins Downloaded from http://eurheartj.oxfordjournals.org/ at St Petersburg State University on November 27, 2013 prevention of AF, Healey et al.128 demonstrated a favourable effect of RAAS inhibition in the primary and secondary prevention of AF.128–140 They concluded that ACE-inhibitors/ ARBs reduced the overall risk of AF by 28% [95% confidence interval (CI) 15–40%, P ¼ 0.0002] across a broad spectrum of patient subgroups (including patients with hypertension, heart failure, post-myocardial infarction, and postcardioversion) Furthermore, the reduction in AF was similar independent of whether an ACE-inhibitor or an ARB was the main drug group used (ACE-inhibitors: 28%, P ¼ 0.01; ARBs: 29%, P ¼ 0.00002).128 There have been several putative mechanisms to explain the favourable actions of ACE-inhibitors and ARBs in the prevention of AF: decreased atrial stretch; lowered enddiastolic left ventricular pressure and subsequent left atrial pressure; the prevention of atrial fibrosis; the modification of sympathetic tone, alteration in ion currents and atrial refractoriness, and direct anti-arrhythmic effects.84,85 However, given the demonstrated important role of the RAAS in inflammation and AF, it could be postulated that interruption of the RAAS may exact positive effects upon the left atrium by reducing atrial inflammation, oxidative stress, and reduce atrial remodelling Unfortunately, none of the trials listed analysed levels of known inflammatory markers simultaneously to the observed beneficial effects in preventing either new onset AF or relapse In addition, several of these trials compared active treatment to placebo, and consequently may have been intrinsically biased The ongoing ONTARGET/ TRANSCEND (the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial/Telmisartan Randomized Assessment Study in ACE Intolerant Subjects with Cardiovascular Disease) and ACTIVE (Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events)-I trials should add further detailed evidence into the potential of RAAS inhibition in the prevention of AF.141,142 Statins reduced the development of subsequent AF, by 23% (P , 0.001) During a mean follow-up of 6.5 years, significantly lower rate of AF development in the statin group (16/218, 7.3%) vs the control group (52/449, 11.6%) No difference in initial cardioversion success or AF prevalence at 6-week follow-up 52% reduction in development of new AF with use of statin (24/263, 9%) compared with non-use (28/186, 15%) 77% relative risk reduction in AF recurrence with statin use, without affecting defibrillation threshold Is AF an inflammatory disorder? 144 Steroids Given the strong evidence, presented so far, in favour of an association between inflammation and AF, it would perhaps seems reasonable to hypothesize that known antiinflammatory drugs, such as steroids, might offer both therapeutic and preventative potential among patients either in AF or at high risk of subsequent development This hypothesis was tested in the potentially landmark paper by Dernellis and Panaretou.58 In a double-blind study, they randomized 104 patients with first presentation persistent AF to low-dose glucocorticoid therapy (16 mg methyl prednisolone for weeks tapered to mg for months) or placebo A primary rhythm control strategy involving amiodarone + cardioversion was adopted in all of the patients as part of the trial protocol All patients were successfully cardioverted and were commenced on oral propafenone post-cardioversion The authors found that methyl prednisolone significantly reduced the primary endpoint of AF recurrence (50% in the placebo group vs 9.6% in the glucocorticoid group) as well as the extended endpoint of permanent AF (29% in the placebo group vs 2% in the glucocorticoid group) In addition, hs-CRP concentrations were a significant predictor of the primary end-point, with higher hs-CRP levels being predictive of AF recurrence, and vice versa In addition, methyl prednisolone significantly lowered hs-CRP by an average of 80% within the first month, and this reduction was maintained for the duration of the 30-month study (P , 0.001).The authors also demonstrated that the risk of AF recurrence was increased by approximately seven times for each mg/dL increase in plasma levels of hs-CRP, providing a strong link between the degree of inflammation and the burden of AF Fish oils Dietary intake of polyunsaturated fatty acids (PUFAs), notably omega (n)-3 fatty acids, have been to shown to have favourable effects on cardiovascular outcomes.170 Their efficacy can only be partly explained by improvement in lipid profile and there is mounting evidence to support potential anti-inflammatory and antioxidant properties of oily fish.171 Indeed, n-3 fatty acids have anti-inflammatory properties and are frequently used clinically to treat symptoms of inflammatory diseases, such as rheumatoid arthritis or Crohn’s disease.172,173 Intake of a diet rich in n-3 fatty acids has been shown to have an inverse relationship with several known inflammatory vascular markers.174,175 These studies have shown that the anti-inflammatory effects of fish oil may result from the inhibitory effects of oxidized n-3 fatty acids on endothelial nuclear factor-kappaB activation via a proliferator-activated receptor alpha-dependent pathway.176 In a prospective, population-based cohort of 4815 older (65 years) Mozaffarian et al.177 demonstrated that consumption of high levels of fish containing n-3 fatty acids was associated with a lower incidence of subsequent AF development However, these results are challenged by an even larger prospective study of 47 949 participants (mean age: 56 years) which investigated the relation between the consumption of n-3 fatty acids from fish, by use of a detailed semi-quantitative food questionnaire, and risk of AF or flutter, but found that consumption of n-3 fatty acids from fish was not associated with a reduction in risk of AF or atrial flutter.178 Finally, in a recently published study of 160 patients pre-treatment with omega-3 fatty acids reduced the incidence of AF post-coronary artery bypass surgery by 58% compared with patients treated with usual care only.179 In this study, g/day of PUFAs was administered at least days before surgery and continued until discharge In addition, treatment with fish oils reduced the length of hospitalization from 8.2 to 7.3 days (P ¼ 0.017) Downloaded from http://eurheartj.oxfordjournals.org/ at St Petersburg State University on November 27, 2013 were observational and non-randomized, and consequently no firm conclusions can be drawn at this point Siu et al.167 were the first to study the prevention of AF with statins They retrospectively studied 62 patients with lone persistent AF lasting 3 months who underwent direct current cardioversion, and observed that statintreated patients (n ¼ 10) had less recurrent AF than the control group of 52 patients (40 vs 84%, P ¼ 0.0007); however, this was a very small and underpowered observational study In a much larger observational study, YoungXu et al.166 studied a cohort of 449 patients with CAD at high risk of AF They observed a significantly lower rate of new AF development among statin users (9%) compared with non-users (15%) Of note, the potential impact of statins on AF development was independent of its cholesterol-lowering ability Also, the efficacy of statins in preventing AF appeared to correlate with the length of statin use, with longer statin use being associated with greater protection against the subsequent development of AF In the largest study so far, Hanna et al.163 performed a cross-sectional analysis of 25 000 patients enrolled in the multicenter Guidant-sponsored Advancement Heart Failure Registry; of these patients, 7027 patients (27%) developed AF, and statin therapy led to a 23% reduction in AF, when compared with those not treated, even after multivariate analysis (odds ratio for AF 0.685; P , 0.001) Finally, there are supportive data from two further studies demonstrating the efficacy of statins to reduce the burden of AF in animal models In the first study, 39 dogs were subjected to rapid atrial tachypacing in the absence and presence of treatment with simvastatin (and vitamins C and E, no effect).168 The investigators were able to demonstrate that compared with controls simvastatin reduced the promotion of AF, following tachypacing In the second animal study, Kumagai et al.169 operatively induced sterile pericarditis in 20 dogs randomized to treatment with or without atorvastain mg/(kg/day) (commenced with week prior to operation) Atorvastatin was shown to both reduce the incidence of AF and the levels of hs-CRP compared with the control group, suggesting that atorvastatin reduced the burden of AF by reducing the inflammatory substrate In addition, these findings were shown to correlate with a lower percentage of fibrosis in all atrial regions in the atorvastatin group compared with the placebo group It was particularly interesting that the authors noted the greater difficulty of inducing AF before vs after the induction of pericarditis, which would support the influence of inflammation in AF generation Thus, there are preliminary data to support the potential utility of statins in the primary and secondary prevention of AF These observed positive effects of statins on the burden of AF appeared to be independent of their cholesterol reducing properties However, further data from large-scale randomized trials are clearly needed C.J Boos et al Is AF an inflammatory disorder? There are mechanistic reasons why it would be presumed that fish oils could be protective against AF For example, n-3 fatty acids have been shown to exert anti-asynchronous effects in rat atrial myocytes, reduce pro-arrhythmic eicosanoids, and inhibit sodium and calcium currents which contribute to the arrhythmic process.180,181 There is also an inverse relationship between n-3 fatty acids and the risk of sudden death (presumably related to ventricular arrhythmias).182 In the Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico (GISSI)-Prevenzione Study (11 324 patients randomized to n-3 fatty acids or placebo on top of standard therapy post-myocardial infarction), there was a 45% reduction in sudden cardiac death in patients randomized to treatment with n-3 fatty acids.183 Ascorbic acid (vitamin C) is potent oxygen scavenger, which may potentially modulate the inflammatory and oxidative abnormalities associated with AF.184 In a novel study, Carnes et al.185 gave supplemental ascorbate to 43 patients before, and for days following, cardiac bypass graft surgery, and found that ascorbate significantly reduced the incidence of post-operative AF (16.3% in ascorbate treated vs 34.9% in control subjects) They also showed that atrial peroxynitrate (a known ROS) formation was increased during rapid atrial pacing and that atrial ascorbate levels were reduced following atrial pacing The current evidence would thus support the hypothesis that vitamin C attenuates atrial electrophysiological remodelling and reduces AF burden, possibly via the scavenging peroxynitrite and other reactive oxygen species, and reducing the inflammatory substrate In a recent study of 46 patients with persistent AF, oral vitamin C reduced the early recurrence of AF following successful cardioversion; also, when compared with baseline values, inflammatory indices (hs-CRP and fibrinogen) were decreased after cardioversion in patients receiving vitamin C, but did not change significantly in the control group.51 Conclusion The obvious limitations of currently available antiarrhythmic drugs highlight the need for alternative yet effect rhythm control strategies There is mounting evidence to support the influence of inflammation in the pathogenesis of AF Unfortunately, association does not equate to causation and further studies are clearly needed to better elucidate this highly complex interaction Nonetheless, AF is clearly associated with increased levels of known inflammatory markers, even after adjustment for confounding factors The RAAS appears to play a key role in this process Atrial biopsies from patients with AF have also confirmed the presence of inflammation Furthermore, there is preliminary evidence to support a number of drug therapies that have the potential to reduce the clinical burden of AF There is also evidence supporting a link between inflammation and AF, and some of the drug therapies, such as the ACE-inhibitors, ARBs, steroids, fish oils, and vitamin C, that might be efficacious in the prevention of AF by modulating inflammatory pathways Conflict of interest: none declared References Fuster V, Ryden LE, Asinger RW, Cannom DS, Crijns HJ, Frye RL, Halperin JL, Kay GN, Klein WW, Levy S, McNamara RL, Prystowsky EN, Wann LS, Wyse DG, Gibbons RJ, Antman EM, Alpert JS, Faxon DP, Fuster V, Gregoratos G, Hiratzka LF, Jacobs AK, Russell RO, Smith SC Jr, Klein WW, Alonso-Garcia A, Blomstrom-Lundqvist C, de Backer G, Flather M, Hradec J, Oto A, Parkhomenko A, Silber S, Torbicki A American College of Cardiology (ACC)/American Heart Association (AHA)/ European Society of Cardiology (ESC) guidelines for the management of patients with atrial fibrillation: executive summary report of the ACC/AHA Task Force on practice guidelines and the ESC Committee for practice guidelines and policy conferences (committee to develop guidelines for the management of patients with atrial fibrillation) developed in collaboration with the North American Society of Pacing and Electrophysiology Circulation 2001;104:2118–2150 Singer DE, Albers GW, Dalen JE, Go AS, Halperin JL, Manning WJ Antithrombotic therapy in atrial fibrillation: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy Chest 2004;126:429S–456S Go AS, Hylek EM, Phillips KA, Chang Y, Henault LE, Selby JV, Singer DE Prevalence of diagnosed atrial fibrillation in adults: national implications for rhythm management and stroke prevention: the anticoagulation and risk factors in atrial fibrillation (ATRIA) study JAMA 2001;285:2370–2375 Kannel WB, Wolf PA, Benjamin EJ, Levy D Prevalence, incidence, prognosis, and predisposing conditions for atrial fibrillation: populationbased estimates Am J Cardiol 1998;82:2N–9N Benjamin EJ, Wolf PA, D’Agostino RB, Silbershatz H, Kannel WB, Levy D Impact of atrial fibrillation on the risk of death: the Framingham Heart Study.Circulation 1998;98:946–952 Lehto M, Snapinn S, Dickstein K, Swedberg K, Nieminen MS; OPTIMAAL Investigators Prognostic risk of atrial fibrillation in acute myocardial infarction complicated by left ventricular dysfunction: the OPTIMAAL experience Eur Heart J 2005;26:350–356 Gronefeld GC, Lilienthal J, Kuck KH, Hohnloser SH; Pharmacological Intervention in Atrial Fibrillation (PIAF) Study Investigators Impact of rate versus rhythm control on quality of life in patients with persistent atrial fibrillation: results from a prospective randomized study Eur Heart J 2003;24:1430–1436 Steger C, Pratter A, Martinek-Bregel M, Avanzini M, Valentin A, Slany J, Stollberger C Stroke patients with atrial fibrillation have a worse prognosis than patients without: data from the Austrian Stroke registry Eur Heart J 2004;25:1734–1740 Saxena R, Lewis S, Berge E, Sandercock PA, Koudstaal PJ Risk of early death and recurrent stroke and effect of heparin in 3169 patients with acute ischemic stroke and atrial fibrillation in the International Stroke Trial Stroke 2001;32:2333–2337 10 Hart RG, Pearce LA, Rothbart RM, McAnulty JH, Asinger RW, Halperin JL Stroke with intermittent atrial fibrillation: incidence and predictors during aspirin therapy Stroke Prevention in Atrial Fibrillation Investigators J Am Coll Cardiol 2000;35:183–187 11 Wattigney WA, Mensah GA, Croft JB Increasing trends in hospitalization for atrial fibrillation in the United States, 1985 through 1999: implications for primary prevention Circulation 2003;108:711–716 12 Boos CJ, Carlsson J, More RS Rate or rhythm control in persistent atrial fibrillation? QJM 2003;96:881–892 13 Tsang TS, Petty GW, Barnes ME, O’Fallon WM, Bailey KR, Wiebers DO, Sicks JD, Christianson TJ, Seward JB, Gersh BJ The prevalence of atrial fibrillation in incident stroke cases and matched population controls in Rochester, Minnesota: changes over three decades J Am Coll Cardiol 2003;42:93–100 14 Hohnloser SH, Kuck KH, Lilienthal J Rhythm or rate control in atrial fibrillation—pharmacological intervention in atrial fibrillation (PIAF): a randomised trial Lancet 2000;356:1789–1794 15 Van Gelder IC, Hagens VE, Bosker HA, Kingma JH, Kamp O, Kingma T, Said SA, Darmanata JI, Timmermans AJ, Tijssen JG, Crijns HJ; Rate Control versus Electrical Cardioversion for Persistent Atrial Fibrillation Study Group A comparison of rate control and rhythm control in patients with recurrent persistent atrial fibrillation N Engl J Med 2002;347:1834–1840 16 Wyse DG, Waldo AL, DiMarco JP, Domanski MJ, Rosenberg Y, Schron EB, Kellen JC, Greene HL, Mickel MC, Dalquist JE, Corley SD; Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) Investigators A comparison of rate control and rhythm control in patients with atrial fibrillation N Engl J Med 2002;347:1825–1833 Downloaded from http://eurheartj.oxfordjournals.org/ at St Petersburg State University on November 27, 2013 Vitamin C 145 146 41 Spodick DH Arrhythmias during acute pericarditis: a prospective study of 100 consecutive cases JAMA 1976;235:39–41 42 Morgera T, Di Lenarda A, Dreas L, Pinamonti B, Humar F, Bussani R, Silvestri F, Chersevani D, Camerini F Electrocardiography of myocarditis revisited: clinical and prognostic significance of electrocardiographic changes Am Heart J 1992;124:455–467 43 Bruins P, te Velthuis H, Yazdanbakhsh AP, Jansen PG, van Hardevelt FW, de Beaumont EM, Wildevuur CR, Eijsman L, Trouwborst A, Hack CE Activation of the complement system during and after cardiopulmonary bypass surgery: postsurgery activation involves C-reactive protein and is associated with postoperative arrhythmia Circulation 1997;96: 3542–3548 44 Maixent JM, Paganelli F, Scaglione J, Levy S Antibodies against myosin in sera of patients with idiopathic paroxysmal atrial fibrillation J Cardiovasc Electrophysiol 1998;9:612–617 45 Nakamura Y, Nakamura K, Fukushima-Kusano K, Ohta K, Matsubara H, Hamuro T, Yutani C, Ohe T Tissue factor expression in atrial endothelium associated with nonvalvular atrial fibrillation: possible involvement in intracardiac thrombogenesis Thromb Res 2003;111:137–142 46 Verheule S, Wilson E, Everett T IV, Shanbhag S, Golden C, Olgin J Alterations in atrial electrophysiology and tissue structure in a canine model of chronic atrial dilatation due to mitral regurgitation Circulation 2003;107:2615–2622 47 Mihm MJ, Yu F, Carnes CA, Reiser PJ, McCarthy PM, Van Wagoner DR, Bauer JA Impaired myofibrillar energetics and oxidative injury during human atrial fibrillation Circulation 2001;104:174–180 48 Kamiyama N Expression of cell adhesion molecules and the appearance of adherent leukocytes on the left atrial endothelium with atrial fibrillation: rabbit experimental model Jpn Circ J 1998;62:837–843 49 Frustaci A, Chimenti C, Bellocci F, Morgante E, Russo MA, Maseri A Histological substrate of atrial biopsies in patients with lone atrial fibrillation Circulation 1997;96:1180–1184 50 Korantzopoulos P, Kolettis TM, Kountouris E, Siogas K, Goudevenos JA Variation of inflammatory indexes after electrical cardioversion of persistent atrial fibrillation: Is there an association with early recurrence rates? Int J Clin Pract 2005;59:881–885 51 Korantzopoulos P, Kolettis TM, Kountouris E, Dimitroula V, Karanikis P, Pappa E, Siogas K, Goudevenos JA Oral vitamin C administration reduces early recurrence rates after electrical cardioversion of persistent atrial fibrillation and attenuates associated inflammation Int J Cardiol 2005;102:321–326 52 Acevedo M, Corbalan R, Braun S, Pereira J, Navarrete C, Gonzalez I C-reactive protein and atrial fibrillation: ‘evidence for the presence of inflammation in the perpetuation of the arrhythmia’ Int J Cardiol 2005 Published online ahead of print June 25, 2005 53 Watanabe E, Arakawa T, Uchiyama T, Kodama I, Hishida H Highsensitivity C-reactive protein is predictive of successful cardioversion for atrial fibrillation and maintenance of sinus rhythm after conversion Int J Cardiol 2005 Published online ahead of print June 16, 2005 54 Asselbergs FW, van den Berg MP, Diercks GF, van Gilst WH, van Veldhuisen DJ C-reactive protein and microalbuminuria are associated with atrial fibrillation Int J Cardiol 2005;98:73–77 55 Roldan V, Marin F, Martinez JG, Garcia-Herola A, Sogorb F, Lip GY Relation of interleukin-6 levels and prothrombin fragment 1ỵ2 to a point-based score for stroke risk in atrial fibrillation Am J Cardiol 2005;95:881–882 56 Watanabe T, Takeishi Y, Hirono O, Itoh M, Matsui M, Nakamura K, Tamada Y, Kubota I C-reactive protein elevation predicts the occurrence of atrial structural remodeling in patients with paroxysmal atrial fibrillation Heart Vessels 2005;20:45–49 57 Psychari SN, Apostolou TS, Sinos L, Hamodraka E, Liakos G, Kremastinos DT Relation of elevated C-reactive protein and interleukin-6 levels to left atrial size and duration of episodes in patients with atrial fibrillation Am J Cardiol 2005;95:764–767 58 Dernellis J, Panaretou M Relationship between C-reactive protein concentrations during glucocorticoid therapy and recurrent atrial fibrillation Eur Heart J 2004;25:1100–1107 59 Anderson JL, Allen Maycock CA, Lappe DL, Crandall BG, Horne BD, Bair TL, Morris SR, Li Q, Muhlestein JB; Intermountain Heart Collaborative Study Group Frequency of elevation of C-reactive protein in atrial fibrillation Am J Cardiol 2004;94:1255–1259 60 Sata N, Hamada N, Horinouchi T, Amitani S, Yamashita T, Moriyama Y, Miyahara K C-reactive protein and atrial fibrillation Is inflammation a consequence or a cause of atrial fibrillation? Jpn Heart J 2004;45:441–445 61 Conway DS, Buggins P, Hughes E, Lip GY Predictive value of indexes of inflammation and hypercoagulability on success of cardioversion of persistent atrial fibrillation Am J Cardiol 2004;94:508–510 Downloaded from http://eurheartj.oxfordjournals.org/ at St Petersburg State University on November 27, 2013 17 Carlsson J, Miketic S, Windeler J, Cuneo A, Haun S, Micus S, Walter S, Tebbe U; STAF Investigators Randomized trial of rate-control versus rhythm-control in persistent atrial fibrillation: the Strategies of Treatment of Atrial Fibrillation (STAF) Study J Am Coll Cardiol 2003;41:1690–1696 18 Opolski G, Torbicki A, Kosior DA, Szulc M, Wozakowska-Kaplon B, Kolodziej P, Achremczyk P; Investigators of the Polish How to Treat Chronic Atrial Fibrillation Study Rate control vs rhythm control in patients with nonvalvular persistent atrial fibrillation: the results of the Polish How to Treat Chronic Atrial Fibrillation (HOT CAFE) Study Chest 2004;126:476–486 19 Boos CJ, More RS, Carlsson J Persistent atrial fibrillation: rate control or rhythm control Rate control is not inferior to rhythm control BMJ 2003;326:1411–1412 20 Marshall DA, Levy AR, Vidaillet H, Fenwick E, Slee A, Blackhouse G, Greene HL, Wyse DG, Nichol G, O’Brien BJ; AFFIRM and CORE Investigators Cost-effectiveness of rhythm versus rate control in atrial fibrillation Ann Intern Med 2004;141:653–661 21 Hagens VE, Vermeulen KM, TenVergert EM, Van Veldhuisen DJ, Bosker HA, Kamp O, Kingma JH, Tijssen JG, Crijns HJ, Van Gelder IC; RACE Study Group Rate control is more cost-effective than rhythm control for patients with persistent atrial fibrillation—results from the Rate Control versus Electrical Cardioversion (RACE) Study Eur Heart J 2004;25:1542–1549 22 Libby P, Ridker PM, Maseri A Inflammation and atherosclerosis Circulation 2002;105:1135–1143 23 Sjoholm A, Nystrom T Endothelial inflammation in insulin resistance Lancet 2005;365:610–612 24 Blann AD Assessment of endothelial dysfunction: focus on atherothrombotic disease Pathophysiol Haemost Thromb 2003–2004;33:256–261 25 Nadar S, Blann AD, Lip GY Endothelial dysfunction: methods of assessment and application to hypertension Curr Pharm Des 2004; 10:3591–3605 26 Silvestro A, Scopacasa F, Ruocco A, Oliva G, Schiano V, Zincarelli C, Brevetti G Inflammatory status and endothelial function in asymptomatic and symptomatic peripheral arterial disease Vasc Med 2003;8:225–232 27 Boos CJ, Lip GYH The role of inflammation in atrial fibrillation Int J Clin Pract 2005;59:870–872 28 Engelmann MD, Svendsen JH Inflammation in the genesis and perpetuation of atrial fibrillation Eur Heart J 2005;26:2083–2092 29 Wijffels MC, Kirchhof CJ, Dorland R, Allessie MA Atrial fibrillation begets atrial fibrillation: a study in awake chronically instrumented goats Circulation 1995;92:1954–1968 30 Hertervig EJ, Yuan S, Carlson J, Kongstad-Rasmussen O, Olsson SB Evidence for electrical remodelling of the atrial myocardium in patients with atrial fibrillation: a study using the monophasic action potential recording technique Clin Physiol Funct Imaging 2002;22:8–12 31 Lau CP, Tse HF Electrical remodelling of chronic atrial fibrillation Clin Exp Pharmacol Physiol 1997;24:982–983 32 Nattel S New ideas about atrial fibrillation 50 years on Nature 2002;415:219–226 33 Boldt A, Wetzel U, Lauschke J, Weigl J, Gummert J, Hindricks G, Kottkamp H, Dhein S Fibrosis in left atrial tissue of patients with atrial fibrillation with and without underlying mitral valve disease Heart 2004;90:400–405 34 Kostin S, Klein G, Szalay Z, Hein S, Bauer EP, Schaper J Structural correlate of atrial fibrillation in human patients Cardiovasc Res 2002;54:361–379 35 Schotten U, Ausma J, Stellbrink C, Sabatschus I, Vogel M, Frechen D, Schoendube F, Hanrath P, Allessie MA Cellular mechanisms of depressed atrial contractility in patients with chronic atrial fibrillation Circulation 2001;103:691–698 36 Kucera JP, Rudy Y Mechanistic insights into very slow conduction in branching cardiac tissue: a model study Circ Res 2001;89:799–806 37 Spach MS, Dolber PC Relating extracellular potentials and their derivatives to anisotropic propagation at a microscopic level in human cardiac muscle: evidence for electrical uncoupling of side-to-side fiber connections with increasing age Cardiovasc Res 1986;58:356–371 38 Haissaguerre M, Marcus FI, Fischer B, Clementy J Radiofrequency catheter ablation in unusual mechanisms of atrial fibrillation: report of three cases J Cardiovasc Electrophysiol 1994;5:743–751 39 Allessie M, Ausma J, Schotten U Electrical, contractile and structural remodeling during atrial fibrillation Cardiovasc Res 2002;54:230–246 40 Manios EG, Kanoupakis EM, Chlouverakis GI, Kaleboubas MD, Mavrakis HE, Vardas PE Changes in atrial electrical properties following cardioversion of chronic atrial fibrillation: relation with recurrence Cardiovasc Res 2000;47:244–253 C.J Boos et al Is AF an inflammatory disorder? 85 Savelieva I, Camm J Atrial fibrillation and heart failure: natural history and pharmacological treatment Europace 2004;5(Suppl 1):S5–S19 86 Boos CJ, Lip GYH Prevention of atrial fibrillation by angiotensinconverting-enzyme inhibitors and angiotensin II receptor blockers: some pathophysiological insights J Am Coll Cardiol, in press 87 Tham DM, Martin-McNulty B, Wang YX, Wilson DW, Vergona R, Sullivan ME, Dole W, Rutledge JC Angiotensin II is associated with activation of NF-kappaB-mediated genes and downregulation of PPARs Physiol Genomics 2002;11:21–30 88 Costanzo A, Moretti F, Burgio VL, Bravi C, Guido F, Levrero M, Puri PL Endothelial activation by angiotensin II through NFkappaB and p38 pathways: involvement of NFkappaB-inducible kinase (NIK), free oxygen radicals, and selective inhibition by aspirin J Cell Physiol 2003; 195:402–410 89 Tamarat R, Silvestre JS, Durie M, Levy BI Angiotensin II angiogenic effect in vivo involves vascular endothelial growth factor- and inflammation-related pathways Lab Invest 2002;82:747–756 90 Tummala PE, Chen XL, Sundell CL, Laursen JB, Hammes CP, Alexander RW, Harrison DG, Medford RM Angiotensin II induces vascular cell adhesion molecule-1 expression in rat vasculature: potential link between the renin–angiotensin system and atherosclerosis Circulation 1999;100:1223–1229 91 Alvarez A, Cerda-Nicolas M, Naim Abu Nabah Y, Mata M, Issekutz AC, Panes J, Lobb RR, Sanz MJ Direct evidence of leukocyte adhesion in arterioles by angiotensin II Blood 2004;104:402–408 92 Neri Serneri GG, Boddi M, Modesti PA, Coppo M, Cecioni I, Toscano T, Papa ML, Bandinelli M, Lisi GF, Chiavarelli M Cardiac angiotensin II participates in coronary microvessel inflammation of unstable angina and strengthens the immunomediated component Circ Res 2004;94: 1630–1637 93 Ruiz-Ortega M, Ruperez M, Lorenzo O, Esteban V, Blanco J, Mezzano S, Egido J Angiotensin II regulates the synthesis of proinflammatory cytokines and chemokines in the kidney Kidney Int Suppl 2002;82:12–22 94 Ishibashi M, Hiasa K, Zhao Q, Inoue S, Ohtani K, Kitamoto S, Tsuchihashi M, Sugaya T, Charo IF, Kura S, Tsuzuki T, Ishibashi T, Takeshita A, Egashira K Critical role of monocyte chemoattractant protein-1 receptor CCR2 on monocytes in hypertension-induced vascular inflammation and remodeling Circ Res 2004;94:1203–1210 95 Omura T, Yoshiyama M, Kim S, Matsumoto R, Nakamura Y, Izumi Y, Ichijo H, Sudo T, Akioka K, Iwao H, Takeuchi K, Yoshikawa J Involvement of apoptosis signal-regulating kinase-1 on angiotensin II-induced monocyte chemoattractant protein-1 expression Arterioscler Thromb Vasc Biol 2004;24:270–275 96 Kiarash A, Pagano PJ, Tayeh M, Rhaleb NE, Carretero OA Upregulated expression of rat heart intercellular adhesion molecule-1 in angiotensin II- but not phenylephrine- induced hypertension Hypertension 2001;37:58–65 97 Jiang B, Xu S, Hou X, Pimentel DR, Cohen RA Angiotensin II differentially regulates interleukin-1-beta-inducible NO synthase (iNOS) and vascular cell adhesion molecule-1 (VCAM-1) expression: role of p38 MAPK J Biol Chem 2004;279:20363–20368 98 Das UN Is angiotensin-II an endogenous pro-inflammatory molecule? Med Sci Monit 2005;11:155–162 99 Suzuki Y, Ruiz-Ortega M, Lorenzo O, Ruperez M, Esteban V, Egido J Inflammation and angiotensin II Int J Biochem Cell Biol 2003; 35:881–900 100 Kranzhofer R, Schmidt J, Pfeiffer CA Angiotensin induces inflammatory activation of human vascular smooth muscle cells Arterioscler Thromb Vasc Biol 1999;19:1623–1629 101 Peng J, Gurantz D, Tran V, Cowling RT, Greenberg BH Tumor necrosis factor-alpha-induced AT1 receptor upregulation enhances angiotensin II-mediated cardiac fibroblast responses that favor fibrosis Circ Res 2002;91:1119–1126 102 Shimada K, Yazaki Y Binding sites for angiotensin II in human mononuclear leucocytes J Biochem 1978;84:1013–1015 103 Paradis P, Dali-Youcef N, Paradis FW, Thibault G, Nemer M Overexpression of angiotensin II type I receptor in cardiomyocytes induces cardiac hypertrophy and remodeling Proc Natl Acad Sci USA 2000;97:931–936 104 Rogg H, de Gasparo M, Graedel E, Stulz P, Burkart F, Eberhard M, Erne P Angiotensin II-receptor subtypes in human atria and evidence for alterations in patients with cardiac dysfunction Eur Heart J 1996; 17:1112–1120 105 Ohmichi N, Iwai N, Shimoike H, Izumi M, Watarida S, Mori A, Nakamura Y, Kinoshita M Assessment of the angiotensin II-forming pathway in human atria Heart Vessels 1997;(Suppl 12):116–118 Downloaded from http://eurheartj.oxfordjournals.org/ at St Petersburg State University on November 27, 2013 62 Conway DS, Buggins P, Hughes E, Lip GY Relationship of interleukin-6 and C-reactive protein to the prothrombotic state in chronic atrial fibrillation J Am Coll Cardiol 2004;43:2075–2082 63 Aviles RJ, Martin DO, Apperson-Hansen C, Houghtaling PL, Rautaharju P, Kronmal RA, Tracy RP, Van Wagoner DR, Psaty BM, Lauer MS, Chung MK Inflammation as a risk factor for atrial fibrillation Circulation 2003;108:3006–3010 64 Dernellis J, Panaretou M C-reactive protein and paroxysmal atrial fibrillation: evidence of the implication of an inflammatory process in paroxysmal atrial fibrillation Acta Cardiol 2001;56:375–380 65 Chung MK, Martin DO, Sprecher D, Wazni O, Kanderian A, Carnes CA, Bauer JA, Tchou PJ, Niebauer MJ, Natale A, Van Wagoner DR C-reactive protein elevation in patients with atrial arrhythmias: inflammatory mechanisms and persistence of atrial fibrillation Circulation 2001; 104:2886–2891 66 Blake GJ, Ridker PM C-reactive protein and other inflammatory risk markers in acute coronary syndromes J Am Coll Cardiol 2003; 41(Suppl 4):37S–42S 67 Venugopal SK, Devaraj S, Jialal I Effect of C-reactive protein on vascular cells: evidence for a proinflammatory, proatherogenic role Curr Opin Nephrol Hypertens 2005;14:33–37 68 Fichtlscherer S, Zeiher AM Endothelial dysfunction in acute coronary syndromes: association with elevated C-reactive protein levels Ann Med 2000;328:515–518 69 Danesh J, Whincup P, Walker M, Lennon L, Thomson A, Appleby P, Gallimore JR, Pepys MB Low grade inflammation and coronary heart BMJ 2000;321:199–204 70 Szmitko PE, Wang CH, Weisel RD, de Almeida JR, Anderson TJ, Verma S New markers of inflammation and endothelial cell activation, Part I Circulation 2003;108:1917–1923 71 Rost NS, Wolf PA, Kase CS, Kelly-Hayes M, Silbershatz H, Massaro JM, D’Agostino RB, Franzblau C, Wilson PW Plasma concentration of C-reactive protein and risk of ischemic stroke and transient ischemic attack: the Framingham study Stroke 2001;32:2575–2579 72 Kaplan MH, Volanakis JE Interaction of C-reactive protein complexes with the complement system I Consumption of human complement associated with the reaction of C-reactive protein with pneumococcal C-polysaccharide and with the choline phosphatides, lecithin and sphingomyelin J Immunol 1974;112:2135–2147 73 Volanakis JE, Wirtz KW Interaction of C-reactive protein with artificial phosphatidylcholine bilayers Nature 1979;281:155–157 74 Naka T, Nishimoto N, Kishimoto T The paradigm of IL-6: from basic science to medicine Arthritis Res 2002;4(Suppl 3):S233–S242 75 Tilg H, Dinarello CA, Mier JW IL-6 and APPs: anti-inflammatory and immunosuppressive mediators Immunol Today 1997;18:428–432 76 Marin F, Corral J, Roldan V, Gonzalez-Conejero R, del Rey ML, Sogorb F, Lip GY, Vicente V Factor XIII Val34Leu polymorphism modulates the prothrombotic and inflammatory state associated with atrial fibrillation J Mol Cell Cardiol 2004;37:699–704 77 Gaudino M, Andreotti F, Zamparelli R, Di Castelnuovo A, Nasso G, Burzotta F, Iacoviello L, Donati MB, Schiavello R, Maseri A, Possati G 174G/C interleukin-6 polymorphism influences postoperative interleukin-6 levels and postoperative atrial fibrillation Is atrial fibrillation an inflammatory complication? Circulation 2003;108(Suppl 1): II195–II199 78 Warner SJ, Libby P Human vascular smooth muscle cells: target for and source of tumor necrosis factor J Immunol 1989;142:100–109 79 Barath P, Fishbein MC, Cao J, Berenson J, Helfant RH, Forrester JS Detection and localization of tumor necrosis factor in human atheroma Am J Cardiol 1990;65:297–302 80 Maksimowicz-McKinnon K, Bhatt DL, Calabrese LH Recent advances in vascular inflammation: C-reactive protein and other inflammatory biomarkers Curr Opin Rheumatol 2004;16:18–24 81 Chia S, Qadan M, Newton R, Ludlam CA, Fox KA, Newby DE Intraarterial tumor necrosis factor-alpha impairs endothelium-dependent vasodilatation and stimulates local tissue plasminogen activator release in humans Arterioscler Thromb Vasc Biol 2003;23:695–701 82 Abdelhadi RH, Gurm HS, Van Wagoner DR, Chung MK Relation of an exaggerated rise in white blood cells after coronary bypass or cardiac valve surgery to development of atrial fibrillation postoperatively Am J Cardiol 2004;93:1176–1178 83 Boos CJ, Lip GY Novel therapies for the prevention of stroke Expert Opin Investig Drugs 2004;13:1615–1630 84 Freestone B, Beevers DG, Lip GY The renin–angiotensin–aldosterone system in atrial fibrillation: a new therapeutic target? J Hum Hypertens 2004;18:461–465 147 148 126 127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142 receptor blockade in hypertensive patients with microinflammation Circulation 2004;110:1103–1107 Li D, Shinagawa K, Pang L, Leung TK, Cardin S, Wang Z, Nattel S Effects of angiotensin-converting enzyme inhibition on the development of the atrial fibrillation substrate in dogs with ventricular tachypacing-induced congestive heart failure Circulation 2001;104:2608–2614 Kumagai K, Nakashima H, Urata H, Gondo N, Arakawa K, Saku K Effects of angiotensin II type receptor antagonist on electrical and structural remodeling in atrial fibrillation J Am Coll Cardiol 2003;41:2197–2204 Healey JS, Baranchuk A, Crystal E, Morillo CA, Garfinkle M, Yusuf S, Connolly SJ Prevention of atrial fibrillation with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers: a meta-analysis J Am Coll Cardiol 2005;45:1832–1839 Maggioni AP, Latini R, Carson PE, Singh SN, Barlera S, Glazer R, Masson S, Cere E, Tognoni G, Cohn JN; Val-HeFT Investigators Valsartan reduces the incidence of atrial fibrillation in patients with heart failure: results from the Valsartan Heart Failure Trial (Val-HeFT) Am Heart J 2005;149:548–557 Wachtell K, Lehto M, Gerdts E, Olsen MH, Hornestam B, Dahlof B, Ibsen H, Julius S, Kjeldsen SE, Lindholm LH, Nieminen MS, Devereux RB Angiotensin II receptor blockade reduces new-onset atrial fibrillation and subsequent stroke compared to atenolol: the Losartan Intervention For End Point Reduction in Hypertension (LIFE) Study J Am Coll Cardiol 2005;45:712–719 Madrid AH, Marin IM, Cervantes CE, Morell EB, Estevez JE, Moreno G, Parajon JR, Peng J, Limon L, Nannini S, Moro C Prevention of recurrences in patients with lone atrial fibrillation: the dose-dependent effect of angiotensin II receptor blockers J Renin Angiotensin Aldosterone Syst 2004;5:114–120 Swedberg K, Cohen-Solal A, Granger C, McMurray J, Olsson L, Pfeffer M, Yusuf S, Ostergren J Prevention of atrial fibrillation in symptomatic chronic heart failure by candesartan: results from the CHARM study (Abstract) J Am Coll Cardiol 2004;23(Suppl A):222A Ueng KC, Tsai TP, Yu WC, Tsai CF, Lin MC, Chan KC, Chen CY, Wu DJ, Lin CS, Chen SA Use of enalapril to facilitate sinus rhythm maintenance after external cardioversion of long-standing persistent atrial fibrillation: results of a prospective and controlled study Eur Heart J 2003;24:2090–2098 Vermes E, Tardif JC, Bourassa MG, Racine N, Levesque S, White M, Guerra PG, Ducharme A Enalapril decreases the incidence of atrial fibrillation in patients with left ventricular dysfunction: insight from the Studies of Left Ventricular Dysfunction (SOLVD) Trials Circulation 2003;107:2926–2931 Madrid AH, Bueno MG, Rebollo JM, Marin I, Pena G, Bernal E, Rodriguez A, Cano L, Cano JM, Cabeza P, Moro C Use of irbesartan to maintain sinus rhythm in patients with long-lasting persistent atrial fibrillation: a prospective and randomized study Circulation 2002;106:331–336 Pizzetti F, Turazza FM, Franzosi MG, Barlera S, Ledda A, Maggioni AP, Santoro L, Tognoni G; GISSI-3 Investigators Incidence and prognostic significance of atrial fibrillation in acute myocardial infarction: the GISSI-3 data Heart 2001;86:527–532 Hansson L, Lindholm LH, Ekbom T, Dahlof B, Lanke J, Schersten B, Wester PO, Hedner T, de Faire U Randomised trial of old and new antihypertensive drugs in elderly patients: cardiovascular mortality and morbidity the Swedish Trial in Old Patients with Hypertension (STOP)-2 study Lancet 1999;354:1751–1756 Pedersen OD, Bagger H, Kober L, Torp-Pedersen C The occurrence and prognostic significance of atrial fibrillation/-flutter following acute myocardial infarction TRACE Study Group TRAndolapril Cardiac Evaluation Eur Heart J 1999;20:748–754 Hansson L, Lindholm LH, Niskanen L, Lanke J, Hedner T, Niklason A, Luomanmaki K, Dahlof B, de Faire U, Morlin C, Karlberg BE, Wester PO, Bjorck JE Effect of angiotensin-converting-enzyme inhibition compared with conventional therapy on cardiovascular morbidity and mortality in hypertension: the Captopril Prevention Project (CAPP) Randomised Trial Lancet 1999;353:611–616 Van Den Berg MP, Crijns HJ, Van Veldhuisen DJ, Griep N, De Kam PJ, Lie KI Effects of lisinopril in patients with heart failure and chronic atrial fibrillation J Card Fail 1995;1:355–363 Zimmermann M, Unger T Challenges in improving prognosis and therapy: the Ongoing Telmisartan Alone and in Combination with Ramipril Global End point Trial programme Expert Opin Pharmacother 2004;5:1201–1208 Hohnloser SH, Connolly SJ Combined antiplatelet therapy in atrial fibrillation: review of the literature and future avenues J Cardiovasc Electrophysiol 2003;14(Suppl 9):S60–S63 Downloaded from http://eurheartj.oxfordjournals.org/ at St Petersburg State University on November 27, 2013 106 Morgan K, Wharton J, Webb JC, Keogh BE, Smith PL, Taylor KM, Oakley CM, Polak JM, Cleland JG Co-expression of renin–angiotensin system component genes in human atrial tissue J Hypertens 1994; 12(suppl.):S11–S19 107 Paul M, Wagner J, Dzau VJ Gene expression of the renin–angiotensin system in human tissues: quantitative analysis by the polymerase chain reaction J Clin Invest 1993;91:2058–2064 108 Goette A, Staack T, Rocken C, Arndt M, Geller JC, Huth C, Ansorge S, Klein HU, Lendeckel U Increased expression of extracellular signalregulated kinase and angiotensin-converting enzyme in human atria during atrial fibrillation J Am Coll Cardiol 2000;35:1669–1677 109 Boldt A, Wetzel U, Weigl J, Garbade J, Lauschke J, Hindricks G, Kottkamp H, Gummert JF, Dhein S Expression of angiotensin II receptors in human left and right atrial tissue in atrial fibrillation with and without underlying mitral valve disease J Am Coll Cardiol 2003;42:1785–1792 110 Cardin S, Li D, Thorin-Trescases N, Leung TK, Thorin E, Nattel S Evolution of the atrial fibrillation substrate in experimental congestive heart failure: angiotensin-dependent and -independent pathways Cardiovasc Res 2003;60:315–325 111 Tsai CT, Lai LP, Lin JL, Chiang FT, Hwang JJ, Ritchie MD, Moore JH, Hsu KL, Tseng CD, Liau CS, Tseng YZ Renin–angiotensin system gene polymorphisms and atrial fibrillation Circulation 2004;109:1640–1646 112 Ogimoto A, Hamada M, Nakura J, Miki T, Hiwada K Relation between angiotensin-converting enzyme II genotype and atrial fibrillation in Japanese patients with hypertrophic cardiomyopathy J Hum Genet 2002;47:184–189 113 Gensini F, Padeletti L, Fatini C, Sticchi E, Gensini GF, Michelucci A Angiotensin-converting enzyme and endothelial nitric oxide synthase polymorphisms in patients with atrial fibrillation Pacing Clin Electrophysiol 2003;26:295–298 114 Roldan V, Marin F, Blann AD, Garcia A, Marco P, Sogorb F, Lip GY Interleukin-6, endothelial activation and thrombogenesis in chronic atrial fibrillation Eur Heart J 2003;24:1373–1380 115 Kamath S, Chin BS, Blann AD, Lip GY A study of platelet activation in paroxysmal, persistent and permanent atrial fibrillation Blood Coagul Fibrinolysis 2002;13:627–636 116 Li-Saw-Hee FL, Blann AD, Gurney D, Lip GY Plasma von Willebrand factor, fibrinogen and soluble P-selectin levels in paroxysmal, persistent and permanent atrial fibrillation: effects of cardioversion and return of left atrial function Eur Heart J 2001;22:1741–1747 117 Marin F, Roldan V, Climent VE, Ibanez A, Garcia A, Marco P, Sogorb F, Lip GY Plasma von Willebrand factor, soluble thrombomodulin, and fibrin D-dimer concentrations in acute onset non-rheumatic atrial fibrillation Heart 2004;90:1162–1166 118 Conway DS, Buggins P, Hughes E, Lip GY Prognostic significance of raised plasma levels of interleukin-6 and C-reactive protein in atrial fibrillation Am Heart J 2004;148:462–466 119 Thambidorai SK, Parakh K, Martin DO, Shah TK, Wazni O, Jasper SE, Van Wagoner DR, Chung MK, Murray RD, Klein AL Relation of C-reactive protein correlates with risk of thromboembolism in patients with atrial fibrillation Am J Cardiol 2004;94:805–807 120 Cipollone F, Fazia M, Iezzi A, Pini B, Cuccurullo C, Zucchelli M, de Cesare D, Ucchino S, Spigonardo F, De Luca M, Muraro R, Bei R, Bucci M, Cuccurullo F, Mezzetti A Blockade of the angiotensin II type receptor stabilizes atherosclerotic plaques in humans by inhibiting prostaglandin E2-dependent matrix metalloproteinase activity Circulation 2004; 109:1482–1488 121 da Cunha V, Tham DM, Martin-McNulty B, Deng G, Ho JJ, Wilson DW, Rutledge JC, Vergona R, Sullivan ME, Wang YX Enalapril attenuates angiotensin II-induced atherosclerosis and vascular inflammation Atherosclerosis 2005;178:9–17 122 Schieffer B, Bunte C, Witte J, Hoeper K, Boger RH, Schwedhelm E, Drexler H Comparative effects of AT1-antagonism and angiotensinconverting enzyme inhibition on markers of inflammation and platelet aggregation in patients with coronary artery disease J Am Coll Cardiol 2004;44:362–368 123 Li QZ, Deng Q, Li JQ, Yi GH, Zhao SP Valsartan reduces interleukin-1beta secretion by peripheral blood mononuclear cells in patients with essential hypertension Clin Chim Acta 2005;355:131–136 124 Graninger M, Reiter R, Drucker C, Minar E, Jilma B Angiotensin receptor blockade decreases markers of vascular inflammation J Cardiovasc Pharmacol 2004;44:335–339 125 Fliser D, Buchholz K, Haller H; EUropean Trial on Olmesartan and Pravastatin in Inflammation and Atherosclerosis (EUTOPIA) Investigators Antiinflammatory effects of angiotensin II subtype C.J Boos et al Is AF an inflammatory disorder? 163 Hanna IR, Dudley SC Jr, King-Hageman D, Bush H, Brosius L, Langberg JL Lipid-lowering therapy reduces the prevalence of atrial fibrillation (Abstract) 2005 Heart Rhythm Society Scientific Sessions, May 4–7, 2005, New Orleans, LA, pp 1–34 164 Merckx KL, Tieleman RG, Folkeringa RJ, Pinto YM, Nieman FH, Cheriex EC, Crijns HJ Use of statins is associated with reduced incidence of atrial fibrillation in patients with left ventricular hypertrophy and left atrial dilatation Heart Rhythm Society 25th Annual Scientific Sessions, 28 May 2004, Abstract ID: 3669 165 Tveit A, Grundtvig M, Gundersen T, Vanberg P, Semb AG, Holt E, Gullestad L Analysis of pravastatin to prevent recurrence of atrial fibrillation after electrical cardioversion Am J Cardiol 2004;93:780–782 166 Young-Xu Y, Jabbour S, Goldberg R, Blatt CM, Graboys T, Bilchik B, Ravid S Usefulness of statin drugs in protecting against atrial fibrillation in patients with coronary artery disease Am J Cardiol 2003;92:1379–1383 167 Siu CW, Lau CP, Tse HF Prevention of atrial fibrillation recurrence by statin therapy in patients with lone atrial fibrillation after successful cardioversion Am J Cardiol 2003;92:1343–1345 168 Shiroshita-Takeshita A, Schram G, Lavoie J, Nattel S Effect of simvastatin and antioxidant vitamins on atrial fibrillation promotion by atrialtachycardia remodeling in dogs Circulation 2004;110:2313–2319 169 Kumagai K, Nakashima H, Saku K The HMG-CoA reductase inhibitor atorvastatin prevents atrial fibrillation by inhibiting inflammation in a canine sterile pericarditis model Cardiovasc Res 2004;62:105–111 170 Hu FB, Manson JE, Willett WC Types of dietary fat and risk of coronary heart disease: a critical review J Am Coll Nutr 2001;20:5–19 171 Connor WE Importance of n-3 fatty acids in health and disease Am J Clin Nutr 2000;71(suppl.):171S–175S 172 James MJ, Cleland LG Dietary n-3 fatty acids and therapy for rheumatoid arthritis Semin Arthritis Rheum 1997;27:85–97 173 Belluzzi A, Boschi S, Brignola C, Munarini A, Cariani G, Miglio F Polyunsaturated fatty acids and inflammatory bowel disease Am J Clin Nutr 2000;71(Suppl 1):339S–342S 174 Pischon T, Hankinson SE, Hotamisligil GS, Rifai N, Willett WC, Rimm EB Habitual dietary intake of n-3 and n-6 fatty acids in relation to inflammatory markers among US men and women Circulation 2003;108:155–160 175 James MJ, Gibson RA, Cleland LG Dietary polyunsaturated fatty acids and inflammatory mediator production Am J Clin Nutr 2000; 71(Suppl 1):343S–348S 176 Mishra A, Chaudhary A, Sethi S Oxidized omega-3 fatty acids inhibit NFkB activation via a PPARa-dependent pathway Arterioscler Thromb Vasc Biol 2004;24:1621–1617 177 Mozaffarian D, Psaty BM, Rimm EB, Lemaitre RN, Burke GL, Lyles MF, Lefkowitz D, Siscovick DS Fish intake and risk of incident atrial fibrillation Circulation 2004;110:368–373 178 Frost L, Vestergaard P n-3 Fatty acids consumed from fish and risk of atrial fibrillation or flutter: the Danish Diet, Cancer, and Health Study Am J Clin Nutr 2005;81:50–54 179 Calo L, Bianconi L, Colivicchi F, Lamberti F, Loricchio ML, de Ruvo E, Meo A, Pandozi C, Staibano M, Santini M N-3 Fatty acids for the prevention of atrial fibrillation after coronary artery bypass surgery: a randomized, controlled trial J Am Coll Cardiol 2005;45:1723–1728 180 Jahangiri A, Leifert WR, Patten GS, McMurchie EJ Termination of asynchronous contractile activity in rat atrial myocytes by n-3 polyunsaturated fatty acids Mol Cell Biochem 2000;206:33–41 181 Harrison RA, Elton PJ Is there a role for long-chain omega3 or oil-rich fish in the treatment of atrial fibrillation? Med Hypotheses 2005;64:59–63 182 Albert CM, Campos H, Stampfer MJ, Ridker PM, Manson JE, Willett WC, Ma J Blood levels of long-chain n-3 fatty acids and the risk of sudden death N Engl J Med 2002;346:1113–1118 183 Marchioli R, Barzi F, Bomba E, Chieffo C, Di Gregorio D, Di Mascio R, Franzosi MG, Geraci E, Levantesi G, Maggioni AP, Mantini L, Marfisi RM, Mastrogiuseppe G, Mininni N, Nicolosi GL, Santini M, Schweiger C, Tavazzi L, Tognoni G, Tucci C, Valagussa F; GISSI-Prevenzione Investigators Early protection against sudden death by n-3 polyunsaturated fatty acids after myocardial infarction: time-course analysis of the results of the Gruppo Italiano per lo Studio della Sopravvivenza nell’ Infarto Miocardico (GISSI)-Prevenzione Circulation 2002;105:1897–1903 184 Galaris D, Korantzopoulos P On the molecular mechanism of metmyoglobin-catalyzed reduction of hydrogen peroxide by ascorbate Free Radic Biol Med 1997;22:657–667 185 Carnes CA, Chung MK, Nakayama T, Nakayama H, Baliga RS, Piao S, Kanderian A, Pavia S, Hamlin RL, McCarthy PM, Bauer JA, Van Wagoner DR Ascorbate attenuates atrial pacing-induced peroxynitrite formation and electrical remodeling and decreases the incidence of postoperative atrial fibrillation Circ Res 2001;89:32–38 Downloaded from http://eurheartj.oxfordjournals.org/ at St Petersburg State University on November 27, 2013 143 Ridker PM, Rifai N, Pfeffer MA, Sacks FM, Moye LA, Goldman S, Flaker GC, Braunwald E The Cholesterol and Recurrent Events (CARE) Investigators Inflammation, pravastatin, and the risk of coronary events after myocardial infarction in patients with average cholesterol levels Circulation 1998;98:839–844 144 Ridker PM, Rifai N, Pfeffer MA, Sacks F, Braunwald E Long-term effects of pravastatin on plasma concentration of C-reactive protein The Cholesterol and Recurrent Events (CARE) Investigators Circulation 1999;100:230–235 145 Shepherd J, Cobbe SM, Ford I, Isles CG, Lorimer AR, MacFarlane PW, McKillop JH, Packard CJ Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia West of Scotland Coronary Prevention Study Group N Engl J Med 1995;333:1301–1307 146 Downs JR, Clearfield M, Weis S, Whitney E, Shapiro DR, Beere PA, Langendorfer A, Stein EA, Kruyer W, Gotto AM Jr Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS Air Force/ Texas Coronary Atherosclerosis Prevention Study JAMA 1998; 279:1615–1622 147 Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S) Lancet 1994;344:1383–1389 148 Sacks FM, Pfeffer MA, Moye LA, Rouleau JL, Rutherford JD, Cole TG, Brown L, Warnica JW, Arnold JM, Wun CC, Davis BR, Braunwald E The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels Cholesterol and Recurrent Events Trial Investigators N Engl J Med 1996;335:1001–1009 149 The long-term intervention with pravastatin in ischaemic disease (LIPID) Study Group Prevention of cardiovascular events and deaths with pravastatin in patients with coronary disease and a broad range of initial cholesterol levels N Eng J Med 1998;339:1349–1357 150 Athyros VG, Papageorgiou AA, Mercouris BR, Athyrou VV, Symeonidis AN, Basayannis EO, Demitriadis DS, Kontopoulos AG Treatment with atorvastatin to the National Cholesterol Educational Program goal versus ‘usual’ care in secondary coronary heart disease prevention The GREek Atorvastatin and Coronary-heart-disease Evaluation (GREACE) Study Curr Med Res Opin 2002;18:220–228 151 Heart Protection Study Collaborative Group MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20 536 high-risk individuals: a randomised placebo-controlled trial Lancet 2002;360:7–22 152 Gotto AM JR, Farmer JA Pleiotropic effects of statins: they matter? Current Opin Lipidol 2001;12:391–394 153 Farmer JA Pleiotropic effects of statins Curr Atheroscler Rep 2000;2:208–217 154 Davignon J Beneficial cardiovascular pleiotropic effects of statins Circulation 2004;109(Suppl 1):39–43 155 Yildirir A, Muderrisoglu H Non-lipid effects of statins: emerging new indications Curr Vasc Pharmacol 2004;2:309–318 156 Martinez-Gonzalez J, Raposo B, Rodriguez C, Badimon L 3-Hydroxy-3methylglutaryl coenzyme A reductase inhibition prevents endothelial NO synthase downregulation by atherogenic levels of native LDLs: balance between transcriptional and posttranscriptional regulation Arterioscler Thromb Vasc Biol 2001;21:804–809 157 Suzumura K, Yasuhara M, Tanaka K, Suzuki T Protective effect of fluvastatin sodium (XU-62–320), a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, on oxidative modification of human low-density lipoprotein in vitro Biochem Pharmacol 1999;57:697–703 158 Plenge JK, Hernandez TL, Weil KM, Poirier P, Grunwald GK, Marcovina SM, Eckel RH Simvastatin lowers C-reactive protein within 14 days: an effect independent of low-density lipoprotein cholesterol reduction Circulation 2002;106:1447–1452 159 Lindahl B, Toss H, Siegbahn A, Venge P, Wallentin L Markers of myocardial damage and inflammation in relation to long-term mortality in unstable coronary artery disease N Engl J Med 2000;343:1139–1147 160 Albert MA, Danielson E, Rifai N, Ridker PM; PRINCE Investigators Effect of statin therapy on C-reactive protein levels—The Pravastatin Inflammation/CRP Evaluation (PRINCE): a randomized trial and cohort study JAMA 2001;286:64–70 161 Joukhadar C, Klein N, Prinz M, Schrolnberger C, Vukovich T, Wolzt M, Schmetterer L, Dorner GT Similar effects of atorvastatin, simvastatin and pravastatin on thrombogenic and inflammatory parameters in patients with hypercholesterolemia Thromb Haemost 2001;85:47–51 162 van Wissen S, Trip MD, Smilde TJ, de Graaf J, Stalenhoef AF, Kastelein JJ Differential hs-CRP reduction in patients with familial hypercholesterolemia treated with aggressive or conventional statin therapy Atherosclerosis 2002;165:361–366 149 ... Korantzopoulos et al 50 2005 Persistent AF Fibrinogen, CRP, WBC NA Korantzopoulos et al 51 2005 Persistent CRP, fibrinogen Acevedo et al 52 2005 Newly diagnosed AF Watanabe et al 53 2005 Asselbergs et... symptomatic AF CRP NA 106 2005 All CRP 7471 Roldan et al 55 2005 Permanent 74 191 Watanabe et al 56 2005 Paroxysmal Plasma IL-6 and F1 ỵ CRP 50 50 Psychari et al 57 2005 Persistent and permanent... findings Val-HeFT129 2005 In sinus rhythm with HF 2205 2190 Lower rate of AF development in valsartan group (113/2205, 5.12%) compared with placebo (174/2190, 7.95%; P ¼ 0.0002) LIFE130 2005 Hypertensive