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Atrial fibrillation, arrhythmia burden and thrombogenesis

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Abstract

Atrial fibrillation (AF) is the most common cardiac arrhythmia, which is associated with substantial risk of stroke and thromboembolism. The epidemiology and health care burden associated with AF have increased significantly, and will continue to rise. Until recently, the concept and/or quantification of disease burden in AF tended to be ignored nor its consequences recognised. However, AF burden can now be assessed more accurately and reliably with the aid of cardiac rhythm management devices.

There is a lot of interest on the issue of ‘how much AF is needed to cause thromboembolism?’ and this article summarises the available literature on this topic, with the aim of providing a better understanding of the clinical importance of device-detected atrial high-rate episodes and an overview of arrhythmia burden on thrombogenesis and clinical thromboembolism.

Introduction

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia. Its prevalence increases from < 1% in patients aged < 60 years old to approximately 10% in patients aged > 80 years [1]. Multiple studies assessing the secular trends of AF have shown an increasing prevalence and incidence over the last two decades. For example, the incidence of AF is estimated to rise, so that there would be about 12 million patients with AF in USA by 2050 [2]. Population studies also suggest the lifetime risk of developing AF of approximately one in four men and women aged ≥ 40 years [3], [4]. This alarming rise in AF patients may be related to the growing elderly population in Western countries, as well as significant improvements in the treatment of cardiovascular disease and improved detection of arrhythmia [5]. AF and its associated complications account for more than 1% of the United Kingdom health care costs [6], [7].

Patients with AF are estimated to have a four to five-fold increase in the risk of stroke and approximately 15% of all strokes may be related to this arrhythmia [8]. Patients with stroke and AF have greater disability and longer in-patient stays [9]. However, the risk of systemic thromboembolism in patients with AF is not homogeneous, and can be related to a number of echocardiographic (dilated left atrium, left ventricular hypertrophy or systolic dysfunction or valvular heart disease) and clinical risk factors (advancing age, hypertension, diabetes, previous stroke or transient ischemic attack, coronary or peripheral vascular disease) [10]. Improvement in device technology now allows greater quantification of AF burden, and it is also intuitively attractive to associate greater frequency and duration of AF (so-called ‘AF burden’) with an increased risk of systemic thromboembolism.

There is a lot of interest on the issue of ‘how much AF is needed to cause thromboembolism?’ and this article summarises the available literature on this topic, with the aim of providing a better understanding of the clinical importance of device-detected atrial high-rate episodes and an overview of arrhythmia burden on thrombogenesis and clinical thromboembolism.

Section snippets

Search strategy

We searched MEDLINE and EMBASE using the terms ‘atrial fibrillation burden’, ‘AF burden’, ‘atrial high rate’, ‘prothrombotic markers’, ‘von Willebrand factor’, ‘soluble P-selectin’, ‘fibrinogen’, ‘tissue factor’, and ‘D-dimer’ until January 2011. Only studies in patients with atrial fibrillation and cardiac devices were included. We excluded animal studies and individual case reports. Articles relating specifically to inflammation were excluded. References from the relevant articles were

Pathophysiology of thrombogenesis in AF

AF confers a prothrombotic and hypercoagulable state by fulfilling the components of Virchow's triad (abnormal stasis, abnormal blood constituents and blood vessel wall abnormalities) [11].

Firstly, abnormal stasis in AF may be consequence of the loss of effective atrial function and progressive abnormal left atrial (LA) remodelling with dilatation. Left atrial size corrected to body surface area has been related to stroke risk in AF [12]. Also, concomitant structural and valvular heart disease

Thrombogenesis in paroxysmal versus permanent AF

Although various biomarkers have been proved to be elevated in general AF population, studies between temporal patterns of AF population (paroxysmal, persistent and permanent) have shown variable results. For example, Li-Saw-Hee et al. showed that patients with permanent AF had significantly raised levels of vWf, soluble P-selectin and fibrinogen, whereas patients with paroxysmal AF had raised levels of vWf and fibrinogen but not P-selectin when compared with healthy controls [56]. Patient with

Atrial high rate episodes and atrial fibrillation

In approximately 25% of elderly patients with AF, the arrhythmia appears to be intermittent with varying temporal patterns of presentation [61]. Despite this, the risk of stroke seems to be comparable, regardless of whether the arrhythmia is paroxysmal, persistent or permanent [62]. A clear limitation in correlating the risk of stroke with this simplistic clinical scheme of classifying AF – and relating it to arrhythmia burden – is that a significant proportion of patients remain asymptomatic

Clinical implications of AHRE

Clinical studies suggest that AHRE are associated with adverse clinical outcomes. For example, Glotzer et al. investigated patients with permanent pacemakers or implantable defibrillators that are able to monitor AF burden (longest AF duration in any day over a 30 day window) and at least 1 risk factor for stroke [81]. Patients were grouped according to the absence (i.e. zero) or presence of AF burden; within latter group, patients were further divided based upon the median AF burden (i.e. 5.5 

Atrial fibrillation, atrial high-rate episodes and thrombogenesis

Thrombogenesis in AF has been related to abnormal surrogate markers of coagulation, fibrin turnover, endothelial damage/dysfunction and platelets [11], [14]. Biomarkers which are related to these changes can be categorised into 4 broad groups (Table 2).

Inflammation plays an important role in the initiation and perpetuation of AF [84], [85]. Indeed, various inflammatory markers have been investigated in relation to AF, and C-reactive protein (CRP) and interleukin-6 (IL-6) are probably the most

Conclusion

In relation to how much AF is needed to cause thromboembolism, the impact of device-detected atrial high-rate episodes and arrhythmia burden on thrombogenesis and clinical thromboembolism is attracting much interest. Ongoing clinical studies such as Rate Registry [101], IMPACT [102] and ASSERT [103] may provide additional data and able to identify patients who require early intervention as well as merit anticoagulation therapy (Table 3). One recent study has even shown that device data on AF

Acknowledgements

The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology [105].

References (105)

  • S. Mondillo et al.

    Correlation between left atrial size, prothrombotic state and markers of endothelial dysfunction in patients with lone chronic nonrheumatic atrial fibrillation

    Int J Cardiol

    (2000)
  • H. Inoue et al.

    Prothrombotic activity is increased in patients with nonvalvular atrial fibrillation and risk factors for embolism

    Chest

    (2004)
  • B. Freestone et al.

    Soluble E-selectin, von Willebrand factor, soluble thrombomodulin, and total body nitrate/nitrite product as indices of endothelial damage/dysfunction in paroxysmal, persistent, and permanent atrial fibrillation

    Chest

    (2007)
  • D. Collen et al.

    Basic and clinical aspects of fibrinolysis and thrombolysis

    Blood

    (1991)
  • F. Marín et al.

    Fibrinolytic function and atrial fibrillation

    Thromb Res

    (2003)
  • K. Sakurai et al.

    Left atrial appendage function and abnormal hypercoagulability in patients with atrial flutter

    Chest

    (2003)
  • T. Nozawa et al.

    D-dimer level influences thromboembolic events in patients with atrial fibrillation

    Int J Cardiol

    (2006)
  • R.G. Hart et al.

    Stroke with intermittent atrial fibrillation: incidence and predictors during aspirin therapy. Stroke Prevention in Atrial Fibrillation Investigators

    J Am Coll Cardiol

    (2000)
  • S. Mittal et al.

    Frequency, duration, and predictors of newly-diagnosed atrial fibrillation following dual-chamber pacemaker implantation in patients without a previous history of atrial fibrillation

    Am J Cardiol

    (2008)
  • A. Capucci et al.

    Monitored atrial fibrillation duration predicts arterial embolic events in patients suffering from bradycardia and atrial fibrillation implanted with antitachycardia pacemakers

    J Am Coll Cardiol

    (2005)
  • C.J. Borleffs et al.

    Clinical importance of new-onset atrial fibrillation after cardiac resynchronization therapy

    Heart Rhythm

    (2009)
  • T.T. Issac et al.

    Role of inflammation in initiation and perpetuation of atrial fibrillation

    J Am Coll Cardiol

    (2007)
  • B. Freestone et al.

    Impaired flow mediated dilatation as evidence of endothelial dysfunction in chronic atrial fibrillation: relationship to plasma von Willebrand factor and soluble E-selectin levels

    Thromb Res

    (2008)
  • E. Watanabe et al.

    High-sensitivity C-reactive protein is predictive of successful cardioversion for atrial fibrillation and maintenance of sinus rhythm after conversion

    Int J Cardiol

    (2006)
  • F.W. Asselbergs et al.

    C-reactive protein and microalbuminuria are associated with atrial fibrillation

    Int J Cardiol

    (2005)
  • S.N. Psychari et al.

    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)
  • J.L. Anderson et al.

    Frequency of elevation of C-reactive protein in atrial fibrillation

    Am J Cardiol

    (2004)
  • D.S. Conway et al.

    Relationship of interleukin-6 and C-reactive protein to the prothrombotic state in chronic atrial fibrillation

    J Am Coll Cardiol

    (2004)
  • D.S. Conway et al.

    Prognostic significance of raised plasma levels of interleukin-6 and C-reactive protein in atrial fibrillation

    Am Heart J

    (2004)
  • T. Watson et al.

    Relationship of indices of inflammation and thrombogenesis to arrhythmia burden in paroxysmal atrial fibrillation

    Chest

    (2010)
  • A.S. Go et al.

    Prevalence of diagnosed atrial fibrillation in adults. Notional implications for rhythm management and stroke prevention: the anticoagulation and risk factors in atrial fibrillation (ATRIA) study

    JAMA

    (2001)
  • Y. Miyasaka et al.

    Secular trends in incidence of atrial fibrillation in Olmsted County, Minnesota, 1980 to 2000, and implications on the projections for future prevalence

    Circulation

    (2006)
  • D.M. Lloyd-Jones et al.

    Lifetime risk for development of atrial fibrillation: the Framingham heart study

    Circulation

    (2004)
  • J. Heeringa et al.

    Prevalence, incidence and lifetime risk of atrial fibrillation: the Rotterdam study

    Eur Heart J

    (2006)
  • W.A. Wattigney et al.

    Increasing trends in hospitalization for atrial fibrillation in the United States, 1985 through 1999: implications for primary prevention

    Circulation

    (2003)
  • S. Stewart et al.

    Population prevalence, incidence, and predictors of atrial fibrillation in the Renfrew/Paisley study

    Heart

    (2001)
  • S. Stewart et al.

    Cost of an emerging epidemic: an economic analysis of atrial fibrillation in the UK

    Heart

    (2004)
  • P.A. Wolf et al.

    Atrial fibrillation as an independent risk factor for stroke: the Framingham study

    Stroke

    (1991)
  • C. Steger et al.

    Stroke patients with atrial fibrillation have a worse prognosis than patients without: data from the Austrian Stroke registry

    Eur Heart J

    (2004)
  • Stroke Risk in Atrial Fibrillation Working Group

    Independent predictors of stroke in patients with atrial fibrillation: a systematic review

    Neurology

    (2007)
  • S.M. Vaziri et al.

    Echocardiographic predictors of nonrheumatic atrial fibrillation. The Framingham Heart Study

    Circulation

    (1994)
  • A. Choudhury et al.

    Atrial fibrillation and the hypercoagulable state: from basic science to clinical practice

    Pathophysiol Haemos Thromb.

    (2004)
  • R.C. Becker

    Biomarker in atrial fibrillation: investigating biologic plausibility, cause, and effect

    J Throm Thrombolysis.

    (2005)
  • E. Ernst et al.

    Fibrinogen as a cardiovascular risk factor: a meta-analysis and review of the literature

    Ann Intern Med

    (1993)
  • G. Maresca et al.

    Measuring plasma fibrinogen to predict stroke and MI: an update

    Arterioscler Thromb Vasc Biol

    (1999)
  • H. Asakura et al.

    Prothrombin fragment F1 + 2 and thrombin–antithrombin III complex are useful markers of the hypercoagulable state in atrial fibrillation

    Blood Coagul Fibrinolysis

    (1992)
  • V. Roldán et al.

    Interleukin-6, endothelial activation and thrombogenesis in chronic atrial fibrillation

    Eur Heart J

    (2003)
  • L.A. Pérez et al.

    Hypercoagulability in atrial fibrillation and its relationship with risk factors for systemic embolism

    Rev Med Chil

    (2002)
  • K. Enta et al.

    Predictive value of coagulative molecular markers for thromboembolism in patients with nonvalvular atrial fibrillation: prospective five-year follow-up study

    J Cardiol

    (2004)
  • A.D. Blann et al.

    The adhesion molecule P-selectin and cardiovascular disease

    Eur Heart J

    (2003)

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