ReviewAtrial fibrillation, arrhythmia burden and thrombogenesis
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)
- et al.
Mechanisms of thrombogenesis in atrial fibrillation Virchow's triad revisited
Lancet
(2009) - et al.
Hemostatic state and atrial fibrillation (the Framingham Offspring Study)
Am J Cardiol
(2001) - et al.
Fibrinogen and albumin levels and risk of atrial fibrillation in men and women (the Copenhagen City Heart Study)
Am J Cardiol
(2006) - et al.
Oral vitamin C administration reduces early recurrence rates after electrical cardioversion of persistent atrial fibrillation and attenuates associated inflammation
Int J Cardiol
(2005) - et al.
C-reactive protein and atrial fibrillation: “evidence for the presence of inflammation in the perpetuation of the arrhythmia”
Int J Cardiol
(2006) - et al.
Atrial fibrillation activates platelets and coagulation in a time-dependent manner: a study in patients with paroxysmal atrial fibrillation
J Am Coll Cardiol
(1997) - et al.
Platelet surface CD62P and CD63, mean platelet volume, and soluble/platelet P-selectin as indexes of platelet function in atrial fibrillation: a comparison of ‘healthy control subjects’ and ‘disease control subjects’ in sinus rhythm
J Am Coll Cardiol
(2007) - et al.
Elevated platelet microparticle levels in nonvalvular atrial fibrillation: relationship to p-selectin and antithrombotic therapy
Chest
(2007) - et al.
A longitudinal population-based study of prothrombotic factors in elderly subjects with atrial fibrillation: the Rotterdam Study 1990–1999
J Thromb Haemost
(2006) - et al.
A cross-sectional and diurnal study of thrombogenesis among patients with chronic atrial fibrillation
J Am Coll Cardiol
(2000)
Correlation between left atrial size, prothrombotic state and markers of endothelial dysfunction in patients with lone chronic nonrheumatic atrial fibrillation
Int J Cardiol
Prothrombotic activity is increased in patients with nonvalvular atrial fibrillation and risk factors for embolism
Chest
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
Basic and clinical aspects of fibrinolysis and thrombolysis
Blood
Fibrinolytic function and atrial fibrillation
Thromb Res
Left atrial appendage function and abnormal hypercoagulability in patients with atrial flutter
Chest
D-dimer level influences thromboembolic events in patients with atrial fibrillation
Int J Cardiol
Stroke with intermittent atrial fibrillation: incidence and predictors during aspirin therapy. Stroke Prevention in Atrial Fibrillation Investigators
J Am Coll Cardiol
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
Monitored atrial fibrillation duration predicts arterial embolic events in patients suffering from bradycardia and atrial fibrillation implanted with antitachycardia pacemakers
J Am Coll Cardiol
Clinical importance of new-onset atrial fibrillation after cardiac resynchronization therapy
Heart Rhythm
Role of inflammation in initiation and perpetuation of atrial fibrillation
J Am Coll Cardiol
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
High-sensitivity C-reactive protein is predictive of successful cardioversion for atrial fibrillation and maintenance of sinus rhythm after conversion
Int J Cardiol
C-reactive protein and microalbuminuria are associated with atrial fibrillation
Int J Cardiol
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
Frequency of elevation of C-reactive protein in atrial fibrillation
Am J Cardiol
Relationship of interleukin-6 and C-reactive protein to the prothrombotic state in chronic atrial fibrillation
J Am Coll Cardiol
Prognostic significance of raised plasma levels of interleukin-6 and C-reactive protein in atrial fibrillation
Am Heart J
Relationship of indices of inflammation and thrombogenesis to arrhythmia burden in paroxysmal atrial fibrillation
Chest
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
Secular trends in incidence of atrial fibrillation in Olmsted County, Minnesota, 1980 to 2000, and implications on the projections for future prevalence
Circulation
Lifetime risk for development of atrial fibrillation: the Framingham heart study
Circulation
Prevalence, incidence and lifetime risk of atrial fibrillation: the Rotterdam study
Eur Heart J
Increasing trends in hospitalization for atrial fibrillation in the United States, 1985 through 1999: implications for primary prevention
Circulation
Population prevalence, incidence, and predictors of atrial fibrillation in the Renfrew/Paisley study
Heart
Cost of an emerging epidemic: an economic analysis of atrial fibrillation in the UK
Heart
Atrial fibrillation as an independent risk factor for stroke: the Framingham study
Stroke
Stroke patients with atrial fibrillation have a worse prognosis than patients without: data from the Austrian Stroke registry
Eur Heart J
Independent predictors of stroke in patients with atrial fibrillation: a systematic review
Neurology
Echocardiographic predictors of nonrheumatic atrial fibrillation. The Framingham Heart Study
Circulation
Atrial fibrillation and the hypercoagulable state: from basic science to clinical practice
Pathophysiol Haemos Thromb.
Biomarker in atrial fibrillation: investigating biologic plausibility, cause, and effect
J Throm Thrombolysis.
Fibrinogen as a cardiovascular risk factor: a meta-analysis and review of the literature
Ann Intern Med
Measuring plasma fibrinogen to predict stroke and MI: an update
Arterioscler Thromb Vasc Biol
Prothrombin fragment F1 + 2 and thrombin–antithrombin III complex are useful markers of the hypercoagulable state in atrial fibrillation
Blood Coagul Fibrinolysis
Interleukin-6, endothelial activation and thrombogenesis in chronic atrial fibrillation
Eur Heart J
Hypercoagulability in atrial fibrillation and its relationship with risk factors for systemic embolism
Rev Med Chil
Predictive value of coagulative molecular markers for thromboembolism in patients with nonvalvular atrial fibrillation: prospective five-year follow-up study
J Cardiol
The adhesion molecule P-selectin and cardiovascular disease
Eur Heart J
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Relationship between device-detected burden and duration of atrial fibrillation and risk of ischemic stroke
2021, Heart RhythmCitation Excerpt :Traditionally, risk stratification for ischemic stroke has given little consideration to the temporal pattern (paroxysmal vs persistent vs permanent) or burden of AF. The increased use of cardiovascular implantable electronic devices (CIEDs) with atrial leads2 and of other digital wearables capable of continuous rhythm monitoring3 not only has increased detection of asymptomatic paroxysms of AF but also has afforded providers the ability to readily quantify the duration of individual paroxysms and the total burden of AF.4 In this context, a recent body of data has suggested that the amount of AF, defined as either a function of total time spent in AF5 (ie, burden) or the longest duration of individual episodes,6–8 among those with nonpermanent AF may influence the risk of stroke.
Can we predict new AF occurrence in single-chamber ICD patients? Insights from an observational investigation
2017, International Journal of CardiologyCitation Excerpt :Similarly, the severity of the clinical profile is associated with an increased AF prevalence, renal impairment being the strongest predictor of new-onset AF in Heart Failure ICD recipients [22]. In a metanalysis reported by Khoo and colleagues [23] AF was detected in 10–60% pacemaker and ICD patients. In our observation, > 16% had an AF episode longer than 12 h and the prevalence of AT/AF lasting ≤ 24 h had a steady increase at long term, whereas long-lasting or persistent AT/AF seemed to reach a rather early ceiling (Fig. 1); we believe that this behavior of arrhythmia duration should be confirmed on a broader patient population for consistency.
Atrial fibrillation burden and atrial fibrillation type: Clinical significance and impact on the risk of stroke and decision making for long-term anticoagulation
2016, Vascular PharmacologyCitation Excerpt :Cardiac implantable electrical devices (CIEDs) can, through an atrial lead, continuously monitor the atrial rhythm and store data on atrial tachyarrhythmias and AF episodes, which can then be summarized in a detailed report (Fig. 1), with data on the presence of arrhythmia, duration of each specific episode of atrial tachyarrhythmia, time of occurrence, distribution during the follow-up period, and time spent in AF. In fact, CIEDs with an atrial lead can detect atrial high-rate episodes (AHRE), corresponding to all atrial tachyarrhythmias above a predefined atrial rate threshold ( higher than 180–220 bpm), therefore including both AF and atrial flutter or regular atrial tachycardias [23,24]. In the process of detecting and recording AHRE episodes in the device memory, a series of technical issues are involved, including atrial sensitivity, and the programming of atrial rate and episode duration cutoffs, with some variability according to the device manufacturer.
Red blood cell distribution width and left atrial thrombus or spontaneous echo contrast in patients with non-valvular atrial fibrillation
2015, International Journal of CardiologyContinuous monitoring of atrial fibrillation in heart failure
2013, Heart Failure ClinicsCitation Excerpt :There is growing clinical interest in symptomatic and asymptomatic device-recorded AHRE as possible precursors of thromboembolic complications in patients with a pacemaker or ICD.2–10 Timely diagnosis of both paroxysmal AF or atrial flutter has important implications for anticoagulant therapy for stroke prevention.11–18 Device-based continuous monitoring of AF in CRT patients has improved the diagnosis and therapy for AF in this group of patients.
Cardioembolic acute myocardial infarction and stroke in a patient with persistent atrial fibrillation
2012, International Journal of Cardiology