The Role of Biomarkers in Atrial Fibrillation

Atrial fibrillation (AF) is the most common sustained arrhythmia and is associated with an increased risk of stroke and cardiovascular mortality.1,2 The prevalence of AF increases with age and reaches approximately 10% in persons ≥80 years. Furthermore, it is projected to increase in the coming decades.3,4 The corner stone of the management of AF patients focuses on relief of symptoms and prevention of AF-associated stroke. However, the AF population is very heterogeneous regarding stroke risk. To address these observations several risk stratification schemes have been developed for AF patients. In 2001 Gage et al presented the CHADS2 score5 that provides clinicians with a structured and simple tool to assess the risk for stroke and the indication for anticoagulant treatment in AF.

Figure 1: Illustration of the AF pathophysiology and areas represented by biomarkers discussed in the mini review.
Figure 1: The Role of Biomarkers in Atrial Fibrillation
With permissions from the European Heart Journal 201325
Recently, vascular disease, age ≥65 years and female gender were added to the CHADS2 score, and make up the widely used CHA2DS2-VASc score.6 Although easy to apply, the clinical risk scores only seem to offer a modest discriminating value for the individual patients, with C-statistics that range from 0.549 to 0.638.6 Biomarkers derived from the blood reflecting inflammation, coagulation activity, renal function, cardiovascular stress and myocardial injury (Figure 1), have an increasing body of evidence showing association with cardiovascular events and may help refine risk stratification and improve care in AF patients.

Cardiac biomarkers

The role of natriuretic peptides as powerful prognostic markers for cardiovascular outcomes and mortality is well established,7-11 although less is known in the setting of AF. Initial studies of natriuretic peptides in AF described elevated levels in patients with AF as compared to matched controls in sinus rhythm.12-14 Thereafter it was reported that levels of natriuretic peptides fall rapidly following restoration of sinus rhythm.15-17 Based on a population of older adults in the community, elevated NT-proBNP levels predicted an increased risk for development of AF independent of other risk factors, including echocardiographic parameters.11,18 Recently, based on two large randomized clinical trials, the RE-LY and ARISTOSTLE studies with a total of almost 21,000 patients, these associations of natriuretic peptides as predictors of thromboembolism, cardiovascular events and mortality were extended to AF populations.19,20 For instance, in both studies the risk for stroke or systemic embolism was doubled and was increased up to 5-fold higher for cardiovascular death when comparing the highest vs. lowest quartile groups of NT-proBNP, respectively.

Cardiac troponin is a sensitive marker of myocardial damage and also an established prognostic marker in several patient populations, with elevations associated with worse outcomes and increased mortality, independent of conventional risk factors.21-23 However, not as much is known with cardiac troponins in AF, and similarly to NT-proBNP, the prognostic properties in the AF setting were just recently described. Based on the RE-LY study, cardiac troponin I was shown to be detectable (≥0.01 ug/L) in 57% of the patients and elevated (≥0.04 ug/L) in almost 10%.19 Further, cardiac troponin displayed powerful prognostic properties in patients with AF, with almost a 2-fold increase of stroke risk and more than a 3-fold increase of cardiovascular mortality when AF patients with elevated vs. undetectable levels were compared. Moreover, cardiac troponin was also associated with major bleeding events, making it a potential interesting biomarker for refining bleeding risk scores. The properties of cardiac troponin as a risk predictor in AF has subsequently been described in an outpatient AF cohort.24 Beyond displaying independent association with stroke or systemic embolism and cardiovascular events, the cardiac biomarkers seem to provide different information in their utility as risk predictors, probably attributable to their different mechanistic pathways as illustrated in figure 1.19,25

Renal function

The gold standard measurement for renal function is complex and difficult to perform in daily clinical practice and therefore is usually estimated from serum levels of endogenous filtration markers such as creatinine. Impaired renal function is associated with a higher prevalence of AF and poorer maintenance of sinus rhythm.26-29 Impaired renal function is also a predictor of increased risk of thromboembolic, cardiovascular, and major bleeding events in patients with non-valvular AF.30-35 In recent analyses adding renal function to existent risk stratification models (e.g. R2CHADS2), or in construction of new risk stratification models (e.g. ATRIA stroke risk score) have displayed significant improvements in risk prediction.36,37 Moreover, renal function is an important indicator of the risk of bleeding during oral anticoagulant treatment as shown in the ARISTOTLE study.35 Each of the novel oral anticoagulants are cleared to some extent by the kidneys. Thus, estimates of renal function have the potential to be of value in estimating risk of events, as well as to selecting the best dose, of the new as well as old oral anticoagulants.

Markers of inflammation and coagulation

Figure 2: Stroke, systemic embolism, pulmonary embolism, myocardial infarction, vascular death (excl hemorrhagic death) in relation to A. Troponin I levels and CHADS2-score, B. NT-proBNP levels and CHADS2-score. Total number of patients given in each bar.
Figure 2: The Role of Biomarkers in Atrial Fibrillation
With permissions from Circulation 201219
In the 1990s inflammatory changes and the prothrombotic state in AF were first described.38-43 Among the markers most frequently studied in AF representing these two pathways are C-reactive protein (CRP) and interleukin 6 (IL-6), both robust markers reflecting inflammation, and plasma D-dimer as an index of thrombogenesis.44-47 Elevated levels of biomarkers of inflammation and coagulation were displayed in patients with AF as compared to control patients.38,41,42,48-52 Biomarkers of both pathways also seem to rise along with the accumulation of clinical risk factors for thromboembolism.52-54 Inflammation and coagulation activity have further displayed prognostic importance in AF populations, as elevated levels have been associated with increased risks of mortality and thromboembolic events.24,55-60

Clinical implications

The addition of biomarkers to clinical risk scores improves risk stratification in AF. The added value of renal function for improved risk stratification has been shown in both the ROCKET-AF and the ATRIA cohort. The value of cardiac biomarkers have been clearly illustrated in the RE-LY and ARISTOTLE biomarker studies showing significantly variable risks depending on biomarker levels within each CHADS2 and CHA2DS2-VASc score, with up to a 5-fold higher event rate of a composite of thromboembolic events based on cardiac biomarker levels in patients with CHADS2 0-1 (Figure 2). Together, these results indicate that biomarkers may provide additional understanding of the development, perpetuation, thrombogenesis, stroke risk and adverse outcomes in AF. The impact of cardiac biomarkers, in particular, seems to be substantial as they constitute powerful predictors of increased risk and provide significant improvements to the currently used clinically based risk stratification models. Biomarker based risk stratification in AF may help improve care and prevent thromboembolic and cardiovascular events. Although typically it is difficult to draw firm conclusions concerning causality and the involvement of a biomarker in the etiology of a disease, biomarkers have increasing clinical importance and will probably play a key role in refining clinical risk assessment in patients with AF as presented in this mini review.


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Keywords: Anticoagulants, Arrhythmias, Cardiac, Atrial Fibrillation, Risk, Stroke

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