Atrial fibrillation (AF) is the most common sustained cardiac arrhythmias and associated with the risk of stroke and death. Continuous development of the diagnostic tool and prognostic stratification may lead to optimal management of AF. The use of biomarkers in the management of AF has been grown as an interesting topic. However, the AF biomarkers are not yet well established in the major guidelines. Among these biomarkers, a lot of data show troponin and brain natriuretic peptides are promising for the prediction of future events. The troponin elevation in AF patients may not necessarily be diagnosed as myocardial infarction or significant coronary artery stenosis, and brain natriuretic peptide elevation may not necessarily confirm heart failure. Troponin T and troponin I may predict postoperative AF. Furthermore, troponin and brain natriuretic peptide gave better prognostic performance when compared with the risk score available today.
Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia in clinical practice and also known as an independent risk factor for stroke [
Stroke, a catastrophic lifelong risk in AF, substantially becomes central investigation in the management of AF and one of the endpoints in AF clinical trials. Stroke in AF tends to be more severe compared to other stroke origins. Therefore, anticoagulation should be good enough to protect from stroke and simultaneously to not putting in high risk for bleeding. The CHA2DS2-VASc score is widely used to predict stroke in AF since 2010 [
Assessments of biomarkers are widely used in the management of myocardial infarction and heart failure; furthermore, certain biomarkers could largely determine the diagnosis, so they require a special handling with no additional work-up [
Cardiac troponins are regulated for intracellular calcium concentration required in myocardial contraction coupling. Cardiac troponins consist of cardiac troponin I (TnI), troponin T (TnT), and troponin C (TnC). These proteins are integral part of structural proteins involved during sliding interaction of actin thin filaments against myosin thick filaments inside the myocardium. In others, striated muscle has expression of these troponins, but cardiac troponin is coded by a specific gene, and hypothetically, these cardiac troponins have unique characteristics possessed by myocardium. Troponin I and troponin T have high sensitivity and specificity for myocardial damage, unlike troponin C. Detection of these proteins to peripheral circulation always indicates myocardial injury [
Guidelines for myocardial infarction suggest the cutoff points of above 99th percentile of the upper reference limit as the diagnosis of myocardial infarction [
Elevated troponin levels and AF might lead to much utilization in clinical practice, to predict the future incidents of postoperative AF (POAF) and to aid the risk stratification in AF. In most studies, overt confounding clinical condition results of elevated troponin were not included (myocardial infarction). Studies on troponin and AF show equivocal result on future AF prediction in perioperative setting, while utilization of troponin for the future risk stratification in AF patients still gives the optimism.
Potential link between AF, abnormal ventricular perfusion, and myocyte dysfunction resulting in troponin release is mediated by the renin angiotensin-aldosterone system. AF increases cardiac tissue angiotensin II levels which further cause oxidative stress that may impair the ventricular microvascular bed resulting in ischemia and myocardial dysfunction [
Leal et al. [
Leal et al. conclude that the TnI level above 0.901 ng/mL distinguished the low risk group from the group at high risk for AF development perioperatively. The proposed mechanism mentioned by Leal et al. was multifactorial and may be linked to heart manipulation, myocardial ischemia, atrial distention, inflammatory process, and previous structural disease [
Narducci et al. [
As the authors stated above, the role of troponin as predictors for POAF is equivocal. Knayzer et al. [
Masson et al. performed a study as the ancillary of the Omega-3 Fatty Acids for Prevention of Post-operative Atrial Fibrillation (OPERA) multicenter randomized trial [
To our knowledge, a study with the largest sample sizes in accordance with troponin and POAF was performed by Koolen et al. [
Masson et al. [
Troponin elevation is almost always related to acute coronary syndromes (ACS). High sensitivity for ACS of these assays should prompt to search other etiologies when facing with nonischemic-related symptoms. In cases of tachycardia, small case series of patients showed convincingly elevation of troponin I in supraventricular arrhythmia including AF with normal epicardial coronary arteries [
Emergency setting of patients with symptomatic AF, ST-segment depression on ECG, and no clear ischemic symptoms with troponin elevation made a diagnosis confusion for the presence of significant coronary artery disease (sCAD). The lack of troponin to predict significant coronary artery disease requiring intervention in AF was found in several prospective studies of acutely symptomatic patients of AF in the emergency setting [
Acute setting of AF presentation at the emergency department usually had a faster heart rate. Several studies showed that the faster heart rate is one of the determinant factors for elevated TnI. This elevation did not have a strong association with significant epicardial coronary artery disease suggested by several studies. Tachycardia could be the point of ischemic stress in this clinical setting as researchers found on multivariate analysis [
Stroke risk stratification is an integral part in the assessment of AF. The CHADS2 score is based on clinical factors such as congestive heart failure, hypertension, age above 75 years, diabetes mellitus, and previous stroke or transient ischemic attack. The CHA2DS2VASc was made as a modification of the previous risk score. The major improvements were the application of two points for previous stroke, age above 75 years, and transient ischemic attack and one point for clinical risk factors (heart failure, hypertension, diabetes mellitus, vascular disease, female gender, and age) [
Association of adverse outcome and AF had been identified by van den Bos et al. [
A substudy from “Randomization Evaluation of Long-Term Anticoagulant Therapy” (RE-LY) covering 6189 patients investigated the prevalence of elevated TnI and its association to cardiovascular events including stroke and death. TnI levels were extremely skewed to the left as expected. Detectable TnI was found in 57% patients and elevated TnI in 24.6% patients. Proportion of the CHADS2 score was significantly correlated to TnI levels. A low CHADS2 risk score (0–1) was significantly prevalent in the undetectable and lower TnI level, while a high CHADS2 risk score (≥3) was significantly prevalent in the elevated TnI level. The interesting findings are the pattern of gradually higher rates of thromboembolic end point concomitant with higher troponin levels correlated to in all CHADS2 scores, including with CHADS2 score 0–1. The highest annual rates of thromboembolic end point of 11.4% were found in high CHADS2 score ≥3 and highest TnI levels compared to lowest annual risk of 1.48% in the CHADS2 score 0–1 and undetectable TnI. The annual vascular death rate was 1.04% in comparison with 6.56% (HR, 4.38; 95% CI, 3.05–6.29) in the highest TnI group. Furthermore, the annual rate of major bleeding was significantly higher in the highest TnI levels compared to undetectable TnI levels. Once again through this big study, the TnI level had a high prevalence in AF patients. The degree of TnI levels independently associated with raised risk of stroke or systemic embolism, mortality, and other cardiovascular events [
Hijazi et al. [
A normal heart secretes hormones in atrial tissue as a response to regulate fluid hemostasis and blood pressure. Atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) are secreted in the response to atrial distention. Integration of biomarkers in heart failure including B-type natriuretic peptide (BNP) as well as N-terminal BNP (NT-pro BNP) is part of many studies in the diagnosis and prognosis assessment. Development of biomarkers in the past decade shows that BNP is used in a variety study purposed for both diagnosis and prognosis of heart failure [
In case of AF, BNP elevation was firstly claimed by Silvet et al. in 72 stable outpatients with AF. AF patients had significantly higher BNP levels compared to the normal subject, and the median BNP level was 131 pg/mL [
A high BNP or NT-pro BNP level in AF without sign of significant heart failure invites area for research. Presence of AF impaired the diagnostic performance of AF. Richards et al. found a diagnostic challenge in patients presenting with acute dyspnea and AF. The BNP level interrupting heart failure is a cause of acute dyspnea [
In the RE-LY substudy carried out by Hijazi et al., it was found that NT-pro BNP significantly associated with age, AF, history of congestive heart failure, and lower creatinine clearance. NT-pro BNP was directly correlated with CHADS2 score, that is, lower NT-pro BNP level associated with smaller CHADS2 score. Adverse outcome also occurred based on the NT-pro BNP level aside the troponin level discussed above including thromboembolic events; furthermore, on multivariate analysis NT-pro BNP was still associated with adverse outcome. But, NT-pro BNP was not associated with bleeding risk [
An increased level of NT-pro BNP was prevalent in 14892 patients recruited in the substudy from Apixaban for the Prevention of Stroke in Subjects with Atrial Fibrillation (ARISTOTLE) trial. The median level of NT-pro BNP was 715 ng/mL, and first quartile was closer to healthy subjects. Univariate and multivariate analyses showed that clinical characteristics such as age, female sex, diabetes, renal dysfunction, and most strongly the AF type were associated with NT-pro BNP. The highest annual rate of stroke and systemic embolism (2.45%) was found in the group with CHA2DS2VASc score 3 and NT-pro BNP level >1250 ng/L compared to the averaged annual rate of stroke 0.56% in CHA2DS2VASc < 2 and level of NT-pro BNP < 363 ng/L. In contrast to other major outcomes, in bleeding risk assessment, NT-pro BNP failed to show its association [
Main clinical study concerning the use of biomarkers in AF.
References | Design | Main findings |
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Knayzer et al. [ |
Prospective study of 156 consecutive patients who underwent isolated coronary artery bypass surgery | (i) Significant correlation between clinical markers of inflammation and post-cardiac surgery elevation in plasma cTnI levels |
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Masson et al. [ |
Prospective study of 562 patients was performed with serial NT-pro BNP and hs-troponin measurement from randomized to perioperative supplementation with oral fish oil or placebo in the Omega-3 Fatty Acids for Prevention of Post-operative Atrial Fibrillation (OPERA) trial | (i) Univariate analysis; POAF group had higher hs-TnT level vs no-POAF groups. hs-TnT showed linear associations with POAF risk until 27 ng/mL, with no additional increase risk thereafter |
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Koolen et al. [ |
Retrospective study of prospectively collected data. 3148 patients undergoing elective CABG were evaluated. Serial troponins were measured. | (i) Perioperative TNT is univariably associated with postoperative AF after CABG, but not independently |
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van den Bos et al. [ |
Prospective study of 407 patients admitted to the cardiology ward or coronary care unit with atrial fibrillation. TnI was measured serially | (i) Minor troponin I elevation was independently correlated to death, MI |
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Hijazi et al. [ |
Randomized controlled trial with 6,189 patients from Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial | (i) Proportion of CHADS2 score was significantly correlated with TnI levels |
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Roldán et al. [ |
Cohort study with 930 patients, permanent AF, and good anticoagulation control with stabile INR values for at least 6 months (INRs, 2.0–3.0; time in therapeutic range (TTR), >70%) | TnI was associated with combination of stroke, TIA, systemic embolism, acute coronary syndrome, acute heart failure, and cardiac death |
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Silvet et al. [ |
Prospective study of 72 outpatients with AF and 49 control patients without AF | First study that has shown BNP levels to be significantly elevated in male and female outpatients with chronic AF compared with patients in sinus rhythm |
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Hijazi et al. [ |
Randomized control trial of 14,892 patients from Apixaban for the Prevention of Stroke in Subjects with Atrial Fibrillation (ARISTOTLE) trial | (i) NT-pro BNP level is elevated in the majority of patients with persistent or permanent AF |
AF: atrial fibrillation; TnI: troponin I; TnT: troponin T; MI: myocardial infarct; BNP: brain natriuretic peptide; NT-pro BNP: N-terminal BNP (NT-pro BNP); POAF: postoperative atrial fibrillation; CABG: coronary artery bypass graft.
There are some evidence to suggest that the renin angiotensin system (RAS) is associated with the development of AF in subjects with systemic hypertension and heart failure [
Some clinical trials on RAS antagonism were conducted for primary prevention of AF in the setting of hypertension, heart failure, and coronary artery disease. However, the results are conflicting; some trials showed benefit of angiotensin-converting enzyme inhibitor (ACEI) and angiotensin receptor blocker (ARB) to reduce AF occurrence, but others showed no effect [
Recently published risk score had mentioned biomarker utilization to predict future stroke and bleeding events, namely, ABC (age, biochemistry, and clinical history) stroke risk score, and ABC bleeding risk score. In the 2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS, the ABC stroke risk score was given class IIb recommendation [
ABC bleeding risk score comprises 3 biomarkers (hemoglobin, growth differentiation factor-15, and hs-troponin). ABC bleeding risk also performed better with high
In the past decade, studies on biomarkers in AF patients are increasing. The troponin and BNP or NT-pro BNP are among biomarkers extensively studied recently and being used as part of stroke and bleeding risk assessment in AF. Some data provide superior results of troponin and brain natriuretic peptide when compared to the risk score recommended by the guideline. However, further studies are warranted to confirm the biomarkers position in determining stroke risk and bleeding risk in AF patients.
The authors declare that they have no conflicts of interest.