Strategies for prediction and early detection of atrial fibrillation: present and future

This editorial refers to ‘CHA2DS2-VASc score and blood biomarkers to identify patients with atrial high-rate episodes and paroxysmal atrial fibrillation’ by P. Wakula et al., on pages 544–551. Atrial fibrillation (AF) represents a major health problem as it carries a substantial risk of thromboembolism, increases long-term morbidity, mortality, and healthcare costs, and reduces quality of life. In the majority of patients, AF progresses inexorably from a silent, paroxysmal form to a persistent or permanent arrhythmia. This progression is, in part, a consequence of underlying disease, but it also depends on the arrhythmia itself. Atrial fibrillation creates an electro-anatomical substrate as a result of structural and electrical remodelling that is responsible for its own perpetuation. Early AF detection is of pivotal importance, because it may allow timely introduction of therapies in order to stop or slow the progression of anatomical and electrical abnormalities that often lead to refractory disease.1,2 Importantly, a significant proportion of patients are initially asymptomatic; however, their risk of stroke and other complications appears to be similar to that of individuals with AF-related symptoms.3 Early diagnosis of short AF episodes in asymptomatic patients remains a challenge as standard diagnostic tools (ambulatory ECG and Holter monitoring) have a low sensitivity to detect these events. Moreover, it has been demonstrated that risk of stroke and bleeding is highest when AF is newly diagnosed and during the initiation of anticoagulant therapy.4 Currently, implantable electronic devices incorporate algorithms to record and store episodes of spontaneous atrial tachyarrhythmias. Stored electrograms allow the clinician to verify the appropriateness of the detection, as well as to confirm the time and duration of the events. Studies show that the identification of atrial high-rate episodes (AHREs) in pacemaker recipients is common. It has been shown that AHRE are associated with subsequent AF.5 In addition, a relationship between AHRE and the incidence of thromboembolism and other complications has been demonstrated. In the Atrial Diagnostics Ancillary Study of the MOST (MOde Selection Trial)5 in patients with sinus node disease, 51.3% of the patients enrolled had at least one AHRE >5 min duration over the median follow-up of 27 months; moreover, those individuals with pacemaker-detected AHREs were twice as likely to die or have a stroke and six times as likely to develop AF. Similarly, in the ASSERT study (Asymptomatic AF and Stroke Evaluation in Pacemaker Patients and the AF Reduction Atrial Pacing Trial)6 that was performed in pacemaker recipients with no history of AF, episodes of device-detected atrial tachyarrhythmias >6 min were found in approximately one-third of the patients; furthermore, these episodes were associated with a 2.5-fold increase in the risk of ischaemic stroke and systemic embolism. However, although the current guidelines recognize the role of implantable devices in prompt and reliable arrhythmia detection, they do not give a clear recommendation which AHREs are of clinical significance and when anticoagulant treatment should be indicated.7 Of note, the clinical implications of AHRE detection would depend not only on the duration of episodes, but also on the clinical risk profile of patients. To date, no randomized trials regarding the role of oral anticoagulation in patients with AHRE have been published. The ARTESiA (Apixaban for the Reduction of Thrombo-Embolism due to SubclInical Atrial fibrillation) study8 will address this important issue, aiming to determine whether treatment with apixaban can reduce the risk of ischaemic stroke and systemic embolism in patients with device-detected sub-clinical AF and additional risk factors for stroke. Besides early arrhythmia diagnosis, the assessment of the risk of AF development deserves significant attention. In recent years, several risk scores for the prediction of AF have been published. Of these, the CHARGE-AF,9 a novel, simple risk model that comprises variables routinely collected in a primary care setting, performs reasonably well in AF prediction. Recently, the CHADS2 and CHA2DS2-VASc scores, initially designed to assess thromboembolic risk in AF, have been directly associated with the incidence of new-onset AF.10 In fact, the components included in the scores are established predictors of arrhythmia occurrence. However, the discrimination of the thromboembolic risk scores as potentially simpler alternatives to AF-specific models seems to be considerably lower.11 In this issue of EP-Europace, Wakula et al.12 describe the role of different tools that could be helpful in AF prediction and early diagnosis: biomarkers, thromboembolic risk scores, and implanted devices. The authors analyse the ability of various blood biomarkers, as well as of the CHA2DS2-VASc score, to predict device-detected AHRE and paroxysmal AF (PAF) in 93 patients with dual-chamber pacemakers. With a case–control design, they first compared markers representing different pathways related to AF in a group of 19 patients with the highest incidence of atrial arrhythmias to another group of 20 patients with no AHREs. Then, the biomarkers which were significantly related to AHREs were tested in the whole cohort. Despite the limited sample size, one interesting finding of this study is that N-terminal-pro-B-type natriuretic peptide (NT-proBNP), N-terminal-pro-A-type natriuretic peptide, tissue inhibitors of metalloproteinases (TIMPs), interleukin-6, and serum amyloid protein A were associated with AHREs, and this association remained significant after multivariate analysis for TIMP-4 and NT-proBNP. Interestingly, they found that the CHA2DS2-VASc score was a weaker predictor of AHRE than the biomarkers alone, but the combination of a CHA2DS2-VASc score and one or two of the biomarkers yielded to a significant improvement in diagnostic ability. Based on these results, TIMP-4 and NT-proBNP, alone or in combination with the CHA2DS2-VASc score, are reliable predictors of atrial arrhythmias in pacemaker recipients. In recent years, there has been increasing interest in the area of cardiovascular diseases. In search for AF predictors, emerging evidence suggests an important role of circulating biomarkers in identifying patients at risk of AF development or recurrence. Biological markers may not only help better understand pathophysiological mechanisms of heart disease, but have also been shown to have prognostic value, contributing to a better identification of patients at risk and, thus, to improve AF management. In AF, biomarkers have been consistently associated with risk of thromboembolism; indeed, a novel risk score for predicting stroke which includes two biomarkers (NT-proBNP and high-sensitivity troponin) and information on age and prior thromboembolism, named ABC-stroke score, has recently shown to perform better than currently used risk scores in terms of stroke risk prediction.13 Interestingly, biomarkers are also useful in the prediction of bleeding and death in AF patients receiving oral anticoagulation, emerging as potential tools assisting antithrombotic treatment decision-making.14 As mentioned above, biomarkers are an attractive tool for AF prediction. In this setting, markers representing different pathophysiological pathways that contribute to AF initiation and perpetuation may be of interest. Emerging evidence suggests a central role of inflammation in AF development and thrombogenesis.15 Natriuretic peptides are an expression myocyte elevated wall stress and studies demonstrate the role of BNP and NT-proBNP as markers of pre-disposition to AF; indeed, the addition of these biomarkers to AF risk scores have shown to improve arrhythmia risk prediction.16 Signs of oxidative stress are also present in AF, where the excess production of reactive oxygen species (ROS) exceeds endogenous antioxidant defences, resulting in tissue injury. Biomarkers of oxidative stress such as nicotinamide-adenine dinucleotide phosphate oxidases (NOXs) play a major role in the production of ROS in the cardiovascular system and there appears to be an association between NOXs levels and AF.17 Atrial fibrosis is a main characteristic of atrial structural remodelling in AF, where the deposition of collagen and extracellular matrix lead to heterogeneous conduction. High levels of markers of fibrosis have been demonstrated in AF patients and have been associated with risk of incident AF.15 Hence, the detection of circulating biomarkers associated with these processes represents an attractive approach to the prediction of arrhythmia occurrence and might allow timely initiation of therapy to prevent or stop arrhythmia progression. Whether biomarkers are initiators, a consequence or merely a reflection of other clinical circumstances related to AF, is still a matter of debate. In summary, AF prediction and early diagnosis is a major issue that could ensure better arrhythmia management, avoiding structural and electrical abnormalities that lead to arrhythmia perpetuation. Implanted devices are a useful tool for prompt arrhythmia detection, but more research is needed to establish the significance and clinical implications of device-detected atrial tachyarrhythmias. Different AF risk prediction schemes have been developed, with a reasonably good performance. Even if thromboembolic risk scores have also been associated with the incidence of new-onset AF, their predictive value seems inferior to that of specific AF-prediction models and, thus, cannot be recommended. The potential value of circulating biomarkers in AF is diverse. First, they may help understand pathophysiological mechanisms of the arrhythmia. Second, they could play an important role in refining the risk of thromboembolism, bleeding, and death in AF patients. Third, as Wakula et al.12 demonstrate, they can act as predictors of AF development, alone or in combination with AF risk prediction scores. In the future, biomarkers might be helpful in identifying the candidates for early antiarrhythmic interventions in order to slow AF progression, they may be useful in selecting the patients who can benefit most from anticoagulation (balancing thromboembolic vs. bleeding risk) and could help tailor best antithrombotic treatment for each patient.18 Until then, further clinical evaluation is needed to better establish the promising role of these interesting tools in the setting of this common arrhythmia. The authors are supported by RD12/0042/0049 (Redes Temáticas de Investigación Cooperativa en Salud) from Instituto de Salud Carlos III and PI13/00513/Fondo Europeo de Desarrollo Regional from ISCIII. Conflict of interest: none declared.