Emerging biomarkers for cardiac arrhythmias

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Emerging biomarkers for cardiac arrhythmias Angelika Hammerer-Lerchera, Mehdi Namdarb, Nicolas Vuilleumierc,d,

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a

Institute of Laboratory Medicine, Cantonal Hospital Aarau AG, Switzerland Division of Cardiology, Cardiology Center, Geneva University Hospital, Geneva, Switzerland Division of Laboratory Medicine, Diagnostic Department, Geneva University Hospital, Switzerland d Department of Internal Medicine Specialities, Medical Faculty, Geneva University, Geneva, Switzerland b c

A R T I C LE I N FO

A B S T R A C T

Keywords: Biomarkers Cardiac arrhythmias Inflammation Fibrosis Autoimmunity

Cardiac arrhythmias are associated with substantial morbidity and mortality. Recent advances in the pathophysiological understanding of cardiac arrhythmia indicate that inflammation, fibrosis, and even autoimmune mechanisms could facilitate the development of arrhythmias by interfering either with fibroblast activationrelated electrical remodeling or with the function of different cardiac ion channels, leading to the emerging concepts of autoimmune and inflammatory channelopathies. In this descriptive review, we considered recent data of the literature focusing on biomarkers reflecting the degree of inflammation, myocardial stretch, fibrosis and sustained B-cell activation as potential additional diagnostic, risk stratification tools and potential therapeutic targets in cardiac arrhythmia.

1. Introduction

rates and are further mitigated by not negligible side effects [7–9]. Furthermore, catheter ablation of AF (CAAF) is plagued by significant recurrence rates varying between 20 and 30 % and potentially lifethreatening complications, depending on i) the degree of arrhythmic disease burden, ii) the technology used and iii) the operator experience [10–12]. Current established predisposing factors for AF recurrence after electrical or pharmacological cardioversion include enlarged left atrium, prolonged AF duration, and presence of structural heart disease [10]. The identification of novel biomarkers reflecting or mediating arrhythmogenic mechanisms in the presence or absence of a structural heart disease represents an unmet clinical need. In this regard, increasing evidence demonstrates that biomarkers reflecting the degree of inflammation, fibrosis, and autoimmunity could facilitate the triggering and/or maintenance of arrhythmias by interfering either with fibroblast activation-related electrical remodeling or with cardiac ion channels [13]. In this descriptive review, our aim was to integrate both experimental and clinical evidences in order to provide an updated overview of candidate biomarkers reflecting mechanisms underlying cardiac arrhythmias through fibrosis, inflammation, neurohumoral activation and autoimmunity. We discuss their potential role to improve prevention, early recognition, and risk stratification of cardiac arrhythmia. Finally, we examined the possible therapeutic impact of these findings.

Cardiac arrhythmias can generally be defined by all conditions where the heart's conduction system is disrupted. Depending upon the etiology and causative mechanisms, the clinical manifestation’s spectrum of cardiac arrhythmia varies widely from asymptomatic/paucisymptomatic disease to sudden cardiac death [1]. Among the numerous existing cardiac arrhythmia classifications, cardiac arrhythmias can roughly be divided into brady- and tachyarrhythmias [2]. The vast majority of supraventricular arrhythmias is not imminently lethal, but atrial fibrillation (AF), the most prevalent arrhythmia, is associated with an increased risk of heart failure and cardio-embolic stroke if not diagnosed and treated adequately [3,4]. On the other hand, ventricular arrhythmia requires immediate diagnosis and preventive therapies since it may present with hemodynamic instability and/or degenerate into ventricular fibrillation (VF) and sudden cardiac death (SCD) [5]. Although coronary artery disease and heart failure are well established causes of malignant arrhythmia, 70% of life-threatening arrhythmias or SCD events occur in patients without any evidence of cardiac structural or molecular abnormalities at autopsy [5,6]. As compared to the normal population, AF is associated with a nearly two-fold higher mortality rate due to heart failure and cardioembolic stroke, emphasizing that optimal therapeutic strategies are still not fully met [5]. Despite advances in the past decades, current antiarrhythmic rate or rhythm control approaches yield only partial success

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Corresponding author at: Division of Laboratory Medicine, Diagnostic Department, Geneva University Hospital, Switzerland. E-mail address: [email protected] (N. Vuilleumier).

https://doi.org/10.1016/j.clinbiochem.2019.11.012 Received 27 May 2019; Received in revised form 1 November 2019; Accepted 24 November 2019 0009-9120/ © 2019 Published by Elsevier Inc. on behalf of The Canadian Society of Clinical Chemists.

Please cite this article as: Angelika Hammerer-Lercher, Mehdi Namdar and Nicolas Vuilleumier, Clinical Biochemistry, https://doi.org/10.1016/j.clinbiochem.2019.11.012

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and infectious diseases) showed that these patients displayed a prolonged QTc interval correlating with cytokine levels, such as tumor necrosis factor-α (TNF-α), and interleukin (IL)-6. Interestingly, these studies showed that the inflammation resolution was accompanied by a concomitant QTc normalization [24–26]. Along the same line, in patients with torsades de pointes (TdP), median CRP and interleukin-6 levels were found to be significantly higher than in controls, and up to 80% of individuals with TdP had CRP values above 2.9 mg/dl, regardless of the underlying etiology of inflammation [27]. From a mechanistic point of view, several cytokines (TNF-α, IL-1, and IL-6) have been shown to modulate the expression and/or function of several cardiac ion channels leading either to a gain or loss of function, suggesting that the link between inflammation and the risk of different forms of arrhythmia may be causal [28]. These changes in cardiac ion channel function and/or expression induced by direct effects of locally or systemically released cytokines gave rise to the concept of “inflammatory channelopathies”, which may also be operative in apparently healthy individuals displaying low-grade inflammation [29]. From a mechanistic point of view, these inflammatory channelopathies have been proposed to results from an IL-6 driven connexin 40 and 43 downregulation, affecting atrial conduction velocity and thus enhancing reentry currents to promote AF maintenance [30]. In accordance with this “inflammatory channelopathies” paradigm, several inflammatory biomarkers have been associated with the risk of incident AF and relapse after CAAF, including tumor necrosis alpha (TNF-α), interleukin (IL)-6, IL-8, IL-10, IL-1β, myeloperoxidase and CRP [31]. Nevertheless, their added value over cardiac biomarkers, such as BNP/NT-proBNP or hs-cTnT, as well as knowing whether these cytokines could represent therapeutic targets amenable to biological inhibition improving AF prognosis or response to CAAF remains to be elucidated.

1.1. Conventional biomarkers in AF Numerous factors associated with atrial structural and electrophysiological remodeling have been identified to play an important role in triggering and maintaining AF in a complex interplay. Interestingly, some of these factors show many pathophysiological features found in ischemic, dilated, or hypertensive cardiopathies [3–5]. Reflecting such pathophysiological complexity, different conventional and emerging cardiac biomarkers related either to myocardial injury (troponin), overload (B-type natriuretic peptides (BNP)), fibrosis/adverse remodeling (galectin-3 (Gal-3), Growth differentiation factor 15 (GDF15), soluble suppression of tumorigenicity (sST2)), or inflammation (Interleukins, Gal-3, CRP), have shown interesting diagnostic and prognostic values in AF, and some of them may also be of interest in predicting success rates after CAAF. 1.1.1. Cardiac biomarkers: troponins and BNP If cardiac troponins constitute to date the best validated diagnostic and prognostic cardiac biomarkers in the field of acute coronary syndromes [14], natriuretic peptides (BNP or NT-proBNP) represent the best available biomarkers in heart failure, by providing i) added diagnostic value in case of intermediate clinical probability, ii) a strong and independent prognostic value, and iii) therapeutic guidance in patients with reduced ejection fraction [15,16]. Respectively reflecting the degree of cardiomyocytes injury and stretch, their possible added prognostic value in the field of AF is under active scrutiny. In the Black Country Atrial Fibrillation Registry (BBC-AF; UK), including 638 patients without known AF screened by Holter-ECG monitoring, 40 candidate biomarkers were investigated to predict the incident risk of AF during follow-up on top of classical clinical parameters. Among them, BNP and fibroblast growth factor 23 (FGF-23) were robustly associated with AF with respective odds ratios for AF of 1.3 (95% confidence interval (95%CI): 1.11–1.63) and 1.7 (95%CI: 1.36–2.34) [13]. Furthermore, adding these two biomarkers to clinical risk factors (age, gender and BMI), improved the prediction of AF when compared to clinical risk factors alone, as demonstrated by the C-statistics increased (from 0.66 to 0.77) [13]. Nevertheless, in this work the demonstration that BNP and FGF23 could be independent predictors of AF was not established [13]. In two large community-based cohorts with a follow-up period of more than 10 years, N-terminal proBNP (NT-proBNP) was found to be the most powerful and only independent predictor of incident AF among all cardiac markers tested, including high-sensitivity cardiac troponin (hs-cTn), GDF-15, cystatin C, and CRP [17]. On the other hand, three independent studies indicated that high-sensitivity cTnT (hs-cTnT) could be a promising independent predictor of incident AF in healthy subjects without apparent cardiovascular diseases [18–20]. After CAAF, a combined biomarker approach including BNP, CRP and estimated glomerular filtration rate, was found to be of added value to clinical factors for the prediction of arrhythmia recurrence in both paroxysmal and non-paroxysmal AF [21]. Similarly, another study indicated that both the pre-CAAF hs-CRP levels and 1-day post-CAAF NTproBNP levels were significantly associated with an increased risk of AF recurrence [22]. Interestingly, a recent meta-analysis found a significant association of periablation cTnT levels with incident AF occurrence and AF recurrence risk as well as stroke or major bleeding, associations which could not be reproduced with cTnI [23].

1.2.2. Fibrosis-related biomarkers The pro-fibrotic protein Gal-3, a β-galactoside-binding lectin, is activated by rapid electrical stimulation in vitro and in vivo and exerts arrhythmogenic effects by structural and electrophysiological remodeling [32]. Initially studied in heart failure (HF) and in particular cases related to cardiac fibrosis (including atrial fibrosis), Gal-3 has been shown to predict incident AF [33]. In the Framingham Offspring cohort, each standard deviation increase in logarithmic transformed Gal-3 values was associated with a 19% increased hazard of incident AF over 10 years, independently of age and gender, but not after accounting for other traditional clinical AF risk factors [34]. Although these findings do not make a strong case for Gal-3 to represent a major AF risk factor, Tang et al. recently demonstrated that elevated Gal-3 levels were independent predictors of left atrial appendage (LAA) thrombi, known to be associated with stroke in AF, independently of the CHA2DS2VASc score [35]. If further validated by other studies, these findings may point to Gal-3 as an additional tool to the CHA2DS2VASc score to optimize stroke risk evaluation. Furthermore, as Gal-3 can be specifically inhibited, it could be foreseen as a potential future therapeutic target in cardiac arrhythmia, but such hypothesis is currently devoid of any clinical evidence. GDF-15 is a member of the transforming growth factor-β cytokine superfamily that is activated upon cellular ischemia and mechanical or oxidative stress, aiming at protecting the myocardium against hypertrophy and fibrosis [36]. GDF-15 concentrations were found to be significantly higher in patients with paroxysmal AF when compared to controls and also associated with LAA thrombi [36], but its association with incident AF risk remains elusive at the present time. The strength of GDF-15 seems to be mostly in the risk assessment of major bleedings in anticoagulated AF patients, where it could improve the bleeding risk estimation of CHA2DS2VASc, HAS-BLED and ORBIT scores [37,38]. Nevertheless, this improvement in bleeding risk stratification has not yet been translated into any clinical practice changes, such as prothrombin time/international normalized ratio (INR) targets, targets for

1.2. Emerging biomarkers 1.2.1. Inflammatory-related biomarkers and the emerging concept of inflammatory channelopathies Lately, inflammation has been revealed as a key player in modulating atrial structural and electrophysiological remodeling, promoting different forms of arrhythmia, including AF. Numerous studies performed in patients suffering from systemic or local inflammatory diseases (inflammatory heart diseases, autoimmune 2

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Table 1 Biomarkers and primary mechanisms involved in arrhythmias and conduction disturbances. Biomarkers Conventional biomarkers BNP, fibroblast growth factor 23 (FGF-23) NT-proBNP, hs-cTn, GDF-15, cystatin C, CRP hs-CRP, NT-proBNP cTnT Emerging biomarkers Inflammatory-related biomarkers TNF-α, IL-6, IL-8, IL-10, IL-1β, myeloperoxidase, CRP IL-6 in context of acute/chronic systemic inflammation Fibrosis-related biomarkers Gal-3

GDF-15 sST2 Auto-antibodies anti-Ro/SSA anti-α1, anti- β1, anti- β2AR, anti-AchR, anti-voltage-gated K + channels, anti- cardiac lipid raft-associated proteins, anti-AT2R anti-apoA-1 IgG Anti-Myosin heavy chain, anti-M2 receptor, anti-HSP 70 and HSP65

Associations/Mechanisms/Sites of action

#Reference

Prediction of AF incidence (OR 1.3&1.7 respectively) Prediction of AF incidence (NT-proBNP being the only independent predictor) hs-CRP before and NT-proBNP 1-day post AF ablation predicting AF recurrence elevated peri-ablation levels associated with AF occurrence and recurrence

[13] [17–20] [22] [23]

elevated risk of incident AF and/or relapse after AF ablation QT-interval prolongation and risk of torsades de pointes

[31] [24–30]

activated by rapid electrical stimulation, pro-fibrotic with structural and electrical remodeling effects, prediction of AF incidence in heart failure if elevated independent predictor of LAA thrombi elevated in patients with paroxysmal AF and associated with LAA thrombi endogenous inhibitor of IL-33 associated with new-onset AF

[33] [34] [35] [36] [41]

maternal anti-Ro/SSA autoantibodies associated with fetal complete AV-block in adults QT-interval prolongation and risk of torsades de pointes associated with POTS

[44] [43] [48–50]

associated with higher basal heart rate after myocardial infarction in humans and in vitro. elevated in AF and associated with recurrence after ablation anti-HSP65 IgG Predictor for post-opersative AF

[47,51,52] [56–60] [58]

Abbreviations: BNP, B-type natriuretic peptide; OR, odds ratio; hs-cTn, high-sensitivity cardiac troponin; GDF-15, growth differentiation factor 15; CRP, C-reactive protein; TNF-α, tumor necrosis factor α; IL, interleukin; AF, atrial fibrillation; Gal-3, galectin 3; LAA, left atrial appendage; sST2, soluble suppression of tumorigenicity; POTS, postural orthostatic tachycardia syndrome; anti-HSP65, anti-heat-shock protein 65.

are frequently retrieved in the general population with a prevalence varying between 0.5% and 15% according to the analytical methods [45], and may reach 60% in patients suffering from TdP [46]. The reported pathogenic mechanisms of anti-Ro/SSA IgG involve a molecular mimicry phenomenon leading to an inhibitory cross-reaction of these antibodies either with cardiac potassium-channels conducting the rapid component of the delayed rectifier K current, with L-type calcium channels (both Cav1.2 and Cav1.3), or with T-type Ca2+channels (CaV3.1 and CaV3.2), leading to major SA and AV conduction abnormalities [43]. Since then, many other pathogenic autoantibodies displaying either agonistic or antagonistic effects on specific calcium, potassium, or sodium channels have been identified and lead to the recent concept of “autoimmune cardiac channelopathies” believed to open novel diagnostic and treatment opportunities, especially in unexplained arrhythmias and SCD [43]. Furthermore, a broad range of other autoantibodies directed against other targets than ion channels, such as lipoproteins or cellular components have been reported in dilated, rhythmic and ischemic cardiopathies [47]. Because several autoantibodies are known to elicit a pro-inflammatory response through innate immune receptor signaling [47], substantial mechanistic overlaps between inflammatory and autoimmune channelopathies are likely to exist [28]. These autoimmune cardiac channelopathies are not only known to be associated with ventricular arrhythmia but also with bradyarrhythmias and conduction disturbances (anti-Ro/SSA antibodies can induce sinus bradycardia and atrioventricular block by interacting with L- and T-type calcium channels, while anti-Nav1.5 autoantibodies have been associated with conduction disturbances) and have been outstandingly reviewed elsewhere [43]. Therefore, we will specifically focus on auto-antibodies associated with sinus tachycardia/ bradycardia and AF, where increasing evidence indicates that humoral autoimmunity may play an important role in modulating not only basal heart rate regulation, but also AF pathogenesis [48].

direct oral anticoagulant drugs or anticoagulation treatment posology modulation in patients with high GDF-15 levels. Soluble ST2 (sST2), an endogenous inhibitor of IL-33 pro-inflammatory signaling in cardiomyocytes, is known to dampen inflammation, myocardial fibrosis, hypertrophy and averse myocardial remodeling [39,40]. High concentrations of sST2 were initially demonstrated to be useful in risk stratification for subsequent adverse cardiovascular events in patients with heart failure and acute myocardial infarction [39,40]. In a recently published analysis including more than 1700 patients with coronary artery disease, only sST2 (and hs-CRP) remained significantly associated with new-onset AF during 5.7 years of follow-up in adjusted analyses [41]. However, sST2 did not provide incremental information when compared to established AF risk factors, as already suggested in an earlier study [42]. Therefore the added clinical value of sST2 in AF still remains to be demonstrated. A summary of these studies is presented in Table 1.

1.2.3. Autoimmune biomarkers in cardiac arrhythmia The presence of circulating autoantibodies can be considered as the biological signature of B-cell auto-reactivity. The role of humoral autoimmunity as a biomarker and mediator of cardiac arrhythmia has recently gained a substantial interest not only in patients with overt autoimmune diseases, but also in a number of arrhythmias currently classified as idiopathic [43]. The first report suggesting that autoantibodies could interfere with the cardiac conduction system was published in 1985 and demonstrated the deposition of maternal antiRo/SSA autoantibodies in the cardiac tissue of fetuses that had died of complete atrio-ventricular (AV) block [44]. These observations gave rise to the concept of autoimmune congenital heart block, characterized by a conduction disturbance affecting the sino-atrial (SA) and AV node of fetuses and neonates in a structurally normal heart, as the result of the transplacental passage of anti-Ro/SSA IgG from the mother to the fetus [43]. Initially thought to only affect neonates’ hearts conduction system, anti-Ro/SSA IgGs (particularly anti-Ro/SSA-52 kD) were shown to be arrhythmogenic in adults by promoting the prolongation of the QT interval, increasing the subsequent risk of TdP, a malignant ventricular arrhythmia [43]. Interestingly, high levels of anti-Ro/SSA IgGs

1.2.3.1. Autoantibodies in sinus tachycardia/bradycardia. Since the initial demonstration in 1986 of autoantibodies against the human sinus node being present in one-fourth to one-third of patients with 3

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[57]. Affinity purified IgG derived from anti-M2 IgG positive patients were found to induce a negative chronotropic effect in an in-vitro model (chick embryos system), followed by atrial premature contractions, supporting a possible causal pathogenic role of these antibodies in AF [57]. In 329 consecutive patients elected for primary coronary artery bypass intervention, pre-operative elevated levels of anti-HSP65 IgGs were reported to be independent predictors of post-operative AF, further suggesting a possible role for antibody-mediated immune response in AF pathogenesis [58]. Nevertheless, the authors did not test the ability of these antibodies to interfere with any pathways related to basal heart regulation, and no other further study on anti-HSP65 have been repeated since more than a decade. Anti-HSP70 IgGs have also been investigated in relation with AF, where high levels were found to be independently associated with persistent AF. Interestingly, the authors noted that patients displaying elevation of anti-HSP70 IgG at 6 months after inclusion had a significant higher risk of AF recurrence after catheter ablation than individuals with stable antibody levels [59]. However, this study did not explore the possible arrhythmogenic effects of these antibodies and these initial findings await further validation. Finally, in hyperthyroid settings – a well-known predisposing condition of AF - a case-control study demonstrated that the levels of antiβ1 adrenoreceptors and anti-M2 autoantibodies were higher in patients with AF when compared to individuals in sinus rhythm, and that the presence of both antibodies was associated with a major increase in the risk of developing AF (Odds Ratio: 33.6; 95%confidence intervals: 1.17–964.1; p = 0.04). Furthermore, when affinity-purified IgGs from autoantibody-positive patients were used in vitro (canine Purkinje fibers), these IgG fractions induced cell hyperpolarization with a decreased action potential duration and enhanced early after-depolarizations [60]. A summary of these findings is presented in Table 1. To summarize, autoantibodies may well represent an underestimated albeit promising class of biomarker candidates in cardiac arrhythmias for three reasons. Firstly, auto-antibodies can be specifically and sensitively measured with an adequate analytical precision on different analytical platforms compatible with automation, allowing clinically compatible throughput, turn-around times and costs. As such they would easily qualify as optimal biomarkers [61]. Secondly, as current evidences point to autoantibodies as active mediators of arrhythmogenic processes that can be reversed by specific available therapeutic means [43,47], autoantibodies are likely to represent emerging therapeutic targets rather than innocent bystanders. Since several efficient means to eliminate autoantibodies have been reported, such as plasmapheresis, non-selective or epitope-targeted apheresis, blocking the antibodies deleterious effects using aptamers or mimetic peptides as high affinity ligands [47], detecting these antibodies could theoretically allow the identification of a specific patient’s subset especially prone to benefit from apheresis or any other immunomodulatory modality. Lastly, as pathogenic autoantibodies are often detected in asymptomatic individuals with worse prognosis [43,45,47], their detection could help identifying patients in an early disease stage where preventive immunomodulatory strategies would be of utmost value. If validated, these concepts, would certainly open innovative perspectives for the development of precision medicine in the field of cardiac arrhythmias.

bradycardia due to sinus node dysfunction, more recent evidence has shown that other specific antibodies could interfere with sinus node function and autonomic system regulation [48]. The role of humoral autoimmunity has been particularly investigated in the postural orthostatic tachycardia syndrome (POTS), characterized by an imbalance of the adrenergic and renin-angiotensin system. In POTS, autoantibodies against adrenergic receptors (anti-α1, anti-β1, and anti-β2-adrenergic antibodies), acetylcholine receptor, voltage‐gated potassium channel complex, cardiac lipid raft‐associated proteins, and angiotensin II receptor (AT2R) have been reported [49,50]. Of note, anti-adrenergic and AT2R IgG seem to be particularly associated with POTS since they are hardly detected in control individuals or in patients with vasovagal syncope [49]. Anti-adrenergic antibodies are known to act either as agonists or antagonists on their cognate receptors, while anti-AT2R IgG seems predominantly to exert a direct agonistic effect which could be blocked in vitro by AT2R antagonists [49]. In POTS, significant positive correlations were retrieved between adrenergic autoantibodies (anti-α1, anti-β1 IgG) and heart rate response, whereas lower minimal blood pressures upon tilt test were found in AT2R IgG-positive patients when compared to patients tested negative for these antibodies [49]. Recently, autoantibodies against a specific lipoprotein of highdensity (HDL) has been also been suspected to interfere with the cardiac conduction system. Indeed, antibodies against apolipoprotein A-1 (antiapoA-1 IgG), the major protein fraction of HDL, have also been associated with a higher basal heart rate after myocardial infarction and the serum of these individuals was found to induce a dose-dependent positive chronotropic response in vitro [47,51,52]. Mechanistic studies indicated that anti-apoA-1 IgGs mediate a positive chronotropic response by a complex mechanism involving the concomitant activation of mineralocorticoid receptor together with the activation of an innate immune receptor complex within lipid rafts to effectively activate Ltype calcium channels, leading to an increase of cardiomyocytes beating frequency in vitro [47,53]. Interestingly, this positive chronotropic effect could be abrogated by classical L-type calcium antagonists and intravenous immunoglobulins [47,51,52]. As an independent cardiovascular risk factor in the general population [52], those antibodies have been associated with incident major adverse cardiovascular complications in high-risk patients [47,51,54], but their clinical relevance to any arrhythmia-related diseases still remains to be demonstrated. Taken together, these results indicate that antibodies directed against different members of the G-protein–coupled receptor family represent the major class of autoantibodies susceptible to affect sinus node function, and basal heart rate regulation. Autoantibodies appear to mediate autonomic system dysregulation by preferentially acting both on the adrenergic and the renin-angiotensin systems. Because HDL levels have been shown to protect individuals against premature atrial contraction [55], knowing whether anti-apoA-1 IgG could affect electrical conduction in the atria by interfering with HDL protective effect remains uncertain. 1.2.3.2. Autoantibodies in atrial fibrillation. The first autoantibodies reported in AF were those directed against the myosin heavy chain [56]. High levels of those autoantibodies were found to be more prevalent in patients with paroxysmal AF refractory to antiarrhythmic therapy when compared to controls (60% vs 10% p < 0.05), but after this initial description they were not further investigated, and their possible pathogenic role is still undefined. Subsequently, autoantibodies against Muscarinic 2 (M2) receptors and against heat-shock protein (HSP) 65 levels were also reported to be elevated in AF [57,58]. In lone AF, the prevalence of high anti-M2 receptors IgG levels (defined as a signal that was 2.5 times higher than background) was higher than in controls [57], and even higher in AF patients with concomitant dilated cardiomyopathy where anti-M2 receptor antibodies were found to be an independent predictor of AF

2. Conclusions Current data in the literature indicate that inflammation, fibrosis, and autoimmunity represent major pathophysiological processes common to both brady- and tachyarrhythmias. Assessing biomarkers reflecting or mediating these processes has shown some promise, but whether any of these will improve current risk prediction models remains uncertain. So far, the integration of non-autoimmune biomarkers into risk prediction scores for AF has been shown to have the potential 4

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to improve risk stratification of patients at risk of cardio embolic stroke, and to possibly anticipate success rates after CAAF. Nevertheless, the demonstration that current cardiac, inflammatory or fibrosis-related biomarkers in arrhythmia are mediators rather than innocent bystanders needs to be further reinforced. In this respect, autoantibodies may be of particular interest being intrinsically biologically active molecules. Depending on their specificity, they seem to mediate arrhythmogenic effects by affecting the functionality of numerous players involved in basal heart rate regulation, such as calcium, sodium, and potassium ion channels involved in the autonomous nervous system regulation. Nevertheless, an extensive evaluation of the possible prognostic and predictive values of each of the numerous autoantibodies reported as associated with arrhythmia is still needed. Furthermore, due to the important diversity of autoantibodies reported so far and their possible differential associations with diseases and prognosis, a multiplex approach allowing the simultaneous assessment of different autoantibodies would be necessary to reach a comprehensive overview of their respective association or role in the various existing forms of arrhythmias.

infarction (2018). Eur. Heart J. 2019; 40(3): 237–269. [15] P. Ponikowski, A.A. Voors, S.D. Anker, H. Bueno, J.G. Cleland, A.J. Coats, V. Falk, et al., Authors/Task Force Members, Document Reviewers. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur. J. Heart Fail 2016; 18(8): 891–975. [16] H.P. Brunner-La Rocca, L. Eurlings, A.M. Richards, J.L. Januzzi, M.E. Pfisterer, U. Dahlström, Y.M. Pinto, et al., Which heart failure patients profit from natriuretic peptide guided therapy? A meta-analysis from individual patient data of randomized trials, Eur. J. Heart Fail 17 (12) (2015) 1252–1261. [17] E. Svennberg, B. Lindahl, L. Berglund, K.M. Eggers, P. Venge, B. Zethelius, M. Rosenqvist, et al., NT-proBNP is a powerful predictor for incident atrial fibrillation - validation of a multimarker approach, Int. J. Cardiol. 223 (2016) 74–81. [18] T. Anegawa, H. Kai, H. Adachi, Y. Hirai, M. Enomoto, A. Fukami, M. Otsuka, et al., High-sensitive troponin T is associated with atrial fibrillation in a general population, Int. J. Cardiol. 156 (1) (2012) 98–100. [19] K.B. Filion, S.K. Agarwal, C.M. Ballantyne, M. Eberg, R.C. Hoogeveen, R.R. Huxley, L.R. Loehr, et al., High-sensitivity cardiac troponin T and the risk of incident atrial fibrillation: the Atherosclerosis Risk in Communities (ARIC) study, Am. Heart J. 169 (1) (2015) 31–38. [20] A.A. Hussein, T.M. Bartz, J.S. Gottdiener, N. Sotoodehnia, S.R. Heckbert, D. LloydJones, J.R. Kizer, et al., Serial measures of cardiac troponin T levels by a highly sensitive assay and incident atrial fibrillation in a prospective cohort of ambulatory older adults, Heart Rhythm. 12 (5) (2015) 879–885. [21] H. Deng, A. Shantsila, P. Guo, X. Zhan, X. Fang, H. Liao, Y. Liu, et al., Multiple biomarkers and arrhythmia outcome following catheter ablation of atrial fibrillation: the Guangzhou Atrial Fibrillation Project, J. Arrhythm. 34 (6) (2018) 617–625. [22] D. Carballo, S. Noble, S. Carballo, J. Stirnemann, H. Muller, H. Burri, N. Vuilleumier, et al., Biomarkers and arrhythmia recurrence following radiofrequency ablation of atrial fibrillation, J. Int. Med. Res. 46 (12) (2018) 5183–5194. [23] Y. Bai, S.D. Guo, Y. Liu, C.S. Ma, G.Y.H. Lip, Relationship of troponin to incident atrial fibrillation occurrence, recurrence after radiofrequency ablation and prognosis: a systematic review, meta-analysis and meta-regression, Biomarkers 23 (6) (2018) 512–517. [24] D. Medenwald, J.A. Kors, H. Loppnow, J. Thiery, A. Kluttig, S. Nuding, D. Tiller, et al., Inflammation and prolonged QT time: results from the cardiovascular disease, living and ageing in Halle (CARLA)study, PLoS One 9 (2014) e95994. [25] P.E. Lazzerini, M. Acampa, P.L. Capecchi, I. Fineschi, E. Selvi, V. Moscadelli, et al., Antiarrhythmic potential of anticytokine therapy in rheumatoid arthritis: tocilizumab reduces corrected QT interval by controlling systemic inflammation, Arthritis Care Res. (Hoboken) 67 (2015) 332–339. [26] A.M. Adlan, V.F. Panoulas, J.P. Smith, J.P. Fisher, G.D. Kitas, Association between corrected QT interval and inflammatory cytokines in rheumatoid arthritis, J. Rheumatol. 42 (2015) 421–428. [27] P.E. Lazzerini, F. Laghi-Pasini, I. Bertolozzi, G. Morozzi, S. Lorenzini, A. Simpatico, E. Selvi, et al., Systemic inflammation as a novel QT-prolonging risk factor in patients with torsades de pointes, Heart 103 (2017) 1821. [28] P.E. Lazzerini, P.L. Capecchi, N. El-Sherif, F. Laghi-Pasini, M. Boutjdir, Emerging arrhythmic risk of autoimmune and inflammatory cardiac channelopathies, J. Am. Heart Assoc. 7 (22) (2018) e010595. [29] P.E. Lazzerini, P.L. Capecchi, F. Laghi-Pasini, Systemic inflammation and arrhythmic risk: lessons from rheumatoid arthritis, Eur. Heart J. 38 (2017) 1717–1727. [30] P.E. Lazzerini, F. Laghi-Pasini, M. Acampa, U. Srivastava, I. Bertolozzi, B. Giabbani, F. Finizola, et al., Systemic inflammation rapidly induces reversible atrial electrical remodeling: the role of interleukin-6-mediated changes in connexin expression, J. Am. Heart Assoc. 8 (16) (2019) e011006. [31] L. Scott Jr, N. Li, D. Dobrev, Role of inflammatory signaling in atrial fibrillation, Int. J. Cardiol. S0167–5273(18) (2018) 35864–35869. [32] H. Shen, J. Wang, J. Min, W. Xi, Y. Gao, L. Yin, Y. Yu, et al., Activation of TGF-β1/αSMA/Col I profibrotic pathway in fibroblasts by galectin-3 contributes to atrial fibrosis in experimental models and patients, Cell Physiol. Biochem. 47 (2) (2018) 851–863. [33] L. Yu, W.P. Ruifrok, M. Meissner, E.M. Bos, H. van Goor, B. Sanjabi, P. van der Harst, et al., Genetic and pharmacological inhibition of galectin-3 prevents cardiac remodeling by interfering with myocardial fibrogenesis, Circ. Heart Fail 6 (1) (2013) 107–117. [34] J.E. Ho, X. Yin, D. Levy, R.S. Vasan, J.W. Magnani, P.T. Ellinor, D.D. McManus, et al., Galectin 3 and incident atrial fibrillation in the community, Am. Heart J. 167 (5) (2014) 729–734. [35] Z. Tang, L. Zeng, Y. Lin, Z. Han, J. Gu, C. Wang, H. Zhang, Circulating galectin-3 is associated with left atrial appendage remodelling and thrombus formation in patients with atrial fibrillation. Heart Lung Circ. 2018 [Epub ahead of print]. [36] X.F. Hu, R. Zhan, S. Xu, J. Wang, J. Wu, X. Liu, Y. Li, et al., Growth differentiation factor 15 is associated with left atrial/left atrial appendage thrombus in patients with non valvular atrial fibrillation, Clin. Cardiol. 41 (1) (2018) 34–38. [37] L. Wallentin, Z. Hijazi, U. Andersson, J.H. Alexander, R. De Caterina, M. Hanna, J.D. Horowitz, et al., Growth differentiation factor 15, a marker of oxidative stress and inflammation, for risk assessment in patients with atrial fibrillation: insights from the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial, Circulation 130 (21) (2014) 1847–1858. [38] Z. Hijazi, J. Oldgren, A. Siegbahn, L. Wallentin, Application of biomarkers for risk stratification in patients with atrial fibrillation, Clin. Chem. 63 (1) (2017) 152–164. [39] R. Kakkar, R.T. Lee, The IL-33/ST2 pathway: therapeutic target and novel

Appendix A. Supplementary data Supplementary data to this article can be found online at https:// doi.org/10.1016/j.clinbiochem.2019.11.012. References [1] D. Mozaffarian, E.J. Benjamin, A.S. Go, D.K. Arnett, M.J. Blaha, M. Cushman, S. de Ferranti, et al., Heart disease and stroke statistics—2015 Update, Circulation 131 (2015) e29–e322. [2] S. Hajeb-Mohammadalipour, M. Ahmadi, R. Shahghadami, K.H. Chon, Automated method for discrimination of arrhythmias using time, frequency, and nonlinear features of electrocardiogram signals. Sensors (Basel) 2018 Jun 29; 18(7). pii: E2090. [3] C.T. January, L.S. Wann, J.S. Alpert, H. Calkins, J.E. Cigarroa, J.C. Cleveland Jr., J. B. Conti, et al., American College of Cardiology/American Heart Association Task Force on Practice Guidelines.2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/ American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J. Am. Coll. Cardiol. 2014; 64(21): e1–76. [4] P. Kirchhof, S. Benussi, D. Kotecha, A. Ahlsson, D. Atar, B. Casadei, M. Castella, et al., ESC Scientific Document Group, 2016 ESC Guidelines for the management of atrial fibrillation developedin collaboration with EACTS, Eur. Heart J. 38 (2016) 2893–2962. [5] S.G. Priori, C. Blomström-Lundqvist, A. Mazzanti, N. Blom, M. Borggrefe, J. Camm, P.M. Elliott, et al., ESC Scientific Document Group.2015 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: The Task Force for the Management of Patients with Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death of the European Society of Cardiology (ESC). Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC). Eur. Heart J. 2015; 36(41): 2793–2867. [6] C. Semsarian, J. Ingles, A.A. Wilde, Sudden cardiac death in the young: the molecular autopsy and a practical approach to surviving relatives, Eur. Heart J. 36 (2015) 1290–1296. [7] D.G. Wyse, A.L. Waldo, J.P. DiMarco, A comparison of rate control and rhythm control in patients with atrial fibrillation, N. Engl. J. Med. 347 (2002) 1825–1833. [8] I.C. Van Gelder, V.E. Hagens, H.A. Bosker, A comparison of rate control and rhythm control in patients with recurrent persistent atrial fibrillation, N. Engl. J. Med. 347 (2002) 1834–1840. [9] S. Singh, R.G. Zoble, L. Yellen, Efficacy and safety of oral dofetilide in converting to and maintaining sinus rhythm in patients with chronic atrial fibrillation or atrial flutter: the symptomatic atrial fibrillation investigative research on dofetilide (SAFIRE-D) study, Circulation 102 (2000) 2385–2390. [10] P. Jais, R. Weerasooriya, D.C. Shah, Ablation therapy for atrial fibrillation (AF): past, present and future, Cardiovasc. Res. 54 (2002) 337–346. [11] S.A. Chen, M.H. Hsieh, C.T. Tai, Initiation of atrial fibrillation by ectopic beats originating from the pulmonary veins: electrophysiological characteristics, pharmacological responses, and effects of radiofrequency ablation, Circulation 100 (1999) 1879–1886. [12] M. Haissaguerre, D.C. Shah, P. Jais, Electrophysiological breakthroughs from the left atrium to the pulmonary veins, Circulation 102 (2000) 2463–2465. [13] W. Chua, Y. Purmah, V.R. Cardoso, G.V. Gkoutos, S.P. Tull, G. Neculau, M.R. Thomas, et al., Data-driven discovery and validation of circulating bloodbased biomarkers associated with prevalent atrial fibrillation, Eur. Heart J. 40 (16) (2019) 1268–1276. [14] K. Thygesen, J.S. Alpert, A.S. Jaffe, B.R. Chaitman, J.J. Bax, D.A. Morrow, H.D. White, ESC Scientific Document Group. Fourth universal definition of myocardial

5

Clinical Biochemistry xxx (xxxx) xxx–xxx

A. Hammerer-Lercher, et al.

biomarker, Nat. Rev. Drug Discov. 7 (10) (2008) 827–840. [40] A. Aleksova, A. Paldino, A.P. Beltrami, L. Padoan, M. Iacoviello, G. Sinagra, M. Emdin, et al., Cardiac biomarkers in the emergency department: the role of soluble ST2 (sST2) in acute heart failure and acute coronary syndrome-there is meat on the bone, J. Clin. Med. 8 (2) (2019) E270. [41] S. Nortamo, O. Ukkola, S. Lepojärvi, T. Kenttä, A. Kiviniemi, J. Junttila, H. Huikuri, et al., Association of sST2 and hs-CRP levels with new-onset atrial fibrillation in coronary artery disease, Int. J. Cardiol. 248 (2017) 173–178. [42] M. Rienstra, X. Yin, M.G. Larson, J.D. Fontes, J.W. Magnani, D.D. McManus, E.L. McCabe, et al., Relation between soluble ST2, growth differentiation factor-15, and high-sensitivity troponin I and incident atrial fibrillation, Am. Heart J. 167 (1) (2014) 109–115. [43] P.E. Lazzerini, P.L. Capecchi, F. Laghi-Pasini, M. Boutjdir, Autoimmune channelopathies as a novel mechanism in cardiac arrhythmias, Nat. Rev. Cardiol. 14 (9) (2017) 521–535. [44] S.E. Litsey, J.A. Noonan, W.N. O’Connor, C.M. Cottrill, B. Mitchell, Maternal connective tissue disease and congenital heart block. Demonstration of immunoglobulin in cardiac tissue, N. Engl. J. Med. 312 (1985) 98–100. [45] M. Satoh, E.K. Chan, L.A. Ho, K.M. Rose, C.G. Parks, R.D. Cohn, T.A. Jusko, et al., Prevalence and sociodemographic correlates of antinuclear antibodies in the United States, Arthritis Rheum. 64 (2012) 2319–2327. [46] P.E. Lazzerini, Y. Yue, U. Srivastava, F. Fabris, P.L. Capecchi, I. Bertolozzi, M.R. Bacarelli, et al., Arrhythmogenicity of anti-Ro/SSA antibodies in patients with torsades de pointes, Circ. Arrhythm. Electrophysiol. 9 (4) (2016) e003419. [47] N. Satta, N. Vuilleumier, Auto-antibodies as possible markers and mediators of ischemic, dilated, and rhythmic cardiopathies, Curr. Drug Targets 16 (4) (2015) 342–360. [48] H.C. Lee, K.T. Huang, X.L. Wang, W.K. Shen, Autoantibodies and cardiac arrhythmias, Heart Rhythm. 8 (11) (2011) 1788–1795. [49] X. Yu, H. Li, T.A. Murphy, Z. Nuss, J. Liles, C. Liles, C.E. Aston, et al., Angiotensin II type 1 receptor autoantibodies in postural tachycardia syndrome, J. Am. Heart Assoc. 7 (8) (2018) e008351. [50] M. Watari, S. Nakane, A. Mukaino, M. Nakajima, Y. Mori, Y. Maeda, T. Masuda, et al., Autoimmune postural orthostatic tachycardia syndrome, Ann. Clin. Transl. Neurol. 5 (4) (2018) 486–492. [51] N. Vuilleumier, M.F. Rossier, S. Pagano, M. Python, E. Charbonney, R. Nkoulou, R. James, et al., Anti-apolipoprotein A-1 IgG as an independent cardiovascular

[52]

[53]

[54]

[55]

[56]

[57]

[58]

[59]

[60]

[61]

6

prognostic marker affecting basal heart rate in myocardial infarction, Eur. Heart J. 31 (7) (2010) 815–823. P. Antiochos, P. Marques-Vidal, J. Virzi, S. Pagano, N. Satta, F. Bastardot, O. Hartley, et al., Association between anti-apolipoprotein A-1 antibodies and cardiovascular disease in the general population. Results from the CoLaus study, Thromb. Haemost. 116 (4) (2016) 764–771. T. Mannic, N. Satta, S. Pagano, M. Python, J. Virzi, F. Montecucco, M.A. Frias, et al., CD14 as a mediator of the mineralocorticoid receptor-dependent anti-apolipoprotein A-1 IgG chronotropic effect on cardiomyocytes, Endocrinology 156 (12) (2015) 4707–4719. N. Vuilleumier, S. Pagano, C. Combescure, B. Gencer, J. Virzi, L. Raber, D. Carballo, et al., Non-linear relationship between anti-apolipoprotein A-1 IgGs and cardiovascular outcomes in patients with acute coronary syndromes, J. Clin. Med. 8 (2019), https://doi.org/10.3390/jcm8071002. D. Conen, M. Adam, F. Roche, J.C. Barthelemy, D. Felber Dietrich, M. Imboden, et al., Premature atrial contractions in the general population: frequency and risk factors, Circulation 126 (19) (2012) 2302–2308. J.M. Maixent, F. Paganelli, J. Scaglione, S. Levy, Antibodies against myosin in sera of patients with idiopathic paroxysmal atrial fibrillation, J. Cardiovasc. Electrophysiol. 9 (6) (1998) 612–617. A.T. Baba, Y. Yoshikawa, T. Fukuda, T. Sugiyama, M. Shimada, M. Akaishi, K. Tsuchimoto, et al., Autoantibodies against M2-muscarinic acetylcholine receptors: new upstream targets in atrial fibrillation in patients with dilated cardiomyopathy, Eur. Heart J. 25 (13) (2004) 1108–1115. K. Mandal, M. Jahangiri, M. Mukhin, J. Poloniecki, A.J. Camm, Q. Xu, Association of anti-heat shock protein 65 antibodies with development of postoperative atrial fibrillation, Circulation 110 (17) (2004) 2588–2590. J. Kornej, C. Reinhardt, J. Kosiuk, A. Arya, G. Hindricks, V. Adams, D. Husser, et al., Response of circulating heat shock protein 70 and anti-heat shock protein 70 antibodies to catheter ablation of atrial fibrillation, J. Transl. Med. 11 (2013) 49. S. Stavrakis, X. Yu, E. Patterson, S. Huang, S.R. Hamlett, L. Chalmers, R. Pappy, et al., Activating autoantibodies to the beta-1 adrenergic and m2 muscarinic receptors facilitate atrial fibrillation in patients with Graves' hyperthyroidism, J. Am. Coll. Cardiol. 54 (14) (2009) 1309–1316. D.A. Morrow, J.A. de Lemos, Benchmarks for the assessment of novel cardiovascular biomarkers, Circulation 115 (8) (2007) 949–952.