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Galectin-3 in atrial fibrillation: Simple bystander, player or both?
CLB-09018; No. of pages: 5; 4C: Clinical Biochemistry xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Clinical Biochemistry journal homepage: www.elsevier.com/locate/clinbiochem
Review
Galectin-3 in atrial fibrillation: Simple bystander, player or both? Giuseppe Lippi a,⁎, Gianfranco Cervellin b, Fabian Sanchis-Gomar c a b c
Laboratory of Clinical Chemistry and Hematology, Academic Hospital of Parma, Parma, Italy Emergency Department, Academic Hospital of Parma, Parma, Italy Research Institute of Hospital 12 de Octubre (“i + 12”), Madrid, Spain
a r t i c l e
i n f o
Article history: Received 18 March 2015 Received in revised form 27 April 2015 Accepted 28 April 2015 Available online xxxx Keywords: Atrial fibrillation Cardiac Fibrosis Heart Failure Galectin-3 Biomarkers
a b s t r a c t Objectives: Galectin-3 promotes fibrosis, and cardiac remodeling is a well-established cause of arrhythmias. Therefore, we reviewed current evidence on the epidemiological and biological association between galectin-3 and atrial fibrillation. Design and methods: We performed an electronic search on Medline, Scopus and Web of Science, using the keywords “galectin” OR “galectin-3” AND “atrial fibrillation” OR “arrhythmia(s)” in the fields “title/abstract/keywords”. Results: Seven cohort studies were identified and reviewed. A significant association between serum galectin-3 values and the risk of atrial fibrillation was found in 4 studies (1 nested case–control, 2 case– control, 1 prospective), whereas the association could not be confirmed in a single case–control investigation. Serum galectin-3 value was also found to be a significant predictor of left atrium fibrosis, reduced left atrial volume, or decreased left ventricle ejection fraction in four studies (2 nested case–control, 2 case–control). A reliable biological explanation may be brought in support of these findings. Activated macrophages release galectin-3, which not only contributes to increase macrophages accumulation in cardiac tissue and perpetuates their activation, but also promotes fibroblast activation and proliferation, thus leading to cardiac fibrosis, cardiac remodeling, myocardiocyte dysfunction and ultimately atrial fibrillation. The onset of atrial fibrillation further amplifies macrophage activation, thus completing a vicious circle that is mirrored by evidence of substantially increased galectin-3 values in patients with persistent atrial fibrillation. Conclusions: It seems reasonable to suggest that galectin-3 measurement holds promise for stratifying risk and outcome of atrial fibrillation. © 2015 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.
Contents Introduction . . . . . . . . . . . . . . . . . . . . Search methodology . . . . . . . . . . . . . . . . . Population cohort studies . . . . . . . . . . . . . . Biological evidence in support of epidemiological findings Conclusions . . . . . . . . . . . . . . . . . . . . . Conflict of interest statement . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . .
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Introduction Atrial fibrillation, the most frequent cardiac arrhythmia leading to serious clinical implications [1], is a worldwide health care problem ⁎ Corresponding author at: U.O. Diagnostica Ematochimica, Azienda Ospedaliero— Universitaria di Parma, Via Gramsci, 14, 43126 Parma, Italy. Fax.: +39 0521 703791. E-mail addresses: [email protected], [email protected] (G. Lippi).
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due to the constantly increasing prevalence and the associated morbidity and mortality [2,3]. The frequency of this condition substantially increases with aging [4]. In 1990, the estimated age-adjusted prevalence rates were 570 in men and 360 in women per 100,000 population, whereas the estimated age-adjusted incidence rates were 61 in men and 44 in women per 100,000 person-years, respectively [3]. In 2010, the estimated number of subjects with atrial fibrillation was 33.5 million around the globe, with prevalence rates increased to 596 and 373
http://dx.doi.org/10.1016/j.clinbiochem.2015.04.021 0009-9120/© 2015 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.
Please cite this article as: Lippi G, et al, Galectin-3 in atrial fibrillation: Simple bystander, player or both? Clin Biochem (2015), http://dx.doi.org/ 10.1016/j.clinbiochem.2015.04.021
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G. Lippi et al. / Clinical Biochemistry xxx (2015) xxx–xxx
per 100,000 population, and prevalence rate approximating 60 per 100,000 person-years in women and 78 per 100,000 person-years in men, respectively [3]. Patients with atrial fibrillation are at increased risk of severe complications, including dementia, heart failure, stroke and premature death [5], and thus generating a remarkable clinical and economic burden on the community and the health care systems [6]. Several risk factors for atrial fibrillation have been identified over the past decades, including advanced age, male gender, diabetes, hypertension, valvular disease, myocardial infarction, heart failure, obesity, elevated concentrations of inflammatory mediators or uric acid, as well as PR interval prolongation [7,8]. Additional subclinical risk factors have been associated with atrial fibrillation, such as pericardial fat, blood pressure in nonhypertensive range, left ventricular diastolic dysfunction, subclinical coronary artery disease, physical activity, chronic kidney disease, and environmental conditions (e.g., elevated air temperature, and humidity) [9,10]. As in other human disorders, the identification of biomarkers that may help predict the risk of atrial fibrillation and related complications is an appealing perspective, and it may also provide further insights into the pathophysiology of this disease for identifying novel targets for therapy [11,12]. Several lines of evidence convincingly suggest that the measurement of galectin-3 may be helpful in risk assessment of cardiac fibrosis and heart failure, both in the general population [13,14], as well as in patients with acute myocardial infarction [15]. Even more importantly, its measurement was proven to be cost-effective in patients with heart dysfunction, so that it might ultimately help the preservation of hospital budgets in a world with limited resources [16]. Since cardiac fibrosis and heart failure are well-established causes of arrhythmias [17,18], this article is aimed to review current evidence on the potential epidemiological and biological associations between galectin-3 and atrial fibrillation. Search methodology In order to identify population studies reporting data on galectin-3 values in patients with atrial fibrillation (or at risk of), we performed an electronic search on Medline (with PubMed interface), Scopus and Web of Science, using the keywords “galectin” OR “galectin-3” AND “atrial fibrillation” OR “arrhythmia(s)” in the fields “title/abstract/keywords”, with no language or date restriction. All articles detected with the search criteria were independently reviewed by two authors (G.L. and G.C.), and the references of these documents were also hand-searched to identify additional clinical studies on this association. Population cohort studies A total number of 14 publications could be identified after elimination of replicate documents throughout the three scientific databases. Seven items were excluded after accurate reading of title, abstract and full text (3 review articles, 3 studies with no specific data on galectin-3 in atrial fibrillation and 1 commentary). Overall, 7 population studies were selected for inclusion after our systematical literature search (3 case–control, 3 nested case–control and 1 prospective) [19–25]. Inter-rater agreement was 100% (kappa statistics, 1.00). The first study investigating the association between galectin-3 and atrial fibrillation was published by Szadkowska et al., in 2013 [19]. The authors studied 145 consecutive patients (41 women and 104 men; mean age, 62 ± 10 years) with a first acute myocardial infarction treated with percutaneous coronary angioplasty with stent implantation, who had a measurement of serum galectin-3 available 3 to 5 days after the onset of symptoms. The frequency of new-onset atrial fibrillation was found to be higher in patients with galectin-3 values in the highest than in the lowest quartile (19% versus 3%; p b 0.005). In univariate analysis, the odds ratio (OR) for atrial fibrillation in patients with a galectin-3 value N 16 ng/mL was 5.7 (95% CI,
1.27–25.5) compared to those with a serum concentration below such threshold. In the fully-adjusted multivariate analysis, baseline galectin-3 value was also found to be a significant predictor of inhospital new-onset atrial fibrillation (OR, 6.2; 95% CI, 1.1–36.0). A second case–control study was published by Sonmez et al. in 2014 [20], including 52 subjects with a diagnosis of non-valvular atrial fibrillation (34 women and 18 men; mean age, 70 ± 10 years) and 33 agematched controls (20 women and 13 men; mean age 70 ± 10 years) in sinus rhythm. The mean galectin-3 value was found to be significantly higher in atrial fibrillation cases than in controls (12.1 versus 11.7 ng/mL; p = 0.001). Interestingly, a significant correlation was also found between galectin-3 values and left atrial volume index (r = 640; p = 0.021). A large prospective investigation was published in the same year by Ho et al. [21], including 3306 participants of the Framingham Offspring cohort (1785 women and 1521 men; mean age, 58 years), who were followed up for a median period of 10 years. A total number of 250 new cases of atrial fibrillation were recorded during follow-up (atrial fibrillation incident rate, 7.6%). The entire population cohort was divided in quartiles of galectin-3 values, and a significantly higher risk of atrial fibrillation was found in parallel with increasing quartiles of this biomarker (p b 0.001 for trend). More specifically, the incidence of new-onset atrial fibrillation was 3.7% in the first quartile, 5.9% in the second, 9.1% in the third and 11.5% in the fourth, respectively. Each 1-standard deviation (SD) increase in galectin-3 values was then associated with a 19% increased risk of incident atrial fibrillation (hazard ratio [HR], 1.19; 95% CI, 1.05– 1.36). Nevertheless, the association between galectin-3 and atrial fibrillation was no longer statistically significant after adjustment for traditional risk factors for atrial fibrillation (HR, 1.12; 95% CI 0.98– 1.28; p = 0.10). Clementy et al. studied 187 patients with symptomatic atrial fibrillation (60 women and 127 men; mean age, 62 ± 10 years) [22]. The serum level of galectin-3 was found to be a significant predictor of reduced left ventricle ejection fraction in both univariate (OR, 5.12; 95% CI, 1.99–13.2) and multivariate (OR, 54.2; 95% CI, 1.27–100) analyses. A higher value of serum galectin-3 was also observed in patients with persistent atrial fibrillation than in those with paroxysmal atrial fibrillation (16.2 versus 13.1 ng/mL; p b 0.001). Interestingly, the serum value of galectin-3 was found to be positively associated with the CHA2DS2VaSC score (p b 0.001). Zakeri et al. performed a case–control study including 79 patients with atrial fibrillation (32 women and 47 men) and 124 subjects in sinus rhythm (67 women and 57 men; mean age, 66 ± 10 years) [23]. The values of serum galectin-3 were found to be higher but nonsignificantly different in patients with atrial fibrillation than in those without (14.3 versus 13.6 ng/mL; p = 0.15). Gurses et al. carried out a case–control study including 76 patients with paroxysmal or persistent atrial fibrillation and preserved left ventricular systolic function (40 women and 36 men; mean age, 59 ± 9 years), and 75 age- and gender-matched controls (40 women and 35 men; mean age, 58 ± 11 years) [24]. The serum values of galectin-3 were found to be higher in patients with atrial fibrillation than in those without (0.6 versus 0.5 ng/mL; p b 0.001). Although the average concentration of galectin-3 was found to be nearly 15 to 20fold lower than in previous studies (i.e., 0.8 versus 12–16 ng/mL), the serum value of this biomarker was found to be a significant predictor of atrial fibrillation in both univariate (OR, 177.9; 95% CI, 17.3– 1829.2) and in the fully-adjusted multivariate analysis (OR, 87.5; 95% CI, 6.1–1265.0). Galectin-3 was also found to be an independent predictor of left atrial volume index (beta coefficient, 0.031; p b 0.001). Interestingly, the concentration of galectin-3 was higher in patients with persistent atrial fibrillation compared to those with paroxysmal atrial fibrillation (0.8 versus 0.5 ng/mL; p b 0.001). More recently, Yalcin et al. performed a nested-case control study including 33 patients (16 women and 17 men; mean age, 58 years) with
Please cite this article as: Lippi G, et al, Galectin-3 in atrial fibrillation: Simple bystander, player or both? Clin Biochem (2015), http://dx.doi.org/ 10.1016/j.clinbiochem.2015.04.021
G. Lippi et al. / Clinical Biochemistry xxx (2015) xxx–xxx
paroxysmal atrial fibrillation who underwent delayed-enhancement magnetic resonance imaging prior to cryoballoon-based atrial fibrillation ablation [25]. A significant correlation was found between serum values of galectin-3 and extent of left atrium fibrosis in both univariate (r = 0.696; p b 0.001) and multivariate (beta coefficient, 0.55; p b 0.001) analyses. Galectin-3 values were also significantly correlated with both intra-left atrial electromechanical delay (r = 0.432; p = 0.012) and inter-atrial electromechanical delay (r = 0.395; p = 0.023). Taken together, the available epidemiological evidence seems to support the existence of an association between serum galectin-3 values and the risk of new-onset atrial fibrillation or its complications. This relationship was described in 4 studies (1 nested case–control, 2 case–control, 1 prospective) [19–21,24], whereas the association could not be confirmed in a single case–control investigation [23] (Table 1). Serum galectin-3 value was also found to be a significant predictor of several parameters of cardiac dysfunction (i.e., left atrium fibrosis, reduced left atrial volume, or decreased left ventricle ejection fraction) in all the four studies that investigated heart structure and function in patients with atrial fibrillation [20,22,24,25] (Table 1). Biological evidence in support of epidemiological findings Some biological explanations may be brought in support of the epidemiological findings linking galectin-3 with atrial fibrillation. Galectin-3 belongs to a family of β-galactoside-binding proteins, which are characterized by highly conserved sequences in specific carbohydrate-recognition domains [26]. An enhanced production and release of galectin-3 has been demonstrated in a number of inflammatory and fibrotic conditions including chronic pancreatitis, cirrhosis and lung fibrosis [17], as well as in patients with heart failure [13,14]. Convincing evidence also suggests that galectin-3 may not be a simple bystander, but also a key player in the pathogenesis of fibrosis. Sharma et al. first showed that galectin-3 is overexpressed by macrophages at an early stage of myocardium dysfunction, even before the onset of heart failure, and continuous infusion of recombinant galectin-3 in mice triggers cardiac fibroblast proliferation, collagen deposition, thus ultimately causing ventricular dysfunction [27]. MacKinnon et al. showed that galectin-3 not only is secreted by, but also mediates macrophage activation through both conventional and alternative pathways, thus generating a kind of a vicious circle culminating in overexpression of galectin-3 from these cells [28]. Lin et al. also showed that overexpression of galectin-3 in macrophage cell lines enhances the synthesis
3
of fibrosis-related factor in fibroblasts [29]. Liu et al. demonstrated that overexpression of galectin-3 in the heart tissue promotes macrophage and mast cell infiltration, but also enhances interstitial and perivascular fibrosis, thus finally triggering cardiac hypertrophy [30]. Most of these effects were found to be mediated by increased expression of tumor growth factor β (TGF-β) and enhanced activity of Smad3. The enhanced cardiac fibrosis, structural remodeling and the related myocardiocyte dysfunction which all recognize galectin-3 as an active player thus create an ideal substrate for the onset and persistence of arrhythmias, especially atrial fibrillation [17,18]. According to this biological evidence, it seems reasonable to assume that a number of conventional risk factors for atrial fibrillation (e.g., hypertension, coronary artery disease, valvular disease) [9] may be effective to promote the release of galectin-3 from macrophages [31], which in turn contributes to increase accumulation of inflammatory cells in cardiac tissue and perpetuates their activation, but also promotes fibroblast activation and proliferation, thus leading to cardiac fibrosis, cardiac remodeling, myocardiocyte dysfunction and ultimately predisposing to atrial fibrillation (Fig. 1). The onset of atrial fibrillation further amplifies macrophage activation, thus completing a vicious circle that is reliably mirrored by the observation that serum levels of galectin-3 are higher in patients with persistent than with paroxysmal atrial fibrillation [22,24]. In support of this hypothesis, several studies showed that inhibition of synthesis or activity of galectin-3 may be regarded as therapeutic options to decrease fibrosis and progression toward cardiac remodeling and heart failure. More specifically, Liu et al. showed that inhibition of the TGF-β/Smad3 signaling pathway by means of N-acetyl-seryl-aspartyl-lysyl-proline was effective to neutralize the profibrotic effect of galectin-3 [30]. In another study, Calvier et al. demonstrated that overexpression of galectin-3 promotes an increased synthesis of type I collagen, whereas its inhibition is associated with an opposite effect [32]. Yu et al. also showed that inhibition of galectin-3 was effective to reduce production, processing, cleavage, cross-linking and deposition of collagen, thus limiting or even reversing the occurrence of cardiac remodeling [33]. In line with these findings, Lax et al. showed that inhibition of galectin-3 signaling was effective to decrease fibrosis and inflammatory biomarkers in myocardium [34]. Conclusions According to the available biological and epidemiological evidence, it seems reasonable that the measurement of galectin-3 may be
Table 1 Description of population cohort studies which measured galectin-3 in patients with (or a risk of) atrial fibrillation. Authors
Study design
Study population
Szadkowska et al. 2013
Nested case–control
Sonmez et al. 2014
Case–control
Incident atrial fibrillation 145 patients with a first acute myocardial infarction undergoing percutaneous coronary angioplasty 52 patients with atrial fibrillation and Presence of atrial 33 matched controls in sinus rhythm fibrillation
Ho et al. 2014
Prospective
3306 subjects followed up for 10 years
Endpoint
Incident atrial fibrillation (incidence rate, 7.6%)
Clementy et al. 2014
Nested case–control
187 patients with atrial fibrillation
Presence of reduced left ventricle ejection fraction
Zakeri et al. 2014
Case–control
Gurses et al. 2015
Case–control
79 patients with atrial fibrillation and 124 controls in sinus rhythm 76 patients with atrial fibrillation and 75 matched controls in sinus rhythm
Presence of atrial fibrillation Presence of atrial fibrillation
Yalcin et al. 2015
Nested case–control
33 patients with atrial fibrillation undergoing delayed-enhancement magnetic resonance imaging
Presence of left atrium fibrosis
Results
Reference
Galectin-3 significant predictor of atrial fibrillation
[19]
Galectin-3 values higher in cases than in controls; Galectin-3 significantly correlated with reduced left atrial volume in univariate analysis Galectin-3 significant predictor of atrial fibrillation in univariate but not in multivariate analysis Galectin-3 significant predictor of reduced left ventricle ejection fraction in univariate and multivariate analysis Galectin-3 values similar in cases and in controls Galectin-3 significant predictor of atrial fibrillation in univariate and multivariate analysis; Galectin-3 significantly correlated with reduced left atrial volume in multivariate analysis Galectin-3 significant predictor of left atrium fibrosis in univariate and multivariate analysis
[20]
[21]
[22]
[23] [24]
[25]
Please cite this article as: Lippi G, et al, Galectin-3 in atrial fibrillation: Simple bystander, player or both? Clin Biochem (2015), http://dx.doi.org/ 10.1016/j.clinbiochem.2015.04.021
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Risk factors for atrial fibrillation MACROPHAGE Infiltration Activation
Activation
Gal-3
Activation Proliferation
Activation
FIBROBLAST
Collagen deposition Cardiac fibrosis/Myocardocyte dysfunction
ATRIAL FIBRILLATION Fig. 1. Galectin-3 (Gal-3) in atrial fibrillation. Potential pathogenetic mechanisms.
regarded as a promising tool to assist risk stratification and outcome prediction of atrial fibrillation. At variance with other biomarkers of heart dysfunction such as soluble ST2 [35], galectin-3 can be measured with fully-automated immunoassays, which are characterized by satisfactory analytical performance, higher throughput and reduced turnaround time [36,37]. Another important advantage is the fact that the concentration of this biomarker in the general population seems to be not significantly influenced by age and gender, as well as by the presence of diabetes and renal or liver dysfunction [38]. Interestingly, the association between galectin-3 and atrial fibrillation appeared to be no longer significant after adjustment for traditional risk factors for atrial fibrillation in one large prospective trial [21]. One possible explanation is that both galectin-3 levels and atrial fibrillation are associated with impaired cardiac structure and function, but without a direct causal link. This finding leads the way to further studies for establishing the pathogenetic role of this biomarker in the setting of atrial fibrillation, and elucidating whether galectin-3 may be considered a simple biomarker of underlying fibrosis or even a player and a potential biological target of adverse cardiovascular outcomes.
[5]
[6]
[7]
[8]
[9] [10]
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[13]
Conflict of interest statement
[14]
All authors do not have any potential conflicts of interest, and all authors have read the journal's policy on conflicts of interest. Moreover, all authors have read the journal's authorship agreement.
[15]
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Please cite this article as: Lippi G, et al, Galectin-3 in atrial fibrillation: Simple bystander, player or both? Clin Biochem (2015), http://dx.doi.org/ 10.1016/j.clinbiochem.2015.04.021
Contents lists available at ScienceDirect
Clinical Biochemistry journal homepage: www.elsevier.com/locate/clinbiochem
Review
Galectin-3 in atrial fibrillation: Simple bystander, player or both? Giuseppe Lippi a,⁎, Gianfranco Cervellin b, Fabian Sanchis-Gomar c a b c
Laboratory of Clinical Chemistry and Hematology, Academic Hospital of Parma, Parma, Italy Emergency Department, Academic Hospital of Parma, Parma, Italy Research Institute of Hospital 12 de Octubre (“i + 12”), Madrid, Spain
a r t i c l e
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Article history: Received 18 March 2015 Received in revised form 27 April 2015 Accepted 28 April 2015 Available online xxxx Keywords: Atrial fibrillation Cardiac Fibrosis Heart Failure Galectin-3 Biomarkers
a b s t r a c t Objectives: Galectin-3 promotes fibrosis, and cardiac remodeling is a well-established cause of arrhythmias. Therefore, we reviewed current evidence on the epidemiological and biological association between galectin-3 and atrial fibrillation. Design and methods: We performed an electronic search on Medline, Scopus and Web of Science, using the keywords “galectin” OR “galectin-3” AND “atrial fibrillation” OR “arrhythmia(s)” in the fields “title/abstract/keywords”. Results: Seven cohort studies were identified and reviewed. A significant association between serum galectin-3 values and the risk of atrial fibrillation was found in 4 studies (1 nested case–control, 2 case– control, 1 prospective), whereas the association could not be confirmed in a single case–control investigation. Serum galectin-3 value was also found to be a significant predictor of left atrium fibrosis, reduced left atrial volume, or decreased left ventricle ejection fraction in four studies (2 nested case–control, 2 case–control). A reliable biological explanation may be brought in support of these findings. Activated macrophages release galectin-3, which not only contributes to increase macrophages accumulation in cardiac tissue and perpetuates their activation, but also promotes fibroblast activation and proliferation, thus leading to cardiac fibrosis, cardiac remodeling, myocardiocyte dysfunction and ultimately atrial fibrillation. The onset of atrial fibrillation further amplifies macrophage activation, thus completing a vicious circle that is mirrored by evidence of substantially increased galectin-3 values in patients with persistent atrial fibrillation. Conclusions: It seems reasonable to suggest that galectin-3 measurement holds promise for stratifying risk and outcome of atrial fibrillation. © 2015 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.
Contents Introduction . . . . . . . . . . . . . . . . . . . . Search methodology . . . . . . . . . . . . . . . . . Population cohort studies . . . . . . . . . . . . . . Biological evidence in support of epidemiological findings Conclusions . . . . . . . . . . . . . . . . . . . . . Conflict of interest statement . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . .
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Introduction Atrial fibrillation, the most frequent cardiac arrhythmia leading to serious clinical implications [1], is a worldwide health care problem ⁎ Corresponding author at: U.O. Diagnostica Ematochimica, Azienda Ospedaliero— Universitaria di Parma, Via Gramsci, 14, 43126 Parma, Italy. Fax.: +39 0521 703791. E-mail addresses: [email protected], [email protected] (G. Lippi).
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due to the constantly increasing prevalence and the associated morbidity and mortality [2,3]. The frequency of this condition substantially increases with aging [4]. In 1990, the estimated age-adjusted prevalence rates were 570 in men and 360 in women per 100,000 population, whereas the estimated age-adjusted incidence rates were 61 in men and 44 in women per 100,000 person-years, respectively [3]. In 2010, the estimated number of subjects with atrial fibrillation was 33.5 million around the globe, with prevalence rates increased to 596 and 373
http://dx.doi.org/10.1016/j.clinbiochem.2015.04.021 0009-9120/© 2015 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.
Please cite this article as: Lippi G, et al, Galectin-3 in atrial fibrillation: Simple bystander, player or both? Clin Biochem (2015), http://dx.doi.org/ 10.1016/j.clinbiochem.2015.04.021
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per 100,000 population, and prevalence rate approximating 60 per 100,000 person-years in women and 78 per 100,000 person-years in men, respectively [3]. Patients with atrial fibrillation are at increased risk of severe complications, including dementia, heart failure, stroke and premature death [5], and thus generating a remarkable clinical and economic burden on the community and the health care systems [6]. Several risk factors for atrial fibrillation have been identified over the past decades, including advanced age, male gender, diabetes, hypertension, valvular disease, myocardial infarction, heart failure, obesity, elevated concentrations of inflammatory mediators or uric acid, as well as PR interval prolongation [7,8]. Additional subclinical risk factors have been associated with atrial fibrillation, such as pericardial fat, blood pressure in nonhypertensive range, left ventricular diastolic dysfunction, subclinical coronary artery disease, physical activity, chronic kidney disease, and environmental conditions (e.g., elevated air temperature, and humidity) [9,10]. As in other human disorders, the identification of biomarkers that may help predict the risk of atrial fibrillation and related complications is an appealing perspective, and it may also provide further insights into the pathophysiology of this disease for identifying novel targets for therapy [11,12]. Several lines of evidence convincingly suggest that the measurement of galectin-3 may be helpful in risk assessment of cardiac fibrosis and heart failure, both in the general population [13,14], as well as in patients with acute myocardial infarction [15]. Even more importantly, its measurement was proven to be cost-effective in patients with heart dysfunction, so that it might ultimately help the preservation of hospital budgets in a world with limited resources [16]. Since cardiac fibrosis and heart failure are well-established causes of arrhythmias [17,18], this article is aimed to review current evidence on the potential epidemiological and biological associations between galectin-3 and atrial fibrillation. Search methodology In order to identify population studies reporting data on galectin-3 values in patients with atrial fibrillation (or at risk of), we performed an electronic search on Medline (with PubMed interface), Scopus and Web of Science, using the keywords “galectin” OR “galectin-3” AND “atrial fibrillation” OR “arrhythmia(s)” in the fields “title/abstract/keywords”, with no language or date restriction. All articles detected with the search criteria were independently reviewed by two authors (G.L. and G.C.), and the references of these documents were also hand-searched to identify additional clinical studies on this association. Population cohort studies A total number of 14 publications could be identified after elimination of replicate documents throughout the three scientific databases. Seven items were excluded after accurate reading of title, abstract and full text (3 review articles, 3 studies with no specific data on galectin-3 in atrial fibrillation and 1 commentary). Overall, 7 population studies were selected for inclusion after our systematical literature search (3 case–control, 3 nested case–control and 1 prospective) [19–25]. Inter-rater agreement was 100% (kappa statistics, 1.00). The first study investigating the association between galectin-3 and atrial fibrillation was published by Szadkowska et al., in 2013 [19]. The authors studied 145 consecutive patients (41 women and 104 men; mean age, 62 ± 10 years) with a first acute myocardial infarction treated with percutaneous coronary angioplasty with stent implantation, who had a measurement of serum galectin-3 available 3 to 5 days after the onset of symptoms. The frequency of new-onset atrial fibrillation was found to be higher in patients with galectin-3 values in the highest than in the lowest quartile (19% versus 3%; p b 0.005). In univariate analysis, the odds ratio (OR) for atrial fibrillation in patients with a galectin-3 value N 16 ng/mL was 5.7 (95% CI,
1.27–25.5) compared to those with a serum concentration below such threshold. In the fully-adjusted multivariate analysis, baseline galectin-3 value was also found to be a significant predictor of inhospital new-onset atrial fibrillation (OR, 6.2; 95% CI, 1.1–36.0). A second case–control study was published by Sonmez et al. in 2014 [20], including 52 subjects with a diagnosis of non-valvular atrial fibrillation (34 women and 18 men; mean age, 70 ± 10 years) and 33 agematched controls (20 women and 13 men; mean age 70 ± 10 years) in sinus rhythm. The mean galectin-3 value was found to be significantly higher in atrial fibrillation cases than in controls (12.1 versus 11.7 ng/mL; p = 0.001). Interestingly, a significant correlation was also found between galectin-3 values and left atrial volume index (r = 640; p = 0.021). A large prospective investigation was published in the same year by Ho et al. [21], including 3306 participants of the Framingham Offspring cohort (1785 women and 1521 men; mean age, 58 years), who were followed up for a median period of 10 years. A total number of 250 new cases of atrial fibrillation were recorded during follow-up (atrial fibrillation incident rate, 7.6%). The entire population cohort was divided in quartiles of galectin-3 values, and a significantly higher risk of atrial fibrillation was found in parallel with increasing quartiles of this biomarker (p b 0.001 for trend). More specifically, the incidence of new-onset atrial fibrillation was 3.7% in the first quartile, 5.9% in the second, 9.1% in the third and 11.5% in the fourth, respectively. Each 1-standard deviation (SD) increase in galectin-3 values was then associated with a 19% increased risk of incident atrial fibrillation (hazard ratio [HR], 1.19; 95% CI, 1.05– 1.36). Nevertheless, the association between galectin-3 and atrial fibrillation was no longer statistically significant after adjustment for traditional risk factors for atrial fibrillation (HR, 1.12; 95% CI 0.98– 1.28; p = 0.10). Clementy et al. studied 187 patients with symptomatic atrial fibrillation (60 women and 127 men; mean age, 62 ± 10 years) [22]. The serum level of galectin-3 was found to be a significant predictor of reduced left ventricle ejection fraction in both univariate (OR, 5.12; 95% CI, 1.99–13.2) and multivariate (OR, 54.2; 95% CI, 1.27–100) analyses. A higher value of serum galectin-3 was also observed in patients with persistent atrial fibrillation than in those with paroxysmal atrial fibrillation (16.2 versus 13.1 ng/mL; p b 0.001). Interestingly, the serum value of galectin-3 was found to be positively associated with the CHA2DS2VaSC score (p b 0.001). Zakeri et al. performed a case–control study including 79 patients with atrial fibrillation (32 women and 47 men) and 124 subjects in sinus rhythm (67 women and 57 men; mean age, 66 ± 10 years) [23]. The values of serum galectin-3 were found to be higher but nonsignificantly different in patients with atrial fibrillation than in those without (14.3 versus 13.6 ng/mL; p = 0.15). Gurses et al. carried out a case–control study including 76 patients with paroxysmal or persistent atrial fibrillation and preserved left ventricular systolic function (40 women and 36 men; mean age, 59 ± 9 years), and 75 age- and gender-matched controls (40 women and 35 men; mean age, 58 ± 11 years) [24]. The serum values of galectin-3 were found to be higher in patients with atrial fibrillation than in those without (0.6 versus 0.5 ng/mL; p b 0.001). Although the average concentration of galectin-3 was found to be nearly 15 to 20fold lower than in previous studies (i.e., 0.8 versus 12–16 ng/mL), the serum value of this biomarker was found to be a significant predictor of atrial fibrillation in both univariate (OR, 177.9; 95% CI, 17.3– 1829.2) and in the fully-adjusted multivariate analysis (OR, 87.5; 95% CI, 6.1–1265.0). Galectin-3 was also found to be an independent predictor of left atrial volume index (beta coefficient, 0.031; p b 0.001). Interestingly, the concentration of galectin-3 was higher in patients with persistent atrial fibrillation compared to those with paroxysmal atrial fibrillation (0.8 versus 0.5 ng/mL; p b 0.001). More recently, Yalcin et al. performed a nested-case control study including 33 patients (16 women and 17 men; mean age, 58 years) with
Please cite this article as: Lippi G, et al, Galectin-3 in atrial fibrillation: Simple bystander, player or both? Clin Biochem (2015), http://dx.doi.org/ 10.1016/j.clinbiochem.2015.04.021
G. Lippi et al. / Clinical Biochemistry xxx (2015) xxx–xxx
paroxysmal atrial fibrillation who underwent delayed-enhancement magnetic resonance imaging prior to cryoballoon-based atrial fibrillation ablation [25]. A significant correlation was found between serum values of galectin-3 and extent of left atrium fibrosis in both univariate (r = 0.696; p b 0.001) and multivariate (beta coefficient, 0.55; p b 0.001) analyses. Galectin-3 values were also significantly correlated with both intra-left atrial electromechanical delay (r = 0.432; p = 0.012) and inter-atrial electromechanical delay (r = 0.395; p = 0.023). Taken together, the available epidemiological evidence seems to support the existence of an association between serum galectin-3 values and the risk of new-onset atrial fibrillation or its complications. This relationship was described in 4 studies (1 nested case–control, 2 case–control, 1 prospective) [19–21,24], whereas the association could not be confirmed in a single case–control investigation [23] (Table 1). Serum galectin-3 value was also found to be a significant predictor of several parameters of cardiac dysfunction (i.e., left atrium fibrosis, reduced left atrial volume, or decreased left ventricle ejection fraction) in all the four studies that investigated heart structure and function in patients with atrial fibrillation [20,22,24,25] (Table 1). Biological evidence in support of epidemiological findings Some biological explanations may be brought in support of the epidemiological findings linking galectin-3 with atrial fibrillation. Galectin-3 belongs to a family of β-galactoside-binding proteins, which are characterized by highly conserved sequences in specific carbohydrate-recognition domains [26]. An enhanced production and release of galectin-3 has been demonstrated in a number of inflammatory and fibrotic conditions including chronic pancreatitis, cirrhosis and lung fibrosis [17], as well as in patients with heart failure [13,14]. Convincing evidence also suggests that galectin-3 may not be a simple bystander, but also a key player in the pathogenesis of fibrosis. Sharma et al. first showed that galectin-3 is overexpressed by macrophages at an early stage of myocardium dysfunction, even before the onset of heart failure, and continuous infusion of recombinant galectin-3 in mice triggers cardiac fibroblast proliferation, collagen deposition, thus ultimately causing ventricular dysfunction [27]. MacKinnon et al. showed that galectin-3 not only is secreted by, but also mediates macrophage activation through both conventional and alternative pathways, thus generating a kind of a vicious circle culminating in overexpression of galectin-3 from these cells [28]. Lin et al. also showed that overexpression of galectin-3 in macrophage cell lines enhances the synthesis
3
of fibrosis-related factor in fibroblasts [29]. Liu et al. demonstrated that overexpression of galectin-3 in the heart tissue promotes macrophage and mast cell infiltration, but also enhances interstitial and perivascular fibrosis, thus finally triggering cardiac hypertrophy [30]. Most of these effects were found to be mediated by increased expression of tumor growth factor β (TGF-β) and enhanced activity of Smad3. The enhanced cardiac fibrosis, structural remodeling and the related myocardiocyte dysfunction which all recognize galectin-3 as an active player thus create an ideal substrate for the onset and persistence of arrhythmias, especially atrial fibrillation [17,18]. According to this biological evidence, it seems reasonable to assume that a number of conventional risk factors for atrial fibrillation (e.g., hypertension, coronary artery disease, valvular disease) [9] may be effective to promote the release of galectin-3 from macrophages [31], which in turn contributes to increase accumulation of inflammatory cells in cardiac tissue and perpetuates their activation, but also promotes fibroblast activation and proliferation, thus leading to cardiac fibrosis, cardiac remodeling, myocardiocyte dysfunction and ultimately predisposing to atrial fibrillation (Fig. 1). The onset of atrial fibrillation further amplifies macrophage activation, thus completing a vicious circle that is reliably mirrored by the observation that serum levels of galectin-3 are higher in patients with persistent than with paroxysmal atrial fibrillation [22,24]. In support of this hypothesis, several studies showed that inhibition of synthesis or activity of galectin-3 may be regarded as therapeutic options to decrease fibrosis and progression toward cardiac remodeling and heart failure. More specifically, Liu et al. showed that inhibition of the TGF-β/Smad3 signaling pathway by means of N-acetyl-seryl-aspartyl-lysyl-proline was effective to neutralize the profibrotic effect of galectin-3 [30]. In another study, Calvier et al. demonstrated that overexpression of galectin-3 promotes an increased synthesis of type I collagen, whereas its inhibition is associated with an opposite effect [32]. Yu et al. also showed that inhibition of galectin-3 was effective to reduce production, processing, cleavage, cross-linking and deposition of collagen, thus limiting or even reversing the occurrence of cardiac remodeling [33]. In line with these findings, Lax et al. showed that inhibition of galectin-3 signaling was effective to decrease fibrosis and inflammatory biomarkers in myocardium [34]. Conclusions According to the available biological and epidemiological evidence, it seems reasonable that the measurement of galectin-3 may be
Table 1 Description of population cohort studies which measured galectin-3 in patients with (or a risk of) atrial fibrillation. Authors
Study design
Study population
Szadkowska et al. 2013
Nested case–control
Sonmez et al. 2014
Case–control
Incident atrial fibrillation 145 patients with a first acute myocardial infarction undergoing percutaneous coronary angioplasty 52 patients with atrial fibrillation and Presence of atrial 33 matched controls in sinus rhythm fibrillation
Ho et al. 2014
Prospective
3306 subjects followed up for 10 years
Endpoint
Incident atrial fibrillation (incidence rate, 7.6%)
Clementy et al. 2014
Nested case–control
187 patients with atrial fibrillation
Presence of reduced left ventricle ejection fraction
Zakeri et al. 2014
Case–control
Gurses et al. 2015
Case–control
79 patients with atrial fibrillation and 124 controls in sinus rhythm 76 patients with atrial fibrillation and 75 matched controls in sinus rhythm
Presence of atrial fibrillation Presence of atrial fibrillation
Yalcin et al. 2015
Nested case–control
33 patients with atrial fibrillation undergoing delayed-enhancement magnetic resonance imaging
Presence of left atrium fibrosis
Results
Reference
Galectin-3 significant predictor of atrial fibrillation
[19]
Galectin-3 values higher in cases than in controls; Galectin-3 significantly correlated with reduced left atrial volume in univariate analysis Galectin-3 significant predictor of atrial fibrillation in univariate but not in multivariate analysis Galectin-3 significant predictor of reduced left ventricle ejection fraction in univariate and multivariate analysis Galectin-3 values similar in cases and in controls Galectin-3 significant predictor of atrial fibrillation in univariate and multivariate analysis; Galectin-3 significantly correlated with reduced left atrial volume in multivariate analysis Galectin-3 significant predictor of left atrium fibrosis in univariate and multivariate analysis
[20]
[21]
[22]
[23] [24]
[25]
Please cite this article as: Lippi G, et al, Galectin-3 in atrial fibrillation: Simple bystander, player or both? Clin Biochem (2015), http://dx.doi.org/ 10.1016/j.clinbiochem.2015.04.021
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Risk factors for atrial fibrillation MACROPHAGE Infiltration Activation
Activation
Gal-3
Activation Proliferation
Activation
FIBROBLAST
Collagen deposition Cardiac fibrosis/Myocardocyte dysfunction
ATRIAL FIBRILLATION Fig. 1. Galectin-3 (Gal-3) in atrial fibrillation. Potential pathogenetic mechanisms.
regarded as a promising tool to assist risk stratification and outcome prediction of atrial fibrillation. At variance with other biomarkers of heart dysfunction such as soluble ST2 [35], galectin-3 can be measured with fully-automated immunoassays, which are characterized by satisfactory analytical performance, higher throughput and reduced turnaround time [36,37]. Another important advantage is the fact that the concentration of this biomarker in the general population seems to be not significantly influenced by age and gender, as well as by the presence of diabetes and renal or liver dysfunction [38]. Interestingly, the association between galectin-3 and atrial fibrillation appeared to be no longer significant after adjustment for traditional risk factors for atrial fibrillation in one large prospective trial [21]. One possible explanation is that both galectin-3 levels and atrial fibrillation are associated with impaired cardiac structure and function, but without a direct causal link. This finding leads the way to further studies for establishing the pathogenetic role of this biomarker in the setting of atrial fibrillation, and elucidating whether galectin-3 may be considered a simple biomarker of underlying fibrosis or even a player and a potential biological target of adverse cardiovascular outcomes.
[5]
[6]
[7]
[8]
[9] [10]
[11] [12]
[13]
Conflict of interest statement
[14]
All authors do not have any potential conflicts of interest, and all authors have read the journal's policy on conflicts of interest. Moreover, all authors have read the journal's authorship agreement.
[15]
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Please cite this article as: Lippi G, et al, Galectin-3 in atrial fibrillation: Simple bystander, player or both? Clin Biochem (2015), http://dx.doi.org/ 10.1016/j.clinbiochem.2015.04.021