Europace Advance Access originally published online on May 7, 2007
Europace 2007 9(8):589-596; doi:10.1093/europace/eum072
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BASIC SCIENCE
Circulating levels of collagen type I degradation marker depend on the type of atrial fibrillation
1 University Cardiology Department, Democritus University of Thrace, Voulgaroktonou 23, 68100 Alexandroupolis, Evros, Greece; 2 Second University Internal Medicine Department, Democritus University of Thrace, Alexandroupolis, Evros, Greece
Manuscript submitted 18 September 2006. Accepted after revision 21 March 2007.
* Corresponding author. Tel: +30 25510 35596; fax: +30 25510 35596. E-mail address: dtziakas{at}med.duth.gr
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Abstract |
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Aims To investigate the hypothesis that circulating levels of collagen type I degradation or synthesis markers are associated with the presence and pattern of atrial fibrillation (AF).
Methods and results We assessed the serum concentrations of amino-terminal propeptide of procollagen type I (PINP) and of carboxy-terminal telopeptide of collagen type I (CITP), indexes of collagen type I synthesis and degradation, respectively, in 98 paroxysmal AF (PAF) patients (65 ± 14 years, 62 men), in 80 persistent AF (PsAF) patients (73 ± 8 years, 32 men), in 114 permanent AF (PmAF) patients (73 ± 10 years, 54 men), and in 180 patients in sinus rhythm (SR) (66 ± 13 years, 88 men) who represented a control group. Serum CITP levels were higher (P < 0.001) in AF patients [0.41 ng/mL, 95% confidence interval (CI) 0.38–0.44] when compared with SR patients (0.29 ng/mL, 95% CI 0.26–0.33) and were significantly different between the three AF pattern groups (P < 0.001). Patients with PAF (0.31 ng/mL, 95% CI 0.26–0.36) had lower CITP levels when compared with patients with PsAF (0.41 ng/mL, 95% CI 0.34–0.47) (P = 0.006), as well as with PmAF patients (0.49 ng/mL 95% CI, 0.43–0.56) (P < 0.001). Levels of CITP tended to be lower (P = 0.219) in PsAF patients when compared with sustained AF patients. No differences were found in PINP levels between AF and SR study groups (P = 0.637) as well as between the three AF pattern groups (P = 0.301).
Conclusion In the clinical setting, circulating levels of collagen type I degradation marker are associated with both type and duration of AF. Further studies are needed to evaluate the clinical use of serum concentrations of CITP as a potential diagnostic, prognostic, and therapeutic target in patients with AF.
Key Words: Atrial fibrillation, Collagen metabolism, Classification, Duration
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Introduction |
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Atrial fibrillation (AF) is characterized by a rapid and irregular activation of the atrium, and in most cases, there is a progression from paroxysmal to sustained AF.1
,2 Cardiac fibrosis is an excessive deposition of extracellular matrix (ECM) and can occur as a result of the action of profibrotic growth factors, of mechanical overload, or of a combination of both.3 Collagens are the major ECM proteins in the heart. Of the collagen isoforms, collagen type I accounts for 80% of the cardiac interstitium.4,5 Collagen type III is also relatively abundant in the myocardium, with an approximate content of 10%.4,5 Atrial dilatation and fibrosis are probably important factors in the occurrence and maintenance of AF.6,7 Recent histopathological studies have demonstrated that AF is associated with atrial fibrosis, that changes in the ECM components in atrium are associated with the development of sustained AF, and that total atrium collagen is correlated with the duration of AF.8–12 Therefore, we assessed the hypothesis that circulating levels of collagen type I degradation or synthesis markers are associated with the presence and pattern of AF, i.e patients with paroxysmal (PAF), persistent (PsAF), and permanent AF (PmAF). |
Methods |
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Patients
We recruited 292 consecutive AF patients who were attending the Atrial Fibrillation Outpatients Clinic of our Cardiology Department. The AF status was documented on a previous or current 12-lead electrocardiogram. A patient's pattern of AF (paroxysmal, persistent, or permanent) was determined on the episodes of AF within the past 12 months as follows: (i) PAF was defined as a history of one or more episodes of medically or self-terminated AF with a duration of <7 days,13
,14 (ii) patients with a history of one or more episodes of AF with a duration of 
7 days who underwent electrical or pharmacological cardioversion to establish normal sinus rhythm (SR) were defined as PsAF,13,14 and (iii) patients with AF with a duration of 30 days and in whom restoring SR was either impossible or not deemed appropriate were defined as PmAF.13,14 In addition, we assessed 180 patients with electrocardiographically documented SR and no previous documentation of AF, who were considered to represent a control group and were matched to the AF group according to the presence of coronary artery disease, heart failure, valvular disease, and hypertension. The present study did not include patients with AF because of transient or reversible causes, i.e. post-operative from cardiothoracic or non-cardiothoracic surgery, febrile, pericardial, lung, or thyroid disease. Patients with AF in the setting of acute coronary syndromes, pre-excitation syndrome, sick sinus syndrome, excessive alcohol intake, prosthetic heart valves, hypertrophic obstructive cardiomyopathy, aortic stenosis, or those with autoimmune, neoplastic, liver, hematological, or renal diseases were also excluded from the study. The study was approved by the Hospital's Ethics Committee and all patients gave written informed consent prior to study entry.
Laboratory analysis
In every patient, peripheral blood samples were obtained during a visit at the Atrial Fibrillation Outpatients Clinic. After centrifugation at 4000 rpm for 10 min, serum samples were frozen and stored at –70°C until assessment. Electrochemiluminescence method was performed to measure serum concentrations of amino-terminal propeptide of procollagen type I (PINP) and of carboxy-terminal telopeptide of collagen type I (CITP), indexes of collagen type I synthesis and degradation, respectively. We used ‘Roche Diagnostics, Basel, Switzerland’ commercially available immunoassay to measure serum PINP on ‘Elecsys 1010’ immunoassay analyser, with a minimum detectable concentration of <5 ng/mL. The intra-assay precision and inter-assay precision of the method were 2.9 and 3.7%, respectively. We used ‘Roche Diagnostics’, commercially available immunoassay to measure serum CITP on Elecsys 1010 immunoassay analyser, with a minimum detectable concentration of <0.01 ng/mL. The intra-assay precision and inter-assay precision of the method were 4.6 and 4.7%, respectively.
Statistical analysis
Results are presented as means with 95% confidence intervals (CIs) for continuous variables and as percentages for categorical data. Normality was tested using the Kolmogorov–Smirnov test. Carboxy-terminal telopeptide of collagen type I and PINP levels and left atrial size were not normally distributed and were therefore logarithmically transformed as required to approach normal distribution and to obtain equal variances. The two-tailed unpaired Student's t-test was used to evaluate differences in continuous variables between AF and SR groups. One-way analysis of variance (ANOVA) with a subsequent post hoc Tukey honestly significant difference (HSD) test was used to evaluate differences in continuous variables between the three AF subgroups, whereas comparisons between categorical variables were performed by 
2 test or Fisher's exact test when required. Analysis of covariance (ANCOVA) was used to evaluate differences in PINP and CITP levels between AF and SR groups and also between the three AF subgroups, independently (i) of variables that were shown to be significantly different on univariate analyses between the under-evaluation groups (Model 1); (ii) of variables that were shown to significantly affect collagen degradation or synthesis marker levels on multiple regression analysis. Variable selection was performed by using the backward deletion method, in which all variables that could influence collagen degradation or synthesis levels were entered in the analysis in a single step and then removed, one at a time to keep only the statistically significant ones (Model 2); (iii) of medications that evidence in the current literature suggests influence collagen metabolism (Model 3); and (iv) of the confounding effect of different AF causes (Model 4). Correlation analysis between variables of the study was carried out using Pearson's correlation coefficient r. A value of P < 0.05 was considered statistically significant.
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Results |
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Influence of atrial fibrillation on circulating markers of collagen metabolism
Baseline characteristics of patients with SR and AF are presented in Table 1. Patients in the SR group were younger and with smaller left atrial sizes compared to those in the AF group. A higher proportion of SR patients had diabetes and hyperlipidaemia. Established risk factors for AF were similar in the two groups (coronary artery disease, heart failure, valvular disease, and hypertension). The medications taken by both groups at study entry were similar with the exception of digitalis, calcium channel blockers, amiodarone, and anticoagulant (acenocoumarol), which, as expected, were significantly more common in the AF group and ß-blockers, statins, ACE inhibitors, and diuretics which were more common among SR patients.
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Serum CITP levels were significantly higher (P < 0.001) in the AF group (0.41 ng/mL 95% CI, 0.38–0.44), compared with the SR group (0.29 ng/mL, 95% CI 0.26–0.33) (Figure 1). Analysis of covariance showed that circulating levels of CITP remained significantly different between the AF and SR groups after adjustment for all the variables that could influence collagen type I degradation marker levels (Table 2). In contrast, we did not find differences in circulating levels of PINP (P = 0.637) between AF (41.3 ng/mL, 95% CI 38.6–44.1) and SR (42.4 ng/mL, 95% CI 38.5–46.3) patients.
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Influence of different atrial fibrillation patterns on circulating markers of collagen metabolism
Table 3 summarizes the baseline characteristics of the three AF subgroups. Serum concentrations of CITP were significantly different between the three groups (P < 0.001). In specific, circulating levels of collagen type I degradation marker were lower in patients with PAF (0.31 ng/mL, 95% CI 0.26–0.36) when compared with those with PsAF (0.41 ng/mL, 95% CI 0.34–0.47) (P = 0.006), as well as those with PmAF (0.49 ng/mL, 95% CI 0.43–0.56) (P < 0.001) (Figure 2). Levels of CITP tended to be lower in PsAF patients when compared with sustained AF patients, without reaching statistical significance (P = 0.219). Analysis of covariance showed that serum concentrations of CITP remained significantly different between the three AF subgroups after adjustment for all the variables that could influence collagen type I degradation marker levels (Table 4). In contrast, we did not find differences in circulating levels of PINP (P = 0.301) between the three different AF pattern groups.
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To investigate further the influence of AF duration on serum concentrations of collagen metabolism markers, we performed pair-wise comparisons (two-tailed unpaired t-tests) between SR group and the three different AF subgroups. Carboxy-terminal telopeptide of collagen type I levels were significantly lower in SR patients when compared with PsAF (P < 0.001) and PmAF patients (P < 0.001), whereas there was no difference when compared with PAF patients (P = 0.569). There was no difference in PINP levels between SR and PAF (P = 0.303), PsAF (P = 0.308), or PmAF (P = 0.609) groups.
Correlation analysis
In the whole patient group (n = 472, SR and AF patients), circulating levels of CITP correlated significantly (r = 0.256, P < 0.001) with echocardiographically defined left atrial size, although this was not the case with PINP levels (r = –0.003, P = 0.956).
This positive association between CITP serum levels and left atrial size was also preserved in the SR (n = 180, r = 0.156, P = 0.037) and AF groups (n = 292, r = 0.131, P = 0.025). Amino-terminal propeptide of procollagen type I (PINP) levels continued not to be associated with left atrial echocardiographic dimensions both in the SR group (r = 0.05, P = 0.504) and in the AF group (r = 0.014, P = 0.817).
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Discussion |
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Atrial fibrillation is associated with a number of changes in the ECM of the atrial myocardium, including interstitial fibrosis, alteration in connexin expression, loss of intermyocyte connections leading to an impairment of atrial conduction, therefore allowing AF recurrence and maintenance.7
,15,16 It is known that systematic differences exist between sustained and paroxysmal AF, with chronic AF exhibiting a shorter cycle length and a higher degree of disorganized activity than paroxysmal AF.17,18 Furthermore, previous histopathological studies have shown that altered collagen metabolism occurs in the left atrium as a function of AF duration.8–11 Our study showed that in patients with a chronic type of AF (persistent or permanent AF), serum concentrations of collagen type I degradation marker are higher when compared with patients in SR. Moreover, the present study also demonstrated that CITP levels differed among different AF types. In specific, patients with sustained AF are characterized with increased CITP levels when compared with patients with paroxysmal or persistent AF and this increase is associated with left atrium dilatation. The finding of our study that CITP levels are not different between patients with SR and patients with paroxysmal AF although not suggestive of an association between CITP levels and the presence of AF per se, substantiates further the hypothesis that circulating concentrations of a collagen degradation marker are associated with maintenance of AF. To the best of our knowledge, the present study is the first study to show an association between circulating levels of ECM remodelling markers and different AF patterns, an indirect measure of duration of AF. Our results are in keeping with the findings of other studies that showed a stepwise increased atrial expression and activity of matrix metalloproteinases (MMPs) from PsAF to PmAF.9 Of interest, MMPs are proteolytic enzymes capable of degrading all the components of the ECM, including collagens, and may be responsible for the turnover of the ECM.19,20
In contrast to our results, previous reports have shown that in the left atrium, collagen content was linearly correlated with AF duration, suggesting that up-regulated collagen synthesis and increased fibrosis are associated with progression and perpetuation of AF.8–11 One explanation to this disparity is that increased myocardial21 or other organ22 fibrosis has been shown to be accompanied by collagen degradation and MMP activation, suggesting that collagen degradation is a prerequisite for collagen synthesis, accumulation, and fibrosis. It is possible that total matrix collagen content is a function of both synthesis and degradation and degraded products of matrix proteins serve as a stimulus for collagen synthesis.23 Alternatively, left atrium dilatation seen with sustained AF may be characterized by an increased synthesis and ratio of collagen type III, a thin fibre collagen that confers increased resilience, distensibility, and susceptibility to stretch rather than by an increased synthesis of collagen type I.24 The collagen synthesis marker (PINP) used in the present study is collagen type I specific and therefore could not detect this type of increased collagen synthesis. Another limitation of the specific marker used (PINP) is that probably the amount of propeptide released during synthesis is not proportional to the total amount of fibrillar collagen formed, i.e the PINP is not completely cleaved and released into the circulation during the conversion of procollagen type I into collagen type I.25 Furthermore, the slow rate with which collagen is synthesized and its long half-life imply that collagen accumulation after degradation is a fairly slow procedure to be detected by a serum marker.24,26 In contrast, other studies have shown that in myocardial infarct tissue, mRNA expressions of collagen type I and type III reach peak values at 2–4 days after myocardial infarction and gradually decrease thereafter.27 The increase of procollagen types I and III mRNA in infracted myocardium was followed by an increased collagen deposition, which reaches peak values at day 2 to 3 weeks, suggesting that although collagen deposition is a slow procedure, the actual collagen synthesis is a process with short duration and thus is difficult to be detected.27 In accordance to our findings, Yoshihara et al.11 detected reduced mRNA expressions of collagen typs I and III, although the collagen volume fraction was significantly higher in left atrial appendage in the AF group when compared with the SR group. In the same study, the authors hypothesized that mRNA expression of collagen is often different from collagen volume fraction and that collagen synthesis depends on time course.11 Finally, measuring collagen content alone in the left atrium does not reliably measure changes in the ECM.28 Indeed, reduced collagen cross-linking rather than collagen content is associated with ventricular dilation in rat models.29 Under the same line of evidence, Mukherjee et al.8 showed an inverse correlation in the amount of soluble collagen I and the duration of AF, suggesting an increase in the collagen cross-linking as AF perpetuates. Irrespective of the possible explanations, the exact mechanism for the discrepancy between our inability to detect an increased expression of mRNA of collagen or increased circulating levels of collagen synthesis markers and increased atrial collagen deposition in AF patients is not known at present.
Of interest in our study hypertension is the most common cause of AF in accordance with the current literature.30 Furthermore, there is evidence that a proportion of patients with lone AF with time might turn out to be hypertensive.31 Hypertension is associated with structural changes in the left atrium, including left atrial enlargement and fibrosis.30 In hypertensive patients, the impaired left ventricular diastolic function and the resulting elevated left ventricular filling pressures lead to increased atrial pressure and stretch.30,32 In addition, the hypertension-associated overexpression of angiotensin II enhances fibroblast activity and promotes fibrosis.32 Finally, a recent study in a chronic ovine model of elevated blood pressure showed that atrial collagen was increased in animals with elevated blood pressure.33 The above observations may explain the increased propensity to AF observed among hypertensive patients. According to the same line of evidence, it is conceivable that latent31 or more severe hypertension34 in the AF group could result in the increased collagen metabolism encountered in this group. Under the same notion, there is a possibility that the presence of hypertension might contribute to the differential expression of CITP levels among the three AF pattern groups. Nonetheless, the findings of our study that circulating levels of collagen type I degradation marker are associated with the presence of AF and also differ among different AF patterns are independent of the presence of hypertension or other AF causes, as shown in the ANCOVA models.
An increasing body of evidence supports the influence of inflammation in the pathogenesis of atrial fibrillation.35 Atrial fibrillation is associated with circulating inflammatory markers35, and atrial biopsies from AF patients have also confirmed the presence of inflammatory infiltrates and oxidative damage.35 The renin–angiotensin–aldosterone system (RAAS) plays a major role in the development of remodelling processes in AF. Patients with paroxysmal or persistent AF have increased tissue levels of angiotensin-converting enzyme (ACE),36 increased atrial angiotensin II levels,23 and different atrial densities of angiotensin II type-1 and type-2 receptors37 when compared with patients in SR. Angiotensin II and aldosterone, the effector hormones of the RAAS, stimulate fibroblast-mediated collagen synthesis.32,38 In addition, angiotensin II possesses several pro-inflammatory properties such as the production of pro-inflammatory cytokines, adhesion molecules, chemokines, and selectins.35 The converse is also true with inflammation stimulating angiotensin II production.35 Tumour necrosis factor–
has been shown to up-regulate angiotensin type I receptors in cardiac fibroblasts39 and also to propagate atrial fibrosis and arrhythmias in mice.40 RAAS is emerging as a key player in AF as the above observations suggest a link between atrial remodelling, fibrosis, and inflammation.
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Conclusion |
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In conclusion, our data showed that in the clinical setting, circulating levels of collagen type I degradation marker are associated with the presence of a chronic type of AF (persistent or permanent AF) and furthermore differ among different AF patterns, suggesting a possible association with the duration of AF. Larger studies are warranted to further investigate the clinical usefulness of the present findings in terms of potential diagnostic, prognostic, or therapeutic targets in patients with AF.
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