Atrial fibrillation and change of extracellular matrix

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Ukrainian Research Institute of Transport Medicine

Odessa Regional Clinical Hospital

Atrial fibrillation and change of extracellular matrix

Goriachiy A.V., Gozhenko A.I., Levchenko E.M., Goriachaya A.V.

Резюме

ЗМІНА ПОЗАКЛІТИННОГО МАТРИКСУ У ПАЦІЄНТІВ З РІЗНИМИ ФОРМАМИ ФІБРИЛЯЦІЇ ПЕРЕДСЕРДЬ

Горячий О.В., Гоженко А.І., Левченко О.М., ropn4a А.В.

Український науково-дослідницький інститут медицини транспорту, Одеська обласна клінічна лікарня

Мета: нами було досліджено зміну сироваткових маркерів колагену у пацієнтів з різними формами фібриляції передсердь (ФП). Методи: Як маркери синтезу колагену використовувалися С-термінальний пропептид колагену I типу (ЦТПК-I), С-термінальний телопептид колагену I типу (ЦТТК-I), матриксна метал- лопротеіназа-I, і тканинні інгібітори матриксної металлопротеінази I. Досліджувану групу склали -- 70 осіб, контрольну -- 20.

Результати: Рівень ЦТПК-I і ЦТТК-I у пацієнтів з ФП був значно вище в порівнянні з контрольною групою (91 ± 27 нг/мл., 67 ± 11 нг/мл, p < 0,001 і 0,38_± 0,20 нг/мл, 0,25 ± 0,08 нг/мл, p < 0,001, відповідно). Рівень ЦТПК-I у пацієнтів з персистуючою та хронічною формами ФП був значно вище (105 ± 28 нг/мл і 126 ±_26 нг/мл проти. 80 ± 21 нг/мл, p < 0,001) в порівнянні з пацієнтами з пароксизмальною формою ФП. У пацієнтів з персистуючою та хронічною формами ФП відзначався значно нижчий рівень матриксної металлопротеінази-1 (ММП-1) проте рівень тканинного інгібітора матриксної металлопротеінази-1 (ТІММП-1) був підвищений в порівнянні з пацієнтами з пароксизмальною ФП (09,67 ± 4,41 нг/мл, 11.90 ± 4,79 нг/мл проти 14,98 ± 6,28 нг/мл, p = 0.03 і 187 ± 49 нг/мл, 155 ± 45 нг/мл проти 130 ± 38 нг/мл, p < 0.001, відповідно). Рівень ТІММП-1 був значно нижче в контрольній групі в порівнянні з пацієнтами з пароксизмальною, перси- стуючою і хронічною формами ФП (102 ± 15 нг/мл, 130 ± 38 нг/мл, 155 ± 45 нг/ мл і 194 ± 49 нг/мл, відповідно, p < 0,001). Висновки: Сироватковий рівень маркерів колагену I типу значно відрізняється між здоровими людьми та пацієнтами з ФП. Більш того ці маркери також відрізняються в залежності від форми ФП. Можна припустити, що інтенсивність позаклітинного синтезу і деградації колагену I типу може бути пов'язана з тяжкістю і типом ФП.

Ключові слова: сывороточный маркер коллагена, фибрилляция предсердий, клеточный синтез.

Резюме

ИЗМЕНЕНИЕ ВНЕКЛЕТОЧНОГО МАТРИКСА У ПАЦИЕНТОВ С РАЗЛИЧНЫМИ ФОРМАМИ ФИБРИЛЛЯЦИИ ПРЕДСЕРДИЙ

Горячий А.В., Гоженко А.И., Левченко А.Н., Горячa A.В.

Украинский научно-исследовательский институт медицины транспорта, Одесская областная клиническая больница

Цель: нами было исследовано изменение сывороточных маркеров коллагена у пациентов с различными формами фибрилляции предсердий (ФП). Методы: В качестве маркеров синтеза коллагена использовались С-терминальный пропептид коллагена I типа (ЦТПК-I), С-терминальный телопептид коллагена I типа (ЦТТК-I), матриксная металлопротеиназа- I, и тканевые ингибиторы мат- риксной металлопротеиназы I. Исследуемую группу составили -- 70 человек, контрольную -- 20. Результаты: Уровень ЦТПК-I и ЦТТК-I у пациентов с ФП был значительно выше по сравнению с контрольной группой (91 ± 27 нг/мл., 67 ± 11 нг/мл, p < 0,001 и 0.38 ± 0,20 нг/мл, 0,25 ± 0,08 нг/мл, p < 0,001, соответственно). Уровень ЦТПК-I у пациентов с персистирующей и хронической формами ФП был значительно выше (105 ± 28 нг/мл и 126 ± 26 нг/мл против. 80 ± 21 нг/мл, p < 0,001) по сравнению с пациентами с пароксизмальной формой ФП. У пациентов с персистирующей и хронической формами ФП отмечался значительно более низкий уровень матриксной металлопротеиназы-1 (ММП-1) однако уровень тканевого ингибитора матриксной металлопротеиназы-1 (ТИММП-1) был повышен в сравнении с пациентами с пароксизмальной ФП (09.67 ± 4.41 нг/мл, 11.90 ± 4.79 нг/мл против 14.98 ± 6.28 нг/мл, p = 0.03 и 187 ± 49 нг/мл, 155 ± 45 нг/мл против 130 ± 38 нг/мл, p < 0,001, соответственно). Уровень ТИММП-1 был значительно ниже в контрольной группе в сравнении с пациентами с пароксизмальной и персистирующей и хронической формами ФП (102 ± 15 нг/мл, 130 ± 38 нг/мл, 155 ± 45 нг/мл и 194 ± 49 нг/мл, соответственно, p < 0,001).

Выводы: Сывороточный уровень маркеров коллагена I типа значительно отличается между здоровыми людьми и пациентами с ФП. Более того эти маркеры также отличаются в зависимости от формы ФП. Можно предположить, что интенсивность внеклеточного синтеза и деградации коллагена I типа может быть связанна с тяжестью и типом ФП.

Ключевые слова: сывороточный маркер коллагена, фибрилляция предсердий, клеточный синтез.

Background

Recent studies have shown a significant increase in the level of collagen deposition in the atria in patients with AF, unlike patients who are on sinus rhythm (SR) [1-3]. Preliminary experimental and clinical data suggested a feedback between the presence of fibrosis in biopsy samples and the presence of arterial hypertension (AH). It was further shown that such markers differ in patients with hypertension and without it, studies of their connection with hypertrophy or other echocardiographic parameters have also led to contradictory [5,6].

Collagen type I is the most common collagen product of cardiac fibroblasts [7 ]. We have estimated the amount of fibrosis in patients with paroxysmal, persistent and chronic isolated forms of AF using enzyme immunoassay [4]. The level of MMP-I and TIMP-I was also evaluated.

Materials and methods

The study was approved by the ethical committee of the Odessa Regional Hospital. It was consistent with the principles set forth in the Helsinki Declaration. All patients signed an informed consent to participate in it.

96 utpatient patients aged 24 -- 78 y. o. with isolated AF were included into it with AF without clinical or echocardiographic signs of cardiopulmonary disease, including AH. Arrhythmia was considered to be paroxysmal with a duration of less than 24 hours and a persistent duration of at least 1 months until the moment of inclusion. Chronic form of AF was called a rhythm disorder for more than one year, resistant to drug therapy. Forms of AF were determined according to the leadership standard of the European Society of Cardiology, 2016 [8]. The control group consisted of 24 patients with no history of AF.

Exclusion criteria: conditions associated with elevated serum marker of myocardial or tissue fibrosis, such as liver disease, renal dysfunction, pulmonary fibrosis, extensive wound surfaces, metabolic bone diseases, malignant neoplasms, connective tissue diseases, chronic inflammatory diseases, recently suffered infectious diseases and surgical interventions, age over 80 y.o. or presence of an implanted pacemaker / implantable cardioverter defibrillator (ICD).

During the study, in the patients of the study and control groups serological markers of type I collagen, the echocardiographic size of the LA and the LA ejection fraction (LAEF) were compared. To control the frequency of ventricular contractions, diltiazem and beta-blockers were used. All AF patients received antithrombotic treatment.

At the time of blood sampling, all patients had AF. Blood samples were collected during a clinical trial and immediately placed on ice and centrifuged for 1 hour. Samples were stored at -80 ° C until analysis.

The serum levels of TIMP-1 and MMP-1 were evaluated using enzyme immunoassay with laboratory kits (Human Biotrack, Amersham Biosciences, USA). The level of CTPK-I type was determined using enzyme immunosorbent assay with kit (Metra CICP, Quidel, USA), while CTTC- I was measured using an Elecsys B- CrossLaps / serum assay (Roche Diagnostics, Mannheim, Germany). The measurement was performed by staff blinded to the clinical information about the patients' condition. Inside and intertest coefficients of variation were < 8 % and < 10 %, respectively.

Statistical analysis. The data obtained were processed statistically using the Statistica 6.1 computer program. Quantitative signs with a normal distribution are presented as M ± у (mean ± standard deviation), with an abnormal distribution -- in the form of a median and interquartile range (Me). To identify the existing differences in ordinal characteristics, the non-parametric Mann- Whitney test was used. Correlation analysis was performed using the Spearman R test for quantitative values. At p < 0.05, differences were considered statistically significant. The study design is represented by an open controlled one.

The results

Patients. The initial clinical and demographic characteristics of the study population are presented in Table 1. Group I comprised 24 patients with paroxysmal AF, Group II -- 26 patients with persistent AF, Group III -- 22 patients with chronic AF and Group IV (control) -- 24 AF-free patients. There were no significant differences in gender (p = 0.40) or age (p = 0.058) between the AF groups and the control group. Patients with persistent and chronic form of AF had lower levels of left ventricular ejection fraction (LVEF) (p = 0.038) and larger sizes of LA (p < 0.001) compared with patients with paroxysmal AF and the control group. serum atrial fibrillation collagen

Table 1 General characteristics of patients

Serum collagen markers. The results obtained are shown in Table 1. The levels of CTPC-I and CTTC-I were significantly higher in patients with paroxysmal, persistent and chronic forms of AF compared with control subjects (p d”0.016). Patients with persistent and chronic forms of AF also had higher levels of CTPC-I compared with patients with paroxysmal form of AF (p < 0.001), whereas there was no significant difference in the levels of CTPC-I (p = 0.57) (Table 1, Fig. 1 and 2).

3) the level of CTTC-I was significantly different in patients of the control group and patients with various forms of AF (Figure 2);

4) the level of MMP-1 was significantly different in patients with persistent, chronic and paroxysmal forms of AF (Figure 3); 0.012

Patients with persistent and chronic forms of AF had lower levels of MMP-1 (p = 0.026), but higher levels of TIMP-1 (p = 0.013) compared with patients with paroxysmal AF (Table 1, Fig. 3, 4). Tissue inhibitor of matrix metalloproteinases-1 was significantly lower (p < 0.001) in control subjects as compared with the studied patients (Fig. 4). The plasma MMP-1 level did not differ significantly between the studied patients of different groups and the control group (Fig. 3).

Finally, in all AF patients, taken together, a positive correlation between the levels of CTPC-I, TIMP-1 and the size of the LA (r = 0.635, p < 0.001 and r = 0.563, p < 0.001, respectively) (Fig. 5), was observed, whereas the relationship between the levels of CTPC-I, TIMP- 1 and LVEF is weakly expressed (r = -0.234, p = 0,05, br = -0.278, p = 0,020, respectively). A positive correlation was observed between the levels of MMP-1 and LVEF (r = 0.30, p = whereas there was an inverse relationship between the levels of MMP-1 and the size of the LA (r = -0.615, p < 0.001).

Fig. 1. The level of CTPC-I in patients with AF.

Fig. 2. The level of CTTK-I in patients with AF

Fig. 3. The level of MMP-1 in patients with AF.

Fig. 4. TIMP-1 level in patients with AF.

Increase in CTPC-I and CTTC-I in the group of patients with AF, taken as a whole and compared with patients on SR. Interestingly, that patients with persistent and chronic forms of AF had the highest serum CTPC-I concentrations, whereas patients with persistent, chronic, and paroxysmal AF had no differences in CTTC-I levels. Thus, CTPC had a gradual growth from the control group to the group of patients with paroxysmal, persistent and then to the permanent form of AF was demonstrated; however, this connection was not observed in CTTC-I, presumably, the intensity of extracellular degradation of collagen type I was Insufficient to compensate for it increased synthesis, which led to an increase in fibrosis in patients with persistent and chronic forms of AF.

In addition, in patients with chronic and persistent forms of AF, the levels of MMP-1 decreased, while levels of TIMP- 1 increased compared with paroxysmal AF patients. The level of TIMP-1 was also higher in patients with paroxysmal AF than in the control group. In addition, a lower level of MMP-1 was observed in the control group than in paroxysmal AF, but higher than in patients with persistent and persistent forms of AF (although the differences did not reach statistical significance). This seems paradoxical, but it can be the result of the activation of MMP-1, which depends on the nature of the stimulus and differs in acute and chronic stimulation [14]. Thus, paroxysmal AF can lead to a sharp overload of pressure or volume, activating the MMP-1 system, which is then compromised by prolongation and stabilization of the stimulus.

Another interesting finding was that the levels of CTPC-I and TIMP-1 correlated positively with the diameter of the left ventricle and are inversely related to LVEF, whereas in patients with AF with larger sizes of LV and lesser LVEF, it is likely that the arrhythmia is longer there were lower levels of MMP-1.

Since only patients with isolated AF were involved in our study, we can assume that the above mentioned changes were associated with the arrhythmia itself, and not with the presence or absence of any concomitant factor with a progressive increase in fibrosis from paroxysmal to chronic AF. In addition, enhanced fibrosis, especially in patients with the chronic form of AF, may also be causative in both initiating and maintaining AF.

Serum markers of type I collagen can provide a non-invasive method of documenting and monitoring the extent and mechanisms of myocardial fibrosis in patients with AF, as well as assessing pharmacological measures for treating this arrhythmia. However, it is necessary to further study and conduct randomized studies to determine the exact role of fibrosis in the formation of AF and assess the clinical importance and value of biochemical monitoring of the level of collagen in this clinical situation. Although cardiac biopsy is the gold standard for documenting and monitoring myocardial fibrosis, non-invasive methods offer an alternative view of solving this problem, which may be more widely used.

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