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UDC 616.127-074:577.12+616.12-008.64-036.1+616.12-008.313:615.849 DOI http://dx.doi.org/10.5281/zenodo.2552464
2A. V. Goryachiy, 1A. I. Gozhenko, 2E. M. Levchenko, 2A. V. Goryachaya
DOES ATRIAL FIBRILLATION INFLUENCE ON THE LEVEL OF MATRIX METALLOPROTEINASE-9?
Ukrainian Research Institute for Medicine of Transport, Odessa;
2Odessa Regional Clinical Hospital
Summary. Goryachiy A. V., Gozhenko A. I ., Levchenko E. M., Goryachaya A. V. DOES ATRIAL FIBRILLATION INFLUENCE ON THE LEVEL OF MATRIX METALLOPROTEINASE-9? The objective: To investigate if there is any relation between atrial fibrillation and levels of matrix metalloproteinase-9 (MMP-9) and to evaluate their significance and role in the various stages of the development of idiopathic atrial fibrillation (AF).
© Goryachiy A. V., Gozhenko A. I Levchenko E. M., Goryachaya A. V.
Methods: The study included patients with idiopathic AF. In accordance with the degree of disease progression, patients were divided into 3 groups: paroxysmal, persistent and chronic AF. The control group consisted of practically healthy patients. To determine the serum levels of MMP-9 used the double-antibody immunoassay with the enzyme label. Results: Each study group consisted of 20 patients; The control group consisted of 40 patients. The level of MMP-9 in the treatment groups was significantly different from the control and amounted to: 170.62 ± 24.65, 202.33 ± 29.18, 252.3 ± 21.87 ng / ml for paroxysmal, persistent and chronic forms of AF and 75.78 ± 14.7 ng / ml in the control group, respectively. As the disease progresses the level of MMP-9 increased (P <0,05). Conclusions: Increased levels of MMP-9 is likely associated with the development and progression of idiopathic AF.
Key words: atrial fibrillation, extracellular matrix, matrix metalloproteinase-9, pathological mechanisms.
Реферат. Горячии А. В., Гоженко А. И., Левченко Е. М., Горячая А. В. ВЛИЯЕТ ЛИ ФИБРИЛЛЯЦИЯ ПРЕДСЕРДИЙ НА УРОВЕНЬ МАТРИКСНОЙ МЕТАЛЛОПРОТЕИНАЗЫ-9? В исследовании были изучены показатели кардиального фиброза у пациентов с различными формами идиопатической фибрилляции предсердий. В исследуемую группу вошли пациенты с пароксизмальной, персистирующей и хронической формами идиопатической фибрилляции предсердий. Были выявлены признаки дилатации левого предсердия и повышения уровня ММП-9 в сравнении с практически здоровыми пациентами. При этом меньшие изменения наблюдались в группе пациентов с идиопатической пароксизмальной формой фибрилляции предсердий. Тогда как в группе пациентов с хронической формой фибрилляции предсердий урoвень повышения ММП-9 был наиболее выражен.
Ключевые слова: фибрилляция предсердий, внеклеточный матрикс, матриксная металлопротеиназа-9, патологические механизмы.
Реферат. Горячий О. В., Гоженко А. I., Левченко О. М., Горяча А. В. ЧИ ВПЛИВАС Ф1БРИЛЯЦП ПЕРЕДСЕРДЬ НА Р1ВЕНЬ МАТРИКСНО1 МЕТАЛОПРОТЕ1НАЗИ -9? Мета: Дослвдити рiвень матриксно! металлопротешази-9 (ММП-9) та ощнити i'i значения i роль на рiзних етапах розвитку щопатично! фiбриляцii передсердь (ФП). Методи: У дослщження увшшли пащенти з вдюпатичною формою ФП. Ввдповщно до ступеня прогресування захворювання пащенти були роздшеш на 3 групи: пароксизмальна, персистуюча та хрошчна ФП. Контрольну групу склали практично здоровi пащенти. Для визначення сироваткового рiвия ММП-9 використовували iмуноферментний аналiз подвшними з антитшами та ферментною мггкою. Результата: Кожна дослщжувана група включала 20 пащенлв, контрольна група склала 40 пащенпв. Рiвень ММП-9 в дослщжуваних групах значно вщлзнявся ввд контрольно! i склав: 170,62 + 24,65, 202,33 + 29,18, 252,3 + 21,87 нг/мл для пароксизмально!, персистуючо! та хронiчноi' форми ФП i 75,78 + 14,7 нг/мл в контрольнш групi вiдповiдно. У мiру прогресування захворювання рiвень ММП-9 шдвищувався (P <0,05). Висновки: Шдвищення рiвня ММП-9 вiрогiдно асоцiюеться з розвитком i прогресуванням iдiопатичноi ФП.
K^40Bi слова: фiбриляцiя передсердь, позаклггинний матрикс, матриксна металлопротеiназа-9, патологiчнi мехашзми.
Introduction. Atrial fibrillation (AF) is one of the most common diseases in clinical practice. Experimental and clinical studies have shown a relationship between AF and changes in atrial electrical properties [1]. Despite this, the pathogenetic mechanisms of AF are still not fully understood. Atrial interstitial fibrosis is an important mechanism of AF [2, 3]. leading to an increase in the size of the left atrium (LA), the thinning of the walls thus leading to its complete remodeling [4]. Endogenous enzymes are involved in the atrial matrix remodeling process, one of which is matrix metalloproteinase (MMP), the substrate of which is a type of collagen. In consequence, MMP-9 serum level is considered a marker of extracellular degradation of collagen [5]. Numerous studies have shown MMP's involvement in the development of myocardial fibrosis. For example, the level of MMP-9 is an important index for myocardial fibrosis [6, 7], and also has a close relationship with other cardiovascular diseases [8, 9].
The objective: to study possible relation between the level of MMP-9 in idiopathic AF patients at various stages of disease progression and healthy persons, and assess the relationship between the level of MMP-9 and the progression of idiopathic AF.
Materials and methods of the research
Idiopathic AF patients who received both outpatient and inpatient care on the basis of the Odessa Regional Clinical Hospital during 2015-2017 were included in the study. Patients were recruited sequentially and divided into three groups depending on the form of idiopathic AF (paroxysmal, persistent, chronic), in accordance with the recommendations of the European Society of Cardiology (2016) for treating patients with AF [10]. Exclusion criteria: organic cardiovascular diseases, hyperthyroidism, pregnancy, infectious diseases, surgery for less than 2 months before the study, the presence of thrombotic masses in the left auricula atrii, history of electrical or medical cardioversion at least 2 months before the study, recent taking ACE inhibitors, corticosteroids or statins, the presence of structural heart disease.
The control group consisted of patients who visited the clinic for a routine medical examination with no discomfort during research, irregularities in the biochemical blood test, ECG, echocardiogram, abdominal ultrasound, chest X-ray.
The study protocol was approved by the ethical committee of the Odessa Regional Clinical Hospital. All participants signed an informed consent to participate in the study.
All the patients under study submitted 4 ml of venous blood the morning on an empty stomach. After adding 100 g / l of sodium citrate as an anticoagulant and centrifugation (4-16K, Sigma-Aldrich, Germany) at 1360 revolutions for 10 minutes at 4° C, the serum was distributed in test tubes (MCT-150-C, Axygen, USA) and stored at -80° C until analysis. Samples were analyzed every 3 months. Serum concentration of MMP-9 was determined using an enzyme immunoassay kit (Human MMP-9 ELISA - Bender MedSystems, Austria) according to the manufacturer's instructions.
Additionally evaluated: body mass index, the diameter of the LA, left ventricula ejection fraction (LVEF), systolic and diastolic blood pressure, serum concentration of Na +, K +.
The results obtained were processed statistically using the Statistica 6.1 computer program. Quantitative signs with a normal distribution are presented as M ± c (mean ± standard deviation), with abnormal distribution - in the form of a median and interquartile range (Me). To identify the existing differences in ordinal characteristics, the Mann - Whitney nonparametric criterion was used. Correlation analysis was performed using Spearman's R test for quantitative values. At p <0.05, differences were considered statistically significant. The study design is represented by an open controlled study.
Results
60 patients with AF were included in this study, 20 patients for each form (paroxysmal, persistent, chronic AF) and 40 patients made up the control group. In the studied groups, there were no significant differences in gender, age, body mass index, diameter of the left ventricle, LVEF, blood pressure or serum Na +, K + concentrations (Table 1).
Table 1
AF PATIENTS CHARACTERICTICS
Parameters Parox. AF, Persist. AF, Chron. AF, Control, n=40
n=20 N=20 n=20
Age, years 57.2+16.2 56.6+15.4 60.1+16.1 55.7+14.9
sex, m/f 15/5 14/6 14/6 32/8
BMI, kg/m2 26+3.8 28+4.3 28+4.9 27+5.1
LA. Diameter, mm 27.7+6.2 28.3+5.9 27.1+7.2 27.2+5.9
LVEF, % 60+12 63+11 61+13 65+9
BP/systolic, mm Hg 125.2+13.2 126.2+10.5 121.2+12.3 119.8+11.8
BP/diastolic, mm Hg 78.2+11.2 80.7+9.2 77.2+11.9 77.2+13.4
Serum Na+, mmol/l 143.2+6.9 142.6+7.4 140.8+7.1 143.2+7.7
Serum K+, mmol/l 4.1+0.6 4.3+0.5 4.2+0.8 4.3+0.6
Data are presented as mean + SD or n, BMI - body mass index, LVEF -left ventricula ejection fraction, no statistical differences were observed (P <0.05)
The level of MMP-9 in all groups under study was significantly higher in comparison with the control group (P <0.01). A significant increase in the level of MMP from paroxysmal to the
permanent form of AF (P <0.05) was noted (Table 2).
Table 2
COMPARISON OF MMP - 9 LEVELS
Parameters Parox. AF, n=20 Persist. AF, n=20 Chron.AF, n=20 Control, n=40
MMP-9 (ng/ml) 170.62 + 24.65a,b 202.33 + 29.18 a,b 252.3 + 21.87 a-b 75 78 + 14.7
Data are presented as mean + SD or n, statistical differences were not observed: P a <0.05 -in comparison groups, P b <0.01 - in comparison with the control group.
Discussion
In physiological state, the extracellular matrix is constantly produced and degraded, thus being in a state of homeostasis. Disruption of the state of homeostasis is closely related to the occurrence of cardiovascular diseases (CVD). MMP in its turn can break down many extracellular matrix proteins, such as collagen, laminin, fibronectin, proteoglycans and elastin [11, 12]. MMP's increased formation and activity is observed in the development of many CVDs. Selectively, MMP-9 is involved in the formation of myocardial fibrosis. It has been shown that MMP-9 induces and generates fragmentation of a collagen matrix, such as endostatin and angiostatin, in patients undergoing coronary artery bypass surgery [13]. In pre-clinical setting, the effect of MMP-9 on structural cardiac tissue remodeling in patients after myocardial infarction (MI) was found: the loss of MMP-9 activity through targeted removal of MMP-9 resulted in a significant decrease of collagen deposition in the affected area. Also in animals with affected MMP-9, a decrease in inflammatory infiltration was observed. Thus, it was suggested that MMP-9 plays an active role in cardiac remodeling [14]. In this research, we studied the relationship between the level of MMP-9 and the occurrence and progression of AF.
We selected patients with idiopathic AF to exclude the possibility of the influence of organic heart disease on the level of MMP-9. A close relationship between the level of MMP-9 and AF was reported in [15]. Chronic rheumatic diseases and AF patients showed an increased level of MMP-1 and MMP-9, which was associated with high-frequency rhythm disturbances [16]. In animal models with heart failure caused by high-frequency atrial stimulation, an increase in MMP-9 activity was shown by 50% compared with animals on sinus rhythm, while the level of specific tissue inhibitors decreased by 50% [17]. In another study, the effect of MMP inhibitors on the reduction of LV dilatation and thinning of the LV wall in patients with tachi-induced cardiac failure [18] was shown. However, there was no evidence of a relationship between the level of MMP-9 and the development and progression of AF in humans.
We found that the level of MMP-9 in the groups under study was significantly higher compared with the control group, which in its turn indicates the possible involvement of MMP-9 in the occurrence and maintenance of AF. MMP-9 may be involved in the process of degradation and reconstruction of the extracellular matrix under the influence of zinc ions: fragmentation of the matrix, regulation of cell adhesion, effects on extracellular components or components of other proteins, activation of proteins, directly or indirectly affect tissue remodeling and healing [18, 19]. When the level of MMP-9 is elevated, all of the above functions are increased. When the levels of MMP-9 are enhanced, which would lead to excessive degradation of the extracellular matrix, an increase in tissue remodeling and myocardial fibrosis, and may contribute to the formation of micro-rientry and ultimately lead to AF [20].
A gradual increase in the level of MMP-9 from paroxysmal, persistent to the chronic form of AF also was found in this study. A significant difference between the three groups of patients was noted. In another study, it was shown that AF is characterized by self-sustaining and gradual progression, in most cases paroxysmal AF eventually turns into a persistent and even chronic form [21]. Although this mechanism is not fully understood. Other studies have focused on electrical remodeling of AF, believing that the remodeling of ion channels is the main cause of AF progression [22].
The limitation of this study can be called its scope. For a more detailed study it is necessary to conduct a more extensive one. Taking into account that AF is a multifactorial disease with unclear etiology, the investigation of other factors associated with MMP-9 is also necessary.
Conclusion. An increase in the level of MMP-9 in patients with AF compared with the control group, the association of MMP-9 with the development and progression of AF really takes
place. However, further research is needed.
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