CC BY
15
УДК 616.127-005.8-008.315-002:577.15:612.13
https://doi.org/10.26641/2307-0404.2018.1(part 1).127244
O. Kuryata, A. Zabida, O. Sirenko
SERUM MATRIX METALLOPROTEINASE (MMP)-2,9 ACTIVITY, GALECTIN-3 AND SYSTEMIC INFLAMMATION IN PATIENTS WITH POSTINFARCTION HEART FAILURE WITH PRESERVED EJECTION FRACTION
SE «DnipropetrovskMedical Academy of Health Ministry of Ukraine»
Department of internal medicine 2
V. Vernadskiy str., 9, Dnipro, 49005, Ukraine
ДЗ «Днтропетровська медична академiя МОЗ Укра'ши»
кафедра внутрiшньоi медицини 2
(зав. - д. мед. н., проф. О. В. Курята)
вул. В. Вернадського, 9, Днтро, 49005, Украша
e-mail: [email protected]
Key words: postinfarction chronic heart failure, metalloproteinase, galectin-3
Ключовi слова: посттфарктна хронiчна серцева недостатнiсть, металлопротешази, галектин-3
Abstract. Serum matrix metalloproteinase-2,9 activity, galectin-3 and systemic inflammation in patients with postinfarction heart failure with preserved ejection fraction. Kuryata O., Zabida A., Sirenko O. The available data suggest that heart failure (HF) after myocardial infarction (MI) is a very frequent event. Recent meta-analysis showed that restrictive mitral filling pattern, the most severe form of diastolic dysfunction, was presented in approximately 10% of the patients with preserved ejection fraction. In addition, restrictive pattern was associated with poor outcome. However, the true prevalence and relevance of diastolic dysfunction after MI remains to be elucidated. Objective: study was designed to evaluate the serum level of MMP-2,9, galactin-3 and C-reactive protein (C-RP) in postinfarction heart failure with preserved ejection fraction (HFpEF) patients. Methods: We divided all included patients into two main groups: 1st group - 20 patients with HFpEF and history of myocardial infarction. 2nd group - 18 patients with HFpEF and stable angina. Standard laboratory blood tests for erythrocyte sedimentation rate (ESR), C-RP, haematological parameters, lipid profile, glucose, renal and liver function tests were performed and calculated body mass index (BMI) for all patients. MMP activity assay and galectin-3 serum level was detected for all patients. Results: It was established significant differences between study groups in MMP-2, MMP-9 levels. Particularly, patients with HFpEF with MI in anamnesis had significantly higher MMP-2, MMP-9 levels on 21.8% and 20.7% respectively. The C-RP and leucocytes levels were significantly higher in 1st group pts. Significant differences in MMP-2, MMP-9 were established in 1st group patients in different age groups (p<0.05) (tab. 3). The MMP 2 level was positively correlated with MMP 9 level (R=0.73, p<0.05), the MMP 9 level - with age (R=0.68, p<0.05). There were no significant differences between galectin-3 level in study group. But we estimated significant differences in galectin-3 level between 1st and 2nd subgroups (p<0.05). Conclusion: Serum MMP-2, MMP-9, CRP and galactin-3 were significantly increased in pts with postinfarction heart failure with preserved ejection fraction compare to pts without myocardial infarction in anamnesis.
Реферат. PiBeHb матричних металопротеТназ-2,9, галектину-3 та системне запалення у хворих з пост-шфарктною серцевою недостатшстю 3i збереженою фракщею викиду. Курята О.В., Забща А., Оренко О.Ю.
Лiтературнi дат свiдчать, що серцева недостатнiсть (CH) пюля перенесенго тфаркту мюкарда (1М) е частою подiею. Однак поширетсть i фактори виникнення дiастолiчноi дисфункцП лiвого шлуночка тсля перенесеного 1Мзалишаються маловивченими. Мета: оцiнити рiвнi сироватковихMMP-2,9, галактину-3 та С-реактивного быка (СРП) при посттфарктнт серцевш недостатностi 3i збереженою фракцiею викиду. Матерiали та методи: у до^дження включено 38 пацiентiв з СН зi збереженою фракщею викиду вком вiд 40 до 80 роюв: 1 група (n=20) з перенесеним шфарктом мюкарда в анамнезi, 2-а група (n=18) пацiентiв зi стабшьною стенокардiею. Виконано стандартн лабораторн аналiзи кровi, визначення CPn, гематологiчних параметрiв, лiпiдного профтю, глюкози, креатитну. Визначення активностi MMP та рiвня галактину-3 в сироватцi кровi проводилось уам пащентам. Результати: пащенти з ХСН з 1М в анамнезi мали достовiрно вищий рiвень MMP-2, ММР-9 на 21,8% та 20,7% вiдповiдно (р<0,05). Рiвнi CPn та лейкоцитiв були достовiрно вищими в пацiентiв 1-i групи (р<0,05). Достовiрнi вiдмiнностi рiвней ММП-2, MMP-9 встановлен в nацiентiв з перенесеним 1Му рiзних вкових групах (р<0,05). Piвень MMP-2 позитивно корелював зрiвнем MMP-9 (R=0,73, p<0,05), рiвень ММР-9 - з вжом (R=0,68, р<0,05). Встановленi достовiрнi вiдмiнностi мiжрiвнем галектину-3 серед nацiентiв рiзного вжу (p<0,05). Висновок: сироватковi рiвнi MMP-2, MMP-9, CPn та галектину-3 були достовiрно вищi у хворих з посттфарктною серцевою недостатнютю зi збереженою фракщею викиду nорiвняно з пащентами без тфаркту мюкарда в анамнезi.
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The available data suggest that heart failure (HF) after myocardial infarction (MI) is a very frequent event [10]. Recent meta-analysis showed that restrictive mitral filling pattern, the most severe form of diastolic dysfunction, was presented in approximately 10% of the patients with preserved ejection fraction.
In addition, restrictive pattern was associated with poor outcome [9, 10]. However, the true prevalence and relevance of diastolic dysfunction after MI remains to be elucidated. Another important issue is that the consequences of cardiac dysfunction after MI are well established, and its presence increases the risk of death by at least 3- to 4-fold [9].
The endothelium may also be central to the pa-thophysiology of heart failure, with endothelial cell damage or dysfunction that is probably more evident than that from vascular disease alone [1, 2, 3]. Certainly, heart failure is associated with abnormalities of thrombogenesis, leading to an increase in thrombosis related complications in this condition [10]. In HF, myocardial ischaemia features prominently (even in dilated cardiomyopathy) and severely depressed myocardial blood flow is a predictor of poor prognosis [15].
Left ventricular (LV) regional remodelling is a continuous process that last for months to years after the acute injury and which will eventually lead to the development of HF. Matrix metalloproteinases (MMPs) and tissue inhibitor metalloproteinase (TIMPs) continue to have an important role in the process of chronic LV remodelling [12, 15].
A region specific portfolio of MMPs is induced after MI and is accompanied by a decline in TIMP levels, indicative of a loss of MMP-inhibitory control. MMP-1 and MMP-9 levels are significantly reduced within the border and MI regions at 8 weeks post-MI, whereas MMP-2 levels increases substantially within the border and MI regions [15], suggesting that MMP-9 mainly is associated with early post-MI events [12, 16]. In contrast to the acute MI setting, a different set of MMPs emerges at 8 weeks after MI. Interestingly, MMP-8, localized to neu-trophils, is increased by over 6-fold within the border and MI regions at 8 weeks after MI, suggesting that MMP-8 is associated with a more chronic inflammatory response [6, 12, 16]. The levels of the collagenase MMP-13, and MT1-MMP are increased by nearly 3-fold in both border and MI region 8 weeks post-MI [15]. MMP-3 is reduced within the MI region and MMP-7 falls within the border and MI regions 8 weeks post-MI. TIMP abundance decreases significantly in the border region after MI, and TIMP-1, -2 and -3 fall to undetectable levels within the MI region. Similar results are obtained by the use of a pig model of MI [12]. These data clearly
demonstrate that targeting of the regional imbalance between specific MMPs and TIMPs within the post-MI myocardium holds a therapeutic potential.
Galectin-3 is a P-galactoside-binding lectin secreted by activated macrophages, which has gained interest as at least a marker of, or possibly even a potential mediator in inflammation and fibrosis, processes that are central to the pathophysiology of LV remodeling [6, 14, 16]. Tsai et al. suggested few important clinical implications of galectine-3: 1) circulating galectine-3 was significantly higher in MI patients than in normal controls; 2) there were significant positive correlations of high circulating galectine-3 to an advanced Killip score, unstable haemodynamics requiring inotropic support, advanced HF and a high CADILLAC risk score; 3) elevated galectin-3 was proven to be a strong independent predictor of 30-day MACO (major adverse clinical outcome) among patients with STEMI undergoing primary percutaneous interventions [16]. Though, Weir et al. had demonstrated that higher galectin-3 concentrations at baseline were significantly associated with lower left ventricle ejection fraction (LVEF) at 24-week follow-up, although there was no significant relationship between ga-lectin-3 and remodeling per se [6].
Zile et al. had demonstrated in one small series that galectin-3 levels were significantly elevated in cohort of patients with HF with HFpEF [14]. Galectin-3 might provide an early warning marker for patients who are at risk for development of HF symptoms and may allow medical intervention. According to other animal and human studies, galectin-3 in addition to clinical and some studies have shown that galectin-3 had independent prognostic value, even after correction for established risk factor such as age, sex, BNP level, renal function, and diabetes mellitus [7].
Prognostic value of galectin-3 levels in plasma appears to be much stronger in the subset of patients with HFpEF in comparison with HF with reduced ejection fraction (HFrEF) [8, 11, 13]. Also, base line levels of galectin-3 seem to be sufficient to predict outcome, because serial measurement did not increase the prognostic yield [4, 7].
Aim of our study to evaluate the serum level of MMP-2, -9, galactin-3 and C-reactive protein (CRP) in postinfarction heart failure with preserved ejection fraction patients.
MATERIALS AND METHODS
Baseline study
The study was conducted with approval from the Ethics committee at State Establishment «Dnipropet-rovsk Medical Academy of Health Ministry of Ukraine» according to principles outlined in the Helsinki declaration.
Patients (n=38) included aged 40 to 80 years, 29 males and 9 females were diagnosed with (HFpEF), according to ESC guidelines (2016) [5], and their functional class according to NYHA classification for HF. All patients got standard treatment for chronic heart failure (CHF) according to ESC guidelines 2016 [10].
Patients with acute myocardial infarction (<6 months), ejection fraction (EF) <40%, 2nd and 3rd degree heart block, diabetes mellitus (DM), kidney insufficiency (glomerular filtration rate: GFR<30 ml/min/1.73m2), hepatic failure, and cancer were excluded.
Standard laboratory blood tests for erythrocyte sedimentation rate, CRP, haematological parameters, lipid profile, glucose, renal and liver function tests were performed and calculated body mass index (BMI) for all patients.
Gelatin zymography (mmp activity assay) The gelatinolytic activity was analyzed by separating serum proteins (100 ^g/track) on 7.5% SDS-PAGE gels copolymerized with gelatin (3 mg/ml). After electrophoresis, the gels were washed twice for 30 min in gold 2.5% (v/v) Triton X-100 to remove SDS, and then 5 times for 5 min in cold bi-distilled water. After washing, gels were incubated
overnight at 37 °C in developing 50 mM tris-HCl buffer (pH 7.6), containing 0.15 M NaCl, 5 mM CaCl2, 1 mM ZnCl2, and 0.02% Tween-80. Zymograms were stained with 0.11% Coomassie Briliant Blue R-250 solution in 30% methanol and 10% acetic acid and destained in the same solution lack of Coomassie Blue. The final gel had a uniform blue background except in those regions to which MMPs had migrated and cleaved the substrate. The gela-tinolytic activity was identified as transparent bands against the background of Coomassie Blue-stained gelatine. The zymograms were visualized and analyzed densitometrically.
All patients were assessed with galectin-3 blood levels by immunoassay analysis using the "Human Galectin-3 Platinum ELISA" kit (GmbH, Austria) on the Stat Fax 2100 (USA) immunoassay plate analyser. The base level was taken as 0 ng/ml.
Study design
We divided all included patients into two main groups:
1st group: 20 patients with HFpEF and history of myocardial infarction.
2nd group: 18 patients with HFpEF and stable angina.
Table 1
Baseline characteristics of the study population
Patients with CHF+MI Patients with CHF+stable angina
Characteristics in anamnesis (n=20) (control group) (n=18) P
Males (%) Gender 16 (80%) 13 (72%)
Females (%) 4 (20%) 5 (28%)
Age, years M±m 66±9 70±4 0,2106
CHFClass 2nd FC according to NYHA 3'd FC 10 (50%) 10 (50%) 11 (61%) 7 (39%)
Heart rate, beat/minute M±m 74±5 77±4 0.137
Body mass index (BMI) M±m 28,00±2.10 30,00±2.50 0.202
Blood glucose, mmol/L M±m 5.45±0.20 5.15±0.25 0.337
Cholesterol, mmol/L M±m 5.50±1.60 4.95±0.25 0.048
Тriglycerides, mmol/L M±m 1.60±0.40 1.20±0.25 0.101
ECHOCARDIOGRAPHY
Left ventricle ejection fraction (EF), % M±m 56.00±10.00 61.00±11.00 0.136
Left ventricle end diastolic volume (LVEDV), ml M±m 137.50±45.50 116.00±35.00 0.028
Estimated Pulmonary artery pressure sPAP, mmHg M±m 30.01±9.12 28.24±7.14 0.547
Treatment history, no, (%)
Beta-blockers 16 (80%) 13 (72%)
Renin angiotensin aldosterone system (RAAS) inhibitors 15 (75%) 14 (78%)
Statins 17 (85%) 15 (83%)
Acetylsalicylic acid (ASA) 19 (95%) 16 (88%)
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RESULTS AND DISCUSSION
Clinical characteristics of patients were sum- (p<0.05). There were no significant differences
marized in table 1. HFpEF patients with MI in between the other indicators and treatment
anamnesis had significantly higher cholesterol level characteristics. and left ventricle end diastolic volume (LVEDV)
Table 2
The level of MMP-2, MMP-9, galectin-3 in patients with HFpEF depending on MI anamnesis
1s group
2nd group
P
MMP-2 (ng/ml) M±m MMP-9 (ng/ml) M±m Galectin-3 (ng/ml) M±m
78.00±18.00 217.50±21.50 8.10±4.23
61,00±16.00 172.50±6.50 7.04±3.12
0.002 0.003 0.347
It was established significant differences between study groups in MMP - 2, MMP-9 levels. Particularly, HFpEF patients with MI in anamnesis had significantly higher MMP-2, MMP-9 levels on 21.8% and 20.7% respectively.
The CRP and leucocytes levels were significantly higher in 1st group pts. (fig.).
Significant differences in MMP-2, MMP-9 were established in 1st group patients in different age groups (p<0.05) (tab. 3). The MMP-2 level was positively correlated with MMP 9 level (R=0.73, p<0.05), the MMP-9 level - with age (R=0.68, p<0.05).
There were no significant differences between galectin-3 level in study group. But we estimated significant differences in galectin-3 level between 1st and 2nd subgroups (p<0.05) (tab. 3).
While cytokines and MMPs have independent effects on the myocardium, past in vitro and animal
studies have identified the ability of cytokines to regulate the transcription and synthesis of various MMPs. For example, TNF over-expression in mice led to increased protein levels of MMP-2 and -9 and TIMP-1 [4, 8, 11, 17]. Regulation of MMP synthesis includes several transcription factors that are downstream of cytokine signaling. Specifically, in fibroblasts, IL-1P stimulation has been reported to increase protein levels of MMP-2 and -9, which were attenuated with the inhibition of the transcription factor NF-kB [11]. Similarly, IL-6 can induce the expression of MMP-1 in macrophages mediated through transcriptional regulation of activator protein-1 and NF-kB [8]. By contrast, the antiinflammatory cytokine IL-10 suppressed MMP-2 synthesis by signaling through the activating transcription factor 3 and binding to the cAMP-responsive element of the MMP-2 gene [4].
Table 3
The level of MMP-2, MMP-9, galectin-3 in patients with HFpEF in different age groups
1st group 2nd group
40-59 y.o. > 65 y.o. 40-59 y.o. > 65 y.o.
MMP-2 (ng/ml) M±m 81.50±14.50* 85.50±8.50* 72.00±5.00 78.00±13.00
MM-9 (ng/ml) M±m 212.50±16.50* 219.50±19.50* 172.5±6.50 175.00±4.00
Galectin-3 (ng/ml) M±m 6.78±2.91 11.31±1.01# 6.21±2.29 9.95±0.22#
Notes: * - p< 0.05 between 1 and 2 groups, # - p<0.05 between 40-59 y.o. and >65 y.o. groups.
Galectin-3 overexpression is also a characteristic together with pathophysiology of diabetes mellitus
feature of "profibrotic" M2 macrophages: naive type 1 by inducing ß-cell apoptosis: mice ß-cells
macrophages stimulated with interleukin-4 (IL-4) from galectin-3 were resistant to inflammation-in-
and IL-13 express higher levels of galectin-3, duced cell death by counteracting mitochondrial
apoptotic pathways [6]. This is in contrast to previous research that demonstrated that intracellular galectin-3 supresses mitochondrial apoptotic pathways by preserving mitochondrial integrity [14].
In summary, the final outcome of the fibro-inflammatory response is determined by a dynamic balance between neutrophil apoptosis, macrophage and T-cell responses, fibroblast activation and
myofibroblast persistence, and intracellular galectin-3 seems to be involved in many of these responses. However, our current understanding of galectin-3-mediated apoptotic mechanisms is limited and further studies are warranted to characterize the role of intracellular galectin-3 in apoptosis of different cell types, especially in immune-cells and collagen-producing cells.
Note . * - p<0.05
CRP, leucocytes levels in patients with HFpEF depending on MI in anamnesis
Limitation
In addition to the few number of patients included in this study, we excluded from our study patients with acute coronary artery diseases and acute heart failure, because of this our results apply only to the patients with chronic coronary artery diseases and chronic heart failure.
There are many matrix metalloproteinases which involved in all cardiovascular diseases, but in our study we measured levels and activity of only MMP-2 and MMP-9.
CONCLUSION
1. Serum MMP-2, MMP-9, CRP and galactin-3 were significantly increased in pts with postinfarction heart failure with preserved ejection fraction comparing to pts without myocardial infarction in anamnesis.
2. Increased level of serum MMP-2, MMP-9, CRP were positively correlated with age reaching maximal concentration with age >65 years old in pts with postinfarction heart failure with preserved ejection fraction.
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УДК 616.2:616.61-036.1-089.843-072.7:615.37 https://doi.org/10.26641/2307-0404.2018.1(part 1).127245
О.В. Курята1, ФУНКЦ1Я ЗОВН1ШНЬОГО ДИХАННЯ
О. О. Штепа ^ у ХВОРИХ П1СЛЯ ТРАНСПЛАНТАЦП НИРКИ
О В Галущак В УМОВАХ IMyHOCynPECTBHOÏ ТЕРАПП
ДЗ «Днтропетровська медична академiя МОЗ Украти»1
кафедра внутрiшньоï медицини 2
(зав. - д. мед. н., проф. О.В. Курята)
вул. В. Вернадського, 9, Днтро, 49044, Украша
КЗ «Днтропетровська обласна клтчна лжарня iM. I.I. Мечникова» 2 вiддiлення дiалiзу (хронiчного гемодiалiзу та амбулаторного гемодiалiзу) пл. Соборна, 14, Днтро, 49005, Укра'та
SE "Dnipropetrovsk medical academy of Health Ministry of Ukraine" 1 Department of internal medicine 2 V. Vernadsky str., 9, Dnipro, 49044, Ukraine
ME "Dnipropetrovsk Regional Clinical Hospita. named after I.I. Mechnikov" 2 Department dialysis (hemodialysis and chronic ambulatory hemodialysis) Soborna sq., 14, Dnipro, 49005, Ukraine e-mail: [email protected]
Ключовi слова: функщя зовтшнього дихання, трансплантацiя нирки, iмуносупресивна тератя, циклоспорин, такролiмус
Key words: function of external respiration, kidney transplantation, immunosuppressive therapy, cyclosporine, tacrolimus
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