1KHAMITOVA A.F., 1DOZHDEV S.S., 1ZAGIDULLIN S.Z., 2LAKMAN I.A., 1GAREEVA D.F., 1,2ZAGIDULLIN N.S.
1Bashkir state Medical University, Russia, 450008, Ufa, Lenin Str. 3
2Ufa State Aviation University, Russia, 450000, Ufa, K. Marx Str.12
Cardiospecific biomarkers in different variants of myocardial infarction
Abstract. Background. Acute coronary syndrome and its complications are one of the main reasons of mortality and invalidization in Russian Federation. New modern biomarkers such as ST2, NTproBNP and Pentraxin-3 (Ptx-3) provide more opportunities in the diagnostics of disease and in calculation of future cardiovascular events.
Keywords: ST2, NT-proBNP, pentraxin-3, cardiovascular events, myocardial infarction.
Contact person:
Khamitova Aisylu Farizovna
cardiologist, post-graduate student of the department of propaedeutics of internal diseases Federal State
Educational Institution of Higher Education BSMU, Russia, 450008, Ufa, Lenin Str. 3, phone: 89874738117, e-mail:
Этот адрес электронной почты защищен от спам-ботов. У вас должен быть включен JavaScript для просмотра.
Abbreviation:
MI - Myocardial infarction,
IHD - Ischaemic Heart Disease,
CAG - coronary angiography,
AIA - anterior interventricular artery,
EA - envelope artery,
RCA - right coronary artery,
LKA - left coronary artery,
LVEF - left ventricular ejection fraction,
Cholesterol - cholesterol,
LDL - low density lipoproteins,
TG - triglycerides,
AST - aspartate aminotransferase,
ALT - alanine aminotransferase,
CPK MB - creatine phosphokinase MB fraction
Background. The mortality from cardiovascular diseases and coronaryheart disease (CHD), in particular, is leading in the Russian Federation [3]. IHD (Ischaemic Heart Disease) and its most formidable manifestation - myocardial infarction (MI) can cause both immediate (cardiogenic shock, ventricular fibrillation, etc.), and long-term complications. In particular, MI increases the incidence of death from cardiovascular events, repeated myocardial infarction, strokes and the development of heart failure. Cardiospecific biomarkers after electrocardiograms are the main method of diagnosis of MI. Their concentration also correlates with the severity of the event, and it is possible to determine the risk of developing cardiovascular events in the future.
Along with classical biomarkers, such as CPK-MB, AST and already entered into clinical practice by cardiospecific troponin, new biomarkers appear. ST2 stimulating growth factor is the interleukin-1 receptor family member (IL-1). The increased ST2 concentration circulating in the blood indicates a high risk of HF and death among patients with MI both with and without ST segment elevation [8, 9, 11, 13]. It is a reliable biomarker of risk stratification for both patients with heart failure and patients with cardiovascular diseases as well as for the population as a whole [2, 5, 17]. Pentraxine-3 (Pentraxin-3, Ptx-3), belongs to the pentraxins superfamily. There is evidence that increased Ptx-3 secretion is typical for patients with Ischemia, including those associated with acute coronary syndrome and high plasma levels of Ptx-3 are adverse clinical outcomes predictors among patients with heart failure [14]. The Ptx-3 level increase in peripheral blood is associated with the diastolic dysfunction presence between both patients without CHF signs and with CHF with a preserved left ventricular ejection fraction (LVEF) [19]. BNP and NT-proBNP are peptide hormones, which are decremented in response to the cardiomyocytes stretching due to increased pressure or volume. Determination of the level of natriuretic peptides, in particular NT-proBNP, is a reliable screening test for the CHF diagnosis, CHF risk stratification and its prognosis [1, 2, 12]. According to a lot of researchers, NT-proBNP concentration dynamics can be judged on the therapy effectiveness and select the medications dose. CONSENSUS II and SAVE [15] confirmed that NT-proBNP evel is a prognostic factor indicating a death risk, acute myocardial infarction recurrence and CHF development among both patients with MI and with unstable angina that lacked signs of cardiomyocyte necrosis, determined by troponin I level increasing. Based on the numerous studies results, NT-proBNP level increase is an independent prognostic factor of mortality while suffering from CHF [1].In accordance with the modern topical MI classification [3], there are different options for MI development, namely Q/non-Q MI, with and without ST elevation. Since biomarkers are associated with various myocardial damage parts, it seems important to analyze the biomarker profile, depending on the myocardial infarction variants.
Aim. To study the biomarker profile characteristics among patients with different myocardial infarction variants.
Materials and methods. The study carried out on the cardiology and intensive care units of the Regional Clinical Hospital of the City Clinical Hospital No. 21 in Ufa basis. 180 patients(61, 4 ± 1, 7 years) who were hospitalized with the «ACS» diagnosis and who had been verified by MI were examined. Diagnosis verification carried out by clinical, electrocardiographic, echocardiographic, laboratory and Xray research methods
Inclusion criteria:
• Age over 18 years;
• The ACS diagnosis upon admission was established according to the recommendations of Russian Society of Cardiology: the presence of damage markers (troponin I and / or CPK MV), clinical symptoms in the form of chest pain lasting more than 20 minutes, not stopped by taking nitroglycerin, the presence on the ECG of ST segment elevation and / or change in the t wave in two adjacent leads, or the first complete blockade of LNPG;
Informed consent.
• Non-inclusion criteria:
• More than 10 days from ACS development moment;
• Congenital and acquired heart defects;
• Heart conduction disorder: sick sinus syndrome, atrioventricular blockade of II and III degrees;
• Chronic kidney disease 2a and more of severity;
• Pulmonary artery thromboembolism and malignant neoplasms in the anamnesis;
• Chronic obstructive pulmonary disease and other respiratory diseases;
• Acute infectious diseases and exacerbation of chronic diseases at the time of enrollment;
• Pregnancy, early postpartum period, lactation period.
The therapy was carried out in accordance with clinical recommendations. The research was carried out in accordance with the good clinical practice standards as well as Helsinki Declaration principles. The reserachwas approved by the local ethics committee at the FGBOU in the BSMU of the Ministry of Health of the Russian Federation and the State Health Insurance Bureau of the City Clinical Hospital No. 21 in Ufa. All participants provided us with written informed consent prior to joining the research. After MI, NT-proBNP, ST2 and pentraxine-3 biomarkers concentration was determined by an enzyme immunoassay using test systems from Critical diagnostics (USA), Biomedica (Slovakia) and Hycult biotech (USA), respectively. The current biomarkers were determined upon admission to
a hospital with acute coronary syndrome. The statistical analysis was carried out with "Statistica 10.0" program help. Data are presented as mean values (M), and errors of the mean square (m). As statistical criteria for determining the differences in subgroups, the parametric t-test for paired variables was used and, in the case of an incorrect distribution, the nonparametric Mann-Whitney criterion. Qualitative features were analyzed while using Chi-square parameter. The null differences absence hypothesis was rejected at a significance level of p <0.05. Pearson correlation used to determine the relationship between the indicators in the groups, where the coefficient was more than 0.70 showed a strong relationship between the indicators, from 0.30 to 0.70 – a moderate relationship, less than 0.30 – a weak relationship.
Results.All patients were divided into several comparison pairs during the research: for the 1st main criterion, the presence/absence of the ST segment was chosen, for the 2nd one - the presence/absence of the abnormal Q wave, for the 3rd and 4th pairs
- the value in norm / above the norm of biomarkers ST2 and NT-proBNP. Men predominated (136) in comparison with women (44) among the patients studied. The following concomitant diseases were met: arterial hypertension (AH, n = 167, 92%), MI (42, 23%) and diabetes mellitus (DM, 31, 17%). Throughout the follow-up, standard therapy was performed among patients with MI, the primary percutaneous intervention (PCI) in the infarct-dependent artery was used among 132 (73.3%) patients and while having contraindications - thrombolytic therapy - 26 (14.4%). ST2, NTproBNP, Ptx-3 were evaluated at the time of admission to hospital. Table 1 shows the patients characteristics in the group (Table 1).
A serum biochemistry was taken and an enzyme immunoassay was performed at the time of admission to the hospital. Table 2 shows the average indicators values (Table 2).
NT-proBNP normal values range from 0-200 pg/ml, and a rise of more than 200 pg/ml is heart failure characteristic. The normal range for men is 8.5 - 49.3 ng/ml and for women - 7.1-33.5 ng/ml for ST2. The normal performance for Ptx-3 hasn’t been currently
developed.
The data were analyzed sequentially in pairs, depending on Q/non-Q myocardial infarction presence; OXpST / OXBESST and depending on the normal ST2 and BNP indicators excess.
Depending on the Q/non-Q myocardial infarctionю The patients number with Q-MI was 149 (82.1%), and with non-QMI-31 (17.2%) - Table 3.
Women in the non-Q-MI group were more met than in the Q- I MI and strokes in the anamnesis were met with approximately the same frequency. High levels of cholesterol and LDL were risk factors for Q-MI (p = 0.0275 and p = 0.042, respectively), but not with non-Q-MI. Besides the standard damage markers concentration (troponin T, CPK MB, AST and ALT) was significantly higher in the group with Q-MI (p <0.05). At the same time, the ST2 and Ptx-3 biomarkers did not differ between groups, in contrast to NT-proBNP (p = 0.013), which was larger in the Q-MI group. In the group with non-Q MI, a strong Pearson correlation was found between ST2 and NTproBNP (r = 0.75, p = 0.034), the mean force between NT-proBNP and P-3 (r = 0.52, p = 0.023), (r = 0.56, p = 0.034), moderate between ST2 and Ptx-3 (r = 0.45, p = 0.066) and serum glucose level and NT-proBNP (r = 0.48, p = 0.013).
Depending on the ST segment presence/absence. Further, the patients were divided into groups with STEMI and nonSTEMI and compared to each other. Patients with nonSTEMI were somewhat older than in the group with STEMI (p = 0.011) and MI in the history was more often determined with STEMI (p = 0.024). At the same time, cholesterol and LDL and HDL were not risk factors for any of the groups (p> 0.05). Standard enzymes also did not differ among themselves, including troponin (p> 0.05). At the same time, in the c group nonSTEMI ST2 and NT-proBNP were significantly higher (both p <0.001), in contrast to Ptx-3 (p = 0.068) (Table 4). Correlation analysis between ST2 and NT-proBNP (r = 0.45, p = 0.023) and between ST2 and Ptx- 3 in the group with STEMI revealed a
moderate correlation (p = 0.056).
Depending on the normal / pathological ST2. Patients with high ST2 occurred more often in older age group (p = 0.01) and significantly more often in women (p = 0.0031). The myocardial infarction and strokes frequency did not differ between groups (p> 0.05),
as well as "standard" biomarkers (AST, ALT, CFC MB), cholesterol and its fractions (p> 0.05), but the differences were determined in "new "Biomarkers - ST2 (p <0.001) and Ptx-3 (p <0.001) (Table 5). In the group with an elevated ST2 level between ST2 and NT-proBNP, a direct correlation was found between the mean force (r = 0.51, p <0.001) and the inverse correlation between NT-proBNP and LVEF (r = -0.51, p <0.001). The mod erate strength correlation between NT-proBNP and serum glucose was determined (r = 0.5, p <0.001) in the group with normal ST2 values.
Depending on the normal/patho logical NT-proBNP. In the group with pathological NT-proBNP, patients were signifi cantly older than in the normal group (55.94 ± 2.16 vs. 64.98 ± 2.24 years, p <0.001) and were more common in women. Cholesterol and LDL cholesterol and HDL cholesterol were comparable between groups (p> 0.05). Glucose was higher in the group with high NT-proBNP (p = 0.015), which corresponds to a difference in the incidence of diabetes between groups (9.84% vs. 22.01%, p = 0.172). If among the "standard" biomarkers only AST was larger in the group of high NT-proBNP, then all 3 "new" biomarkers significantly differed among themselves (p <0.05) (Table 6). In the group with high NT-proBNP, a moderate correlation relationship between ST2 and NT-proBNP (r = 0.45, p = 0.018) was determined.
Discussion. Biomarkers are the ACS diagnosis cornerstone. They are able to assess the complications risk in the early and remote period. When comparing the groups with Q/non-Q, the risk factors for Q-MI development were males, high cholesterol and LDL.
Besides the standard biomarkers (troponin, CPK MB, AST and ALT) were significantly higher for Q-MI. As is known, Q-MI is characterized by a large damage amount to the myocardium [3, 16]. The significant NT-proBNP level in the Q-MI group is probably associated
with both ischemic damage to cardiomyocytes and the onset of remodeling processes in the myocardium. ST2 and Ptx-3 in this group did not differ between the subgroups and NT-proBNP appeared to be more sensitive and specific for the characteristics of this group. In the STEMI group compared to nonSTEMI group, factors such as glucose level, presence of diabetes, ST2 and NT-proBNP were more significant. Since the ST segment rise is typical for an earlier MI development period, it is assumed that these biomarkers levels are associated with the inflammation processes and endothelial dysfunction development. In the group with high ST2, greater age factors (p = 0.003), male gender, high glucose level and Ptx-3 were significant. Moderate increase in the concentration of ST2 is probably protective, which is manifested among patients with a favorable disease course [2, 8]. However, adverse effects are developing with the marked ST2 level increase. It is known that the transmembrane form protects the myocardium from overload, while the soluble ST2 form interferes with this defense mechanism by binding interleukin-33, and blocks its cardioprotective effect [10, 16]. Probably, ST2 concentration increase in the unfavorable MI course is associated with an increase in the soluble marker form formed when cardiomyocytes are damaged. At the same time, MI activates the humoral and cellular links of the immune response, which is a necessary condition for scarring of the necrosis zone and contributing to ST2 level increase [17, 18]. Stimulating factor concentration increase appears due to the pronounced decompensation of hemodynamics and the proinflammatory status activation in ischemia/reperfusion conditions [11]. Ptx-3 value turned out to be significant in this subgroup for the same reason. In addition, research of patients with myocardial infarction or heart failure also showed that ST2 levels correlated with glucose and were higher in diabetic patients than those who did not have diabetes [7].
The elevated ST2 and NT-proBNP biomarkers level in this group only confirms the fact that ST2 is a marker of both hemodynamic stress and can reflect inflammation, fibrosis, and the unfavorable myocardial remodeling processes [8]. It should be noted that ST2 correlates with both insulin resistance/endothelial dysfunction markers and LV dysfunction, as reflected in various researches [4, 8, 9, 12]. Significant factors in the group with a high level of NTproBNP were age, sex, glucose, AST and new biomarkers. This correlation in the NT-proBNP group probably indicates that it is a more specific and sensitive biomarker, which level changes together with new and traditional biomarkers. More than once in studies there was a low specificity of ST2, for example, in the CLARITY-TIMI 28 research, NT-proBNP was compared and ST2: ST2 level was only moderately correlated with NT-proBNP (r = 0.14). In the joint ST2 analysis with NT-proBNP, statistical reliability increased from 0.82 (95% CI 0.77-0.87) to 0.86 (95% CI 0.81- 0.90, p = 0.017). The combination of ST2 with NT-proBNP significantly increases risk stratification [17]. Although there is evidence that, an assessment of the level of ST2 allows you to predict the risk of developing maladaptive remodeling with greater sensitivity and specificity compared to NT-proBNP [2].
The use of two or more biomarkers from different pathogenetic classes in multimarker analysis allows obtaining additional prognostic information and seems to be a rational and reliable modern strategy for the risk of stratification of patients with ACS [5, 6, 12]. Most multimarker approaches include the addition of new promising biomarkers to well-studied risk factors [6, 15]. Further, the determination of cardiovascular endpoints in 1-2 years, taking into account the results obtained in this study, will allow forming a multimarker scale of risk assessment for development of adverse cardiovascular end points (deaths, heart attacks, strokes, hospitalizations).
Conclusion.
1. High levels of glucose, ST2 and NT-proBNP, and DM were risk factors for MI with ST-segment elevation.
2. Male gender, high levels of cholesterol and LDL cholesterol was characteristic for Q-IM.
3. The group with high ST2 was characterized by male sex, older age, high glucose levels and Ptx-3, and in the group with elevated NT-proBNP – similar factors and increased "new" biomarkers and AST.
4. Long-term monitoring determining the final cardiovascular endpoints will facilitate the creation of predictive assessment of short-term and longterm risk.
Acknowledgments: was accomplished with "Umnik" grant support.
Literature
1. Бугримова М. А. Мозговой натрийуретический пептид как маркер и фактор прогноза при хронической сердечной недостаточности / Бугримова М. А., Савина Н. М., Ваниева О. С., Сидоренко Б. А. // Кардиология. – 2006. –№ 1. – С. 51–57.
2. Груздева О.В. Значение стимулирующего фактора роста ST2 и NTproBNP в оценке постинфарктного ремоделировании сердца / Груздева О.В., Дылева Ю.А., Учасова Е.Г. и др. // Российский кардиологический журнал. – 2015. -№12(128). –С. 63-71.
3. Редакционная статья Третье универсальное определение инфаркта миокарда / Редакционная статья // Российский кардиологический журнал. -2013.-№2. – С. 3-16.
4. Bayes-Genis A. ST2 pathogenetic profile in ambulatory heart failure patients / Bayes-Genis A., Januzzi J.L., Gaggin H.K., et al. // J Card Fail. – 2015. - №21 (4). – С. 355-361.
5. Bayes-Genis A. Multimarker testing with ST2 in chronic heart failure / BayesGenis A., Richards A.M., Maisel A.S., et al. // Am J Cardiol.- 2015. - №115 (7 Suppl). - С. 76B-80B.
6. Chow S.L. Role of Biomarkers for the Prevention, Assessment, and Management of Heart Failure /Chow S.L. Maisel A.S., Anand I., et al. // A Scientific Statement from the American Heart Association. – 2017. -№135 (22). -С.1054-1091.
7. Fousteris E. Toll/interleukin-1 receptor member ST2 exhibits higher soluble levels in type 2 diabetes, especially when accompanied with left ventricular diastolic dysfunction / Fousteris E., Melidonis A., Panoutsopoulos G. et al. // CardiovascDiabetol. – 2011. -№10. - 101.
8. Jenkins W.S. Prognostic Value of Soluble ST2 after Myocardial Infarction: A Community Perspective / Jenkins W.S., Roger V.L., Jaffe A.S. // Am J Med. - 2017. - №130 (9). - 1112.e9-1112.e15.
9. Yu J. Improved early risk stratification of patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention using a combination of serum soluble ST2 and NT-proBNP / Yu J., Oh P.C., Kim M., et al. // PLoS One. -2017.- №12 (8).- e0182829.
10. Kischkel F.C. Apo2L/TRAIL-dependent recruitment of endogenous FADD and caspase-8 to death receptors 4 and 5 / Kischkel F.C., Lawrence D.A., Chuntharapai A., et al. // Immunity. – 2000. –№12. - P. 611-620.
11. Kohli Т.Р. Role of ST2 in Non–ST-Elevation Acute Coronary Syndrome in the MERLIN-TIMI 36 / Kohli Т.Р., Bonaca M.P., Kakkar R. et al. // Clinical Chemistry. – 2012. - №58. – Р.257–266.
12. Ky B. Multiple biomarkers for risk prediction in chronic heart failure. / Ky B., French B., Levy W.C., et al. // Circ Heart Fail. – 2012. - №5 (2). - P. 183-90.
13. Lupón J. Combined use of the novel biomarkers high-sensitivity troponin T and ST2 for heart failure risk stratification vs conventional assessment / Lupón J., de Antonio M., Galán A. // Mayo Clin Proc. – 2013. - №88 (3). – Р. 234-243.
14. Matsubara J. Pentraxin 3 is a new inflammatory marker correlated with left
ventricular diastolic dysfunction and heart failure with normal ejection fraction / Matsubara J., Sugiyama S., Nozaki T. et al. // J Am CollCardiol. - 2011. - №57 (7). – Р. 861–869.
15. Mukherjee R. Selective spatiotemporal induction of matrix metalloproteinase-2 and matrix metalloproteinase-9 transcription after myocardial infarction /Mukherjee R., Mingoia J.T., Bruce J.A., et al. // Am J Physiol Heart Circ Physiol. - 2006. - №291. – Р.2216-2228.
16. Nilsson L. Soluble TNF receptors are associated with infarct size and ventricular dysfunction in ST-elevation myocardial infarction / Nilsson L., Szymanowski A., Swahn E., et al. // PLoS One. – 2013. - №8. - e55477.
17. Sabatine M.S. Complementary roles for biomarkers of biomechanical strain ST2 and N-terminal prohormone B-type natriuretic peptide in patients with ST-elevation myocardial infarction / Sabatine M.S., Morrow D.A., Higgins L.J. et al. // Circulation. – 2008.-№117. – Р. 1936–1944.
18. Soejima H. Increased serum matrix metalloproteinase-1 concentration predicts advanced left ventricular remodeling in patients with acute myocardial infarction / Soejima H., Ogawa H., Sakamoto T. et al. // Circ J. – 2003. - №67. – Р. 301-304.
19. Suzuki S. Pentraxin 3, a new marker for vascular inflammation, predicts adverse clinical outcomes in patients with heart failure /Suzuki S., Takeishi Y., Niizeki T. et al. // Am Heart J. – 2008. - №155 (1). – Р. 75–81.
