Резюме
Дорошенко О.В. Значення підвищеного тропоніну у клінічній практиці.
Огляд присвячено тропонін-діагностиці в клінічній практиці, диференційній діагностиці підвищеного рівня тропоніну при різних причинах пошкодження міокарда, як ішемічних, так і не пов’язаних з ішемією. Розглядаються основні причини, механізми підвищення тропоніну, прогностична цінність у хворих із неішемічними причинами розвитку пошкодження міокарда.
Ключові слова: тропонін, пошкодження міокарда, діагноз, прогноз.
Резюме
Дорошенко О.В. Значение повышенного тропонина в клинической практике.
Обзор посвящен тропонин-диагностике в клинической практике, дифференциальной диагностике повышенного уровня тропонина при различных причинах повреждения миокарда, как ишемических, так и не связанных с ишемией. Рассматриваются основные причины, механизмы повышения тропонина, прогностическая ценность у больных с неишемическими причинами развития повреждения миокарда.
Ключевые слова: тропонин, повреждение миокарда, диагноз, прогноз.
Summary
Doroshenko O.V. The value of increased troponin in clinical practice.
The review is devoted troponin-diagnosis in clinical practice, differential diagnosis of elevated troponin at different causes of myocardial damage as ischemia and non-ischemia. The main causes, mechanisms elevations, predictive value in patients with non ischemic causes of myocardial injury.
Key words: troponin, myocardial injury, diagnosis, prognosis.

Рецензент:  д.мед.н., проф. Ю.Г. Бурмак

УДК 616-07-036

Харківська медична академія післядипломної освіти

Харьковская медицинская академия последипломного образования

61176, г. Харьков, ул.Корчагинцев, 58

Kharkov medical academy of Postgraduate Education

61176, Kharkov, 58 str.Korchahyntsev 

dorosenkoo@i.ua

Determining the level of cardiac troponins I and T are the basis of modern laboratory diagnosis of myocardial infarction [35]. New high-sensitivity troponins (hscTn) can detect minimal myocardial  injury, increasing the number of patients with elevated troponin and thus humper  interpretation of troponin results. In clinical practice, it is difficult to interpret changes in troponin in conditions such as stroke, pulmonary embolism, sepsis, acute pericarditis, myocarditis,  Tako-tsubo, acute heart failure, tachycardia, etc. .. Should be able to properly evaluate elevated troponin  and differentiate acute coronary syndrome from other states.

Acute myocardial infarction ( MI ) is defined as myocardial cell death due to prolonged myocardial ischemia. According to the recommendations of the European Society of Cardiology (ESC), the American College of Cardiology Foundation (ACCF), American Heart Association (AHA), the World Heart Federation (WHF) [ 40] , the definition of MI is based on the identification of rise and/or fall of cardiac biomarkers ( mainly - troponin ) together with ischaemic symptoms, electrocardiography (ECG) changes of new ischaemia, development of pathological Q-waves in the ECG or evidence of new loss of myocardial viability or  new regional wall motion abnormality.

The Tn protein complex is a part of the contractile system of muscle cells and is highly specific regulatory proteins of myocardial contractile elements linked to miofilaments [19]. It is composed of three proteins: troponin T, which forms a bond with tropomyosin, troponin I, which blocks ATP- activity and troponin C, which has a significant affinity for Ca 2 + [17]. The content of cardiac troponin T dominated over the level of troponin I. Troponin T cardiac muscle differs from troponin T from other muscles. The priority is to identify troponin T and I because of the high sensitivity and specificity.

The death of cardiomyocytes is not immediately, it takes about 20 minutes [ 22]. Complete necrosis of all myocardial cells at risk requires at list 2-4 hours or longer depending on the presence of collateral circulation  in the ischemic zone, persistent or intermittent coronary artery occlusion, the sensitivity of myocytes to ischemia, etc. [ 40]. The release of myocardial proteins may be due to different mechanisms, as a result of the normal process of replacement cells apoptosis, the release of  products degradation of troponins, high  cell membrane permeability and myocardial necrosis [43]. Small amounts of myocardial injury with necrosis may be detected, which are associated with heart failure (HF), renal failure, myocarditis, arrhythmias, pulmonary embolism, percutaneous coronary interventions or surgical coronary procedures. These should not be determined as MI or a complication of the procedures, but rather as myocardial injury [ 40]. Quite difficult to distinguish between the causes of an acute increase of troponins from chronic.

Blood samples for the measurement of cTn should be drawn on first assessment and repeated 3–6 h later. Later samples are required if further ischaemic episodes occur, or when the timing of the initial symptoms is unclear [4].

To establish the diagnosis of MI, a rise and/or fall in values with at least one value above the decision level is required. Increasing the level of appropriate quality control is defined as troponin values ​​exceeding the 99th percentile of normal values ​​for the reference population (upper reference limit - URL). 99th percentile as a diagnostic level, above which MI is diagnosed, should be determined in each laboratory with adequate quality control [28]. Optimum precision  the coefficient of variation  (CV) at the  99th percentile URL for each assay should be as ≤ 10 %. Better precision (CV ≤10%) allows for more sensitive assays [6].

Troponin in myocytes contained in two pools: a structural, located in myofibrils, and cytosolic - free from myofibrils condition. This cytosolic pool  get into the blood in the early development of myocardial injury. hscTn tests fix  this early exit cytosolic troponins to blood flow and reflect the dynamics of the process. Relatively long out of troponins damaged myofibrils associated with more severe myocardial damage. It is believed that troponin leaks out of structural pool is synonymous with cell death, and the leaks from the cytosolic pool can be either reversed or permanent damage [21]. This is due to the difficulty of standardizing hscTn tests. Highly sensitive determination of troponins based on monoclonal antibodies that recognize different epitopes cTn. Such epitopes may be too much. Moreover, in different patients they may be different, but in the same patient ratio of these epitopes may change during development of ACS, and it is possible varies in recurrent ACS. This variability of epitops and dynamics of heterogeneous populations of circulating troponins leads to include in test a lot of different antibodies to improve their sensitivity. As a result, tests of different companies have different sensitivity values​​, different values of  ​​the 99th percentile ​​and different diagnostic levels. For example, the 99th percentile from hscTnI Singulex Erenna is 8.0 ng / L, test hscTnI Abbott ARCHITECT - 12 ng / l, test hscTnT Roche - 14 ng / l, test hscTnI PATHFAST Mitsubichi - 20 ng / L, test hsTnI ADVIA Centaur Siemens - 40 ng / L) [1]. Overall, these data show that the comparison of absolute concentrations of troponins obtained by testing different companies, it is impossible [30].

A new approach to the diagnosis of ACS was to develop a highly sensitive method of measuring the concentration of cardiac troponins (hscTn - high sensitive cardiac troponin). Through the use of new technologies lower levels of cardiac troponins reduced to 10-100 times. Average normal value is 2.5 ng / l, and at 99th percentile - 14-20 ng / l, coefficient of variation <10 %. Better, but not highly sensitive cTn tests detect troponin in less then 50 % of healthy individuals, first generation hscTn tests - at 50-75% , the second generation hscTn tests - from 75 to 95% , the third generation hscTn tests – at 95% of "healthy" individuals [3].

For the diagnosis of MI must be at least once rise of  troponin with clinical symptoms. Determination of rise of  troponin with its further reduction is necessary for differential diagnosis of acute and chronic increases of troponin associated with heart disease [35].

Rise of  troponin without further its dynamics, or without   typical clinical features should give the idea of ​​another etiology of myocardial injure as myocarditis, aortic dissection, pulmonary embolism, heart failure and other non- ischemic causes ( Table 1)

TABLE 1. Diagnostic value of hs-cTnT [18]

In the group of asymptomatic patients with end-stage renal disease (ESRD) exceeded the value of the troponin 99th percentile using a new highly sensitive test analysis in 100 % of cases. For patients with ESRD is recommended concentration of troponin ≥ 20 % for the diagnosis of MI in patients with rise of troponin defined through 6-9 hours after admission [29]. The recommendations for the diagnosis and treatment of renal diseases indicated that elevations in ESRD due to heart failure and increased left ventricular mass, left ventricular dysfunction, increased natriuretic hormone NT-proBNP, rather than atherosclerosis or ischemia [24]. It is believed that patients with reduced renal function elevations not associated with reduced renal clearance, but associated with  the risk of adverse outcome [34 ].

In clinical pactice, the increased concentration of troponin sometimes observed after prolonged episodes of supraventricular tachyarrhythmias probably even healthy individuals. The most likely mechanism in this case may be  shortening of diastole followed by subendocardial ischemia [23]. In animal studies, myocardial stretch is believed to represent a second possible mechanism for tachycardia-mediated troponin elevation as there exists a direct association between a parallel rise in natriuretic peptide and troponins concentrations in patients with various tachycardias [8]. It was hypothesized that the release from viable cardiomyocytes  can be mediated by stimulation of  stretch-responsive integrins, mechanotransducer molecules that link the extracellular matrix to the intracellular cytoskeleton [37]. A recent study GISSI-Atrial Fibrillation investigators found that higher concentrations of myocardial strain or injury markers like hsTnT, MR-proANP, NT-proBNP, and endothelin predicted higher risk of a first recurrence of AF in 382 patients having sinus rhythm but with a history of recent AF [25 ]. These data suggest that concomitant structural heart disease is closely associated with the recurrence of AF [41 ].

In the ADHERE study examined 67,924 patients with acute decompensated heart failure (HF ) and proven relationship between elevated  troponin and adverse events [2]. Use less sensitive troponin determinations led to positive results in 6% of patients. These patients had lower systolic blood pressure at admission and lower ejection fraction, higher hospital mortality than patients with negative troponin. The results of this study confirmed by another study involving 1256 patients with acute decompensated heart failure [31]. Causes of elevated troponin in acute heart failure has not been fully resolved. It is consider that increased ventricular preload causing myocardial strain may cause troponin release [32 ]. May suggest that elevated baseline troponin is the result of physiological loss as a result of myocardial necrosis and apoptosis. Approximately 1 g of myocardial mass is lost per year [16]. However, the relative contribution of necrosis and apoptosis is difficult to establish. In a study [42 ], which included 40 patients with acute HF, demonstrated that troponin significantly lower in patients with dilated cardiomyopathy than in those with ischemic cardiomyopathy. At present not clear whether the different levels of troponin in patients with acute versus chronic heart failure.

Despite the fact that troponin is not in the pericardium, its level is elevated in approximately 32-49 % of cases of acute pericarditis as a result of involvement of the epicardium in the inflammatory process [7]. Troponin elevations reflect myocardial lesion as acute pericarditis with signs of myocarditis ( global or regional myocardial dysfunction or elevated troponin ) is defined as myopericarditis. Clinical studies in patients with myopericarditis rare. When comparing patients with pericarditis and myopericarditis we can see that patients with myopericarditis were younger, more often occurred febrile syndrome, gastrointestinal symptoms and/or myalgia, and ST- segment elevation [ 27]. Limited data have been published about myopericarditis. Seroepidemiologic studies indicate that most cases of Coxsackie B virus have a benign course. Increased troponin indicates myocardial involvement in the inflammatory process, but unlike acute coronary syndrome, it is not a sign of adverse prognosis in patients with myopericarditis. During long-term follow-up it has been reported a good clinical outcome [11]. After 12 months, the frequency of complications was similar in patients with pericarditis and myopericarditis with normalization of echocardiography, ECG, tredmil-test in most cases. Pathophysiology of myocarditis is poorly studied. Primary myocarditis, suggest results from the development of acute viral infection or post-viral autoimmune response. In patients with myocarditis is demonstrated the advantage of coronary vasospasm [12]. Thus, myocardial inflammation and viral persistence, or both factors can cause coronary vasomotor disorders with coronary vasospasm, which may be the cause of atypical chest pain in patients with myocarditis requiring differential diagnosis of ischemic heart disease [41 ]. In this case, a powerful diagnostic tool is a magnetic resonance imaging (MRI ) [ 13].

The clinical course of pulmonary embolism can have a wide range of clinical outcomes - from quick recovery to sudden death. Patients with pulmonary embolism and signs of shock or hypotension have a high mortality rate. It is believed that these patients should receive thrombolytic therapy [38]. If thrombolytic therapy is contraindicated, preferred surgical embolectomy. Can be made catheter embolectomy or remove fragments of thrombus [38]. Among patients with stable hemodynamics at admission, right ventricular dysfunction by echocardiography to detect patients at risk nosocomial mortality [ 33]. Among patients with PE elevations observed in 32-50 % of cases. It is assumed that the release of troponin is the result of  right ventricle dilation due to increased pressure in the pulmonary artery, and a decrease in coronary perfusion, hypoxia as a result of disturbance of perfusion and ventilation. However, troponin levels significantly lower than the concentration in the MI and remains elevated for a short period of time. In patients with pulmonary embolism, which is accompanied by elevated levels of troponin, the risk of adverse prognosis increased more than 10 times [20]. Elevated troponin was associated with higher mortality in the subgroup of patients with stable hemodynamics [5].

About 50 % of patients with severe sepsis and septic shock have impaired ventricular function. Elevations in troponin correlate with the presence of left ventricular systolic dysfunction [ 9, 10 ]. Among patients with sepsis in the 12-85 % found elevated levels of troponin [ 26]. Several studies have shown that elevated levels of troponin is a predictor of mortality in patients with sepsis [39 ] and is caused by fever, tachycardia, systemic hypoxia, microcirculatory dysfunction, hypotension and anemia. As a result consumption of  oxygen by myocardium does not meet their needs and leads to ischemia and damage of cardiomyocytes. Local and systemic factors of inflammation , including tumor necrosis factor α, interleykyn -6, bacterial endotoxins lead to the direct damage of the myocardium [15].

Increased troponin levels determined for all types of stroke - ischemic, haemorrhage intracerebral, subarachnoid haemorrhage [36]. In a recent meta- analysis of 15 studies including 2901 patients with acute stroke, 18% of patients had elevated troponin levels [14]. Most studies showed a link between elevated troponin and adverse prognosis. According to the meta-analysis, acute stroke with positive troponin often accompanied by myocardial ischemia on ECG and the risk of death compared with patients with normal troponin levels [14].

Thus, we can conclude that the determination of troponin is the standard for diagnosis of acute myocardial infarction, serial measurement of hscTn can confirm or exclude the diagnosis of AMI in the first hours after admission. Level hscTn, corresponding to 99th percentile, is specific for different diagnostic kits from different manufacturers. Elevated hscTn may be associated with non-ischemic causes that should be identify and interpret. In all cases, increased hscTn is predictor of adverse events.

Література

1. Вельков В.В. Революция в кардиологии; высокочувствительное измерение кардиальных тропонинов: «тропонин-отрицательных больше нет» / В.В. Вельков // Клинико-лабораторный консилиум. - 2011. - № 4 (40). - C. 24-43.
2.  ADHERE Investigators. Cardiac troponin and outcome in acute heart failure / W.F. Peacock, T. De Marco, G.C. Fonarow [et al.] // N. Engl. J. Med. - 2008. - Vol. 358. - P.2117–2126.
3. Apple F.S. A new season for cardiac troponin assays: it’s time to keep a scorecard / F.S. Apple // Clin. Chem. – 2009. - Vol. 55. - P. 1303–1306.
4. Assessing the requirement for the six-hour interval between specimens in the American Heart Association classification of myocardial infarction in epidemiology and clinical research studies / A.R. MacRae, P.A. Kavsak, V. Lustig [et al.] // Clin. Chem. - 2006. - Vol. 52. - P. 812-818.
5. Becattini C. Prognostic value of troponins in acute pulmonary embolism: a meta-analysis / C. Becattini, M.C. Vedovati, G. Agnell // Circulation. - 2007. - Vol. 116. - P. 427–433.
6. Being rational about – precision: a statement from the Biochemistry Subcommittee of the Joint European Society of Cardiology/American College of Cardiology Foundation/ American Heart Association/World Heart Federation Task Force for the definition of myocardial infarction / A.S. Jaffe, F.S. Apple, D.A. Morrow [et al.] // Clin. Chem. - 2010. - Vol. 56. - P. 941-943.
7. Brandt R.R. Circulating cardiac troponin I in acute pericarditis / R.R. Brandt, K. Filzmaier, P.Hanrath // Am. J. Cardiol. - 2001. - Vol. 87. - P. 1326–1328.
8. Cardiac natriuretic peptides and continuously monitored atrial pressures during chronic rapid pacing in pigs / W. Qi, H. Kjekshus, R. Klinge[et al.] // Acta Physiol. Scand. - 2000. - Vol. 169. - P. 95–102.
9. Cardiac troponin I predicts myocardial dysfunction and adverse outcome in septic shock / N.J. Mehta, I.A. Khan, V. Gupta [et al.] // Int. J. Cardiol. - 2004. - Vol. 95. - P.13–17.
10. Cardiac troponins I and T are biological markers of left ventricular dysfunction in septicshock / K.M. Ver Elst, H.D. Spapen, D.N. Nguyen [et al.] // Clin. Chem. - 2000. - Vol.46. - P. 650–657.
11. Clinical outcome and left ventricular function 23 years after acute Coxsackie virus myopericarditis / J. Remes, M. Helin, P. Vaino [et al.] // Eur. Heart J. - 1990. - Vol. 11. - P. 182–188.
12. Coronary vasospasm as the underlying cause for chest pain in patients with PVB19 myocarditis / A. Yilmaz, H. Mahrholdt, A. Athanasiadis [et al.] // Heart. - 2008. - Vol. 94. - P. 1456–1463.
13. Delayed enhancement cardiovascular magnetic resonance assessment of nonischemic cardiomyopathies / H. Mahrholdt, A. Wagner, R.M. Judd [et al.] // Eur. Heart J. - 2005. - Vol. 26. – Р. 1461–1474.
14. Elevated troponin after stroke: a systematic review / G. Kerr, G. Ray, O. Wu [et al.] // Cerebrovasc Dis. - 2009. - Vol. 28. - P. 220–226.
15. Endotoxin and tumor necrosis factor challenges in dogs simulate the cardiovascular profile of human septic shock / C. Natanson, P.W. Eichenholz, R.L. Danner [et al.] // J. Exp. Med. - 1989. - Vol. 169. - P. 823–832.
16. Gender differences and aging: effects on the human heart / G. Olivetti, G. Giordano, D. Corradi [et al.] // J. Am. Coll. Cardiol. - 1995. – Vol. 26. - P. 1068–1079.
17. Higgins J.P. Elevation of cardiac troponin I indicates more than myocardial ischemia / J.P. Higgins, J.A. Higgins // Clin. Invest. Med. - 2003. - Vol. 26 (3). - P. 133–147.
18. High-sensitive cardiac troponin: friend or foe? / R. Twerenbolder, T. Reichlin, M. Reiter [et al.] // Swiss Med. Wkly. - 2011. - Vol. 141. - P. E1-E5.
19. Human cardiac troponin T: identification of fetal isoforms and assignment of the TNNT2 locus to chromosome 1q / P.J. Townsend, H. Farza, C. MacGeoch [et al.] // Genomics. - 1999. - Vol. 21 (2). - P. 311–316.
20. Independent Prognostic Value of Cardiac Troponin T in Patients With Confirmed Pulmonary Embolism / E. Giannitsis, M. Muller-Bardorff, V. Kurowski [et al.] // Circulation. – 2000. – Vol. 102. – Р. 211-217.
21. Jaffe A.S. Troponin Release—Reversible or Irreversible Injury? Should We Care? / A.S. Jaffe, A.H. Wu // Clinical Chemistry. - 2012. - Vol. 58. - P. 148–150.
22. Jennings R.B. Structural changes in myocardium during acute aschemia / R.B. Jennings, C.E. Ganote // Circ. Res. - 1974. - Vol 35, Suppl. 3. - P. 156-172.
23. Jeremias A. Alternative causes for elevated cardiac troponin levels when acute coronary syndromes are excluded / A. Jeremias, M.Gibson // Ann. Intern. Med. - 2005. - Vol.142. - P. 786–791.
24.  Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2012 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease // Kidney international. - 2013. - Suppl. 3. - P. 1–150.
25. Latini R. Circulating cardiovascular biomarkers in recurrent atrial fibrillation: data from the GISSI-Atrial Fibrillation Trial / R. Latini, S. Masson, S. Pirelli [et al.] // J. Intern. Med. – 2011. - Vol.266, Iss.2. - P. 160-171.
26. Lim W. Elevated cardiac troponin measurements in critically ill patients/ W Lim, I Qushmaq, P.J. Devereaux // Arch. Intern. Med. - 2006. - Vol.166. - P. 2446–2254.
27. Myopericarditis vs. viral or idiopathic acute pericarditis. Frequency, clinical clues to diagnosis, and prognosis / M. Imazio, E. Cecchi, B. Demichelis [et al.] // Heart. - 2008. - Vol. 94. - P. 498–501.
28. National Academy of Clinical Biochemistry and IFCC committee for standardization of markers of cardiac damage laboratory medicine practice guidelines: analytical issues for biochemical markers of acute coronary syndromes/ F. Apple, R.L. Jesse, L.K. Newby [et al.] // Circulation. - 2007. - Vol. 115. - P. 352-355.
29. National Academy of Clinical Biochemistry laboratory medicine practice guidelines: use of cardiac troponin and B-type natriuretic peptide or N-terminal proB-type natriuretic peptide for etiologies other than acute coronary syndromes and heart failure / A.H. Wu, A.S. Jaffe, F.S. Apple [et al.] // Clin. Chem. - 2007. - Vol. 53. - P. 2086–2096.
30. Negative interference in cardiac troponin I immunoassays by circulating troponin autoantibodies / S. Eriksson, H. Halenius, K. Pulkki [et al.] // Clin. Chem. - 2005. - Vol. 51. - P.839–847.
31. NT-proBNP testing for diagnosis and short-term prognosis in acute destabilized heart failure: an international pooled analysis of 1256 patients: the International Collaborative of NT-proBNP Study / J.L. Januzzi, R. van Kimmenade, Lainchbury [et al.] // Eur. Heart J. - 2006. - Vol. 27. - P. 330–337.
32. Preload induces troponin I degradation independently of myocardial ischemia / J. Feng, B.J. Schaus, J.A. Fallavollita [et al.] // Circulation. - 2001. - Vol. 103. - P. 2035–2037.
33. Prognostic role of echocardiography among patients with acute pulmonary embolism and a systolic arterial pressure of 90 mm Hg or higher / N. Kucher, E. Rossi, M. De Rosa, [et al.] // Arch. Intern. Med. - 2005. - Vol. 165. - P. 1777–1781.
34. Prognostic value of troponin T and I among asymptomatic patients with end stage renal disease: a meta-analysis / N.A. Khan, B.R. Hemmelgarn, M. Tonelli [et al.] // Circulation. - 2005. - Vol. 112. - P. 3088.
35.  Recommendations for the use of cardiac troponin measurement in acute cardiac care / K. Thygesen, J. Mair, H. Katus [et al.] // Eur. Heart J. - 2010. - Vol. 31. - P. 2197-2204.
36.  Relation of cardiac troponin I levels with in-hospital mortality in patients with ischemic stroke, intracerebral hemorrhage, and subarachnoid hemorrhage / R. Sandhu, W.S. Aronow, A. Rajdev [et al.] // Am. J. Cardiol. - 2008. - Vol. 102. - P. 632–634.
37. Release of cardiac troponin I from viable cardiomyocytes is mediated by integrin stimulation / M.H. Hessel, D.E. Atsma, E.J. van der Valk [et al.] // Pflugers Arch. - 2008. - Vol. 455. - P. 979–986.
38. Task force for the diagnosis and management of acute pulmonary embolism of the European society of cardiology. Guidelines on the diagnosis and management of acute pulmonary embolism: the task force for the diagnosis and management of acute pulmonary embolism of the European society of cardiology (ESC) / A. Torbicki, A. Perrier, S. Konstantinides [et al.] // Eur. Heart J. - 2008. - Vol. 18. - P. 2276–2315.
39. The cardiovascular response of normal humans to the administration of endotoxin / A.F. Suffredini, R.E. Fromm, M.M. Parker [et al.] // N. Engl. J. Med. - 1989. - Vol. 321. - P. 280–287.
40. The writing group on behalf of the joint ESC/ACCF/AHA/WHF task force for the universal definition of myocardial infarction. Third universal definition of myocardial infarction / K. Thygesen, J. S. Alpert [et al.] // Circulation. - 2012. - Vol.126. - P. 2020-2035.
41. Troponin elevation in coronary vs non-coronary disease / S. Agewall, E. Giannitsis, T. Jernberg [et al.] // Heart J. - 2011. - Vol. 32. - P. 404–411.
42. Troponin, B-type natriuretic peptides and outcomes in severe heart failure: differences between ischemic and dilated cardiomyopathies / W.L. Miller, K.A. Hartman, M.F. Burritt [et al.] // Clin. Cardiol. - 2007. - Vol. 30. - P. 245–250.
43. White H.D. Pathobiology of troponin elevations / H.D. White // J. Am. Coll. Cardiol. - 2011. - Vol. 57. - P. 2406-2408.