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SYMPOSIUM: CRITICAL POINT OF CARE BIOMARKERS IN EMERGENCY CARE
Year : 2014  |  Volume : 4  |  Issue : 3  |  Page : 261-265

Role of point of care - ST 2 , Galectin-3 and adrenomedullin in the evaluation and treatment of emergency patients


1 Department of Emergency Medicine, Baylor College of Medicine, Houston, India
2 Department of Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, India
3 Department of Emergency Medicine, University of Florida, Gainesville, Florida, USA
4 Department of Medicine, University of Delhi, New Delhi, India

Date of Web Publication23-Sep-2014

Correspondence Address:
Sarathi Kalra
Post-Doctoral Fellow, The University of Texas, Anderson Cancer Center, 1885 El Paseo Street, Apartment-515, Houston, Texas - 77054
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2229-5151.141482

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   Abstract 

There have been many technological advances improving the work up and treatment of patients in the emergency department (ED). Point of care testing (POCT) is becoming more common, especially in the time compressed clinically high-pressured environment of the emergency department. In present times, emphasis of POCT has spurred search of novel biomarkers which promise earlier and more specific detection of disease. This article reviews the role of ST 2 , Galectin-3 and Adrenomedullin in the acute care setting addressing the screening, diagnostic, and prognostic role of each marker for stratification of patients. Use of these markers has shown a strong correlation with early identification and efficient management in the ED.

Keywords: Adrenomedullin, biomarker, galectin-3, point of care, ST 2


How to cite this article:
Siler-Fisher A, Tucci V, Kalra S, Galwankar SC, Khose SD, Sanjeevani S, Goel A, Peacock FW. Role of point of care - ST 2 , Galectin-3 and adrenomedullin in the evaluation and treatment of emergency patients. Int J Crit Illn Inj Sci 2014;4:261-5

How to cite this URL:
Siler-Fisher A, Tucci V, Kalra S, Galwankar SC, Khose SD, Sanjeevani S, Goel A, Peacock FW. Role of point of care - ST 2 , Galectin-3 and adrenomedullin in the evaluation and treatment of emergency patients. Int J Crit Illn Inj Sci [serial online] 2014 [cited 2019 Oct 23];4:261-5. Available from: http://www.ijciis.org/text.asp?2014/4/3/261/141482


   Introduction Top


There have been many technological advances improving the work up and treatment of patients in the emergency department (ED). Point of care testing (POCT) is one of those advances which is becoming more common, especially in the time compressed clinically pressured environment of the emergency department. [1] POCT utilizes microtechnology in a near patient setting where testing is done at the patient's bedside with the phlebotomist, technician, and physician all in close proximity. Absence of specimen transport and storage reduces the pre-analytical phase of the testing which gives POCT an advantage. Due to development of biosensors and miniaturization of clinical laboratory analyzers, POCT has been implemented in EDs globally. The introduction of new biomarkers has undoubtedly been a giant leap forward; however, there are various novel issues that need to be validated with adequate research. POCT, if implemented properly, can play a pivotal role in rapid diagnosis and providing timely life-saving or sustaining interventions with as little as 60 μl (two drops of whole blood). Cardiac patients in the ED have the most to gain from immediate diagnosis and treatment. More than 50% of deaths occur within 6 hours of Acute Myocardial Infarct (AMI) onset and earlier intervention with reperfusion therapy can reduce the mortality of AMI. cTN levels are considered the gold standard cardiac biomarker of myocardial injury and POCT is playing a greater role in decreasing therapeutic turnaround time (TTAT). The documented decrease in TTAT is driving the interest in its further development and expanded utilization. More particularly in ACS where "time is myocardium", early treatment has reduced mortality by a large number. [2]

In the setting of emergency departments, where identification of high-risk patients carries the major concern, POCT can play an important role in triage. Triage systems help to prioritize patients with regard to severity of illness and resource needs. Historically, triage systems are based on the clinical judgment of the nurse or provider, but recently newly available POCT with handheld devices present an opportunity to add important clinical information to the ED triage process. [3] This helps to identify patients requiring immediate care or those that could benefit from earlier evaluation and treatment; for example, elevated lactate is an indication commonly used to detect tissue hypo-perfusion, particularly in the case of sepsis that requires early resuscitation to improve outcomes. In addition, several studies have demonstrated a reduction in length of stay and time in the Emergency Department bed when POCT is utilized.


   Novel biomarkers Top


In present times, emphasis on POCT has spurred interest in the search for novel biomarkers. Generally, a biomarker reflects the presence of some clinical condition yielding diagnostic and or prognostic value which allows disease staging and therapy monitoring in some cases. Biomarkers usually give insights into variable pathophysiological features such as oxidative stress, inflammation, neuro-hormonal activity, and platelet activation. The ideal biomarker must be readily available as well as reproducible with high specificity and sensitivity for an available clinical indication.

In recent years, a number of novel biomarkers have been developed which promise earlier and more specific detection of disease. Most commonly used biomarkers especially in acute cardiac care include natriuretic peptides, cardiac troponins, and C-reactive protein (CRP). When a patient has a myocardial infarction, measuring biomarkers, such as troponin released by damaged myosin, signify acute myocardial injury. Similarly this same principle applies to acute kidney injury. [4] Neutrophil gelatinase associated lipocalin (NGAL) is one of the most promising AKI biomarkers. [5],[6] Some of the major biomarkers studied in this review are ST 2 , Galectin-3, and Adrenomedullin.

ST 2

ST 2 gene is a member of the interleukin 1(IL-1) receptor family. Receptor of ST 2 consists of extra-cellular, transmembrane (ST 2 L), and intracellular domain which are homologous to the IL-1 receptor, although IL-1 does not bind to this site. [7] ST 2 also has a decoy receptor which is the soluble ST 2 . [8] The ligand of ST 2 L is interleukin-33, which plays a role in reducing fibrosis and hypertrophy of mechanically strained tissues. ST 2 L transduces the effects of IL-33 whereas excess soluble ST 2 causes cardiac fibrosis and ventricular dysfunction. [9],[10],[11],[12] Concentrations of sST 2 are not affected by age, renal function or body mass index. [13]

Soluble ST 2 is detected in the serum of patients early after acute myocardial infarction and inversely correlates with ejection fraction. sST 2 along with natriuretic peptides has been a strong contender in predicting prognosis for patients presenting with acute dyspnea. A secondary analysis of the PRIDE study demonstrated that there was a concentration dependent relationship between sST 2 and many clinical markers which predict the severity of heart failure (HF) including left ventricular ejection fraction and NYHA functional classification. sST 2 elevation showed a significant correlation in acutely decompensated HF patients (HR = 9.3, P = 0.003) and dyspnea patients (HR = 5.6, P < 0.001) in multivariable analyses and surpassed NT-proBNP for 1-year mortality. The AUC for predicting 1-year mortality was 0.80 (P < 0.001). Also, the combination of sST 2 and NT-proBNP was a stronger predictor of death than either alone. [14],[15],[16],[17]

These results were validated in another study of acutely decompensated heart failure patients where the percent change in sST 2 levels during treatment for acute HF was also predictive of 90-day mortality (AUC 0.783, P < 0.001). [16] Further analysis of 1100 patients with chronic HF in an outpatient setting showed that patients with the highest decile of sST 2 concentration had a HR of 3.2 (95% CI = 2.2-4.7, P < 0.0001) compared to those with the lowest decile of sST 2 . [18]

The role of sST 2 in cardiovascular disease diagnostics is strong, both acutely after myocardial infarction and chronically in severe chronic heart failure. As the development of sST 2 progresses, the potential utility continues to grow in guiding therapy for prevention of complications from heart failure.

Galectin-3 (Gal-3)

A member of the lectin family, Gal-3 consists of tandem repeats of short amino-acid sequences which are able to recognize beta-galactose. [19] Sharma et al. showed that gal-3 may play a biological role in the pathophysiology of heart failure through fibrosis and inflammation. That the expression of the Gal-3 gene is markedly elevated in rat models with heart failure, and the pericardial instillation of gal-3 results in a significant amount of collagen deposition, suggests that Gal-3 may play a pathophysiologic role in the genesis of heart failure. [20]

After macrophage activation, cytosolic Gal-3 shifts close to the plasma membrane and integrates in the extruding vesicles. [21] Cardiac macrophages are activated at an early stage of heart failure, and in the hypertrophied heart macrophages express Gal-3. [20] Gal-3 is also expressed in cancer cells, stromal cells and atherosclerotic lesions, although systemic levels may not be significantly elevated. [22],[23] Disseminated cancers, such as metastatic adenocarcinoma may have high levels of Gal-3 which may limit its utility as a bio-marker in heart failure, however, differentiation between disseminated cancer and heart failure can usually be done by history and physical examination. [24],[25]

One of the first clinical measurements of Gal-3 was also done in the PRIDE study, where higher levels of Gal-3 were observed in HF patients (9.2 ng/ml) compared to those without HF (6.9 ng/ml, P < 0.001). After adjusting for traditional risk factors, Gal-3 had superior ability to predict 60-day mortality after heart failure than NT-proBNP; however, NT-proBNP outperformed Gal-3 for diagnosis of heart failure. [24]

Various other studies in patients with chronic, ambulatory heart failure have shown a correlation in long-term outcomes and Gal-3. [26],[27],[28] The predictive value of Gal-3 appeared to be stronger in patients with heart failure with preserved ejection fraction (HFPEF). [29] The Controlled Rosuvastatin Multinational Trial in Heart Failure study showed that lower Gal-3 concentrations predicted an improved response to therapy with cholesterol lowering, suggesting that Gal-3 may be useful in triaging patients to different treatment groups. [28]

Adrenomedullin (ADM)

In the last few years, there has been a rising interest in mid-regional pro-adrenomedullin (MR-proADM), which is a stable portion of the prohormone adrenomedullin, released from the adrenal medulla, heart, lungs, and kidneys. [30] ADM is widely expressed and synthesized during severe infections and is a potent vasodilator, with inotropic, diuretic, natriuretic with immunomodulating properties. It also has a bactericidal activity that is further enhanced by modulation of complement activity and regulation. The plasma levels of MR-proADM increase with disease severity. [31],[32]

Khan et al. compared MR-proADM and NT-pro-BNP levels in patients after acute myocardial infarction. Both biomarkers were equally strong predictors of cardiovascular death or heart failure. [32] In the BACH study, MR-proADM was shown to be a strong predictor of death at 90 days, which added a prognostic value in addition to what was available with natriuretic peptide. [33] These results were reinforced by the data from the PRIDE study, where MR-proADM showed the best AUC for mortality at 1 year in 560 patients. However, after a year, higher AUC were seen for MR-proANP and NT-proBNP. [17],[34] Measurements of MR-proADM provided additional prognostic value when combined with those of NT-pro-BNP as the accuracy of risk prediction is enhanced.

For patients with chronic heart failure, MR-proADM has shown promising prognostic results. In a randomized trial of 297 patients with left ventricular failure, MR-proADM was measured before and after treatment with carvedilol. It was noticed that patients who had levels of MR-proADM higher than the median, had an increased risk of mortality (risk ratio = 3.92, 95%CI = 1.76-8.7) and hospitalization (risk ratio = 2.4, 95% CI = 1.3-4.5). [35]

In patients with acute dyspnea of unknown etiology, a high MR-proADM level might be a strong reason for hospitalization to an intensive care unit as opposed to a lower acuity admission disposition. Also, patients with poor prognostic markers like MR-proADM can be more closely followed up by a clinician after discharge from hospital to reduce the rate of relapse and readmission. Finally, it may also serve as a surrogate marker in therapeutic heart failure trials, although both of these latter suggestions require validation. According to one study it appears that MR-proADM might be more prognostic in patients with acute dyspnea than biomarkers currently used in clinical arena. [36] Recently MR-proADM has been shown to be a helpful prognostic tool for individual risk assessment in sepsis. MR-proADM levels increase with increasing severity of CAP. [37] Its levels have a similar prognostic accuracy as the PSI score (pneumonia severity score) and also represent an additional and easy to measure prognostic tool. Although proADM has no role to determine etiology of both acute dyspnea and sepsis, it can be used to determine a short-term prognosis. Further studies are needed where the role of MR-proADM can be considered more independently for clinical use.


   Conclusions Top


Higher ED volumes coupled with higher acuity patients requiring early identification and immediate care have prompted increased research and clinical interest in novel and more specific markers. Point of care testing plays an important role in early diagnosis, prognostication and stratification of the patients ensuring early identification and efficient management [Table 1]. A comprehensive plan involving multi-biomarker approach is not too far from implementation in the EDs and further studies would help in validation of the existing data, thereby, tailoring the needs of patients.
Table 1: Summary of studies on evaluating biomarkers ST2, Galectin-3, and Adrenomedullin in POCT

Click here to view


 
   References Top

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14.Januzzi JL Jr, Peacock WF, Maisel AS, Chae CU, Jesse RL, Baggish AL, et al. Measurement of the interleukin family member ST2 in patients with acute dyspnea: Results from the PRIDE (Pro-Brain Natriuretic Peptide Investigation of Dyspnea in the Emergency Department) study. J Am Coll Cardiol 2007;50:607-13.  Back to cited text no. 14
    
15.Rehman SU, Mueller T, Januzzi JL Jr. Characteristics of the novel interleukin family biomarker ST2 in patients with acute heart failure. J Am Coll Cardiol 2008;52:1458-65.  Back to cited text no. 15
    
16.Boisot S, Beede J, Isakson S, Chiu A, Clopton P, Januzzi J, et al. Serial sampling of ST2 predicts 90-day mortality following destabilized heart failure. J Card Fail 2008;14:732-8.  Back to cited text no. 16
    
17.Gaggin HK, Januzzi JL Jr. Biomarkers and diagnostics in heart failure. Biochim Biophys Acta 2013;1832:2442-50.  Back to cited text no. 17
    
18.Ky B, French B, McCloskey K, Rame JE, McIntosh E, Shahi P, et al. High-sensitivity ST2 for prediction of adverse outcomes in chronic heart failure. Circ Heart Fail 2011;4:180-7.  Back to cited text no. 18
    
19.Dumic J, Dabelic S, Flogel M. Galectin-3: An open-ended story. Biochim Biophys Acta 2006;1760:616-35.  Back to cited text no. 19
    
20.Sharma UC, Pokharel S, van Brakel TJ, van Berlo JH, Cleutjens JP, Schroen B, et al. Galectin-3 marks activated macrophages in failure-prone hypertrophied hearts and contributes to cardiac dysfunction. Circulation 2004;110:3121-8.  Back to cited text no. 20
    
21.Hughes RC. Secretion of the galectin family of mammalian carbohydrate-binding proteins. Biochim Biophys Acta 1999;1473:172-85.  Back to cited text no. 21
[PUBMED]    
22.Liu FT, Rabinovich GA. Galectins as modulators of tumor progression. Nat Rev Cancer 2005;5:29-41.  Back to cited text no. 22
    
23.Nachtigal M, Al-Assaad Z, Mayer EP, Kim K, Monsigny M. Galectin-3 expression in human atherosclerotic lesions. Am J Pathol 1998;152:1199-208.  Back to cited text no. 23
    
24.vanKimmenade RR, Januzzi JL, Ellinor PT, Sharma UC, Bakker JA, Low AF, et al. Utility of amino-terminal pro-brain natriuretic peptide, galectin-3, and apelin for the evaluation of patients with acute heart failure. J Am Coll Cardiol 2006;48:1217-24.  Back to cited text no. 24
    
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26.Lainscak M, Coletta AP, Sherwi N, Cleland JG. Clinical trials update from the Heart Failure Society of America Meeting 2009: FAST, IMPROVE-HF, COACH galectin-3 substudy, HF-ACTION nuclear substudy, DAD-HF, and MARVEL-1. Eur J Heart Fail 2010;12:193-6.  Back to cited text no. 26
    
27.Lok DJ, Van Der Meer P, la Porte de PW, Lipsic E, Van Wijngaarden J, Hillege HL, et al. Prognostic value of galectin-3, a novel marker of fibrosis, in patients with chronic heart failure: Data from the DEAL-HF study. Clin Res Cardiol 2010;99:323-8.  Back to cited text no. 27
    
28.Gullestad L, Ueland T, Kjekshus J, Nymo SH, Hulthe J, Muntendam P, et al. Galectin-3 predicts response to statin therapy in the Controlled Rosuvastatin Multinational Trial in Heart Failure (CORONA). Eur Heart J 2012;33:2290-6.  Back to cited text no. 28
    
29.de Boer RA, Lok DJA, Jaarsma T, van der Meer P, Voors AA, Hillege HL, et al. Predictive value of plasma galectin-3 levels in heart failure with reduced and preserved ejection fraction. Ann Med 2011;43:60-8.  Back to cited text no. 29
    
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[PUBMED]    
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32.Khan SQ, O′Brien RJ, Struck J, Quinn P, Morgenthaler N, Squire I, et al. Prognostic value of midregional pro-adrenomedullin in patients with acute myocardial infarction: The LAMP (Leicester Acute Myocardial Infarction Peptide) study. J Am Coll Cardiol 2007;49:1525-32.  Back to cited text no. 32
    
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34.Shah RV, Truong QA, Gaggin HK, Pfannkuche J, Hartmann O, Januzzi JL Jr. Mid-regional pro-atrial natriuretic peptide and pro-adrenomedullin testing for the diagnostic and prognostic evaluation of patients with acute dyspnea. Eur Heart J 2012;33:2197-205.  Back to cited text no. 34
    
35.Richards AM, Doughty R, Nicholls MG, MacMahon S, Sharpe N, Murphy J, et al. Plasma N-terminal pro-brain natriuretic pep-tide and adrenomedullin: Prognostic utility and prediction of benefit from carvedilol in chronic ischemic left ventricular dysfunction. Australia-New Zealand Heart Failure Group. J Am Coll Cardiol 2001;37:1781-7.  Back to cited text no. 35
    
36.Maisel A, Mueller C, Nowak RM, Peacock WF, Ponikowski P, Mockel M, et al. Midregion prohormone adrenomedullin and prognosis in patients presenting with acute dyspnea: Results from the BACH (Biomarkers in Acute Heart Failure) trial. J Am Coll Cardiol 2011;58:1057-67.  Back to cited text no. 36
    
37.Christ-Crain M, Morgenthaler NG, Stolz D, Müller C, Bingisser R, Harbarth S, et al. Pro-adrenomedullin to predict severity and outcome in community-acquired pneumonia. Crit Care 2006;10:R96.  Back to cited text no. 37
    



 
 
    Tables

  [Table 1]


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