Role of point of care - ST2, Galectin-3 and adrenomedullin in the evaluation and treatment of emergency patients.

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 ST2, 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.

INTRODUCTION

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

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.[56] Some of the major biomarkers studied in this review are ST2, Galectin-3, and Adrenomedullin.

ST2

ST2 gene is a member of the interleukin 1(IL-1) receptor family. Receptor of ST2 consists of extra-cellular, transmembrane (ST2L), and intracellular domain which are homologous to the IL-1 receptor, although IL-1 does not bind to this site.[7] ST2 also has a decoy receptor which is the soluble ST2.[8] The ligand of ST2L is interleukin-33, which plays a role in reducing fibrosis and hypertrophy of mechanically strained tissues. ST2L transduces the effects of IL-33 whereas excess soluble ST2 causes cardiac fibrosis and ventricular dysfunction.[9101112] Concentrations of sST2 are not affected by age, renal function or body mass index.[13]

Soluble ST2 is detected in the serum of patients early after acute myocardial infarction and inversely correlates with ejection fraction. sST2 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 sST2 and many clinical markers which predict the severity of heart failure (HF) including left ventricular ejection fraction and NYHA functional classification. sST2 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 sST2 and NT-proBNP was a stronger predictor of death than either alone.[14151617]

These results were validated in another study of acutely decompensated heart failure patients where the percent change in sST2 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 sST2 concentration had a HR of 3.2 (95% CI = 2.2-4.7, P < 0.0001) compared to those with the lowest decile of sST2.[18]

The role of sST2 in cardiovascular disease diagnostics is strong, both acutely after myocardial infarction and chronically in severe chronic heart failure. As the development of sST2 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.[2223] 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.[2425]

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.[262728] 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.[3132]

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.[1734] 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

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