Indian Journal of Biochemistry & Biophysics Vol. 55, October 2018, pp. 303-313

A Review

A review on application of biomarkers in

Bobbala Indumathi, Shiva Krishna Katkam & Vijay Kumar Kutala* Department of Clinical Pharmacology & Therapeutics, Nizam’s Institute of Medical Sciences, Hyderabad-500 082, India Received 03 May 2018; revised 22 May 2018

Heart failure (HF) remains the leading cause of death in the elderly population. Since last decade there is an advance in the field of biomarkers in managing these patients. Hence identifying novel and potential biomarkers that help in accessing the risk, predicting the disease and monitoring the prognosis is very crucial in reducing the overall morbidity and mortality. These biomarkers are elevated mainly in response to myocardial stress, dynamic changes in extracellular matrix, myocyte necrosis, oxidative stress, and inflammation. The that has good clinical correlations may be useful in diagnosis, prognosis, and therapeutic management of HF. Understanding the role of each biomarker and their clinical implication is very crucial. In this review, we summarize the attainments and challenges of using different types of biomarkers in HF.

Keywords: Atrial natriuretic peptide, B-type natriuretic peptide, Galectin-3, Heart failure, High sensitivity , Natriuretic peptides, Neutrophil gelatinase-associated lipocalin, Peptides, ST2

Heart failure (HF) is generally a chronic condition and is heart to pump blood at proportionate rate to the major public health problem in developed countries metabolizing tissues during regular activity9. The like the USA with a prevalence of over 5.8 million, and various factors such as ischemic heart disease (IHD), over 23 million worldwide1,2. India is the second most hypertension, obesity, diabetes, age, sex, smoking, populous country in the world and cardiovascular alcohol consumption, renal disease, sleep apnea, and diseases (CVDs) are the main cause of morbidity and depression are known to be the risk factors for HF10,11. mortality3-6. The global burden of the disease study has HF is seen more in men than women, and its revealed that the age-standardized cardiovascular disease prevalence greatly increases with aging. Different death rate was 272/100000 population in India, which is models (hemodynamic model, cardio-renal model, higher than the global average of 235/100000 neurohumoral model, abnormal Ca+2 cycling model, population7. A recent study survey from rural north India cell death model) have been proposed to explain adult population of 10163 patients revealed that 1.3% of unique mechanisms involving in HF12. The them exhibit chronic breathlessness and 9% (1.2/1000) hemodynamic changes that result in HF are primarily of the population had HF, among which 33% of the ventricular remodeling, renal failure, extracellular patients were found to have systolic dysfunction. In the matrix (ECM) remodeling, myocardial fibrosis and same study, they also showed that the prevalence of HF myocardial necrosis. As a result of these pathogenic in individuals below 30 years was 22.5% and above mechanisms, the various kinds of biomarkers will be 50 years was 14.9%, indicating that most of the young released into the body fluids which are useful in population are affected with HF8. diagnosis, severity and estimating the HF prognosis Heart failure is a pathological state in which an with appropriate therapy. abnormality of myocardial function, failure of the Biomarkers ————— Biomarkers are substances that are elevated in an *Correspondence: Phone (Mob.): +91-9395532288 early stage of disease and also during the disease E-mail: [email protected] progression which helps in assessing the risk Abbreviations: ANP, Atrial Natriuretic Peptides; BNP, Brain associated with each stage of the disease. The natriuretic peptide; CHF, Chronic heart failure; CNPs, Circulating biomarkers play an important role in HF which natriuretic peptides; EF, Ejection fraction; Gal-3, Galectin-3; GDF- provides the information about the mechanisms 15, Growth differentiation factor-15; H-FABP, Heart-type Fatty involved in specific types of HF and helps in identify Acid Binding protein, HF, Heart Failure; NGAL, Neutrophil 13 gelatinase-associated lipocalin; NT-proBNP, N-terminal pro b-type the patients at higher risk . The biomarkers are natriuretic peptide; ST2, Growth stimulating expressed gene 2 proteins that are released from the particular sites in 304 INDIAN J. BIOCHEM. BIOPHYS., VOL. 55, OCTOBER 2018

the body in response to stress or damage and that can these markers have been tested and introduced for be objectively measured and evaluated as an indicator their clinical use in chronic HF (Fig. 1). of normal biologic or pathogenic processes or the 14 response to a therapeutic intervention (Table 1). Natriuretic peptides Several promising novel biomarkers have been Natriuretic peptides (NPs) are considered the gold identified for the diagnosis and prognosis of HF and standard and they were recognized as important tested for their clinical utility in chronic HF which predictors in patients with HF16. The heart secretes includes those of myocardial stretch: brain natriuretic natriuretic peptides in response to the homeostatic peptide (BNP), NT-proBNP, mid-regional pro- signal to maintain the cardio-renal homeostasis. In adrenomedullin (MR-pro ADM), markers of myocyte humans, the peptides are classified based on the origin injury such as and other biomarkers that which consists of peptides with a 17-amino acid show promising utility in HF are C-reactive protein disulfide ring structure those are cardiac origin- ANP, (CRP), Galectin-3 (Gal-3), Interleukin-6 (IL-6), ST-2, BNP, renal origin-urodilatin, and endothelial origin- neutrophil gelatinase-associated lipocalin (NGAL), circulating natriuretic peptides (CNPs). These three growth differentiation factor-15 (GDF-15)15. Some of peptides are involved in the maintenance of cardio-

Table 1—Heart failure diagnostic performance of various biomarkers

Biomarker Optimal cut-point Rule out Grey zone Rule in Sensitivity specificity Ref BNP 100 pg/mL <100 pg/mL 100-400 pg/mL >400 pg/mL 100% 97.1% 36 NT-proBNP 300 pg/mL <300 pg/mL 300-450 pg/mL >450 pg/mL - - 36 NT-proBNP <50 years - - - >450 pg/mL 97% 93% 36 NT-proBNP 50-75 years - - - 900 pg/mL 90% 82% 36 NT-proBNP >75 years - - - 1800 pg/mL 85% 73% 36 ST2 140.0 pg/mL - - 263.3 pg/mL - - 42 Galectin-3 1.4-94.8 ng/mL - - - - - 50 GDF-15 1200-1800 ng/mL - - - - - 70 NGAL 60-123 ng/mL - - - - - 81 hsTnT 14 ng/mL - - - - - 94

Fig. 1—Various biomarkers and pathways involved in the development of heart failure INDUMATHI et al.: ROLE OF BIOMARKERS AND THEIR CLINICAL IMPLICATIONS 305

renal homeostasis and all have cardio-renal protective be useful in the assessment of the efficacy of the properties. NPs elicit their physiological action treatment for HF. However, in the last few years, due through natriuretic peptide receptors (NPR) A, B, and to higher stability, BNP determinations were preferred C binding, which activates the guanylate cyclase to to ANP for diagnostic and prognostic use in HF. produce cGMP, a classic intracellular second messenger. The protein kinases G (PKGs) are like Circulating natriuretic peptides serine and threonine kinases that are activated by Circulating natriuretic peptides (CNPs) belongs to a cGMP binding to exert their mechanism of action on family of natriuretic peptides, mainly produced by targeted tissues17. endothelial cells plays an important role in cardiovascular homeostasis, regulation of local blood Atrial natriuretic peptides (ANP) flow, systemic blood pressure, and vascular tone25. A Atrial natriuretic peptide (ANP) is a 28-amino acid study reported that exogenous and endogenous CNPs peptide that is secreted from the atria in response to may protect the heart from ischemia-reperfusion atrial wall stretch caused by increased intravascular injury26. CNPs infusion in post- 18,19 volume or cardiac transmural pressure . The reduces cardiac fibrosis and LV hypertrophy26. Another biosynthesis of ANP takes place in the ventricles and study found that CNPs levels were higher in patients its expression increased in HF. In order to maintain the with low EF, which clearly indicates that CNPs acts as normal cardio-renal homeostasis, the secreted ANP an antihypertrophic and antifibrotic factor in the perfuse into the coronary sinus and distributed into heart27. 20 various target organs to exert endocrine functions . In other study observed that the plasma levels of ANP exerts a wide range of protective effects on cGMP and CNPs were significantly elevated in HF various organs, including the heart, blood vessels, compared with the levels observed before the HF kidneys, and lung and possesses natriuretic, vasoactive, induction. CNPs infusion caused similar (about and renin-inhibiting actions. In humans, it causes 2.5 fold) increases in plasma cGMP concentrations diuresis and natriuresis and reduces the blood from baseline and were significantly higher in HF, 21 pressure . The plasma levels of ANP in normal suggesting an enhanced response in HF28. The individuals are found to be 20 pg/mL and are elevated intravenous infusion of CNPs decreases blood 10-100 fold in patients with CHF. Both ANP and pressure, cardiac output, urinary volume, and sodium NT-proANP have been used as markers for the excretion. Furthermore, the hypotensive effects of diagnosis of asymptomatic LV dysfunction and plasma CNPs are less than those of ANP and BNP, but ANP levels have been shown to correlate with the strongly stimulate cGMP production and inhibit 22 severity of symptomatic HF . Ham et al. have reported VSMC proliferation20. While all 3 NP isoforms inhibit that elevated plasma ANP levels in patients with low the renin–angiotensin–aldosterone system (RAAS), ejection fraction, reflects the severity of CHF and CNPs unlike ANP and BNP failed to induce 22 cardiac dysfunction . It has been reported that in significant hemodynamic changes in sheep, such as patients with severe chronic CHF, ANP infusions in depression of cardiac output, reduction in blood pharmacologic doses have to shown to possess the pressure, and plasma volume contraction20,29, beneficial effects on cardiac function by reducing the supporting the widely accepted concept that ANP and 23 preload and after load . In a study, Bold et al. have BNP are the major circulating NPs, whereas CNPs is reported that ANP is elevated in the presence of HF in largely considered a local regulator of vascular proportion to the severity of the disease, suggesting structure/tone. that ANP might be important in the pathophysiology of 24 cardiac failure . In another study Okamoto et al. have B-type natriuretic peptide (BNP) investigated the molecular mechanism of ANP/GC-A Brain natriuretic peptide (BNP) is a member of a signaling in endothelial cells, and observed that ANP family of four human natriuretic peptides that share a acts on vascular endothelial cells and exerts protective common 17-peptide ring structure30. Brain natriuretic effects like anti-fibrotic and inflammatory effects in peptide (BNP), also referred to as B-type natriuretic BLM-induced pulmonary fibrosis by attenuating the peptide and emerged as an important biomarker in the phosphorylation of Smad2 in TGF-β signaling24. The diagnosis of CHF, myocardial infarction, right-sided determination of plasma ANP levels is a sensitive heart failure and in acute pulmonary embolism (PE). indicator of the degree of severity of CHF and it might The function of BNP is to counteract volume overload 306 INDIAN J. BIOCHEM. BIOPHYS., VOL. 55, OCTOBER 2018

by inducing vasodilation, natriuresis, and diuresis31. gender influence the plasma BNP levels, BNP is released in response to myocardial stretch due interpretation should be made for the independent to pressure or volume overload conditions in patients effects of age and sex39. In recent study, it with CHF and promotes diuresis and vasodilation and was observed that elevated hs-CRP levels and they correlated with New York Heart Association NT-proBNP ≥25 ng/mL in men aged 50 years were functional classifications31. Generally, BNP is found to be predictive biomarkers for HF over a produced as a 108 amino acid polypeptide precursor, 21 years follow up40 known as pro BNP and subsequently cleaved to the 76-peptide, which is biologically inert N-terminal ST2 cardiac biomarker fragment and the 32-peptide, biologically active BNP ST2 is a protein biomarker which is encoded by the hormone. Both the fragments are released into the gene called IL1RL1. ST2 is an interleukin (IL)-1 plasma in equimolar ratio, and have clinical importance receptor family member and has two isoforms namely in evaluation and management of CHF32,33. as soluble ST2 (sST2) and a membrane-bound receptor form (ST2L). ST2 protein is elevated when Daily monitoring of concentrations of BNP levels cardiac myocytes encounter mechanical stress. ST2L and body weight for 60 days on 163 patients with HF exhibits function like antihypertrophic, antifibrotic signs and symptoms of acute clinical heart failure and antiapoptotic effects by binding to the functional decompensation (ADHF) has indicated that the utility ligand, interleukin-33 (IL-33)41. Soluble ST2 form of home finger-stick BNP measurements and competes for IL-33 and makes it unavailable to the improves the clinical outcome and prevents hospital ST2 receptor, which results in the blockage of the readmissions34. BNP has a lesser half-life of 20 min, IL-33/ST2 pathway (cardio protective), hence elevated which exactly reflects ventricular status, whereas sST2 levels may cause increased cardiac stress. NT-proBNP has a half-life of 1-2 h35. While the use Patients with pulmonary arterial hypertension of cut-off value has been criticized for clinical showed increased serum sST2 levels and associated usefulness, the specific cut-off values may provide with right ventricular dilatation and systolic criterion in correlating with relevant statistical dysfunction signifying sST2 as a candidate biomarker thresholds. Defined cut off values has been given to in the setting of pulmonary arterial hypertension42. both BNP and NT-proBNP. Normal healthy The sST2 levels were measured in 100 patients with individuals without HF may have BNP levels AMI resulting in LV systolic dysfunction and gradual <100 pg/mL. If the levels exceeding >400 pg/mL the decrease of median sST2 levels from 263.3pg/mL at person may likely to have HF. Whereas, NT-proBNP baseline to 140.0 pg/mL at 24 weeks (P >0.001).This levels >450 pg/mL at age <50 years, between at age study confirms that the serum sST2 levels may be 50-75 years, >900 pg/mL and at age >75 years, useful in understanding the pathophysiological >1800 pg/mL likely to have HF36. The elevated levels changes in ventricular and infarct re-modelling after of the plasma BNP are shown to be more particularly AMI43. A nested case-control study on 36 cases of related to left ventricular hypertrophy (LVH) and sudden cardiac deaths (SCD) and 63 control patients serve as a vital plasma biomarker for ventricular observed with elevated sST2 concentrations are hypertrophy in dialysis patients with end-stage renal predictive of SCD in patients with chronic HF44. A disease (ESRD). BNP levels were much higher in study on 151 patients with chronic HF due to left patients with CHF than in those without CHF ventricular systolic dysfunction was followed up over (990±550 vs 80±67 pg/mL, P <0.0001) and also 10 months and measured NT-proBNP, sST2, patients with systolic dysfunction had higher BNP GDF-15, and hsTnT on every follow-up. Among all levels than those with preserved systolic function the studied biomarkers, only sST2 serial measurement (1180±641 vs 753±437 pg/mL, P =0.03). A cutoff have found to be independently associated with the BNP blood concentration of 200 pg/mL had a cardiovascular (CV) risk and predicted the reverse sensitivity of 100%, a specificity of 97.1%, the myocardial remodeling45. A study on 1401 patients positive predictive value of 97.3%, and negative (age of 67 years among which 61% of them were predictive value of 100%. Hence the measurement of men) with myocardial infarction were followed up to BNP levels is a very useful biomarker in the diagnosis 5 years and their sST2 measurements revealed 51% of of CHF in patients presenting to the emergency the patients exhibited increased levels of sST2, 388 department with dyspnea37,38. But as the age and persons died and 360 developed HF indicating that INDUMATHI et al.: ROLE OF BIOMARKERS AND THEIR CLINICAL IMPLICATIONS 307

sST2 levels are associated with the HF and high risk P =0.003), sudden death [HR: 1.83, 95% CI: of death46. 1.14-2.94), P =0.012], and the coronary end point (HR: 1.48, 95%CI 1.03-2.12, P =0.035). However, Galectin-3 adjustment for NT-proBNP had no longer Galectin-3 (Gal-3) is a β-galactosidase binding significance indicating the limited use of Gal-3 in the lectin, is majorly produced from activated prognosis of elderly patients with systolic HF in macrophages and binds to extracellular matrix clinical practice55. The data from 2 large cohorts proteins, such as fibronectin or laminin and cell [CORONA and Coordinating study evaluating surface receptors. Gal-3 is primarily involved in the Outcomes of Advising and Counseling in Heart inflammation and cardiac fibrosis which is an important Failure (COACH)] of patients revealed that repeated contributor to the pathophysiology of LV systolic and measurements of Gal-3 levels may provide an diastolic dysfunction47. Gal-3 has also had a role in important prognostic value in identifying patients tumour development, progression of atherosclerosis, with HF at elevated risk for subsequent HF morbidity diabetes and pulmonary hypertension48-50. and mortality56. A study on 592 patients with HF In normal human hearts, the expression of galectin- revealed that Galectin-3 levels were correlated with 3 is minimal and is detectable in the plasma of all the higher IL-6 and CRP levels (P =0.002) and also age categories with the clinical reference range of LVEF has an interaction with the predictive value of 1.4-94.8 ng/mL. However, as the disease progresses, plasma galectin-3 in patients with preserved LVEF (n Gal-3 becomes rapidly and significantly up regulated at =114) compared to patients with reduced LVEF 57 peak of fibrosis. Analysis of 1092 healthy individuals (P=0.001) . A follow-up study on 232 patients with aged ≥55 years showed that the 95% of them have mean age of 71 ± 10 years, 72% were male with normal reference interval of 3.8-21.0 ng/mL51. Gal-3 chronic HF (96% were in New York Heart concentrations were found to be higher in women Association functional class III) revealed that 98 along with men and the concentrations were also patients died and Gal-3 was a significant predictor of 57 shown to be influenced by age, diabetes, mortality risk after adjustment for age and sex . Gal- hypertension, hypercholesterolaemia, body mass 3 was also associated with renal dysfunction index and renal function52. (r =−0.619, P = 0.001) and increased in patients with Myocardial tissue biopsies collected from the higher NT-proBNP levels (r =0.265, P =0.001). Both murine models showed that increased expression of galectin-3 levels (20.1 ± 8.1 vs. 17.5 ± 7.4 ng/mL, Gal-3 along with activated myocardial macrophages P =0.01) and NT-proBNP levels (577 ± 751 vs. specifically in the rats that later rapidly developed 363 ± 477 pmol/L, P =0.01) were significantly 58 into HF. Further, the infusion with Gal-3 in the elevated in patients who died, than in survivors . pericardial sac of normal, healthy rats led to the Serial echocardiography was performed at baseline development of cardiac re-modelling with left and at 3 months on 240 HF patients and showed ventricular dysfunction and 3fold elevated expression decreased left ventricular end-diastolic volume of collagen I over collagen III indicating its critical (LVEDV) was associated with lower levels of Gal-3 role in the HF and disease progression53. Gal-3 compared to patients in whom the LVEDV was stable concentrations were measured in 3353 participants in or increased indicating Gal-3 is an independent the Framingham Offspring Cohort and they were marker for ventricular re-modelling and mortality in 59 follow-up for a period of 11.2 years among which 166 patients with chronic HF . Galectin-3 is found to be participants developed HF and 468 died during the superior to sST2 in distinguishing heart failure with follow-up time and Gal-3 was associated with risk for preserved ejection fraction (HFpEF) from controls 60 incident HF and mortality (HR 1.28, CI 1.14 to and HFrEF . The inhibition of galectin-3 using 1.43, P =0.0001)54. In a controlled rosuvastatin N-acetyl lactosamine inhibitor attenuates the cardiac multinational study in heart failure (CORONA) on fibrosis, LV dysfunction, and development of HF. 1462 participants, aged >60 years with systolic Hence, the drugs against Gal-3 may be useful in 59 ischemic heart failure (HF) revealed that Gal-3 was preventing HF with extensive fibrosis . significantly associated with the primary endpoint (HR 1.53 CI 1.10-2.12, P =0.011) as well as all-cause Growth differentiation factor-15 (GDF-15) (HR:1.61, 95% CI 1.20-2.29, P =0.002) and GDF-15 is a member of the TGF-β cytokine super- cardiovascular mortality (HR: 95%1.70 CI 1.19-2.42, family, which is expressed in response to tissue hypoxia, 308 INDIAN J. BIOCHEM. BIOPHYS., VOL. 55, OCTOBER 2018

inflammation, acute injury and oxidative stress. GDF-15 ST-segment elevated myocardial infarction with was first cloned from a human placental cDNA library increased levels of GDF-15 and found to be and the deduced sequence revealed that identical to associated with the higher risk of death during the macrophage inhibitory cytokine-1 (MIC-1)61. GDF-15 is one-year follow-up. The mortality rates at 1 year were generally expressed on the surfaces of various tissues 2.1, 5.0, and 14.0% in patients with GDF-15 levels including the heart, lung, brain, prostate and colon62. 1200, 1200-1800, and >1800 ng/L, respectively GDF-15 is involved in the various biological process (P =0.001)72. Similarly, Anand et al. measured the including growth arrest, differentiation, cell protection, circulating concentration of GDF-15 and observed and immune response61. It is a stress-responsive cytokine abnormally high (>1200 ng/L) in 85% of patients with widely expressed in cardiomyocytes, macrophages, HF. The higher levels of plasma GDF-15 was found adipocytes, vascular smooth muscle cells, and to be associated with features of worse HF and endothelial cells in a pathological condition, its biomarkers of neurohormonal activation, expression is induced and increased by several stimuli inflammation, myocyte injury, and renal such as inflammatory cytokines, ischemia/reperfusion, dysfunction73. Dinh et al. observed significantly and neurohormones62. elevated levels of GDF-15 in patients with LVDD 74 GDF-15 is emerging as a prognostic biomarker grade I (P <0.001) compared to controls (P =0.003) . in patients with HF. GDF-15 gene is shown to be Several studies have also reported the higher plasma up-regulated in cultured cardiomyocytes due to GDF-15 levels in patients with cardiovascular nitrosative stress and also GDF-15 level was also pathologies such as CAD or CHF that provides induced in cardiomyocytes subjected to simulated prognostic information well beyond the established 75,76 ischemia/reperfusion (I/R) and protects from I/R clinical and biochemical markers . 63 injury . GDF-15 levels were higher in CAD patients Neutrophil gelatinase-associated lipocalin (NGAL) with CHF than those in coronary atherosclerosis Neutrophil gelatinase-associated lipocalin (NGAL) 64,65 patients without CHF and healthy controls . Plasma is also known as lipocalin-2 (lcn2) which is a 25 kDa GDF-15 is an independent predictor of ischemic protein and member of the lipocalin super family77. 66 stroke in patients with hypertension . GDF-15 levels NGAL is majorly expressed by neutrophils and 67 are associated with LVH in hypertensive patients various epithelial cells in response to inflammation and can differentiate HF with a normal diastolic and oxidative stress77. NGAL is primarily, a kidney 68 function from asymptomatic LVDD . GDF-15 have a biomarker and is elevated in blood and urine samples role in the metabolism of type I and type III collagen of humans in response to acute kidney injury (AKI). turnover specifically collagen degradation that may Recent studies have identified NGAL as a potential 69 affect the cardiac function . Doubling in biomarker which is elevated in acute and chronic concentrations of GDF-15 was associated with a heart failure (AHF, CHF), coronary heart disease 2.5 fold increased rate of cardiovascular events in (CHD), and stroke78-82. 70 patients with stable ischemic heart disease . The evaluation of serum NGAL levels in 91 A study measured GDF-15, together with patients with acute decompensated heart failure C-reactive protein, cardiac troponin I, CKMB and (ADHF) (n=91) revealed that patients had NT-proBNP levels in plasma at time points of 12 h significantly higher serum NGAL levels who later and 36 h after surgery. The GDF-15 level was found developed worsening renal function versus than those to be increased significantly at 12 h after surgery, without worsening renal function (194 ng/mL vs attaining nearly 2.5 times the baseline levels 128 ng/mL, P =0.001) and 7.4 fold increased risk of (P <0.001) correlated positively with cTnI developing WRF, with a sensitivity of 86% and (P =0.003). The release of the cardiac-enriched GDF- specificity of 54%83. A study on 121 patients admitted 15 reflected the extent of myocardial injury as for acute HF was screened for BNP, cystatin C, measured by cTnI release into circulation71. and NGAL. Patients with higher NGAL levels Postoperative plasma GDF-15 was found to be the (167.5 ng/mL) were associated with 2.7 fold-increase best biomarker to predict the pre-operative cardiac in the risk of death84. Elderly patients with CHF injury, compared with cTnI, CK-MB, and Euro showed a significantly higher levels of NGAL SCORE II71. Kempf et al. determined the mortality 458.5 ng/mL vs 37.8 ng/mL (P =0.0001) in case rate to the risk of death during one-year follow-up in control study and also increased in parallel with the INDUMATHI et al.: ROLE OF BIOMARKERS AND THEIR CLINICAL IMPLICATIONS 309

clinical severity of CHF. Hence the prognostic value release is either due to myocyte stretch or injury, may of NGAL may be beneficial for elderly patients in the contribute to the pathophysiology of HF97. assessment of survival85. The elevated levels of urinary NGAL levels were observed in CHF patients Heart-type Fatty Acid Binding protein (H-FABP) compared to controls (175 μg/g Cr vs 37 μg/g Cr) and Heart-type Fatty Acid Binding Protein is a 15 kDa small hydrophilic protein consisting of 132 amino significantly associated serum creatinine (r =0.26, 98 P =0.006) and eGFR (r =0.29, P =0.002)86. In a study acids . It is found in large quantities within cardiomyocytes and in much lower quantities in the out of 71 children underwent cardiopulmonary 98 bypass, 20 children (28%) developed an acute renal kidneys, skeletal muscle , and brain tissue . H-FABP injury. A significant increase in NGAL levels of urine is associated with the inflammatory conditions such as HF, CHD, sepsis, metabolic syndrome, non-alcoholic (1.6 ug/L vs 147 ug/L) and serum (3.2 ug/L vs 99 61 ug/L) in this 28% of the cases was observed87. fatty liver disease (NAFLD) and insulin resistance . Early detection of NGAL in urine will allow the Injury to myocardial cells allows this small protein to clinician to provide the prompt and effective quickly leak into the bloodstream in proportion to the treatment of human acute renal failure. extent of damage and as a result, has been suggested as an alternative to other biomarkers, in a multi- 98 High-sensitivity troponin marker approach for diagnosing AHF . Evidence The troponins comprise 3 proteins (troponin T, I, and suggests that H-FABP may be a viable biomarker for C) that regulate actin and myosin interactions during a variety of high-risk cardiac populations and may be muscle contraction. Troponins T and I have distinct useful in the emergency department setting100. isoforms that exist in skeletal and cardiac muscle88. The In healthy humans, the normal range of H-FABP in majority of cardiac troponin (cTn) is bound to serum or plasma has been reported to vary between myofilaments, and the remaining is free in the cytosol 0.0 and 5.5 ng/mL101. In view of the importance of which accounts for 3-8% of the total amount89. In H-FABP in myocardial function, its measurement in peripheral blood, cTnT levels were increased within the plasma formed a reliable test for myocardial three to four hours after the onset of myocardial injury ischemia. A sandwich enzyme-linked immunosorbent and remain increased for 10-14 days90. The release of assay (ELISA) has been developed for H-FABP that these proteins into the bloodstream from cardiomyocyte showed that the assay range of 0-250 ng/mL, with the necrosis shows their utility as biomarkers of acute minimum detection limit of the assay of 1.25 ng/mL. coronary syndromes91. There is an increasing interest in By using this assay, the plasma and urine H-FABP the role of circulating cardiac troponin (cTn) in detecting values were 3.65 ± 1.81 ng/mL and 3.20 ± 2.70 ng/mL, myocardial injury in those with HF91. Subsequently, a respectively in normal healthy subjects102. high-sensitivity (hs) cTnT assay was introduced into Specifically, in a study evaluating H-FABP alone routine clinical practice. This assay can measure cTn and in combination with hs-cTnT for the diagnosis of concentrations in the single digit range of nanograms per AHF in emergency department patients presenting litre (ng/L) and some research assays even allow with symptoms of (ACS) detection of concentrations <1 ng/L92,93 . Missov et al. found that the addition of H-FABP to hs-cTnT has used a highly sensitive research assay to demonstrate increased the area under the curve (AUC) of hs-cTnT elevated concentrations of troponin I in 35 patients with alone from 0.893 (95%, CI: 0.812-0.974) to 0.908 advanced HF94. Latini et al found that hsTnT was the (95%, CI: 0.839-0.977), although this difference was most significant predictor of all-cause mortality in HF95. not statistically significant (P =0.07). The addition of Reichlin et al developed an algorithm for the 2h rule-out H-FABP at 5.8 ng/mL to hs-cTnT (14 ng/l) has strategy in patients with acute myocardial injury (AMI), increased both sensitivity and negative predictive they ruled-out initial hsTnT< 14ng/L and 2h hsTnT< value (NPV) for NSTEMI diagnosis. The authors 4ng/L in AMI patients with 98.7% sensitivity and 99.8% observed that the H-FABP is not an alternative to specificity96. hs-TnT were elevated in a well- CK-MB or cTn, but rather should be considered an characterized heart failure with preserved ejection additive marker for the rule-out of HF100. Conversely, fraction (HFpEF) population, which was associated with patients enrolled in the APACE (the Advantageous larger left ventricular and atrial size, as well as Predictors of Acute Coronary syndrome Evaluation) associated with the higher NT-proBNP (r =0.43; study were evaluated to determine the incremental P <0.001). These findings suggest that chronic troponin diagnostic value of H-FABP to hs-cTnT in early 310 INDIAN J. BIOCHEM. BIOPHYS., VOL. 55, OCTOBER 2018

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