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Cardiac Biomarkers Overview

 

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Biomarkers generally represent a biochemical change at a tissue or a body organ level. Therefore, they are associated with a biologic or pathologic process. However, the clinical outcomes from these processes in terms of biomarkers as disease indicators could be different. For example, troponin elevation up to a certain degree can be present in congestive heart failure, pulmonary embolism and more conventionally and classically in acute myocardial ischemia/infarction. Moreover, biomarkers that are intended to be used in clinical practice can be useful if changes in their levels adequately mirror improvement in the disease process itself when the disease is being treated (predictive biomarkers), thereby reflecting an improvement in patient outcome. For example, blood B-type natriuretic peptide (BNP) concentrations increase with worsening heart failure status. Additionally, a clinically useful biomarker should be able to provide meaningful information about prognosis and/or guide clinical decision making and not simply duplicate information that is already available clinically. Derivation and validation to associate a biomarker to a disease process should also be carried out in different subsets of population. In general, biomarkers predicting disease risk perform much better in the derivation cohort compared to a validation cohort. Universal biomarker standards have also been proposed according to their intended use for disease diagnosis and prognosis.

 

 

 

Newer cardiovascular biomarkers under evaluation

 

There are numerous CVD biomarkers under evaluation and a detailed review is beyond the scope of this review. Several classifications exist currently to classify CVD biomarkers. Most commonly, biomarkers can be grouped based on disease specificity such as biomarkers of heart failure (BNP, N-terminal prohormone of brain natriuretic peptide [NT-proBNP], atrial natriuretic peptide [ANP], ST-2 etc), of atherosclerotic coronary disease (troponin T or I, creatinine phosphokinase-MB etc.), or they can be grouped according to their use such as in acute changes (copeptin, high sensitivity Troponin, galectin-3, ST2) versus in the chronic stage of CVD to estimate prognosis (coronary calcium by CT). Alternatively, CVD biomarkers can be grouped according to the pathologic process they represent, such as inflammation (e.g., C-reactive protein, interleukin 6, Fibrinogen, monocyte chemotactic protein-1, tumor necrosis factor alpha etc) oxidative stress (e.g., isoprostanes), and metabolic (e.g., lipoprotein (a), low-density lipoproteins, high density lipoprotein, ApoB 100, Lipoprotein-associated phospholipase A2, Homocysteine, vitamin D, fibroblast growth factor 23, adiponectin, glycated hemoglobin, haptoglobin etc). In the next section we present some examples of novel biomarkers which are currently being investigated for heart failure and emphasize some of the key concepts influencing their use in clinical practice.

 

Major Novel Heart Failure Biomarkers

 

Individual investigators have proposed classification of heart failure biomarkers according to the pathologic process they indicate. Previous reviews have described relevant limitations of novel heart failure biomarkers for use as treatment guidance and sex differences when using these biomarkers for clinical use. Further consensus statements have recommended establishing a consortium to allow novel biomarkers to be concomitantly analyzed in a pooled sample of randomized clinical trials and hypotheses to be generated for testing each biomarker in biomarker-guided trials.

 

Myocardial stretch    
   Proudct  Catalog #
Troponin I (TnI) Human Troponin I (cTnI) ELISA kit inquiry
Troponin T (TnT) Troponin T Antibody (monoclonal)  ASA-B1928
  Recombinant human cTnT inquiry
  Porcine cTnT, native inquiry 
  Human cTnT ELISA kit inquiry
Troponin C (TnC) Troponin IC Human  AS-P05675
  TNC Human AS-P05545
  TNC Rabbit AS-P05546
  Human cTnC ELISA kit inquiry
H-FABP/FABP3 Human FABP3 ELISA Kit  AYQ-E10919
  FABP3 Human AS-P01690
CK-MB CK-MB ELISA kit inquiry
sTRAIL Human TRAIL/TNFSF10 ELISA Kit  AYQ-E11184
  TRAIL Antibody  ASA-B1908
  TRAIL Antibody  ASA-B1909
  TRAIL Human Protein  AS-P05652
HSP60 Human Total HSP60 ELISA Kit  AYQ-E10654
  Mouse Total HSP60 ELISA Kit AYQ-E10655
  Porcine Total HSP60 ELISA Kit  AYQ-E10658
  Canine Total HSP60 ELISA Kit  AYQ-E10657
  HSP60 Antibody  ASA-B0916
  Hsp60 Antibody ASA-B0917
  HSP60 Antibody (monoclonal)  ASA-B0915
     
Inflammation    
     
CRP CRP (19-224 a.a) Human AS-P01126
  CRP Antibody AS-P01127
  CRP Human AS-P01128
  CRP Human Recombinant AS-P01129
  CRP Rat AS-P01130
  Human C-Reactive Protein/CRP ELISA Kit AYQ-E11268
ST2 Human ST2/IL-33 R ELISA Kit  AYQ-E11208
TNF alpha Anti TNF alpha Antibody (polyclonal) A0211B
  Mouse TNF alpha Antibody ASA-B1308
  TNF alpha Antibody ASA-B1882
  TNF alpha Antibody ASA-B1883
GDF-15 Human GDF-15 ELISA Kit AYQ-E11222
  GDF15 D Human AS-P01975
  GDF15 Human AS-P01976
  GDF15 Human, His AS-P01977
  GDF15 Mouse AS-P01978
Fas/APO-1 Anti Fas Antibody (polyclonal) A0217B
  FAS Antibody AS-P01722
  Fas Antibody ASA-B0683
  Fas Antibody ASA-B0684
  FAS Human AS-P01724
  Fas Ligand Antibody ASA-B0685
  Fas Ligand Antibody ASA-B0686
  Fas Ligand Antibody ASA-B0687
  Human Fas/TNFRSF6/CD95 ELISA Kit AYQ-E11079
  Human CD178 (Fas-L) Antibody ASB-G0586
  Human CD178 (Fas-L) APC Antibody ASB-G0054
  Human CD178 (Fas-L) Biotin Antibody ASB-G0055
LP-PLA2 Lipoprotein-associated phospholipase A2 (Lp-PLA2), in vitro, antibody inquiry
  Recombinant human lipoprotein-associated phospholipase A2 (Lp-PLA2) inquiry
YKL-40/CHI3L1 Human Chitinase 3-like 1 ELISA Kit AYQ-E11262
  CHI3L1 Human AS-P00950
  CHI3L1 Antibody AS-P00949
  CHI3L1 (22-383) Human AS-P00948
IL-1 Canine IL-1 RAPL1/IL-1 R8 ELISA Kit AYQ-E10074
  Human IL-1 alpha/IL-1F1 ELISA Kit AYQ-E11101
  Human IL-1 beta/IL-1F2 ELISA Kit AYQ-E10802
  Human IL-1 RAcP/IL-1 R3 ELISA Kit AYQ-E10969
  Human IL-1 RAPL1/IL-1 R8 ELISA Kit AYQ-E10071
  Human IL-1 RI ELISA Kit AYQ-E11217
  Human IL-1 RII ELISA Kit AYQ-E11156
  Human IL-1ra/IL-1F3 ELISA Kit AYQ-E11310
  Mouse IL-1 RAPL1/IL-1 R8 ELISA Kit AYQ-E10072
  Porcine IL-1 RAPL1/IL-1 R8 ELISA Kit AYQ-E10075
  Rat IL-1 RAPL1/IL-1 R8 ELISA Kit AYQ-E10073
Osteoprotegerin(OPG) Human Osteoprotegerin/TNFRSF11B ELISA Kit AYQ-E10925
  Osteoprotegerin Antibody ASA-B1441
Pentraxin Canine Pentraxin 2/SAP ELISA Kit AYQ-E10424
  Human Pentraxin 2/SAP ELISA Kit AYQ-E10421
  Human Pentraxin 3/TSG-14 ELISA Kit AYQ-E10851
  Mouse Pentraxin 2/SAP ELISA Kit AYQ-E10422
  Porcine Pentraxin 2/SAP ELISA Kit AYQ-E10425
  Rat Pentraxin 2/SAP ELISA Kit AYQ-E10423
Procalcitonin Human Procalcitonin ELISA Kit AYQ-E11280
  Procalcitonin Canine AS-P04456
  Procalcitonin Human AS-P04457
  Procalcitonin Human, His AS-P04458
  Procalcitonin Mouse AS-P04459
  Procalcitonin Porcine AS-P04460
  Procalcitonin Rat AS-P04461
  Procalcitonin Rhesus AS-P04462
sEndoglin Endoglin Human, His AS-P01577
  Human CD166 (Endoglin) PE Antibody ASB-G0010
PR3 PR3 (c-ANCA) ELISA kit inquiry
Adiponectin Adiponectin Antibody ASA-B0040
  Adiponectin Antibody ASA-B0041
  Adiponectin Antibody ASA-B0042
  Human Adiponectin/Acrp30 ELISA Kit AYQ-E10899
     
Neurohormonal therapy    
     
Norepinephrine N/A  
Renin Human Renin ELISA Kit AYQ-E11243
Angiotensin II Angiotensin AS-P00209
  Angiotensin Converting Enzyme 1 Antibody ASA-B0087
  Angiotensin Converting Enzyme 1 Antibody ASA-B0088
Aldosterone N/A  
Arginine vasopressin Vasopressin AS-P05855
  AVPR1A Antibody ASA-B0181
Copeptin N/A  
Endothelin-1 N/A  
Urocortin N/A  
Chromogranin A Chromogranin A Antibody ASA-B0453
  CHGA Antibody AS-P00943
  CHGA Human AS-P00944
  CHGA Human, GST AS-P00945
  CHGA Human, His AS-P00946
  Human Chromogranin A ELISA Kit AYQ-E11150
Chromogranin B CHGB Human AS-P00947
MR-proADM N/A  
     
Extracellular Matrix Remodeling    
     
MMP-2 Canine MMP-2 ELISA Kit AYQ-E10518
  Human MMP-2 ELISA Kit AYQ-E10515
  MMP-2 Human, HEK AS-P03664
  Mouse MMP-2 ELISA Kit AYQ-E10516
  Porcine MMP-2 ELISA Kit AYQ-E10519
  Rat MMP-2 ELISA Kit AYQ-E10517
MMP-3 Human Total MMP-3 ELISA Kit AYQ-E10811
  MMP 3 Human AS-P03651
  MMP 3 Human, GST AS-P03652
  MMP 3 Human, HEK AS-P03653
MMP-9 Human MMP-9 ELISA Kit AYQ-E11249
  MMP 9 Human AS-P03658
  MMP 9 Rabbit AS-P03659
  ProMMP 9 Human AS-P04476
TIMP1 Bovine TIMP-1 ELISA Kit AYQ-E10736
  Human TIMP-1 ELISA Kit AYQ-E10735
  TIMP1 Antibody ASA-B1862
  TIMP1 Human AS-P05520
  TIMP1 Human, HEK AS-P05521
  TIMP1 Human, Sf9 AS-P05522
  TIMP1 Mouse AS-P05523
  TIMP1 Rat AS-P05524
IL-6 Human IL-6 ELISA Kit AYQ-E11056
  Human IL-6 R alpha ELISA Kit AYQ-E11090
  IL-6 Antibody ASA-B0992
  IL-6 Matched Antibody Pair ASC-025P
  IL-6 Mouse, His AS-P03043
  IL-6 PAT1F10AT Antibody AS-P03044
  IL 6 Antibody AS-P02953
  IL 6 Human AS-P02954
  IL 6 Human, CHO AS-P02955
  IL 6 Human, HEK AS-P02956
  IL 6 Human, His AS-P02957
  IL 6 Mouse AS-P02958
  IL 6 Mouse, Sf9 AS-P02959
  IL 6 Rat AS-P02960
  IL 6 Rhesus Macaque AS-P02961
  sIL 6R Human AS-P05081
Collagen propetides, PICP Canine Pro-Collagen I alpha 1 ELISA Kit AYQ-E10379
  Human Pro-Collagen I alpha 1 ELISA Kit AYQ-E10376
  Mouse Pro-Collagen I alpha 1 ELISA Kit AYQ-E10377
  Porcine Pro-Collagen I alpha 1 ELISA Kit AYQ-E10380
  Rat Pro-Collagen I alpha 1 ELISA Kit AYQ-E10378
N-terminal collagen type III peptide, PIIINP N/A  
Myostatin Myostatin Antibody AS-P03766
  Myostatin Human AS-P03767
  Myostatin Human, HEK AS-P03768
  Myostatin Human, His AS-P03769
  Myostatin Human, Plant AS-P03770
  Myostatin Propeptide Human AS-P03771
  Myostatin Propeptide Human, HEK AS-P03772
Syndecan-4 Human Syndecan-4 ELISA Kit AYQ-E10872
  Syndecan 4 Antibody ASA-B1824
Galectin-3 Bovine Galectin-3 ELISA Kit AYQ-E10756
  Galectin 3 Antibody ASA-B0755
  Galectin 3 Antibody ASA-B0756
  Human Galectin-3 ELISA Kit AYQ-E10833
  Human Galectin-3 ELISA Kit AYQ-E10755
  Human Galectin-3BP/MAC-2BP ELISA Kit AYQ-E11227
     
Oxidative stress    
     
Oxidized LDL N/A  
MPO MPO Human AS-P03683
  Myeloperoxidase Antibody ASA-B1336
  Myeloperoxidase Antibody ASA-B1337
Urinary biopyrrins N/A  
Urinary and plasma isoprostanes N/A  
Urinary 8-hydroxyl-2'-deoxygunosine N/A  
Plasma malondialdehyde N/A  
     
Myocyte injury    
     
BNP BNP Human AS-P00517
  BNP Human AS-P00518
  BNP Human, His AS-P00519
NT-proBNP Human NT Pro-BNP ELISA Kit AYQ-E11044
  Human recombinant NT-proBNP (amino terminal human brain natriuretic peptide precursor) inquiry
MR-proANP N/A  
ST2 Dengue NS1 ST2 AS-P01350
  Human ST2/IL-33 R ELISA Kit AYQ-E11208
GDF-15 GDF15 D Human AS-P01975
  GDF15 Human AS-P01976
  GDF15 Human, His AS-P01977
  GDF15 Mouse AS-P01978
  Human GDF-15 ELISA Kit AYQ-E11222
     
Others    
     
IGFBP4 Human IGFBP-4 ELISA Kit AYQ-E11011
  IGFBP 4 Human AS-P02778
Myoglobin Myoglobin Antibody ASA-B1339
  Myoglobin Antibody ASA-B1340
  Myoglobin Antibody AS-P03762
  Myoglobin Antibody (monoclonal) ASA-B1338
  Myoglobin His Human AS-P03763
  Myoglobin Human AS-P03764
  Myoglobin Human AS-P03765
D-dimer Human D-Dimer ELISA Kit AYQ-E11342
sCD40L sCD40L Human AS-P04939
  sCD40L Human, His AS-P04940
  sCD40L Mouse AS-P04941
  sCD40L Mouse, sf9 AS-P04942
Cystatin C Cystatin C Antibody ASA-B0558
  Human Cystatin C ELISA Kit AYQ-E11248
Human serum albumin Human Serum Albumin ELISA Kit AYQ-E11199
SAA SAA Human AS-P04905
  SAA1 Human AS-P04906
  SAA1 Human, His AS-P04907
  SAA1 Monkey AS-P04908
  SAA4 Human AS-P04909
RBP4 Canine RBP4 ELISA Kit AYQ-E10780
  Human RBP4 ELISA Kit AYQ-E10929
  Human RBP4 ELISA Kit AYQ-E10779
  RBP4 Antibody AS-P04697
  RBP4 Antibody ASA-B1617
  RBP4 Human AS-P04698
  RBP4 Human, His AS-P04699
Glycogen phosphorelase isozyme BB (GPBB) GPBB Human AS-P02142
S100B Bovine S100B ELISA Kit AYQ-E10791
  Human S100B ELISA Kit AYQ-E10787
  Mouse S100B ELISA Kit AYQ-E10788
  Porcine S100B ELISA Kit AYQ-E10790
  Rat S100B ELISA Kit AYQ-E10789
  S100b Human AS-P04894
  S100B Human, GST AS-P04895
  S100B Human, His AS-P04896
  S100b Mouse AS-P04897
  S100b Mouse, His AS-P04898
  S100b Rhesus Macaque AS-P04899


 

 

Myocardial stretch leads to production of pro BNP compound that is later broken down into BNP and NT proBNP (inert form). Higher concentration of BNP in the blood of a patient who presents to an emergency room is associated with greater probability of a diagnosis of heart failure. Moreover, higher BNP concentration on admission to the hospital is also associated with greater in-hospital mortality. NT proBNP, which is a more stable form of BNP, is also predictive of a diagnosis of heart failure. Medications and other therapies utilized currently to treat heart failure are also known to reduce BNP levels effectively; however with some exceptions. It is important to understand, however, that BNP levels are inversely associated with obesity, and may also be influenced by presence of kidney disease. Circulating ANP on the other hand is overall more unstable in blood compared to BNP or NT proBNP and therefore has a limited use in diagnosis or prognosis. However, a mid-regional ANP, a prohormone isolated from mid region of the molecule (MR-proANP) has shown promise in diagnosis of heart failure in a multinational biomarker study (BACH trial) in acute heart failure patients although its added incremental utility over BNP for diagnostic purposes is yet to be fully proven. So far, the research shows that MR-proANP could be of added advantage for the diagnosis of heart failure in obese, elderly and patients with renal disease when compared to BNP. MR-proANP is also being evaluated for prognosis of heart failure as well. 

Cardiomyocyte necrosis releases Troponin I or T (cardiac isomers of proteins from troponin-tropomyosin complex) in circulation of an individual and they are typically useful in detection of myocardial ischemia. High sensitive assays of Troponin T and I, however, are also elevated in the blood of patients with severe heart failure and therefore have been appropriately studied for the prediction of heart failure and for prognostication in those with established heart failure. Another biomarker that is associated with both ischemic and heart failure is Copeptin, a precursor protein of arginine vasopressin (ADH). Copeptin levels are elevated in the immediate post ischemic period and also correlate with higher risk of death and new-onset heart failure. Some investigators have reported the superiority of copeptin over BNP and NT-proBNP concentrations for predicting death, although the caveat is that these biomarkers are often closely related.

Neutrophil gelatinase-associated lipocalin (NGAL), another glycoprotein covalently bound to matrix metaloproteinase-9, is released by renal tubular cells in response to renal inflammation and injury, and it has also shown to offer added prognostic and diagnostic value along with BNP in the GALLANT trial. However, subsequent studies with corresponding biomarker data from other heart failure trials did not replicate these findings. Therefore, the clinical utility of this biomarker above and beyond other commonly used biomarkers in chronic heart failure patients with renal injury is questionable.

Galectin-3 is an exciting biomarker with an important role in development and regulation of cardiac fibrosis and remodeling. In patients diagnosed with acute decompensated heart failure, blood Galectin-3 level has shown to be predictive of mortality on short-term follow up. In fact, investigators have also suggested the superiority of galectin-3 or enhanced predictive power for mortality when used along with BNP levels in patients with both preserved and reduced left ventricular ejection fraction. Overall, researchers currently underscore the added advantage of using a multimarker approach in heart failure; however, the independent use of Galectin-3 alone in heart failure patients is not as well supported by literature for the prediction of prognosis. Other markers of extracellular matrix such as metalloproteins which degrade collagen (MMPs), specific tissue inhibitors of metalloproteins (TIMPs), procollagen type III amino-terminal propeptide (PIIINP), or procollagen type I carboxy terminal peptide (PICP) that have been traditionally related to hypertensive heart disease are currently explored as biomarkers with implications for assessing disease severity, prognosis and response to treatment among patients with heart failure with preserved ejection fraction (HFpEF).

Additionally, higher levels of blood Procalcitonin, an acute phase reactant, have been associated with a greater likelihood of the presence of infection in patients with heart failure. Therefore, procalcitonin can sometimes be useful for excluding infections or pneumonia in patients seen in the emergency room with shortness of breath who are suspected to have a diagnosis of acute on chronic heart failure.

ST-2 is a receptor from interleukin family (IL-33) with two gene forms – soluble (sST2) and transmembrane form. Like other biomarkers, blood ST-2 levels are also shown to predict mortality and new onset heart failure. Researchers have also examined the predictive ability of ST-2 levels complementary to other traditional risk factors and NT-proBNP levels in ST-elevation myocardial infarction patients. It also has a role over traditional heart failure risk factors for determining prognosis. These findings have led researchers to explore the use of ST-2 as part of a multi-marker approach for assessing the prognosis of patients with heart failure.

Mid-regional pro-adernomedullin (MR-proADM) is a stable prohormone fragment of adernomedullin, a vasodilatory peptide, and elevated circulating levels are strongly associated with the presence of chronic heart failure. MR-proADM has been shown to be superior to both BNP and NT-proBNP in predicting 90-day mortality among patients with dyspnea and heart failure.

Growth differentiation factor – 15 – is classified as a biomarker with anti-hypertrophic effects (apoptosis) and investigators have linked the elevated levels of this biomarker to assess prognosis in chronic heart failure patients and among community dwelling adults as a predictor of all-cause mortality, including non-cardiovascular mortality above and beyond the information provided by blood NT-proBNP and C-reactive protein levels.

 

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