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Table 2 Cardiac biomarkers (modified with permission) [67]

From: Sex differences in ischemic heart disease and heart failure biomarkers

Biomarkers Biology Conditions associated with elevations
Biomarkers of inflammation and atherogenesis
 hs-CRP hs-CRP is an acute phase protein produced predominantly by hepatocytes. Elevations are associated with an increased risk for coronary artery disease and ACS, but it is unclear if it is causally related. ACS
 Metalloproteinases (MMP-9, MMP-11) Metalloproteinases (MMP-9, MMP-11) are proteases produced by fibroblasts, osteoblasts, and vascular smooth muscle cells. They are highly expressed in unstable plaques. ACS
 PAPP-A PAPP-A (pregnancy-associated plasma protein A) is a high molecular weight, zinc-binding metalloproteinase that is associated with vulnerable plaque and may predict cardiovascular disease and mortality. ACS
 Cathepsin S Cathepsin-S promotes intra- and extra-cellular proteolysis and is associated with the development of cardiovascular disease and cancer. CAD
 IL-1β IL-1β is an inflammatory cytokine involved in myocardial remodeling post-MI and in CHF. ACS, CHF
 IL-1Ra IL-1Ra is inactive protein that binds to the IL-1 receptor, functioning as antagonist to IL-1 (functionally as an anti-inflammatory protein). ACS
 IL-6 IL-6 is an interleukin that acts as both an inflammatory and anti-inflammatory cytokine. IL-6 is also considered a myokine, a cytokine produced by muscle, and is secreted in response to muscle contraction. Increased IL-6 has been associated with decreased cardiac functional status in CHF. CHF, AFIB, ischemia, CV risk
 Chemotactic molecules (MCP-1, CCR1, CCR2) CCR2 and CCR5 are two CC chemokine receptors. Chemokines are the main modulators of inflammatory and repair processes. CCR1, in particular, may have a key role in heart repair after MI. MCP-1 (monocyte chemotactic protein-1) plays a critical role in the development of cardiovascular diseases. CAD, ACS
 Myeloperoxidase Myeloperoxidase is a leukocyte-derived enzyme that catalyzes the formation of reactive oxidants and may promote plaque formation and rupture. ACS, CHF
 Neopterin Neopterin is a marker of macrophage/monocyte activation. It is associated with atherosclerosis, plaque instability, and CHF. Increased levels may serve as predictors of future cardiovascular events. CAD, ACS, CHF
 Growth differentiation factor-15 Growth differentiation factor-15 is a member of the transforming growth factor beta (TGFβ) superfamily. Produced by cardiomyocytes, activated macrophages, endothelial cells, vascular smooth muscle cells, and adipocytes, it regulates inflammatory and apoptotic pathways needed for development, differentiation, and tissue repair. It is upregulated in many tissues following injury, ischemia, and other forms of stress. CAD, ACS
 Placental growth factor vascular endothelial growth factor Placental growth factor is a member of the vascular endothelial growth factor family (VEGF). Originally described in the placenta, it recruits macrophages into atherosclerotic lesions, stimulates pathological angiogenesis, and is associated with worse prognosis in ACS. CAD, ACS
 Markers of fibrosis (galectin-3) Galectin 3 is a β-galactoside-binding protein expressed by a number of cell types, including neutrophils and macrophages. In the heart, levels are almost undetectable in cardiomyocytes, whereas cardiac fibroblasts express higher levels. It is thought to represent a link between inflammation and fibrosis. Elevated Gal-3 is associated with increased CHF and mortality risk. CHF
 Fetuin-A Fetuin-A is a hepatic secretory protein that inhibits arterial calcification. CAD
 Vascular calcification (osteoprogeterin) osteoprotegerin Osteoprotegerin (OPG) is a glycoprotein member of the tumor necrosis factor receptor superfamily that acts as a decoy receptor for receptor activator of nuclear factor κB ligand (RANKL) and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Elevated OPG is associated with coronary and peripheral artery disease and subclinical atherosclerosis, and coronary artery calcium, although its role in atherosclerotic calcification remains speculative. It is associated with vascular mortality and has been reported to be higher in patients with acute MI. CAD
 Myeloid-related proteins 8/14 (MRP8/14) Myeloid-related proteins − 8 and − 14 are calcium-binding proteins expressed and secreted by neutrophils, monocytes, and subsets of macrophages. They are a useful biomarker of disease activity in inflammatory disorders. Increased levels are associated with increased cardiovascular events. ACS
Biomarkers of endothelial function
 E-selectin E-selectin is an endothelial cell adhesion molecule expressed only on endothelial cells activated by cytokines. Like other selectins, it plays an important part in inflammation, recruiting leukocytes to the site of injury. E-selectin and PECAM-1 may play an important role in inflammatory reaction and development of vulnerable plaque. ACS, CAD
 Pentraxin 3 (PTX3) PTX3 is released as a response to vascular damage and therefore may provide more information on development and progression of atherosclerosis than other less specific markers such as CRP. CAD
 VCAM-1 VCAM-1 (vascular cell adhesion molecule-1) binds monocytes and T lymphocytes, the types of leukocytes found in early atherosclerotic plaques. It also functions in leukocyte-endothelial cell signal transduction, and it may play a role in the development of atherosclerosis. CAD
 ICAM-1 ICAM-1 (intercellular adhesion molecule-1) may play a role in signal transduction associated primarily with proinflammatory pathways. In particular, ICAM-1 signaling seems to produce a recruitment of inflammatory immune cells such as macrophages and granulocytes. CAD
Biomarkers of thrombosis
 vWF vWF (von Willebrand factor) is a large multimeric glycoprotein present in blood plasma and produced by Weibel-Palade bodies in endothelium, megakaryocytes, platelet α-granules, and subendothelial connective tissue. VWF plays a pivotal role in platelet adhesion and aggregation at sites of high shear rates (e.g., in coronary arteries that have stenotic or ruptured atherosclerotic plaque lesions) in patients with pre-existing vascular disease. CAD, ACS
 Tissue factor Tissue factor (TF) TF is the cell surface receptor for the serine protease factor VIIa. The best known function of TF is its role in blood coagulation. The complex of TF with factor VIIa catalyzes the conversion of the inactive protease factor X into the active protease factor Xa. TF is expressed by cells which are normally not exposed to flowing blood such as smooth muscle cells and cells surrounding blood vessels (e.g., fibroblasts). This can change when the blood vessel is damaged by physical injury or rupture of atherosclerotic plaques. ACS, invasive cardiology
 sCD40L Soluble CD40 ligand (sCD40L) is contained in platelet granules, and thus, its presence in the blood is a marker of platelet activation. By interacting with CD40, which is found on endothelial and smooth muscle cells, sCD40L may trigger the release of inflammatory mediators, lead to increased activity of matrix metalloproteinases, and activate the coagulation cascade. sCD40L is an independent predictor of ACS outcomes. ACS
 Prothrombin fragment 1.2 Prothrombin fragment 1.2 (F1.2) is an activation peptide generated during the conversion of prothrombin to thrombin. As a marker of thrombin generation, F1.2 has clinical potential in assessing thrombotic risk. ACS, CAD
 Thrombin precursor protein Thrombus precursor protein (TpP) is a biomarker that is used to measure soluble fibrin polymers, which are the penultimate products in fibrin formation. In patients with ACS, increased levels of TpP are associated with an increased risk of death or ischemic complications. ACS
 D-dimer D-dimer is a fibrin degradation product (FDP), a small protein fragment present in the blood after a blood clot is degraded by fibrinolysis. It is an excellent marker of fibrinolytic activity. ACS
Biomarkers of oxidative stress
 Lp-PLA2 Lp-PLA2 is a protein produced by inflammatory cells. It circulates mainly with LDL (< 20% is associated with HDL or remnant lipoproteins), and it is responsible for hydrolyzing oxidized phospholipids in LDL. It is highly upregulated in atherosclerotic plaques and may be directly involved in development of atherosclerosis and plaque rupture. ACS, CAD
 Oxidized amino acids Amino acids are the building blocks of protein, and oxidative stress plays a central role in the pathogenesis of diverse chronic inflammatory disorders including cardiovascular disease. For example, elevated levels of homocysteine, an amino acid in the blood, increase the oxidation of LDL cholesterol which in turn contributes to the formation of fatty deposits along the arterial walls leading to atherosclerosis. CAD
 Oxidized apoA1 Apolipoprotein A1 (apoA1) is a major protein component of high-density lipoprotein, or HDL cholesterol. Oxidized HDL impairs cholesterol efflux from monocytes and macrophages and may result in a loss of anti-inflammatory effects and a resulting change to a proinflammatory state. CAD
 ADMA and other arginine metabolism products Asymmetric dimethylarginine (ADMA), a naturally occurring chemical found in blood plasma, is an endogenous nitric oxide synthase inhibitor that has been linked to cardiovascular risk. It is closely related to L-arginine, a conditionally essential amino acid. ADMA interferes with L-arginine in the production of nitric oxide, a key chemical involved in normal endothelial function. CAD
 Secretory phospholipase A2 SPLA2 is a member of a family of enzymes that catalyze the breakdown of phospholipids into fatty acids and lysophospholipids, thereby contributing to cholesterol loading of macrophages, and activation of inflammatory and atherogenic pathways. CAD
Biomarkers of ischemia/necrosis
 Creatine kinase-MB The MB fraction (or isoenzyme) is the most clinically used assays for CK-MB and is increased with myocardial necrosis; however, it is not as specific for ACS or other myocardial damage as hstroponin. MI, CHF, CAD
 High-sensitivity cardiac troponin High-sensitivity cardiac troponin is increased with myocardial necrosis; however, it is not specific to ACS as it can be increased in any condition that results in myocardial damage, including CHF, pulmonary embolism, or severe HTN. MI, CHF, CAD
 Malondialdehyde-modified low-density lipoprotein MDA-modified low density lipoprotein plays an important role in the development of atherosclerosis as its uptake by macrophages and smooth muscle cells leads to formation of foam cells. MDA-modified LDL has a diagnostic accuracy as an independent biochemical marker for atherosclerosis. CAD
 Fatty acid binding protein Heart-type fatty acid-binding protein (H-FABP) is a small cytoplasmic protein (15 kDa) released from cardiac myocytes following an ischemic episode. It is an early biomarker for myocardial infarction, detected in the blood within 1 to 3 h of ACS. ACS
Biomarkers of hemodynamic stress
 BNP and/or NT-proBNP The concentration of B-type natriuretic peptide (BNP) or N-terminal pro-B-type natriuretic peptide (NT-proBNP) are increased with myocardial (ventricular, and to a lesser extent, atrial) stretch. Both peptides are accepted markers for cardiac dysfunction. Elevated levels of either of these peptides are associated with and are equally useful as an aid in the diagnosis of CHF. CHF
 Copeptin Copeptin is the stable C-terminal part of pro-arginine-vasopressin (AVP). It is released with AVP after hemodynamic or osmotic stimuli and is also an endocrine stress hormone. It is released into the circulation early after MI onset and may aid in rapid diagnosis. ACS, CHF
 Mid-region pro-adrenomedullin Mid-region pro-adrenomedullin causes vasodilation via stimulation of nitric oxide production and is upregulated in CHF as a compensatory mechanism for the associated hemodynamic abnormalities. CHF
 Urocortin-1 Urocortin-1 is a vasoactive member of the corticotropin-releasing factor family. Lower levels provoke increases in heart rate, cardiac output, and coronary blood flow; at very high concentrations, it causes vasodilation and a decline in total peripheral resistance. CHF
 Arginine vasopressin Arginine vasopressin (AVP) is an antidiuretic and vasoconstrictive hormone that is released from the hypothalamus in response to changes in plasma osmolality and hypovolemia and has two principal sites of action: kidneys and blood vessels. AVP is upregulated in CHF. CHF
 Endothelin-1 Endothelin-1 is produced by the endothelium in response to angiotensin II, inflammatory mediators, and vascular shear stress. It is responsible for vasoconstriction, activation of reactive oxygen species, and ventricular remodeling. CHF, HTN
Biomarkers of heart failure mortality
 ST-2 ST-2 is an interleukin-1 receptor family member expressed as both transmembrane (ST2L) and soluble (sST2) isoforms. Plasma levels of sST2 are elevated in inflammatory diseases such MI and heart failure, as well as COPD, pneumonia, and sepsis. MI, CHF
Biomarkers of renal dysfunction
 Cystatin-C Cystatin-C is a cysteine protease inhibitor synthesized by all nucleated cells in the body. It is freely filtered by the glomerulus, reabsorbed completely, and is not secreted. A rise in serum cystatin C is a marker of renal dysfunction and may have a role as a prognostic marker in patients with coronary artery disease and heart failure as it appears to have additive prognostic value to creatinine. Acute kidney injury, CAD, CHF
 Neutrophil gelatinase-associated lipocalin (NGAL) Neutrophil gelatinase-associated lipocalin (NGAL) is highly upregulated at an early stage of renal injury and can be rapidly detected in the urine. Acute kidney injury, CHF
 KIM-1 KIM is a type 1 transmembrane glycoprotein not detectable in normal kidney tissue or urine, but it is expressed at very high levels in dedifferentiated proximal tubule epithelial cells in kidneys and appears in urine after ischemic or toxic injury. Acute kidney injury
Biomarkers of metabolic/lipid dysregulation
 Adiponectin Adiponectin is an adipokine protein hormone that modulates a number of metabolic processes, including glucose regulation and fatty acid oxidation. A low level of adiponectin is an independent risk factor for developing metabolic syndrome or diabetes mellitus. Low levels of adiponectin are associated with obesity-linked cardiovascular diseases, including ischemic heart disease and peripheral artery disease. CAD, MetS
 Leptin Leptin is a 16-kDa protein hormone that plays a key role in regulating energy intake and energy expenditure, including appetite/hunger and metabolism. In the absence of established CHD, the association between obesity and CHF may be mediated by plasma leptin. In those with CHD, obesity appears to increase the risk of CHF independent of leptin. CHF
 Resistin Resistin (an adipokine) also known as adipose tissue-specific secretory factor (ADSF) or C/EBP-epsilon-regulated myeloid-specific secreted cysteine-rich protein (XCP1) is a cysteine-rich protein encoded by the RETN gene. Resistin increases the production of LDL in human liver cells and also stimulates degradation of LDL receptors in the liver. CHF, CAD
 C-peptide C-peptide is a cleavage product of proinsulin and is a marker of insulin production. C-peptide levels help to distinguish between type 1 and type 2 diabetes and to evaluate insulin resistance and hypoglycemia. CHF
 Phospholipid fatty acids (EPA and DHA) EPA+DHA are the major fatty acids contributing to the total omega-3 fatty acids in human serum phospholipid. EPA and DHA omega-3 fatty acids are enriched in oily fish. In fatal ischemic heart disease, combined EPA+DHA levels comprising at least 4.6% of total fatty acids in serum were associated with 70% lower cardiovascular risk than those with lower levels of these fatty acids. CAD
 Apolipoprotein E ApoE is synthesized by the liver as part of VLDL; it functions in the transport of triglycerides to the liver tissue. It is also incorporated into HDL (as HDL-E) and functions in cholesterol distribution among cells. CAD
 Cholesteryl ester transfer protein activity Cholesteryl ester transfer protein (CETP), also called plasma lipid transfer protein, is a plasma protein that facilitates the transport of cholesteryl esters and triglycerides between the lipoproteins. Inhibiting CETP activity raises high-density lipoprotein cholesterol and may be cardioprotective; however, lower plasma CETP activity has also been associated with greater CVD risk. CAD
Biomarkers of brain damage
 S100 beta S100 calcium binding protein B (S100 Beta) is a protein of the S-100 protein family. S100 proteins are involved in the regulation of a number of cellular processes such as cell cycle progression and differentiation. In a recent study, in patients with cardiac arrests, patients with good outcomes had significantly lower S100B levels at all time points and lower neuron-specific enolase (NSE) levels on days 1 and 3 compared with those with poor outcomes. ACS, CABG
 Neuron-specific enolase Neuron-specific enolase (NSE) is an enzyme used as a biomarker of hypoxic brain damage and may predict death or vegetative state in comatose cardiac-arrest survivors. ACS