Cardiac Biomarkers

Read in PDF

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 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.

AssaySolution is proud to provide scientists globally with high quality ELISA kits  for detecting and quantifying cardiac biomarkers. Our qualified scientists work with integrity and are trained in precision techniques to deliver above satisfactory products into the hands of customers. Please check out our full catalog of ELISA kits and also our premier IHC antibodies for your needs.

IHC Antibodies (Premier) Catalog

2019 ELISA Kits Catalog