Cardiac Biomarkers for the Diagnosis of Cardiovascular Disease
Author: Michelle Ntola
Cardiovascular disease (CVD) is the leading cause of death globally. According to a 2015 epidemiological report, CVD is responsible for 45% of all deaths, (>4 million per year) in Europe (1). The high mortality rate and the high costs associated with diagnosis make point-of-care diagnostics with the capability of accurate early detection an urgent necessity. The most common symptom of CVD, acute central chest pain, was responsible for an estimated 20 – 30% of emergency hospital admissions, pre-Covid-19 pandemic (2). This is due to the concern about the possibility of unstable coronary heart disease. However, less than 50% of those admitted have a final diagnosis of heart disease; therefore, approximately 10% of all hospital admissions can be safely managed with no admission (2). This is particularly dire in the current situation with the Covid-19 pandemic, where emergency healthcare resources are already under strain and unnecessary admission increases the patient’s risk of contracting Covid-19.
The current approach for patients presenting to the accident and emergency department with acute chest pain is ‘admit and investigate.’ Accurate and reliable point-of-care diagnostics could be a gamechanger as it would enable faster and reliable ‘rule in’ or ‘rule out’ criteria for admissions on suspicion of acute CVD. This ensures that high-risk patients are given urgent lifesaving treatment and low-risk patients avoid unnecessary hospital admissions.
One of the major challenges for healthcare providers is to predict the patients’ risk for CVD. A significant amount of research has gone into identifying biological markers (biomarkers) of CVD. Disease biomarkers are a result of the pathophysiological processes initiated by disease. Currently known biomarkers for CVD include C-reactive protein (CRP), cardiac troponin I or T (cTnI/T), myoglobin, lipoprotein-associated phospholipase A (2), interleukin-6 (IL-6), interleukin-1 (IL-1), low-density lipoprotein (LDL), myeloperoxidase (MPO) and tumour necrosis factor-alpha (TNF-α) (3). These have been used to detect and predict CVD events.
Cardiac troponins are regulatory proteins that control the contraction of heart muscles. They exist as a complex of three subunits: troponin I (cTnI), troponin C (cTnC), and troponin T (cTnT). While cTnI is produced by both cardiac and skeletal muscle, cTnI and cTnT are produced exclusively by cardiac muscle and is released in response to injury of cardiac myocytes (4). Myocardial infarction is a result of a partial or complete blockage of arteries in cardiac muscle, leading to the restriction of blood flow to parts of the heart, which eventually leads to the death or permanent injury of heart muscle cells. Consequently, blood circulation is compromised, leading to a deterioration in the quality of life and/or mortality.
Figure 1: Showing the levels of cardiac troponin associated with the severity of myocardial infarction (Adapted from reference 5)
cTnI and other cardiac biomarkers are elevated from the basal values within 2 – 3 hrs of the onset of chest pain and increase until a peak is reached within 12- 48 hrs (5). Biomarker levels are elevated by different magnitudes depending on the severity of the disease (Figure 1).
Accurate diagnosis of an acute coronary syndrome may require both the measurement of blood biomarkers as well as an ECG, for instance in the case of Non-ST Elevation Myocardial Infarction (NSTEMI) and unstable angina, where it is challenging to distinguish the two conditions by ECG traces alone. Even in the most serious cases of myocardial infarction, ST-segment elevation myocardial infarction (STEMI), biomarkers levels are already elevated before notable changes on ECG (6). These conditions require urgent treatment and monitoring as they are potentially fatal.
Ultra-sensitive and rapid point-of-care sensors for cardiac biomarkers could reduce the amount of time required to identify and accurately diagnose high-risk patients ensuring they receive the appropriate treatment urgently. This will enable significant improvement to patient outcomes by rapid rule-in of high-risk patients and positively impact healthcare costs by rapid and accurate rule out of low-risk patients, reducing the number of admissions and avoiding time- and resource-consuming laboratory tests.
Traditional immunoassays that are currently employed in clinical settings usually require long waiting times for the healthcare providers to get the results and make an urgent, informed decision. In addition, point-of-care sensors could enable more accurate monitoring of the changes in biomarker levels over time, which could open opportunities for first responders (e.g., paramedics) to conduct pre-hospital biomarker tests and allow healthcare providers to monitor patients at home and be alerted when significant changes occur (6).
The challenge now remains with the development of clinically relevant point-of-care sensors that are accurate, dependable, affordable, and portable. The combination of graphene nanotechnology coupled with electrochemical sensing techniques holds great promise in delivering robust, low-cost sensors with easily interpretable readouts.
Our 3D foam graphene electrodes are versatile platforms with a remarkably high surface area, giving them a high loading capacity for immobilisation of recognition elements. Our Gii-sens electrodes are ideal candidates for ultra-sensitive detection of cardiac biomarkers with potentially much lower limits of detection compared to other electrodes. Gii-Sens is an affordable and customisable platform, also available with pre-immobilised linking molecules e.g., N-Hydroxysuccinimide (-NHS) or carboxyl (-COOH) functionalised electrodes (see our Gii-sens+ products) or fully customised sensor platforms, complete with specific recognition elements for cardiac biomarkers.
References:
Townsend, N., Nichols, M., Scarborough, P. & Rayner, M. Cardiovascular disease in Europe — epidemiological update 2015.Eur. Heart J.36, 2696–2705 (2015).
Capewell, S. & McMurray, J. ‘Chest pain-please admit’: is there an alternative?. A rapid cardiological assessment service may prevent unnecessary admissions.BMJ320, 951–952 (2000).
Qureshi, A., Gurbuz, Y. & Niazi, J. H. Biosensors for cardiac biomarkers detection: A review.Sensors Actuators B Chem.171–172, 62–76 (2012).
Wang, X.-Y., Zhang, F., Zhang, C., Zheng, L.-R. & Yang, J. The Biomarkers for Acute Myocardial Infarction and Heart Failure.Biomed Res. Int.2020, 2018035 (2020).
Fathil, M. F. M.et al.Diagnostics on acute myocardial infarction: Cardiac troponin biomarkers. Biosens. Bioelectron. 70, 209–220 (2015).
Aarts, G. W. A., van der Wulp, K. & Camaro, C. Pre-hospital point-of-care troponin measurement: a clinical example of its additional value.Netherlands Hear. J.28, 514–519 (2020).