Limitations of Cardiac Biomarker Diagnostics
Author: Holly Young
Cardiovascular disease (CVD) is a condition that affects the heart and blood vessels. It is one of the leading causes of death worldwide, responsible for over 17 million deaths: accounting for 32% of global deaths in 2019 (1). The “prevalence, high mortality and rehospitalisation rates” of CVD are all causes for further research into methods for early detection and diagnosis. Newer technologies will provide the patient with an improved prognosis and treatment plan whilst reducing the financial burden of the disease (2,3).
A biomarker is a substance that can be measured and indicate the occurrence of a biological process. Disease biomarkers in CVD occur due to pathophysiological processes. A variety of biomarkers have been used in diagnostics of and in management of CVD, which have shown great promise. They tend to be useful as CVD can occur with no obvious signs or symptoms. However, a “lack of sensitivity and specificity to cardiac muscle necrosis” means that there is a need for more specific biomarkers (4).
Current CVD diagnostic methods involve patients having to meet two of the following three criteria:
Characteristic chest pain
Diagnostic electrocardiogram (ECG) changes
Elevation of the biochemical markers in their blood samples.
The use of an ECG in diagnosing CVD is described as a poor method as around half of A&E patients have a normal ECG making early diagnosis of CVD trickier. This means that the measurement of cardiac biomarkers is crucial in helping the diagnosis of CVD (5).
However, cardiac biomarkers must exhibit specific characteristics to be defined as a biomarker. These include having a large presence in the heart tissue (as well as an absence in other tissues); it should be absent in healthy individuals; have a high clinical sensitivity and specificity; must be released quickly into the bloodstream to allow for early diagnosis and the level of the biomarker must remain elevated in the blood for a period of time; and it must be able to be assayed quantitatively (2, 5).
An issue with the use of cardiac biomarkers use in diagnostics is that most biomarkers are also markers of common inflammation. This then makes it difficult to determine if CVD could be the problem present, as inflammatory issues can be present without CVD which means false positives are likely to occur (5).
C-reactive protein (CRP) is a nonspecific marker of inflammation used in CVD diagnosis, levels rise on the second day after a myocardial infarction has occurred and then peak on the fourth day. However, due to the biomarker being non-specific this does not make it as reliable as other biomarkers such as cTn biomarkers. There are many reasons why CRP levels will rise that are not cardiac related such as surgery, trauma, burns or sepsis (6). To overcome this problem, a combination of biomarkers tends to be used, both inflammatory and non-inflammatory (5).
The most utilised cardiac biomarkers, cardiac troponin I and T (cTnI and cTnT) are highly sensitive and specific compared to other biomarkers (8). These proteins are specific to the heart: whilst they are found in skeletal muscle too, they present differently which enables them to be used as a cardiac-specific biomarker. However, cTn biomarkers do have their limitations, their assay sensitivity is low during an acute myocardial infarction (AMI). This means that samples often must be taken for around 6-9 hours to obtain a result, leading to prolonged periods of hospitalisation involving extensive tests for the patient (9).
Myoglobin is a cardiac biomarker; it is expressed in skeletal muscle and in the myocardium. It is released following injury to the myocardium. It is not found within other tissue so it tends to be useful in excluding acute myocardial infarction (AMI) as a possibility when a patient is admitted to the hospital. However, its specificity can be questioned as it is not found solely in the myocardium (10). Myoglobin more recently has been identified as a potential biomarker for spinal and bulbar muscular atrophy, it is known to be upregulated in various other diseases such as skeletal muscle diseases/injury and chronic renal disease (11, 12). An incorrect diagnosis could be fatal for the patient, it would increase the wait for the patient to start the correct course of treatment and risk the wrong course of treatment to be taken, negatively impacting patients’ prognosis and shortening their lifespan.
Biomarkers are useful in determining treatment options available for CVD and in the monitoring of disease progression, however, there is a lack of biomarkers that can be utilised in routine work on their own. These biomarkers can indicate patients that are at a higher risk of developing CVD. Therefore a “multimarker” approach is thought to be more appropriate, as it is the most accurate, however, this involves several different tests for a variety of biomarkers (8). One study found that measuring cardiac biomarkers high-sensitivity C-reactive protein (hs-CRP) and N-terminal proB-type natriuretic peptide (NT-proBNP) at the same time proved more useful in predicting a cardiac event than measuring them individually (13).
It is clear there is still a great deal of scope for further research into biomarkers. Whilst useful in assisting with a diagnosis there are still many uncertainties associated with them whether that be their specificity, sensitivity or use across different diseases. The main method of improving CVD prognosis is to accurately diagnose the disease before it has the chance to develop and become too complicated to treat. Therefore, further development of cardiac biomarkers and how they can be utilised would prove crucial in CVD diagnostics.
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