Cardiac biomarkers – new weapons against cardiovascular disease

Although formally defined as recently as the early 2000s, biomarkers have quickly begun to gain acceptance in clinical practice. Many experts believe they will become an indispensable tool for the diagnosis and management of a wide variety of medical conditions in the near future.

Cardiovascular disease now a global priority
One of the priority applications for biomarkers is likely to be for cardiovascular diseases (CVD) – the leading cause of mortality and disability in the Western world. In Europe, CVD causes 1.9 million deaths a year, while the toll in the US is about 1 million.
The prevalence of CVD is also increasing rapidly in newly industrializing countries, especially among the more affluent urban populations adopting Western lifestyles. Indeed, “CVD is now more numerous in India and China than in all economically developed countries in the world added together.”

Mapping the disease progression pathway
It has, for some time, been accepted that CVD follows a relatively clear-cut pathway from subclinical to overt status. The Multi-Ethnic Study of Atherosclerosis (MESA), sponsored in the year 2000 by the US National Institutes of Health, has been seeking to assess the characteristics of subclinical CVD and means to predict its progression to clinically overt cardiovascular disease. More recently, in 2010, Spain’s Banco Santander and the Istituto de Salud Carlos III launched a similar effort in Europe called PESA (Progression of Early Subclinical Atherosclerosis).
Such efforts are targeted at providing clinicians with tools to help assess CVD and identify vulnerable, at-risk patients. In many respects, they complement the world’s most ambitious effort in the area, the Framingham Heart Study, which began in 1948 in a town in Massachusetts in the US with 5,209 adult subjects. The Study, which has now enrolled its third generation of participants, has resulted in the publication of over 1,000 medical papers. It has also provided many commonplace tools for the contemporary understanding of CVD, including the impact of smoking, diet and exercise, medications such as aspirin etc. – as well as the term ‘risk factor’.

The Framingham project: clarifying the role of biomarkers
Biomarkers began to be part of the Framingham project in the 2000s, although initial results were unclear. For instance, enthusiasm about elevated levels of the inflammation marker C-reactive protein (CRP) as an independent risk factor for future CVD events were dispelled in a 2005 study supported by the Framingham sponsors.
In September 2012, a study in the American Heart Association’s journal ‘Circulation’ pointed to one reason for such conflicting assessments, namely the “lack of cardiovascular specificity” in many of the new biomarkers. The authors sought to address such limitations by studying three key CVD biomarkers (soluble ST2, growth differentiation factor-15 and high-sensitivity troponin I) in almost 3,500 patients. The findings were conclusive: “Multiple biomarkers of cardiovascular stress,” they said “add prognostic value to standard risk factors for predicting death, overall cardiovascular events, and heart failure.”
In 2014, another study of 2,680 Framingham participants sought to associate circulating biomarkers with The American Heart Association Cardiovascular Health score (CVH score). The authors concluded there was an “inverse association” between ideal CVH and CVD incidence, and that this was partly attributable to its “favourable impact on CVD biomarker levels and subclinical disease.” The list of CVD biomarkers in the 2014 study includes natriuretic peptides (N-terminal pro-atrial and B-type natriuretic peptide), plasminogen activator inhibitor-1, aldosterone, C-reactive protein, D-dimer, fibrinogen, homocysteine and growth differentiation factor-15.

Identification of at-risk patients
One of the most promising biomarkers seems to be cardiac troponin, first identified in the early 1990s. Changes in cardiac troponin T (cTnT) levels over time appear to correlate with heart failure risk, especially in a major study of elderly subjects.
The potential of circulating cTnT may also extend beyond the heart failure setting. Some argue that circulating cTnT is representative of subclinical myocardial dysfunction. In the general population, studies show that elevated cTnT is associated with subclinical cardiac injury, and marks an increased risk for structural heart disease and all-cause mortality.
Other studies have found that myeloperoxidase (MPO) and high-sensitivity C-reactive protein (hsCRP) in apparently healthy populations can predict risk of coronary disease, allowing for early preventative treatment. Together, MPO and C-reactive protein have also shown promise in prognostic risk assessment for patients with systolic heart failure.

Enabling targeted and timely treatment
While screening the general population is bound to draw considerable attention, the more immediate application of CVD biomarkers is to enable treatment in a risk-stratified and timely fashion.
One of the biggest challenges faced by physicians is to differentiate between patients with unstable angina and acute myocardial infarction (AMI) in an emergency setting. Here too cTnT – as well as cardiac troponin I (cTnI) – have catalysed some of the greatest excitement, due to their high sensitivity and specificity for cardiac damage.
In 2007, the US National Academy of Clinical Biochemistry Laboratory Medicine Practice recommended the use of cardiac troponin as a ‘preferred’ biomarker for MI diagnosis, in conjunction with clinical evidence of myocardial ischemia. Creatine kinase-MB was positioned as an ‘acceptable alternative’. These recommendations were endorsed by the joint European Society of Cardiology/American College of Cardiology/American Heart Association/World Heart Federation task force for the definition of myocardial infarction.

Cardiac troponin ‘the best single marker’
Levels of cardiac troponin are dependent on infarct size, and directly indicate the prognosis following MI. Indeed, in recent years, some experts suggest that CTnI and CTnT have “displaced myoglobin and creatine kinase-MB as the preferred markers of myocardial injury.”
In 2013, a Health Technology Asssessment (HTA) by Britain’s National Institute for Health Research (NIHR) concurred with this view, observing that “high-sensitivity cardiac troponin is the best single marker in patients presenting with chest pain.” Additional measurements of myoglobin or creatine kinase-MB, it noted were “not clinically effective or cost-effective.”

Debate on troponin not over
Nevertheless, considerable debate remains about the utility of troponin in real world CVD management. Although patients with undetectable troponins are considered to have excellent short-term prognosis, levels may be undetectable “for six hours after the onset of myocardial cell injury,” making myoglobin “a preferred early marker” for MI. This limitation, which seems to go against the 2013 NIHR Health Technology Assessment, is also acknowledged by some proponents of troponin, who admit that although it “may be useful for risk assessment and management” in asymptomatic populations, there is no evidence that it confers “an advantage in the context of MI diagnosis.” In addition, they also note that “cTnI assays are not standardized; thus, there can be a substantial difference in values depending on the assay used.”

Defining assay sensitivity, differentiating troponin I and T
One challenge lies in the definition of a ‘high sensitivity’ assay, which can measure cTn in the single digit range of nanograms per litre. The term is used by vendors “for marketing purposes,” and there “is still no consensus” regarding its application. Making matters tougher is the fact that most manufacturers’ claims for assay precision “cannot be achieved in clinical laboratories.”
In effect, the jury on troponin is likely to be out for some time to come, accompanied by continuing uncertainties.
For instance, Britain’s respected health advisory site patient.co.uk suggests that troponin I and T “are of equal clinical value” while a 2010 guideline from NICE (National Institute for Healthcare and Clinical Excellence) advises taking a blood sample for troponin I or T as “preferred biochemical markers to diagnose acute MI.”
However, a very recent study published by the Journal of the American College of Cardiology finds that patients with neuromuscular disease can show elevated levels of troponin T but not I, thus questioning the guidelines which regard both as being “equally sensitive and specific for the diagnosis of myocardial injury.”
These may be some of the reasons why the US Food and Drug Administration (FDA) decided in June 2014 to discuss clarification of claims and protocols with vendors of troponin assays, in order to “modernize the performance evaluation and regulatory review.” In Britain, NICE is currently updating its 2010 guideline.

The role of B-type natriuretic peptide
Once acute MI is confirmed, a variety of other biomarkers are used to help make assessments.
One of the most promising of these is B-type natriuretic peptide or BNP, designated by the FDA in the year 2000 as a Class II diagnostic device.
Nevertheless, it is important to underline that only troponin has been used to direct therapeutic intervention. Though it is evident that the adoption of proven new biomarkers will increase prognostic accuracy, they have yet to be tested to alter outcomes of therapeutic intervention.
Thus, in spite of statements from reputable sources claiming that BNP is “already used to diagnose heart failure,” the truth is somewhat different, with the difference in the details. At the end of 2013, the US Agency for Healthcare Research and Quality (AHRQ), investigated BNP and the related N-terminal proBNP (NT-proBNP) for detecting heart failure (HF). The findings were guarded: “BNP and NT-proBNP had good diagnostic performance for ruling out HF but were less accurate for ruling in HF.” In addition, it found that the “therapeutic value was inconclusive.”

Other biomarkers remain valuable
In the meanwhile, clinicians in emergency settings have recourse to a variety of other established CVD risk markers, such as cholesterol. “Research is also under way on markers with strong predictive value that are not used in the clinic for cardiovascular disease risk prediction, such as fibrinogen, vitamin D, and cystatin C.” Some of these “are of special interest as these may prove to be valuable biomarkers in the future.”
To have clinical utility, however, such biomarkers will need to provide risk assessments independently of other established markers. They also require the presence of standardized assays which are specific and sensitive for the markers, with easy-to-interpret results.
In effect, biomarker-mediated approaches to CVD need to yield superior patient outcomes compared to current standard-of-care management schemes.