{"id":5347,"date":"2020-08-26T09:43:54","date_gmt":"2020-08-26T09:43:54","guid":{"rendered":"https:\/\/clinlabint.3wstaging.nl\/cardiac-biomarkers-new-weapons-against-cardiovascular-disease\/"},"modified":"2021-01-08T11:36:52","modified_gmt":"2021-01-08T11:36:52","slug":"cardiac-biomarkers-new-weapons-against-cardiovascular-disease","status":"publish","type":"post","link":"https:\/\/clinlabint.com\/cardiac-biomarkers-new-weapons-against-cardiovascular-disease\/","title":{"rendered":"Cardiac biomarkers – new weapons against cardiovascular disease"},"content":{"rendered":"

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.<\/strong><\/p>\n

Cardiovascular disease now a global priority<\/strong>
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, \u201cCVD is now more numerous in India and China than in all economically developed countries in the world added together.\u201d<\/p>\n

Mapping the disease progression pathway<\/strong>
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\u2019s 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\u2019s 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 \u2018risk factor\u2019.
\n
The Framingham project: clarifying the role of biomarkers<\/strong>
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\u2019s journal \u2018Circulation\u2019 pointed to one reason for such conflicting assessments, namely the \u201clack of cardiovascular specificity\u201d 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: \u201cMultiple biomarkers of cardiovascular stress,\u201d they said \u201cadd prognostic value to standard risk factors for predicting death, overall cardiovascular events, and heart failure.\u201d
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 \u201cinverse association\u201d between ideal CVH and CVD incidence, and that this was partly attributable to its \u201cfavourable impact on CVD biomarker levels and subclinical disease.\u201d 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.<\/p>\n

Identification of at-risk patients<\/strong>
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. <\/p>\n

Enabling targeted and timely treatment <\/strong>
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 \u2018preferred\u2019 biomarker for MI diagnosis, in conjunction with clinical evidence of myocardial ischemia. Creatine kinase-MB was positioned as an \u2018acceptable alternative\u2019. 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.<\/p>\n

Cardiac troponin \u2018the best single marker\u2019<\/strong>
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 \u201cdisplaced myoglobin and creatine kinase-MB as the preferred markers of myocardial injury.\u201d
In 2013, a Health Technology Asssessment (HTA) by Britain\u2019s National Institute for Health Research (NIHR) concurred with this view, observing that \u201chigh-sensitivity cardiac troponin is the best single marker in patients presenting with chest pain.\u201d Additional measurements of myoglobin or creatine kinase-MB, it noted were \u201cnot clinically effective or cost-effective.\u201d <\/p>\n

Debate on troponin not over <\/strong>
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 \u201cfor six hours after the onset of myocardial cell injury,\u201d making myoglobin \u201ca preferred early marker\u201d 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 \u201cmay be useful for risk assessment and management\u201d in asymptomatic populations, there is no evidence that it confers \u201can advantage in the context of MI diagnosis.\u201d In addition, they also note that \u201ccTnI assays are not standardized; thus, there can be a substantial difference in values depending on the assay used.\u201d

Defining assay sensitivity, differentiating troponin I and T<\/strong>
One challenge lies in the definition of a \u2018high sensitivity\u2019 assay, which can measure cTn in the single digit range of nanograms per litre. The term is used by vendors \u201cfor marketing purposes,\u201d and there \u201cis still no consensus\u201d regarding its application. Making matters tougher is the fact that most manufacturers\u2019 claims for assay precision \u201ccannot be achieved in clinical laboratories.\u201d
In effect, the jury on troponin is likely to be out for some time to come, accompanied by continuing uncertainties.
For instance, Britain\u2019s respected health advisory site patient.co.uk suggests that troponin I and T \u201care of equal clinical value\u201d while a 2010 guideline from NICE (National Institute for Healthcare and Clinical Excellence) advises taking a blood sample for troponin I or T as \u201cpreferred biochemical markers to diagnose acute MI.\u201d
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 \u201cequally sensitive and specific for the diagnosis of myocardial injury.\u201d
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 \u201cmodernize the performance evaluation and regulatory review.\u201d In Britain, NICE is currently updating its 2010 guideline.

The role of B-type natriuretic peptide <\/strong>
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 \u201calready used to diagnose heart failure,\u201d 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: \u201cBNP and NT-proBNP had good diagnostic performance for ruling out HF but were less accurate for ruling in HF.\u201d In addition, it found that the \u201ctherapeutic value was inconclusive.\u201d

Other biomarkers remain valuable<\/strong>
In the meanwhile, clinicians in emergency settings have recourse to a variety of other established CVD risk markers, such as cholesterol. \u201cResearch 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.\u201d Some of these \u201care of special interest as these may prove to be valuable biomarkers in the future.\u201d
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.<\/p>\n","protected":false},"excerpt":{"rendered":"

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 priorityOne of the priority applications for […]<\/p>\n","protected":false},"author":2,"featured_media":0,"comment_status":"closed","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"_monsterinsights_skip_tracking":false,"_monsterinsights_sitenote_active":false,"_monsterinsights_sitenote_note":"","_monsterinsights_sitenote_category":0,"footnotes":""},"categories":[52],"tags":[],"_links":{"self":[{"href":"https:\/\/clinlabint.com\/wp-json\/wp\/v2\/posts\/5347"}],"collection":[{"href":"https:\/\/clinlabint.com\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/clinlabint.com\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/clinlabint.com\/wp-json\/wp\/v2\/users\/2"}],"replies":[{"embeddable":true,"href":"https:\/\/clinlabint.com\/wp-json\/wp\/v2\/comments?post=5347"}],"version-history":[{"count":0,"href":"https:\/\/clinlabint.com\/wp-json\/wp\/v2\/posts\/5347\/revisions"}],"wp:attachment":[{"href":"https:\/\/clinlabint.com\/wp-json\/wp\/v2\/media?parent=5347"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/clinlabint.com\/wp-json\/wp\/v2\/categories?post=5347"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/clinlabint.com\/wp-json\/wp\/v2\/tags?post=5347"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}