Editorial Biomarker and no end to it?

Bernhard Maisch1

1 Department of Internal Medicine – Cardiology, Angiology and Cardioprevention, University Hospital of Marburg and Gießen/UKGM GmbH, Faculty of Medicine, Philipps University of Marburg, Germany.

At a recent marketing meeting of an internationally operating company of diagnostics, I asked the forum of experts, which they considered to be the most important biological information or biomarker in the cardiovascular continuum to be obtained from the patient? The answers were prompt and not unexpected: the most frequently named biomarkers were the troponins, high-sensitivity C-reactive protein (hsCRP), and B-type natriuretic peptide (BNP).
At an international symposium on biomarkers this year, I asked the attendees – almost all of them were physicians, internists, and cardiologists – the same question, yet the result was different: it was no single serologic biomarker to be named first place, it was simply the patients biography with his symptoms. Is this disappointing or rather a return to the roots of medicine?
The term biomarker has various meanings and different implications. According to an FDA-based consensus definition a biomarker is a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, of pathogenetic processes or pharmacologic responses to a therapeutic intervention. In a broader sense, we can identify clinical biomarkers (the patients symptoms, blood pressure, auscultation, etc.), imaging biomarkers from noninvasive assessment like echocardiography or magnetic resonance imaging (MRI), and from invasive diagnostics, e.g., left and right ventricular angiography, coronary angiography, endomyocardial biopsy, pericardioscopy, epicardial and pericardial biopsy.
In its stricter sense, a biomarker is, however, a biochemical entity (e.g., a protein, DNA/RNA sequence) fit for purpose as a surrogate endpoint. It should be noninvasive and accessible, should have demonstrated clinical utility, and should lead the way to targeted therapy and personalized medicine. Biomarkers so defined cannot (always) substitute for hard endpoints such as mortality or MACE (major adverse cardiac events), but they are helpful in the evaluation of prognosis and treatment benefit in patients.
There are a number of key questions to be asked when examining the increasing list of biomarkers:
Are biomarkers just a diagnostic hype for something we already know for years: patients symptoms and characteristic and substantiating biochemical findings?
Are they true diagnostic tools for initial diagnosis and for follow-up?
Do they assess disease activity correctly?
Are they even causative contributors to the disease?
Which is their sensitivity and their specificity, their positive and negative predictive value?
Can we do without new biomarkers?
This issue of Herz – Cardiovascular Diseases tries to answer these questions from different perspectives.
Berliner et al., in their contribution, address the clinically critical question, if biomarkers in heart failure do better than history or echocardiography [1]. Their answer is not so clear-cut, however. While the diagnostic accuracy of anamnesis, clinical signs and symptoms is poor, and chest X-ray or electrocardiography show reasonable specificity but poor sensitivity, transthoracic echocardiography appears well suited for the diagnosis of heart failure, but is relatively costly and depends on the availability and the skills of the investigator. A recent Health Technology Assessment from the UK using individual patient data of all major natriuretic peptide studies confirmed the relative specificity of clinical evaluation and the sensitivity of natriuretic peptide measurement in various clinical settings (primary care, emergency admission), thus reviving a classic physicians approach to a patient with heart failure. Of note, the rate of correct heart failure diagnoses in primary care is poor, however. When analyzing the results of their cluster-randomized trial comparing the use of miniaturized echocardiography and/or point-of-care BNP testing in patients with suspected heart failure in primary care, the Handheld-BNP study, the diagnostic yield is decreasing in patients with many comorbidities. In addition, hand-held echocardiography may be adequate for systolic but inadequate for diastolic heart failure. In a multimarker approach, adrenomedullin (ADM) as a marker of myocyte stress and ST2, the receptor for interleukin-33, as a marker of myocyte stretch have also been considered to be of prognostic impact.
Lainscak et al. [2], while reviewing different biomarkers in heart failure, also point out that due to the focused attitude in clinical practice the wealth of information available in polymorbid chronic heart failure patients might be overlooked. Particularly in chronic diseases, only the combination of all available findings into a homogeneous clinical message will provide the best possible management for the patients. Classic biomarkers such as the natriuretic peptides and BNP, NT-proBNP or the newly advocated mid-regional atrial natriuretic peptide (MR-proANP; BRAHMS), the growth differentiation factor-(GDF-)15 as a general prognostic marker or the cysteine-proteinase inhibitor cystatin C, which is elevated in renal dysfunction and in patients with left ventricular hypertrophy and diastolic heart failure, should be accompanied by important additional but also classic information such as anemia. Anemia has strong prognostic implications as data from the ELITE II and the COMET trial clearly indicate. Thus, in the near future a multimarker strategy is likely to become more than a marketing slogan.
The emerging role of GDF-15 as a global marker of risk prediction has been further elaborated by Kempf & Wollert [3]. GDF-15 is a stress-responsive cytokine, which has shown prognostic impact for patients beyond established biomarkers such as the natriuretic peptides or the troponins particularly in coronary artery disease (CAD). It thus makes it a good additional candidate for a multimarker strategy.
Giannitsis & Katus focus on the cardiac troponins (cTn) both in CAD and in heart failure [4]: cTn is the established marker of necrosis in acute myocardial ischemia and infarction, but it has also been found useful for detection of myocardial cell death in other conditions such as acute pulmonary embolism, myocarditis, heart failure, sepsis, and end-stage renal disease. With the high-sensitivity troponin the precision criteria required by the Joint European Soci -ety of Cardiology/American College of Cardiology/American Heart Association/World Heart Federation Task Force for the Redefinition of Acute Myocardial Infarction are now better fulfilled. This increase of sensitivity for myocardial necrosis in the gray zone of the present tests will also increase positive results in patients with cardiomyopathy, myocarditis and heart failure, but might thus lower the specificity for coronary obstruction.
Among blood biomarkers, C-reactive protein (CRP), measured by high-sensitivity assays (hsCRP), has received widespread interest as inflammation marker and with regard to its potential role as a predictor of cardiovascular risk in coronary heart disease (CHD), although observed associations between circulating CRP and CHD are unlikely to be causal, as Karakas & Koenig point out in their contribution [5]. In the JUPITER trial, a remarkable detail points to the fact that it assesses truly the total inflammatory burden. Improved outcome that can be attributed not only to lipid lowering but also to the pleiotropic anti-inflammatory effects of rosiglitazone has emerged as subgroup of patients, that should also receive this treatment.
The differentiation between inflammatory and noninflammatory cardiomyopathy by classic biomarkers remains a problem, which at present can only be solved by endomyocardial biopsy. The algorithm of noninvasive markers suggested by Noutsias et al. [6] includes the integrated approach by using serologic biomarkers for inflammation (hsCRP) and necrosis (hsTnI), cardiac MRI as imaging marker for function and inflammation, and endomyocardial biopsy for the assessment of etiology and inflammation in addition to the loss of function.
The concept of a multimarker approach in pericardial diseases is also followed by Karatolios et al. [7], who demonstrated that the combination of information by different biomarkers can differentiate be -tween hydropericardium, viral, bacterial and autoreactive pericardial effusion on the one hand, and neoplastic effusions on the other. Undoubtedly, this has impact on treatment and prognosis.
In patients with HIV infection, cardiac involvement can be, but often is not regularly assessed by echocardiography. When analyzing 802 HIV-infected patients in their original contribution for cardiac involvement or effects of antiretroviral therapy, Neumann et al. [8] found out that patients with a BNP concentration of > 50 pg/ml had a significantly higher rate of heart failure, cardiomyopathy and CAD than the rest. They therefore advocate that BNP should be included in the regular HIV screening program.
The contributions by Frick et al. on the role of biomarkers after heart transplantation and by Reinhold et al. on Are biomarkers worth the price will be part of issue 1/2010 of Herz.
By summing up the contributions in this issue of Herz, one comes to the conclusion that cardiovascular diseases and heart failure in particular still depend on a comprehensive approach comprising the patients history as well as clinical, laboratory and technical examinations. In this scenario, biomarkers represent one important and promising modality.

Address for Correspondence
Prof. Dr. Bernhard Maisch
Direktor der Klinik für Innere Medizin – Kardiologie, Angiologie und Kardioprävention
UKGM GmbH und Philipps-Universität Marburg
Baldingerstraße
35043 Marburg
Germany
Phone (+49/6421) 586-6462,
Fax -8954
e-mail: maisch@staff.uni-marburg.de

References
1.Berliner D, Angermann CE, Ertl G, Störk S. Biomarkers in heart failure – better than history or echocardiography? Herz 2009;34:581–588.
2.Lainscak M, Anker MS, von Haehling S, Anker SD. Biomarkers for chronic heart failure. Diagnostic, prognostic, and therapeutic challenges. Herz 2009;34:589–593.
3.Kempf T, Wollert KC. Growth differentiation factor-15: a new biomarker in cardiovascular disease. Herz 2009;34: 594–599.
4.Giannitsis E, Katus HA. Troponins and high-sensitivity troponins as markers of necrosis in CAD and heart failure. Herz 2009;34:600–606.
5.Karakas M, Koenig W. CRP in cardiovascular disease. Herz 2009;34:607–614.
6.Noutsias M, Pankuweit S, Maisch B. Biomarkers in inflammatory and noninflammatory cardiomyopathy. Herz 2009; 34:615–623.
7.Karatolios K, Alter P, Maisch B. Differenzierung von malignen und nichtmalignen, inflammatorischen Perikardergüssen mit Biomarkern. Herz 2009;34:624–633.
8.Neumann T, Reinsch N, Neuhaus K, et al. Wertigkeit des Biomarkers BNP bei HIV-infizierten Patienten. Herz 2009; 34:634–640.