Petr Jarolim, MD, PhD,     Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA. Email: pjarolim@partners.org

Cardiac troponins I and T have been the cornerstone of diagnostics of acute coronary syndrome for almost 20 years. Natriuretic peptides have established themselves in heart failure during the last decade. These and additional promising biomarkers, such as ST-2, galectin-3, GDF-15, copeptin, midregional proadrenomedullin, and the markers of glomerular filtration rate and kidney injury, are reviewed in groups corresponding to the pathophysiological processes they probe—cardiomyocyte injury, myocyte stress, inflammation, oxidative stress, plaque instability, extracellular-matrix remodeling, or those markers grouped in the neurohormone category. Biomarkers linking the renal and cardiac functions and microRNAs and metabolomic markers are addressed as well.

Keywords

Laboratory medicine

Cardiac markers

Biomarkers

Cardiovascular disease

Acute myocardial infarction

Heart failure

Adverse event

Risk factor

Key points

Introduction

The recent growth in the rate of discovery, number of clinical trials, and new clinical applications of disease biomarkers has been truly amazing (Box 1). This is particularly true for biomarkers of cardiovascular diseases, be they acute coronary syndrome (ACS), heart failure (HF), or various cardiomyopathies. Applications or cardiovascular biomarkers are no longer limited to diagnosis. Biomarker assays are increasingly used to predict short- and long-term disease-free survival or risk of adverse events and readmissions. Very importantly, baseline biomarker levels are beginning to serve as a tool for selecting the right therapy and sequential monitoring of certain biomarkers, which are used as guidance for adjusting medication dosages.

The list of potentially useful cardiovascular biomarkers is seemingly endless. However, on closer inspection, most of these markers still only qualify as “potentially useful or promising,” whereas some have already fallen or are beginning to descend into the “outdated” category. At the end of the day, in addition to the handful of firmly established markers such as cardiac troponins (cTn) and natriuretic peptides, there are just a few additional biomarkers that are clearly becoming clinically useful, either by providing solid diagnostic and prognostic information or by enabling monitoring of therapeutic interventions.

There are many criteria a biomarker must meet to become clinically useful. According to the National Institutes of Health consensus conference,1 a biomarker is a characteristic that is objectively measured and evaluated as an indicator of normal biologic processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention.

There are many other definitions of a biomarker. An ideal biomarker should meet the following criteria: (1) An accurate, reproducible assay should be available at a reasonable cost and have an acceptable turnaround time; (2) the assay should be highly sensitive and specific for the outcome it is expected to identify, and the test result should explain a reasonable proportion of the outcome independent of established predictors; (3) the test should be acceptable and understandable to the patient, and the test results should be easily interpretable by the clinicians; (4) very importantly, knowledge of the biomarker’s level should change patient management.

Examples of biomarkers may include anything from body weight, body mass index, or simple clinical chemistry and hematology tests all the way to complex laboratory tests that are performed in blood, urine, other body fluids, or various tissues. Most current cardiovascular biomarkers are measured in plasma or serum using more complex clinical chemistry assays, in particular, immunoassays. In fact, when the word biomarker is used, many researchers automatically interpret it as a protein, protein fragment, or polypeptide. It should be emphasized that in addition to the above-mentioned physical parameters, biomarkers also include small molecules and metabolites, nucleic acid sequences, RNAs, and microRNAs. Such “alternate” biomarkers are briefly reviewed at the end of this article.

The cardiovascular biomarker pie can be sliced in multiple ways. Cardiovascular biomarkers can be divided into the established and novel groups, or according to their use for diagnosis of an acute event or short- or long-term prognosis or for guiding therapy. Most reviews categorize cardiac biomarkers by the pathophysiological process they capture, be it inflammation, ischemia and necrosis, myocyte stress, oxidative stress, plaque instability, volume overload, extracellular matrix remodeling, or other. These categories are used in this overview, although one has to keep in mind that there are multiple overlaps among these categories—a biomarker of inflammation may be associated with plaque instability, oxidative stress, or other. Finally, one can categorize cardiovascular biomarkers according to the disease entity they are most useful for—ACS, HF, hypertrophic cardiomyopathy (HCM). Such classification is shown in Box 2.