MicroRNAs as novel myocardial biomarkers.

The search for new biomarkers of cardiovascular disease remains a large and growing enterprise. Biomarkers are used to identify the risk, presence, and/or severity of disease; to guide diagnostic and therapeutic interventions; and to provide clues to disease mechanisms and pathophysiological distinctions within clinically similar populations. Among cardiovascular biomarkers, those used for identifying the presence or severity of myocardial injury have the most extensive history. Beginning with the first report 55 years ago that circulating transaminases are increased in acute myocardial infarction (1 ), the search for new and better biomarkers of myocardial injury has continuously evolved. As recently reviewed (2 ), cardiac troponin has emerged after decades of clinical and laboratory investigation as a highly diagnostically sensitive and specific biomarker of myocardial injury, with a currently indispensable role in the accurate and timely diagnosis of patients with suspected acute coronary syndromes (ACSs). Central to this preeminence is the tissue specificity of cardiac troponin isoforms, increases in assay sensitivity, and an extensive body of evidence validating the diagnostic, prognostic, and therapy-guiding utility of cardiac troponins in diverse clinical settings. Because the benefits of ACS treatments are favorably influenced by the speed with which they are applied, the ideal myocardial injury biomarker must also permit rapid measurement; cardiac troponin assays have also proved satisfactory in this regard. Despite the established strengths of cardiac troponins for prompt and reliable detection of myocardial injury, the ability to reliably detect ischemia in the absence of myocyte necrosis and the ability to distinguish alternative causes and mechanisms of myocyte damage (inflammation, oxidative stress, apoptosis) represent unmet needs and opportunities for new biomarkers, which have been highlighted in recent reviews (2, 3 ). Resistance to inaccuracy caused by confounding factors such as renal failure is another favorable attribute that is not ideally achieved with cardiac troponin assays. Although most testing of clinically applied biomarkers has involved measurement of circulating peptides or proteins with biochemical or immunoassay techniques, advances in molecular biology and technology have fueled an increasing interest in nucleotidebased biomarkers that might address unmet needs and/or enhance diagnostic or therapeutic effectiveness. For example, additional valuable insight might be derived from biomarkers that identify patient-specific factors, such as DNA polymorphisms, that modulate a patient’s risk and responses to treatment. Alternatively, mRNA in peripheral blood cells (PBCs) may provide unique insights into the interplay between the myocardium and the circulation, and PBC mRNA has recently been used to noninvasively detect rejection of cardiac allografts. For that application, early studies identified 40 mRNA transcripts derived from PBCs with a favorable dynamic range, differential expression in patients with and without allograft rejection, and regression of pathologic expression in association with histologic regression (4 ). Further development of this approach led to the commercialization of a clinical diagnostic tool (5 ) and identified the potential to achieve greater diagnostic clarity in areas in which standard histologic techniques have difficulty discriminating rejection from other biological responses (6 ). Although RNA profiling of PBCs in transplant medicine continues to evolve, it is clear that the early parallel sampling of myocardial and blood samples propelled the identification and validation of less invasive biomarkers. In this issue of Clinical Chemistry, Ji et al. applied an analogous experimental approach to identify circulating microRNAs (miRNAs) that might accurately reflect myocardial injury in vivo (7 ). In these studies, a systematic search used standard real-time reversetranscription PCR (RT-PCR) techniques to identify miR-208, a cardiac-specific miRNA detectable in circulating plasma after myocardial injury. Moreover, miR-208 was detectable in the plasma of rats with isoproterenol-induced cardiac injury but not in healthy control rats, after renal infarction, after left ventricular hypertrophy, or after bilateral nephrectomy. Importantly, increases in plasma miR-208 after isoproterenol administration were correlated with increases in circulating concentrations of cardiac troponin. Together, these findings indicate that plasma miR1 Cardiovascular Institute, University of Pennsylvania School of Medicine, Philadelphia, PA. * Address correspondence to the author at: University of Pennsylvania School of Medicine, Rm. 608 BRB II/III, 421 Curie Blvd., Philadelphia, PA 19104. Received July 29, 2009; accepted August 4, 2009. Previously published online at DOI: 10.1373/clinchem.2009.131649 2 Nonstandard abbreviations: ACS, acute coronary syndrome; PBC, peripheral blood cell; miRNA, microRNA; RT-PCR, reverse-transcription PCR; LVAD, left ventricular assist device. Clinical Chemistry 55:11 000 – 000 (2009) Editorials