Biomarkers: Where We Are, Where We’re Going

Cardiac biomarkers are the focus of the July 24 special issue of JACC—reviewing both what has been learned and where research is headed. "More and more of the patients we see have numerous co-morbidities. Biomarkers allow us to help differentiate one disease from the other, and thus can be very valuable for the health care practitioner," said Alan S. Maisel, MD, the JACC Associate Editor in charge of the special issue.

The papers in the issue, including a description of new circulating miRNAs and the risk of myocardial infarction (MI), demonstrate one of the main goals of this field of research: identifying new uses for old biomarkers, as well as the discovery of novel biomarkers useful for diagnosis and/or prognosis. Dr. Maisel told CardioSource WorldNews, "Actionable treatments on the basis of biomarkers are what we see as the future. This issue (of JACC) will help illustrate that and, in a small way, guide us forward."

Breathing Not Properly 10 Years Later

Dr. Maisel, who is from the division of cardiology, Veterans Affairs San Diego Healthcare System in La Jolla, California, and a professor at the University of California San Diego, School of Medicine, co-authored the issue's State-of-the-Art paper reviewing the progress made since the first publication of the seminal Breathing Not Properly study 10 years ago. That study established the utility of B-type natriuretic peptide (BNP) in diagnosing heart failure and how these initial observations have shaped the search for other diagnostic and prognostic biomarkers.

According to Dr. Maisel and co-author Lori B. Daniels, MD, MAS, the prospective, multinational BNP trial, published in the New England Journal of Medicine in 2002, ushered BNP into clinical practice. "In just 10 years, BNP has gone from being an unknown biomarker to one of the most useful in cardiology and beyond," they wrote. Initially, its major strengths were clarifying the differential diagnosis of patients presenting with dyspnea, but numerous studies from the past 10 years have demonstrated the usefulness of BNP and other natriuretic peptides (NPs). They added, "One of the most rapid and successful areas of expansion in the use of NP levels over the past 10 years has been in risk prediction in a multitude of clinical settings beyond the one originally targeted, acute heart failure," including pre-operative evaluations, treating challenging presentations of valvular heart diseases, discharge monitoring to reduce readmission rates, and identifying chemotherapy patients at risk for drug-induced cardiotoxicity.

The BNP study set the bar as to how to evaluate new biomarkers. As Maisel and Daniels explained, "If the new biomarker is not diagnostic, then its prognostic utility must be clinically actionable, either targeting a specific treatment or risk stratifying the patient into a milieu where a more aggressive form of care will be delivered." What's next for NPs, which have evolved from an initial role in diagnosing acute patients to a more ubiquitous role as a prognostic aid in both inpatients and outpatients? "In the next 10 years," Dr. Maisel said, "new biomarkers are likely to emerge and share the spotlight, but NP levels are unlikely to be cast aside by any of them."

Small RNA Biomarkers Come of Age

In another article appearing in the special issue of JACC, Anna Zampetaki, PhD, highlights circulating microRNAs (miRNAs), an emerging class of potential cardiac biomarkers. MiRNAs have been identified as signatures for type 2 diabetes, but in the current study, Dr. Zampetaki, from King's British Heart Foundation Centre, King's College, London, and colleagues sought to identify changes in circulating miRNAs and explore their association with incident myocardial infarction (MI).

The investigators analyzed miRNA levels in 820 participants from a prospective population-based survey who had experienced MI. A total of 19 candidate miRNAs were quantified by real time polymerase chain reactions in these participants; of seven considered potential targets, three miRNAs were consistently and significantly associated with incident MI. Multivariate analysis revealed that miR-126 was positively associated with disease risk (hazard ratio = 2.69; 95% CI 1.45-5.01; p = 0.002), while miR-223 (hazard ratio = 0.47; 95% CI 0.29-0.75; p = 0.002) and miR-197 were inversely associated with disease risk (hazard ratio = 0.56; 95% CI 0.32-0.96; p = 0.036).

Zampetaki et al. also sought to determine cellular origin by provoking changes in plasma miRNA levels through a controlled intervention (consisting of 30 minutes of thigh cuff inflation resulting in leg ischemia and repetitive sampling post-injury to mimic MI) in healthy volunteers. Analysis of plasma miRNA changes supported co-regulation of the three identified miRNAs, as they were all upregulated in plasma alongside two additional miRNAs (miR-21 and miR-24).

In an accompanying editorial, Stefan Engelhardt, MD, PhD, wrote "The intervention part in healthy volunteers provides interesting clues with regard to the potential origin of some biomarker miRNAs." Compared with the wealth of information about protein biomarkers, the field of miRNA biomarker research is relatively "immature," but, Dr. Engelhardt said, the research by Zampetaki et al. shows promise. "Taken together, this study is evidence that the field of miRNAs as biomarkers is about to mature. Work such as the present one will show in the not-too-distant future whether quantitation of these tiny RNA molecules will eventually prove useful as biomarkers for clinical practice."

Using NGAL to Predict Adverse Events in STEMI

The biomarker neutrophil gelatinase-associated lipocalin (thankfully abbreviated NGAL) has been previously established as a sensitive marker of both clinical and subclinical acute kidney injury (AKI), but its prognostic role in predicting adverse events in patients with STEMI treated with PCI has not been fully studied. Based on data indicating that plasma NGAL is significantly elevated in the presence of coronary artery disease and in patients with acute MI, Søren Lindberg, MD, Gentofte University Hospital, Copenhagen, Denmark, and colleagues hypothesized that NGAL may be an independent predictor of all-cause mortality and cardiovascular events in patients with STEMI treated with PCI.

In total, 584 STEMI patients were evaluated; mean plasma level was 134.2 μg/L. During follow-up, all-cause mortality was 12% (n = 69), including 7% (n = 38) from cardiovascular causes. Six percent (n = 36) were hospitalized with a new acute MI and 9% (n = 55) with heart failure. Overall, 19% (n = 116) reached the combined endpoint of major adverse cardiac events (MACE).

High NGAL (>75th percentile) was associated with age, current smoking status, C-reactive protein (CRP), and creatinine levels. After adjusting for various risk factors (including the occurrence of AKI), patients with high NGAL were significantly more likely than those with low NGAL to experience all-cause mortality and MACE (p < 0.001).

Also, Lindberg et al. found that when both NGAL and CRP were elevated, mortality risk was significantly increased (hazard ratio = 6.6; 95% CI 3.5-12.2; p < 0.001). However, in terms of MACE, patients with high NGAL had significantly increased risk, regardless of CRP. Those with high NGAL also were more likely to experience cardiac events earlier in the 30 days post-STEMI than those with low NGAL, indicating a potential relationship between NGAL and vascular inflammation.

Thus, the study suggests that high NGAL independently predicts all-cause mortality and MACE after AMI, but, the authors concluded, "Whether this is caused by AKI, increased inflammation or both, and whether plaque rupture contributes as well remains to be elucidated."

Keywords: Biomarkers, MicroRNAs, Myocardial Infarction, Prognosis

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