Author + information
- ↵∗Reprint requests and correspondence:
Dr. James L. Januzzi, Jr., Massachusetts General Hospital, 32 Fruit Street, Yawkey 5984, Boston, Massachusetts 02114.
Although heart failure (HF) remains a fundamentally clinical diagnosis, substantial advances in the understanding of the underlying biology and pathophysiology of this syndrome has led to a greater interest in objective means to quantify its presence, severity, and potential future progression. Among the most intensively studied tools to achieve these goals are circulating biomarkers. The National Institutes of Health define a biomarker as a “characteristic that is objectively measured and evaluated as an indicator of normal biologic processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention” (1). Although this definition could encompass a wide array of assessments, conventionally speaking, the term “biomarker” is more often used to refer to substances detectable in blood, urine, or other bodily fluids. As clinical tools, biomarker measurements have the potential advantages of being readily available, quantitative, reproducible, generally inexpensive, and without requiring specialized expertise for interpretation.
Following the development, commercialization, and clinical successes of the natriuretic peptides as biomarkers of HF, there has been substantially increased interest in HF biomarker science. In conjunction with advances in proteomics and clinical chemistry that have allowed for higher throughput in identifying new potential biomarkers, a dizzying array of candidate markers have been identified that may have potential clinical application in HF (Table 1). This remarkable flurry of activity has led to a metaphorical tsunami in the number of research publications focused on biomarkers in HF (Fig. 1). Although many biomarker studies have provided important information that has led to progress in the optimal care of patients suffering from HF, it is fair to say that substantial heterogeneity exists with regard to the quality and impact of biomarker publications in the medical literature. With many biomarker studies suffering from inadequate or poorly described methods, optimistically interpreted results, publication bias, and conflation of opinion versus fact, an understandable degree of skepticism exists with regard to the potential clinical utility of new biomarkers. Indeed, recent data support this concern, noting selective reporting biases may be common with emerging biomarkers for cardiovascular disease (2).
With so many studies emerging in the HF biomarker realm, there has come an increased scrutiny on quality, both in terms of analytic properties of the biomarker assay itself, as well as the methodology used in the studies reporting their assessment (3). Relative to judging the strength of a biomarker candidate, it has been argued that measurement of a novel biomarker should be easily achieved through use of assays with acceptable analytical precision and should provide accurate results with well-defined biological variation. The biomarker candidate should primarily reflect important pathways involved in the pathophysiology of HF and should not recapitulate clinical information already available at the bedside, including that gained from measurement of gold standard biomarkers such as the natriuretic peptides. The design and methodology of the study should be appropriate to the clinical use being evaluated, whether it is about diagnosis, prognosis, or selection and guiding of therapy. Additionally, the approach to the study of novel biomarkers should be rigorous: new assays should be evaluated across a wide range of HF patients and the statistical methods used to evaluate the biomarker (relative to clinical variables as well as other biomarkers) should be contemporary and robust (3,4). Last, overly optimistic interpretation or presentation should be avoided, in order to preserve forward progress of the field.
Since the launch of JACC: Heart Failure, 1 in 4 submissions received have focused on the use of biomarkers, an experience recently shared by most academic journals. In light of this large wave of biomarker-related papers, it is worth considering what attributes make a biomarker paper worth publishing. Although the concept of what makes a “good paper” is not readily distilled into a simple formula, this issue of JACC: Heart Failure contains 3 examples of studies of established and emerging biomarkers that provide unique insights to the reader. One provides information regarding fundamental pathophysiologic mechanisms; another establishes important hypotheses in a uniquely underinvestigated group of HF patients; and a third study extends practical clinical understanding with a well-performed comparison between emerging and established markers.
One fundamental attraction of biomarker research is the ability to provide quantitative insights into molecular processes in vivo. In the current issue, Costello-Boerritger et al. (5) examined the transcardiac gradient of the pro-hormone of B-type natriuretic peptide, so-called proBNP1-108, in patients with and without HF. The prior identification of circulating forms of BNP other than the mature biologically active BNP1-32 and its amino-terminal (NT) fragment NT-proBNP1-76 has had major implications for the use of these markers as diagnostics, given the potential cross-reactivity of available assays with proBNP1-108 as well as potential ramifications for developing new therapies. The current study demonstrates the myocardial production of proBNP1-108 in both failing and nonfailing hearts using simultaneous peripheral and coronary sinus sampling. Additionally, the investigators used careful analytical methodology to prove the assay employed did not cross-react with other BNP species. This small but interesting study provides a platform from which future studies of myocardial biology and natriuretic peptide production may be based.
Patients with advanced HF and cardiogenic shock represent a small subset of the overall HF population but 1 with substantial utilization of health-care resources and extraordinarily high morbidity and mortality. A better understanding of the pathophysiology of this complex patient population would be welcome, yet studies in this very ill group are limited. In this issue, Shah et al. (6) examined serial assessment of an array of biomarkers in 21 patients suffering from refractory cardiogenic shock receiving mechanical circulatory support with a percutaneous ventricular assist device. In this model of acute ventricular unloading, the investigators measured a panel of biomarkers reflecting multiple pathophysiologic processes (neurohormonal activation, ventricular wall stress, inflammation, apoptosis, and extracellular matrix turnover) both before and after percutaneous ventricular assist device support. This hypothesis-generating analysis does not overstep the boundaries imposed on it by the small number of subjects, but it does provide some unique insights into the systemic and myocardial response to mechanical circulatory support.
Whereas the studies by Costello-Boerritger et al. (5) and Shah et al. (6) provide more mechanistic insights into physiology in HF, the third biomarker paper in this issue by Richards et al. (7) provides an immediately useful, clinically relevant look at the impact of atrial fibrillation on the diagnostic value of natriuretic peptides, including mid-regional proANP (MR-proANP). In this analysis from the BACH (Biomarkers in Acute Heart Failure) study, the investigators demonstrate that atrial fibrillation reduces the diagnostic accuracy of MR-proANP for acutely decompensated HF among a very large population of subjects with dyspnea. In a very detailed fashion, the investigators not only examined MR-proANP, but they also compared it to the gold standard diagnostic/prognostic biomarkers, BNP and NT-proBNP, showing that the performance of all 3 peptides suffer similarly from atrial fibrillation. Such comparisons across members of the same class of markers are unfortunately all too rare. The work by Richards et al. (7) benefits from a large sample size, robust statistical methods, and an unbiased summary of the results. These data have important implications for both the clinical interpretation of biomarker data in patients with acute HF, as well as for design of clinical trials using natriuretic peptide measurements as inclusion criteria.
Quality standards for biomarker studies continue to evolve and have been the subject of several recent publications (3,4). Further development of standardized quality criteria for evaluating biomarker research (as has been done for reporting of data from randomized clinical trials (8)) will continue to help provide guidance for researchers, editors, and reviewers alike to the surf the growing wave of biomarker literature that seems likely to increase further in the years to come.
↵∗ Editorials published in the JACC: Heart Failure reflect the views of the authors and do not necessarily represent the views of JACC: Heart Failure or the American College of Cardiology.
Dr. Januzzi is supported in part by the Desanctis Endowed Distinguished Scholar Fund; and has received grants from Roche Diagnostics, Critical Diagnostics, BG Medicine, Thermo Fisher, and Siemens AG. Dr. Felker has received grant support from the National Heart, Lung, and Blood Institute, Roche Diagnostics, Amgen, and Otsuka; and has acted as a consultant for Amgen, Novartis, Roche Diagnostics, Medtronic, Merck, Singulex, BG Medicine, Trevena, Celladon, St. Jude Medical, and Zensun.
- American College of Cardiology Foundation
- Hlatky M.A.,
- Greenland P.,
- Arnett D.K.,
- et al.,
- American Heart Association Expert Panel on Subclinical Atherosclerotic Diseases and Emerging Risk Factors and the Stroke Council
- Costello-Boerrigter L.C.,
- Lapp H.,
- Boerrigter G.,
- et al.
- Shah N.R.,
- Bieniarz M.C.,
- Basra S.S.,
- et al.
- Richards M.,
- Di Somma S.,
- Mueller C.,
- et al.