Author + information
- Christopher Pemberton, PhD∗ ()
- Christchurch Heart Institute, Department of Medicine, University of Otago, Christchurch, New Zealand
- ↵∗Address for correspondence:
Dr. Christopher Pemberton, Department of Medicine, Christchurch Heart Institute, University of Otago, Christchurch, 2 Riccarton Avenue, Christchurch 8011, New Zealand.
Circulating natriuretic peptides, especially B-type natriuretic peptide, are important and recommended diagnostic and prognostic markers for the management of patients experiencing heart failure (HF). In recent years, a wide range of markers, such as sST2, proADM, and GDF-15 (1), have all been shown to possess comparable, independent, and in some areas, superior performance to B-type natriuretic peptide in HF risk management. However, there is a continuing need for markers that can add to this armamentarium, especially with regard to reflecting the often present multiple comorbidities in patients and the complicated nature of the inflammatory immune response that is present in HF.
In this issue of JACC: Heart Failure, Koller et al. (2) present their results based on measurement of the marker known as soluble urokinase-type plasminogen activator receptor (suPAR) in the circulation of patients with chronic heart failure (CHF). suPAR is the soluble form of the urokinase-type plasminogen activator receptor (uPAR), which is bound by urokinase plasminogen activator (uPA) to promote uPAR binding to the matrix protein vitronectin (3) and stimulate adhesion of cells to a vitronectin substratum. It has been known for some time that plasma and tissue expressions of suPAR/uPAR are predictive of outcomes in patients with cancer (4), a high burden of infectious disease (5), or at high risk of chronic kidney disease and associated declines in estimated glomerular filtration rate (6). Now, the emerging published data are extending the prognostic capability of suPAR to cardiovascular disease.
Thus, in the Swedish Malmo Diet and Cancer study of over 4,000 individuals, circulating levels of suPAR have been shown to correlate with levels of N-terminal pro–B-type natriuretic peptide (NT-proBNP) and to predict incidence of HF and increased risk of carotid plaque, stroke, and coronary artery disease (7). In acute coronary syndromes (ACS), suPAR provides improved risk prediction, over and above currently measured variables, for mortality and events in non–ST-segment elevation ACS and also for predicting recurrent myocardial infarction in ST-segment elevation ACS patients undergoing percutaneous coronary intervention (8). In general populations, a number of publications show that suPAR provides excellent risk assessment power for the prediction of mortality and cardiovascular events and the scoring of coronary artery calcification in the presence of coronary artery disease in healthy and “at risk” patient groups (9).
The current findings of Koller et al. (2) now significantly add to the published data by more precisely defining the potential role of suPAR in HF risk prediction. Koller et al. (2) first derived their findings from a prospective observational study of 319 outpatient clinic subjects who were in a stable condition and followed for a median of 3.2 years. From this initial group, it was determined by univariate regression that plasma levels of suPAR strongly predicted mortality, with an optimal cutoff of 4.4 ng/ml. Multivariable analysis confirmed the independence of this association. Interestingly, suPAR had a significantly higher hazard ratio for mortality than sST2, and unlike suPAR, sST2 lost its overall and cardiovascular mortality associations in a fully adjusted model. By contrast, suPAR was significantly associated with and additive to NT-proBNP utility, and patients with high levels of both markers had the highest hazard ratio of 6.57 for all-cause mortality. In terms of discrimination and reclassification of patients, suPAR could significantly improve the C-statistic of NT-proBNP and the multivariable model, as well as net reclassification improvement and integrated discrimination improvement values. In short, suPAR significantly improved clinical model and NT-proBNP–based assessments of overall and cardiovascular-specific mortality in their derivation cohort population.
In their validation cohort of 346 patients with advanced CHF, who were followed for a median of 3.6 years, all of the previously mentioned findings were confirmed with minimal changes to hazard ratio cutoffs (4.2 ng/ml vs. 4.4 ng/ml) and net reclassification improvement/integrated discrimination improvement statistics. Thus, the authors conclude that: 1) suPAR provides superior mortality risk information over and above sST2; and 2) suPAR significantly improves the performance of standard clinical and NT-proBNP risk assessment in CHF. There are caveats to these impressive findings. First, the derivation and validation cohorts used are markedly different in disease status and also with respect to sample age; the validation cohort samples were from sicker patients and the samples were nearly 10 years older. This latter point needs clarification; how stable is suPAR in plasma? Furthermore, measurements made by Koller et al. (2) derive from an assay that measures full-length and cleaved forms of the receptor: could better results be obtained from specific assays for either form? Second, although mortality events (n > 100) were sufficient from this group of patients for analysis, the size of the cohorts was not sufficient to analyze other follow-up indexes, such as recurrent presentation with acute decompensated HF, infection, or all-cause readmission. Next, the effect of other comorbidities such as chronic obstructive pulmonary disease, pneumonia, previous myocardial infarction, and arrhythmia was not assessed. The latter indexes should be included in clinical multivariate models for assessing any effect upon the impressive mortality statistics generated by suPAR.
Finally, 1 major problem that suPAR may encounter for inclusion into cardiovascular risk assessment is its general nature as a marker of ill health; indeed, suPAR predicts cancer, cardiovascular disease, diabetes, kidney disease, and mortality in general populations (6,10). Such a wide spectrum of indications, which are not unexpected from an endpoint effector of the immune system, make it more important for adequately powered studies to more precisely define suPAR’s potential. Nevertheless, the contribution provided by Koller et al. (2) substantially adds to our knowledge concerning the utility of suPAR and points to obligatory further work to confirm its impressive potential.
↵∗ Editorials published in 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. Pemberton has reported that he has no relationships relevant to the contents of this paper to disclose.
- 2017 American College of Cardiology Foundation
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