Cardiac natriuretic peptides in plasma: from prediction to precision medicine
Authors: Jens P Goetze, Nora E Zois
Journal: The Lancet Diabetes & Endocrinology (2016)

In The Lancet Diabetes and Endocrinology, the Natriuretic Peptides Study Collaboration1Natriuretic Peptides Studies CollaborationNatriuretic peptides and integrated risk assessment for cardiovascular disease: an individual-participant-data meta-analysis.Lancet Diabetes Endocrinol. 2016; (published online Sept 2.)http://dx.doi.org/10.1016/S2213-8587(16)30196-6Google Scholar show plasma measurement of the cardiac hormone N-terminal pro-B-type natriuretic peptide (NT-proBNP) to be predictive not only of coming coronary heart disease, but also future stroke in individuals without known cardiovascular disease at the time of measurement (risk ratio for combination of coronary heart disease and stroke 1·76 [95% CI 1·56–1·98]). The individual-participant-data meta-analysis included 40 prospective cohorts comprising over 95 000 individuals and is thus the largest study of its kind of NT-proBNP measurement in plasma. The authors conclude that addition of NT-proBNP measurements to conventional risk assessment in people without cardiovascular disease might improve accuracy in cardiovascular and stroke risk prediction, which means that some individuals at increased risk might be identified for possible therapeutic or lifestyle interventions. Measurement of cardiac natriuretic hormones and their precursors in plasma has mostly been a matter of congestive heart failure. Today, plasma measurement is included in all high-income country guidelines for heart failure assessment, for which the natriuretic hormones and prohormones best serve to rule out the presence of congestive heart failure. Strikingly, this use basically mirrors the very first observation of atrial natriuretic peptide concentration measurement in plasma published in 1986 by Burnett Jr and colleagues.2Burnett Jr, JC Kao PC Hu DC Atrial natriuretic peptide elevation in congestive heart failure in the human.Science. 1986; 231: 1145-1147Crossref PubMed Scopus (784) Google Scholar Since then, plasma measurement has been complicated by the fact that the endocrine heart seems much more endocrine than first assumed, meaning that post-translational processing of both proatrial natriuretic peptide and NT-proBNP results in the existence of multiple peptide species, rather than just one active hormone (here B-type natriuretic peptide) and one inert fragment (here NT-proBNP).3Goetze JP B-type natriuretic peptide: from posttranslational processing to clinical measurement.Clin Chem. 2012; 58: 83-91Crossref PubMed Scopus (30) Google Scholar This finding, in turn, means that measurement of peptides in plasma strongly relies on the biochemical method used; the Natriuretic Peptides Study Collaboration1Natriuretic Peptides Studies CollaborationNatriuretic peptides and integrated risk assessment for cardiovascular disease: an individual-participant-data meta-analysis.Lancet Diabetes Endocrinol. 2016; (published online Sept 2.)http://dx.doi.org/10.1016/S2213-8587(16)30196-6Google Scholar quantified NT-proBNP calibrated against non-glycosylated NT-proBNP 1–76. In terms of general mechanism, whether or not glycosylated NT-proBNP concentration assessment as well as assessment for the other cardiac peptides would provide the same or even additional information, as suggested by other studies at least in heart failure assessment, would be valuable to see.4Maisel A Mueller C Nowak R et al.Mid-region pro-hormone markers for diagnosis and prognosis in acute dyspnea: results from the BACH (Biomarkers in Acute Heart Failure) trial.J Am Coll Cardiol. 2010; 55: 2062-2076Summary Full Text Full Text PDF PubMed Scopus (443) Google Scholar New markers of risk always have a way to go before they might or might not be implemented in clinical practice. One could argue that the true challenge for any given risk marker is whether or not it can progress from mere prediction without obvious intervention to precision medicine with defined therapeutic treatment or lifestyle interventions for the individual. What is the general practitioner going to do with a patient for whom an incidental measurement of plasma NT-proBNP concentration is 137 pmol/L? From the study by the Natriuretic Peptides Study Collaboration,1Natriuretic Peptides Studies CollaborationNatriuretic peptides and integrated risk assessment for cardiovascular disease: an individual-participant-data meta-analysis.Lancet Diabetes Endocrinol. 2016; (published online Sept 2.)http://dx.doi.org/10.1016/S2213-8587(16)30196-6Google Scholar that particular patient is at markedly increased risk of cardiovascular disease and stroke, yet the practical consequence of this information is not straightforward. This is particularly true in view of the fact that several therapeutic interventions come with their own risk profiles (eg, medicine for stroke prevention). Prediction studies might hold more information than just the overall, simplified sum of risk. In the study by the Natriuretic Peptides Study Collaboration1Natriuretic Peptides Studies CollaborationNatriuretic peptides and integrated risk assessment for cardiovascular disease: an individual-participant-data meta-analysis.Lancet Diabetes Endocrinol. 2016; (published online Sept 2.)http://dx.doi.org/10.1016/S2213-8587(16)30196-6Google Scholar, for instance, a particular group of individuals are highlighted in whom risk assessment would be justified on the basis of other risk factors. The authors follow this line to some extent, showing that the risk information garnered from NT-proBNP concentration measurements seems greater in older than in younger individuals and in patients with diabetes than in those without. The endocrine heart still remains a subject of science as cardiac production of natriuretic peptides might be affected by diabetes.5Zois NE Bartels ED Hunter I Kousholt BS Olsen LH Goetze JP Natriuretic peptides in cardiometabolic regulation and disease.Nat Rev Cardiol. 2014; 11: 403-412Crossref PubMed Scopus (131) Google Scholar Likewise, glucagon-like peptide 1 analogues might affect secretion of natriuretic peptides.6Kim M Platt MJ Shibasaki T et al.GLP-1 receptor activation and Epac2 link atrial natriuretic peptide secretion to control of blood pressure.Nat Med. 2013; 19: 567-575Crossref PubMed Scopus (351) Google Scholar In essence, NT-proBNP concentration in plasma could therefore simply reflect the severity of the diabetes and hence its concurrent treatment status. Studies of natriuretic peptide measurement in patients with diabetes stratified according to disease severity and treatment modules are certainly needed. Yet, the study by the Natriuretic Peptides Study Collaboration1Natriuretic Peptides Studies CollaborationNatriuretic peptides and integrated risk assessment for cardiovascular disease: an individual-participant-data meta-analysis.Lancet Diabetes Endocrinol. 2016; (published online Sept 2.)http://dx.doi.org/10.1016/S2213-8587(16)30196-6Google Scholar causes consideration of the possible future place for NT-proBNP concentration measurement in precision medicine. Clearly, identification of individuals before disease onset is a growing field, one that has the potential to truly improve general health and quality of life. However, biomarkers should undergo extreme scrutiny and critical assessment before treatment is introduced on the basis of such surrogate measures of risk. Basic science should be pursued alongside prospective intervention studies assessing the use of such biomarkers. Essentially, the key question is how the endocrine heart can foresee coming cardiovascular disease and stroke. New therapeutic interventions might be possible and thus biomarkers might be able to help not only identify risk of coming disease but also allow for the best intervention for that particular risk in that particular person.7Tschöp MH DiMarchi RD Outstanding Scientific Achievement Award Lecture 2011: defeating diabesity: the case for personalized combinatorial therapies.Diabetes. 2012; 61: 1309-1314Crossref PubMed Scopus (30) Google Scholar Perhaps then prediction assessment can be moved to precision medicine, with the worthy outcome of improvement of human quality and length of life. We declare no competing interests. Natriuretic peptides and integrated risk assessment for cardiovascular disease: an individual-participant-data meta-analysisIn people without baseline cardiovascular disease, NT-proBNP concentration assessment strongly predicted first-onset heart failure and augmented coronary heart disease and stroke prediction, suggesting that NT-proBNP concentration assessment could be used to integrate heart failure into cardiovascular disease primary prevention. Full-Text PDF Open Access