Donald W. Reynolds Cardiovascular Clinical Research Center and the Department of Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA
* Corresponding author: Division of Cardiology, UT Southwestern Medical Center, 5909 Harry Hines Boulevard, Room HA9.133, Dallas, TX 75390-9047, USA. Tel: +1 214 645 7500; fax: +1 214 645 7501. E-mail address: james.delemos{at}utsouthwestern.edu
This editorial refers to What is the normal range for N-terminal pro-brain natriuretic peptide? How well does this normal range screen for cardiovascular disease?
by G.I.W. Galasko et al., on page 2269
Ancient Greek philosophy and medicine described four humours that permeated the body: phlegm (associated with phlegmatic temperament), black bile (melancholic), yellow bile (choleric), and blood (sanguine). Hippocrates, Galen, and others believed imbalances, or dyskrasia of the humours led to various human disease states. A healthy person was thought to have eukrasia, or a proper balance of the humours. Obviously, the ancients did not have specific measurable markers to test for these imbalances, so they relied on physical observation and retrospective analysis to decide why and how certain patients became ill. Over the centuries, physicians and scientists have sought simple ways to define and describe dyskrasias through specific markers. Could the B-type natriuretic peptides (BNP) fulfil this role in modern cardiovascular medicine?
Following the development of accurate and commercially available assays for BNP and N-terminal pro-BNP (NT-proBNP), investigators have demonstrated that measurement of these peptides facilitates the diagnosis of heart failure and helps to estimate prognosis in patients with heart failure, acute coronary syndromes, valvular heart disease, and a wide array of other cardiac conditions.14 BNP and NT-proBNP are released in response to cardiomyocyte stretch, which may occur due to many different pathophysiological processes. In patients with established cardiac disease, the level of BNP or NT-proBNP appears to function as an integrative measure of these diverse pathophysiological stimuli (including ventricular systolic and diastolic dysfunction, cardiac hypertrophy, increased intracardiac filling pressures, ischaemia, and renal insufficiency).5 It is thus not surprising that BNP and NT-proBNP have emerged as dominant markers of the risk for future death and heart failure in patients with known cardiac disease.
In the past few years, efforts have focused on extending these observations to the general population without a history of heart failure or structural heart disease. Initial studies that focused primarily on the detection of left ventricular (LV) systolic dysfunction reported relatively poor operating characteristics.6,7 More recently, however, investigators have focused on the use of natriuretic peptide screening to predict clinical events in the general population. In an analysis from the Framingham Heart Study, Wang et al.8 reported that higher BNP levels were incrementally associated with higher rates of death, heart failure, atrial fibrillation, and stroke or transient ischaemic attack (TIA). They found that a BNP level above the 80th percentile was associated with a hazard ratio of 1.62 for death over a follow-up period of 5.2 years, after adjusting for other known risk factors. In another study, Kistorp et al.9 compared NT-proBNP with C-reactive protein and urinary albumin/creatinine in a healthy population of patients. Values above the 80th percentile of NT-proBNP were associated with an adjusted hazard ratio of 3.24 (95% CI, 1.334.05) for first major cardiovascular events, including non-fatal myocardial infarction, fatal coronary disease, unstable angina, heart failure, stroke, or TIA. As a prognostic marker, NT-proBNP was more powerful than C-reactive protein or urinary albumin/creatinine. These important studies suggest that BNP and NT-proBNP may perform better as markers for overall cardiovascular risk than they do as screening tests for isolated cardiac structural abnormalities such as LV systolic dysfunction or hypertrophy.
Galasko et al.10 take further steps to define the role of NT-proBNP as a tool to screen for cardiovascular disease in the community. As a pre-requisite for such an evaluation, they carefully established the normal range of the assay using subjects phenotypically free from cardiac disease, a critical step that had not previously been performed with such rigor. Using an upper reference value of greater than 97.5th percentile, they determined that NT-proBNP levels should properly be stratified by age and gender, a finding also confirmed by other studies. The cause of higher NT-proBNP levels in women is currently unknown but may be related to sex hormones. In an important multivariable analysis, the authors confirmed the integrative value of NT-proBNP. Older age, LV structural or functional abnormalities, atrial fibrillation, coronary or peripheral vascular disease, abnormal lung function, and renal insufficiency each contributed independently to higher NT-proBNP levels. Most importantly, they calculated the screening characteristics and best cut-off values of NT-proBNP for multiple cardiovascular diagnoses. These diagnoses included atrial fibrillation, LV systolic dysfunction, valvular heart disease, diastolic heart failure, and LV hypertrophy. If adjusted for age and gender, NT-proBNP had a high negative predictive value (NPV) for a combination of these conditions in both the general population (84%) and the high-risk group (78%). The NPV was even higher if one considered only the presence of atrial fibrillation, LV dysfunction, and valvular disease. In addition, 95% of the patients with NT-proBNP levels over four times normal had evidence of cardiovascular disease.
By recognizing the integrative nature of NT-proBNP and increasing the number of conditions screened for, Galasko et al.10 have improved the performance characteristics compared with previous studies.6,7 However, it should be acknowledged that the sensitivity and specificity of NT-proBNP, even with proper age and gender cutoffs, are only modest, especially when considering its utility in screening for a particular cardiovascular condition (i.e. LV hypertrophy or systolic dysfunction). Moreover, although BNP and NT-proBNP elevation appears to identify something wrong with the patient (i.e. cardiac dyskrasia), further evaluation of the patient will be needed to determine the aetiology of BNP or NT-proBNP elevation, given the diverse stimuli for release of these peptides.
Research on natriuretic peptides for population screening is still in its infancy and much remains to be learned from future studies. Head to head trials of BNP and NT-proBNP and careful costbenefit analyses in high- and low-risk subgroups still need to be performed before widespread population screening can be recommended. Additionally, it is not known whether serial measurements of BNP or NT-proBNP can be used to guide aggressive risk factor modification to lower BNP, and if doing so will reduce subsequent cardiovascular risk. However, studies such as the one reported by Galasko et al.10 open the door for future trials evaluating preventive therapies, targeted to high-risk asymptomatic subjects identified on the basis of natriuretic peptide screening.
Although we no longer hold to the concept of dyskrasia due to imbalance of the four humours, measurement of BNP and NT-proBNP would likely have been admired by the ancient Greek physicians for its ability to predict a generalized cardiovascular disturbance. One simple blood test appears to provide useful screening information for many disparate components of overall cardiovascular health and opens the door for earlier identification of patients at risk for adverse cardiovascular outcomes.
Conflict of interest: J.A. de Lemos is a consultant for, and has received grant support and honoraria from, Biosite, and has received grant support from Roche.
D.W.M. has no conflict of interest.
Footnotes
The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.
References
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