This is the first population based study to confirm that the plasma concentration of NT-proBNP increases with age and that it is consistently higher in women than in men. In addition, we have identified several different factors of independent significance for the plasma concentration of the marker.
It has been shown repeatedly that the natriuretic peptides have significant potential as markers for left ventricular systolic impairment and increased left ventricular dimensions, as well as for the clinical syndrome of heart failure. In population based studies, these biochemical markers have proved their legitimacy to such a degree that the European Society of Cardiology has recently included a raised concentration of any one of these peptides in the diagnosis of heart failure.15
Focus has concentrated on BNP and its amino terminal portion NT-proBNP, and as these markers are likely to be incorporated into clinical practice within the foreseeable future, an increased understanding of the physiology and pathophysiology of the markers in a general population setting is needed, particularly to establish normal reference intervals.
It is generally accepted that BNP and thus NT-proBNP are mainly released locally from the left ventricle in response to increased wall tension or stretch,16
accounting for their value as diagnostic markers in heart failure—a condition often characterised by high left ventricular wall stress owing to increased left ventricular dimensions and wall thinning.
The identification of dyspnoea,17
valvar heart disease,18–21
a low left ventricular ejection fraction,7
and an abnormal ECG22
as variables of independent significance for the value of plasma NT-proBNP in the present study are all readily explicable by this well known association with left ventricular wall stress, and may thus account for the diagnostic value of the marker.
The finding that plasma concentrations of NT-proBNP were higher in women than in men, regardless of age or normality status, has previously been reported in one population based study,23
and seems to be an important factor that needs to be taken into account when defining future reference intervals for the marker. The association is, however, not easily explained, though a lower volume of distribution in women than in men could partly account for the difference.
The plasma concentration of NT-proBNP almost doubled per age decade in the present study, regardless of sex or normality status. This association has previously been reported in normal subjects and probably reflects increased myocardial mass,24
chamber specific alterations in gene expression,25
and a possible reduction in the renal clearance of natriuretic peptides with aging, not reflected completely by the plasma creatinine concentration.26
The finding that a high plasma creatinine was independently associated with a high plasma NT-proBNP in our study came as no surprise, as high natriuretic peptide concentrations have been reported in patients with renal failure27–30
and in heart failure patients with increased plasma creatinine.23,31
As well as a reduced clearance of the natriuretic peptides, increased cardiac afterload caused by fluid retention, leading to increased left ventricular wall stress, is a possible explanation for the effect of impaired renal function on the plasma concentration of NT-proBNP.20,32,33
This may also be part of the reason why a diagnosis of diabetes mellitus was independently related to a high plasma NT-proBNP, as previous studies have shown raised BNP concentrations in diabetic patients with and without microalbuminuria, probably explained by the presence of an early stage of diabetic nephropathy not yet affecting the plasma creatinine level.34
It was striking that when diabetic subjects were excluded from analysis in our study, a high urine albumin concentration remained independently associated with a high plasma NT-proBNP concentration, probably reflecting the onset of nephropathy.
We have no explanation for the surprising finding of a low glycosylated haemoglobin concentration as a predictor of a high plasma NT-proBNP concentration, nor for the finding that a low heart rate was independently predictive of a high plasma NT-proBNP concentration. The latter association was unaffected by exclusion of subjects on treatment with β blocking agents.
Our population based results indicate that a single reference interval for normal plasma NT-proBNP will probably not suffice, as adjustments for the independent effects of age and sex appear necessary. In addition, we have identified various other confounders involved in the interpretation of a given plasma NT-proBNP concentration, among which impaired renal function seems to be the most important.