Nowadays, the burden of cardiovascular disease represents a major global public health issue, both for its economic and social consequences. Along with improved prevention and treatment strategies, a prompt diagnosis is therefore a mainstay in cardiovascular patients’ management. Following a paradigm shift which occurred over the last decades, the diagnostic approach to cardiovascular problems is no longer limited to identification of a disease in patients with clinical symptoms, but rather it currently involves early detection of individuals with elevated risk of developing cardiovascular alterations (due to the presence of risk factors or preclinical organ damage), in whom targeted interventions aimed at interfering with the progression along the ‘cardiovascular continuum’ may significantly change the natural history of the disease.
Many indicators of increased cardiovascular risk have been identified over the years. Along with the classic cardiovascular risk factors such as elevated blood pressure (BP), low-density lipoprotein cholesterol, diabetes, renal dysfunction, etc., other, less commonly used parameters, including brain natriuretic peptide (BNP) and BP variability (BPV), have been demonstrated to be independently associated with cardiovascular outcomes . BNP is a hormone secreted by cardiomyocytes under conditions characterized by various types of cardiac overload  and its secretion reflects hemodynamic alterations and left ventricular dysfunction. As a hallmark of heart failure, BNP has become an essential element in diagnosis, management and prognostic stratification of heart failure patients. More recently, however, it was shown that elevations of BNP (or of its precursor N-terminal proBNP) may also be associated with preclinical stages of cardiac disease: its level increases in the presence of left ventricular hypertrophy in patients with hypertension  and, even in the absence of overt cardiac structural abnormalities, it may identify those whose left ventricular mass will increase over time . A role of NT-proBNP as an independent predictor of cardiovascular events in patients without clinically relevant heart disease has also been suggested .
BPV is a complex phenomenon which includes the extent of BP fluctuations over different time windows. In fact, BP is characterized by marked short-term fluctuations occurring within the 24 h, and by long-term changes over more prolonged periods (days, weeks, seasons). These fluctuations are the result of multiple interactions between extrinsic environmental and behavioural factors and intrinsic regulatory mechanisms (humoral and neural, central or reflex, influences). Although the mechanisms underlying BPV are not completely understood, an increased BPV has been associated with organ damage in hypertension and found to predict cardiovascular events [6,1]. This relationship may depend on the direct haemodynamic effect of BP oscillations (changes in shear stress and wall tension) possibly leading to alterations in arterial wall structure, but may also represent an epiphenomenon, reflecting an impairment of cardiovascular regulatory mechanisms as observed in patients with autonomic failure (e.g. in diabetic neuropathy). Although most of previous research was concentrated on short-term BPV (within 24 h) [6,1], more recently the attention of many researchers has focused on BPV measured over longer periods (between clinic visits or between days in home measurements) [7,8].
In this setting, examining the relationship between two independent cardiovascular risk markers with quite different characteristics and underlying mechanisms, such as BNP and BPV, may improve the understanding of how cardiovascular disease (in particular in hypertensive patients) develops. It may also contribute to the early identification of high-risk patients, in whom a better control of risk factors and a closer follow-up could provide important long-term benefits. An important contribution in this field is provided by the study by Satoh et al. published in the current issue of the Journal of Hypertension.
Aim of the study by Satoh et al. was to investigate whether NT-proBNP is related with day-to-day variability in home BP and in home heart rate (HR) . The analysis was performed within the frame of the Ohasama population study, a research project which has been providing important evidence since its beginning in 1987, particularly in the field of out-of-office BP measurement. A subgroup of 664 individuals, who took part in a health check, agreed to participate and fulfilled selection criteria, were included in the present analysis . BPV was computed as the standard deviation of home BP measurements obtained daily over a 4 weeks’ period. The authors found significant positive associations of an elevated BPV and an elevated HR variability (HRV) with the prevalence of elevated NT-proBNP (defined as values ≥125 pg/ml), the effects of elevated BPV and HRV on NT-proBNP being additive. These relationships remained significant after the adjustment for major confounders, including mean home BP and HR levels.
This interesting study provides new evidence on the relationship between two recently proposed cardiovascular risk factors. Its main merit comes from the fact that data collection was performed in a large sample of participants coming from a very well controlled population, which strengthens the impact of the evidence provided. However, this study is not free from a number of important limitations. Being cross-sectional in nature, this study obviously cannot establish whether the observed association is causal nor can it determine the direction of the observed relationship. Moreover, the hypothesis that elevated NT-proBNP in clinically healthy individuals represents a sign of early cardiac damage is not supported by more direct assessment of cardiac structure and function, for example, by means of echocardiography. Also, a large number of individuals were excluded from the analyses (962 participants vs. 664 included), mainly because of incomplete home BP data. The excluded participants had a less favourable risk profile (more men, smokers and patients with previous stroke) which may have introduced a bias and limit the external validity of the results.
An important aspect which has to be considered in studies on BPV is related to methodological issues, which make the interpretation of BPV data and their comparison among different studies difficult. In fact, although a few studies showed that BPV estimates obtained from home measurements have prognostic relevance, this approach is by no means standardized. For instance, the European consensus document on home BP monitoring proposes that home BP should be monitored for 7 days, with at least two morning and two evening measurements , whereas in the study by Satoh et al. home BP was measured only once each day in the morning over 4 weeks . Although the latter approach also provides clinically and prognostically relevant information, it is not clear to what extent the BPV estimates it provides are comparable with those obtained through other approaches. Furthermore, the mechanisms underlying increased day-to-day BPV are largely unknown and probably complex. For instance, poor treatment adherence and compliance may lead to a less-stable effect of antihypertensive drugs from day-to-day and, consequently, to an increased day-to-day BPV. At any rate it seems that cardiovascular variability might have a different meaning depending on the time frame over which it is assessed. This is clearly exemplified by the finding, in the study by Satoh et al., of an elevated NT-proBNP in participants with high HRV. This finding is in line with a previous report from the Ohasama study showing a direct association between day-to-day HR variability and the risk of cardiovascular events , but it is clearly in contrast with what is known about short-term HRV (assessed over minutes or hours), which is known to reflect autonomic and in particular parasympathetic cardiac modulation, and which has an inverse relationship with cardiovascular risk [6,7].
Interestingly, the results of the study by Satoh et al. are in contrast with a recent study by Masugata et al. who found no relationship between BPV and BNP level. However, the latter study was probably underpowered (n = 44), included only treated hypertensive patients (in the study of Satoh et al. the association between BPV and NT-proBNP appeared weaker in this group) and focused on visit-to-visit BPV. The latter aspect further emphasises the existence of major differences among different types of BPV (depending on the time windows over which it is assessed), that are frequently disregarded when the results of studies on BPV are discussed.
Clearly, the findings by Satoh et al. from the Ohasama study are far from having direct clinical applications. This is because of a still very limited knowledge on both the meaning of NT-proBNP elevation in individuals without overt cardiac disease and the most appropriate methods of assessment of home BPV as well as its clinical significance. Nonetheless, they are of interest because they provide novel evidence regarding the relationship between early changes in different districts of the cardiovascular system. In fact, compared with the well known association between the presence of subclinical alterations of cardiac structure and function (left ventricular hypertrophy, diastolic dysfunction) and elevated BP levels, the association between NT-proBNP and BPV reported by Satoh et al. may characterize an even earlier stage in the development of cardiovascular disease. It remains to be seen whether this association is confirmed in other populations, how it relates to the development of clinically evident cardiovascular disease and whether a true cause–effect relationship exists between NT-proBNP and BPV or whether their association represents merely an epiphenomenon. In particular, it would be important to understand whether NT-proBNP elevation is due to repeatedly occurring acute increases in cardiac afterload induced by BP oscillations or if it is a sign of chronically altered haemodynamic status. Finally, it would be interesting to find out whether also differences in NT-proBNP below the currently used threshold level have clinical relevance (as in the case of high-sensitivity C-reactive protein).
In conclusion, although the results reported by Satoh et al. do not seem to have direct clinical applicability yet, this study generates stimulating hypotheses that may promote further research on mechanisms determining early cardiac alterations in relation to changes in cardiovascular dynamics. Further information is also needed on the possible relevance of elevated levels of natriuretic peptides in identifying participants still without overt cardiovascular disease but prone to develop it in the future.
Conflicts of interest
There are no conflicts of interest.
1. Parati G, Ochoa JE, Lombardi C, Bilo G. Assessment and management of blood-pressure variability. Nat Rev Cardiol
2. Yasue H, Yoshimura M, Sumida H, Kikuta K, Kugiyama K, Jougasaki M, et al. Localization and mechanism of secretion of B-type natriuretic peptide in comparison with those of A-type natriuretic peptide in normal subjects and patients with heart failure. Circulation
3. Charles CJ, Kaaja RJ, Espiner EA, Nicholls MG, Pemberton CJ, Richards AM, Yandle TG. Natriuretic peptides in sheep with pressure overload left ventricular hypertrophy. Exp Hypertens
4. Nadir MA, Gandy S, Ireland S, MacDonald T, Dow E, Houston G, et al. An increased B-type natriuretic peptide in the absence of a cardiac abnormality identifies those whose left ventricular mass will increase over time. JACC Heart Fail
5. Di Angelantonio E, Chowdhury R, Sarwar N, Ray KK, Gobin R, Saleheen D, et al. B-type natriuretic peptides and cardiovascular risk: systematic review and meta-analysis of 40 prospective studies. Circulation
6. Mancia G, Bombelli M, Facchetti R, Madotto F, Corrao G, Trevano FQ, et al. Long-term prognostic value of blood pressure variability in the general population: results of the Pressioni Arteriose Monitorate e Loro Associazioni Study. Hypertension
7. Kikuya M, Ohkubo T, Metoki H, Asayama K, Hara A, Obara T, et al. Day-by-day variability of blood pressure and heart rate at home as a novel predictor of prognosis: the Ohasama study. Hypertension
8. Rothwell PM, Howard SC, Dolan E, O’Brien E, Dobson JE, Dahlof B, et al. Prognostic significance of visit-to-visit variability, maximum systolic blood pressure, and episodic hypertension. Lancet
9. Satoh M, Hosaka M, Asayama K, Kikuya M, Inoue R, Metoki H, et al. Association between N
-terminal pro B-type natriuretic peptide and day-to-day blood pressure and heart rate variability in a general population: the Ohasama study. J Hypertens
10. ESC/ESH Task Force for the Management of Arterial Hypertension. 2013 Practice guidelines for the management of arterial hypertension of the European Society of Hypertension (ESH) and the European Society of Cardiology (ESC). J Hypertens
11. Masugata H, Senda S, Inukai M, Himoto T, Hosomi N, Okada H, Goda F. Analysis of association between brain natriuretic peptide levels and blood pressure variability. Exp Ther Med