B-type natriuretic peptide-guided hypertension management?

With evidence accumulating for clinical and prognostic importance of high night-time blood pressure (BP) [1], and with 24-h ambulatory BP unavailable or unfunded in many healthcare jurisdictions, whether the impact of antihypertensive therapy on nocturnal BP can be inferred indirectly now is a question of more than academic interest. In heart failure studies involving patients with both impaired and preserved systolic function, B-type or brain natriuretic peptide (BNP) has been shown to track left-ventricular end-diastolic [2] and end-systolic [3] wall stress and to decline when these stimuli are reduced by augmented diuretic or after-load reducing therapy. Consequently, the concept of BNP-guided heart failure therapy has become a subject of considerable investigation [4]. Although not as elevated as in heart failure patients [5], in primary hypertension plasma BNP concentrations increase in concert with sodium retention [6] and with alterations in ventricular and vascular structure and function [7–9]. In addition to providing prognostic information [10,11], could natriuretic peptide measurement guide hypertension management, as has been suggested previously in this Journal [12]? In the present issue, Shimuzu et al. from the Jichi Medical University in Tochigi, Japan report the findings of a subsidiary analysis from the Japan Morning Surge-Target Organ Protection (J-TOP) Study [13]. J-TOP, an open-label multicenter trial, recruited 454 hypertensive patients with home morning or evening SBP of at least 135 mmHg who were then allocated randomly to receive the angiotensin receptor blocker (ARB), candesartan, either on awakening, or on retiring to bed [14]. Over a 3-year period, candesartan was up-titrated on the basis of self-measured home BP to achieve SBP values less than 135 mmHg both in the morning and in the evening. Other antihypertensive medications taken were not changed with respect to dose or timing. Diuretics were added, if needed, to achieve these BP goals. The principal finding of the J-TOP with respect to the study end-point of microalbuminuria was a greater reduction with bedtime than with morning ARB dosing. Within the hypertensive population, plasma BNP concentrations are four-fold higher in those individuals whose BP rises at night than in those whose circadian rhythm exhibits the normal fall during sleep [15]. With the focus of J-TOP being timing of antihypertensive therapy, it was logical for its investigators to proceed, in the present sub-study, to test the hypotheses that any decrease in BNP observed with treatment would associate more closely with BP reductions during sleep than during wakefulness, and that the magnitude of the BP fall from wakefulness to sleep could be predicted by changes in BNP. In 450 of the J-TOP participants, morning venous blood was drawn in the fasting state both at baseline and after 6 months of treatment for subsequent core laboratory determination of BNP concentrations by high-sensitivity radioimmunoassay. (Considering the short half-life of BNP [16], and the specific sub-study hypothesis, the timing of this blood draw was ideal.) Of this cohort, 254 patients were said to have agreed to a weekday 24-h ambulatory BP recording (TM-2425 or TM-2430, A&D Co Inc., Japan) upon enrolment and also after 6 months of treatment. (If individuals from whom valid BP measurements were obtained in less than 80% of attempts during both wakefulness and sleep, and individuals reporting severely disturbed sleep were excluded from analysis, as stated, the number who did agree must have been greater.) Values for BP and heart rate (HR) were obtained at 30-min intervals. Patients noted, in diaries, times of retiring to bed and rising from bed. Remarkable, for a study of this nature, was the broad age range of these patients [from 21 to 92 years, with a standard deviation (SD) of 13 about a mean of 68.2 years], a 59 : 41 female-to-male ratio, and a mean body mass index (BMI) on enrolment of 24 kg/m2. Because of the profound influences of age and sex on natriuretic peptide concentrations in the Japanese population [17], in the present context less emphasis should be placed upon comparison of present baseline median (22 pg/ml) and mean (41 pg/ml) values for BNP with prior literature than on the within-patient changes observed after 6 months of antihypertensive treatment. At baseline, log-transformed BNP correlated directly with age, and inversely with BMI and estimated glomerular filtration rate (eGFR), but was not related to any unadjusted measure of SBP. There was a significant but rather weak (r2 = 0.03, P = 0.005) inverse correlation between the night-time fall in BP and morning BNP. Partial correlations, after adjusting for age, were, however, significant for each of 24 h SBP, awake SBP, asleep SBP, and nocturnal fall in SBP and log-transformed BNP, and after adjustment for clinically relevant variables asleep SBP associated significantly with log-transformed BNP, independently of the awake SBP. The BP effects of antihypertensive therapy of principal interest to these investigators were the changes after 6 months in 24-h ambulatory SBP, in awake BP, in asleep BP, and in the nocturnal BP fall, that is the magnitude of the awake–asleep difference. Corresponding changes in diastolic BP (DBP) were of secondary interest. ARB plus or minus diuretic therapy lowered 24-h SBP by −13.5 mmHg, awake SBP by −14.3 mmHg and asleep by −12.0 mmHg, but had no significant effect on the magnitude of the nocturnal SBP fall (augmented by only 0.4 mm Hg overall), regardless of whether participants received candesartan in the morning or in the evening. Consequently, and perhaps surprisingly, given the nature and timing of drug administration, the proportion of patients classified as ‘dippers’ (i.e. those with a day to night fall in SBP ≥10%) at baseline (62%) tended to decrease (59.4%), rather than increase, after 6 months, with no difference with respect to morning or evening dosing. In the present context, it is notable that despite these significant reductions in absolute values for day and night-time SBP, and despite a respectable sample size (n = 254), plasma BNP concentrations were not reduced significantly in either the entire study population (−3.1%, P = 0.472), or in the prespecified morning and evening treatment groups. Some might conclude at this point that these neutral overall results do not permit further analyses. However, since the perceived aim of these authors was to establish, from this derivation data set, a framework for its subsequent refinement or validation, they next sought to determine whether within-patient changes in BP might relate to changes in log-transformed morning BNP values over the course of this 6-month treatment period. The key sub-study finding within this context, was the detection of a direct correlation between changes in SBP during sleep and changes in BNP (r = 0.27, P < 0.001) that remained significant even after adjusting for concurrent reduction in daytime SBP. Even though the 0.4 mmHg trend to a greater nocturnal fall in BP was itself not significant, an increase in this response correlated weakly also with a decrease in BNP (r2 = −0.02, P = 0.038). Similar positive relationships emerged when the morning and evening dosing subgroups were studied separately, and in those who received diuretics. Significant correlations, but less robust, between DBP indices and changes in BNP also were evident. The authors were careful in focusing their conclusion only on the observation that the decrease in plasma BNP observed was associated with asleep BP reduction over and above the awake BP reduction, regardless of the time of administration, but they did propose that repeated measurements of BNP during antihypertensive treatment might be useful to assess changes in BP during sleep. Although these findings provide evidence to suggest potential value in a BNP-guided therapy for hypertension, the authors’ interpretation, and the extrapolation of these conclusions to the broader population of patients with primary hypertension are ultimately impaired by the constraints imposed by their derivation from the J-TOP data set. These include the relatively small sample size, considering the heterogeneity of the participant inclusion criteria, the relative infrequency (30 min) of BP measurement (a consideration of particular importance if any of the ‘nondipper’ patients had a marked increase in night-time BP variability due to co-existing obstructive sleep apnea), the absence of a control group, the lack of treatment effect overall either on morning plasma BNP concentrations, or on the magnitude of the night-time fall in SBP, and finally the unstructured prescription of diuretics, and the lack of detail as to their specific class, dose, and effect on body weight or intra-vascular volume. Comparison of responses between diuretic and non-diuretic-treated patients did not yield definitive results, but the observations made are nonetheless informative. At baseline, BNP was significantly higher (P < 0.001) in the 143 participants receiving also diuretics at 6 months than in the 111 participants who were not. Whereas BNP decreased by −16.7% (P = 0.003) between baseline and 6 months in those using diuretics, this reduction was offset by a +17.5% increase (P = 0.017) in those who did not receive diuretics. The decrease in the log-transformed BNP associated with the decrease in the asleep SBP, independently of the decrease in the awake SBP and other known confounders, only in the group prescribed diuretics (P = 0.004). Despite this finding, the investigators were unable to demonstrate a significant difference in these specific correlation coefficients between participants taking and not taking a diuretic. From a mechanistic standpoint, these changes are more likely to reflect the effect of diuresis on BNP than simply a regression to the mean. However, whether this dichotomous response was a consequence of diuretic-induced reductions in nocturnal end-diastolic volume or pressure or in end-systolic pressure cannot be determined from the available data. By monitoring large, well characterized populations, and by coupling such information with clinical, imaging, and outcomes, the group led by Kario has contributed greatly to present appreciation of the usefulness of ambulatory BP. What of the present thesis that morning plasma BNP concentrations might serve as a surrogate, to illuminate the darkness of nocturnal BP? In this J-TOP sub-study the proportion of the treatment effect on sleep BP associated with changes in morning BNP was quite modest. Thus, if these findings are to be referenced in future studies, one would anticipate that this would be for the purpose of estimating nocturnal BP responses to therapy within groups, rather than in individual patients. The more interesting challenge would be to consider this derivation data set a prelude to a future validation study of a BNP-guided approach to hypertension, addressing perhaps initially in a more narrowly defined population a modest question: in patients monitored with home BP data, can the acquisition of morning BNP values guide treatment to improve night-time BP, the new frontier of effective hypertension management? ACKNOWLEDGEMENTS Financial support: The author holds the Canada Research Chair in Integrative Cardiovascular Biology, and receives financial support for his research from the Heart and Stroke Foundation of Ontario and the Canadian Institutes of Health Research. Conflicts of interest The author has no conflict of interest with respect to the subject matter of this editorial.

Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.