What matters is not only how often but also how much blood pressure rises. Limitations of blood pressure load

Twenty-four-hour ambulatory blood pressure monitoring (ABPM) offers information not only on average blood pressure (BP) levels over 24 h, daytime and night-time, but also on fluctuations over the recording period. This is relevant on the background of the evidence that not only average BP levels but also an increased BP variability within the 24 h has a significant impact on cardiac, vascular and renal organ damage [1,2] as well as on cardiovascular events and mortality [3,4]. In such a context, the percentage of ambulatory BP (ABP) readings above threshold values (i.e. SBP/DBP values ≥135/85 mmHg for daytime and ≥120/70 mmHg for night-time) has been suggested as a clinically useful parameter complementing the quantification of corresponding average ABP levels [5]. Such a percentage has been termed ‘BP load’ based on the hypothesis that it might be an index of hemodynamic burden on the cardiovascular system in addition to the information carried by average ABP levels [5,6]. Following its initial description, evidence was provided that measures of BP load are as consistent and reproducible as average BP levels are, when repeatedly computed over 24-h ABPM tracings obtained on successive days [7]. A number of articles have also discussed the clinical relevance of BP load in patients with variable BP elevation. Although in patients with sustained BP elevation over 24 h, calculation of BP load was shown to be of limited relevance, being by definition close to 100%, its assessment in patients with normal and even more so with high normal office BP elevation appears to be of much greater interest. Indeed, in these patients BP load might quantify the degree of BP fluctuations above normal limits during daily life activities, thus possibly representing an additional measure of BP variability. In such a condition, calculation of BP load might indeed be clinically useful, as it could improve the diagnostic approach to hypertension, by assessing the frequency of abnormally elevated blood pressure readings in ambulatory conditions over 24 h when office BP values are still within normal ranges. Identification of patients with normal office and/or average ABP values but with a significantly increased BP load might allow implementation of early interventions aimed at improving patients’ lifestyle and at detecting/preventing subclinical organ damage, because these patients could theoretically be exposed to a higher risk of future sustained hypertension as compared to patients with BP values always lying within normal range [8,9]. Along the same line, also in treated hypertensive patients assessment of BP load was proposed as a clinically useful tool, as it may represent an additional measure of the efficacy of antihypertensive drugs [10]. Based on these assumptions, a series of studies were conducted both in treated and untreated hypertensive patients aimed at exploring the relationship among average ABP values, BP load and indices of subclinical organ damage. In many of these studies, an increased BP load, expressed either as percentage of recorded values or as integrated area under the BP curve, was shown to be significantly associated with left ventricular hypertrophy [9,11–13], alterations at fundus oculi examination [14], microalbuminuria [14] and endothelial dysfunction [15]. Of note, some of these reports showed BP load to be a better determinant of cardiac or vascular abnormalities than either clinic BP or average ABP levels [9]. Recently, a prospective study in elderly patients found increasing values of SBP load (i.e. daytime SBP load ≥24.5%) to be independently associated with an increased risk of cardiovascular events [16]. However, despite the interesting results on the relation of BP load with target organ damage and cardiovascular events they provided, most of these studies were limited by several factors such as small sample size, methodological problems related to performance of ABPM recordings, short duration of follow-up, skewed distribution of BP load values as well as inability to properly deal with the collinearity between BP average levels and BP load. It should also be mentioned that not all studies have univocally shown a significant association of BP load with measures of target organ damage, independent of 24-h average BP levels. The study by Liu, et al.[17] published in the current issue of Journal of Hypertension, provides additional critical evidence on the prognostic value of BP load for subclinical organ damage. The main objective of this cross-sectional study was to explore whether BP load, defined as the percentage of abnormally elevated ABP readings, is associated with target organ damage, and whether such association survives after accounting for the impact of average ABP levels. The study included a large sample of 869 patients referred to have 24-h ABPM done for suspected hypertension but not on antihypertensive medications for at least 2 weeks before the study. All study participants were assessed for the presence of vascular, cardiac, and renal organ damage. Arterial stiffness was assessed by means of brachial-ankle (baPWV) and carotid-femoral (cfPWV) pulse wave velocity; left ventricular hypertrophy was assessed through echocardiographic estimation of left ventricular mass index (LVMI); and renal function was explored by calculation of urinary albumin-to-creatinine ratio (ACR). BP load was defined as the percentage of daytime and night-time SBP/DBP readings equal or greater than 135/85 mmHg and 120/70 mmHg, respectively, and participants were divided into tertiles of SBP load. Although increasing values of SBP load were significantly associated with increasing values of baPWV, cfPWV, LVMI and ACR, the differences in indices of target organ damage across tertiles of SBP load were no longer significant after adjustment for the corresponding differences in average 24-h SBP levels. In addition, when treating BP load as a continuous variable, while addition of 24-h SBP level significantly improved the goodness-of-fit of models relating BP load to measures of target organ damage, the opposite was not the case. In fact, addition of BP load did not improve a model, which already included all confounding variables and 24-h average BP levels as determinants of organ damage. These results are in contrast with the findings of previous studies, most of which of smaller size, indicating that SBP load has a significant impact on different indices of target organ damage even after accounting for the impact of average BP levels [9,11–15]. The study by Liu et al.[17] has the merit to include a large sample of patients, but it also has some limitations that should be considered for a proper interpretation of its results. First, as the study population was constituted by patients undergoing 24-h ABPM to confirm a diagnosis of hypertension, a large number of study participants were found to be sustained hypertensive patients, and in these patients, by definition, both average BP levels and BP load were elevated. Indeed, 67% of participants were untreated mild hypertensive patients on the basis of 24-h ABPM, whereas only in 33% of the general study population average 24-h SBP and DBP values were within the normal range. Thus, only in a minor portion of this population the relative impact of BP load and of average BP levels elevation on organ damage could be explored and compared. Second, because of its cross-sectional nature and because of the high number of patients already having elevated BP levels, the present study could not assess the risk of developing hypertension associated with an increased BP load, a possibility previously suggested in patients with high-normal BP levels. Both these limitations, related to the clinical characteristics of the population included, and to lack of longitudinal observations, should have suggested to the authors to be more cautious in drawing conclusions on the actual relevance of BP load in clinical practice. Third, while analyzing their data, authors classified patients into tertiles of SBP load. However, previous reports have suggested that only SBP load values greater than 50% significantly correlate with target organ damage (e.g. left ventricular hypertrophy) [10,12,18], thus hypothesizing a threshold value for BP load above which its effects on subclinical organ damage can be seen. In consideration of these findings, some guidelines for ABPM have proposed that SBP load values between 25 and 50% may identify uncomplicated ambulatory hypertension, whereas SBP load values more than 50% may identify severe ambulatory hypertension at risk for end-organ damage [6]. Fourth, calculation of BP load can be heavily affected by artifacts during ABPM recording, and by the criteria used for selection of daytime and night-time periods. Although in the study by Liu et al.[17] authors discarded subjects with recordings of poor quality (i.e. with a too low number of valid measures) and removed artefactual readings as well as outlier values from the analysis, they used a potentially inaccurate method to define daytime and night-time periods, based on wide fixed intervals. In fact the use of wide-fixed criteria (i.e. defining daytime from 0600 to 2000 h and night-time from 2000 to 0600 h of the following day) may lead to errors in identifying the actual awake and asleep periods in individual patients, given the variable bed time and wake-up times between individuals as well as between geographical regions and cultural habits, which could have led to inappropriate selection of threshold levels for computing BP load. A better assessment of the BP load over such subperiods could have been obtained by defining daytime and night-time based on subjects’ diary or using narrow-fixed criteria (i.e. by excluding a few hours in the evening and in the early morning in order to skip periods of transition between wakefulness and sleep). Fifth, BP load can also be a rough index of BP variability. It is well known that BP values continuously fluctuate within the 24 h around a reference set point as a consequence of behavioral, environmental, humoral, and neural central or reflex influences [3]. These fluctuations may thus be somehow reflected by BP load. It is also well known that increasing average BP values are associated with increased BP variability, which in turn may be reflected by an increased BP load. Thus is it not surprising that the positive relationship between BP load and short-term BP variability reported in the study by Liu et al. disappeared after accounting for 24-h average SBP levels. In spite of these limitations, however, the concerns raised by Liu et al. on the prognostic relevance of BP load appear to be appropriate. In fact, it should be considered that BP load (estimated as % of ABP values above threshold) only measures how frequently ABP readings are above a predetermined threshold, without providing any quantitative information on how much each BP reading exceeds such a threshold. Thus BP load provides only semi quantitative information, by focusing on the frequency of BP elevations, but not on their size in mmHg. This is why we may find an increased BP load in patients with normal average BP levels, in whom BP readings might be frequently elevated but by only a small amount (Fig. 1b). Thus, given that cardiovascular risk increases proportionally to BP elevation, a proper assessment of BP burden on circulation should consider also the magnitude and not only the rate of BP elevations, which makes BP load an imperfect index of BP-related cardiovascular risk because of its inability to quantify the degree of BP rise above threshold.FIGURE 1: Examples of 24-h ambulatory SBP tracings obtained in normotensive and hypertensive patients. (a) Normotensive patient with all ambulatory SBP levels below threshold; (b) normotensive patient with increased BP load during daytime; (c) hypertensive patient with markedly increased BP load over 24 h (close to 100%). Dotted lines indicate threshold values for ambulatory systolic hypertension during daytime (≥135 mmHg) and during night-time (≥120 mmHg). Grey bars indicate night-time sleep.In conclusion, the study by Liu et al. shows that BP load is associated with target organ damage, but not independently of 24-h mean BP levels, thus supporting a prevailing role of mean BP levels in predicting organ damage. Such a conclusion, however, is not that surprising in a study mostly including patients with sustained hypertension, if we consider that average BP levels and BP load are affected by significant collinearity, so that, after adjustment by increased average 24-h BP levels, BP load loses its prognostic value. Based on their data, authors also conclude that hypertension management should focus on control of average BP levels and that BP load has limited clinical value in daily practice. Such a conclusion, however, would need to be further tested in longitudinal studies, carried out in patients with normal or high-normal BP levels, in which the ability of BP load to predict the risk of developing hypertension as well as target organ damage and cardiovascular outcomes could be more properly assessed. ACKNOWLEDGEMENTS Conflicts of interest There are no conflicts of interest.