The study by Protogerou et al. , published in this issue of the Journal of Hypertension, sheds light on the role of 24-h ambulatory aortic blood pressure (BP) as a correlate of target organ damage in hypertension. The main findings of the study are that both 24-h aortic and 24-h brachial BP are superior to conventional office BP measurements in predicting BP-related cardiac damage, and that 24-h ambulatory aortic BP is more closely associated with left ventricular hypertrophy than 24-h ambulatory brachial BP. On account of the results of this study, the authors suggest that the information on aortic BP derived from ambulatory BP monitoring (ABPM) improves the ability of regression models to detect the presence of left ventricular hypertrophy and to discriminate between individuals with and without left ventricular hypertrophy.
There is a general consensus that 24-h ABPM is a better method for diagnosing hypertension and predicting BP-related cardiovascular risk than conventional office brachial BP measurements. Twenty-four-hour ambulatory BP (ABP) shows a stronger correlation with subclinical organ damage than office BP  and, more importantly, is a significantly better predictor of cardiovascular events [3–6]. The prognostic information offered by 24-h ABPM is independent of and incremental to that provided by office BP measurements [4–7]. In particular, ABP has the unique ability to provide information on 24-h average BP, on nocturnal BP and day–night BP changes, as well as on 24-h BP variability, which all provide independent prognostic information over and above that provided by office BP measurements [8–12]. The clinical relevance of ABPM is, therefore, clearly established in both treated and untreated hypertensive individuals . The question is now whether the clinical value of ABPM might be further increased by incorporating information on ambulatory central BP. The possibility to combine the advantages of 24-h ABPM with those of central BP assessment by using devices which offer the estimate of central BP over the 24 h, in addition to the assessment of ambulatory brachial BP, sounds indeed attractive from both the clinical and experimental point of view.
Central BP, that is, BP in the ascending aorta, is considered an important physiologic parameter as it reflects the hemodynamic relationship between the heart and the aorta, both in systole and in diastole. In the systolic phase, central BP represents the pressure against which the left ventricle has to eject blood during systolic contraction. Thus, central arterial pressure reflects both left ventricular stroke volume and afterload, defines cardiac work, and contributes to the development of left ventricular hypertrophy in hypertensive individuals. In the diastolic phase, central BP is a key determinant of the blood flow delivery to the myocardium. Thus, central SBP is an accurate marker of the actual pressure load imposed on the left ventricle and represents a more informative measurement, from a clinical perspective, than peripheral SBP, as shown by a few important clinical studies. Safar et al.  showed in end-stage renal disease patients undergoing hemodialysis that carotid pulse pressure (PP), directly measured by carotid tonometry, was a more powerful predictor of overall mortality than brachial PP. In that study, a lower peripheral BP amplification, that is, a greater central BP for any given level of brachial BP, was a significant predictor of all-cause (including cardiovascular) mortality, independent of age and other standard confounding factors. The Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT)  showed a lower incidence of cardiovascular events among patients treated with the calcium-channel blocker amlodipine than with the β-blocker atenolol, with a small difference in the reduction of brachial SBP values between the treated groups. However, the Conduit Artery Functional Endpoint (CAFE) study , a substudy of the ASCOT, showed a lower central SBP and PP in the individuals randomized to receiving an amlodipine-based compared with those receiving a beta-blocker-based treatment, in spite of the similar values in brachial SBP. Therefore, the authors suggested that, in ASCOT, the greater reduction in cardiovascular events in the group randomized to amlodipine could be because of a greater effect of this drug in lowering central SBP. In a systematic review and meta-analysis, Vlachopoulos et al.  showed that central SBP and indices of central pulse amplification carry a significant predictive value for cardiovascular events and all-cause mortality. As a result of the anatomical proximity, the stress imposed on the heart, kidneys, and the brain is indeed driven more directly by aortic than by peripheral pressure . Indeed, central BP has a closer relation to left ventricular mass and concentric geometry , and to carotid intima–media thickness and glomerular filtration rate , than peripheral BP.
Despite all the above evidence, however, the 2013 European Society of Hypertension (ESH) and European Society of Cardiology (ESC) guidelines for the management of arterial hypertension  did not recommend the routine clinical measurement of central BP, with the exception of isolated systolic hypertension in the young, in whom the increase of SBP measured at the brachial artery may be because of a high amplification phenomenon, with normal values of central BP.
There are important reasons why the ESH and ESC hypertension guidelines have been so cautious in recommending a more extensive clinical use of central BP. First, the additive predictive value of central BP beyond brachial BP was either marginal or not statistically significant in most studies . Second, at least two serious methodological problems in relation to central BP measurement, both clearly highlighted in the study by Protogerou et al. , have not yet been satisfactorily addressed: the actual reliability of the methods used to measure central BP and the difficulties related to calibration of the tonometric pressure waveform to derive central BP.
Central BP can be estimated either directly from the common carotid waveform or from the peripheral (radial or brachial) waveform with the use of a transfer function . It has been widely documented that the shape of the pressure wave in the common carotid artery is comparable to that recorded in the ascending aorta [23–25]. Several studies comparing carotid tonometry with the invasive method concluded that applanation tonometry at the carotid artery level is a valuable tool for aortic pulse-wave recording and central (aortic) BP values assessment [24,25]. On the other hand, over the last few years, a large number of devices have been proposed aimed at assessing central BP using individual and generalized inverse transfer functions to reconstruct the aortic waveform from radial or brachial artery waveforms. One of the main challenges of this indirect method is related to the difficulty in recording and analyzing the brachial arterial pressure wave. Another important and yet unresolved problem is the current uncertainty about the reliability of the transfer functions applied either to radial or to brachial noninvasive arterial waveforms, especially when obtained under peculiar hemodynamic conditions, like those characterizing pregnancy, heart failure, and the elderly or young individuals. In the study by Protogerou et al. , central BP was assessed by means of an indirect method based on a generalized transfer function applied to the brachial pulse waves recorded through an oscillometric system. Although a validation study of this system has been published , in this validation study only central SBP values obtained from 30 patients were reported, and no data were provided on pulse waveform characteristics of the same individuals. Moreover, invasive validation studies concerning devices for assessing central BP, which only focus on central SBP values, carry the risk of providing misleading results, whenever they ignore the concomitant validation of the device ability to assess the arterial wall properties. In fact, given the significant and close linear correlation found by a number of studies between invasive central SBP, measured directly in the ascending aorta by a catheter, and brachial SBP, measured by an oscillometric method, one might come to the paradoxical suggestion that a relatively accurate measurement of aortic SBP might simply be obtained by subtracting 10 mmHg from brachial oscillometric SBP values, with no need of pulse waveform analysis .
Thus, given the importance of this topic, and because of the diverse approaches followed by the available validation studies, more rigorous criteria should urgently be provided by scientific international societies in order to establish reliable protocols and methods for a better standardized validation of devices aimed at assessing central BP.
A major limitation of all systems currently proposed to estimate central BP is their inability to provide absolute values of aortic pressure. A calibration of the pulse waveform obtained through tonometric recordings is indeed always required, and two alternative calibration methods are usually followed, both of which have been evaluated in the study by Protogerou et al. . According to the first approach, brachial SBP and DBP values determined by a validated conventional sphygmomanometric method are assigned to the peak and trough points of the tonometric pressure wave recorded at the level of the reference artery (i.e. brachial artery in the study by Protogerou et al. ). With the second approach, the brachial pulse waveform is calibrated using mean BP and DBP values again obtained by a validated conventional sphygmomanometric method. The latter calibration procedure is based on the observation that mean BP is constant throughout the large artery tree and that DBP does not change substantially from the central to the peripheral part of the arterial system [28,29]. In the study by Protogerou et al. , the correlation of central BP with cardiac damage was markedly different when different calibration methods were used. When mean and diastolic brachial BP values were applied for the calibration of the peripheral pressure waveform, 24-h average aortic SBP was significantly better associated with left ventricular mass than 24-h average brachial SBP. On the contrary, the correlation of 24-h aortic SBP with left ventricular mass was worse than that of 24-h brachial SBP when systolic and diastolic brachial BP values were used for calibration. Remarkably, however, SBP values were higher in aorta than in brachial artery when pulse waves were calibrated using mean and diastolic brachial BP. This counterintuitive finding contrasts with the widely held physiologic assumption that SBP actually increases ongoing from the aorta to peripheral arteries. The authors justify this result with a possible underestimation of the brachial SBP by the oscillometric method, suggesting that systolic and diastolic (rather than mean and diastolic) oscillometric BP values should be applied in calibration of peripheral pulse waveforms when assessing the amplification phenomenon. This suggestion appears, however, to be inconsistent with the demonstration provided by the authors themselves of a greater predicting value of central BP when calibrated based on the mean and diastolic brachial BP values, and weakens the clinical value of the correlation found in this study between the central pressure estimated in this way and cardiac damage. Several other studies showed that the two methods of calibration may lead to absolute differences in central SBP estimation of up to 15 mmHg between each other, and compared with invasive measurements, independently of the used device [26,30,31]. Also, imprecision in determining brachial mean pressure by oscillometry may negatively affect the accuracy of central BP estimation . Understanding and addressing these discordances is, therefore, a crucial issue in the process of clinical implementation of central BP measuring devices. Despite the clear theoretical advantages of central 24-h BP monitoring, more investigations and technical improvements are thus needed before recommending central BP for routine clinical use, as wisely suggested by the 2013 ESH and ESC guidelines for the management of arterial hypertension .
Even more caution is needed when proposing ambulatory estimates of central BP all over the 24 h. Indeed, all available methods for estimating central BP have been tested and more or less properly validated at rest, with no systematic validation of their performance in ambulant individuals over 24 h. Such a dynamic validation, admittedly, is not an easy task and has to face a number of methodological difficulties. Similar difficulties are faced also when validating oscillometric devices for ABPM at the brachial artery level, a validation which is commonly done only at rest . The accuracy at rest of ABPM devices is then somehow uncritically extrapolated to the dynamic conditions of a truly ambulatory recording. The only partial justification for this procedure is that individuals are advised to stop any activity and to keep their arm still at the time of each oscillometric cuff inflation . In the past, only a few studies attempted to validate ABPM devices in truly dynamic conditions, and this was done against ambulatory intra-arterial BP recordings. These studies clearly showed that the discrepancy between automated BP readings and intra-arterial BP values was much greater in ambulatory conditions than at rest . This approach can no longer be recommended nowadays, both for technical and ethical reasons. Research is, therefore, still needed to develop more suitable protocols to validate devices for ambulatory central or peripheral BPM. These protocols, for example, should allow the dynamic assessment of the accuracy of devices for central and peripheral ABPM against noninvasive reference standards in a laboratory environment by simulating some of the activities and recording conditions of daily life.
In conclusion, the study by Protogerou et al.  provides interesting suggestions on the possible clinical relevance of central ABPM. However, a number of yet unresolved methodological issues related to the calibration and accuracy of central BP estimates, in particular when obtained under ambulatory conditions, still do not allow to recommend this approach in clinical practice and strongly suggest the need of additional studies in this stimulating field.
All authors had access to the data and a role in writing this article.
Conflicts of interest
P.S. is a consultant for DiaTecne s.r.l. The other authors have no conflicts to report.
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