An increasing number of physiological studies, as well as pathophysiological, epidemiological and pharmacological studies, have underlined the importance of measuring not only brachial SBP and pulse pressures (PPs), but also central aortic SBP and PPs [1]. Reference values for central aortic SBP and PPs have been published in healthy populations and in patients with cardiovascular risk factors [2]. A major concept has gained an important audience these last years: this is central aortic blood pressure (BP) rather than brachial BP that reflects the true load imposed on target organs and thus explains the occurrence of cardiovascular events [1,3–4]. This concept relies on the following four lines of evidence [3,4]: there are major discrepancies in central aortic BP among people with similar brachial BP, an independent relationship has been demonstrated between central aortic BP and end-organ damage, antihypertensive medications differentially influence central and brachial BP and end-organ changes after antihypertensive therapy are more strongly related to central aortic BP than brachial BP.
Because end-organ damage is a major predictor of cardiovascular events, it is expected from the above evidences that central aortic BP predicts cardiovascular events and mortality independent of brachial BP [5]. However, this has not been consistently demonstrated. Indeed, in a meta-analysis of 11 studies [6], only a marginal superiority of central PP over brachial PP for predicting cardiovascular events was observed, and there was no superiority of central aortic SBP over brachial SBP. One additional study [7], not included in the meta-analysis and derived from the same population as the patients of this editorial [8], also failed to show higher predictive values of central aortic PP compared with brachial PP. By contrast and more recently, in large cohorts, central aortic BP and derived central hemodynamic indices of central aortic BP, such as reflection magnitude, SBP rate constant and PP amplification, predicted cardiovascular events [9–11] beyond brachial BP. On balance, the magnitude of independent prognostic value of central hemodynamic indices could be regarded as borderline, despite statistical significance among several studies. There is thus an ongoing controversy on whether the lack of consistently higher predictive value of central BP compared with brachial BP reflects a true pathophysiological issue or is potentially biased by an inadequate method used for central aortic BP measurement. Indeed, on the one side, because central and brachial BP are strongly correlated, it may be optimistic to look for an incremental risk prediction. On the other side, recent data imply that refining the methods to calibrate peripheral arterial waveforms could unmask the incremental risk prediction of central BP [12,13].
The article by Mitchell et al.[8] published in the present issue of Journal of Hypertension provides an important contribution with regard to this controversy. The authors aimed at demonstrating whether central aortic BP obtained by using the SphygmoCor (AtCor Medical, Sydney, Australia) transfer function was predictive of cardiovascular events beyond the predictive value of brachial SBP. They included 2183 participants of the Framingham Heart Study. Radial tonometry waveforms were calibrated using two alternative approaches: by using the brachial cuff SBP and DBP according to the SphygmoCor algorithms and by using the integrated brachial mean and DBPs obtained from brachial artery tonometry. During a mean follow-up of 7.8 years, 149 cardiovascular events occurred. The major finding was that central aortic SBP and PPs were not related to cardiovascular events in multivariate models once adjusted for brachial SBP (in addition to other classical cardiovascular risk factors), regardless of the calibration method used. These results confirm previous findings in the same population that central aortic PP did not show superiority over brachial PP to predict cardiovascular events when central aortic PP was directly measured by applanation tonometry over the common carotid artery and then calibrated with brachial BP measurements [7]. Together with a recent meta-analysis [6], these findings are contrary to the prevailing expectation that central aortic BP should have incremental risk prediction when computed using a transfer function.
The study by Mitchell et al.[8] has several strengths. First, a large community-based sample of patients was studied, who benefited from the methodology and reputation of the Framingham Heart Study. Second, hemodynamic indices were measured and calculated according to a standardized methodology. Third, the authors attempted to account for another source of error from brachial-to-radial SBP amplification. The amplitude of this physiological phenomenon has been largely debated these last years, and therefore it is important to consider its consequences on estimated central pressure. Indeed, additional amplification of the pressure waveform between brachial and radial sites may result in underestimation of central pressure if brachial cuff pressure is used to calibrate the radial pressure waveform [1,14–16]. In the present study, the lack of predictive value of central aortic BP beyond brachial BP was observed regardless of the calibration method used.
The results of the study by Mitchell et al.[8] are also stimulating in the light of two recent systematic reviews and meta-analyses [17,18]. In the first study, the noninvasive estimation of central aortic SBP by peripheral measurements shows a large variability for prediction of invasive aortic BP [17]. Thus, the demonstration of an incremental risk prediction may be limited to invasive measurements only [19,20]. This point is crucial as it is a proof of concept that accurately measured central BP has strong and independent predictive value for cardiovascular events. However, the application to routine clinical practice is limited as invasive measurements are restricted to patients suspected of having coronary artery disease, that is patients at very high cardiovascular risk in whom the added predictive value of measuring central aortic BP is obviously low. Second, in another systematic review and meta-analysis, there was only a slight superiority of noninvasive central aortic BP compared with brachial BP in determining target-organ damage [18]. Thus, the initial concept that this is central rather than brachial BP that reflects the true load imposed on target organs and thus explains the occurrence of cardiovascular events may not hold true in the light of accumulating evidence with noninvasive measures of central aortic BP. In this regard, better calibration methods to derive more accurate central aortic BP [12,13], or new methods such as cardiac magnetic resonance, may represent a major advance [21].
The study by Mitchell et al.[8] has also limitations that are intrinsic to the methodology used. First, a high degree of correlation between central aortic, carotid, brachial and radial SBP and PPs was observed, like in previous studies [2,8–10] because of the calibration method. The high collinearity may have masked any incremental prognostic information of central above peripheral pressure in a population of that size and may have required a much larger number of patients to be demonstrated. Second, BP calibration leads to accumulation of errors. Indeed, when an arterial waveform is measured with a certain degree of imprecision and then calibrated with a BP value that is also flawed with respect to accuracy, then errors are cumulated. This is even worse when a third measurement is required for a further calibration. Compared with indirect measurements, direct ones have regularly demonstrated their robustness and repeatability. As discussed above, this is why we need to favor direct measurements, in addition to better calibrations methods, in our search for more accurate noninvasive methods for estimating true aortic BP.
In conclusion, the study by Mitchell et al.[8] provides an interesting contribution to ongoing research on the predictive role of central aortic BP for cardiovascular events. These results confirm that, in the present state of technology, noninvasively measured central aortic pressure did not show superiority over brachial pressure to predict cardiovascular events whether central aortic PP be directly measured or computed by using a transfer function of the radial artery pressure waveform after appropriate calibration. These findings urge the research community to develop more accurate noninvasive methods for estimating true aortic BP and to further test the incremental risk prediction of central aortic BP beyond brachial BP. An alternative is to demonstrate that central aortic BP is a true surrogate end-point [5,22], that is the decrease in central aortic BP translates better than the decrease in brachial BP into a reduction in cardiovascular events.
ACKNOWLEDGEMENTS
This work was made possible for J.S. through funding from the High Blood Pressure Research Council of Australia Franco-Australian Exchange Program, the Menzies Institute for Medical Research and a Mobility Scholarship from L’Institut Servier.
Conflicts of interest
There are no conflicts of interest.
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