24-h central haemodynamics and cardiovascular outcomes: is calibration the key?

Interest in central blood pressure (BP) and its potential role in routine clinical practice continues to underpin many observational and interventional cardiovascular studies. Indeed, since the realisation that systolic BP can vary by up to 40mmHg between the aorta and brachial artery 1,2, and with the development of simple, noninvasive techniques allowing central BP to be measured in the clinic, an impressive body of evidence has accumulated which generally supports the notion that clinic-based measurements of central BP confer important information concerning cardiovascular risk, which is not apparent from the assessment of brachial BP alone 3–7. It is now well accepted that out-of-office brachial BP readings provide superior prognostic value for the prediction of cardiovascular events, compared with clinic-based measures, both in the general population and in patients with essential hypertension 8,9. This has, of course, driven recent advances in technology, such that it is now also possible to assess ambulatory central BP, using commercially available, validated devices 10. These devices tend to follow the general principle of recording brachial pressure waveforms using an oscillometric cuff and applying proprietary generalized transfer functions to construct corresponding aortic waveforms, from which estimates of central pressure are derived. The devices also allow assessment of related vascular parameters, such as the augmentation index (AIx) – a measure of arterial wave reflections, and pulse wave velocity (PWV) – a measure of arterial stiffness, both of which are related to cardiovascular outcomes when measured in the clinic 11–13. However, it should be noted that PWV derived from oscillometry provides an algorithm-based estimated, rather than direct, measure of arterial stiffness, which is heavily dependent on age and systolic BP, among other variables 14. Indeed, this approach has drawn considerable criticism 15, not least because the yielded values tend to be those which would be expected for a given age and BP, rather than a reflection of arterial properties per se. Accumulating data now show that ambulatory central systolic BP is more strongly correlated with left ventricular mass index, hypertrophy and diastolic dysfunction than corresponding ambulatory brachial systolic BP values 16–18. Moreover, in a recent prospective, randomized multicentre trial of hypertensive patients, 24-h central ambulatory systolic BP distinguished between the effects of two different antihypertensive drug regimens, whereas brachial ambulatory pressures did not 19. Therefore, the case for including out-of-office assessments of central pressure in risk screening appears to be strong and provides a sound rationale for examining the association between ambulatory central pressure and cardiovascular outcomes. To date, such outcome studies are limited to three publications in high-risk groups of haemodialysis patients 20–22, where ambulatory PWV tended to be the only variable remaining independently associated with clinical outcomes, after adjustment for other risk factors – a likely consequence of the extreme arterial stiffening characteristic of this patient population, which is influenced to a lesser extent by age and BP. Although these data provide some support for routine monitoring of central ambulatory haemodynamics, the question still remains as to whether this form of monitoring provides superior prognostic information in lower risk populations. It is against this background that this issue of the Journal features an analysis of the VASOTENS Registry – an international observational prospective registry study of 24-h ambulatory haemodynamic data obtained using the BPLab device 23. In a sub-set of 591 patients with hypertension, with a mean age of 58 years and followed up for 4.2 years, increased 24-h central pulse pressure, PWV and AIx were all significantly associated with a worse prognosis in terms of nonfatal and fatal cardiovascular and renal events or all-cause death. However, two key points emerge from the analyses: once the analyses were fully adjusted for other cardiovascular risk factors (age, sex, antihypertensive therapy, dyslipidaemia or diabetes, and preexisting cardiovascular disease), the associations between central PP, AIx, PWV and poor survival disappeared and neither brachial nor central ambulatory BP readings were associated with the risk of achieving the study end-point. While many factors impact on arterial haemodynamics, both PWV and AIx are heavily dependent on BP and influenced by other risk factors, in particular, age 24. Indeed, as discussed above, age is integral to the estimation of ambulatory PWV. Therefore, it is perhaps unsurprising that in this relatively low-risk population, any univariate associations between ambulatory variables and clinical outcomes disappeared after appropriate statistical adjustment. As for the lack of association between blood pressure and clinical outcomes, the authors suggest that the inclusion of individuals with only mildly elevated brachial BP, which appeared to be well controlled on antihypertensive therapy in the majority of patients, may be the explanation. In this regard, the inclusion (or availability) of a greater number of patients across a broader spectrum of risk factors may have allowed these associations to become apparent. One must also consider the advantages and potential shortcomings of large-scale registry studies, especially those dealing with the retrospective collection of haemodynamic parameters, where subtle variations in measurement protocols between sites could lead to considerable bias. In this regard, the prospective nature of the VASOTENS registry is an advantage. One question which remains unanswered by the VASOTENS study is the extent to which the method of brachial waveform calibration might impact on the association of central ambulatory BP with cardiovascular outcomes. The device used in the VASOTENS registry 25 used brachial systolic and diastolic BP values to calibrate the recorded brachial waveforms and, because of the phenomenon of systolic pressure amplification, central systolic BP values will typically be lower than their corresponding brachial systolic pressure values, in nearly all but perhaps the very oldest individuals 26. In this situation, the brachial and central systolic BP values are typically very highly correlated 27, limiting the power to distinguish between any respective associations of brachial and central BP with cardiovascular risk. However, an alternative method of waveform calibration applies the brachial mean and diastolic BP, producing a significantly different estimation of central systolic BP. Although this calibration method can yield values of central pressure which are sometimes higher than the measured brachial pressure, they are thought to better reflect the 'true', that is, intra-arterial aortic systolic BP 10,28. Indeed, central systolic BP obtained using this calibration method relates more closely to hypertension-associated end-organ damage 16,29 and clinical end-points 30. Determining whether this method of calibration applied to ambulatory BP readings relates more closely to clinical end-points is an obvious next step and the results of further studies utilising different methods of calibration are awaited with interest. ACKNOWLEDGEMENTS Conflicts of interest There are no conflicts of interest.