Why do we need to measure more than central ... - AtCor Medical

Why do we need to measure more than central blood pressure alone
While the prognostic value of brachial blood pressure is well established, there is now ample evidence of
the pathophysiological importance of central haemodynamic measurements. Central (aortic) systolic and
diastolic pressures are determinants of cardiac loading and coronary perfusion and are significant in
identifying and understanding the development of cardiovascular disease.
Central blood pressure and measurements taken from the central arterial pulse wave have been shown to
be powerful predictors of major cardiovascular events, independent of the traditional risk factors, including
brachial blood pressure. Furthermore, they are important markers for evaluating the effect of treatment.
THE European Society of Hypertension 1 , as well as leading clinicians and researchers have recognized the
importance of these values, specifically central SBP, PP and Aix. These measures of arterial wave reflection
indices and central pressure (along with aortic PWV) provide a comprehensive and integrated approach to
total cardiovascular assessment of a patient [1, 2, 3, 4, 5].
PWA and central blood pressure
In healthy and compliant arteries the pressure waves (generated by the left ventricle) travel through the
arterial tree and are reflected at multiple peripheral sites. As a result, the arterial pressure waveform at any
site is a combination of the forward travelling waveform and the backward (or reflection) waveform. The
two waveforms merge during diastole and augment coronary perfusion. With ageing, the arterial wall
thickens and the arteries get stiffer resulting in the pressure waves travelling faster and the reflected
pressure wave returning during the systolic phase. This increases aortic systolic pressure, widens pulse
pressure and increases left ventricular load [6].
Analysis of the aortic pressure waveform provides a measure of central blood pressure and indices of
systemic arterial stiffness, such as Augmentation Pressure (AP) and Augmentation Index (AIx), as shown in
Figure 1. These indices are related to the reflected pressure waves from the peripheral arterial system,
either as in a direct increase in pressure at the heart from the reflected wave (AP) or as a percentage of
pulse pressure (AIx). AIx represents a complex measure of wave reflection and includes a component of
arterial stiffness.
Augmentation
pressure (AP)
Figure 1. Central pressure waveform. The central (aortic) pressure waveform as derived from the radial artery waveform (via a
validated transfer function (as provided by the SphygmoCor). Identification of early and late systolic peaks allows for central
SBP, PP, AP and AIx. (Adapted from: Woodman RJ and Watts GF. Measurement and application of arterial stiffness in clinical
research: focus on new methodologies and diabetes mellitus. Med Sci Monitor 2003;9: RA101-109.)
A salient feature of the arterial pressure waveform is that it changes shape as it travels away from the
heart. The diastolic and mean pressure change little across the arterial tree, but the systolic pressure is
amplified as it travels from the aorta to the periphery [7]. This pulse pressure amplification is important
1 The Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of
the European Society of Cardiology (ESC). 2007 Guidelines for the Management of Arterial Hypertension. European
Heart Journal 2007;28:1462-1536.

when considering the relationship between brachial and central blood pressure as the pulsatile
components may vary significantly. This was demonstrated in the Anglo-Cardiff Collaborative Trial II where
data from 10,600 individuals showed that central pressure cannot be reliably inferred from peripheral
pressure due to the variation in the gradient between central and peripheral pressures [8].
The most widely used device in clinical studies for PWA, the SphygmoCor, measures the arterial pressure
waveform at the radial artery and applies a validated generalised transfer function to provide the central
pressure waveform [2, 9, 10]. Along with central systolic blood pressure, a number of PWA indices provided
have been shown to have clinical relevance.
Predictors of disease and events
Central blood pressure and AIx have been shown to be a significant predictor of all-cause mortality and or
major cardiovascular events in observational studies and over a range of diseases, such as coronary artery
disease, end stage renal disease and diabetes as well as in the elderly [11, 12, 13, 14, 15, 16, 17, 18, 19, 20,
21, 22]. Moreover, these measurements have been shown to be independent of brachial blood pressure.
Pulse pressure (PP), and in particular central PP have been shown to better predict cardiovascular events
than brachial blood pressure [11]. Data from the Strong Heart Study 2 found that central pulse pressure
predicted cardiovascular events more strongly than brachial pulse pressure, independently of traditional
risk factors, such as age, smoking, gender and cholesterol [11]. Furthermore, data from the same study
showed in a 5-year follow-up that quartiles of central PP predicted cardiovascular outcomes more strongly
than quartiles of brachial PP. Having a central PP, ≥ 50 mmHg, doubled the risk of heart attack or stroke in
both men and women, in the presence or absence of diabetes, and in people younger or older than 60
years of age [12], as shown in Figure 2 .
Figure 2 Quartiles of central pressure plotted against events rate for incident cardiovascular events in
individuals from the STRONG heart study. The event rate in Q4 ≥ 50mmHg exceeded 20% compared to 10% in
Q1 and Q2 * No significant difference between Q1, Q2 and Q3 . ** Significant compared to Q1. (Data from:
Roman MJ, Devereux RB, Kizer JR, et al. High central pulse pressure is independently associated with adverse
cardiovascular outcome the strong heart study. J Am Coll Cardiol 27-10-2009,54:1730-1734.
Central pressure has also been shown to be more closely related to other important cardiovascular
intermediate endpoints such as left ventricular hypertrophy (LVH). LVH is commonly seen in hypertension
and increases the risk for cardiac events, mostly as a result of increased left ventricular mass due to an
increase in afterload of the left ventricle [23]. Recent work from the Strong Heart Study has shown that
central systolic pressure has a has a stronger association with LVH than brachial or pulse pressure [24, 25].
Central AIx has also been shown to have a significant correlation with LVH, as seen in end stage renal
patients [26]. In a group of renal patients on haemodialysis, an increased AIx was associated with the
development of LVH, independent of other factors known to influence cardiac structure in ESRD patients,
as shown in Figure 3. Furthermore, AIx is a strong independent predictor of cardiovascular (and all-cause)
mortality in end stage renal failure. For each 10% increase in AIx, the risk of cardiovascular events or allcause
mortality increases by approximately 50% (RR of 1.51 and 1.48, respectively) [20].
2 The Strong Heart Study is an observational study of prevalent and incident cardiovascular disease and their risk factors in
American Indians.

Figure 3 A scatterplot showing the correlation between AIx and left ventricular mass index in end-stage renal disease
patients. From: Marchais SJ, Guerin AP, Pannier BM, et al. Wave reflections and cardiac hypertrophy in chronic uremia.
Influence of body size. Hypertension 1993,22:876-883.
Similarly, central AIx has been shown to be an independent predictor of severe cardiovascular events in
patients with coronary artery disease [17, 18] and even in males in the general population without a history
of cardiovascular disease [13].
A recent systematic review of pooled data of over 5500 patients confers that central AIx is predictive of
cardiovascular events and all cause mortality in a range of populations [3]. For an absolute increase in AIx
of 10% the risk for cardiovascular events increased by 31.8% and the risk for all cause mortality increased
by 38.4%.
The ability to measure central blood pressure and indices of wave reflection, such as AIx contributes
valuable information on the cardiovascular risk of a patient.
Precursor to hypertension
Recent findings from a large a comprehensive longitudinal study have found that central AIx and forward
wave amplitude are related to future systolic blood pressure, PP and incident hypertension. The
community-based study of around 1700 normotensive participants (from the Framingham Offspring
cohort 3 ) examined over a 7-year period showed that an increase in arterial stiffness was predictive of
developing hypertension [27]. Treatments targeting arterial stiffness and function may play a significant
role in prevention of incident hypertension. Arterial stiffness, as measured by Aix, may become a treatment
target in the future.
Response to treatment
Over the last decade there has been an increasing awareness that beneficial effect of pharmacological
therapies beyond brachial blood pressure. As such, it is considered that the additional effects
antihypertensive drugs have on central haemodynamics is associated with their ability to modify arterial
properties, such as stiffness of large vessels (via pulse wave velocity) and pressure wave reflections via AIx.
Although the current antihypertensive drugs have not been specifically designed to lower arterial stiffness,
it is possible to assess the effect they have had either directly or indirectly on these arterial properties.
In the largest prospective evaluation of cardiovascular drugs on central blood pressure and haemodynamics
to date, the CAFÉ study 4 , differential effects of treatment can be seen in central blood pressure despite a
3 The Framingham Heart study has followed three generation of participants since 1948 to identify common factors or
characteristics that contribute to cardiovascular disease. The Original Cohort consisted of 5209 participants aged 30-
62 years. In 1971 the Offspring Cohort Study commenced and included 5124 men and women consisting of offspring
from the Original Cohort and their spouses. Participants have undergone cardiovascular examinations every 4-6 years
and PWA and PWV measurements have been included since cycle 7 (1998-2001).
4 CAFÉ study – Conduit Artery Function Evaluation study was a makor sub-study within the Anglo-Scandinavian Cardiac
Outcome Trial (ASCOT) conducted across 5 centres in the UK and Ireland. Over 2000 patients with either untreated or

similar effect on brachial blood pressure. The improvement in central systolic and pulse pressures following
amlodipine/perindopril therapy are considered to have played a role in the superior cardiovascular
outcomes observed in the larger ASCOT trial and would not have been detected if only brachial blood
pressure was measured [28].
In a similar study of high risk patients with essential hypertension that extended over 12 months (REASON 5
trial) brachial and central SBP, PP and AIx were all significantly lower in patients on combination therapy
(perindopril/indapamide), with central changes being more pronounced than brachial changes [29]. These
results are consistent with a number of smaller short term studies in hypertension [30, 31, 32, 33, 34, 35,
36, 37].
A recent study has also shown that an individual class of hypertensive drug should not be considered as a
homogenous group and differences in hemododynamics can be observed. In this study, a relatively new
beta blocker, Nebivolol, which is considered to have ancillary vasodilatory properties, provided a
significantly greater reduction in central PP, AIx and PP amplification compared with atenolol, a standard
beta blocker, in patients with essential hypertension [32].
Atenolol has also been shown to significantly increase central AIx, while still being able to reduce both
brachial and central SBP.
These studies highlight the importance of measuring central haemodynamic measures including Aix and
central pulse pressure in patient treatment. This may help to explain why some drugs with a similar effect
on brachial pressure but a different affect on central blood pressure and significantly different
cardiovascular outcomes.
Perspective
Central arterial blood pressure and measures of arterial stiffness and wave reflection are important
measures for assessment of cardiovascular risk and evaluation of treatment. Central SBP, PP and AIx have
all been shown to be powerful predictors of major cardiovascular events across a range of diseases. Central
SBP has consistently been shown to be better than brachial blood pressure in the determination of
cardiovascular risk and the measurement of central PP, AP and AIx provide additional information on the
arterial stiffness of a patient, known to be a risk factor for the development of hypertension. As a result, all
of these measurements should be measured and taken together to develop an accurate assessment of the
patient’s cardiovascular risk. These measurements have also become significant markers in the evaluation
of, as well as potential targets for treatment.
When selecting a device to measure arterial stiffness, it is imperative that the device measures central SBP
as well as central PP, AP and AIx using validated methods. The SphygmoCor device is the most widely used
device in clinical trials and provides this information easily using gold standard techniques.
References
1. Mancia G, De BG, Dominiczak A, et al. 2007 Guidelines for the Management of Arterial Hypertension:
The Task Force for the Management of Arterial Hypertension of the European Society of
Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens 2007,25:1105-1187.
2. Agabiti-Rosei E, Mancia G, O'Rourke MF, et al. Central blood pressure measurements and
antihypertensive therapy: a consensus document. Hypertension 2007,50:154-160.
treated hypertension participated in the study for up to 4 years, during which time multiple blood pressure
measurements were made.
5 REASON project – pREterax in regression of Arterial Stiffness in a controlled double blind study was a multicentre
trial conducted across 13 countries.

3. Vlachopoulos C, Aznaouridis K, O'Rourke MF, et al. Prediction of cardiovascular events and all-cause
mortality with central haemodynamics: a systematic review and meta-analysis. Eur Heart J
2010,31:1865-1871.
4. London GM and Pannier B. Arterial functions: how to interpret the complex physiology. Nephrol Dial
Transplant 2010,25:3815-3823.
5. Gurovich AN and Braith RW. Pulse wave analysis and pulse wave velocity techniques: are they ready
for the clinic Hypertens Res 2011,34:166-169.
6. McDonald's Blood Flow in Arteries. Theoretcial, experimental and clinical principles. 5th edition
Hodder Arnold London 2005 370-373.
7. Nichols WW and O'Rourke MF. McDonald's Blood Flow in Arteries. 5th Edition.2005,49-65.
8. McEniery CM, Yasmin, McDonnell B, et al. Central pressure: variability and impact of cardiovascular
risk factors: the Anglo-Cardiff Collaborative Trial II. Hypertension 2008,51:1476-1482.
9. Gurovich AN and Braith RW. Pulse wave analysis and pulse wave velocity techniques: are they ready
for the clinic Hypertens Res 2011,34:166-169.
10. London GM and Pannier B. Arterial functions: how to interpret the complex physiology. Nephrol Dial
Transplant 2010,25:3815-3823.
11. Roman MJ, Devereux RB, Kizer JR, et al. Central pressure more strongly relates to vascular disease
and outcome than does brachial pressure: the Strong Heart Study. Hypertension 2007,50:197-203.
12. Roman MJ, Devereux RB, Kizer JR, et al. High central pulse pressure is independently associated with
adverse cardiovascular outcome the strong heart study. J Am Coll Cardiol 27-10-2009,54:1730-1734.
13. Janner JH, Godtfredsen NS, Ladelund S, et al. High aortic augmentation index predicts mortality and
cardiovascular events in men from a general population, but not in women. Eur J Prev Cardiol 30-5-
2012,Epub ahead of print:
14. Jankowski P, Kawecka-Jaszcz K, Czarnecka D, et al. Pulsatile but not steady component of blood
pressure predicts cardiovascular events in coronary patients. Hypertension 2008,51:848-855.
15. Danchin N, Benetos A, Lopez-Sublet M, et al. Aortic pulse pressure is related to the presence and
extent of coronary artery disease in men undergoing diagnostic coronary angiography: a multicenter
study. Am J Hypertens 2004,17:129-133.
16. Weber T, Auer J, O'Rourke MF, et al. Arterial stiffness, wave reflections, and the risk of coronary
artery disease. Circulation 20-1-2004,109:184-189.
17. Weber T, Auer J, O'Rourke MF, et al. Increased arterial wave reflections predict severe cardiovascular
events in patients undergoing percutaneous coronary interventions. Eur Heart J 2005,26:2657-2663.
18. Weber T, O'Rourke MF, Lassnig E, et al. Pulse waveform characteristics predict cardiovascular events
and mortality in patients undergoing coronary angiography. J Hypertens 2010,28:797-805.

19. Cohen DL and Townsend RR. Central blood pressure and chronic kidney disease progression. Int J
Nephrol 2011,2011:407801
20. London GM, Blacher J, Pannier B, et al. Arterial wave reflections and survival in end-stage renal
failure. Hypertension 2001,38:434-438.
21. Schram MT, Kostense PJ, van Dijk RA, et al. Diabetes, pulse pressure and cardiovascular mortality: the
Hoorn Study. J Hypertens 2002,20:1743-1751.
22. Pini R, Cavallini MC, Palmieri V, et al. Central but not brachial blood pressure predicts cardiovascular
events in an unselected geriatric population: the ICARe Dicomano Study. J Am Coll Cardiol 24-6-
2008,51:2432-2439.
23. Kaplan NM and Douglas PS. Clinical implications and treatment of left ventricular hypertrophy in
hypertension.2011,
24. Roman MJ, Okin PM, Kizer JR, et al. Relations of central and brachial blood pressure to left ventricular
hypertrophy and geometry: the Strong Heart Study. J Hypertens 2010,28:384-388.
25. Wohlfahrt P, Wichterle D, Seidlerova J, et al. Relation of central and brachial blood pressure to left
ventricular hypertrophy. The Czech Post-MONICA Study. J Hum Hypertens 25-8-2011,
26. Marchais SJ, Guerin AP, Pannier BM, et al. Wave reflections and cardiac hypertrophy in chronic
uremia. Influence of body size. Hypertension 1993,22:876-883.
27. Kaess BM, Rong J, Larson MG, et al. Aortic stiffness, blood pressure progression, and incident
hypertension. JAMA 5-9-2012,308:875-881.
28. Williams B, Lacy PS, Thom SM, et al. Differential impact of blood pressure-lowering drugs on central
aortic pressure and clinical outcomes: principal results of the Conduit Artery Function Evaluation
(CAFE) study. Circulation 7-3-2006,113:1213-1225.
29. Asmar RG, London GM, O'Rourke ME and Safar ME. Improvement in blood pressure, arterial stiffness
and wave reflections with a very-low-dose perindopril/indapamide combination in hypertensive
patient: a comparison with atenolol. Hypertension 2001,38:922-926.
30. Mackenzie IS, McEniery CM, Dhakam Z, et al. Comparison of the effects of antihypertensive agents on
central blood pressure and arterial stiffness in isolated systolic hypertension. Hypertension
2009,54:409-413.
31. Mackenzie IS, Wilkinson IB and Cockcroft JR. Assessment of arterial stiffness in clinical practice. QJM
2002,95:67-74.
32. Mahmud A and Feely J. Beta-blockers reduce aortic stiffness in hypertension but nebivolol, not
atenolol, reduces wave reflection. Am J Hypertens 2008,21:663-667.
33. Schneider MP, Delles C, Klingbeil AU, et al. Effect of angiotensin receptor blockade on central
haemodynamics in essential hypertension: results of a randomised trial. J Renin Angiotensin
Aldosterone Syst 2008,9:49-56.

34. Dhakam Z, McEniery CM, Yasmin, et al. Atenolol and eprosartan: differential effects on central blood
pressure and aortic pulse wave velocity. Am J Hypertens 2006,19:214-219.
35. Matsui Y, Eguchi K, O'Rourke MF, et al. Differential Effects Between a Calcium Channel Blocker and a
Diuretic When Used in Combination With Angiotensin II Receptor Blocker on Central Aortic Pressure
in Hypertensive Patients. Hypertension 10-8-2009,54:716-723.
36. Jiang XJ, O'Rourke MF, Zhang YQ, et al. Superior effect of an angiotensin-converting enzyme inhibitor
over a diuretic for reducing aortic systolic pressure. J Hypertens 2007,25:1095-1099.
37. Morgan T, Lauri J, Bertram D and Anderson A. Effect of different antihypertensive drug classes on
central aortic pressure. Am J Hypertens 2004,17:118-123.
Note alternative picture to Figure 1.
From: Janner,J.H.; Godtfredsen,N.S.; Ladelund,S.; Vestbo,J.; Prescott,E. Aortic augmentation index:
reference values in a large unselected population by means of the SphygmoCor device. Am.J Hypertens.
2010;23:180-185