Effect of antihypertensive drugs on central blood pressure over and above brachial blood pressure: focusing on blood pressure amplification




Athanase D. PROTOGEROU,MD
1st Propaedeutic Department of Internal Medicine
“Laiko” Hospital, Medical School of National and Kapodistrian
University of Athens
Athens, GREECE

by A. D. Protogerou,Greece

The recorded blood pressure (BP) waveform at each arterial site derives from the “summation” of the forward and backward traveling waves. As a consequence of arterial stiffness/diameter gradient and pressure wave reflections along the arterial bed, the final pattern of the waveformvaries substantially between the peripheral and central arteries. Its amplitude (pulse pressure [PP]) increases gradually as it propagates distally. PP amplification between two arterial sites is not constant. It depends on “vascular age” (ie, arterial stiffness and wave reflections), heart rate, cardiovascular (CV) risk factors, and vasoactive substances. Although limitations exist regarding noninvasive central blood pressure (CBP) assessment, accumulating data from clinical studies suggest that it is associated with CV risk more closely than peripheral blood pressure (PBP); thus PP amplification is emerging as a new biomarker of CV risk. Current evidence indicates, beyond any doubt, that antihypertensive drugs affect PBP and CBP differentially and alter PP amplification. It is also becoming evident that important differences between classes of antihypertensive drug exist regarding their effects on PP amplification, due to different modes of action and effects on arterial stiffness and wave reflections. A review of the current data suggest that newer antihypertensive drugs with vasodilating properties (such as the angiotensin-converting enzyme inhibitors and dihydropyridine calciumchannel blockers), as well as their combinations, appear to have a more beneficial effect on PP amplification than older drugs (particularly _-blockers, but also diuretics) by decreasing CBP over and above PBP.

Medicographia. 2010;32:254-261 (see French abstract on page 261)

In the mid fifties, invasive studies which were curried out at the laboratories of Earl Wood at the Mayo Clinic1 in both healthy volunteers (the physicians themselves) and patients undergoing diagnostic catheterizations showed that the contour of the pressure waveform changes dramatically from the central (aortic/carotid) to the peripheral (brachial/radial) arteries. This was also true for the arterial segment between the subclavian and brachial/radial arteries, which is conventionally used for blood pressure (BP) recording in clinical practice and clinical trials. The main qualitative differences regarding the shape of the pressure waveform between the central and peripheral arteries that were observed in early studies1 were (Figure 1)2: (i) The presence of an early (S1) and a late systolic peak (S2) of the central arteries in contrast to a blunted second systolic peak (S2) and at the same time an accentuated diastolic wave (D) of the brachial and radial arteries.

Figure 1
Figure 1. Schematic representation of: (i) the morphological
differences of the pulse wave between the aorta and the brachial artery in young healthy subjects (upper panel [A]); and (ii) the effect of heart rate (upper panel [A] versus lower panel [B]) on systolic blood pressure augmentation and pulse wave amplification, for the same reflected pressure wave and similar pulse height of the forward ejected pressure wave.

Abbreviations: aortic S1, 1st systolic peak attributed to the forward wave; aortic S2: 2nd late systolic peak due to the augmentation by the reflected pressure wave; brachial S1, 1st systolic peak attributed to the forward wave; brachial S2, systolic peak due to the reflected wave from the upper limb; D, accentuated diastolic wave due to the delayed arrival of the reflected wave from the lower body; ED, ejection duration; T0, onset of the forward ejected wave; Tr, time to return at the aorta of the backward reflected wave from T0.
Modified from reference 2: Safar et al. Circulation. 2009;119:9-12.
© 2009, American Heart Association, Inc.

(ii) A clear widening (amplification) of the pulse pressure (PP) from the subclavian towards the brachial/radial sites.

In those early days, the so-called pressure amplification phenomenon, due to the amplification of the amplitude (ie, the PP) of the pressure waveform from the aorta to the radial artery, was attributed principally to the presence of multiple peripheral pressure wave reflections.1

It is now accepted that the pressure waveform is distorted as it travels distally from the aorta to the upper limb, however without substantial energy loss (Figure 1).2 This was clearly stated in the recently published experts’ opinion statement, which reviewed the available data.3 The characteristics of the contour as well as the PP of the waveform change substantially between the central and peripheral arterial sites.

It is important to note that, as described by both invasive and noninvasive studies3,4: (i) the mean BP (as well as diastolic blood pressure [DBP]) remain almost constant, ie, the energy is preserved. In contrast, systolic blood pressure (SBP) gradually increases as the wave travels distally; and (ii) for that reason, there is a gradual widening of the amplitude of the pressure wave. In practice, PP amplification is quantified as the ratio of the PP amplitude between a distal (eg, brachial [PP2]) and a proximal (eg, aorta [PP1]) location, ie, PP2/PP1, or as their difference, ie, PP2-PP1.

Additional data from invasive as well as noninvasive studies are needed in order to further verify the applicability of these basic physiological concepts in various ages, as well as various cardiovascular (CV) states and diseases.

Pathophysiology of pulse pressure amplification

The physiology of this phenomenon is not fully elucidated. Its genesis follows the principal laws of biophysics regarding wave travel and reflection.3 In terms of the currently available methodology and data,3 pressure amplification is attributed to:
(i) the presence of stiffness and diameter gradient across the arterial tree;
(ii) the presence of wave reflections (originating from various sites due to arterial bifurcations, calcification, and impedance mismatch); and
(iii) to the spatial variation that is observed in the timing of the incident (forward traveling) and reflected (backward traveling) pressure waves.

Therefore, apart from total peripheral resistance, the arterial properties of the micro- and the macrocirculation, ie, large artery stiffness (commonly assessed by pulse wave velocity [PWV])5 and wave reflections (commonly assessed as augmentation pressure or augmentation index [AI]) (Figure 1)2 are the principal modulators of the amplification phenomenon.3 Two other cardinal modulators of PP amplification are: (i) the “distance”; and (ii) the heart rate. The notion of “distance” should be appreciated as the length between the site of wave recording and the site of generation of the wave reflection (ie, the “effective reflecting distance,” which is more a statistical notion than an actual one). In synergy with the alterations in heart rate (ejection phase duration), the “distance” covered by the backward reflected pressure wave regulates the “timing/ synchronization” with the forward traveling wave (ejected wave from the heart). “Early timing” in the systolic phase of the ejected wave is associated with augmentation of the systolic area of the pressure waveform, whereas “late timing” leads to the opposite effect (Figure 1).2

Figure 2
Figure 2. Absolute (left) and relative (right) amplifications of the pressure pulse from the carotid artery to the brachial artery (orange bars),
and from the brachial artery to the radial artery (green bars).

The relative amplification was calculated with carotid pulse pressure as the reference; carotid pulse pressure was recorded by direct carotid tonometry and the carotid wave was calibrated with diastolic and mean brachial pressure.
Modified from reference 6: Segers et al; Asklepios Investigators. Hypertension. 2009;54:414-420. © 2009, American Heart Association, Inc.

PP amplification is affected by several nonmodifiable and modifiable factors. Aging (mainly due to “normal vascular aging,” ie, large artery stiffening and increased wave reflections) is the main nonmodifiable factor leading to attenuation of PP amplification, as suggested by cross-sectional data in healthy subjects (Figure 2).6-8 Gender is the second important nonmodifiable determinant; for all ages, females exhibit lower PP amplification than males (Figure 2).6-8 Modifiable traditional CV risk factors, including high blood pressure, diabetes mellitus, hypercholesterolemia, smoking, and established CV disease, are also associated with lower PP amplification,8,9 and vasoactive substances can alter PP amplification.3 As a consequence, PP amplification presents substantial variability within and between subjects3,7,8; it may vary enormously (from 0 to more than 30 mm Hg).3,6,8 The actual magnitude of PP amplification is an issue of debate and it depends on the methodology used.7 Its assessment requires both central and peripheral hemodynamic signals (pressure or diameter). The main drawback derives from the obvious limitations of invasive methods, but also from the limitations of the noninvasive methodologies3,10 and particularly the way that the central signal is calibrated with brachial BP.11

Prospective data regarding the natural history of PP and the effect of CV risk factors are still lacking.

Clinical implications of blood pressure amplification

More and more data are accumulating regarding the superiority of central blood pressure (CBP) over peripheral blood pressure (PBP) in the prognosis of CV disease.12,13 The European Society of Hypertension has acknowledged this emerging possibility in the latest guidelines.14 Recent findings in an unselected geriatric population showed that CBP, compared to brachial BP, was associated more closely with CV events.15 These data imply that even in the elderly, who are characterized by low PP amplification, central BP is superior to brachial BP for the prognosis of CV events.

From the point of view of pathophysiology, lower PP amplification is expected to be associated with unfavorable hemodynamic effects on the central arteries and the heart. For a given peripheral PP, a person with low PP amplification when compared to another with high PP amplification is subject:
(i) per se to higher left ventricular afterload and potentially to lower subendocardial viability (systolic/diastolic area under the pressure waveform); as well as
(ii) to more intense cyclic stress imposed on the renal and cerebral micro- and macrovessels.16-18

Prospective data in subjects with end-stage renal disease18 show that the reduction (disappearance) of PP amplification is an independent predictor of both all-cause and CV mortality. Data from a cross-sectional observational study in hypertensive subjects (with or without metabolic syndrome)19 have also shown that PP amplification was associated with a calculated risk for myocardial infarction. A more recent crosssectional study verified the association of low PP amplification with target-organ damage and CV risk, as assessed by the Framingham equation.20 Additional data regarding the association of PP amplification with target-organ damage has also been presented21 in untreated subjects with essential hypertension, associating a regression of left ventricular mass index after one year of treatment with an increase in PP amplification, and not with brachial BP reduction.

Although prospective data regarding the association of PP amplification and CV risk are still limited, PP amplification is emerging as a new biomarker of CV disease.

Antihypertensive drugs: theoretical mode of action on central BP over and above peripheral BP

Available antihypertensive drugs have been designed to decrease PBP by reducing total peripheral resistance, via vasodilatation at the level of the arterioles (microcirculation) and by decreasing cardiac output, through reduction of the stroke volume, heart rate, or both. Currently, there is no drug specifically designed to improve intrinsic elasticity-related arterial wall properties. Theoretically, an increase in PP amplification can be achieved by two potential mechanisms: (i) a reduction in the intensity of the wave (reduction of the reflection coefficient); or (ii) a resynchronization of the timing of the reflected wave within systole, in such a way that peak SBP is less enhanced (Figure 1).2 The latter mechanism may be a result of: (i) the delayed arrival of the reflected wave (Tr) (Figure 1)2 due to either decreased PWV or distal shift of the origin of the reflected wave (effective reflecting distance); or (ii) shortening of the left ventricular ejection time (due to acceleration of the heart rate) (Figure 1).2

PWV is, at least in some cases, passively reduced as a consequence of BP lowering due to attenuation of arterial wall passive distension. In this respect, all drugs exert potential further favorable actions on CBP, over and above PBP.

Evidence of class-related effects of antihypertensive drugs on pulse pressure amplification

There is now solid evidence suggesting that important differences between classes of antihypertensive drugs exist regarding their direct effect on the arterial wall and elasticity-associated arterial properties (arterial compliance and reflection coefficient).22 These differences underlie the differential effect of antihypertensive drugs on PP amplification, as will be briefly addressed below.

_ Diuretics
The available evidence on diuretics (six studies with 457 subjects in total)23-28 suggests that diuretics (as monotherapy or single add-on therapy) have no additional effect on CBP over and above PBP (Tables I and II, page 258).29 This conclusion is in line with the reviewed data elsewhere regarding the effect of diuretics on aortic stiffness and pressure wave reflections that show that diuretics have no, or a minimal, beneficial effect on these two arterial parameters when used as monotherapy.22,30-33

_ β-Blockers
The data regarding the effect of βblockers derive from studies (six studies with 193 subjects in total) that have almost exclusively evaluated atenolol, whereas inadequate data are available for newer βblockers with vasodilating properties24,25,34-37 (Tables I and II).29 These results clearly show that atenolol decreases central PP less than the observed reduction at the level of the brachial artery. Most importantly, in two of the studies,32,37 central PP actually increased, although peripheral PP decreased. In three studies,24,36,37 proof of substantial clinical increase of left ventricular afterload was provided. All the six available studies, as well as a recent post hoc analysis of the Anglo-Scandinavian Cardiac Outcomes Trial Conduit Artery Function Evaluation (ASCOT-CAFE),38 verify that the principal mechanism explaining the nonfavorable effect of β-blocker on CBP is the increase of AI due to the deceleration of heart rate and the resynchronizing of the reflected pressure wave earlier in the systolic phase (thus increasing AI) (Tables I and II).29 A decrease in the heart rate by 10 beats/min, induced by atenolol, is associated with an increase in aortic AI of 4%.

Table I
Table I. Studies classified according to group of antihypertensive drug and outcome (positive/negative/neutral/missing data) regarding the effect on central blood pressure over and above peripheral blood pressure, as well as mode of action (aortic stiffness, pressure wave reflections, heart rate, left ventricular function, and synchronization of the pressure [forward and backward] traveling waves).

Abbreviations: ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; BP, blood pressure; CCB, calcium channel blocker (dihydropyridine).
Modified from reference 29: Protogerou et al. Curr Pharm Des. 2009;15:267-271. © 2009, Bentham Science Publishers Ltd.

Table II
Table II. Summary of the available evidence on the effects of antihypertensive drug classes on central blood pressure–lowering capacity over and above peripheral blood pressure–lowering (ie, increase of blood pressure amplification).

Abbreviations: ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; CCB, calcium channel blocker (dihydropyridine).
Modified from reference 29: Protogerou AD, Papaioannou TG, Lekakis JP, Blacher J, Safar ME. Curr Pharm Des. 2009;15:267-271. Copyright © 2009, Bentham Science Publishers Ltd.

_ Dihydropyridine calcium channel blockers
The available data (4 studies with 175 subjects in total) imply that dihydropyridine calcium channel blockers (CCBs) increase PP amplification by decreasing CBP over and above PBP (Tables I and II).24,25,28,29,39 All the studies suggested that dihydropyridine CCBs increase PP amplification by reducing pressure wave reflections, even in the presence of bradycardia.28

This implies an effect of dihydropyridine CCBs on the reflection coefficient of the peripheral arteries and/or a distal shift of the effective reflecting distance, which delays the arrival of the reflected wave at the central artery, as previously reported in a number of studies.30 This action is related to the main mode of action of dihydropyridine CCBs, ie, the vasodilator effect at the level of the conduit arteries.40 Additionally, substantial aortic stiffness reduction has been reported with CCBs in studies that lasted more than 4-6 weeks.28,30,32,39

_ Angiotensin-converting enzyme inhibitors
Angiotensin-converting enzyme (ACE) inhibitors are the most extensively studied class of antihypertensive drug regarding the ability to reduce CBP over and above PBP.24-27,35,39,41-45 The weight of evidence (Tables I and II)29 clearly supports the presence of additional CBP-lowering capacity by ACE inhibitors over and above PBP. This effect was observed in eight out of the eleven available studies and it was associated, in almost all of the studies, with a reduction in the reflected pressure wave. Data on concomitant arterial stiffness reduction and resynchronization of the reflected wave were not widely available in these studies. However, revised data from a large number of studies on arterial properties22,30,32 show that ACE inhibitors have a beneficial action on both arterial stiffness and wave reflections. These actions are in part mediated by the classic vasodilating effect due to angiotensin II inhibition leading to smooth muscle relaxation and collagen/elastin fiber rearrangement. Yet several other mechanisms of action exist and are at least partly independent of angiotensin II reduction, including the reduction of oxidative stress and inflammation, which leads to direct beneficial effects on the endothelium, smooth muscle cells, the collagen/elastin ratio, and extracellular matrix composition.40,46

_ Angiotensin receptor blockers
Five noninvasive studies23,36,43,45,47 (95 subjects in total) (Tables I and II)29 have evaluated the effect of angiotensin receptor blockers (ARBs), as monotherapy or single add-on therapy, on CBP over and above PBP. Although the literature regarding the effect of ARBs on pressure wave reflections and aortic stiffness30,32 suggests that this class of drugs can reduce both parameters, the available evidence on the effect of ARBs on CBP reduction over and above PBP is still very weak. Only two studies provided positive evidence. Given the fact that only small differences between ACE inhibitors and ARBs have so far been documented and pleiotropic effects have been attributed to both classes,40 further clinical proof is awaited from larger studies.

Direct evidence regarding the inferiority of â-blockers versus the new classes of antihypertensive drugs (ACE inhibitors, ARBs, and CCBs) has been presented in four studies.24,25,36,37 Similarly, direct comparison of diuretics with ACE inhibitors and CCBs verified the superiority of the latter.24-27

Evidence regarding the effect of combination treatment on pulse pressure amplification

The Conduit Artery Function Evaluation (CAFE) study,48 a substudy of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT), showed for the first time that the combination of new antihypertensive drugs, ie, an ACE inhibitor (perindopril) with a dihydropyridine CCB (amlodipine) has more favorable effects on PP amplification than the combination of a diuretic (bendroflumethiazide) with a β-blocker (atenolol). In 2199 subjects after almost 6 years of follow-up, it was clearly shown that subjects in the amlodipine/perindopril regimen arm had significantly lower levels of central SBP and PP during the study than subjects on the atenolol/bendroflumethiazide regimen. Most importantly, it was clearly shown that these differences could not be detected at the level of the brachial artery. This clear beneficial effect on BP amplification (ratio) (atenolol/ diuretic vs amlodipine/perindopril, 1.21 vs 1.31; P<0.001) in the amlodipine-based combination was attributed to the significant decrease of pressure wave reflections (expressed by AI) rather than PWV (aortic stiffness was available only in 114 subjects), and mostly to a change in the timing of the reflected wave (taking place earlier in the systolic phase of the ejected aortic wave due to the slowing of the heart rate by the β-blocker).

Limitations and conclusions

There are considerable limitations regarding the extrapolation of the above data in daily clinical practice due to the fact that most of the data derive from small and short-term studies, which differ in design, primary end points, dosage of active drug, and the applied methodology for CBP and PBP assessment. Nevertheless, several conclusions can be drawn based on the consistency of the results.

First, it is clear that there are important differences between the classes of antihypertensive drugs regarding their effects on BP amplification. These differences are based on the differential effects of drugs on arterial wall properties and the autonomic nervous system.

Second, it seems that the newer antihypertensive drugs (especially ACE inhibitors and dihydropyridine CCBs) have a more beneficial effect on BP amplification than the older drugs (diuretics and particularly β-blockers). The common features of these newer classes of drugs appear to be their arterial dilating capacity and their ability to reduce pressure wave reflections, as expressed by AI. Third, there is compelling evidence regarding the detrimental effect of β-blockers (mainly atenolol) on CBP. This is largely attributable to the bradycardia induced, which leads to augmentation of aortic SBP primarily due to the earlier timing of the reflected pressure within the systolic phase of the ejected wave. Whether newer β-blockers with vasodilating properties are devoid of these effects remains to be proven. Fourth, among newer drug classes, ACE inhibitors are by far the best studied regarding their effects on CBP.

There is convincing evidence that ACE inhibitors increase BP amplification, mainly by decreasing wave reflections. The most probable mode of action includes chronic remodeling of the small arteries leading to reduced reflection coefficients. Finally, the combination of ACE inhibitors and dihydropyridine CCBs appears to be the most promising treatment for CBP reduction at the moment, over and above PBP. _

References
1. Remington JW, Wood EH. Formation of peripheral pulse contour in man. J Appl Physiol. 1956;9:433-442.
2. Safar ME, Protogerou AD, Blacher J. Statins, central blood pressure, and blood pressure amplification. Circulation. 2009;119:9-12.
3. Avolio AP, Van Bortel LM, Boutouyrie P, et al. Role of pulse pressure amplification in arterial hypertension: experts’ opinion and review of the data. Hypertension. 2009;54:375-383.
4. Pauca AL, Wallenhaupt SL, Kon ND, Tucker WY. Does radial artery pressure accurately reflect aortic pressure? Chest. 1992;102:1193-1198.
5. Laurent S, Cockcroft J, Van Bortel L, et al; European Network for Non-invasive Investigation of Large Arteries. Expert consensus document on arterial stiffness: methodological issues and clinical applications. Eur Heart J. 2006;27:2588-2605.
6. McEniery CM, Yasmin, Hall IR, Qasem A, Wilkinson IB, Cockcroft JR; ACCT Investigators. Normal vascular aging: differential effects on wave reflection and aortic pulse wave velocity: the Anglo-Cardiff Collaborative Trial (ACCT). J Am Coll Cardiol. 2005;46:1753-1760.
7. Segers P, Mahieu D, Kips J, et al; Asklepios Investigators. Amplification of the pressure pulse in the upper limb in healthy, middle-aged men and women. Hypertension. 2009;54:414-420.
8. McEniery CM, Yasmin, McDonnell B, et al; Anglo-Cardiff Collaborative Trial Investigators. Central pressure: variability and impact of cardiovascular risk factors: the Anglo-Cardiff Collaborative Trial II. Hypertension. 2008;51:1476-1482.
9. Mahmud A, Feely J. Effect of smoking on arterial stiffness and pulse pressure amplification. Hypertension. 2003;41:183-187.
10. Papaioannou TG, Protogerou AD, Stamatelopoulos KS, Vavuranakis M, Stefanadis C. Non-invasive methods and techniques for central blood pressure estimation: procedures, validation, reproducibility and limitations. Curr Pharm Des. 2009;15:245-253.
11. Mahieu D, Kips J, Rietzschel ER, et al; Asklepios Investigators. Noninvasive assessment of central and peripheral arterial pressure (waveforms): implications of calibration methods. J Hypertens. 2010;28:300-305.
12. Protogerou AD, Papaioannou TG, Blacher J, Papamichael CM, Lekakis JP, Safar ME. Central blood pressures: do we need them in the management of cardiovascular disease? Is it a feasible therapeutic target? J Hypertens. 2007; 25:265-272.
13. Wang KL, Cheng HM, Chuang SY, et al. Central or peripheral systolic or pulse pressure: which best relates to target organs and future mortality? J Hypertens. 2009;27:461-467.
14. Mancia G, De Backer G, 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). Eur Heart J. 2007;28:1462-1536.
15. 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. 2008;51:2432-2439.
16. Watanabe H, Ohtsuka S, Kakihana M, Sugishita Y. Coronary circulation in dogs with an experimental decrease in aortic compliance. J Am Coll Cardiol. 1993; 21:1497-1506.
17. Schillaci G, Pirro M, Mannarion MR, et al. Relation between renal function within the normal range and central and peripheral arterial stiffness in hypertension. Hypertension. 2006;48:616-621.
18. Safar ME, Blacher J, Pannier B, et al. Central pulse pressure and mortality in end-stage renal disease. Hypertension. 2002;39:735-738.
19. Protogerou AD, Blacher J, Mavrikakis M, Lekakis J, Safar ME. Increased pulse pressure amplification in treated hypertensive subjects with metabolic syndrome. Am J Hypertens. 2007;20:127-133.
20. Nijdam ME, Plantinga Y, Hulsen HT, et al. Pulse pressure amplification and risk of cardiovascular disease. Am J Hypertens. 2008;21:388-392.
21. Hashimoto J, Imai Y, O’Rourke MF. Indices of pulse wave analysis are better predictors of left ventricular mass reduction than cuff pressure. Am J Hypertens. 2007;20:378-384.
22. Blacher J, Protogerou AD, Safar ME. Large artery stiffness and antihypertensive agents. Curr Pharm Des. 2005;11:3317-3326.
23. Klingbeil AU, John S, Schneider MP, Jacobi J, Weidinger G, Schmieder RE. AT1-receptor blockade improves augmentation index: a double-blind, randomized, controlled study. J Hypertens. 2002;20:2423-2428.
24. Deary AJ, Schumann AL, Murfet H, Haydock S, Foo RS, Brown MJ. Influence of drugs and gender on the arterial pulse wave and natriuretic peptide secretion in untreated patients with essential hypertension. Clin Sci (Lond). 2002; 103:493-499.
25. Morgan T, Lauri J, Bertram D, Anderson A. Effect of different antihypertensive drug classes on central aortic pressure. Am J Hypertens. 2004;17:118-123.
26. Dart AM, Cameron JD, Gatzka CD, et al. Similar effects of treatment on central and brachial blood pressures in older hypertensive subjects in the Second Australian National Blood Pressure Trial. Hypertension. 2007;49:1242-1247.
27. Jiang XJ, O’Rourke MF, Zhang YQ, He XY, Liu LS. Superior effect of an angiotensin- converting enzyme inhibitor over a diuretic for reducing aortic systolic pressure. J Hypertens. 2007;25:1095-1099.
28. 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. 2009;54:716-723.
29. Protogerou AD, Papaioannou TG, Lekakis JP, Blacher J, Safar ME. The effect of antihypertensive drugs on central blood pressure beyond peripheral blood pressure. Part I: (Patho)-physiology, rationale and perspective on blood pressure amplification. Curr Pharm Des. 2009;15:267-271.
30. Mahmud A. Reducing arterial stiffness and wave reflection—Quest of the holy grail? Artery Res. 2007;1:13-19.
31. Safar M, Levy B. The response of large arteries to antihypertensive treatment. In: O’Rourke M, Safar M, Dzau V, eds. Pharmacological Aspects in Arterial Vasodilation. Philadelphia, Pa: Lea and Febiger; 1993:2;157-166.
32. Asmar R. Effect of antihypertensive agents on arterial stiffness as evaluated by pulse wave velocity: clinical implications. Am J Cardiovasc Drugs. 2001;1: 387-397.
33. Vlachopoulos C, Stefanadis C. The pharmacodynamics of arterial stiffness. In: Laurent S, Cockcroft J, eds. Central Aortic Blood Pressure. Elsevier; 2008:75-81.
34. Asmar RG, London GM, O’Rourke ME, Safar ME; REASON Project Coordinators and Investigators. 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.
35. Hirata K, Vlachopoulos C, Adji A, O’Rourke MF. Benefits from angiotensinconverting enzyme inhibitor ‘beyond blood pressure lowering’: beyond blood pressure or beyond the brachial artery? J Hypertens. 2005;23:551-556.
36. Dhakam Z, McEniery CM, Yasmin, Cockcroft JR, Brown MJ, Wilkinson IB. Atenolol and eprosartan: differential effects on central blood pressure and aortic pulse wave velocity. Am J Hypertens. 2006;19:214-219.
37. Dhakam Z, Yasmin, McEniery CM, Burton T, Brown MJ, Wilkinson IB. A comparison of atenolol and nebivolol in isolated systolic hypertension. J Hypertens. 2008;26:351-356.
38. Williams B, Lacy PS. Impact of heart rate on central aortic pressures and hemodynamics: analysis from the CAFE (Conduit Artery Function Evaluation) study: CAFE-Heart Rate. J Am Coll Cardiol. 2009;54:705-713.
39. London GM, Pannier B, Guerin AP, Marchais SJ, Safar ME, Cuche JL. Cardiac hypertrophy, aortic compliance, peripheral resistance, and wave reflection in end-stage renal disease. Comparative effects of ACE inhibition and calcium channel blockade. Circulation. 1994;90:2786-2796.
40. Kaplan NM. Treatment of hypertension. In: Kaplan NM, Victor RG, eds. Clinical Hypertension. 5th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 2006.
41. London GM, Pannier B, Vicaut E, et al. Antihypertensive effects and arterial haemodynamic alterations during angiotensin converting enzyme inhibition. J Hypertens. 1996;14:1139-1146.
42. Mitchell GF, Izzo JF Jr, Lacourcière Y, et al. Omapatrilat reduces pulse pressure and proximal aortic stiffness in patients with systolic hypertension: results of the conduit hemodynamics of omapatrilat international research study. Circulation. 2002;105:2955-2961.
43. Stokes GS, Barin ES, Gilfillan KL. Effects of isosorbide mononitrate and AII inhibition on pulse wave reflection in hypertension. Hypertension. 2003;41:297-301.
44. Ahimastos AA, Natoli AK, Lawler A, Blombery PA, Kingwell BA. Ramipril reduces large-artery stiffness in peripheral arterial disease and promotes elastogenic remodeling in cell culture. Hypertension. 2005;45:1194-1199.
45. Aznaouridis KA, Stamatelopoulos KS, Karatzis EN, Protogerou AD, Papamichael CM, Lekakis JP. Acute effects of renin-angiotensin system blockade on arterial function in hypertensive patients. J Hum Hypertens. 2007;21:654-663.
46. Safar M. Pathophysiological Mechanisms. In: Safar ME, O’Rourke MF, eds. Arterial Stiffness in Hypertension. Amsterdam, The Netherlands: Elsevier Biomedical; 2006:75-225.
47. Mahmud A, Feely J. Favourable effects on arterial wave reflection and pulse pressure amplification of adding angiotensin II receptor blockade in resistant hypertension. J Hum Hypertens. 2000;14:541-546.
48. Williams B, Lacy PS, Thom SM, et al; CAFE Investigators; Anglo-Scandinavian Cardiac Outcomes Trial Investigators; CAFE Steering Committee and Writing Committee. 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. 2006;113:1213-1225.

Keywords: central blood pressure; pulse pressure amplification; arterial stiffness; wave reflections; antihypertensive drug treatment