Antihypertensive efficacy and destiffening strategy

Michel E. SAFAR,MD
Université Paris Descartes
Assistance Publique-Hôpitaux de Paris, Hôtel-Dieu
Centre de Diagnostic et de Thérapeutique

by M. E. Safar,France

“Destiffening therapy” means that, in controlled therapeutic trials, a significant and selective reduction of systolic blood pressure (BP) has been obtained in long-termtreatment by comparison with a control group. The demonstration requires a reduction of central BP in association with a significant decrease of arterial stiffness and/or attenuation of wave reflections. For this purpose, all clinical trials in recent years have used angiotensin II blockade, mainly through angiotensin-converting enzyme inhibition, and frequently in combination with a diuretic and/or a calcium antagonist. Cardiovascular outcomes are significantly better than in controls, particularly when such controls involve a β-blocking agent.

Medicographia. 2010;32:234-240 (see French abstract on page 240)

Prospective studies from Framingham have focused attention on brachial systolic blood pressure (SBP) as a better guide than brachial diastolic blood pressure (DBP) for evaluation of cardiovascular (CV) risk.1-3 In large populations, antihypertensive drug therapy frequently achieves adequate DBP control (90 mm Hg), but SBP control (SBP 140 mm Hg) is much more difficult to attain.4 The findings have focused attention on the factors that modulate central (aortic) SBP and pulse pressure (PP) levels in hypertensive individuals, and therefore on the role of increased arterial stiffness and/or wave reflections in the mechanism of hypertension, and hence CV risk.

A major function of central (aortic) arteries is to change the PP arriving from the heart into a steady pressure at the peripheral level, thus obtaining optimal oxygenation of tissues. This major modification is a consequence of the so-called Windkessel effect.1-3 During systole, part of the stroke volume flows directly toward the periphery, causing systolic perfusion. The other part of stroke volume is stored within the elastic thoracic aorta wall and restored during diastole, causing diastolic perfusion. The combination of systolic and diastolic perfusion is responsible for a continuous and steady flow, which contrasts with the alternating cyclic movement initiated by the heart. This Windkesse effect has a major impact on central SBP and PP regulation, through alterations produced by aortic stiffness and wave reflections.

This review consists of 2 parts: (i) the hemodynamic and epidemiological basis of propagation of the pressure wave along the vascular tree; and (ii) the principal strategies to lower large artery stiffness and wave reflections in the treatment of hypertension.

Hemodynamic and epidemiological basis of pressure wave propagation
_ Components of the BP curve
There are 2 different components of the blood pressure (BP) curve in the arterial tree: a steady component and a pulsatile component. The former is expressed by mean arterial pressure (MAP), the product of blood flow by vascular resistance, which represents the main index reflecting the status of small arteries, mainly their diameter. The latter is PP, the difference between SBP and DBP. This parameter is determined by stroke volume, aortic stiffness, and wave reflections. The two latter factors, but not stroke volume, contribute, through the aorta’s elastic properties, to the Windkessel effect. Although MAP and PP are associated within the same BP curve, each of these parameters is a significant and independent predictor of CV risk.5 Whereas MAP is a predictor of overall CV risk (stroke, heart failure, renal insufficiency), PP is mainly related to the unique presence of coronary risk. Central PP, not brachial PP, is the more powerful predictor in this context.5-8

_ BP propagation and aortic stiffness
Following ventricular contraction, the pressure pulse generated by the heart travels along the aorta as a wave.6 The velocity of propagation of this wave (ie, pulse wave velocity [PWV]) along the aorta is calculated from the interval between two BP curves located at two different sites in the aortic tree (Figure 1).6 Because a fundamental principle is that pulse waves travel faster in stiffer arteries, PWV measurement is considered the best surrogate to evaluate aortic stiffness in man. Its value is 3-5 m/s in young persons at rest, but increases considerably with age (Figure 1).6 Carotid-femoral (aortic) PWV is nowadays considered as a significant and powerful predictor of CV risk independent of age and MAP.5 PWV of the upper and lower limbs has no predictive value.

When BP measurements are recorded simultaneously at different points along the aorta, the pressure wave changes shape as it travels down the aorta. Whereas SBP and PP actually rise with distance from the heart, DBP and MAP fall slightly (about 4 mm Hg) during the same course along the aortic pathway (Figure 2).2 Thus, pressure oscillation amplitude between systole and diastole, ie, PP, nearly doubles. This SBP and PP amplification (Figure 2)2 is a physiological finding and approximately 14 mm Hg between the thoracic root of the aorta and the brachial artery.

Figure 1
Figure 1. Principle of arterial stiffness measurement by pulse wave velocity with the foot-to-foot method.
Abbreviations: L, distance; t, time.
Modified after reference 6: Laurent et al. Eur Heart J. 2006;27:2588-2605. © 2006, The European Society of Cardiology.

Figure 2
Figure 2. Wave amplification of systolic blood pressure and pulse pressure along
the aorta of a 24-year-old.
After reference 2: Nichols WW, O’Rourke MF. McDonald’s Blood Flow in Arteries. Theoretical, Experimental and Clinical Principles. 4th ed. London, UK: Edward Arnold; 2006. © 2006, Edward Arnold.

_ Central wave reflections and age If an individual’s body length is about 2 m at most and aortic PWV is approximately 5 m/s, something must happen to the BP-curve shape within each beat if heart rate is 60 beats/min. What happens is the generation of wave reflections7 and their summation with the incident wave, as summarized in (Figure 3, upper part on the left, page 236). The incident wave is driven away from the heart through highly conductive arteries. However, it encounters impedance mismatch at the junction of the highly conductive artery and high resistance arterioles, blocking its entry into the arterioles, and it is reflected backwards towards the heart. Thus, the shape of every pulse wave results from the summation of the incident (forward-traveling) and reflected (backward-traveling) pressure waves (Figure 3, upper part on the right).

Reflected waves initiate from any discontinuity of the arterial or arteriolar wall, but mainly issue from high resistance vessels and their arteriolar bifurcations.2,3 Nevertheless, pulse-wave propagation and reflection vary considerably according to age (Figure 3, lower part). In young adults with maximum elasticity of their central arteries (low PWV), the summation of the incident arterial pressure wave and the reflected wave results in progressive PP amplification, so that SBP is higher in the brachial artery than the ascending aorta. Because PWV is relatively low in the thoracic aorta, the reflected wave comes back during diastole, thereby maintaining DBP and boosting coronary perfusion (Figure 3). Hence, optimal arterial function is obtained along with adequate coronary perfusion.

Figure 3
Figure 3. BP curve with description of its principal components.
In the upper part on the left, a schematic representation of the BP curve and its two components, forward and reflected waves. While on the right, the totality of the BP curve is represented. In the lower part, the BP curve is represented using 2 different shapes, dependent on age (see text). The augmentation index (AIx) is the ratio between: (i) the difference between peak SBP and the shoulder of the ascending part of the BP curve; and (ii) pulse pressure. AIx measured in % (or AI in mm Hg) represents the supplementary increase in SBP due to wave reflections. This hemodynamic profile is observed in the elderly, not in young people. MAP corresponds to the pressure needed if the cardiac work was constant.
Abbreviations: AIx, augmentation index; BP, blood pressure; MAP, mean arterial pressure; PP, pulse pressure; SBP, systolic blood pressure.
After reference 6: Laurent et al. Eur Heart J. 2006;27:2588-2605. © 2006, The European Society of Cardiology.

The development of increasing arterial stiffness (high PWV) and altered wave reflections with aging completely abolishes the differences between central and peripheral PP by the age of 50-60 years, with major consequences on ventricular load and coronary perfusion. The increased PWV means that the reflected waves return to the aortic root earlier, during late systole. In this case, the reflected waves summate with the forward-traveling wave to create an increased “augmentation” in central SBP and ventricular load (Figure 3, lower part). Central SBP and PP, and also the disappearance of PP amplification, are thus the more significant predictors of CV risk.8 In elderly persons with isolated systolic hypertension, aortic SBP can be elevated by 30-40 mm Hg as a result of the early return of wave reflections.2,3 Furthermore, because the backward pressure returns in systole, and not in diastole, as a consequence of enhanced PWV, DBP and coronary blood flow tend to be reduced, a situation promoting coronary ischemia. It can be noted that, in clinical practice, several factors can modulate the transit of wave reflections and thus central SBP and PP. First, reduced heart rate shifts wave reflections from diastole to systole, thus increasing “augmentation pressure” and central SBP.7 Second, angiotensin II inhibition and calcium blockade as well as insulin administration reduce wave reflections and central SBP.9 Insulin resistance has a reverse effect on central wave reflections.

_Modulation of aortic stiffness and wave reflections
In the long term, mechanical forces (shear or tensile stress) participate in the modulation of arterial stiffness, wall thickness, and wave reflections. In the absence of drug treatment, hypertensive remodeling is characterized, according to the Laplace law, by an increased wall/lumen ratio of arteries and arterioles, which represent the main site of vascular resistance and microcirculation, but also the origin of wave reflections.10-13 Druginduced regression of arteriolar hypertrophy is associated with a reduction in vascular resistance and reflection coefficients, thereby attenuating wave reflections, and, in the end, decreasing central SBP and PP.11-13 This process becomes significant approximately 1 year after the beginning of drug treatment of hypertensive subjects. Reduction of arteriolar hypertrophy is consistently obtained with angiotensin or calcium blockade, but never with â-blocking agents or hydrochlorothiazide.12 Endothelial dysfunction may affect this process, mainly through attenuation of NO dysfunction and/or oxidative stress under drug treatment.2,3,10-14

Pulsatile arterial hemodynamics and the basis of risk-reduction strategies in hypertension Risk reduction strategies should reduce together and independently increased MAP and PP. While the latter is principally sensitive to angiotensin II blockade alone, the former requires the addition of diuretics and/or calcium channel blockers, but not of traditional â-blocking agents (with the exception of coronary ischemic disease). This entire process is explained.

_ Importance of angiotensin blockade Renin-angiotensin system blockade either by angiotensin-converting enzyme (ACE) inhibition or, to a lesser extent, AT1 receptor blockade is classically associated with reductions of vascular resistance and MAP. However, the effects on aortic PWV and central and peripheral PP have been incompletely investigated until recently, but are important to develop.

Studies on animal models and hypertensive subjects have shown that angiotensin II blockade, mainly with the ACE inhibitor perindopril, is associated with reverse remodeling of both small and large arteries via specific mechanisms, including anti-inflammatory and antifibrotic effects as well as changes in arterial attachments linking á5â1-integrin to its specific ligand fibronectin.15-17 These mechanisms are very important to consider in order to obtain a significant and selective reduction in central PP and arterial stiffness with angiotensin II blockade. Their effect on mechanotransduction is primarily subject to the mitogen-activated protein kinase system.

In hypertensive rats fed a low-salt diet, angiotensin II blockade by the angiotensin receptor blocker (ARB) valsartan normalizes central PP (<50 mm Hg), whereas MAP is not normalized (>100 mm Hg) with the same drug dosage.15,16 Furthermore, in hypertensive subjects under angiotensin II blockade with a normal sodium diet, not only is PWV decreased, but central BP and wave reflections are also attenuated and carotid-brachial SBP and PP amplifications are increased. Angiotensin II blockade improves or even normalizes the wall thickness of small resistance arteries and, at the same time, reduces carotid wave reflections, suggesting a cause-and-effect relationship between the two factors. This is the basis of all the new strategies using destiffening drug therapy.1-3

However, to further reduce MAP, angiotensin blockade may be given in combination either with diuretics or calcium channel blockers (CCBs), but not usually with conventional â-blockers, as described below.

Figure 4
Figure 4. Change in MBP and aortic PWV with drug treatment in endstage renal disease patients. On the left, surviving patients have a parallel and significant decrease in MBP and PWV. On the right, deceased patients are characterized by decreased MBP, but increased PWV.
Abbreviations: BP, blood pressure; MBP, mean blood pressure; PWV, pulse wave
Modified from reference 18: Guerin et al. Circulation. 2001;103: 987-992. © 2001,
American Heart Association, Inc.

_ Angiotensin II blockade and diuretics
The main therapeutic trial demonstrating the predictive role of aortic stiffness in hypertensive subjects was conducted in end-stage renal disease patients on hemodialysis.18 The objective was to lower CV morbidity and mortality through a therapeutic regimen involving successively: salt and water depletion by dialysis; then, after randomization, an ACE inhibitor or CCB; and, finally, the combination of the two agents and/or their association with a â-blocker. Using this protocol, it was possible to evaluate with long-term follow-up (51 months) whether or not the drug-induced mean blood pressure (MBP) reduction was associated with a concomitant decrease in arterial stiffness impacting on CV risk.

During follow-up, it was clearly shown that in survivors, MBP, brachial PP, and aortic PWV were concomitantly lower (Figure 4). In contrast, for patients who died from CV events, MBP had been reduced to the same extent as in survivors, but neither PWV nor brachial PP had been significantly modified by drug treatment (Figure 4). Thus, survival in end-stage renal disease patients was significantly better when aortic PWV declined in response to BP lowering. The adjusted relative risks for all-cause and CV mortality rates in those with unchanged PWV in response to BP changes were: 2.59 (95% confidence interval [CI], 1.51 to 4.43) and 2.35, respectively (95% CI, 1.23 to 4.51); P<0.01. The prognostic value of PWV sensitivity to BP reduction on survival was independent of age, BP changes, and blood-chemistry abnormalities. The results indicated that arterial stiffness was not only a risk factor contributing to the development of CV disease, but also a marker of established, more advanced, and less reversible arterial lesions. Finally, in this trial, survival seemed to be more closely associated with the use of an ACE inhibitor than other drugs. The use of â-blockers and/or CCB had no direct impact on the outcomes.18 The Complior study was the first study to show the feasibility of a large-scale interventional trial using PWV as the end point in 1703 hypertensive patients (mean age 50±12 years old; mean baseline SBP, 158±15 mm Hg; mean baseline DBP, 98±7 mm Hg; mean baseline carotid-femoral PWV, 11.6±2.4 m/s). Patients were treated for 6 months with the ACE inhibitor perindopril, adding indapamide if BP still was above 140/90 mm Hg. Significant decreases (P<0.001) in BP (SBP, –23.7±16.8 mm Hg; DBP, –14.6±10 mm Hg) and carotid-femoral PWV (–1.1±1.4 m/s) were obtained at 2 and 6 months.19 The REASON (pREterax in regression of Arterial Stiffness in a contrOlled double- bliNd study) study11,20 was the first trial to investigate the long-term interactions between central PP, arterial stiffness, and wave reflections, on the one hand, and drug treatment or end-organ damage (cardiac mass) of hypertensive subjects inmiddle age, on the other hand. The ACE inhibitor perindopril, combined with low-dose indapamide, was compared for 1 year of treatment with the â-blocker atenolol. For the same DBP and MBP decreases, perindopril/indapamide lowered SBP and PP more than atenolol. This finding was observed using not only routine BP measurement, but also 24-hour BP measurements.21 The reduction was more pronounced centrally (carotid artery) than peripherally (brachial artery). While the two drug regimens lowered PWV equally, only perindopril/indapamide (and not atenolol) reduced central PP and AIx (Figure 3).11,20 In addition, perindopril/indapamide decreased cardiac hypertrophy more than atenolol, and that decrease was attributed to the augmentation index (AIx) decrease, indicating that reduction of cardiac end-organ damage was mainly associated with a reduction of central SBP, PP, and wave reflections.11,20 In contrast, atenolol increased wave reflections and AIx through reduction of heart rate and a shift of the backward pressure wave from diastole to systole, thus excluding this drug from the destiffening strategy. Similar findings were observed when atenolol was compared to the ARB irbesartan.22 Figure 5
Figure 5. Effect of amlodipine±perindopril versus atenolol±bendroflumethiazide on central aortic blood pressure. Results of the ASCOT-CAFE study.
Abbreviations: ASCOT-CAFE, Anglo-Scandinavian Cardiac Outcomes Trial–Conduit Artery Function Evaluation; PP, pulse pressure.
Modified from reference 23: Williams et al. Circulation. 2006;113:1213-1225. © 2006, American Heart Association, Inc.