Antihypertensive strategies to reverse arterial wall modifications






Charalambos VLACHOPOULOS, MD
Dimitrios TERENTES-PRINTZIOS, MD
Hypertension Unit and Peripheral Vessels Unit, 1st Department of Cardiology, Hippokration Hospital
Athens Medical School
Athens, GREECE

Antihypertensive strategies to reverse arterial wall modificationsy


by C. Vlachopoulos and D. Terentes-Printzios, Greece



Among other promising biomarkers of cardiovascular disease that are related to arterial wall structure and function, aortic stiffness has proven to be an important asset for the assessment of cardiovascular risk. While hypertension may lead by itself to arterial stiffening, it is aortic stiffness that primarily leads to the development of hypertension. Of the different approaches for estimating arterial stiffness, aortic stiffness assessed by carotid-femoral pulse wave velocity has emerged as the gold standard method because of the wealth of evidence demonstrating its association with cardiovascular hard end points in different populations and disease states, including hypertensive populations, over and beyond traditional risk factors. Recent studies with pharmacological and nonpharmacological antihypertensive interventions suggest that aortic stiffening is a dynamic and modifiable target that could be useful for identifying hypertensive patients at high risk for cardiovascular events, monitoring treatment efficacy, and serving as a treatment target in hypertension. Of the antihypertensive agents available, renin-angiotensin- aldosterone system blockers are the most effective in reducing arterial stiffness in a blood pressure–independent manner. Calcium channel blockers exert beneficial effects on arterial stiffness. Data on β-blockers are equivocal; β-blockers with vasodilating properties show a superior overall profile. Diuretics may reduce arterial stiffness, mainly through blood pressure reduction. The impact of attenuating arterial stiffness on prognosis has been shown in end-stage renal disease, but more studies are warranted in other disease states and populations.

Medicographia. 2015;37:404-411 (see French abstract on page 411)


Aortic stiffness in hypertension: why we should care

Many arterial biomarkers, such as ankle-brachial index, carotid intima-media thickness, and endothelial function, have been proposed for clinical use in hypertensive populations.1-5 Of these, the biomarker that has shown essential pathophysiological, clinical, and prognostic links with hypertension is arterial stiffness. While a wealth of data relates to aortic stiffness, promising results have also been produced by assessment of arterial stiffness in other arteries, such as the carotid and femoral.6,7 Aortic pulse wave velocity (PWV), considered the “gold-standard” measure of arterial stiffness, can be measured easily and noninvasively by a variety of methods.1,2 The mechanisms of aortic stiffening are complex and depend on the underlying disease. Age and blood pressure are the major determinants of aortic stiffness.8,9 The relationship between aortic stiffness and hypertension is bidirectional. Hypertension can cause stiffening through both functional and structural mechanisms. Stiffening of elastic tubes (arteries in our case) is increased as distending pressure increases due to hydraulic laws. From a structural standpoint, while thinning, splitting, fraying, and fragmentation of elastic fibers are consequences primarily of aging, sustained hypertension is a cause of the rearrangement of arterial wall elements and changes in their relative composition. evidence from the Framingham Heart Study suggests that higher blood pressure levels can accelerate aortic stiffening, giving rise to a vicious cycle of accelerated hypertension and further stiffening of large arteries.10 Moreover, annual increases in PWV are higher in hypertensive subjects, suggesting early development of stiffness.11 However, the other side of the bidirectional relationship between aortic stiffness and hypertension is more intriguing and important. Indeed, substantial data show that aortic stiffening in normotensive individuals was a predictor of increased systolic blood pressure and development of hypertension.12

PWV has been shown in large studies to be a marker of increased cardiovascular risk and to improve risk prediction in addition to, and beyond, traditional risk factors.3-5 One of the first studies on the prognostic role of PWV was conducted in hypertensive patients, and it demonstrated the independent role of PWV in predicting both all-cause and cardiovascular mortality.13 In the Framingham Heart Study, higher PWV was found to be associated with a 48% increase in the risk of incident cardiovascular events.4 In a meta-analysis of 17 published studies,3 aortic PWV data from 15 877 subjects followed up for a mean of 7.7 years were compiled. Subjects from the general population and patients with hypertension, diabetes, end-stage renal disease, and coronary artery disease were included. Aortic stiffness was found to be a strong predictor of future cardiovascular events and all-cause mortality; an increase in aortic PWV of 1 m/s was associated with an increase in the risk of total cardiovascular events, cardiovascular mortality, and all-cause mortality of 14%, 15%, and 15%, respectively, after adjustment for age, gender, and cardiovascular risk factors. The results of this meta-analysis were confirmed by another recent meta-analysis5 with individual data from 17 635 subjects, where the addition of PWV improved risk prediction by 13% (Figure 1).14 Of note, reference values and cut-off points, along with a standardized method of PWV assessment, were recently published to facilitate the clinical integration of aortic stiffness in everyday practice.1,15,16 Taken together, this piece of evidence led the European Society of Cardiology/European Society of Hypertension to recommend aortic PWV for the evaluation of the hypertensive patient (level of evidence IIa).17





From a therapeutic standpoint, aortic stiffness is a worthwhile treatment target. Several studies have investigated the effects of different pharmaceutical agents on aortic stiffness.18-20 These studies can be grouped according to the length of intervention, as acute, short/medium-term (<3 months), or long term (>3 months). Earlier effects are usually due to smooth muscle cell relaxation, while longer-term effects involve distinct components of the arterial wall and changes in the geometry of the vessel. Of special interest are comparative studies between different classes of agents that are scarce and, in most cases, underpowered to provide conclusive results. In general, renin-angiotensin-aldosterone system (rAAS) blockers and calcium channel blockers have produced better results than diuretics and β-blockers.18


Figure 1
Figure 1. Relative risk (RR) and 95% confidence interval (CI) for a
1–standard-deviation increase in aortic pulse wave velocity and
clinical events.

Abbreviation: CV, cardiovascular.
Adapted from reference 14: Vlachopoulos et al. J Am Coll Cardiol. 2014;63:
647-649. © 2014, American College of Cardiology Foundation.



Despite strong pathophysiological links, the question of whether amelioration of aortic stiffening leads to an improvement in prognosis has not yet been proven beyond doubt. To date, there has only been one study,21 in end-stage renal disease patients, showing that improvement in outcome was mediated through an improvement in aortic stiffness (Figure 2).21 More studies are needed to confirm these promising results, and ongoing studies such as SPARTE (Stratégie de Prévention Cardiovasculaire Basée sur la Rigidité Arterielle) will further elaborate the role of PWV as a therapeutic target.22

Summarized below is current evidence on the effect of different antihypertensive agents on arterial stiffness, with emphasis on pathophysiological mechanisms. Areas for future research have also been highlighted.

Pathophysiological mechanisms of arterial stiffness in hypertension and in antihypertensive treatment

When trying to put the effects of drugs into clinical perspective, several issues should be considered.

Interpretation of effects
First, duration of drug administration is of the essence.18-20 Acute effects of drug intervention should not be extrapolated to imply long-term efficacy, and it should not be forgotten that long-term administration may be required to induce changes. Equally important is the dose of the administered drug; favorable effects are usually observed with higher rather than lower doses.23


Pressure dependency/independency
The changes that a drug induces in the stiffness of the aorta (an elastic artery) may be indirect, ie, due to reduction in blood pressure (pressure-dependent), since elastic tubes reduce their stiffness when the distending pressure inside them is reduced. Blood pressure reduction in this case occurs in part through a decrease in wave reflections in response to the dilation of small resistant arteries. On the other hand, effects may be direct (pressure-independent), occurring via alteration of arterial wall elastic components, ie, medial smooth muscle cells (mainly acute changes) or elastin and collagen (chronic changes). Pressure-dependent effects are usually acute, while pressure-independent effects occur with long-term treatment. Contrary to elastic-type arteries, muscular arteries (such as the brachial artery) contribute a small percentage of total arterial stiffness. Furthermore, their stiffness is less prone to increase with age, unlike larger elastic-type arteries. However, modification of their stiffness through smooth muscle relaxation can reduce wave reflection and reduce stiffness of large arteries in a pressure-dependent way. A final, important point to emphasize is that the effects of a drug on a specific type of artery (eg, elastic-type, like the aorta or carotid artery) cannot be directly extrapolated to another type of artery (eg, muscular- type, like the brachial or radial artery), since agents may act preferentially on specific wall elements.

Effects at the cellular level
Depending on the specific pharmaceutical agent, the underlying mechanism at the cellular level varies, and often the result is a combination of different mechanisms.19,20 Low-grade inflammation has been associated with both chronic arterial stiffening (via inflammatory markers/mediators) and acute arterial stiffening (via cause-and-effect associations).24 Interestingly, RAAS blockers may additionally exert anti-inflammatory effects. Moreover, endothelial function has an important regulatory role in PWV; thus improvement of endothelial function by drugs such as RAAS blockers may explain their effects. Genetic predisposition may also play its part, since findings that a reduction in PWV in response to angiotensin-converting enzyme (ACE) inhibition depends on AT1 (angiotensin II receptor type 1) gene polymorphisms support the involvement of genetic background. Collagen turnover has also been implicated, as angiotensin II stimulates the production of various types of collagen fibers. Inhibition of aldosterone, a potent activator of fibrosis, may also be involved.


Table I
Table I. Antihypertensive treatments and their effects on arterial
stiffness.

Key for effect on arterial stiffness: beneficial,●; neutral,●; deleterious,●.
Abbreviations: ACE, angiotensin-converting enzyme; AT1, angiotensin II receptor
type 1; PDE5, phosphodiesterase type 5.
Modified from reference 2: Laurent et al. Eur Heart J. 2006;27:2588-2605.
© 2006, The European Society of Cardiology.


Effects of different antihypertensive agents on arterial stiffness

Despite the fact that all antihypertensive agents have a direct and substantial effect on lowering blood pressure, their effects on arterial stiffness are more complex (Table I, Figure 3).2

Renin-angiotensin-aldosterone system (RAAS) blockade
ACE inhibitors
ACE inhibitors are the oldest and best-studied class of RAAS inhibitors. Acute beneficial effects of ACE inhibitors have been well established. As regards mid- and long-term effects, a significant body of studies suggests that the reduction of aortic stiffness may be, in part, independent of blood pressure lowering in hypertensive patients.25

Several initial experimental studies supported the hypothesis that RAAS promotes arterial stiffening by regulating both the composition of the vascular extracellular matrix, as a potent profibrotic system, and vascular tone.18 Drugs acting on the RAAS appear to have a greater effect on arterial stiffness (independent of blood pressure lowering) than other classes of drugs. This is also consistent with the fact that these regimens can control fibronectin expression together with vascular tone.

In the Complior study (2187 patients with essential hypertension), treatment with perindopril significantly decreased carotid femoral PWV at 2 months, an effect that was still present 6 months after starting treatment.26 Other studies with ACE inhibitors have also shown reductions in large artery stiffness independent of blood pressure change, implying a beneficial class effect. A meta-analysis confirmed that ACE inhibitors are associated with beneficial effects on PWV as well as on aortic augmentation index (AIx), an index of wave reflections.27


Figure 3
Figure 3. Effect of different classes of antihypertensive agents on
arterial stiffness. The width of the arrows represents the size effect
on arterial stiffness and the darkness of the arrows, the degree
of blood pressure–independent effects on top of effects dependent
on blood pressure reduction (darker arrows imply more
blood pressure–independent effects).



Moreover, recent studies have shown that blood pressure– independent changes in aortic stiffness are feasible with most antihypertensive drugs, but predominantly with RAAS inhibitors, and that these changes are amplified with a higher dose and long-term treatment.25 Plausible explanations for these results are the delayed response to the long-term normalization of blood pressure and cardiovascular risk factors and the slow turnover rate of the extracellular matrix with arterial remodeling. Results extend to all types of arteries and are generally not related to a specific agent. Perindopril reduced stiffness of the carotid artery in hypertensive patients with type 2 diabetes with long-term administration, a finding that was dose-dependent and blood pressure–independent, indicating favorable effects with high-dose perindopril via inward remodeling.28 These results were corroborated by two meta-analyses that showed that long-term administration of treatment, including ACE inhibitors, has a beneficial blood pressure– independent effect on aortic stiffness (Figure 4, page 408).25,29


Two essential prospective long-term studies investigated whether arterial stiffness and wave reflections indices had an effect on cardiovascular events (in the CAFE [Conduit Artery Function evaluation] study,30 an ancillary study of ASCOT [Anglo- Scandinavian Cardiac Outcomes Trial]) or surrogate end points, such as blood pressure in REASON(pREterax in regression of Arterial Stiffness in a contrOlled double-bliNd study).31 Both favored the use of ACE inhibitors. In the CAFE study, amlodipine± perindopril was superior to atenolol±bendroflumethiazide in reducing central pressures and wave reflection indices, despite similar reduction in blood pressures at the brachial level and no change in aortic stiffness. Specifically, aortic systolic pressure was some 4.3 mm Hg lower, and aortic pulse pressure 3.0 mm Hg lower in those randomized to the amlodipine±perindopril regimen (Figure 5).30 Although modest, this differential effect could explain most of the observed difference in outcome in the main ASCOT study. Wave reflection indices are determined by aortic stiffness, which affects the timing of the merging of the incident and reflected wave by modifying PWV. However, indices of wave reflection are also determined by the balance between vasoconstriction and vasodilation in the peripheral circulation, which affects the magnitude of the reflected wave. Accordingly, changes in wave reflection indices by drugs do not necessarily imply modification of aortic stiffness and thus cannot be used interchangeably.24 These results underline that aortic stiffness and wave reflections do not always change in parallel or to the same degree, and they may have different clinical value. In the REASON study,31 the combination of perindopril/indapamide produced larger decreases in systolic blood pressure than atenolol. This was attributed to superior reduction in wave reflections with the perindopril/indapamide combination, as reduction in PWV was similar with the two regimens. This hemodynamic superiority of the combination is believed to translate into survival improvement in hypertensive patients with high cardiovascular risk.

Angiotensin II receptor type 1
(AT1 receptor) blockers
AT1 receptor blockers also improve aortic stiffness to an extent that is comparable, and often additive, to that of ACE inhibitors. Data support a reduction in arterial stiffness independent of blood pressure changes with both short- and long-term treatment.23 However, it must be stressed that despite the fact that combining ACE inhibitors and AT1 receptor blockers produced appealing aortic stiffness results in hypertension,32 these results were not associated with clinical benefit in large survival studies like ONTARGET (ONgoing Telmisartan Alone and in combination with Ramipril Global endpoint Trial), due to the increased risk of adverse reactions with the drugs.33 On the other hand, a combination of an AT1 receptor blocker with a calcium channel blocker has shown evident superiority compared with a β-blocker/calcium channel blocker combination.34


Direct renin inhibitors
The direct renin inhibitor aliskiren has been shown to decrease aortic stiffness when administered in hypertensive patients.35

However, not only does it not seem to provide any additional clinical prognostic benefit beyond that of existing antihypertensive therapies, but it might even be harmful.

Calcium channel blockers
Calcium channel blockers differ substantially to ACE inhibitors in their mechanisms of action, and the effect of calcium channel blockers on aortic stiffness compared to ACE inhibitors is somewhat smaller.18-20 Dihydropyridines are the best-studied agents, especially amlodipine.

Diuretics
Studies on the effect of diuretics on aortic stiffness have provided mixed results, both neutral and positive.18-20 Diuretics appear to reduce wave reflections; however, this has not been shown in all studies. In elderly patients with isolated systolic hypertension, hydrochlorothiazide in combination with amiloride was equally effective to ACE inhibitors in reducing arterial stiffness; this effect was mediated through blood pressure reduction.36 While the combination of diuretics with AT1 receptor blockers or ACE inhibitors has an additive effect in improving arterial stiffness, the combination of AT1 receptor blockers or ACE inhibitors with calcium channel blockers seems to provide greater improvement.19,20

Aldosterone levels are associated with arterial stiffness in hypertensive patients. eplerenone, a highly selective aldosterone antagonist, was as effective as amlodipine in reducing PWV in elderly hypertensive patients.18,20 Another aldosterone antagonist, spironolactone, has been shown to reduce aortic PWV in a partially blood pressure–independent manner without changing brachial artery stiffness.18,20 The beneficial effect of spironolactone has been confirmed in dilated cardiomyopathy, as well as in chronic kidney disease.37

Β-Blockers
Most studies suggest that β-blockers reduce aortic stiffness18-20 in a pressure-dependent way, most likely due to an increase in systolic ejection time and a decrease in dP/dt.38 It is easier for an aorta to accommodate a stroke volume that is ejected at a lower pace and does not lead to an increase in distending pressure. However, β-blockers increase wave reflection indices by increasing systolic and diastolic period, thus allowing the reflected wave to return to the aorta at a relatively earlier point in the cardiac cycle (in systole instead of diastole). Additionally, they may increase wave reflections by peripheral vasoconstriction, as with atenolol. Nevertheless, data suggest that the case may be different for β-blockers with direct vasodilating properties (carvedilol, dilevalol) or those that are nitric oxide (NO) donors, such as nebivolol. In several studies, nonvasodilating β-blockers, such as atenolol, have been shown to be less successful than vasodilating drugs— such as calcium channel blockers, RAAS antagonists, or other β-blockers such as nebivolol (a selective β1-receptor blocker with a NO-potentiated vasodilatory effect)—in reducing wave reflections and central hemodynamics, although aortic stiffness seems to be similarly reduced with all these drug classes.

The REASON trial, which compared a perindopril/indapamide combination with atenolol, showed that normalization of brachial systolic blood pressure is achieved with a significantly greater reduction in carotid systolic blood pressure after a 12-month treatment with the combination. This suggests that brachial measurements tend to underestimate the effect of the combination on aortic systolic pressure.39 In the same study, the perindopril/indapamide combination was associated with a greater loss in left ventricular mass, compared with atenolol, and this was related to carotid, but not brachial, blood pressure.

Other antihypertensive agents
Data on α-blockers are scarce. However, doxazosin, the most investigated drug in this class, showed a modest favorable effect on arterial stiffness. Nitrates have a beneficial effect, predominantly on muscular arteries. Sildenafil and vardenafil, phosphodiesterase type 5 inhibitors prescribed for erectile dysfunction and primary pulmonary hypertension, produced mainly beneficial results in decreasing aortic stiffness after short and medium-term administration, respectively.40,41

Effect of antihypertensive treatment on arterial stiffness and prognosis

While aortic stiffness provides useful prognostic information regarding cardiovascular events, evidence for the value of aortic stiffness for the reduction in cardiovascular events in patients on treatment is less well founded. The relevant, key question is whether a reduction in indices, such as PWV, is associated with a concomitant reduction in cardiovascular events, independently of the normalization of classic cardiovascular risk factors. To date, the only evidence for the predictive value of attenuating aortic stiffness for the reduction of cardiovascular events has been provided by Guerin et al in end-stage renal disease patients,21 in whom insensitivity of PWV to reduced blood pressure was an independent predictor of mortality.

Furthermore, it must be noted that in two recent studies, in which central blood pressures and AIx were used as therapeutic targets in hypertensive and heart failure patients, respectively,42,43 there were modest but clinically apparent benefits for the patients. Clearly, there is a need for studies addressing this key question in the general population, populations with risk factors, and populations with other disease states, such as hypertension (currently under investigation in the ongoing SPARTE study).

Conclusions

Aortic stiffness is an indicator of target-organ damage in hypertensive patients and a prominent biomarker of cardiovascular risk. While there are ample double-blind, randomized, controlled trials attesting to the beneficial effect of pharmacological antihypertensive interventions on arterial stiffness, they suffer from a relatively small number of subjects, short follow-up periods, and lack of hard end points. Further large prospective studies with PWV-guided therapy are warranted to confirm the clinical applicability of these findings in everyday practice. Nevertheless, differences in the effects of several pharmacological agents on arterial stiffness form a partial basis for explaining the results of large prospective survival studies that demonstrated superior cardiovascular risk reduction with RAAS blockers and calcium channel blockers compared with diuretics and β-blockers. Arterial stiffness is emerging as a valuable surrogate end point and treatment target.


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Keywords: arterial stiffness; pulse wave velocity; wave reflections; central blood pressure; cardiovascular risk; hypertension; angiotensin