Michel E. Safar and Alberto Avolio doi: 10.1161/01.HYP.0000112026.60309.32

Letter: Aldosterone Antagonism and Arterial Stiffness
Michel E. Safar and Alberto Avolio
Hypertension. 2004;43:e3; originally published online December 29, 2003;
doi: 10.1161/01.HYP.0000112026.60309.32
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Letters to the Editor
Letters to the Editor will be published, if suitable, as space permits. They should not exceed 1000 words
(typed double-spaced) in length and may be subject to editing or abridgment.
Aldosterone Antagonism and Arterial Stiffness
To the Editor:
We wish to congratulate White et al1 for their evaluation of the
effects of the comparative aldosterone blocker eplerenone versus
the calcium antagonist amlodipine in old subjects with systolic
hypertension. Until recently, eplerenone was presented as a
standard antihypertensive agent, acting mainly on diastolic blood
pressure, but with limited affinity for the progesterone and
androgen receptors as the main interest. Nevertheless, based on
previously published data in animal and human hypertension,
there were several lines of direct evidence that eplerenone might
act more selectively on systolic and pulse pressures through
specific effects on the large artery wall. First, in hypertensive
rats, spironolactone is known to prevent aortic collagen accumulation and reduce aortic stiffness.2 Second, in rats on a highsodium diet, chronic aldosterone administration increases the
stiffness of the aortic wall material, independently of mechanical
stress, a process completely reversed by eplerenone.3 Finally, in
hypertensive subjects, increased plasma aldosterone and increased arterial stiffness are positively correlated independent of
blood pressure level.4
In the study of White et al,1 several particularities of the
protocol may have minimized the effects of eplerenone on
hypertensive conduit arteries. Effectively, although the 2 drugs
caused the same systolic blood pressure reduction, amlodipine
reduced more diastolic blood pressure than eplerenone. This
difference may be due either to a higher vasodilating effect of
amlodipine on small arteries or to a more pronounced effect of
eplerenone on large artery elasticity. In other words, it is
important to verify in each group of the trial whether the diastolic
blood pressure reduction was influenced by baseline pulse wave
velocity. Indeed, in the Ephesus study,5 subjects who had the
more important reduction of cardiovascular mortality under
eplerenone were those with the higher baseline pulse pressure. In
the work by White et al,1 it is noteworthy that baseline carotidfemoral pulse wave velocity was the “gold standard” to evaluate
arterial stiffness. Indeed, the baseline values of carotid-radial
pulse wave velocity given by the authors were below those of
carotid-femoral pulse wave velocity, which is completely not
usual6 and possibly a typing error.
In the study by White et al,1 there are several other reasons that
the effects of eplerenone on large arteries had been minimized.
First, because, based on the literature, the effects of eplerenone
seem to predominate on structural (aortic collagen accumulation)
rather functional arterial changes, it is possible that the duration
of follow-up (24 weeks) was too short to compare eplerenone
and amlodipine on the basis of systolic blood pressure reduction.
In the Reason project, the selective effect of the perindoprilindapamide combination on systolic blood pressure was achieved
only after a 1-year follow-up.7 Second, the evaluation of the
changes in conduit arteries under eplerenone involved only pulse
wave velocity measurements in a sample of the population and
needs also determinations of wave reflections and central blood
pressure.6,7
Michel E. Safar
Diagnostic Center, Hotel-Dieu Hospital
Paris, France
Alberto Avolio
University of New South Wales
Sydney, Australia
1. White WB, Duprez D, St Hilaire R, Krause S, Roniker B, Kuse-Hamilton
J, Weber MA. Effects of the selective aldosterone blocker eplerenone
versus the calcium antagonist amlodipine in systolic hypertension. Hypertension. 2003;41:1021–1026.
2. Benetos A, Lacolley P, Safar ME. Prevention of aortic fibrosis by spironolactone in spontaneously hypertensive rats. Arterioscler Thromb
Vasc Biol. 1997;17:1152–1156.
3. Lacolley P, Labat C, Pujol A, Delcayre C, Benetos A, Safar M. Increased
carotid wall elastic modulus and fibronectin in aldosterone-salt-treated
rats. Circulation. 2002;106:2848 –2853.
4. Blacher J, Amah G, Girerd X, Kheder A, Ben Maı̈z H, London GM, Safar
ME. Association between increased plasma levels of aldosterone and
decreased systemic arterial compliance in subjects with essential hypertension. Am J Hypertens. 1997;10:1326 –1334.
5. Pitt B, Remme W, Zannad F, Neaton J, Martinez F, Roniker B, Bittman
R, Hurley S, Kleiman J, Gatlin M. Eplerenone, a selective aldosterone
blocker, in patients with left ventricular dysfunction after myocardial
infarction. N Engl J Med. 2003;348:1309 –1321.
6. Avolio AP, Chen SG, Wang RP, Zhang CL, Li MF, O’Rourke MF.
Effects of aging on changing arterial compliance and left ventricular load
in a northern Chines urban community. Circulation. 1983;68;50 –58.
7. Asmar RG, London GM, O’Rourke ME, Safar ME. Improvement in
blood pressure, arterial stiffness and wave reflections with a verylow-dose perindopril/indapamide combination in hypertensive patient.
Hypertension. 2001;38:922–926.
Response
We appreciate the comments by Drs Safar and Avolio regarding our publication from earlier this year.1 As noted, both
eplerenone and amlodipine were highly effective agents in
reducing systolic blood pressure (BP) in older patients with
hypertension. Furthermore, they were both associated with significant changes from baseline in pulse wave velocity. The
authors noted that amlodipine induced slightly larger changes
from baseline in clinic diastolic BP compared with eplerenone.
However, the difference in ambulatory diastolic BP reductions
between these 2 agents was just 3 mm Hg, which did not reach
statistical significance. Thus, the clinical and physiologic significance of this small reduction in diastolic BP in relation to pulse
wave velocity is not known. In any event, other studies have
shown that aldosterone plays a major role in arterial stiffness,
independent of the level of systemic BP in both arterial hypertension as well as in congestive heart failure.2,3
In regard to the pulse wave velocity substudy, there were no
baseline differences for either the carotid-femoral or the carotidradial measurements between treatment groups. Furthermore, the
baseline values for carotid-femoral and carotid-radial velocities
were not stated incorrectly. It was noteworthy that there was a
progressively lower carotid-femoral pulse wave velocity after 24
weeks of eplerenone treatment than there was at the 14-week
period. Thus, one might speculate that antagonizing the detrimental effect of aldosterone by eplerenone for a longer period
could have had a more beneficial effect on arterial elasticity.
More pronounced results have been obtained in animals exposed
to long-term aldosterone administration and a high-sodium diet,
with and without eplerenone, than were found in our study of
humans with systolic hypertension4; however, it is not presently
possible to speculate on the etiology of these differences.
As the authors of this letter note, we also recognize that there
are a variety of techniques to evaluate the conduit arteries as well
as to study wave reflections. Furthermore, there is even recent
evidence that peripheral BP measurement might be as good as
applanation tonometry in predicting BP in the ascending aorta.5
1
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2
Letter to the Editor
William B. White
Section of Hypertension and Clinical Pharmacology
University of Connecticut School of Medicine
Farmington, Conn
Daniel Duprez
Division of Cardiology
University of Minnesota School of Medicine
Minneapolis, Minn
1. White WB, Duprez D, St Hilaire R, Krause S, Roniker B, Kuse-Hamilton
J, Weber MA. Effects on the selective aldosterone blocker eplerenone
versus the calcium antagonist amlodipine in systolic hypertension. Hypertension. 2003;41:1021–1026.
2. Duprez DA, De Buyzere M, De Backer T, Kaufman JM, Van Hoecke J,
Vermeulen A, Clement C. Influence of the arterial blood pressure and
nonhemodynamic factors on the brachial artery pulsatility index in mildto-moderate essential hypertension. Am J Cardiol. 1993;71:350 –353.
3. Duprez DA, De Buyzere M, Rietzschel E, Kaufman JM, Clement DL,
Morgan D, Cohn J. Relationship between aldosterone and arterial compliance in chronically treated heart failure patients. Eur Heart J. 1998;
19:1371–1376.
4. Lacolley P, Labat C, Pujkol A, Delcayre C, Benetos A, Safar M.
Increased carotid wall elastic modulus and fibronectin in aldosterone-salttreated rats. Circulation. 2002;106:2848 –2853.
5. Davies JI, Band MM, Pringle S, Ogston S, Struthers AD. Peripheral blood
pressure measurement is as good as applanation tonometry at predicting
ascending aortic blood pressure. J Hypertens. 2003;21:571–576.
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