Download Differential Effects of Antihypertensive Drug Therapy on Arterial

AJH
2002; 15:1096 –1100
Differential Effects of Antihypertensive
Drug Therapy on Arterial Compliance
Lawrence M. Resnick and Melvin H. Lester
Although vascular compliance, ⌬V/⌬P, is abnormal in
essential hypertension and can be improved by antihypertensive drug therapy, it is not clear whether drug-induced
changes in compliance are attributable solely to lower
achieved blood pressure (BP), and thus equally likely with
different drugs possessing similar antihypertensive efficacy. Therefore, we used computerized arterial pulse
waveform analysis (CAPWA) to measure capacitive (C1)
and oscillatory (C2) components of arterial compliance in
essential hypertensive subjects (n ⫽ 39) before, and 1 and
3 months after achieving normotensive BP values with
administration of either dihydropyridine calcium channel
antagonists (CaBl, n ⫽ 11), converting enzyme inhibitors
(CEI, n ⫽ 9), angiotensin receptor blockers (ARB, n ⫽ 9),
or ␤-blockers (BBl, n ⫽ 10).
Despite equivalent effects on BP (CaBl: ⫺19 ⫾ 4/⫺15
⫾ 2 mm Hg; CEI: ⫺12 ⫾ 3/⫺13 ⫾ 2 mm Hg; ARB: ⫺10
⫾ 3/⫺12 ⫾ 2 mm Hg; and BBl: ⫺14 ⫾ 3/⫺12 ⫾ 2 mm
C
Hg; P ⬍ .005 for each drug v pretreatment), CaBl, CEI,
and ARB significantly increased arterial compliance
(CaBl: %⌬C1 ⫽ 30.0 ⫾ 5.8, %⌬ C2 ⫽ 43.7 ⫾ 23.3; CEI:
%⌬C1 ⫽ 32.7 ⫾ 5.4, %⌬C2 ⫽ 26.7 ⫾ 7.1; ARB: %⌬C1
⫽ 36.3 ⫾ 11.8, %⌬C2 ⫽ 43.6 ⫾ 23.1; P ⬍ .01 for CaBl,
CEI, and ARB v pretreatment), but BBl did not (%⌬C1 ⫽
⫺3.9 ⫾ 7.6, %⌬C2 ⫽ ⫺7.0 ⫾ 11.5, P ⫽ not significant v
pretreatment, sig ⫽ 0.01 v other drugs). We conclude that
for an equivalent effect on BP, arterial compliance improves after therapy with some, but not all antihypertensive drugs. We hypothesize that a greater clinical benefit
may result from the preferential use of drugs that concomitantly improve arterial compliance. Am J Hypertens
2002;15:1096 –1100 © 2002 American Journal of Hypertension, Ltd.
Key Words: Arterial compliance, arterial stiffness,
pulse waveform analysis, drug therapy.
urrent recommendations for the evaluation and
treatment of hypertension are defined in terms of
blood pressure (BP) measurements.1 However, hypertension is clinically heterogeneous, and similar BP
values are associated with different vascular consequences
in different patients. Although target organ assessment of
the heart and kidneys may better predict clinical outcomes,
management decisions are usually made without further
physical assessment of the tissue most directly affected by
hypertension, ie, blood vessels.
Measurements of other physical properties of the circulation such as arterial compliance, defined as ⌬V/⌬P,
the change in blood vessel dimension (⌬V) with each heart
beat at a given pulse pressure (⌬P), may allow for a more
subtle and precise assessment of the vascular impact of the
hypertensive process.2 Although initially limited to academic research facilities, the development of more simplified measurement techniques allows arterial compliance to
now be assessed in a clinical outpatient setting.3 We
recently demonstrated that computerized arterial pulse
waveform analysis (CAPWA) provides compliance values
corresponding to values obtained by other techniques, and
to nonpressure-related markers of cardiovascular risk.4,5
In this preliminary study, we investigated the effects of
antihypertensive drugs on arterial compliance. Because the
relative clinical benefit after the administration of different
drug classes remains controversial, we wondered whether
drug-induced changes in arterial compliance necessarily
follow lower achieved BP or pulse pressure values. If not,
then arterial compliance measurements may help to distinguish the differential vascular benefit of different drug
therapies, as well as provide an additional basis on which
to individualize therapeutic recommendations.
Received November 30, 2000. First decision February 28, 2001. Accepted August 7, 2002.
From the Hypertension Center (LMR), New York Presbyterian Hospital–Cornell University Medical Center, New York, New York and
University Vascular Center (LMR,MHL) Wayne State University, South-
field, Michigan.
Address correspondence and reprint requests to Dr. Lawrence M.
Resnick, Hypertension Center, New York Presbyterian Hospital/Cornell
U. Medical Center, 525 E. 68th Street/Starr 4, New York, NY 10021;
e-mail: [email protected]
0895-7061/02/$22.00
PII S0895-7061(02)03058-3
Methods
Essential hypertensive subjects evaluated at a suburban
university-affiliated outpatient practice specializing in hypertension were either previously unmedicated, or were
withdrawn from all antihypertensive therapy for 4 to 6
© 2002 by the American Journal of Hypertension, Ltd.
Published by Elsevier Science Inc.
AJH–December 2002–VOL. 15, NO. 12
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Table 1. Clinical and laboratory data
N
Age (y)
Sex (M/F)
Weight (lb)
SBP (mm Hg)
DBP (mm Hg)
PRA (ng/mL/min)
C1 (mL/mm Hg) (⫻10)
C2 (mL/mm Hg) (⫻100)
CaBl
CEI
ARB
BBl
11
57 ⫾ 3
4/7
163 ⫾ 8
161 ⫾ 4
94 ⫾ 3
0.6 ⫾ 0.2*
9.3 ⫾ 1
3.1 ⫾ 0.6
9
52 ⫾ 7
5/4
182 ⫾ 11
155 ⫾ 5
92 ⫾ 2
3.4 ⫾ 1.1
9.5 ⫾ 1.4
2.7 ⫾ 0.6
9
52 ⫾ 3
6/3
161 ⫾ 13
162 ⫾ 4
91 ⫾ 2
3.0 ⫾ 0.9
10.2 ⫾ 1.3
3.5 ⫾ 0.7
10
56 ⫾ 3
6/4
179 ⫾ 10
160 ⫾ 4
94 ⫾ 2
2.5 ⫾ 0.8
9.4 ⫾ 0.9
3.8 ⫾ 1.1
SBP ⫽ systolic blood pressure; CaBl ⫽ calcium channel antagonist; CEI ⫽ converting enzyme inhibitor; ARB ⫽ angiotensin receptor blockers;
BBl ⫽ beta blockers; DBP ⫽ diastolic blood pressure; PRA ⫽ plasma renin activity; C1 ⫽ capacitive compliance; C2 ⫽ oscillatory compliance.
* sig ⫽ 0.05 v other treatment groups.
weeks before initiating drug therapy. Essential hypertension sufficient to warrant antihypertensive drug therapy
was diagnosed on the basis of at least three independent
BP readings exceeding 150/90 mm Hg. The choice of
antihypertensive agent was based at least in part on renin–
sodium profiling,6 and as part of standard procedures,
these subjects were evaluated before, and 1 and 3 months
after monotherapy was initiated with either dihydropyridine calcium channel antagonists (n ⫽ 11), converting
enzyme inhibitors (n ⫽ 9), angiotensin II receptor blockers
(n ⫽ 9), or ␤-blockers (n ⫽ 10). The 39 consecutive
subjects from 1998 to 1999 whose diastolic BP on single
drug therapy decreased below and was sustained at ⬍90
mm Hg for the 3-month period are the subject of this
report.
At each visit, subjects arrived at the University Vascular Center between 9 AM and noon after an overnight fast.
Blood pressure and arterial compliance were measured in
the supine position by a CAPWA device (CV Profilor,
Hypertension Diagnostics, Inc., Eagan, MN). A BP cuff
was placed on the nondominant arm, and an applanation
tonometer was placed over the radial pulse of the dominant arm. After measurement of the BP, a signal-averaged
arterial pulse waveform was recorded for 30 sec. Based on
a modified Windkessel model of the circulation, the diastolic decay of the averaged pulse waveform was analyzed, and two components of vascular compliance were
then calculated, capacitive (C1) and oscillatory (or reflective) compliance (C2), corresponding to the components
of compliance attributable to large and small arteries,
respectively.
Values for BP and arterial compliance at 1 and 3
months of drug therapy did not differ significantly from
each other, and were averaged and compared with pretreatment values. Differences among the different drug
classes for these variables were compared by a one-way
analysis of variance, with post-hoc Bonferroni tests to
determine statistical significance.
Results
Basal clinical and laboratory characteristics of the subjects
studied are listed in Table 1. No significant differences in
demographic characteristics, pretreatment BP, or arterial
compliance values were noted among the different treatment groups. Based on the initial choice of these in agents
in accordance with plasma renin activity (PRA) values,
lower PRA values were observed among those subjects
who became normotensive on calcium channel antagonist
therapy, compared to subjects responding to converting
enzyme inhibitor therapy, angiotensin II receptor blockade, or ␤-blockade.
The BP and arterial compliance responses to antihypertensive drug therapy are depicted in Fig. 1. On calcium
channel antagonists (amlodipine, felodipine, or nifedipineGITS), systolic and diastolic BP decreased ⫺19 ⫾ 4/⫺15
⫾ 2 mm Hg, and C1 and C2 compliance values increased
30.0% ⫾ 5.8% and 43.7% ⫾ 23.3%, respectively. On
converting enzyme inhibitors (enalapril, fosinopril, or
quinapril), BP decreased ⫺12 ⫾ 3/⫺13 ⫾ 2 mm Hg, and
C1 and C2 increased 32.7% ⫾ 5.4% and 26.7% ⫾ 7.1%,
respectively. On angiotensin II receptor antagonists (losartan, candesartan, or irbesartan), BP decreased ⫺10 ⫾
3/⫺12 ⫾ 2 mm Hg, and C1 and C2 increased 36.3% ⫾
11.8% and 43.6% ⫾ 23.1%, respectively. On ␤-blockers
(atenolol or metoprolol), BP decreased ⫺14 ⫾ 3/⫺12 ⫾ 2
mm Hg, but C1 (⫺3.9% ⫾ 7.6%) and C2 (⫺7.0% ⫾
11.5%) compliance values did not change.
Thus, the changes in systolic and diastolic BP did not
differ significantly on the different drug therapies (Fig. 1A
and B), and all post-treatment pressures differed significantly (P ⬍ .005) from pretreatment values. Calculated
pulse pressure values also did not change significantly.
However, compared to pretreatment values, and despite
equivalent changes in pressure, a dissociation was observed between the drug-induced changes in pressure and
in arterial compliance. Specifically, a significant increase
in both C1 and C2 compliance components occurred in
those subjects on calcium channel antagonists, converting
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AJH–December 2002–VOL. 15, NO. 12
FIG. 1. Effects of antihypertensive therapy on systolic (⌬SBP) and diastolic (⌬DBP) blood pressures (A and B), and on capacitive (%⌬C1) and
reflective (%⌬C2) components of arterial compliance (C and D). CaBl ⫽ calcium channel blockers; CEI ⫽ converting enzyme inhibitors; ARB
⫽ angiotensin II receptor blockers; BBl ⫽ beta-blockers. *sig ⫽ 0.01 v other drug classes.
enzyme inhibitors, and angiotensin II blockers (P ⬍ .05 v
pretreatment), but not in those on ␤-blockers (sig ⫽ 0.01
v other drug classes) (Fig. 1C and D).
Discussion
Current therapeutic recommendations in hypertension
therapy are limited by the poor correspondence between
the level of BP in a given individual and the occurrence of
subsequent vascular disease. Consequently, many individuals are treated to benefit only a few, especially in subjects
with only minimally elevated pressures. The use of echocardiography and urinary protein measurements to identify
early cardiac and renal effects of hypertension has begun
to distinguish among equally hypertensive individuals
who may or may not already exhibit different degrees of
organ disease and who can be targeted for more aggressive
therapy.
However, although blood vessels are the primary target
organ of hypertension, BP has until recently remained the
only easily available measurement of the vasculature. The
recent development of arterial compliance (⌬V/⌬P) measurements routinely performed in an outpatient setting
allows us to ask: Does assessment of arterial compliance
provide additional information as to whether and which
different antihypertensive drugs might benefit individual
subjects independently of their effect on BP per se?7
We have begun to address this question by comparing
CAPWA-based arterial compliance measurements before
and 1 and 3 months after antihypertensive drug therapy
with different individual drugs from among four different
drug classes. By comparing the effects of these drugs in
subjects whose BP were both equivalent at the start of
therapy, and who all achieved equivalent diastolic BP
values ⬍90 mm Hg on monotherapy with individual
agents, we sought to make the data obtained more easily
interpretable in clinical practice. We also used renin–
sodium profiling as a pathophysiologic and practical guide
to the choice of initial drug therapy, rather than a random
assignment of drugs, which may help to explain the large
BP responses obtained with the drugs in this study, exceeding average published responses among the general
hypertensive population. This is quite consistent with the
known enhanced responsiveness of low renin subjects to
calcium channel blockade, and of normal– high renin subjects to agents interfering with the secretion (␤-blockers),
activation (converting enzyme inhibitors), or action (angiotensin receptor blockers) of the renin-angiotensin system (Table 1, Fig. 1A and B).8
The chief finding of this preliminary study is that for
the same decrease in BP, and without significant changes
in pulse pressure, short-term antihypertensive monotherapy with agents that block L-type calcium channels,
angiotensin converting enzyme, or the angiotensin II type
1 receptor, all significantly increase both C1 and C2 components of arterial compliance. However, this was not true
for ␤-blockade. This differential sensitivity of the vasculature to equally antihypertensive therapies suggests 1)
that assessment of arterial compliance provides information above and beyond that of BP or even pulse pressure,
and 2) that choosing agents that improve both BP and
arterial compliance might further enhance the potential
clinical benefit of drug therapy in hypertension.
Our present results further support other studies also
suggesting the relevance of arterial compliance measurements in the clinical assessment of hypertension. We have
AJH–December 2002–VOL. 15, NO. 12
previously applied different techniques to measure arterial
compliance in normal and hypertensive subjects, and to
investigate the biologic determinants of this vascular property. We found, in agreement with previous studies, that
essential hypertension is associated with decreased arterial
compliance, that these values are closely linked to ambient
BP, predict the degree of cardiac hypertrophy, and reflect
numerous other cardiovascular risk factors, including age,
urinary sodium excretion, fasting blood glucose, abdominal visceral fat, and intracellular free magnesium levels,
all contributing to vascular function independently of
BP.2–5,7, 9 –14 Furthermore, we found that the technique of
computerized pulse waveform analysis used in this study
provides values for arterial compliance closely corresponding to overall systemic compliance calculated as the
ratio of stroke volume to pulse pressure, and with direct
magnetic resonance imaging-based assessment of aortic
distensibility.5
Our results are also consistent with previous reports in
the literature in which the effects of antihypertensive drugs
on arterial compliance have been evaluated. Specifically,
in separate reports, both calcium blockers as well as converting enzyme inhibitors were shown to significantly
improve arterial compliance, whereas metoprolol or atenolol did not. This was true despite equal lowering of
BP.11,12 Furthermore, the present report confirms recent
data demonstrating that angiotensin II receptor antagonists
also improve arterial compliance.15,16 That these effects on
compliance may be independent of BP further suggests
that the regulation of cardiovascular homeostasis by the
renin-angiotensin system is not limited to the control of
BP alone.15
Certain caveats also need to be considered. First, because we did not measure isobaric compliance in this
study, we may not have adequately demonstrated druginduced changes in intrinsic arterial wall properties. Nevertheless, because vascular disease clinically occurs at and
progresses under the influence of ambient BP levels similar to those measured in the present study, we consider the
results obtained to be at least of functional, as well as
clinical, significance. Second, a variety of individual drugs
were used in each drug class, representing the average
office practice of this university-based clinic, and the small
number of subjects reported emphasizes the preliminary
nature of this study. It is possible, of course, that not all
individual ␤-blockers fail to significantly improve arterial
compliance, or that not all calcium channel blockers, angiotensin converting enzyme inhibitors, or angiotensin II
receptor blockers improve it. This clearly warrants future
studies.
At the same time, however, these easily distinguishable
as well as statistically significant differences were observed with a relatively small number of subjects, not
requiring the massive numbers of subjects usually necessary to demonstrate statistically significant differences between drugs effects on other “target organ” events in
clinical trials defined by BP, such as left ventricular mass
BP DRUGS AND ARTERIAL COMPLIANCE
1099
or urinary protein responses. This also suggests arterial
compliance as a more proximate, subtle, and direct reflection of antihypertensive drug effects on the underlying
hypertensive disease process compared to previously used
clinical variables, and support the increased use of these
measurements as a valuable marker of the vascular impact
of hypertension.
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