(Circulation. 1995;91:1052-1062.)
© 1995 American Heart Association, Inc.
Articles |
Differential Effects of Chronic Oral Antihypertensive Therapies on Systemic Arterial Circulation and Ventricular Energetics in African-American Patients
From the Noninvasive Cardiac Imaging Laboratories, the University of Chicago Hospitals, Section of Cardiology, Department of Medicine, Chicago, Ill.
Correspondence to Roberto M. Lang, MD, and Sanjeev G. Shroff, PhD, Noninvasive Cardiac Imaging Laboratories, University of Chicago Medical Center, 5841 S Maryland Ave, MC 5084, Chicago, IL 60637.
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Abstract |
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 Top Abstract IntroductionMethods Results Discussion References |
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Background A comprehensive evaluation of arterial load characteristics and left ventricular energetics in systemic hypertension has been limited by the need for invasive techniques to access instantaneous aortic pressure and flow. As a consequence of this methodological limitation, no data exist on the effects of long-term antihypertensive therapy on global arterial impedance properties and indexes of myocardial oxygen consumption (M
O2). Using recently
validated
noninvasive techniques, we compared in hypertensive patients the
effects of chronic oral treatment with ramipril, nifedipine, and
atenolol on arterial impedance and mechanical power dissipation as well
as indexes of MO2.
Methods and Results Sixteen African-American subjects with
systemic hypertension were studied with a randomized, double-blind,
crossover protocol. Instantaneous central aortic pressure and flow,
from which arterial load characteristics can be derived, were estimated
from calibrated subclavian pulse tracings (SPTs) and continuous-wave
aortic Doppler velocity in conjunction with two-dimensional (2D)
echocardiographic measurements of the aortic annulus, respectively. To
derive ventricular wall stress and indexes of
MO2, left ventricular
short-
(M-mode) and long-axis (2D echo) images were acquired simultaneously
with SPTs. Data were collected at the end of a 2-week washout period
(predrug control) and after 6 weeks of treatment with each agent.
Although all three agents reduced diastolic blood pressure to the same
extent, different effects on mean and systolic pressures and vascular
impedance properties were noted. Nifedipine reduced total peripheral
resistance (TPR; 1744±398 versus 1290±215 dyne-s/cm5)
and
increased arterial compliance (ACL; 1.234±0.253 versus
1.776±0.415 mL/mm Hg). This improvement in arterial compliance was
not entirely accounted for by the reduction in distending pressure.
Ramipril also decreased TPR (1740±292 versus 1437±290
dyne-s/cm5) and increased ACL (1.214±0.190
versus 1.569±0.424 mL/mm Hg), but with this agent, the change in
arterial compliance was explained solely on the basis of a reduction in
distending pressure. Atenolol, in contrast, did not affect either TPR
or ACL. In agreement with the compliance results,
nifedipine and ramipril significantly lowered the first two harmonics
of the impedance spectrum, but atenolol did not. None of these agents
resulted in a significant change in characteristic impedance or in the
relative amplitude of the reflected pressure wave. Total vascular
mechanical power and percent of oscillatory power remained unaltered
with all antihypertensive treatments. Only ramipril and nifedipine
reduced the integral of both meridional and circumferential systolic
wall stresses, indicating that
MO2 per
beat was reduced with these agents. Stress-time index, a measure of
MO2 per unit time,
decreased
significantly with ramipril but not with nifedipine because of an
increase in heart rate noted in 10 of 16 patients (mean increase, 10
beats per minute). Thus, a reduction in
MO2 coupled with unchanged
total
vascular mechanical power suggests improved efficiency of
ventriculoarterial coupling with ramipril and with nifedipine in the
subset of patients in whom heart rate remained unchanged. In contrast,
there was no evidence of a reduction in wall stress, stress integral,
or stress-time index with atenolol.
Conclusions The noninvasive methodology used in this study
constitutes a new tool for serial and simultaneous evaluation of
arterial hemodynamics and left ventricular energetics in systemic
hypertension. In this study, we demonstrate the differential effects of
chronic antihypertensive therapies on systemic arterial circulation and
indexes of MO2 in
African-American
subjects. Consideration of drug-induced differential responses of
arterial load and indexes of
MO2 with
each drug may provide a more physiological approach to the treatment of
systemic hypertension in individual patients.
Key Words: antihypertensive agents • circulation • arteries • ventricles
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Introduction |
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TopAbstractIntroductionMethods Results Discussion References |
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Systemic hypertension is characterized by complex alterations in arterial hemodynamics, including elevated total peripheral resistance and characteristic impedance, reduced arterial compliance, and abnormal propagation/reflection of pressure and flow waves.1 2 3 These pulsatile and steady components of arterial load impede left ventricular ejection and may adversely affect left ventricular energetics and ventriculoarterial coupling.4 Despite the high prevalence of hypertension, few studies have examined the long-term effects of different antihypertensive agents on any of these parameters.1 5 The paucity of such longitudinal studies is largely attributable to the absence of noninvasive methods for acquisition of instantaneous aortic pressure and flow required for the computation of pulsatile load characteristics and indexes of left ventricular energetics.
We recently developed and validated a new noninvasive method to estimate instantaneous aortic flow and pressure, based on simultaneous recordings of continuous-wave aortic Doppler and calibrated subclavian pulse tracings, respectively.6 In addition, by combining echocardiographic measurements of left ventricular geometry with calibrated subclavian pulse tracings, it is possible to obtain indexes of left ventricular energetics noninvasively.7
This study was designed to test the hypothesis that long-term oral therapy with different antihypertensive agents elicits differential responses in arterial load and left ventricular energetics that are not predictable from analysis of traditional hemodynamic variables. Accordingly, we studied the effects of 6-week treatment with three widely used classes of antihypertensive agents in a cohort of African-American patients with moderate systemic hypertension: an angiotensin-converting enzyme (ACE) inhibitor (ramipril), a calcium channel antagonist (nifedipine), and a ß-blocker (atenolol).
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Methods |
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TopAbstractIntroductionMethods Results Discussion References |
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Study Population
Seventeen African-American patients with essential moderate hypertension were enrolled. This group included 11 men and 6 women ranging in age from 33 to 60 years (mean±SD, 49±8 years). Because of the lack of increased left ventricular mass in our study group (see below), we believe that the duration of hypertension was relatively short, although precise information regarding this issue is unavailable. Patients either were previously untreated (n=3) or had antihypertensive therapy discontinued for 2 weeks before enrollment into the study (n=14). Moderate hypertension was defined as duplicate measurements of diastolic blood pressure ranging between 90 and 110 mm Hg obtained at two consecutive clinic visits at least 1 week apart. Exclusion criteria included (1) previous history of stroke, (2) clinical or ECG findings suggestive of coronary artery disease, (3) segmental wall motion abnormalities on two-dimensional (2D) echocardiography, (4) Doppler echocardiographic evidence for significant valvular heart disease, (5) significant cardiac arrhythmias, (6) asthma or any other contraindication to the administration of atenolol, nifedipine, or ramipril, and (7) renal failure. The protocol was approved by the Institutional Review Board of the University of Chicago Medical Center, and each patient provided written informed consent before entering the study.
Study Design
A double-blind, randomized, three-way crossover
study design
(Fig 1
) was used to investigate the responses to
ramipril, an ACE inhibitor; a long-acting preparation of nifedipine
(dihydropyridine calcium channel antagonist); and atenolol
(ß-adrenoceptor blocker). Each agent was given as a single daily oral
dose for 6 weeks. Doses were increased at 2-week intervals (5, 10, and
20 mg for ramipril; 30, 60, and 90 mg for nifedipine; and 25, 50, and
100 mg for atenolol) to achieve a diastolic blood pressure <90 mm Hg.
Each 6-week treatment cycle was followed by a 2-week washout period
(during which placebo was administered) before initiation of the
subsequent agent as dictated by the randomization protocol. In each
subject, data were acquired at six different visits: at the end of each
2-week washout period (predrug control) and after 6 weeks of therapy
with each agent (Fig 1).
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Data Acquisition and Processing
Patients underwent two
sequential phases of data acquisition.
First, aortic pressure and flow data were recorded to obtain arterial
characteristics, followed by echocardiographic imaging to determine
left ventricular mechanics and energetics.
Aortic Pressure-Flow
Data
The following data were acquired simultaneously: ECG,
phonocardiogram, continuous-wave aortic Doppler, and calibrated
subclavian pulse tracing. In addition, measurements of aortic annular
diameter were obtained with 2D echocardiography at each visit. The ECG,
phonocardiogram, and subclavian pulse tracing were connected to the
echocardiographic unit (Sonos 1500, Hewlett-Packard Inc) via a
custom-made multichannel physiological signal module. An example of
these data is shown in Fig 2.
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Noninvasive instantaneous aortic pressures were determined from subclavian pulse tracings obtained with a plastic funnel positioned over the right subclavian artery at its point of maximal impulse in the supraclavicular fossa and connected by Silastic tubing to a strain-gauge transducer (model 03040170, Cambridge Instrument Co).6 The waveform was recorded by a physiological pulse wave recording system (bandwidth, 0.05 to 50 Hz) and was calibrated according to the proximal brachial artery pressure determined with an oscillometric sphygmomanometer (model 1846 SX, Dinamap Vital Signs Monitor, Critikon Inc). Systolic and diastolic pressures were assigned to the peak and nadir of the subclavian pulse tracing, respectively, and instantaneous pressures over the cardiac cycle were derived by linear interpolation.
Noninvasive estimates of instantaneous aortic flow were generated from continuous-wave Doppler velocity recordings and 2D echocardiographic measurements of aortic annular area. Ascending aortic blood velocity was recorded with a 1.9-MHz continuous-wave Pedof Doppler transducer (Hewlett Packard Inc) positioned at the cardiac apex. The aortic annular diameter (Dao, cm) was measured from parasternal long-axis 2D echocardiographic recordings obtained with a 2.5-MHz transducer by the trailing-to-leading-edge technique. Annular cross-sectional area (CSA, cm2) was calculated assuming a circular orifice:
 | (1) |
Instantaneous aortic flow (QAo, mL/s) was obtained as the product of the instantaneous Doppler blood flow velocity and CSA.8
Three cardiac cycles were selected for analysis according to the following criteria for beat selection6 : (1) the magnitude of the baseline shift in diastolic pressure was <10% of the pulse pressure; (2) the Doppler envelope was well demarcated, and peak velocities for the three cycles were within 10% of each other; and (3) the cardiac rhythm was sinus with interbeat RR interval variations of <15%. The pressure trace and flow velocity envelope were digitized at 200 Hz on a digitizing tablet (Bit Pad Two, Summagraphics Corp) and stored on a personal computer (Gateway 2000, 486/33 C). The propagation delay between the ascending aorta and the subclavian artery was calculated as the time interval between the first high-frequency component of the second heart sound (A2) on the phonocardiogram and the incisura of the pressure waveform. The digitized pressure tracings were offset accordingly. Pressure and flow data of the three cardiac cycles were then averaged and subsequently processed with custom software for computation of hemodynamic parameters.
Left Ventricular Echocardiographic Imaging
The following data were acquired simultaneously: ECG,
phonocardiogram, calibrated subclavian pulse tracing, and 2D targeted
M-mode echocardiogram (Fig 3, top). Care was taken to
record the largest left ventricular minor-axis dimension (D) at the
level of the superior aspect of the papillary muscles (equator of the
ventricle). In addition, the left ventricular long-axis dimension (L)
was measured from the apical four-chamber view as the distance between
the apex and the mitral annulus (Fig 3, bottom). The apical
endocardium
was defined as the point within the left ventricle at which the septum
and lateral wall form the sharpest angle. To avoid tangential imaging
of the left ventricle, both L and the mitral annulus dimensions were
maximized. End-diastolic dimensions and wall thickness were
measured at the time of the R wave on the ECG, and end-systolic
measurements were performed at the time of the first high-frequency
component of A2 on the phonocardiogram.
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Instantaneous left ventricular dimension, wall thickness, and aortic ejection pressure were digitized by use of the off-line data analysis system described above. Left ventricular mass as well as meridional and circumferential wall stress during cardiac ejection were derived.
Computed Parameters
General Hemodynamics
Parameters calculated were heart rate (HR, beats per minute);
mean aortic pressure (MAP, mm Hg), calculated as the total area under
the calibrated subclavian pressure waveform divided by cardiac cycle
length; stroke volume (SV, mL), calculated as the product of the aortic
flow velocity–time integral and the aortic cross-sectional area;
cardiac output (CO, L/min), calculated as stroke volume multiplied by
heart rate; and left ventricular shortening fraction (FS), calculated
as (Ded-Des)/Ded, where
Ded is end-diastolic diameter and
Des is end-systolic diameter.
Arterial Load
Characteristics
Total peripheral resistance (TPR,
dyne-s/cm5) was
calculated as mean aortic pressure divided by cardiac output. The
aortic input impedance spectrum was obtained for each condition by use
of Fourier transformation of the pressure and flow
signals.9 Characteristic impedance (Zc,
dyne-s/cm5) was calculated as the average of high-frequency
impedance harmonics (harmonics 4 through 10).1 To minimize
the effect of noise, only those harmonics with flow amplitude of >5%
of the first harmonic were included in the averaging process. Arterial
compliance (AC, mL/mm Hg) was calculated according to the area method
described by Liu et al10 for both linear (ACL)
and nonlinear (exponential, ACNL) models of the arterial
pressure-volume relation. The compliance estimation was performed over
the diastolic range defined by two points, P1 and
P2. The maximum aortic pressure after the dicrotic notch
was denoted as P1, while P2 was the
end-diastolic aortic pressure.
 | (2) |
 | (3) |
Ad is defined as the area under the aortic pressure curve bounded by P1 and P2, and P represents the pressure at which ACNL is calculated. The coefficient b, which characterizes large arteries, is relatively independent of vessel tone3 10 and was assumed to be a constant (-0.01 mm Hg-1) for all patients under all conditions.3
Unlike TPR, which completely characterizes the arterial load to steady flow, the load for pulsatile flow cannot be quantified in terms of a single number. Several indexes were used for this purpose, each quantifying different aspects of pulsatile arterial load: characteristic impedance (Zc), the magnitudes of the first (Z1) and second (Z2) harmonics of the impedance spectrum, and arterial compliance (ACL or ACNL).
Wave Reflection
To quantify wave
reflection and propagation, two indexes were
used. Pressure and flow waveforms were decomposed into forward and
backward components according to the linear transmission line
theory.11 The first reflection index (RI1) was
the ratio of backward to forward pressure wave peak-to-peak amplitudes.
The second reflection index (RI2) was calculated as the
amplitude of the first harmonic of the global reflection coefficient
(
G), derived from the aortic input impedance
spectrum.11 12 Relative to control, a higher value of
RI1 or RI2 indicates a greater contribution of
wave reflections to measured pressure and flow waveforms.
External Mechanical Power
Total power
(
tot, watts), steady power
(std, watts), oscillatory power
(osc, watts), and percent
oscillatory power
(%osc) were calculated from
instantaneous aortic
pressure [P(t)] and flow [Q(t)] as follows13 :
 | (4) |
 | (5) |
 | (6) |
 | (7) |
where
T is the cardiac cycle duration and P and
Q are the mean pressure and flow, respectively.
osc represents the energy expended
in
pulsatile phenomena, which does not contribute to net forward
flow.
Left Ventricular Mass Index
Left ventricular
mass index (LVMI, g/m2) was
calculated by use of the formula described by Devereux et
al.14
Left Ventricular Meridional and
Circumferential Wall
Stresses
Left ventricular meridional wall stress
(
m, g/cm2) was computed throughout
ventricular ejection according to the following angiographically
validated formula15 :
 | (8) |
where D and h are left ventricular short-axis diameter and thickness, respectively.
Left ventricular circumferential stress
(c,
g/cm2) was calculated by use of the formula of Sandler and
Dodge16 :
 | (9) |
where
L is left ventricular long-axis dimension. Since L was
measured at three discrete points during systole, c was
computed at the onset of ejection (time of the initial pressure
upstroke), at the time of peak meridional stress, and at end systole
using the corresponding values of P, D, L, and h.
Indexes
of Myocardial Oxygen Consumption
Integrals of left ventricular
meridional and circumferential
systolic wall stress (
m and
c, respectively, g-s/cm2) were
computed as the areas under the respective stress curves during the
ejection period. These integrals correlate with myocardial oxygen
consumption (MO2) per
beat.17
Meridional and circumferential left ventricular
stress-time indexes
(STIm and STIc, respectively,
g-s/cm2-min), were calculated as the product of heart rate
and m and c, respectively. These
indexes are related to MO2
per unit
time.18 19
Statistical Analysis
For each variable, data were compared by
one-way
repeated-measures ANOVA. When assumptions of normality or equal
variance were violated, a nonparametric test (Friedman
repeated-measures ANOVA on ranks) was used. If differences among
treatment groups were found to be statistically significant
(P<.05), pairwise multiple comparisons were performed by
the Student-Newman-Keuls method.
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Results |
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TopAbstractIntroductionMethods Results Discussion References |
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Of the 17 patients initially enrolled into the study, one had to be excluded because of inadequate subclavian pulse tracings. Thus, aortic pressure-flow relations were studied in 16 patients. Left ventricular echocardiographic measurements were obtained only in patients who had technically adequate recordings at all six visits (n=12). All patients required the highest dose of each antihypertensive agent (ie, ramipril 20 mg, nifedipine 90 mg, and atenolol 100 mg) to achieve diastolic blood pressures
90 mm Hg, with the exception of
patient 12, who became normotensive with 50 mg of atenolol and 5 mg of
ramipril. A representative data set of pressure and flow
tracings obtained in 1 subject before and after 6 weeks of treatment
with ramipril, nifedipine, and atenolol is shown in Fig 4.
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for increase, 
for decrease, and = for no change. TPR indicates
total peripheral resistance; AC, arterial compliance; Zc,
characteristic impedance; % Osc. Power, fraction of oscillatory power;
and Reflect. Ind., reflection index.
All hemodynamic parameters returned to baseline values after the 2-week
washout periods. Hemodynamic effects of ramipril, nifedipine, and
atenolol on heart rate, blood pressure, stroke volume, and cardiac
output are presented in Table 1. Heart rate remained
unchanged with ramipril but decreased with atenolol (-19%,
P<.05). With nifedipine, a variable heart rate response was
observed: 10 of 16 patients increased heart rate (mean increase of 10
beats per minute). The reduction in heart rate with atenolol was
associated with an increase in stroke volume that was not observed with
the other agents. As a result, cardiac output was unchanged with all
three drugs. Systolic blood pressure decreased most with nifedipine and
least with atenolol, but all three drugs reduced diastolic blood
pressure to a similar extent.
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The effects of each agent on TPR, ACL, and
Zc are summarized in Table 2, and the
individual patient data are depicted in Fig 5. TPR
decreased with ramipril (P<.05) and nifedipine
(P<.05) but not with atenolol. Arterial compliance,
calculated with a linear pressure-volume model, increased with both
nifedipine (P<.05) and ramipril (P<.05) but was
unchanged with atenolol. When a nonlinear model was used, only
nifedipine increased ACNL for any level of distending
pressure (Fig 6).
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used to estimate ACL (see
text): open symbols indicate before treatment; filled symbols, after
treatment. Note that ACL values are identical to
ACNL values at
The averaged aortic input impedance spectra of the 16 patients before
and after each treatment are shown in Fig 7. Significant
reductions in impedance moduli of the first (Z1) and second
(Z2) harmonics of the impedance spectrum were observed
after ramipril and nifedipine but not after atenolol (Table 2
).
The
reduction in Z1 was greater with nifedipine than with
ramipril. No change in characteristic impedance was observed with any
antihypertensive agent (Table 2).
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Although they did not reach statistical significance, the changes in
reflection indexes (RI1 and RI2) tended to
follow the changes in TPR noted with each agent (Table 2).
Neither
total power nor percent oscillatory power was significantly affected by
any of the three antihypertensive agents.
Left ventricular dimensions and thicknesses, as well as shortening
fraction data, are shown in Table 3. Although
end-diastolic short- and long-axis dimensions remained
unchanged with all drugs, a small but statistically significant
reduction in end-systolic dimensions was noted only with ramipril
and nifedipine. There was a tendency for the shortening fraction to
increase with ramipril and nifedipine and to decrease with atenolol.
The values of left ventricular mass index were within the normal range
at the onset of the study and remained essentially unchanged after 6
weeks of antihypertensive therapy with either ramipril, nifedipine, or
atenolol (Table 3).
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Fig 8 illustrates the effects of each antihypertensive
agent on circumferential and meridional left ventricular systolic wall
stress at three time points: the onset of ejection, time of peak
meridional stress, and end systole. Overall, ramipril and nifedipine
reduced wall stress throughout ventricular ejection, but atenolol did
not. Consequently, the integrals of circumferential and meridional wall
stress per beat were reduced only with ramipril and nifedipine (Table
3). Since there was a tendency for heart rate to increase with
nifedipine and not with ramipril (Table 1), circumferential
stress-time
index was reduced only after ramipril (Table 3).
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Discussion |
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TopAbstractIntroductionMethods Results Discussion References |
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Using recently validated noninvasive techniques, we were able to identify differential hemodynamic responses to three commonly used oral antihypertensive agents in a cohort of hypertensive African-American patients. Despite similar reductions in diastolic blood pressure, nifedipine and ramipril were more effective than atenolol in reducing systolic and mean blood pressures. These effects on blood pressure were associated with differential responses in heart rate, arterial load characteristics, and left ventricular energetics. Both the steady and pulsatile components of arterial load, as well as the integrals of circumferential and meridional wall stress during ventricular ejection, decreased with ramipril and nifedipine but not with atenolol. The circumferential stress-time index, reflecting left ventricular M
O2 per unit time, was
reduced
significantly with ramipril. With nifedipine, this reduction was
blunted as a result of increased heart rate noted in some patients. In
terms of coupling, the maintenance of constant total vascular
mechanical power at a time that
MO2
decreased indicated an improved efficiency of ventriculoarterial
coupling.
Steady Versus Pulsatile Arterial Load
TPR, a major
determinant of arterial load, is the sole parameter
used by most clinicians to characterize the systemic arterial
circulation. However, this parameter describes only the load or
opposition to steady flow. Since arterial pressure and flow are
pulsatile, additional vascular parameters should be considered to
describe arterial load more accurately. As can be seen from the
impedance spectra in Fig 7, the opposition to flow is high for
steady
flow (impedance at zeroth harmonic or TPR) and rapidly falls as
frequency increases. This fall is governed by arterial geometric and
viscoelastic properties as well as wave propagation-reflection
phenomena. Such a design ensures maintenance of adequate mean blood
pressure with minimal opposition to pulsatile ejection. Therefore, it
is important to examine both the steady and pulsatile components of
arterial load. Although the physical properties and phenomena mentioned
above are distributed over the entire vasculature, they are
represented in simplified models of the arterial
circulation as lumped parameters. For example, arterial compliance, as
calculated in this study, incorporates arterial elasticity and geometry
as well as wave propagation and reflection phenomena. Characteristic
impedance of the aorta, on the other hand, is a function of local
aortic material and geometric properties.20 21 The
importance of including parameters other than TPR to describe
instantaneous aortic pressure-flow relations is illustrated in Fig
9.
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Methodological Considerations for the Noninvasive
Technique
Clinical application of any pulsatile model of the
cardiovascular
system has been limited by the requirement for invasive procedures to
obtain the necessary instantaneous pressure and flow data. Invasive
studies, however, are not suited for the serial assessment of chronic
pharmacological interventions. As a result, the potential diagnostic
and therapeutic applications of these more physiological models of the
circulation are not well appreciated.
We have previously demonstrated that noninvasively acquired subclavian pulse waveforms are morphologically similar to high-fidelity ascending aortic pressure recordings.6 The subclavian pulse tracing was calibrated according to brachial measurements obtained with an oscillometric sphygmomanometer. This method of calibration has been validated against high-fidelity central aortic pressure in children22 and adults.23 The validity of this calibration procedure in hypertensive individuals derives further circumstantial support from the well-described attenuation of pulse wave amplification during chronic hypertension.24
Many investigators have demonstrated that the transaortic continuous-wave Doppler-derived spectral velocity envelope in conjunction with 2D echocardiographic estimation of cross-sectional area at the level of the aortic valve annulus provides an adequate noninvasive estimation of stroke volume.25 We have recently validated the accuracy of transthoracic continuous-wave aortic Doppler against electromagnetic flowmeters for measurements of instantaneous aortic inflow characteristics in both open-chest monkeys and humans.6 8 In these studies, Doppler flows were slightly higher than their electromagnetic counterparts during early ejection and were accurate during the remainder of systole. These minor differences in morphology did not impact significantly on the derived hemodynamic parameters of interest, such as arterial compliance, characteristic impedance, and total peripheral resistance.6
Values for arterial compliance and characteristic impedance are in the range of previously published results in untreated hypertensive patients when invasive techniques were used.1 3 5 Similarly, values for external mechanical power (total, steady, and oscillatory) and reflection indexes are comparable to those reported by Ting et al in hypertensive patients.1
Effects of Antihypertensive Agents on the Arterial
Circulation
We found similar reductions in diastolic blood pressure
for all
three classes of antihypertensive therapy. Interdrug differences were
noted for systolic and mean blood pressure responses. Atenolol appeared
to be less efficacious than both ramipril and nifedipine in achieving
systolic blood pressure reduction, whereas nifedipine was slightly more
effective than ramipril. Overall, these differential responses are
similar to those reported by Materson et al26 in
African-American patients of a similar age group. It has been suggested
that the low renin levels reported in African-American patients may
account for the reduced antihypertensive efficacy of ACE inhibitors
relative to nifedipine.27 28
Both ramipril and
nifedipine markedly decreased TPR (parameter of
steady arterial load) and slightly increased cardiac output. In
contrast, atenolol caused proportional reductions in pressure and flow
with no change in TPR for the entire group. Some patients experienced
slightly increased TPR with atenolol. Interestingly, these patients
were the ones who had low TPR values at baseline. Atenolol, in the
doses used in this study, is largely selective for cardiac
ß1-receptors. Therefore, it is unlikely, yet possible,
that this drug would elicit unopposed 
-activity resulting in an
increase in TPR. Irrespective of the mechanism, the observation of
increased TPR with a ß-blocker in some hypertensive patients is not
unique to our study.1
Likewise, nifedipine and ramipril reduced Z1 and Z2 (parameters of pulsatile load), whereas atenolol did not. Since heart rate remained unchanged, these impedance reductions reflected true vascular changes. The failure of atenolol to alter Z1 and Z2 may be a result of the offsetting effect of the reduction in heart rate. None of the drugs altered characteristic impedance (Zc) significantly. Zc is a function of aortic material and geometric properties as well as distending pressure and is not influenced by the distal vasculature.20 Discordant responses among the multiple determinants of Zc may explain the invariance of this parameter during antihypertensive therapy. The lack of response of Zc to ß-blockers has been reported previously in acute studies using invasive techniques after intravenous propranolol.1
The increase in linear arterial compliance
observed with nifedipine and
ramipril, but not atenolol, corroborates findings obtained in the
brachial and forearm arterial circulation after chronic treatment with
these agents.29 30 31 32 When
an exponential pressure-volume
model was used to compare compliance values independent of distending
pressure, only nifedipine was found to increase arterial compliance
(Fig 6), indicating that the pressure drop induced by this
agent does
not entirely account for the increase in ACNL. These
findings, also reported by Simon et al30 on the brachial
circulation after treatment with nicardipine and nitrendipine, have
been attributed to dihydropyridine calcium channel antagonist–induced
smooth muscle tone reduction. In contrast, the increase in
ACL observed after ramipril treatment can be accounted for
solely by the reduction in distending pressure. This finding differs
from those reported by Simon et al,30 who reported a
direct effect of ramipril on arterial compliance and Levy et
al,33 who noted an increase in arterial compliance after 8
weeks of oral treatment with ACE inhibitors that was associated with a
reduction in medial collagen content of rat carotid arteries. The
absence of direct improvement in arterial compliance after ramipril in
our patients may reflect the shorter duration of treatment, differences
in dosing, or ethnic differences in the populations studied.
Although not statistically significant, the reflection indexes (RI1 and RI2) tended to follow the TPR responses to each antihypertensive agent. This observation is in agreement with the findings of Ting et al,1 who reported no change in wave reflection index after vasodilatation with nitroprusside in hypertensive patients but found an increase after intravenous propranolol, which also increased TPR. It should be noted that the indexes used in this study do not examine timing aspects of wave reflections. Systemic hypertension is a condition in which pulse wave velocity is usually increased, resulting in early return of wave reflections, with potentially deleterious effects on ventriculovascular coupling.2
None of the antihypertensive treatments tested
in this study resulted
in a significant decrease in total vascu-lar mechanical power
(tot). For ramipril and nifedipine,
this was the
result of a slight increase in cardiac output that counterbalanced the
decrease in pressure. For atenolol, pressure and flow decrements were
not sufficient to significantly reduce
tot. The
fraction of the total energy dissipated in pulsation
(%osc) was small (<15% of
tot)
and was not reduced by any antihypertensive treatment. Conflicting
results have been published on whether blood pressure reduction in
hypertensive patients decreases
%osc,
thereby indicating an improvement in efficiency of power dissipation in
the arterial system.1 5 34 Recent
theoretical findings,
however, indicate that there are multiple determinants of oscillatory
power (eg, TPR, pulse wave velocity, arterial
compliance).35 Thus, offsetting effects of simultaneous
changes in these determinants might account for the lack of change
observed in %osc after ramipril and
nifedipine.
Effects of Antihypertensive Agents on the Left Ventricle
At
the onset of the study, left ventricular mass index values were
within the normal range (Table 3). The lack of noticeable
change in
left ventricular mass index with all treatments is possibly related to
the absence of initial hypertrophy.
Left ventricular circumferential
and meridional wall stresses were
significantly reduced throughout ventricular ejection after ramipril
and, to a lesser extent, nifedipine treatment (Fig 8). This
resulted from the combined effects of blood pressure reduction and
decreased systolic chamber dimensions with a tendency toward increased
systolic wall thickening. In contrast, atenolol tended to increase left
ventricular chamber size, which blunted the beneficial effect of
pressure reduction in terms of wall stress.
Reduced wall stress and unchanged left ventricular ejection times with ramipril and nifedipine resulted in a decrease in the integrals of circumferential and meridional systolic wall stresses, indexes of oxygen consumption per beat. With atenolol, these integrals increased (meridional) or tended to increase (circumferential) as a result of the prolonged ejection time and slightly elevated wall stress.
Stress-time
index, the product of heart rate and integral of systolic
wall stress, has been closely correlated to
MO2.18 19
Since the
majority of myocardial fibers are oriented in near-circumferential
direction and since most of the fiber shortening occurs in the same
direction, the circumferential stress-time index (STIc) may
better reflect changes in
MO2. Thus,
in this study, alterations in STIc should accurately
reflect changes in MO2,
provided that left ventricular contractility remained relatively
unchanged with all agents. Ramipril significantly reduced
STIc because of its beneficial effect on the integral of
wall stress without a concomitant increase in heart rate. Although this
index tended to decrease with nifedipine, it did not attain statistical
significance. Given that the integral of systolic wall stress was
reduced with nifedipine, the increased heart rate noted in 10 of 16
patients was responsible for this finding. With atenolol, the
stress-time index remained unchanged because of the offsetting effects
of decreased heart rate coupled with a trend toward an increase in the
integral of systolic wall stress.
In terms of ventriculoarterial coupling, the reduction in myocardial oxygen consumption with unaltered total vascular mechanical power indicates an improvement in the efficiency of the cardiovascular system after treatment with ramipril in African-American hypertensive patients. Similar improvements in efficiency were observed with nifedipine in the subgroup of patients whose heart rate remained unchanged with this agent.
Relevance and Limitations of the Present Study
To the best of
our knowledge, there are no human studies that have
simultaneously assessed the long-term effects of different
antihypertensive agents on pulsatile and nonpulsatile arterial load and
left ventricular energetics. Most previous longitudinal studies with
antihypertensive agents have examined the effects on the peripheral
circulation (eg, brachial and
forearm).29 30 31 32 Our
noninvasive methodology enables serial assessments of the systemic
arterial circulation, ventricular energetics, and ventriculoarterial
coupling. Since this study was performed on a selected homogeneous
group, ie, African-Americans with moderate hypertension without left
ventricular hypertrophy, extrapolation of our results to other
hypertensive ethnic populations with and without hypertrophy should be
made with caution. However, given that systemic hypertension is
extremely prevalent in the African-American community, our results
remain relevant.
Summary and Clinical Implications
We have shown the
feasibility of noninvasive, serial
quantification of arterial load characteristics and indexes of left
ventricular energetics. Using these techniques, we were able to
identify differential responses to three commonly used antihypertensive
agents with respect to pulsatile and steady arterial load, ventricular
energetics, and ventriculoarterial coupling. It may now be possible to
classify hypertensive patients according to specific ventricular and
arterial load profiles that would help select pharmacological therapy
in individual patients. Further studies are necessary to determine
whether therapeutic strategies based on this physiological approach can
reduce mortality in patients with hypertension.
|
Acknowledgments |
|---|
This study was supported in part by grants from the Upjohn Co to Dr Lang, from NIH-NHLBI (HL-36185) to Dr Shroff, and from the French Ministère des Affaires Etrangères (Fondation Lavoisier) to Dr Cholley. We are indebted to Fetima Davis, RN, Linda B. Roberts, RN, and Barbara Bates, RN, for their expert nursing assistance throughout the study. We thank Errol C. Rubenstein and Donna Barrett for their help with the preparation of the manuscript.
Received June 17, 1994; revision received September 12, 1994; accepted October 2, 1994.
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