(Circulation. 1997;96:2385-2396.)
© 1997 American Heart Association, Inc.
Articles |
Modulation of the Renin-Angiotensin Pathway Through Enzyme Inhibition and Specific Receptor Blockade in Pacing-Induced Heart Failure
I. Effects on Left Ventricular Performance and Neurohormonal Systems
From the Division of Cardiothoracic Surgery, Medical University of South Carolina, Charleston, and the Pharmaceutical Division, Novartis, Basel, Switzerland (M. de G., S.W.)
Correspondence to Francis G. Spinale, MD, PhD, Cardiothoracic Surgery and Physiology, Medical University of South Carolina, Charleston, SC 29425.
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Abstract |
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Background The goal of this study was to determine the effects of ACE inhibition (ACEI) alone, AT1 angiotensin (Ang) II receptor blockade alone, and combined ACEI and AT1 Ang II receptor blockade on LV function, systemic hemodynamics, and neurohormonal system activity in a model of congestive heart failure (CHF).
Methods and Results Pigs were randomly assigned to each of 5 groups: (1) rapid atrial pacing (240 bpm) for 3 weeks (n=9), (2) ACEI (benazeprilat, 0.187 mg · kg-1 · d-1) and rapid pacing (n=9), (3) AT1 Ang II receptor blockade (valsartan, 3 mg · kg-1 · d-1) and rapid pacing (n=9), (4) ACEI and AT1 Ang II receptor blockade (benazeprilat/valsartan, 0.05/3 mg · kg-1 · d-1) and rapid pacing (n=9), and (5) sham controls (n=10). In the pacing group, LV fractional shortening (LVFS) fell (13.4±1.4% versus 39.1±1.0%) and end-diastolic dimension (LVEDD) increased (5.61±0.11 versus 3.45±0.07 cm) compared with control (P<.05). With AT1 Ang II blockade and rapid pacing, LVEDD and LVFS were unchanged from pacing-only values. ACEI reduced LVEDD (4.95±0.11 cm) and increased LVFS (20.9±1.9%) from pacing-only values (P<.05). ACEI and AT1 Ang II blockade reduced LVEDD (4.68±0.07 cm) and increased LVFS (25.2±0.9%) from pacing only (P<.05). Plasma norepinephrine and endothelin increased by more than fivefold with chronic pacing and remained elevated with AT1 Ang II blockade. Plasma norepinephrine was reduced from pacing-only values by more than twofold in the ACEI group and the combination group. ACEI and AT1 Ang II receptor blockade reduced plasma endothelin levels by >50% from rapid-pacing values.
Conclusions These findings suggest that the effects of ACEI in the setting of CHF are not solely due to modulation of Ang II levels but rather to alternative enzymatic pathways and that combined ACEI and AT1 Ang II receptor blockade may provide unique benefits for LV pump function and neurohormonal systems in the setting of CHF.
Key Words: myocardium • heart failure • angiotensin • cardiovascular disease
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Over the past decade, morbidity and mortality from CHF have greatly increased.1 2 3 Past clinical and laboratory studies have provided convincing evidence that interruption of the renin-angiotensin pathway through the use of ACE inhibitors after the development of CHF improves LV function and survival.4 5 6 7 8 9 In addition to reducing Ang II production, ACEI can influence a number of enzymatic pathways.10 11 12 13 14 15 Thus, whether the effects of ACEI in the setting of CHF are due to reduced Ang II production and therefore diminished AT1 Ang II receptor activation remains unclear. Specific AT1 Ang II receptor antagonists have been described16 17 18 19 20 21 and have been demonstrated to be effective in the setting of hypertension.16 17 18 19 20 The use of specific AT1 Ang II receptor antagonists with developing CHF may provide insight into the mechanisms of action of ACEI. Past studies have provided evidence that alternative enzymatic pathways exist for the production of Ang II within the myocardium.22 23 Increased activity of these alternative myocardial Ang II–forming pathways with CHF may result in only partial prevention of Ang II production and AT1 Ang II receptor activation with ACEI. It has recently been reported that combined ACEI and AT1 Ang II receptor blockade may act in an additive manner to reduce systemic vascular resistance.20 Thus, combined ACEI and AT1 Ang II receptor blockade may provide unique effects in the setting of CHF by enhancing the effects of ACEI as well as preventing AT1 Ang II receptor activation from alternative Ang II–forming pathways. Accordingly, the overall goal of this study was to examine the direct effects of ACEI alone, AT1 Ang II receptor blockade alone, and combined ACEI and AT1 Ang II receptor blockade on LV function, systemic hemodynamics, and neurohormonal system activity in a model of CHF. Past reports from this laboratory and others have demonstrated that chronic pacing tachycardia in animals causes progressive and time-dependent changes in LV geometry and pump function and neurohormonal system activation.9 24 25 26 27 28 29 These functional and neurohormonal changes that occur with chronic rapid pacing are similar to the clinical spectrum of CHF3 30 31 32 33 and provide an opportunity to determine the effects of pharmacological interruption of neurohormonal signaling pathways during the development and progression of the CHF process. Accordingly, a model of pacing-induced CHF was used to test the central hypothesis that combined ACEI and AT1 Ang II receptor blockade will provide enhanced beneficial effects on LV function and neurohormonal activity compared with either treatment alone.
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Methods |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Rationale
The present project used a rapid-pacing model of CHF in pigs that has been described previously.24 25 The first objective of this study was to select an appropriate dosing strategy for ACE inhibition, AT1 Ang II receptor blockade, and combined ACEI and AT1 Ang II receptor blockade. The criterion for dose selection was to obtain an
50% inhibition of the
Ang I and Ang II pressor response but one that would not produce
significant differential effects on resting blood pressure. The
beneficial effects of ACEI in the setting of chronic LV dysfunction
appear to be due to local myocardial effects rather than alterations in
systemic loading conditions.34 35 Through minimization of
the effects of drug treatment on resting blood pressure, the potential
myocardial effects of ACEI, AT1 Ang II receptor blockade,
or combination treatment could be more carefully determined. After
identification of suitable dosing regimens, the second objective of the
present study was to institute concomitant ACEI, AT1
Ang II receptor blockade, or combined therapy with chronic rapid
pacing. After 21 days of concomitant treatment and pacing
tachycardia, terminal studies were performed in which LV
function and geometry, neurohormonal profiles, and myocardial ACE
activity and Ang II receptor density were examined. For comparison
purposes, age-matched pigs that underwent chronic pacing without
treatment and sham controls were used.
Dose-Selection Studies
Fifteen Yorkshire pigs (20 kg, male) were chronically
instrumented for measurement of arterial blood pressure in
the conscious state. The pigs were anesthetized with isoflurane
(3%, 1.5 L/min) and a mixture of nitrous oxide and oxygen (50:50),
intubated with a cuffed endotracheal tube, and ventilated at a flow
rate of 22 mL · kg-1 ·
min-1 and a respiratory rate of 15 breaths per
minute. The left internal carotid artery was exposed, and a catheter
was connected to a vascular access port (model GPV, 9F, Access
Technologies), advanced to the aortic arch, and sutured in place. The
access port was buried in a subcutaneous pocket over the thoracolumbar
fascia. After a recovery period of 7 to 10 days, the animals were
returned to the laboratory for an initial Ang I and Ang II pressor
response study. For these studies, the animals were sedated with
diazepam (20 mg PO; Valium, Hoffmann-La Roche) and placed in a
custom-designed sling that allowed the animal to rest comfortably. All
studies were performed with the pig in the conscious state without
additional sedation. The vascular access port was entered with a
12-gauge Huber needle (Access Technologies), and basal and resting
arterial pressures and heart rate were recorded.
Pressures from the fluid-filled aortic catheter were obtained with an
externally calibrated transducer (Statham P23ID, Gould). The ECG and
pressure waveforms were recorded with a multichannel recorder
(Hewlett Packard) and digitized on computer for subsequent
analysis at a sampling frequency of 250 Hz (80386 processor,
Zenith Data Systems). After these baseline measurements, an incremental
infusion of Ang I (1 to 9 µg, Sigma) was administered. Each dose of
Ang I was infused over a period of 30 seconds, and
hemodynamic measurements were recorded 5 minutes
after each infusion. After the Ang I pressor test and a 60-minute
stabilization period in which hemodynamic indices had
returned to basal-state values, an Ang II (1 to 9 µg, Sigma) infusion
protocol was performed in an identical fashion. The animals were
allowed to recover from the pressor studies for 48 hours and then
entered into the dose-determination protocols described in the
following paragraph. To maintain a constant steady-state blood level of
all compounds used in these studies, osmotic minipumps (2ML1, Alza
Corp) were implanted in the peritoneum. Ang I and Ang II pressor
response measurements were obtained 72 hours after placement of the
osmotic pumps.
Pigs were randomly assigned to receive the ACE inhibitor
benazeprilat (2 to 30 mg/d), the AT1 Ang II receptor
antagonist valsartan18 (2 to 60 mg/d),
or a combination of these two compounds. From these studies, 3.75
mg/d of benazeprilat was determined to have no significant
effect on resting blood pressure values but to significantly reduce the
Ang I pressor response with no effect on the Ang II pressor response
(Fig 1
). For the AT1 Ang II
receptor antagonist, 60 mg/d of valsartan
significantly reduced the Ang I and II pressor responses without a
significant effect on resting blood pressure (Fig 1). The average
plasma level of valsartan for this series of studies was 486±117
nmol/L, with a range of 373 to 800 nmol/L. Plasma
concentrations of valsartan were determined by an AT1 Ang
II receptor binding assay using smooth muscle cell membrane
preparations as described previously.36 For these assays,
the plasma samples were first treated with ethanol to remove plasma
proteins. For the combination treatment, it was necessary to reduce the
dose of benazeprilat from monotherapy values to prevent a significant
fall in resting blood pressure. In these studies, a dose of
benazeprilat/valsartan 1/60 mg/d, respectively, yielded an
50% reduction in the pressor response to Ang I and an 40%
reduction to Ang II without a significant fall in basal blood pressure
(Fig 1). The average computed plasma level of valsartan in this portion
of the study was 658±150 nmol/L, with a range of 486 to 1220
nmol/L.
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Experimental Protocol and Animal Model Preparation
After the dose-selection studies, the effects of concomitant
treatment with ACEI alone, AT1 Ang II receptor blockade
alone, and combination therapy with chronic rapid pacing was examined.
Forty-six age- and weight-matched pigs (Yorkshire, 20 to 21 kg) were
randomly assigned to one of five groups: (1) rapid atrial pacing (240
bpm) for 3 weeks (n=9), (2) concomitant ACEI (benazeprilat, 3.75
mg/d) and rapid pacing (n=9), (3) concomitant AT1
Ang II receptor blockade (valsartan, 60 mg/d) and rapid pacing
(n=9), (4) concomitant ACEI and AT1 Ang II receptor
blockade (benazeprilat/valsartan, 1/60 mg/d, respectively) and
rapid pacing (n=9), and (5) sham controls (n=10). The drug treatment
protocols were begun at the initiation of pacing and continued for the
entire 21-day pacing protocol.
Pacemakers were implanted or sham procedures performed with animals anesthetized with isoflurane (3.0%, 1.5 L/min) and a mixture of nitrous oxide and oxygen, and animals were intubated. Through a left thoracotomy, a shielded stimulating electrode was sutured onto the left atrium, connected to a modified programmable pacemaker (8329, Medtronic, Inc), and buried in a subcutaneous pocket. The pericardium was approximated, the thoracotomy closed, and the pleural space evacuated of air. Vascular access ports were also implanted as described in the previous section. Seven to 10 days after recovery from the surgical procedure, the protocols described above were begun. Cardiac auscultation and an ECG were performed frequently during the pacing protocol to ensure proper operation of the pacemaker and the presence of 1:1 conduction. In this porcine preparation, atrioventricular conduction can be maintained at this pacing rate and therefore provide a homogeneous pattern of ventricular myocardial electrical activation. The sham-operated controls were cared for in identical fashion with the exception of the pacing protocol. All animals were treated and cared for in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals (National Research Council, Washington, DC, 1996).
LV Function and Hemodynamic Measurements
On the day of study, the animals were brought to the laboratory,
and an ECG was established. In the rapid-pacing groups, the pacemaker
was deactivated and the animals were allowed to return to a
normal sinus rhythm. During this stabilization period, the animal was
allowed to acclimate to the laboratory surroundings. Travill and
colleagues37 demonstrated that after induction of pacing
CHF and deactivation of the pacemaker, indices of LV function,
neurohormonal system activity, and heart rate remained stable for up to
4 hours. In the present study, all measurements were performed at
an ambient resting heart rate within 30 to 40 minutes after pacemaker
deactivation. Two-dimensional and M-mode
echocardiographic studies (ATL Ultramark VI, 2.25 MHz
transducer) were used to image the LV from a right parasternal
approach.9 25 27 LV fractional shortening was calculated
as (end-diastolic dimension-end-systolic
dimension)/end-diastolic dimension and was expressed as a
percentage. Mean aortic blood pressure was simultaneously
measured from the arterial access port. From the
arterial catheter, 30 mL of blood was drawn into chilled
tubes containing EDTA (1.5 mg/mL) and centrifuged
(2000g, 10 minutes, 4°C). The plasma was placed in
separate tubes, frozen in liquid nitrogen, and stored at -80°C until
the time of neurohormonal assay. To obtain a full
hemodynamic profile, catheterization
studies were also performed under identical anesthetic conditions. The
animal were anesthetized with isoflurane (0.5%, 1.5 L/min)
through a nonrecirculating anesthesia circuit. A multilumen
thermodilution catheter (7.5F, Baxter Healthcare Corp) was positioned
in the pulmonary artery via the right external jugular vein.
This catheter was used to measure thermodilution-derived cardiac
output, pulmonary artery pressures, and PCWP. To ensure that
there was no attenuation of the arterial pressure trace, a
20-cm sheath was placed into the left carotid artery and advanced to
the ascending aorta for additional pressure measurements. Aortic and
pulmonary artery pressures measured from the fluid-filled
catheters were connected to previously balanced and calibrated pressure
transducers (Statham P23ID). Thermodilution cardiac output measurements
were performed in triplicate. The ECG and pressure waveforms and
thermodilution curves were recorded with a precalibrated
multichannel recorder (Western Graphtec, FWR3701). From the
pressure recordings and cardiac output measurements,
pulmonary and systemic vascular resistances were computed. The
mean velocity of circumferential fiber shortening (Vcf) was calculated
by use of the LV echocardiographic dimension
measurements and the arterial pressure trace as described
previously.38 The LV ejection time used in the calculation
of Vcf38 was rate-corrected to a heart rate of 60 bpm by
multiplying by the square root of the RR interval.38 Thus,
this index of LV pump function was normalized for differences in
ambient resting heart rates. Peak circumferential wall stress was
computed with a spherical model: 
(g/cm2)=[PD/4h(1+h/D)]x1.36, where P is
systolic blood pressure, D is minor axis dimension, and h is
wall thickness.
All hemodynamic and LV function studies were performed under identical anesthetic conditions, and measurements were collected at identical blood pressures, which had been obtained when pigs were awake. After collection of echocardiographic and catheterization measurements, a sternotomy was performed, the heart was quickly extirpated and placed in a phosphate-buffered ice slush, and the coronary arteries were flushed. The great vessels were removed at the aortic and pulmonary valves, and the LV was quickly weighed. The LV apex and midventricular region and the right atrium were cut into 1x1-cm cubes and snap-frozen in liquid nitrogen for subsequent biochemical studies.
Neurohormonal Assays
The plasma samples were assayed for renin activity, endothelin
concentration, and norepinephrine levels. Plasma renin
activity was determined by computation of angiotensin I
production with a radioimmunoassay (NEA-026, New England
Nuclear). The interassay variation for the plasma renin activity
measurements was 15%. Plasma aldosterone was determined
with a radioimmunoassay procedure (ARUP Laboratories) with an
interassay variation of 10%. For the endothelin assays, the plasma was
first eluted over a cation exchange column (C-18 Sep-Pak, Waters
Associates) and then dried by vacuum centrifugation.
The samples were reconstituted in 0.02 mol/L borate buffer, and
a high-sensitivity radioimmunoassay was performed (RPA545, Amersham).
The recovery from the extraction procedure was 75±5%, based on plasma
spiked standards (4 to 20 fmol/mL). The interassay variation was
10% and the intra-assay variation was 9% for the endothelin
radioimmunoassay procedure. Plasma norepinephrine and
epinephrine were measured with high-performance liquid
chromatography and normalized to pg/mL plasma.
All assays were performed in duplicate.
Myocardial ACE Activity
Myocardial ACE activity was measured by a modified procedure
described by Cushman and Cheung.39 Briefly, LV and atrial
myocardial samples were thawed and homogenized in phosphate
buffer (50 mmol/L, pH 7.5) containing Triton X-100 (0.3%).
The resulting suspension was centrifuged and the supernatant
collected. Protein concentration of supernatant was determined by a
colorimetric assay (Bio-Rad Laboratories). In a water
bath maintained at 37°C, collected supernatant was incubated 1:3 with
sodium phosphate buffer (50 mmol/L, pH 7.5) containing
hippuryl-His-Leu for 10 minutes. The formation of His-Leu, which
reflects ACE activity, was then stopped with the addition of excess
NaOH, and the reaction mixture was labeled with 2%
o-phthaldialdehyde. The labeled product formed was then
quantified fluorometrically (Turner-112 Fluorometer, Sequoia-Turner
Corp) and normalized for protein concentration (nmol His-Leu ·
mg protein-1 ·
min-1).
Myocardial Ang II Receptor Assays
Myocardial Ang II receptor density, affinity, and subtype
distribution was determined by radiolabeled competition binding assays
as described previously.36 39 40 41 42 Previously frozen LV and
atrial myocardial samples (1 g) were homogenized in a
250 mmol/L sucrose buffer and centrifuged at
1000g for 20 minutes at 4°C. The supernatant was then
subjected to ultracentrifugation (40 000g,
4°C) for 30 minutes, and the resulting pellet was washed with a
solution containing 600 mmol/L KCl and 30
mmol/L L-histidine and centrifuged again.
The final pellet was resuspended in Tris-HCl (pH 7.4, 1
mmol/L EDTA) and stored in 0.5-mL aliquots at -80°C until the
time of assay. In a total incubation volume of 250 µL, 100 µg of
membrane protein was incubated with 250 pmol/L
125I-[Sar1,Ile8]Ang II (Anawa)
with or without competitors for 2 hours at 25°C. The incubation
buffer was Tris-HCl (20 mmol/L, pH 7.4) containing 1
mmol/L EDTA, 1 mmol/L benzamidine, 100
µg/mL bacitracin, and 2 mg/mL BSA. Competition curves
were constructed with unlabeled
[Sar1,Ile8]Ang II (Novabiochem) at
concentrations between 0.01 and 1000 nmol/L. The reaction was
terminated by immediate filtration through Whatman GF/F filters washed
4 times with 3 mL of ice-cold PBS. Filters were pretreated with 2
mg/mL BSA to reduce nonspecific binding. Nonspecific binding was
determined in the presence of 1 µmol/L unlabeled
[Sar1,Ile8]Ang II. The relative percentage of
AT1 Ang II receptors in the membrane preparations was
determined by Ang II receptor binding studies performed in the presence
of 10 µmol/L valsartan.18 The relative
percentage of AT2 Ang II receptors was determined by
incubation studies performed in the presence of 0.1
µmol/L of the AT2 Ang II receptor
antagonist CGP42112B.36 40 41 The receptor
binding data were subjected to analysis by the Ligand program
(Biosoft) to determine maximal Ang II receptor density
(Bmax, fmol/mg) and affinity
(Kd, nmol/L).
Data Analysis
Indices of LV function and systemic hemodynamics
were compared among the treatment groups by ANOVA. If the ANOVA
revealed significant differences, pairwise tests of individual group
means were compared by Bonferroni probabilities. For comparisons of
neurohormonal profiles, myocardial ACE activity, and Ang II receptor
data, the Student-Newman-Keuls test was used. All statistical
procedures were performed with the BMDP statistical software package
(BMDP Statistical Software Inc). Results are presented as
mean±SEM. Values of P<.05 were considered to be
statistically significant.
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Results |
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All of the pigs that were entered into the rapid-pacing protocol were successfully studied. After 3 weeks of chronic rapid pacing, all of the pigs in the untreated group demonstrated clinical symptoms consistent with CHF, which included tachypnea, lethargy, and reduced appetite during the last week of rapid pacing. In the pigs that underwent either monotherapy or combined ACEI and AT1 Ang II receptor blockade with chronic rapid pacing, these clinical symptoms of CHF were not as readily apparent. In the concomitant AT1 Ang II receptor blockade and rapid-pacing group, valsartan plasma levels were 558±86 nmol/L, and in the ACEI and AT1 Ang II blockade group, plasma levels were 375±109 nmol/L, with no significant difference between groups (P=.22). These plasma levels for the AT1 Ang II antagonist fell within the target therapeutic range determined from the initial dose-response studies.
LV Function With Pacing CHF: Effects of ACEI, AT1 Ang
II Blockade, and Combination Therapy
LV geometry and indices of pump function for controls, for pigs
with chronic rapid pacing, and for the different treatment groups are
summarized in Table 1. After 3 weeks of
chronic rapid pacing, basal resting heart rate was increased and mean
arterial pressure was reduced from control values. Mean
arterial pressure in all three treatment groups was similar
to rapid pacing–only values. LV end-diastolic dimension
increased by 65% and fractional shortening decreased by 67% in the
rapid-pacing group compared with the control group. Vcfc
fell more than twofold in the rapid-pacing group compared with control
values. With chronic rapid pacing, LV peak wall stress and PCWP
increased by more than threefold and cardiac output decreased by more
than threefold from control values. In the concomitant ACEI and
rapid-pacing group, basal resting heart rate and LV
end-diastolic dimension were reduced and fractional
shortening and Vcf increased compared with rapid pacing–only values.
LV peak wall stress and PCWP were lower in the ACEI and rapid-pacing
group than in the rapid pacing–only group. However, LV pump function
with concomitant ACEI and rapid pacing remained lower than control
values. In the concomitant AT1 Ang II receptor blockade and
rapid-pacing group, resting heart rate, LV end-diastolic
dimension, and systemic hemodynamics were similar to
rapid pacing–only values. In the AT1 Ang II blockade and
rapid-pacing group, cardiac output was higher than pacing-only values.
In the combined ACEI and AT1 Ang II blockade group, basal
resting heart rate was not different from control values. In the
combined ACEI and AT1 Ang II blockade group, LV
end-diastolic dimension, peak wall stress, and PCWP were
reduced and indices of LV pump function (fractional shortening, Vcf,
cardiac output) were increased compared with rapid pacing–only
values.
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With respect to comparisons among treatment groups, combined ACEI and
AT1 Ang II blockade resulted in a reduced LV
end-diastolic dimension and increased LV fractional
shortening, Vcf, and cardiac output compared with monotherapy-alone
values. In the AT1 Ang II receptor blockade group, LV
end-diastolic dimension and peak wall stress were increased
compared with the ACEI or combined treatment groups. LV stroke work,
systemic vascular resistance, and pulmonary vascular resistance
for all treatment groups are summarized in Fig 2. LV stroke work was significantly
higher in all three treatment groups compared with rapid-pacing-alone
values. However, in the ACEI and AT1 Ang II blockade group,
LV stroke work was higher than monotherapy-alone values.
Pulmonary and systemic vascular resistance were reduced in all
three treatment groups compared with rapid pacing–only values.
However, both pulmonary and systemic vascular resistances were
significantly lower in the combined ACEI and AT1 Ang II
receptor blockade group compared with monotherapy-alone values. There
were no significant changes in LV mass in any of the rapid-pacing
groups compared with the control group.
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Neurohormonal Activity With CHF: Effects of ACEI, AT1
Ang II Blockade, and Combination Therapy
Changes in plasma norepinephrine, endothelin, and
plasma renin activity with chronic rapid pacing and with concomitant
ACEI, AT1 Ang II blockade, and a combination treatment are
summarized in Table 2. Plasma
norepinephrine increased by nearly 10-fold and
epinephrine increased by 5-fold with chronic rapid pacing
compared with control values. In the chronic rapid-pacing group, plasma
endothelin levels increased by 280% and plasma renin activity
increased by 333% compared with the control group. In the ACEI group,
plasma norepinephrine fell significantly from rapid
pacing–only values but remained higher than control values. In the
AT1 Ang II receptor blockade group, plasma
norepinephrine was unchanged from rapid pacing–only
values. In the ACEI and AT1 Ang II blockade group, plasma
norepinephrine fell from rapid-pacing values but remained
higher than control values. In all three treatment groups, plasma
epinephrine was reduced from rapid pacing–only values and was
similar to control levels. In the ACEI-only group, plasma endothelin
levels fell from rapid pacing–only values, but this did not reach
statistical significance (P=.25). In the AT1 Ang
II receptor blockade group, plasma endothelin levels were unchanged
from rapid-pacing values. Plasma endothelin levels were significantly
reduced in the ACEI and AT1 Ang II blockade group compared
with rapid-pacing and monotherapy values. Plasma
aldosterone levels increased by nearly 20-fold in the rapid
pacing–only group compared with control values. In the ACEI group,
plasma aldosterone was reduced from rapid-pacing values but
remained higher than control values. In the AT1 Ang II
receptor blockade group, plasma aldosterone levels were
similar to rapid pacing–only values. With combined ACEI and
AT1 Ang II blockade during rapid pacing, plasma
aldosterone levels were similar to control values and
significantly lower than untreated CHF and monotherapy values
(P<.05). Consistent with pharmacological
interruption of the renin-angiotensin system, plasma renin
activity was increased in all rapid-pacing and treatment groups and was
higher than rapid pacing–only values. Plasma creatinine
values were similar in the control and pacing-induced CHF group
(1.5±0.1 and 1.6±0.1 mg/dL, respectively) and were unchanged
by concomitant ACEI (1.2±0.1 mg/dL), AT1 Ang II
receptor blockade (1.4±0.1 mg/dL), or combined treatment
(1.5±0.2 mg/dL).
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Myocardial ACE Activity and Ang II Receptor Profiles
LV and right atrial myocardial ACE activities with chronic rapid
pacing, concomitant ACEI, AT1 Ang II blockade, or
combination treatment are summarized in Table 3. Myocardial ACE activity was
significantly reduced in the chronic rapid-pacing group compared with
controls. In the atrial myocardium, ACEI, AT1
Ang II receptor blockade, or combination treatment increased ACE
activity from rapid pacing–only values, but it remained lower than in
controls. In the LV myocardium, ACE activity was normalized
with either monotherapy or combination treatment. In atrial
myocardium, Ang II receptor density was reduced with
chronic rapid pacing compared with controls (P=.09), with no
change in affinity. In the LV myocardium, a 50% reduction
in Ang II receptor density occurred with chronic rapid pacing, with no
change in affinity. With concomitant ACEI, both atrial and myocardial
Ang II receptor densities were similar to rapid pacing–only values.
With concomitant AT1 Ang II receptor blockade, Ang II
receptor density was similar to rapid-pacing values, but affinity was
reduced by >30% from control values. With combined treatment, Ang II
receptor density and affinity were normalized in both the atrial and LV
myocardium. The AT1 Ang II receptor subtype
composed the majority (>80%) of the Ang II receptors in both atrial
and LV myocardial preparations. There was no change in the Ang II
receptor subtype composition with chronic rapid pacing or in any of the
three treatment groups.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Increased activity of the myocardial and systemic renin-angiotensin system have been implicated as playing a contributory role in the progression of CHF.4 5 6 Although chronic ACEI has been shown to provide significant benefits in patients with CHF, the fundamental mechanisms responsible for these effects remain unclear. The goals of the present study were twofold: first, to define whether the effects of ACEI in the setting of developing CHF are due solely to reduced AT1 Ang II receptor activation and second, to determine the potential beneficial effects of combined ACEI and AT1 Ang II receptor blockade on LV function and systemic hemodynamics in the setting of CHF. To address these overall goals, the present study used a model of pacing-induced CHF in which chronic ACEI, AT1 Ang II receptor blockade, or a combination of both treatments was instituted with the initiation of chronic rapid pacing. Consistent with past reports,9 24 25 26 27 28 29 chronic rapid pacing caused LV dilation, pump dysfunction, and neurohormonal activation similar to the clinical spectrum of CHF. Chronic rapid pacing and concomitant ACEI reduced the degree of LV dilation, significantly improved LV pump function, and reduced the levels of circulating catecholamines. These effects of chronic ACEI in this model of pacing-induced CHF are consistent with a recent report from this laboratory.9 Chronic rapid pacing and AT1 Ang II receptor blockade did not confer protective effects on LV function and geometry similar to those of ACEI. Specifically, the degrees of LV dilation and pump dysfunction were similar in the untreated pacing CHF group and the chronic AT1 Ang II receptor blockade group. In contrast, combined ACEI and AT1 Ang II blockade provided significant beneficial effects on LV geometry and function and neurohormonal activation, which were greater than that obtained by ACEI alone. Moreover, combined ACEI and AT1 Ang II blockade reduced pulmonary and systemic vascular resistance to a much greater degree than did ACEI alone. The unique results from this study demonstrated that in a model of CHF, combined ACEI and AT1 Ang II blockade provided further beneficial effects on LV function and geometry and systemic hemodynamics compared with either ACEI or AT1 Ang II blockade alone.
In human studies and in animal models of hypertension, it has been demonstrated that specific AT1 Ang II antagonists can significantly reduce systemic blood pressure.17 18 19 20 21 Initial studies have demonstrated that AT1 Ang II receptor blockade can be safely instituted in patients with CHF.17 Moreover, combined ACEI and AT1 Ang II receptor blockade has been demonstrated to provide additional effects with respect to lowering systemic blood pressure.20 However, whether and to what degree AT1 Ang II receptor blockade or combined treatment with ACEI may influence LV function and geometry with the progression of CHF remained unclear. An important objective of the present study was to minimize the confounding influences of alterations in systemic loading conditions with the different treatment protocols with respect to LV function and wall stress patterns. In all drug treatment groups, mean arterial pressure was similar to and unchanged from rapid pacing–only values. In this manner, the direct effects of AT1 Ang II receptor blockade, ACEI, or a combination of both treatments at the level of the LV myocardium could be more carefully examined. In preliminary dose-response studies, a dosing strategy was developed that would reach a steady-state plasma level for the AT1 Ang II receptor antagonist that would achieve adequate inhibition of the Ang II pressor response. In the pacing-induced CHF studies, the plasma levels of the AT1 Ang II antagonist were maintained within this pharmacologically effective range. Monotherapy with AT1 Ang II receptor blockade with chronic rapid pacing significantly increased plasma renin activity, increased myocardial ACE activity, and altered myocardial Ang II receptor affinity. Taken together, these findings would suggest that the dosing strategy for AT1 Ang II receptor blockade chosen for the present study, although it did not influence basal resting blood pressure, had significant effects on both systemic and myocardial AT1 Ang II receptor activity. Thus, it is unlikely that the differences in the effects between AT1 Ang II receptor blockade and ACEI with respect to LV size and function in this model of CHF were due to insufficient AT1 Ang II receptor blockade.
LV Function
Consistent with past reports from this laboratory
and others,9 24 25 26 27 28 29 chronic rapid pacing causes LV dilation
and pump dysfunction. Concomitant ACEI with chronic rapid pacing
reduced the degree of LV dilation and improved indices of LV pump
function. These findings are consistent with a recent report
from this laboratory in which rapid ventricular pacing and
ACEI in dogs reduced LV end-diastolic volume and increased
ejection fraction.9 In the present study, concomitant
AT1 Ang II receptor blockade during rapid pacing did not
attenuate the degree of LV dilation compared with pacing CHF values. LV
fractional shortening and stroke volume were also not improved with
concomitant AT1 Ang II blockade during chronic rapid
pacing. However, because of the persistently elevated basal heart rate
in the AT1 Ang II receptor blockade group, cardiac output
was higher than pacing CHF values. Most importantly, combined treatment
with ACEI and AT1 Ang II receptor blockade during chronic
rapid pacing reduced the degree of LV dilation and improved pump
function compared with either monotherapy group. With combined therapy
during chronic rapid pacing, indices of LV afterload were reduced.
Thus, a contributory factor for the improved LV pump function with
combined ACEI and AT1 Ang II receptor blockade was a
reduction in LV afterload. In all treatment groups, pulmonary
artery pressure was reduced compared with pacing-induced CHF values.
These observations suggest that AT1 Ang II receptor
activation may contribute significantly to pulmonary vascular
resistance in the setting of CHF. The present study also
demonstrated that combined ACEI and AT1 Ang II receptor
blockade reduced pulmonary vascular resistance over monotherapy
values. Thus, this combined therapy may be of particular benefit in
improving flow through the pulmonary circuit in the setting of
CHF.
In the rapid-pacing CHF group, ambient resting heart rate was increased from normal control values, probably as a result of heightened sympathetic tone, as evidenced by increased catecholamines, as well as increased activation of the baroreceptor reflex due to diminished LV stroke volume and arterial pressure. With concomitant ACEI, ambient resting heart rate was reduced from rapid pacing–only values. This reduction in resting heart rate with ACEI is probably due to the concomitant reduction in circulating catecholamine levels and improved LV stroke volume. Concomitant AT1 Ang II receptor blockade with chronic rapid pacing resulted in ambient resting heart rates that were similar to untreated CHF values and were probably due to persistently elevated catecholamine levels and reduced LV stroke volume. In the combined ACEI and AT1 Ang II receptor blockade group, ambient heart rate was similar to normal control values. In this combined treatment group, plasma catecholamine and endothelin levels were reduced and LV stroke volume was increased compared with rapid pacing or monotherapy values. In a rat model of chronic ischemia, Sakai and colleagues43 demonstrated that acute infusion of an endothelin receptor antagonist decreased heart rate. Thus, contributory mechanisms for the reduced ambient heart rate with combined ACEI and AT1 Ang II receptor blockade most likely included a reduction in sympathetic tone and endothelin receptor activity, as well as improved LV stroke volume. In light of the differences in ambient resting heart rates between the treatment groups, an index of LV pump performance was examined by use of Vcfc.38 Consistent with a past report,44 Vcfc was significantly reduced in this pacing model of CHF compared with normal control values. With concomitant ACEI, Vcfc was increased from untreated pacing CHF values, but a similar improvement was not observed with concomitant AT1 Ang II receptor blockade. Combined ACE and AT1 Ang II receptor blockade improved Vcfc from both rapid pacing–only and monotherapy values. Thus, several indices of LV pump performance (fractional shortening, stroke volume, and Vcfc) were improved to a greater degree with combined ACEI and AT1 Ang II receptor blockade than with monotherapy. However, it must be recognized that all of these indices of LV pump function are load dependent and do not address whether inherent changes in contractile function occurred with either monotherapy or combined therapy during the development of pacing CHF. The issue of myocyte contractile performance in this model of CHF with these specific treatment strategies formed the basis of a subsequent investigation.45
LV Remodeling
Consistent with past reports,9 24 25 26 27 28 29 44 the
LV dilation that occurred with chronic rapid pacing was not associated
with a concomitant increase in LV mass. Thus, significant LV myocardial
remodeling must occur in this model of pacing-induced CHF. In the
present study, ACEI, AT1 Ang II receptor blockade, or
combination treatment did not affect LV mass. LV volumes were lower
with ACEI and combination therapy than with untreated pacing CHF
values. However, compared with control values, significant LV dilation
occurred. Thus, LV myocardial remodeling occurred despite ACEI or
combined therapy. In a model of murine viral myocarditis, Kanda et
al21 demonstrated that monotherapy with either ACEI or
AT1 Ang II reduced the degree of LV dilation. However, the
results from this past report also provided evidence that
AT1 Ang II blockade may not be as effective as ACEI in this
model of cardiomyopathic disease. McDonald and
colleagues8 reported that AT1 Ang II receptor
blockade failed to prevent LV dilation in a canine model of myocardial
injury, whereas ACEI attenuated the degree of LV dilation. In the
present study, specific AT1 Ang II receptor blockade
failed to prevent LV dilation, which invariably occurs with chronic
rapid pacing. In contrast, ACEI alone or in combination with
AT1 Ang II receptor blockade significantly reduced the
degree of LV dilation associated with chronic rapid pacing. A past
study from this laboratory demonstrated that the reduction in LV
dilation was associated with preservation of myocardial collagen
structure and composition.9 An important cellular
constituent of the LV myocardium is the fibroblast, and it
has been implicated as playing a contributory role in the myocardial
remodeling process.46 LV myocardial fibroblasts have been
reported to contain AT1 Ang II as well as AT2
Ang II receptors.47 48 Sadoshima and Izumo47
demonstrated changes in protein synthesis and expression in myocardial
fibroblasts after Ang II stimulation. In volume overload–induced
hypertrophy in rats, myocardial fibroblast response after
AT1 Ang II receptor stimulation was
enhanced.48 Taken together, these findings would suggest
that changes in the in vivo activity of the fibroblast AT1
Ang II receptor may not be the only contributory factor toward the LV
remodeling process in this model of CHF. However, additional in vivo
and in vitro studies will be necessary to determine the potential role
of AT1 Ang II and AT2 Ang II receptor
activation on fibroblast function and myocardial remodeling in the
setting of CHF.
Neurohormonal System Activity
Increased sympathetic activity is a hallmark in clinical forms of
CHF.3 30 31 During the progression of pacing-induced CHF,
it has been demonstrated that early and sustained elevations in plasma
catecholamines occur.9 26 27 28
Consistent with a recent report,9 the present
study demonstrated that plasma catecholamines were
significantly reduced by concomitant ACEI during chronic rapid pacing.
However, the present study demonstrated that concomitant
AT1 Ang II receptor blockade during rapid pacing did not
cause a similar reduction in plasma norepinephrine levels.
Interestingly, both ACEI and AT1 Ang II receptor blockade
during chronic rapid pacing normalized plasma epinephrine
values. Because the probable source of plasma epinephrine is
the adrenal medulla, the findings of the present study suggest that
increased AT1 Ang II receptor activation within the adrenal
gland is an important mechanism for epinephrine synthesis and
release in the setting of CHF.
Increased plasma endothelin levels have been identified with the development of severe CHF in patients.32 33 Consistent with this clinical neurohormonal profile of CHF, the present study demonstrated that the development of severe LV pump failure due to chronic rapid pacing is associated with increased plasma endothelin levels. Increased plasma levels of this potent vasoactive peptide with CHF reflect "spillover" due to enhanced local endothelin production.49 Although the controlling mechanisms for the synthesis and release of endothelin in the setting of CHF remain to be established, plasma endothelin may be a useful indicator for the degree of hemodynamic compromise and the transition to severe LV failure. In the present study, combined ACEI and AT1 Ang II receptor blockade during chronic rapid pacing significantly reduced plasma endothelin from pacing-induced CHF levels. This significant reduction in plasma endothelin was not achieved by either ACEI or AT1 Ang II receptor blockade alone. In patients with CHF, a relationship between circulating levels of endothelin and the degree of pulmonary vascular resistance has been reported.33 50 For example, Tsutamoto and colleagues50 demonstrated that in patients with severe CHF, endothelin spillover in the pulmonary circuit occurred and correlated with the degree of pulmonary vascular resistance. Increased endothelin production in the pulmonary system and subsequently increased pulmonary vascular resistance in patients with CHF may negatively influence right ventricular pump function as well as oxygenation capacity.51 Kiowski et al52 reported that acute administration of the nonselective endothelin receptor antagonist bosentan significantly reduced pulmonary vascular resistance in patients with CHF. Thus, in the present study, the reduction in circulating endothelin levels with combined treatment during rapid pacing may have contributed to a reduction in both systemic and pulmonary vascular resistance, which in turn would improve ventricular performance.
Consistent with severe forms of CHF, plasma renin activity increased with pacing-induced CHF. Concomitant ACEI with rapid pacing produced an expected rise in plasma renin activity,9 which is consistent with interruption of this enzymatic pathway. Concomitant AT1 Ang II receptor blockade or combined therapy causes an increase in plasma renin activity similar to that observed with ACEI. To more closely examine the effects of monotherapy and combined therapy with respect to the renin-angiotensin-aldosterone system, plasma levels of aldosterone were measured. With the development of pacing-induced CHF, plasma aldosterone increased significantly from normal control values. In past clinical studies, ACEI instituted after the development of CHF has been demonstrated to significantly attenuate plasma aldosterone levels.53 54 55 In the present study and consistent with these past clinical reports, ACEI instituted during the development of pacing CHF reduced aldosterone levels from untreated pacing CHF values. However, plasma aldosterone levels remained persistently elevated with rapid pacing and concomitant AT1 Ang II receptor blockade. Past studies have demonstrated that production of plasma aldosterone may not be totally dependent on Ang II formation and subsequent AT1 Ang II receptor activation.56 57 Specifically, with prolonged ACEI in patients with CHF, plasma aldosterone levels have been reported to gradually increase over time; this phenomenon has been called "aldosterone escape."57 In the present study, combined ACEI and AT1 Ang II receptor blockade with rapid pacing normalized plasma aldosterone levels. Thus, in this model of CHF, AT1 Ang II receptor blockade potentiated the effects of ACEI on plasma aldosterone levels. Some evidence suggests that aldosterone inhibits myocardial uptake of norepinephrine.56 58 Thus, the reduction in plasma aldosterone that occurred with combined therapy in this model of CHF may have reduced the degree of myocardial sympathetic activity.
Myocardial ACE Activity and Ang II Receptors
Past clinical and experimental reports have demonstrated that
enzymatic pathways exist within the myocardium for the
conversion of Ang I to Ang II.21 34 35 59 60 61 In the
present study, abundant myocardial ACE activity could be detected
in normal porcine LV and atrial samples, which was reduced with pacing
CHF. In the present study and consistent with past
reports,24 25 26 27 28 29 the development of pacing-induced CHF
resulted in increased LV volumes with no significant change in LV mass.
Thus, this chronic pacing model more closely resembles that of a
dilated cardiomyopathic state. Urata and
colleagues23 reported a 50% reduction in LV myocardial
ACE activity with the development of idiopathic dilated
cardiomyopathy in humans. The relative reduction in
myocardial ACE activity that occurred after the development of pacing
CHF in the present study is very similar to this past clinical
report of human end-stage CHF. Chronic rapid pacing and treatment with
either ACEI, AT1 Ang II receptor blockade, or combination
treatment increased myocardial ACE activity from pacing CHF values.
These findings suggest that all three treatment protocols used in the
present study had direct effects on local myocardial ACE activity
and that the reduction in myocardial ACE with pacing-induced CHF may be
due to a local feedback mechanism.23 34 However, it must
be recognized that myocardial ACE activity was determined with an in
vitro assay system, which may not reflect in vivo pathways of Ang II
formation.62 63 64 Thus, future studies in which intracardiac
Ang II formation is examined in vivo after monotherapy with either
ACEI, AT1 Ang II receptor blockade, or combination
treatment would be appropriate. Nevertheless, the present study
demonstrated that chronic ACEI improved LV function and geometry,
whereas treatment with an AT1 Ang II receptor
antagonist did not provide similar effects in a pacing
model of CHF. These findings would suggest that local Ang II
production and subsequent AT1 Ang II receptor
activation, irrespective of the myocardial enzymatic pathway, is not
the sole determinant of progressive LV dilation and pump dysfunction in
this model of CHF.
The predominant Ang II subtype appears to be species dependent and may change in cardiac disease states.40 41 42 65 66 In the present study, receptor binding studies performed in porcine myocardium revealed that the AT1 Ang II receptor subtype was the predominant Ang II receptor located within both the atria and LV. With the development of pacing-induced CHF, total LV myocardial Ang II receptor density was decreased, with no change in the proportion of AT1/AT2 Ang II receptors. Thus, the predominant Ang II receptor subtype expressed in both normal and failing porcine myocardium was the AT1 Ang II receptor, and potential confounding influences of AT2 Ang II receptor activity were thereby minimized. Monotherapy using either ACEI or AT1 Ang II receptor blockade with chronic rapid pacing failed to normalize myocardial Ang II receptor density, whereas combination therapy returned myocardial Ang II receptor density to near control levels. These results suggest that regulatory mechanisms for myocardial AT1 Ang II receptor expression are not solely due to receptor occupancy or activational states. Although monotherapy with AT1 Ang II receptor blockade did not influence myocardial Ang II receptor density or subtype expression, atrial receptor affinity was reduced, which suggests that chronic AT1 Ang II inhibition may influence receptor binding kinetics. In light of this finding, future studies that more carefully examine AT1 Ang II receptor kinetics and transduction in the setting of chronic AT1 Ang II receptor blockade may be appropriate. Nevertheless, the findings from the present study demonstrated that in a porcine model of CHF in which the predominant Ang II receptor subtype is the AT1 subtype, monotherapy with an AT1 Ang II receptor antagonist did not provide effects similar to that of ACEI with respect to LV function and geometry.
Potential Mechanisms for the Effects of Combined Therapy With
CHF
It is well established that ACE inhibitors can
influence other enzyme systems and bioactive peptide levels such as
bradykinin production, neurotensin, and substance
P.10 11 12 13 14 15 67 Thus, the beneficial effects of ACEI on LV and
myocyte function observed in the present study may be due to
modulation of these active peptide systems. Significant evidence
suggests that kallikrein-kinin proteolytic cascade systems exist within
the myocardium.12 13 14 15 Bradykinin, a nonapeptide
that is produced by the kallikrein cascade, has been implicated as
playing a direct role in myocardial remodeling and functional recovery
from myocardial ischemia.13 Moreover, ACEI appears
to prevent the rapid degradation of bradykinin and thereby potentiate
the beneficial effects of this peptide in the setting of myocardial
ischemia.13 14 15 Thus, a contributory mechanism for
the beneficial effects of concomitant ACEI observed in the present
study may be due to enhanced bradykinin levels within the
myocardium. McDonald and colleagues68
demonstrated that in a canine model of myocardial injury, the
beneficial effects of ACEI could be attenuated by the administration of
a bradykinin antagonist. The present study demonstrated
that combination therapy with ACEI and AT1 Ang II receptor
blockade provided additional beneficial effects with respect to LV
function and geometry. A potential explanation for this effect is that
concomitant AT1 Ang II receptor blockade potentiated the
effects of ACEI on these alternative enzyme systems within the
myocardium. Combined therapy in this model of pacing CHF
reduced plasma endothelin and aldosterone levels more than
monotherapy with either ACEI or AT1 Ang II receptor
blockade did. The additive effects of combined treatment on these
neurohormonal systems probably contributed to the beneficial effects on
vascular resistance properties and may have provided protective effects
on LV myocardial contractile performance. The specific
mechanisms by which combined ACEI and AT1 Ang II receptor
blockade improve LV pump function and systemic
hemodynamics in the setting of CHF warrant further
investigation. The specific effects of monotherapy and combined therapy
on inherent LV myocyte contractile processes with pacing CHF is the
subject of a subsequent study.45
Study Limitations
The present project used a model of chronic rapid pacing
that produces changes in LV functional and neurohormonal
characteristics similar to that of the clinical spectrum of CHF. Using
this animal model of developing CHF provides an opportunity to
determine the effects of ACEI and AT1 Ang II receptor
blockade in the absence of confounding influences, such as multiple
drug therapies, duration and degree of symptoms, and duration of
treatment, that would be encountered in clinical studies. However, it
must be recognized that any animal model will not fully
represent the complex clinical spectrum of CHF. Specifically,
the changes in LV myocardial structure that occur with pacing-induced
CHF are not similar to clinical forms of CHF due to chronic
ischemia or hypertensive disease. Thus, extrapolation of the
findings from this project to clinical forms of CHF should be done
with caution. Although monotherapy with AT1 Ang II receptor
blockade during the development of pacing-induced CHF did not prevent
the LV dilation and dysfunction, this treatment did produce beneficial
effects on systemic and pulmonary vascular resistance.
Furthermore, it should also be emphasized that in this model of severe
CHF, chronic AT1 Ang II receptor blockade was not
associated with any detrimental effects on LV pump function. In a past
clinical study, AT1 Ang II receptor blockade with
losartan reduced systemic vascular resistance in the setting of
CHF, which appeared to be dose dependent.17 Similar to
this past clinical study, our pacing-induced CHF and AT1
Ang II receptor blockade reduced systemic vascular resistance. However,
in the present study, the dosage of AT1 Ang II was
selected on the basis of attenuating the Ang II pressor response
without significant effects on basal mean arterial
pressure. Thus, the present experimental design could not address
whether higher doses of either ACEI, AT1 Ang II receptor
blockade, or a combination of both therapies in which a significant
blood pressure–lowering effect is achieved may provide further
beneficial effects on LV function and hemodynamics in
the setting of CHF. The development of CHF has been demonstrated to
cause changes in plasma and myocardial Ang II
levels.23 34 35 69 Although the present study examined
myocardial ACE activity and relative Ang II receptor abundance, direct
assessment of local and circulating Ang II levels was not performed. In
light of the findings of the present study, future studies that
directly examine Ang II production within the LV as well as
steady-state plasma levels after ACEI, AT1 Ang II receptor
blockade, or combination therapy in this model of CHF would be
appropriate.
Summary
ACEI is now realized to be a fundamental therapeutic modality in
patients with CHF. One of the mechanisms for the effects of ACEI in the
setting of CHF has been historically assumed to be reduced myocardial
AT1 Ang II receptor activation. Using a model of
pacing-induced CHF, the present study demonstrated that specific
AT1 Ang II receptor blockade did not provide protective
effects similar to those of ACEI with respect to LV function and
geometry. To the best of our knowledge, this is the first study to
examine the effects of combined ACEI and AT1 Ang II
receptor blockade on LV function and geometry in the setting of CHF.
The results from this study clearly demonstrated that combined therapy
provided additive beneficial effects on LV geometry and pump function
with pacing-induced CHF. Contributory mechanisms for the enhanced
beneficial effects of combined ACEI and AT1 Ang II receptor
blockade include a reduction in the degree of LV dilation and improved
loading conditions and neurohormonal activity. Thus, dual therapy with
both ACEI and AT1 Ang II receptor blockade may provide
further beneficial effects in the setting of CHF.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This study was supported by National Institutes of Health grant HL-45024 (Dr Spinale), a Basic Research Grant from Novartis (Dr Spinale), an American Heart Association Grant-in-Aid (Dr Spinale), and an AHA Medical Student Fellowship Award (D.M. Melton). Dr Spinale is an Established Investigator of the American Heart Association. The authors wish to express their appreciation to Charles Basler, Jennifer Hendrick, and Julie Iannini for their excellent technical assistance in this project.
Received February 3, 1997; revision received May 21, 1997; accepted May 28, 1997.
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