2616
Intracoronary Angiotensin-Converting Enzyme
Inhibition Improves Diastolic Function
in Patients With Hypertensive
Left Ventricular Hypertrophy
Howard L. Haber, MD; Eric R. Powers, MD; Lawrence W. Gimple, MD; Clarence C. Wu, MSE;
Komathi Subbiah, ME; William H. Johnson, RN; Marc D. Feldman, MD
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Background There is increasing recognition of myocardial
angiotensin-converting enzyme, which is induced with the
development of left ventricular hypertrophy (LVH). The potential physiological significance of subsequent increased angiotensin I to II conversion in the presence of LVH is unclear
but has been postulated to cause abnormal Ca2' handling and
secondary diastolic dysfunction. Accordingly, we hypothesized
that acute angiotensin-converting enzyme inhibition would
result in decreased production of angiotensin II and improved
active (Ca2"-dependent) relaxation in patients with hyperten-
sive LVH.
Methods and Results Intracoronary (IC) enalaprilat was
administered to 25 patients with and without LVH secondary
to essential hypertension. Indexes of diastolic and systolic LV
function were determined from pressure (micromanometer)volume (conductance) analysis at steady state and with occlusion of the inferior vena cava. Patients were divided into those
receiving high- (5.0 mg, n= 15) and low-dose (1.5 mg, n= 10) IC
enalaprilat during a 30-minute infusion at 1 mL/min. The
high-dose patients were further divided along the median
normalized LV wall thickness of 0.671 cm/M2. The time
constant of isovolumic relaxation (TauL) was prolonged at
baseline in patients receiving high-dose enalaprilat with wall
Angiotensin-converting enzyme inhibitors have
gained widespread use in the therapy of
chronic hypertension and secondary left ventricular hypertrophy (LVH). This is due in part to the
recognition of the role of the circulating renin-angiotensin system in the pathophysiology of essential hypertension and LVH.1 More recently, the existence of a
physiologically active cardiac renin-angiotensin system
has been demonstrated, with evidence of local synthesis
of angiotensinogen, renin, angiotensin-converting enzyme, and angiotensin-converting enzyme mRNA in the
Received August 20, 1993; revision accepted February 25, 1994.
From the Department of Internal Medicine, Cardiovascular
Division, University of Virginia Health Sciences Center,
Charlottesville.
Presented in part at the 65th Scientific Sessions of the American
Heart Association, New Orleans, La, November 1992, and selected
for a Young Investigator Award (M.D.F.), Scientific Conference
on the Molecular Biology of the Normal, Hypertrophied, and
Failing Heart of the American Heart Association, August 1993,
Pacific Grove, Calif.
Correspondence to Marc D. Feldman, MD, Director, Cardiac
Catheterization Laboratory, University of Pittsburgh Medical
Center, 200 Lothrop St, Pittsburgh, PA 15213.
thickness >0.671 cm/m2 (TauL, 56±2 versus 44±2 and 45±2
milliseconds, respectively, P<.01 by ANOVA) and shortened
only in this patient group (TauL, 49±3 versus 46±2 and 43±2
milliseconds, respectively, P<.01 versus baseline and other
groups by ANOVA). The improvement in TauL was directly
proportional to the degree of LVH (r=.92, P<.001). Although
there was a decrease in LV end-diastolic pressure (23±2 to
15±1 mm Hg, P<.01) and volume (86±8 to 67±9 mL/m2,
P<.05) in those patients with a reduction in TauL, this is due
to movement down a similar diastolic pressure-volume relation
with no change in chamber elastic stiffness (0.023±0.002 to
0.025±0.004 mL-1, P=NS).
Conclusions Intracoronary enalaprilat resulted in an improvement in active (Ca 2-dependent) relaxation in those
patients with more severe hypertensive LVH. The improvement in active relaxation was directly proportional to the
severity of LVH. These results support the hypothesis that the
cardiac renin-angiotensin system is an important determinant
of active diastolic function in hypertensive LVH. (Circulation.
1994;89:2616-2625.)
Key Words * hypertrophy * diastole * angiotensin .
enzymes * enalaprilat
heart.2-9 Nevertheless, the local physiological effects of
angiotensin II on cardiac function remain to be clarified.
The effects of the cardiac renin-angiotensin system on
ventricular function may be important in the pathophysiology and hemodynamic consequences of LVH. The
binding of angiotensin II to its cardiac receptor activates
phospholipase C, resulting in an increased cellular
content of inositol phosphates and changes in the
mobilization and reuptake of cytosolic free [Ca2+]1.1o
Since cardiac hypertrophy is associated with abnormalities in Ca2' extrusion by the sarcolemma and reuptake
by the sarcoplasmic reticulum, these increases in cytosolic free [Ca21]i due to angiotensin II could impair
myocardial relaxation during diastole.11-14 In an isovolumic perfused rat heart model of pressure-overload
hypertrophy from aortic banding, angiotensin I administration caused an increased LV end-diastolic pressure
in hypertrophied hearts compared with controls.7'8 In a
similar model, the administration of the angiotensinconverting enzyme inhibitor enalaprilat attenuated the
increase in LV end-diastolic pressure of hypertrophied
hearts in response to low-flow ischemia.'5 The clinical
significance of these molecular and hemodynamic ab-
Haber et al Intracoronary Enalaprilat and Diastolic Function
normalities in human LVH is unknown. We hypothesized that angiotensin-converting enzyme inhibition
would acutely improve active (Ca2+-dependent) relaxation in patients with LVH caused by systemic hypertension. Furthermore, we hypothesized that the severity
of LVH would be related to the extent of induction of
cardiac angiotensin-converting enzyme and, hence, to
the degree in improvement in active relaxation with
acute angiotensin-converting enzyme inhibition. To test
these hypotheses, we administered intracoronary (IC)
enalaprilat to 25 patients with and without LVH secondary to systemic hypertension and measured indexes
of LV diastolic and systolic function.
Methods
Patient Selection Criteria
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Patients scheduled for elective cardiac catheterization at the
University of Virginia were eligible for enrollment. Twentyfive patients referred for cardiac catheterization for the evaluation of dyspnea and chest pain syndromes with a clinical
history of hypertension of at least 1 year were enrolled in this
study. No patient in this group had any history of myocardial
infarction or any segmental wall motion abnormality during
left ventriculography. Patients were excluded from study if
they had any exposure to angiotensin-converting enzyme inhibitors within 6 weeks. Other exclusions included atrial
fibrillation or significant valvular disease. All medications were
withheld for at least 16 hours before the cardiac catheterization. Written informed consent was obtained from each patient, and the protocol was approved by the Human Investigation Committee at the University of Virginia.
Data Acquisition
For echocardiographic LV wall thickness, standard M-mode
and two-dimensional images were obtained within 24 hours of
cardiac catheterization. Measurements of the interventricular
septum and LV posterior wall from the M-mode parasternal
long-axis view were made with a quantitative image processing
system (IMAGEPRO). These values were averaged and normalized to the body surface area.
Conductance Catheter Technique
A detailed description of the principles and technique of the
conductance catheter are described elsewhere.16'17 The present study used an 8F conductance catheter (Webster Laboratories) and a 2F micromanometer catheter (Millar Instru-
ments) fully extended within its lumen. The catheters were
positioned under fluoroscopic guidance along the long axis of
the left ventricle (LV) and connected to a signal-conditioner/
processor (Sigma 5DF, Cardiodynamic) operating at 20 kHz.
The system uses a dual excitation algorithm via two pairs of
stimulating electrodes positioned at the apex and base of the
ventricle. Resistances measured across intervening electrode
pairs are inversely related to segmental volumes, and individual segment volumes are summed to yield total chamber
volume. Real-time pressure-volume loops were displayed on a
PC-based data acquisition and analysis system (Halcom Inc).
Pressure and volume data were acquired at 200 samples per
second.
Protocol
Patients underwent routine right and left heart catheterization, coronary angiography, and left ventriculography. Nonionic contrast was used (Isovue, Squibb Diagnostics) to minimize the negative inotropic effects of contrast media. After the
diagnostic study, the 8F conductance and 2F micromanometer
catheters were advanced into the LV cavity as described
previously. Subsequently, a 7F 40-mm balloon occlusion catheter (Cordis Corp) was placed in the right atrium to perform
2617
inferior vena caval occlusion. Baseline hemodynamic parameters recorded at least 30 minutes after the diagnostic cardiac
catheterization included heart rate, mean right atrial pressure,
pulmonary capillary wedge pressure (PCWP), LV pressure
(LVP), thermodilution cardiac output, and stroke volume.
Subsequently, inferior vena caval occlusion was performed,
and pressure-volume loops were recorded on a beat-by-beat
basis for up to 50 seconds.
A 6F Judkins left coronary catheter was inserted into the
left main coronary artery for the purpose of IC drug administration. Patients received a 30-minute IC infusion of enalaprilat (flow rate, 1 mL/min) for a total dose of 1.5 mg in the
first 10 patients and a total dose of 5 mg in the remaining 15
patients. Hemodynamic measurements were then repeated
and pressure-volume loops recorded after inferior vena caval
occlusion as described. Left ventriculography was repeated for
recalibration of the conductance volume signal.
Data Analysis
Data obtained from the conductance and micromanometer
catheters were analyzed off-line by computer (Halcom Inc).
The pressure and volume recordings were smoothed with a
three-point, nonweighted moving average filter before hemodynamic parameters were determined. Absolute volume measurements from the conductance catheter were calibrated with
corrections for offset and gain before and after the administration of IC enalaprilat. The gain correction was calculated as
the ratio between thermodilution stroke volume and conductance stroke volume. The offset correction was computed as
the product of the gain correction and the conductance
end-diastolic volume, subtracted by the right anterior oblique
left ventriculographic end-diastolic volume (determined with
the Kennedy-Dodge regression).18 The time-varying ventricular volume was then calculated as the gain correction multiplied by the conductance ventricular volume, subtracted by the
offset correction.
The series of pressure-volume loops used to generate the
end-systolic and end-diastolic pressure-volume relations commenced with the beat preceding a visual fall in volume and
ended either at nadir volume or with baroreflex activation
(defined as a 5% increase in heart rate on three consecutive
beats). All premature and postpremature beats were excluded
from the analysis. The following variables were determined.
LV Afterload: Effective Arterial Elastance (E.)
Ea was calculated from the ratio of end-systolic pressure
(Pc,) and stroke volume (SV), or Ea=PesISV, as previously
defined.19'20
Diastolic Parameters
1. Time constant of isovolumic LVP relaxation, TauL. TauL
was calculated from the ln(LVP)-versus-time relation, as derived by Weiss et al,21 which assumes that during isovolumic
relaxation, LVP decayed in a monoexponential manner to
Tau measures the active diastolic properties of the LV
and represents the time constant for calcium dissociation from
the myofilaments.22-24 The goodness of fit for the calculation of
TauL in the present study was r2= .998.
2. Time constant of isovolumic LVP relaxation, TauG. TauG
was calculated from the dP/dt-versus-pressure relation, as
derived by Raff and Glantz.25 The goodness of fit for the
calculation of TauG in the present study was r2= .973.
3. Peak LV filling rate (dV/dtm,a.). The peak LV filling rate
was calculated from the maximum value of the first derivative
of the calibrated conductance volume signal.
4. Minimum LVP (LVPmin). The minimum LVP was determined during early diastole.
5. Early diastolic transmitral gradient (PCWP-LVPmin). The
early diastolic transmitral gradient was approximated by subtracting the minimum early LVP from the maximum PCWP
obtained from the peak of the "v" wave.
zero.
Circulation Vol 89, No 6 June 1994
2618
Pre
',e..-
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1
A
1
1
A
. L~ ~ ~ ~ A~XL'
in
I
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Post
a 1
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'
~
I
A
a
L:
I
A_
if\f\\f\r\%Wr~n~.
l
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Pressure-Volum Loop Plot ... File: PAT151.ATI
Pressure-Volum Loop Plot ... File: PATISI.CTI
2001
200
Downloaded from http://circ.ahajournals.org/ by guest on June 16, 2017
150'
150-
0M
E
E
E
E
1(00
100~
CU)
U)
0
C-
CL
C-
In
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50
so.
C-
CL
C4
.-,.--
40
80
120
so.
9) i
t
.
40
90
120
Volume (ml)
(ml)
FIG 1. Tracings showing example data from a patient with left ventricular thickness/body surface area ratio >0.671. Left, Pre-enalaprilat;
right, postenalaprilat. Real-time right atrial, ECG, left ventricular volume, and left ventricular pressure data are displayed during occlusion
of the inferior vena cava. Resultant pressure-volume relations are shown below. A visual fall in end-systolic elastance and preload is
Volume
evident.
6. Chamber elastic stiffness (B). The diastolic pressurevolume relation was derived from the last 50% of diastolic
filling ending immediately before atrial systole. A single point
within this interval was selected for the baseline pressurevolume loop and each subsequent pressure-volume loop obtained during a load change with inferior vena caval occlusion.
These points were fixed at a set interval before end diastole.
The diastolic pressure-volume relation was obtained by connecting these points. Chamber elastic stiffness was calculated
by fitting these diastolic pressure-volume points to an elastic
model, P=P0+a(eBv-1), with a Marquardt nonlinear leastsquares algorithm, where B is passive chamber elastic stiffness
(milliliter-1), P0 is the baseline pressure (mm Hg), and a is a
constant. Thus, chamber elastic stiffness is a measure of the
passive late diastolic properties of the LV.
Systolic Parameters
1. LV stroke work index (SWI). SWI was calculated from the
integrated area circumscribed by each pressure-volume loop
normalized by body surface area.
2. Preload recruitable stroke work (M,). LV stroke work
was plotted against LV end-diastolic volume for each of the
pressure-volume loops generated after inferior vena caval
occlusion. M,, represents the slope of this relation by linear
regression.26
3. End-systolic elastance (E,,). The end-systolic pressurevolume point of each loop was selected as the data point with
the maximum (P/[V-VJ). A least-squares linear regression of
those points was applied, generating slope (E,j) and intercept
(VO) estimates. With this estimate of intercept, points of
maximal (P/[V-V0]) for each cycle were obtained, and a
subsequent regression was used to determine new estimates for
Ees and V.. This process was repeated until there was no change
in either parameter with subsequent iterations (Fig 1).27
Statistical Analysis
Data were compiled and analyzed on a minicomputer (VAX
8200, Digital Equipment Corp) using RS/1 (Bolt, Beraneck
and Newman). Continuous variables were expressed as
mean±SEM, and differences between groups were estimated
by either a t test with pooled variance or a one-way ANOVA.
Categorical data were expressed as proportions, and differences between groups were estimated by the Fisher exact test
or X 2. Differences between groups were considered significant
at a value of P<.05 (two-tailed with Bonferroni correction).
Results
Clinical Patient Characteristics
The characteristics of the 25 patients enrolled in this
study are shown in Table 1. Patients given the 1.5-mg
dose of IC enalaprilat (n=10) composed a younger
group of predominantly male patients without severe
LVH. Patients in the 5-mg IC enalaprilat group
(n=15) composed an older group of predominantly
female patients with a spectrum of LVH. The median
Haber et al Intracoronary Enalaprilat and Diastolic Function
2619
TABLE 1. Patient Characteristics
LV Thickness/BSA, cm/m2
1.5-mg Dose
<0.671
(n=10)
5.0-mg Dose
<0.671
(n=7)
>0.671
(n=8)
Age, y
48±2*
59±3
64±4
Male, n (%)
7 (70)
1 (14)
4 (50)
LVEF, %
59±3
64±2
60±6
LV thickness, cm/M2
0.57±0.02
0.61 ±0.02
0.79±0.04*
2 (20)
Coronary disease, n (%)
(0)
2 (25)
0
LV indicates left ventricular; BSA, body surface area; and LVEF, angiographic left ventricular ejection
fraction.
*P<.01 vs other groups (ANOVA).
Downloaded from http://circ.ahajournals.org/ by guest on June 16, 2017
normalized LV thickness in the 5-mg dose group was
0.671 cm/m2. Patients in the 5-mg dose group were
divided into groups with and without severe LVH on
the basis of this median value. Although all patients
were referred for cardiac catheterization because of
dyspnea and chest pain syndromes, only four patients
(16%) had epicardial coronary artery disease. The
distribution of coronary stenoses in these four patients
was isolated right coronary artery disease, two-vessel
coronary artery disease involving the diagonal and
obtuse marginal branches in one and the left anterior
descending and right coronary arteries in another, and
three-vessel coronary disease in the last. Finally, 23
patients (92%) had never been exposed to an angiotensin-converting enzyme inhibitor before this
study. The remaining two patients (8%) had not taken
an angiotensin-converting enzyme inhibitor for at
least 6 weeks before study.
Effect of Intracoronary Angiotensin-Converting
Enzyme Inhibition on Chronotropy and Load
The effects of IC enalaprilat on heart rate, preload,
and afterload in patients who received the 1.5-mg dose
and those with and without severe LVH who received
the 5.0-mg dose are shown in Table 2. At baseline, load
and heart rate were similar in all three groups of
patients. LV preload (LV end-diastolic volume index)
fell only in patients given high-dose IC enalaprilat.
Among those patients who received the high dose, the
greatest preload reduction was observed in those with
TABLE 2. Effect of Intracoronary Enalaprilat on Chronotropy and Load
LV Thickness/BSA, cm/m2
5.0-mg Dose
1.5-mg Dose
<0.671
(n=10)
<0.671
(n=7)
>0.671
74±4
74±4
84±4
84±4
77±4
73±6
81±3
80±3
74±4
65±2*
86±8
...
...
1492±129
1508±118
1485±124
1493±118
2.36±0.22
2.24±0.24
2.87±0.52
2.68±0.42
2.55±0.38
2.60±0.40
(n=8)
HR, bpm
Pre
Post
EDVI, mL/m2
Pre
Post
67±9*t
SVR, dynes . s/cm5
Pre
Post
Ea, mm Hg/mL
Pre
Post
PVR, dynes * s/cm5
Pre
Post
168±28
103±8
123±16
185±30
111±8
132±14
LV indicates left ventricular; BSA, body surface area; HR, heart rate; bpm, beats per minute; EDVI,
left ventricular end-diastolic volume index; SVR, systemic vascular resistance; Ea, effective arterial
elastance; PVR, pulmonary vascular resistance; Pre, before enalaprilat; and Post, after enalaprilat.
*P<.05 Pre vs Post; tP<.05 change vs other groups (ANOVA).
2620
Circulation Vol 89, No 6 June 1994
TABLE 3. Effect of Intracoronary Enalaprilat on Diastolic Function
LV Thickness/BSA, cm/m2
1.5-mg Dose
<0.671
(n=10)
5.0-mg Dose
<0.671
(n=7)
>0.671
(n=8)
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PCWP, mm Hg
16+2
13±2
13±1
Pre
11±1*
9±1
12±1
Post
LVEDP, mm Hg
23±2
17±3
20±2
Pre
15±1*
12±1
1 7±2t
Post
RAP, mm Hg
9±1
9±1
8±1
Pre
7+1
8+1
8+1
Post
TauL, ms
44±2
45±2
Pre
56+22t
49+3*§
46+2
43±2
Post
TauG, ms
55+3
64±5
67±2
Pre
61±2*§
57+3
63±6
Post
LVPmin, mm Hg
13±2
10±2
9±1
Pre
7±1
9±1
Post
8±1t
dV/dtma,, mL/min
515+41
526±55
448±40
Pre
405±31
490±36
493±50
Post
mm
PCWP-LVPmin,
Hg
4±1
3±1
3±1
Pre
3±1
2±1
3+1
Post
B, mL-1
0.023±0.002
0.019+0.001
Pre
0.021 ±0.001
0.025±0.004
0.019±0.003
0.020±0.002
Post
LV indicates left ventricular; BSA, body surface area; PCWP, pulmonary capillary wedge pressure;
LVEDP, left ventricular end-diastolic pressure; RAP, right atrial pressure; TauL, time constant of
isovolumic relaxation (logarithmic); TauG, time constant of isovolumic relaxation (dP/dt vs LVP);
LVPmin, minimum left ventricular pressure; dV/dtma,, peak left ventricular filling rate; and B, chamber
elastic stiffness.
*P<.01 Pre vs Post; tP<.05 Pre vs Post; tP<.01 baseline vs other groups (ANOVA); §P<.01
change vs other groups (ANOVA).
severe LVH. Afterload and heart rate did not change
after treatment with IC enalaprilat in any group of
patients in the present study.
Effect of Intracoronary Angiotensin-Converting
Enzyme Inhibition on Diastolic Function
The diastolic hemodynamic parameters of the patients
given the 1.5-mg dose (n= 10) and the patients given the
5.0-mg dose (n= 15) of IC enalaprilat are shown in Table
3. At baseline, TauL was significantly prolonged in patients with severe LVH given high-dose enalaprilat
(P=.003 by ANOVA). Furthermore, patients with severe
LVH tended to have greater abnormalities in passive LV
diastolic function, as measured by LV chamber stiffness
(P=.058 by ANOVA). After IC enalaprilat, PCWP and
LV end-diastolic pressure were reduced in patients with
severe LVH given the 5.0-mg dose.
Active relaxation was improved with the 5.0-mg
dose of IC enalaprilat in those with severe LVH, as
indicated by improvements in the time constants of
isovolumic relaxation (TauL and TauG) and minimum
LVP (LVPmin). Conversely, the early transmitral gradient (PCWP-LVP,,i,,n) and the peak filling rate (dV/
dtmax) were unchanged with IC enalaprilat despite an
improvement in active relaxation in patients with
severe LVH. Passive LV diastolic function (chamber
elastic stiffness) was also unaffected by IC enalaprilat
administration.
2621
Haber et al Intracoronary Enalaprilat and Diastolic Function
20
24
r=O.92
m
10
1 5 mg dose
<0.671 cm/M2
p'CO.OO 1
0
-
0
0
12
0
° E
OK
-10
_
-0
e
--*
-20
0.50
-°
0
0.60
0.70
0.80
0.90
1.00
100
LV THICKNESS/BSA
200
5.0 mg dose
<0.671 cm/M2
Pressure
(mm Hg)
12
.--
Downloaded from http://circ.ahajournals.org/ by guest on June 16, 2017
The magnitude of the improvement in active relaxation with IC enalaprilat (reduction in TauL) was directly proportional to the degree of LVH in these
patients (Fig 2, r=.92, P<.001). Similar results were
found for TauG (r=.81, P<.001). The mean LV diastolic
pressure-volume relations before and after IC enalaprilat for each of the three groups studied are shown in
Fig 3. Visual assessment of these three sets of relations
demonstrates no significant changes in chamber compliance. There was no significant change in the LV diastolic pressure-volume relation in the low-dose enalaprilat group. However, there were preload reductions at
high dose, with movement down a similar diastolic
pressure-volume relation.
Effect of Intracoronary Angiotensin-Converting
Enzyme Inhibition on Systolic Function
The systolic hemodynamic parameters of the patients
given the 1.5-mg dose (n= 10) and the patients given the
5.0-mg dose (n=15) of IC enalaprilat are shown in
Table 4. At baseline, the three groups of patients were
similar with respect to all systolic hemodynamic parameters. Among patients who received the 5.0-mg dose of
IC enalaprilat, LV systolic pressure, SWI, and preload
recruitable stroke work fell in the patients without
severe LVH, whereas cardiac index and end-systolic
elastance fell in the patients with severe LVH. Nevertheless, the effects of IC enalaprilat administration on
all systolic hemodynamic parameters were similar in the
three groups by ANOVA.
Discussion
The present study demonstrates the beneficial acute
hemodynamic effects of local cardiac angiotensin-converting enzyme inhibition in patients with hypertensive
LVH. Intracoronary enalaprilat administration resulted
in an improvement in active (Ca'+-dependent) relaxation in those with more severe LVH. Furthermore, this
improvement in active relaxation was directly proportional to the severity of LVH in these patients. The
greater the LVH, the greater the improvement in active
(Ca'+-dependent) relaxation. The reduction in PCWP
in high-dose patients with severe LVH provided an
additional hemodynamic benefit. This benefit, however,
was not due to improvements in early diastolic filling or
Post
24
(cmlm2)
FIG 2. Graph showing relation between normalized left ventricular (LV) wall thickness and change in the time constant of
isovolumic relaxation (TauL) after intracoronary administration of
enalaprilat in the 15 patients who received the 5.0-mg dose.
There is a linear relation between an improvement in active
relaxation and increasing LV hypertrophy (r=.92; P<.001). BSA
indicates body surface area.
Pre
o
a
.5
0
100
-
Pre
Post
200
24
5.0 mg dose
>0.671 cn/M2
12
Pre
Post
0
0
100
Volunm (ml)
200
FIG 3. Graphs showing mean diastolic pressure-volume relations for the 1.5-mg enalaprilat dose, left ventricular (LV) wall
thickness <0.671 cm/M2 patients (n=1 0); the 5.0-mg enalaprilat
dose, LV wall thickness <0.671 cm/M2 patients (n=7); and the
5.0-mg enalaprilat dose, LV wall thickness >0.671 cm/M2 patients (n=8). * indicate baseline diastolic pressure-volume relations (pre); cl indicate enalaprilat relations (post). There is no
visual change, pre versus post, in patients receiving the low
dose of enalaprilat. However, there is visual movement down a
given mean diastolic pressure-volume relation for all patients
receiving the 5.0-mg enalaprilat dose, regardless of degree of LV
hypertrophy, consistent with a reduction in preload.
LV compliance, since the peak LV filling rate (dV/
dtmax) and chamber stiffness were unaffected by acute
IC angiotensin-converting enzyme inhibition. LV filling
pressures were reduced because of movement down a
similar LV diastolic pressure-volume relation secondary
to a reduction in preload rather than any intrinsic
change in passive LV diastolic function.
The results of the present study support the hypothesis that the cardiac renin-angiotensin system is an
important determinant of active diastolic function in
hypertensive LVH. Angiotensin II administration has
been shown to increase the L-type Ca'+ current independently of adenylate cyclase, with a subsequent
decrease in relaxation velocity,28 and affects the mobilization and reuptake of cytosolic free [Ca2]i via phospholipase C activation and inositol phosphate second
messengers.10 The reductions observed in Tau and
LVP,i, in LVH patients given the higher dose of
angiotensin-converting enzyme inhibitor are consistent
2622
Circulation Vol 89, No 6 June 1994
TABLE 4. Effect of Intracoronary Enalaprilat on Systolic Function
LV Thlckness/BSA, cm/m2
5.0-mg Dose
1.5-mg Dose
<0.671
(n=7)
>0.671
(n=8)
159+9
156+7
173+10
159+10*
179+12
172+14
3.10+0.23
2.92±0.20
3.33±0.32
3.02±0.23
3.00±0.16
2.54±0.15t
42±2
40±2*
38±3
36±2
39±2
35±2*
39±3
40±3
36±4
29±2
42±9
39±7
4486±322
4175±318
4747±428
4057±341 t
4906±695
4256±519
1.78±0.39
1.75±0.33
2.42±0.42
2.09±0.19
1.81±0.49
1.26±0.29*
<0.671
(n=10)
Downloaded from http://circ.ahajournals.org/ by guest on June 16, 2017
LVSP, mm Hg
Pre
Post
Cl, L min-1 . m-2
Pre
Post
SVI, mL/m2
Pre
Post
ESVI, mL/m2
Pre
Post
SWI, mm Hg* mLlm2
Pre
Post
Ees, mm Hg/mL
Pre
Post
MSW,
mm
Hg
76±8
83±13
92±9
Pre
76±7
90±12
71±9*
Post
surface
left
ventricular
LV indicates left ventricular; BSA, body
systolic pressure; Cl,
area; LVSP,
cardiac index; SVI, stroke volume index; ESVI, left ventricular end-systolic volume index; SWI, left
ventricular stroke work index; Ees, end-systolic elastance; and MSW, preload recruitable stroke work.
*P<.05 Pre vs Post; tP<.01 Pre vs Post.
with the premise that inhibition of cardiac angiotensin
II production would result in improvement in active
(Ca2-dependent) relaxation. Furthermore, the fact
that the degree of improvement in Tau with IC angiotensin-converting enzyme inhibition is directly proportional to the severity of LVH provides physiological
evidence that the cardiac renin-angiotensin system is
induced to a greater extent with increasing LVH.2,7-915
These findings are even more impressive because the
mode of administration of enalaprilat via only the left
coronary artery might be expected to cause regional
asynchrony, which should retard active relaxation rather
than improve it.
The reduction in preload after high-dose IC enalaprilat administration merits further comment. There
were significant reductions in LV end-diastolic volume
indexes seen in patients with and without severe LVH
who received high-dose IC enalaprilat. It is unlikely that
this observed preload reduction could have been due to
volume depletion secondary to the nonionic contrast
used during the diagnostic cardiac catheterization, because patients given the low dose of IC enalaprilat did
not demonstrate any significant hemodynamic effects
despite a similar experimental protocol (see Fig 3). This
probably reflects a systemic concentration of enalaprilat
despite its IC route of administration, with inhibition of
bradykinin degradation in the venous system.29 Bradykinin has been shown to produce venodilation both
because of direct effects30,31 and secondary to its effects
on prostaglandins30,32 and endothelium-derived relaxing
factor.30,33 This preload reduction may be responsible
for the absence of improvement in the rate of early LV
filling. An improvement in active diastolic function
might be expected to improve the rate of early LV filling
by increasing the early transmitral gradient.3435 Although IC enalaprilat administration improved active
diastolic function (Tau) in patients with LVH, the
expected secondary improvement in peak early LV
filling (dV/dtmax) did not occur. This may have been due
to the accompanying preload reduction. Nevertheless,
the reductions in LV filling pressures with angiotensinconverting enzyme inhibition provide additional hemodynamic benefit in patients with hypertensive LVH.
The present study demonstrated that although IC
angiotensin-converting enzyme inhibition improved active relaxation, it did not affect the passive late diastolic
properties of the LV as assessed either by a calculated
LV chamber stiffness or the visual appearance of the LV
diastolic pressure-volume relation. These results are
contrary to those of others,78 who concluded in an
Haber et al Intracoronary Enalaprilat and Diastolic Function
Downloaded from http://circ.ahajournals.org/ by guest on June 16, 2017
isolated perfused rat heart model that alterations of the
cardiac renin-angiotensin system acutely changed diastolic compliance in hypertrophied hearts compared
with controls. They further postulated that these effects
on passive diastolic function must be secondary to
changes in active Ca2' handling mediated by the cardiac
renin-angiotensin system. However, these changes were
observed in an isovolumic preparation. The present
study provides the first description of the effect of IC
angiotensin-converting enzyme inhibition on passive LV
diastolic function in ejecting hypertrophic ventricles.
The observations of the present study appear to demonstrate an uncoupling of active and passive diastolic
function in patients with abnormal active relaxation.
Unfortunately, although measures of Tau may quantify
the rate of LV relaxation, there are no direct measures
of the extent of relaxation.36 Therefore, previous investigators have used the rate of relaxation as an indirect
surrogate for the extent of relaxation and demonstrated
that the end-diastolic pressure-volume relation of the
normal filling canine LV was unaffected by changes in
active relaxation provided that end diastole occurred
more than 3.5 TauL37 or 3.7 to 5.4 Tau38,39 after dP/dtffi.
By these criteria, one would not expect IC enalaprilat to
alter the LV diastolic pressure-volume relation in patients with hypertrophy in the present study, since all
should have had complete LV relaxation at baseline.
The direct effect of the renin-angiotensin system on
LV systolic function in different species has been the
subject of considerable interest. The positive inotropic
effects of angiotensin II in cardiac tissues of most
mammalian species have been well documented.40-44
These effects have been ascribed to specific receptors
localized on cardiomyocytes40'45A'6 and on intramyocardial sympathetic nerve terminals.47"48 These findings
may be species specific, however, in view of the lack of
a positive inotropic response to angiotensin II in myocardium from the guinea pig49 and the adult rat.50
Angiotensin II receptors have been identified in the
myocardium and cardiac nerve terminals of human
myocardium.51 More recently, the positive inotropic
effects of angiotensin II on human cardiac muscle in
vitro have been demonstrated.52 These results imply
that IC administration of angiotensin-converting enzyme inhibitors to patients should exert a negative effect
on myocardial contractility, which has been confirmed
in patients with dilated cardiomyopathy.53 In the present study, IC administration of high-dose enalaprilat
exerted at most a modest negative inotropic effect,
unlike its more profound effects on active relaxation.
Limitations of the Study
There are several potential limitations to this study.
The first involves the accuracy and linearity of the gain
and offset calibration of the conductance volume signal.54,55 Although the gain calibration for the conductance volume signal is nonlinear over a large volume
range, previous investigators have demonstrated that
even during an acute load change, the calibrated conductance volume signal is accurate within the range of
volume from end-diastolic volume to end-systolic volume of the baseline loop.55 Since IC enalaprilat did not
reduce late diastolic volumes below that of the endsystolic volume of the baseline loop, the LV diastolic
pressure-volume relation reported in the present study
2623
should be accurate. Another potential limitation is that
the offset calibration caused by the parallel conductance
of adjacent structures was assumed to be constant
during the load change of inferior vena caval occlusion.
This assumption should be valid, because previous
investigators have demonstrated that the offset calibration of the conductance volume signal is relatively
insensitive to changes in right ventricular volume16 or
LV thickness and shape changes during the cardiac
cycle.56 The possibility that the effect of enalaprilat on
diastolic function may have been due to improvement in
ischemia rather than via a direct myocardial effect
merits further comment. Although LVH is associated
with subendocardial ischemia during stress, it is unclear
whether patients with LVH manifest chronic subendocardial ischemia while at rest. In a canine renal
hypertension model of LVH, Mueller et a157 did not
observe any abnormalities in endocardial perfusion or
endocardial/epicardial flow compared with control animals. Although Rembert et al58 observed mild resting
abnormalities in the resting endocardial/epicardial systolic (but not diastolic) flow ratio at rest in a canine
coarctation banding model of LVH, they concluded that
these animals were unlikely to have resting subendocardial ischemia because they were not in a state of maximal
vasodilatation at rest, as evidenced by their more than
twofold increase in flow with adenosine. Another limitation involves the use of the PCWP-LVP,ffi difference to
estimate the early transmitral gradient during early diastole. The fluid-filled PCWP was obtained despite the
abnormal frequency response and time delay through the
pulmonary circulation. Although simultaneous left atrial-LV micromanometer pressure recording would have
eliminated this technical limitation, it would have required an additional transseptal catheterization in an
already heavily instrumented patient. The final limitation
reflects infusion of enalaprilat only into the left coronary
artery. We may have underestimated the benefit of
angiotensin-converting enzyme inhibition on active relaxation, because this nonuniform mode of administration
might be expected to cause regional asynchrony, which
could retard active relaxation.
Conclusions
This study confirmed the hypothesis that angiotensinconverting enzyme inhibition acutely improves active
(Ca2+-dependent) relaxation in patients with LVH secondary to systemic hypertension. Furthermore, we confirmed a secondary hypothesis that the severity of
hypertensive LVH would be related to the extent of
induction of cardiac angiotensin-converting enzyme.
The greater the LVH, the greater the improvement in
active (Ca2+-dependent) relaxation. As a result, this
study represents the first demonstration of an acute
direct benefit of an antihypertensive medication on
hypertensive LV diastolic dysfunction.
Acknowledgments
This study was supported by a fellowship (H.L.H.) from the
American Heart Association, Virginia Affiliate, Inc (VA-91F-61); a Merck Medical School Program Grant (M.D.F.); and
a FIRST award (M.D.F.) from the National Heart, Lung, and
Blood Institute (R29-HL-47046-01). This study could not
have been performed without the assistance and excellent
clinical care offered by the entire staff of the Cardiac Cathe-
2624
Circulation Vol 89, No 6 June 1994
terization Laboratory at the University of Virginia and the
superb editorial skills of Dorothy Grabman. We would like to
thank Robert Abbott, PhD, for his statistical assistance and
Drs Michael R. Zile and Blase Carabello for their critical
evaluation of this project.
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Intracoronary angiotensin-converting enzyme inhibition improves diastolic function in
patients with hypertensive left ventricular hypertrophy.
H L Haber, E R Powers, L W Gimple, C C Wu, K Subbiah, W H Johnson and M D Feldman
Downloaded from http://circ.ahajournals.org/ by guest on June 16, 2017
Circulation. 1994;89:2616-2625
doi: 10.1161/01.CIR.89.6.2616
Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
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