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THERAPY AND PREVENTION
CORONARY ARTERY DISEASE
Improvement in regional wall motion and left
ventricular relaxation after administration of
diltiazem in patients with coronary artery disease
HAROLD DASH, M.D., GARY L. COPENHAVER, B.S.,
AND
SUSAN ENSMINGER, B.A.
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ABSTRACT To assess the effect of diltiazem on left ventricular systolic regional wall motion and
diastolic function in patients with coronary artery disease (CAD), 22 patients underwent biplane left
ventricular cineangiography before and after intravenous diltiazem (plasma concentration 154 + 12
ng/ml). Left ventricular and right ventricular pressures were measured by micromanometer-tipped
catheters. Regional wall motion was assessed quantitatively with an area ejection fraction technique.
Diltiazem decreased mean arterial pressure 11.5% (p < .0001) and heart rate 6.8% (p < .005); it
increased cardiac index 8.8% (p < .025) and global ejection fraction 9.1% (p < .0001). However, left
ventricular end-diastolic pressure increased 14.2% (p < .001) and the left ventricular end-systolic
pressure-volume (P-V) ratio decreased 8.8% (p < .02). Diltiazem decreased the time constant of left
ventricular relaxation by 14.3% (p < .002), despite lack of change in the left ventricular diastolic P-V
relationship, in 16 patients. Diltiazem caused a significant increase in area ejection fraction in 53% of
hypokinetic areas supplied by diseased arteries compared with 13% of normokinetic areas supplied by
diseased arteries (p < .0001). Response of ejection fraction to diltiazem in areas supplied by normal
coronary arteries was less (p < .05) than that in hypokinetic areas supplied by arteries affected by
disease. In conclusion, diltiazem improves regional wall motion abnormalities in patients with CAD
and the improvement is associated with better left ventricular relaxation but not with a change in the
diastolic P-V relationship. Global indexes of left ventricular systolic performance are favorably influenced by diltiazem, despite a mild negative inotropic effect.
Circulation 72, No. 2, 353-363, 1985.
DILTIAZEM HYDROCHLORIDE is a calcium-channel blocker that is effective in the therapy of exertionall" 2 and variant3 angina pectoris. Like other calcium-channel blockers, it has complex cardiovascular
effects": it dilates peripheral and coronary arteries, is
a negative inotropic agent, and depresses conduction
in the atrioventricular and sinus nodes. The primary
hemodynamic effect of intravenous or oral diltiazem is
peripheral vasodilation, usually occurring without reflex sympathetic stimulation so that there is no change
or a decrease in heart rate.6' 7 The consequent decrease
in the rate-pressure product is thought to be a major
mechanism by which diltiazem exerts its protective
effect in patients with exercise-induced angina pecFrom the Division of Cardiology, Department of Medicine, Pennsylvania State University College of Medicine, The Milton S. Hershey
Medical Center, Hershey, PA.
Supported in part by grants from The South Central Pennsylvania
Chapter of the American Heart Association and from Marion Laboratories, Inc.
Address for correspondence: Harold Dash, M. D., The Everett Clinic,
Colby at 39th, Everett, WA 98201.
Received May 30, 1984; revision accepted April 30, 1985.
Vol. 72, No. 2, August 1985
toris." 7 Other mechanisms that might protect the myocardium from ischemia have not been demonstrated
conclusively. Measurements of total coronary blood
flow have shown little change after diltiazem,7' 8 and it
has not been possible to demonstrate a clinically apparent negative inotropic effect of the drug4'9' '0 except
during acute myocardial ischemia5 or in an animal
preparation of high-output congestive heart failure."
Early in the course of coronary artery disease
(CAD), patients develop abnormalities of regional left
ventricular contraction'2 1' and alterations in diastolic
function, 14 15 even in the absence of myocardial infarction. Given the critical role that calcium plays in the
processes of cardiac contraction and relaxation, one
might expect that the calcium-channel blockers might
affect these abnormalities of systolic and diastolic
function seen in patients with CAD. Studies2' 16 1 have
shown that diltiazem improves resting left ventricular
global ejection fraction and attenuates the hemodynamic and global ejection fraction abnormalities that
develop during exercise-induced angina, but there has
been no comprehensive evaluation of the effects of
353
DASH et al.
diltiazem on systolic and diastolic ventricular function
in patients with CAD. We designed this investigation
to assess the effects of diltiazem on left ventricular
systolic regional wall motion, left ventricular relaxation, and diastolic compliance in patients with CAD.
Methods
Patient population. Twenty-two patients undergoing cardicatheterization for the evaluation of chest pain syndromes
comprised the study population. All were men and their mean
age was 56.5 ± 8.6 (range 41 to 71) years. Criteria for exclusion from the study were presence of unstable angina, acute
myocardial infarction within 3 months of catheterization, severe
congestive heart failure or hypotension, valvular heart disease,
atrial fibrillation, uncontrolled arrhythmias, and second- or
third-degree atrioventricular block. All cardioactive medications except long-acting nitrates were discontinued at least 48 hr
before catheterization. Long-acting nitrates were discontinued
at least 12 hr before the study. The experimental protocol was
approved by the Clinical Investigation Committee of The Milton S. Hershey Medical Center, and all patients participating
gave informed consent.
Experimental protocol. All patients underwent catheterization, while they were in the fasting state and without premedication, from the femoral approach. Arterial pressure was measured with a cannula inserted into the left radial artery. Baseline
right heart pressures were measured with a flow-directed pulmonary artery catheter inserted percutaneously into the right
femoral vein. Cardiac output was measured by indicator-dilution technique. The flotation catheter was then exchanged for a
No. 7F micromanometer-tipped catheter (Millar Instruments,
Inc.), which was positioned in the right ventricle. A No. 8F
micromanometer-tipped pigtail injection catheter was then inserted percutaneously into the right femoral artery and advanced
to the left ventricle.
Both micromanometer-tipped catheters were calibrated to external transducers, and the calibration was checked at intervals
throughout the study. The 0 mm Hg reference level for the
external transducer was at the midchest level. All measurements
were made during a held, gentle, submaximal inspiration.
When performed properly, such a respiratory maneuver results
in stable intracardiac pressures."8 We confirmed that each patient performed the maneuver properly by observing respiratory
motion fluoroscopically and intracardiac pressures during pressure recordings. We collected the pressure data on an Electronics for Medicine VR 12 recorder set at a 2500 Hz filter and
interfaced with an Electronics for Medicine Catheterization
Laboratory Computer with a sampling rate of 200 Hz.
After measuring baseline intracardiac pressures, we performed biplane 30 degree right anterior oblique/60 degree left
anterior oblique left ventricular cineangiography with 40 ml of
66% diatrizoate meglumine and 10% diatrizoate sodium (Renografin-76) injected at a rate of 12 ml/sec. Film speed was 60
frames/sec. Pressures were measured during the left ventricular
cineangiographic examination, and an electrically triggered
cine tracer marked the x-ray film and sent a timing signal to the
VR 12 recorder to allow for simultaneous measurement of pressure and volumes.
After a rest period of 15 to 20 min, intracardiac pressures
were again measured to confirm that hemodynamics had returned to baseline. Previous studies'8-20 have documented that
such a rest period eliminates any effects of the radio-iodinated
contrast agent from the first left ventricular cineangiogram on
the systolic and diastolic left ventricular function as determined
at the second cineangiographic examination. We then adminisac
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354
tered diltiazem intravenously as an initial bolus of 0.25 mg/kg
followed by a continuous infusion of 0.0014 mg/kg/min for 10
min. The continuous infusion was increased every 2 min by
0.0014 mg/kg/min as necessary to maintain a faIl in mean arterial pressure of approximately 10% from baseline. Plasma diltiazem levels were measured before and after the infusion. At the
end of 10 min, when systemic arterial pressure was stable, we
repeated intracardiac pressure measurements and then obtained
a second biplane left ventricular cineangiogram with the use of
an identical dose of contrast agent.
After the completion of the protocol, all patients underwent
selective coronary angiographic examination by the femoral
approach.
Data analysis. We analyzed hemodynamic and volumic data
from the first adequately opacified sinus beat within the first
five cardiac cycles after injection of contrast agent and did not
use postpremature beats. Left ventricular cineangiographic film
frames were projected with a Vanguard XR-35 projector and the
left ventricular silhouettes were digitized with a Graf-Pen ultrasonic digitizer interfaced with a PDP 1 1/05 computer. Right and
left anterior oblique grids obtained at the time of each study
were also digitized to correct for x-ray magnification and distortion. For each patient, the two left ventricular cineangiograms
were projected in random order and the investigator was blinded
as to their order and identity. Volumes were determined by the
biplane area-length method. We measured volumes serially every 33.3 msec.
The digitized pressure data were stored on a magnetic disk for
analysis by the PDP 11105 computer. Simultaneous left ventricular pressures and volumes from the time of minimal diastolic
pressure to end-diastolic (post-a wave) pressure were fitted to
the polynomial equation
P = aV + bV2 + cV3 + dV4 + e
(1)
where P = left ventricular pressure (mm Hg) and V
left
ventricular volume index (ml/m2). We used multiple linear
analysis21 of the control and diltiazem diastolic pressure-volume
(P-V) relationships to assess the adequacy of the P-V fits for
each experimental condition. To determine the short-term effect
of diltiazem on the left ventricular P-V relationship, we then
performed a multiple linear regression analysis of the combined
data with the following equation:
=
P
=
aV4
+
bV3 + cV2 + dV + e + f(DTZ) + g(DTZ x V)
(2)
where DTZ = 0 during the control state and DTZ = 1 during
the drug study. The coefficients a, b, c, d, and e in equation 1
are not necessarily identical to those in equation 2. This type of
P-V analysis is a modification of that described by Glantz.22
Linear regression analysis can tell us whether the terms f(DTZ)
and g(DTZ X V) contribute significantly to the diastolic P-V
relationship. If f(DTZ) is statistically significant, then diltiazem
causes a significant shift in the intercept of the P-V fit; if
g(DTZ x V) is statistically significant, then diltiazem causes a
significant shift in the slope of the diastolic P-V fit.
The polynomial relationship is an empiric fit between pressure and volume during diastole and thus makes no assumptions
about the physiologic interaction of pressure and volume. As a
consequence, the coefficients of the equation do not represent
indexes of ventricular chamber stiffness. We used such an approach rather than the more traditional exponential analysis
because we wanted to evaluate the effect of diltiazem on the
entire period of left ventricular filling. The left ventricular diastolic P-V relationship approximates an exponential function
only during passive filling when elastic properties of the left
ventricle are of paramount importance.22 23 Deviation from the
exponential occurs during rapid filling and at end-diastole,
CIRCULATION
THERAPY AND PREVENTION-CORONARY ARTERY DISEASE
0
22 r
B
A
x
20 F P=(2.17
107)V4-(0.0015)V2
+9.3+0.17(DTZ x V)
18 r P=(9.82 x 106) V3(2.93 x 10-4)V2+5.72
0
W
2:
16 F R=0.962
I
EE
14
k
12
F
14
h
0
CL
0/7
-
0@
10 F
12
0~VN
0-
(n
J)
a-
E
E
0
18 F R =0.974
p=0.006, DTZ x V
16 F
_Q
0
h
10
_i
8
8
0
6
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0
o
Control
o
*
DTZ
* DTZ
6
--
50
60
70
80
90
100
0
110
LV Volume (mu/M2)
40
50
60
70
80
Control
90
100
LV Volume Index (mu/M2)
FIGURE 1. A, Left ventricular (LV) diastolic pressure volume fit (R = .962) in a patient with no change in compliance after
diltiazem (DTZ) despite an increase in LV diastolic pressure (P) and volume (V). B, LV diastolic pressure volume fit (R = .974)
in a patient with a decrease in LV compliance after diltiazem. DTZ = 0 for the control study and DTZ = I for the diltiazem
study. The change in slope after DTZ is reflected by the inclusion of the term "DTZ x V' in the equation with p = .006.
when viscous properties of the left ventricle are apparent.24
Using the polynomial fit we were able to quantify the shifts in
the overall left ventricular diastolic P-V relationship caused by
diltiazem and using linear regression analysis we were then able
to determine whether shifts in the left ventricular diastolic P-V
relationship in individual patients were statistically significant
(figure 1). This contrasts to previous studies of left ventricular
diastolic function in which investigators used grouped data25-27
to evaluate the effects of an intervention on left ventricular
diastolic P-V relationships or assessed the individual P-V fits
visually.28-30 The advantages of the polynomial approach have
been discussed previously.22
To assess the effect of diltiazem on left ventricular relaxation,
we measured the time constant (T) of the negative monoexponential pressure decay during isovolumetric left ventricular relaxation. T was derived according to the method suggested by
Craig and Murgo3' and verified by Thompson et al.32 Pressure
was measured during isovolumetric relaxation every 5 msec
from maximum negative dP/dt to a pressure that was 5 mm Hg
above the left ventricular end-diastolic pressure of the next beat
and fit to the equation
P(t) = (P0 - PB) e t/T + pB
=
where P pressure; t = time; P0 = pressure at t = 0; PB
base pressure if isovolumetric left ventricular pressure decay
continued indefinitely (t = so); T = time constant. By taking
the derivative, the equation is transformed to
dP(t)/dt = P(t)/T + PB/T
resulting in a linear relationship between dP/dt and P with a
slope that is the negative reciprocal of T. T is then derived by
linear regression analysis. The validity of such a model depends
on how well the model describes the physiologic system. Others
have reported that isovolumetric left ventricular relaxation is not
exactly a negative monoexponential decay.33 Consequently, for
Vol. 72, No. 2, August 1985
each beat analyzed we determined the correlation coefficient of
the linear relationship between T and left ventricular negative
dP/dt. We also used least squares analysis to reconstruct the
original equatioti (the monoexponential equation) from the calculated T. The SEE of such an analysis indicates how closely
the mathematic model actually fits the raw pressure data. We
measured at least 25 beats in every patient. In all cases an R
value greater than .953 and an SEE less than 1.7 mm Hg were
obtained, indicating that in our patients, T accurately described
the time constant of left ventricular relaxation. Because recent
work has suggested that T is load dependent,33 we assessed the
effects of diltiazem-induced changes in load on T by linear
regression analysis. The other index of left ventricular relaxation measured was maximum negative dP/dt.
We evaluated left ventricular systolic function by measuring
the ejection phase indexes of global ejection fraction and mean
velocity of circumferential fiber shortening (Vcf), the isovolumetric index of maximurn positive dP/dt, and the left ventricular
end-systolic P-V ratio.34
In addition to global left ventricular systolic function, we
assessed regional wall motion with a quantitative area ejection
fraction technique.35 The left ventricle was divided into eight
areas. End-diastolic and end-systolic left ventricular silhouettes
were identified with use of frame-by-frame analysis. For each
area
end-systolic area
End-diastolic area
where EF is ejection fraction. Normokinesis was considered to
be present when the area ejection fraction was within 1 SD of the
normal mean value for our laboratory; hypokinesis was defined
as an area ejection fraction of less than 1 SD of the normal mean
value. A statistically significant change in area ejection fraction
caused by diltiazem was defined as a change beyond the 95%
confidence intervals of random variability in this value as deterEnd-diastolic
area
-
Area EF -
355
DASH et al.
The two patients with normal coronary arteries had
atypical chest pain and normal resting left ventricular
function. They have been included in the study because eliminating their data from the analysis did not
alter the results.
mined in our laboratory.36 Such an approach allowed us to
quantitate significant changes in regional wall motion not only
in individual patients, but also in individual left ventricular
regions.
Downloaded from http://circ.ahajournals.org/ by guest on June 16, 2017
Significant CAD was defined as a coronary stenosis of greater
than 70% of luminal diameter. For each patient, the relationship
between regional CAD and myocardial area was documented.
Those areas jeopardized by CAD were defined as CAD areas.
The effect of diltiazem on area ejection fraction and its relation
to CAD areas was determined by chi-square analysis.
To assess the influence of baseline left ventricular function on
the results, we divided the patients into two groups according to
the presence or absence of baseline left ventricular dysfunction,
as defined by the range of normal values for our laboratory. The
criteria used were an elevated left ventricular end-diastolic volume index (> 100 ml/m2), elevated left ventricular end-diastolic
pressure ( 17 mm Hg when measured during ventriculography), or a depressed global ejection fraction (<0.54).
To compare data obtained at control and after diltiazem in
individual patients, we used the paired t test. Group comparisons of continuous data were evaluated with the t test for differences between group means or, when multiple comparisons
were made, analysis of variance. All data are mean + SEM.
Effect of diltiazem on hemodynamics and left ventricular
volume. Table 1 shows that diltiazem caused significant
decreases in mean arterial pressure (1 1.5%), left ventricular systolic pressure (13.5%), calculated systemic
vascular resistance (20.8%), and heart rate (6.8%).
Cardiac output increased 8.8% and left ventricular
stroke volume index increased 16.7%. Significant
changes in the ejection phase indexes of left ventricular
function indicated an improvement in left ventricular
systolic performance: Global ejection fraction increased9.1 %from 0.55
0.02 to0.60 + 0.02 and
left ventricular mean Vcf increased 10.3%. In addition, left ventricular end-systolic volume index decreased by 7.6%. The findings indicate that diltiazem
given intravenously reduced afterload acutely and improved global left ventricular systolic performance.
The extent of improvement in left ventricular systolic
function as assessed by percentage increase in global
ejection fraction correlated with the percentage decrease in left ventricular systolic pressure (R = .564,
p < .01).
Despite the improvement in global left ventricular
systolic performance, diltiazem had some intrinsic
negative inotropic effects (table 1). The significant fall
Results
Clinical characteristics. Twenty of the 22 patients had
CAD. All had stable angina pectoris and 14 had suffered prior myocardial infarction. Multivessel CAD
was common: 13 patients had three-vessel disease,
four had two-vessel disease, and three had one-vessel
disease. Left ventricular asynergy was present in 19 of
the 20 patients with CAD and in neither of the patients
with normal coronary arteries. The amount of left ventricle jeopardized by CAD averaged 65.9 + 6.2%.
TABLE 1
Hemodynamics and left ventricular volumes and function before and after diltiazem (n -22)
C
Heart rate (beats/min)
Mean systemic arterial pressure (mm Hg)
LV systolic pressure (mm Hg)
LV end-diastolic pressure (mm Hg)
LV maximum positive dP/dt (mm Hg/sec)
LV maximum negative dP/dt (mm Hg/sec)
T (msec)
PB (mmHg)
RV systolic pressure (mm Hg)
RV end-diastolic pressure (mm Hg)
Cardiac index (1/min/m2)
Systemic vascular resistance (dynes-sec-cm - 5)
LV end-diastolic volume index (m1/m2)
LV end-systolic volume index (m1/M2)
LV stroke volume index (ml/m2)
LV global EF
LV mean Vcf (circ/sec)
LV end-systolic P-V ratio
All data are mean ± SEM.
C = control; D = diltiazem; LV
356
=
D
68.7 +3.3
101.3 2.6
141.2+4.2
17.6+ 1.1
1470+66
1782+87
68.5 7.3
-14.2+2.8
29.0+1.8
9.3 0.7
3.20+0.14
1290 ± 52
86.9+3.3
39.7 2.6
47.2 1.9
0.55+0.02
1.07+0.09
3.29 0.24
left ventricular; RV
=
64.0 - 2.6
89.6 ±2.0
122.1 +3.9
20.1 1.0
6.8
11.5
- 13.5
+ 14.2
10.5
-7.1
14.3
+45.8
+5.9
+ 7.5
+8.8
- 20
O. 8
+5.6
- 7.6
+ 16.7
<. 005
< .000 1
-
58.7 5.5
-7.7+2.3
30.7+1.6
10.0 0.6
3.48+0.12
1022 ± 39
91.8+3.3
36.7 +2.4
55.1 ±2.5
0.60±0.02
1.18±0.08
3.00 ± 0.20
=
p
value
-
1315+53
-1655+88
right ventricular; EF
cc
Change
+-9.1
+ 10.3
-
8.8
<.0001
<.001
<.001
<.02
<.002
<.0001
<.03
NS
<. 025
<.0001
<.005
<.002
<.001
<. 0001
<.025
<. 02
ejection fraction.
CIRCULATION
THERAPY AND PREVENTION-CORONARY ARTERY DISEASE
of 10.5% in left ventricular maximum positive dP/dt
may have reflected the decrease in afterload rather than
negative inotropy, but the left ventricular end-systolic
P-V ratio also decreased by 8.8% after diltiazem. Diltiazem increased left ventricular end-diastolic pressure
significantly (14.2%) from 17.6 ±- 1.1 to 20.l +- 1.0
mm Hg. This increase in pressure was paralleled by a
mild increase in right ventricular systolic pressure, but
occurred without any significant change in end-diastolic pressure in the right ventricle. In addition to the
increase in left ventricular end-diastolic pressure, diltiazem also significantly increased the left ventricular
end-diastolic volume index by 5.6%.
Effect of diltiazem on the left ventricular diastolic P-V
relationship and left ventricular relaxation. We were able
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to generate left ventricular diastolic P-V fits in 20 of
the 22 patients. In the other two patients, the cine
tracer failed, preventing us from correlating simultaneous left ventricular pressures and volumes. In the 20
patients, the diastolic P-V fits to polynomial equation 1
for both control and diltiazem P-V curves were excellent, with the correlation coefficients ranging from
.955 to .996. The mean correlation coefficient for
these left ventricular diastolic P-V relationships was
.976 + .002. When the data obtained at control and
after diltiazem were combined and analyzed with polynomial equation 2, the correlation coefficients ranged
from .956 to .988, with a mean of .972 ± .002. Thus,
combining the two sets of data to create a single polynomial equation did not degrade the "goodness" of fit
of the diastolic P-V analysis.
In 16 of the 20 patients there was no change in the
left ventricular diastolic P-V relationship after diltiazem (figure 1, A). In three patients there was an upward shift after diltiazem caused by a change in slope
in two patients (figure 1, B) and a change in intercept in
one patient. In none of these three patients did right
ventricular end-diastolic pressure increase more than 1
mm Hg after diltiazem. In one patient there was a
downward shift in the intercept of the left ventricular
diastolic P-V relationship after diltiazem. This patient
experienced no change in right ventricular end-diastolic pressure after diltiazem. Thus, in most patients diltiazem had no effect on the left ventricular diastolic PV relationship, despite increasing left ventricular
end-diastolic pressure and volume.
Diltiazem improved left ventricular relaxation significantly (table 1), shortening T by 14.3% (p < .002).
T decreased in 18 of the 22 patients. The improvement
in relaxation rate was not accompanied by an increase
in left ventricular maximum negative dP/dt, perhaps
because of the load dependency of maximum negative
Vol. 72, No. 2, August 1985
15.0
n z 22
R =0 180
P - NS
A
75
*
-30
-25
-20
ALVSP (mmlHg)
-15
K~
0
. -10
75
-.15 (
,a1
msec)
22.5
30.0
37 5
45 0
B
15.0
75
0.0
75
n
v =
(m sec) 15,0
22
-0.29
X
101
R - -0.777
p'
0.00 1
22.5
-30.0
-37.5
-45 0
FIGURE 2. A, Lack of correlation between the change in left ventiicular systolic pressure (ALVSP) after diltiazceii and the change in relaxation rate (AT). B, Correlation (R = -.777) between the baselinc
relaxation rate (T) and the change in AT after diltiazeni.
dP/dt. The effect of load on T is illustrated in figure 2,
A; the changes in T did inot correlate with changes in
left ventricular pressure (R < .200). We obtairned similar results when T was comnpared with left ventricular
end-diastolic pressure or end-systolic volume. PB0 the
asymptote of the monoexponential equation describing
isovolumetric relaxation, was negative in patients at
rest (PB - - 14.2 ± 2.8 mm Hg) and became less
negative (by 45.8%) after diltiazein. Changes in P,,
were unrelated to changes in left ventricular end-systolic volume (R
.294).
Influence of baseline left ventricular function on the effects of diltiazem. Thirteen patients had abnormnal and
nine normal baseline left ventricular function. There
were no significant differences in the effects of diltiazem on hemodynamic variables, left ventricular volumes, global left ventricular systolic function, or left
ventricular relaxation in the two groups of patients.
However, the three patients in whom there was an
upward shift in the left ventricular diastolic P-V relationship after diltiazem all had normial baseliie left
357
=
DASH et a!.
A
a
7.5
22
-0.29 x +7.5
= 0.497
p<0.02
n
y
R
6.0
4.5
E
E
0
0
=
=
0
V
14.0
v
.
n = 22
R = -0.191
p =NS
10.5 F
.
*
3.0
N
7.0
1
E
c
WG
Ji
17.5
1.5
0
00
0
*
3.5 _
.
491
0.0
7.0
-1.5:
14.0
0.0
X21.0
i
60
LVEDP (mmHG)
70*
80
-3.5 _
-3.0
100
90
EDVI (m[/M2 )
110
.
-7.0 _
B
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FIGURE 3. There was a weak correlation (R = -.497) between
resting left ventricular end-diastolic pressure (LVEDP) and the change
in end-diastolic pressure (ALVEDP) after diltiazem.
0.175
n =
0.150
R
=
p =
ventricular function and the one patient in whom the
shift was downward had abnormal baseline left ventricular function. Figure 3 demonstrates that the
change in left ventricular end-diastolic pressure correlated weakly with the baseline left ventricular enddiastolic pressure (R = -.497, p < .02). Thus, the
negative inotropic effect of diltiazem was somewhat
less apparent at higher baseline levels of left ventricular end-diastolic pressure. On the other hand, figure 4
illustrates that changes in left ventricular end-diastolic
volume and global ejection fraction were completely
unrelated to the baseline values. Figure 2, B, shows
that the effect of diltiazem on left ventricular relaxation
was strongly correlated with the baseline relaxation
rate (R = -.777? p < .001). Diltiazem improved left
ventricular relaxation the most when baseline T was
markedly prolonged.
Effect of diltiazem on left ventricular systolic regional
wall motion. We were able to analyze regional wall
motion in 21 of the 22 patients. One patient shifted his
position between cineangiograms, preventing evaluation of comparable areas for the control and diltiazem
studies. There were 47 areas supplied by normal coronary arteries or in which CAD was nonocclusive and
there were 121 areas supplied by arteries with significant CAD. Response of area ejection fraction was unrelated to regional CAD in general: there was significant improvement in area ejection fraction in 40 (33%)
CAD areas after diltiazem compared with 13 (28%)
areas supplied by normal arteries (p
NS). A significant decrease in area ejection fraction after diltiazem
was noted in only four areas: two CAD areas with
358
120
AEF
0.125
F
0.100
F
22
-0.331
NS
0.075
0
a
0
0.050 _
.
0.025
0.0
(,c
0.42
-0.025
a
i
0.46
.
0.50o
l
0.54
0.58
0.62
0.66
EF
FIGURE 4. A, Lack of correlation between resting left ventricular enddiastolic volume index (EDVI) and the change in end-diastolic volume
index (AEDVI) after diltiazem. B, Lack of correlation between resting
global ejection fraction (SF) and the change in ejection fraction (AEF)
after diltiazem.
resting hypokinesis and two areas supplied by normal
coronary arteries with resting normokinesis.
Of the 121 CAD areas, baseline contraction was
normal in 60 and hypokinetic in 61. After diltiazem,
there was a significant increase in area ejection fraction
in 32 (53%) hypokinetic CAD areas compared with
only eight (13%) normokinetic CAD areas (p < .001).
This is reflected in the magnitude of the area ejection
fraction response to diltiazem, as depicted in figure 5.
In the normokinetic CAD areas, area ejection fraction
increased from 0.51 + 0.015 to 0.53
0.017 after
diltiazem, a small but statistically significant (p < .02)
improvement. In the hypokinetic CAD areas thete was
a larger increase in area ejection fraction from 0.33 +
CIRCULATION
THERAPY AND PREVENTION-CORONARY ARTERY DISEASE
CONTROL LV GRAM, EF = 0.60
RAO
.60
DTZ LV GRAM, EF = 0.67
RAO
.50
.40
LA-
.30
.20
a
0
C DTZ
NORMOKINETIC
C DTZ
HYPOKINETIC
(n=61)
(n=60)
Downloaded from http://circ.ahajournals.org/ by guest on June 16, 2017
FIGURE 5. Response of area ejection fraction (AEF) to diltiazem in
areas supplied by coronary arteries with significant disease. Areas with
normokinesis at baseline are on the left; areas with hypokinesis at
baseline are on the right. C = control; D = diltiazem.
0.014 to 0.42 + 0.014 (p < .0001). When both regional CAD and resting wall motion abnormalities
were taken into consideration, the percent increase in
area ejection fraction in the hypokinetic CAD areas
after diltiazem was significantly greater than the percent increases in the hypokinetic areas supplied by
normal arteries or the normokinetic CAD and "nonCAD" areas (figure 6). Figure 7 illustrates the effect of
diltiazem on regional wall motion abnormalities in a
patient with a 90% stenosis of the proximal right coronary artery. The inferior wall hypokinesis (areas 4 and
5) that was present at baseline improved significantly
after diltiazem.
30
r
20
[
LW
p
NS
I~~~NS
p
1
LLI
pNS
1
10
0
NK
NK
NO CAD CAD
HK
HK
NO CAD CAD
(n=29) (n=61) (n=18) (n=60)
FIGURE 6. Percent increase in area ejection fraction ( T AEF) after
diltiazem compared with at baseline. NK, NO CAD = normokinetic
areas supplied by normal coronary arteries; NK, CAD = normokinetic
areas supplied by coronary artery disease; HK, NO CAD = hypokinetic
areas supplied by normal coronary arteries; HK, CAD = hypokinetic
areas supplied by coronary artery disease.
Vol. 72, No. 2, August 1985
FIGURE 7. Control left ventricular cineangiogram (LV Gram) and LV
Gram obtained after diltiazem (DTZ) in the right anterior oblique
(RAO) projection with the ventricle divided into five areas. The solid
line is the end-diastolic LV tracing and the dashed line is the endsystolic LV tracing. The patient had single-vessel coronary artery disease with a severe proximal right coronary stenosis. There was baseline
inferior hypokinesis (ejection fraction [EF] of area 4 = 0.28 and of area
5 = 0.27). After diltiazem, there was a significant increase in EF to
0.44 in both areas.
Plasma diltiazem levels. No patient had a measurable
level of diltiazem during the control study. At the time
of the postdiltiazem left ventricular cineangiographic
study the mean plasma diltiazem level was 154 + 12
ng/ml.
Discussion
Effects of diltiazem on global left ventricular systolic
function. The results of this study indicate that diltiazem has complex effects on cardiac function in patients
with CAD. The plasma diltiazem levels achieved in
our patients were similar to those reported in studies37
of patients taking oral diltiazem for the therapy of
angina pectoris. Thus, the hemodynamic effects that
we have documented here are probably comparable to
those that can be expected in clinical practice.
Our data confirm the results of others2, 16.16 that diltiazem improves such afterload-dependent indexes of
global left ventricular systolic performance as ejection
fraction, cardiac index, and stroke volume index. On
the other hand, we found in our patients that diltiazem
did have some intrinsic negative inotropic effects,
causing a decrease in the left ventricular end-systolic
P-V ratio in conjunction with an increase in left ventricular end-diastolic pressure and volume. In addition, it is possible that the slower heart rate after diltiazem, by lengthening the diastolic filling period,
resulted in some increase in left ventricular end-diastolic volume. Our findings are in contrast to those
reported recently by Walsh et al.'0 in a group of patients with congestive heart failure. In their patients,
left ventricular filling pressure decreased after diltiazem and a negative inotropic effect was not demonstra359
DASH et al.
ble. Differences in both method and patient populations most likely account for the discrepant results.
Walsh's patients had a greater decrease in arterial pressure than our patients and their baseline left ventricular
function was much worse. Of interest, therefore, is our
finding that the negative inotropic effect of diltiazem
tended to be least apparent in those patients with the
highest resting left ventricular end-diastolic pressures
(figure 3).
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Effect of diltiazem on abnormalities of diastolic function
in patients with CAD. Previous investigations have demonstrated that left ventricular relaxation is often
slowed`5 and left ventricular compliance diminished'4
in patients with CAD. Although abnormalities are
most marked during episodes of acute myocardial ischemia when the left ventricular diastolic P-V relationship shifts upward acutely and left ventricular relaxation is prolonged,25 28 38 they are also present at rest.
In some cases, myocardial scarring may account for
the resting abnormalities in diastolic function; in others, the pathophysiologic mechanism is uncertain. It
has been suggested that chronic ischemia is present;
however, no myocardial lactate production is noted in
patients with stable angina pectoris when they are studied in the asymptomatic state. Braunwald and Kloner39
recently hypothesized the concept of the "stunned
myocardium," in which postischemic myocardium is
depleted of ATP reserves and calcium metabolism is
deranged, to account for the left ventricular systolic
regional wall motion abnormalities that occur in patients with CAD in the absence of myocardial infarction or active ischemia. Because left ventricular relaxation depends on calcium sequestration in the
sarcoplasmic reticulum of myocardial fibers and is an
energy-dependent process, the stunned myocardium
may not only result in abnormalities of contraction but
also those of relaxation.
The beneficial effect of diltiazem on diastolic function in our patients was confined to early diastolic
events, with a significant improvement in left ventricular relaxation rate as measured by T. Diltiazem may
have influenced relaxation in several ways. First, relaxation is a process often dependent on load.40 In our
patients, the effects of dilatiazem on load were variable, with a decrease in afterload and an increase in
load at end-diastole. Although we found no relationship between T and systolic or end-diastolic pressure,
it is possible that had we measured a more sensitive
index of load, such as wall stress, we might have found
a relationship. Second, impairment of calcium sequestration4' may prolong the myocardial inactivation process in patients with CAD, leading to delayed relax360
ation. Although the effects of diltiazem on intracellular
calcium metabolism are unknown, it is possible that
the drug improved left ventricular relaxation by direct
effects on myocardial inactivation. Third, left ventricular relaxation rate depends on the degree of uniformity of contraction throughout the ventricle.40 In patients
with CAD, Gibson et al.42 have demonstrated localized
delays in left ventricular relaxation with resting asynergy. Thus, the improvement in systolic regional wall
motion after diltiazem may have led to an increase in
left ventricular relaxation rate.
In contrast to our results with diltiazem, Ludbrook et
al.27 found that nifedipine did not affect left ventricular
relaxation. The differing results may in part be related
to the different methods used for calculating T, different mechanisms of action of the two drugs,4 or to the
different patient populations in the two studies. Most
of our patients had left ventricular asynergy, whereas
most patients in the previous study did not. The effect
of diltiazem on left ventricular relaxation in our patients was greatest in those with the most abnormal
baseline left ventricular relaxation rate (figure 2, B).
Therefore, the difference between the previous study
and ours may in part be one of degree. It is of interest to
note that nifedipine did improve left ventricular relaxation in patients with hypertrophic cardiomyopathy,29
a condition in which left ventricular relaxation is seriously deranged.
We found that, in addition to its effect on T, diltiazem also significantly altered PB' but how PB is related
to left ventricular relaxation is uncertain. Yellin et al.43
have reported that left ventricular pressure becomes
negative if the mitral valve orifice is occluded transiently and left ventricular relaxation is allowed to
continue uninterrupted by left ventricular filling. They
reported that the extent of left ventricular relaxation
correlated inversely with left ventricular end-systolic
volume, with more negative pressure at smaller endsystolic volumes. Our finding that PB is usually less
than zero is in agreement and is supported by the work
of Thompson et al.44 However, we found no correlation between PB and left ventricular end-systolic volume. If PB did represent the extent of left ventricular
relaxation, then it should have become more negative
as T shortened and relaxation rate increased. Our results with diltiazem were the opposite: PB became less
negative after diltiazem. Others have reported similar
directional changes in PB and T.44 4S It is therefore
probable that PB does not represent the extent of left
ventricular relaxation but rather is a theoretic term that
contributes to the mathematic description of left ventricular pressure decay during isovolumetric relaxCIRCULATION
THERAPY AND PREVENTION-cORONARY ARTERY DISEASE
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ation. The interaction of left ventricular filling with left
ventricular relaxation most likely invalidates any direct calculation of the extent of left ventricular relaxation in the intact heart.
The lack of effect of diltiazem on the left ventricular
diastolic P-V relationship was unexpected given the
drug's beneficial effect on left ventricular relaxation.
In our patients, left ventricular relaxation may not have
been sufficiently impaired in the resting state to affect
the left ventricular diastolic P-V relationship. Other
factors that may shift the left ventricular diastolic P-V
relationship acutely, such as right ventricular diastolic
dynamics26 and coronary perfusion,46 were probably
not affected by diltiazem. Diltiazem did not alter right
ventricular diastolic pressure in our patients; therefore,
ventricular interaction was not important. This is in
contrast to studies of nifedipine2' and nitroglycerin26 in
which downward shifts in the left ventricular diastolic
P-V relationship occurred in conjunction with decreases in right heart pressures. We did not measure
coronary perfusion, but two recent studies7' 8 have suggested that total coronary sinus flow does not change
after intravenous diltiazem in patients with CAD. The
upward shifts in the left ventricular diastolic P-V relationship in three patients with normal baseline left ventricular function remain unexplained. These three patients had no clinical characteristics or hemodynamic
responses to diltiazem that distinguished them from the
other patients with normal left ventricular function at
baseline. Similarly, the reason for the downward shift
in the left ventricular diastolic P-V relationship after
diltiazem in one patient with abnormal baseline left
ventricular function is unknown, since he had hemodynamic responses to the drug similar to those of the
other patients with abnormal baseline function.
Systolic regional wall motion response to diltiazem. Given the beneficial effect of diltiazem on global left ventricular relaxation and the known association between
abnormalities of relaxation and contraction in patients
with CAD, it is not surprising that the drug significantly improved area ejection fraction in hypokinetic areas
supplied by diseased arteries (figures 5 to 7). The increase in area ejection fraction in hypokinetic areas did
not occur at the expense of normokinetic areas because
the latter did not decrease area ejection fraction after
diltiazem. Reversal of resting systolic regional wall
motion abnormalities has been reported previously
after administration of nitroglycerin,13 but not after the
administration of other calcium-channel blockers.
Vliestra et al.47 reported no change in regional wall
motion after administration of intravenous verapamil.
Two studies48'49 have shown that nifedipine did not
Vol. 72, No. 2, August 1985
alter resting wall motion abnormalities in patients with
CAD, although it did prevent exercise-induced abnormalities. The differences reported here may relate to
varying mechanisms of action of the three agents,
methodologic differences among various studies, and
the differing patient populations.
Several mechanisms may have contributed to the
favorable effect of diltiazem on left ventricular systolic
regional wall motion. The improvements in regional
systolic contraction may have correlated with more
rapid local left ventricular relaxation. Ludbrook et al.50
noted improvement in regional left ventricular relaxation associated with reversal of regional wall motion
abnormalities after administration of nitroglycerin in
patients with CAD. We did not measure regional relaxation and this must be considered a limitation of our
study, but the increase in global left ventricular relaxation rate after diltiazem that was associated with improvement in regional left ventricular systolic function
does support the concept that in our patients, relaxation
and contraction abnormalities in CAD areas were interrelated.
The arterial vasodilating effect of diltiazem contributed to the improvement in global left ventricular systolic function and may have played a role in increasing
regional contraction as well. Our analysis of regional
left ventricular systolic contraction suggests that other
factors were also important, because clinically evident
increases in area ejection fraction occurred primarily in
left ventricular areas that were supplied by stenosed
coronary arteries and were hypokinetic at rest. If the
improvements were secondary only to afterload reduction, area ejection fraction would be expected to increase similarly in all regions. Mechanisms that might
account for the ability of diltiazem to improve regional
contraction selectively in asynergic areas of the left
ventricle supplied by diseased arteries include effects
on regional coronary blood flow, calcium metabolism,
and ATP utilization. Although intravenous diltiazem
does not alter total myocardial blood flow," 8 Bache
and Dymek5' have shown that it partially corrects the
derangement in the subendocardial/subepicardial flow
ratio that occurs in a dog preparation of acute myocardial ischemia. Moreover, Malacoff et al.52 showed that
another calcium-channel blocker, nifedipine, improves regional myocardial flow distal to stenosed
coronary arteries. Nifedipine also prevents the accumulation of intracellular calcium that occurs during
acute myocardial ischemia." Of note, therefore, is the
observation of Weishaar et al.53 in a dog preparation of
regional ischemia that diltiazem reduces ATP depletion, diminishes lactate production, and improves con361
DASH
et
al.
tractility in the ischemic area of the left ventricle. No
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studies have been performed to evaluate the effects of a
calcium-channel blocker on regional left ventricular
function in a preparation that simulates the stunned
myocardium, which was likely present in the patients
studied here. But if the stunned myocardium does represent a postischemic state in which coronary flow is
marginal, ATP is depleted, and calcium metabolism is
deranged, then diltiazem might potentially exert its
beneficial effects through any of the mechanisms described above.
In conclusion, intravenous diltiazem in a dose that
provided a plasma level comparable to that reported for
effective therapy of angina pectoris improved global
left ventricular systolic performance, regional wall
motion, and left ventricular relaxation rate in patients
with CAD. The favorable effects of diltiazem on left
ventricular performance occurred despite evidence of a
mild negative inotropic effect. The improvement in
regional contraction was confined to areas supplied by
diseased arteries in which there was resting hypokinesis. The increase in left ventricular relaxation rate occurred without any overall effect on the left ventricular
diastolic P-V relationship.
We could not have completed this study without the assistance of the technicians and nurses in the Cardiac Catheterization Laboratory. We are grateful to Lori Skalland for providing
biostatistical assistance and to Susan Landucci and Verna Ebersole for typing the manuscript. Robert Zelis provided helpful
suggestions during the preparation of the
manuscript.
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Improvement in regional wall motion and left ventricular relaxation after administration
of diltiazem in patients with coronary artery disease.
H Dash, G L Copenhaver and S Ensminger
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Circulation. 1985;72:353-363
doi: 10.1161/01.CIR.72.2.353
Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
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