LABORATORY INVESTIGATION
PHARMACOLOGY
Differential effects of diltiazem and nitroprusside on
left ventricular function in experimental chronic
volume overload
CHARLES B. PORTER, M.D., RICHARD A. WALSH, M.D., FREDERICK R. BADKE, M.D.,
ROBERT A. O'Rourke, M.D.
AND
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ABSTRACT To compare the hemodynamic effects of a calcium-channel blocker with those of a
conventional vasodilator in the awake preinstrumented dog, diltiazem and nitroprusside were administered in equihypotensive infusions before (decrease in mean aortic pressure by 10%; p < .001, n = 6)
and after (decrease in mean aortic pressure by 12%; p < .001) chronic volume overload (CVO)
produced by an infrarenal aortocaval fistula. Diltiazem had no effect on preload either before or after
CVO. The maximal rate of change in left ventricular pressure (dP/dtmax) was unaffected by diltiazem
before the aortocaval fistula (decrease in dP/dtmax by 6%; p = NS) but was significantly reduced by
calcium-channel blockade after CVO (decrease in dP/dtmax by 22%; p < .001). By contrast, at matched
aortic pressures nitroprusside significantly reduced left ventricular end-diastolic dimension (LVEDD)
and pressure (LVEDP) in the same animals before (decrease in LVEDD by 10%, p < .05; decrease in
LVEDP by 7 2 mm Hg, p< .001) and after CVO (decrease in LVEDD by 7%, p < .05; decrease in
LVEDP by 5 2 mm Hg, p < .001) without altering dP/dtma . We conclude that the calcium entry
blocker diltiazem, unlike conventional vasodilators, may depress left ventricular function in CVO by
direct negative inotropic properties in amounts that are without myocardial depressant effects in the
presence of normal left ventricular performance.
Circulation 68, No. 3, 685-692, 1983.
DILTIAZEM, a calcium-channel blocker, has two major potential direct hemodynamic effects: coronary and
peripheral arterial vasodilation and myocardial depression. In addition to these direct effects, reflex sympathetic stimulation, induced by peripheral vasodilation,
may offset or mask the negative inotropic and chronotropic effects of calcium-channel blockade. 14 However, net cardiocirculatory response to such drugs may be
markedly different in the presence of congestive heart
failure with its variable alterations in level of sympathetic reserve. Several clinical investigations detailing
the beneficial effects of calcium-channel blockade as a
means of vasodilator therapy for congestive heart failure have appeared.7-'0 However, acute pulmonary edeFrom the Division of Cardiology, Department of Medicine, The
University of Texas Health Science Center, and Veterans Administration Hospital, San Antonio.
Supported in part by grant 80-17 from the American Heart Association, Texas Affiliate, the Veterans Administration, and NIH grants HL
07350 and 1F32 HL 06539.
Address for correspondence: Richard A. Walsh, M.D., Department
of Medicine, Division of Cardiology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Dr., San Antonio, TX
78284.
Received Feb. 14, 1983; revision accepted May 12, 1983.
Presented in part at the 54th Annual Scientific Sessions of the American Heart Association.
Vol. 68, No. 3, September 1983
ma after parenteral verapamil"I and severe hypotension
with reduced cardiac output after 20 to 30 mg of oral
nifedipine have been reported. 12
By contrast, there are no investigations detailing the
hemodynamic actions of diltiazem, which in equimolar doses has the least negative inotropic effects in
vivo'-"' and in vivo6 of the clinically available drugs,
in experimental or clinical heart failure. Furthermore,
the comparative effects of afterload reduction by calcium-channel blockade and conventional vasodilators
have not been assessed.
We therefore used an animal model for chronic volume overload (CVO) to assess the peripheral and myocardial effects of diltiazem before and after the onset of
congestive heart failure. To study potential negative
inotropic effects of this drug independent of the direct
and reflex effects of peripheral arterial vasodilation,
we chose to compare its effects with those of nitroprusside, a widely used vasodilator without direct myocardial actions. 16 The potency, rapid onset of action, and
short half-life of this drug permitted us to precisely
match the reduction in mean arterial pressure induced
by diltiazem in the same animal before and after aortocaval fistula.
685
PORTER et al.
Methods
peak negative rate of change in left ventricular pressure (dp/dt),
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Surgical instrumentation. Six mongrel dogs, weighing 18
to 30 kg, were surgically instrumented (figure 1) for long-term
physiologic monitoring by methods previously described for
this laboratory.17
Specifically, a left thoracotomy was performed under halothane (l.5%) anesthesia with xylazine and sodium pentobarbital
induction (figure 1). We placed 16-gauge polyvinyl catheters in
the descending aorta, apical left ventricle, and left atrium. A
solid-state pressure transducer (P-18; Konigsberg Instruments,
Inc., Pasadena), precalibrated with a mercury manometer, was
placed in the apex of the left ventricle. Paired 5 MHz piezoelectric crystals with resin-focusing lenses were positioned for anteroposterior measurement of a left ventricular transverse diameter. The dogs were allowed to recover at least 2 weeks, and
control studies were performed with the animals unsedated and
lying quietly in a sling. An infrarenal 0.5 cm aortocaval fistula
was constructed during a second operation via a midline abdominal incision. Shunt patency was confirmed in each animal
by the presence of intraoperative and postoperative bruit/thrill,
hemodynamic data, and postmortem examination. Animals
were restudied in an identical fashion to the control animals 2 to
4 weeks after aortocaval fistula.
Measurements. Analog signals wre recorded with a Beckman RM oscillograph. Analog-to-digital signal conversion with
an on-line minicomputer (Minc 11; Digital Equipment Corp.,
Marlborough, MA) was performed at a rate of 100 Hz and data
were stored on floppy discs for subsequent analyses. Transit
time between the piezoelectric crystals was measured by a multichannel sonomicrometer (Scheussler and Associates, Cardiffby-the-Sea, CA) and was converted to distance by assuming a
constant velocity of sound in blood of 1.55 m/msec.'8 The
resolution of this system has been reported at 0.07 mm with 5
MHz signals. 19 The percent of shortening of the anteroposterior
diameter (%AD) was calculated as the difference between the
left ventricular end-diastolic diameter (LVEDD) and left ventricular end-systolic diameter (LVESD) divided by the LVEDD
and multiplied by 100. End-diastolic length was defined as the
diameter of the ultrasonic transverse dimension signal at the
"'Z" point of the high-fidelity left ventricular pressure signal.
End-systolic length was measured as the transverse diameter at
which occurs within 10 msec of aortic valve closure. External
manometers (P23 Db; Statham Instruments, Oxnard, CA) measured aortic and ventricular pressures. Before each experiment,
the solid-state transducer was calibrated to the left ventricular
pressure tube signal.
High-fidelity left ventricular pressure was differentiated to
determine the maximal rate of rise of left ventricular pressure
(dP/dtm.) by an active resistance capacitance circuit with a
linear frequency response to 75 Hz with a 3 dB variance at 100
Hz. Analog dP/dt was calibrated from the digitized data obtained from analog-to-digital conversion of the solid-state transducer with software developed in our laboratory and processed
by a minicomputer.
Drug protocol (figure 2). Diltiazem HCl (Marion Laboratories, Kansas City, MO) was administered as a 200 jig/kg left
atrial bolus and as a continuous infusion at 40 .tg/kg/min, a dose
we had noted previously to produce a decline in mean arterial
pressure of approximately 10% from that in control in the absence of an arteriovenous (AV) fistula (unpublished observations). Recordings of heart rate, left ventricular pressure by
solid-state transducer, left ventricular end-diastolic pressure
(LVEDP) on an expanded scale, LVEDD, LVESD, and aortic
pressure were made at paper speeds of 25 mm/sec at 30 sec, 3
min, and 10 min after the initial diltiazem bolus. Signals from
10 consecutive beats were averaged for each data point.
We dissolved 2.5 mg of sodium nitroprusside (Roche Laboratories, Nutley, NJ) in 50 ml of 5% dextrose in water, which was
administered by continuous infusion at least 30 min after diltiazem after hemodynamic parameters had returned to control levels. Nitroprusside dosage was then titrated to match the diltiazem-induced fall in blood pressure as recorded by the
oscillograph in that animal (mean dose = 1.75 ± 0.2 ug/kg/
min). Hemodynamic measurements were made 30 sec, 3 min,
and 10 min after the diltiazem-matched blood pressure fall was
attained.
Statistical analysis. Statistical analyses20 were performed by
two-way analysis of variance (2-way ANOVA) for repeated
measures of the same parameters for intergroup drug interactions. One-way analysis of variance (1-way ANOVA) was used
for intragroup dose interactions. The Newman-Keuls test and
Dunnet's t test were used to assess intergroup and intragroup
Stage 1: Thoracotomy
Atrial Catheter
Aortic Catheter
XDCX LV Diameter
Micromanometer
Catheter
FIGURE 1. Schematic illustration of the two-stage
surgical procedure used for instrumentation and construction of aortocaval fistula.
Inferior
Vena Cava
Stage 2: Laparotomy
0.5 cm
Aorto-Caval Fistula
686
CIRCULATION
LABORATORY INVESTIGATION-PHARMACOLOGY
statistical significance between means, respectively. The level
of significance was chosen as p .05. Results are expressed as
the mean + SE.
-
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Results
Control data. Baseline hemodynamic parameters in
animals before construction of aortocaval fistula during control runs before diltiazem and nitroprusside differed only in that the heart rate was slightly higher
before nitroprusside (72 + 7 vs 82 ± 7 beats/min; p <
.05). In experiments performed after construction of
aortocaval fistula, there was no significant difference
in any parameter between the prediltiazem and prenitroprusside controls (table 1).
Effects of aortocaval fistula. Hemodynamic changes
produced by the construction of aortocaval fistulae
appear in table 2 and are evident in figures 2 through 5.
Significant increases in heart rate (before aortocaval
fistula = 77 ± 7 beats/min vs after aortocaval fistula
= 131 + 7 beats/min; p < .001), LVEDD (before
aortocoval fistula = 42.4 + 1.7 mm vs after aortocaval fistula = 45.1 + 1.5 mm; p < .01), LVEDP
(before aortocaval fistula = 8 + 1 mm Hg vs after
aortocaval fistula = 13 + 2 mm Hg; p < .01), and
%AD (before aortocaval fistula = 19 + 1%, after
aortocaval fistula = 23 + 2%; p < .01), and a decline
in aortic diastolic blood pressure (before aortocaval
fistula = 68 + 2 mm Hg, after aortocaval fistula = 49
± 2 mm Hg; p < .01) were observed. The dP/dtm.,
also increased significantly after aortocaval fistula
from 2590 ± 260 to 3519 + 323 mm Hg/sec (p <
.01).
Drug effects before and after aortocaval fistula. Figure 3
shows selected portions of analog recordings made of
typical experiments during steady-state infusions of
equihypotensive doses of diltiazem and nitroprusside
in a single dog before and after aortocaval fistula.
Diltiazem had no effect on dP/dtm. before aortocaval
fistula but depressed dP/dtma, from 3650 to 2883 mm
Hg/sec after AV fistula. In addition, the calcium-channel blocker had no effect on LVEDD or LVEDP before
or after CVO. By contrast, nitroprusside before and
after aortocaval fistula reduced preload but had no
effect on dP/dtma.x
Effects of nitroprusside. Group hemodynamic effects
observed after equihypotensive calcium-channel
blockade and vasodilator infusion before and after
shunting are recorded in table 1. Heart rate increased
significantly for the group above control levels during
nitroprusside infusion before aortocaval fistula (control = 82 ± 1 beats/min, nitroprusside = 113 + 7
beats/min; p < .001), but no significant change from
DRUG PROTOCOLS
Pre and Post (range 2-3 weeks) Aortocaval Fistula
CONTROL I - Pre Diltiazem
Diltiazem bolus 200 pg/kg followed by
40 pg/kg/min infusion
Measurements 1/2, 3, 10 minutes post drug
initiation
Return to baseline hemodynamic status
(20-30 minutes)
FIGURE 2. Simplified illustration of the experimental drug protocol used before and after CVO by aortocaval fistula.
CONTROL 11 - Pre Nitroprusside
Nitroprusside infusion (x = 1.5 pg/kg/min)
titrated to match decline in MAP produced
by diltiazem
Measurements 1/2, 3, 10 minutes from onset of
steady state matched decline in MAP
Vol. 68, No. 3, September 1983
687
PORTER
et
al.
TABLE 1
Hemodynamic effects of diltiazem and nitroprusside infusions before and after aortocaval fistula (mean ± 1 SEM, n = 6)
Pre-AVF
Nitroprusside
Control
30 sec
3 min
10 min
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Diltiazem
Control
30 sec
3 min
10 min
Post-AVF
Nitroprusside
Control
30 sec
3 min
10 min
Diltiazem
Control
30 sec
3 min
10 min
dP/dtnax
HR
(beats/min)
MAP
(mm Hg)
LVEDP
(mm Hg)
LVEDD
(mm)
%zAD
(mm Hg/sec)
82+7A
106 ± 9B
106±7B
113±
+B
87±2
8±2
5 +2c
1±2B
42±2
40± 2
39 + 2C
38 ± 2c
18±1
19± 1
19± 1
17 ± 1
2584±246
2818 ± 265
2706±207
2730±334
72 ± 7
99 ±4B
93+4B
94+4B
84 ± 2
79±3C
79+4C
77+3B
8± 1
8±2
9±2
7±2
43 ± 2
42± 2
42±2
42±2
19 ± 1
21 ± 2
18±1
19± 1
2602±276
2795 ±357
2507±260
2431 ±251
130±7
130±5
132±6
136±6
74 ± 5
66 ± 4B
65±5B
65±4B
12 ± 1
8±1c
7±lc
7 2c
45 ±2
43 ± 2c
43±2c
42+2c
22 ± 2
23 ± 2
23±2
23±2
3746 ±344
3677 ±393
3690±398
3759±348
133±6
124±13
123 ± 13
118± 13
75±4
13±2
13±3
45±2
46±2
46±2
45±2
23±2
24±2
23 ± 2
23±2
3493±274
2907+378B
2908+369B
2774+355B
84± Ic
79 ± 2c
79 ± 2B
64+5B
65 +6B
66±6b
5 ± 2c
13 2
15±2
Pre-AVF = before aortocaval fistula; Post-AVF = after aortocaval fistula; HR - heart rate; MAP = mean arterial
pressure; LVEDP = left ventricular end-diastolic pressure; LVEDD = left ventricular end-diastolic dimension; %AD =
percent shortening of the minor diameter = (LVEDD - LVESD/LVEDD) x 100; dP/dtm. = maximal rate of left
ventricular pressure increase.
Ap < .05 vs diltiazem control.
Bp < .001 vs control by ANOVA.
cp < .05 vs control by ANOVA.
control levels was observed with nitroprusside infusion during mechanical circulatory overload produced
by the aortocaval fistula (control = 130 + 8 beats/
min, nitroprusside = 135 ± 6 beats/min; p = NS).
Nitroprusside produced significant declines in mean
aortic pressure (MAP) (figure 4) at 30 sec, 3 min, and
10 min periods in both preconstruction of aortocaval
fistula (control = 87 + 3 mm Hg, 10 min = 80 + 2
mm Hg; p < .001), and at all three periods in the post
construction aortocaval fistula state (control 74 + 5
mm Hg, 10 min = 65 + 4 mm Hg; p < .001). LVEDP
(figure 5) was also significantly lower during the nitro=
prusside infusion (before aortocaval fistula: control =
8
2mmHg, 10min = 1 + 2mmHg,p< .001,
after aortocaval fistula: control = 12 + 1 mm Hg, 10
min = 8 ± 2 mm Hg, p < .05), as was LVEDD
(before aortocaval fistula: control = 42.0 ± 1.6 mm,
10 min = 38.8 ± 1.5 mm, p < .05; after aortocaval
fistula: control = 45.0 + 1.5 mm, 10 min 42.5 +
1.9 mm, p < .05) (table 1). Neither dP/dtm. (figure 6)
nor %z\D were significantly affected by nitroprusside
in either circulatory state.
Comparative effects of diltiazem (table 1). Like nitroprusside, diltiazem produced an increase in heart rate
=
TABLE 2
Baseline hemodynamic data before and after aortocaval fistula (mean ± 1 SEM, n = 6)
Pre-AVF
Post-AVF
dP/dtmax
LVEDP
(mm Hg)
LVEDD
(mm)
%AD
(mm Hg/sec)
68±+-2.0
8.3±1.3
49+4.4A
12.6+l1.8A
42.5 -+1.7
45.1±1.5A
18.7 ±+1.2
22.5±+2.OA
2590± 260
3519±323A
HR
(beats/min)
MAP
(mm Hg)
Diastolic BP
(mm Hg)
77-+-6.9
131 +6,9A
86 ± 2.2
75 +4.6
BP = blood pressure; other abbreviations as in table 1.
Ap < - .01 vs pre-AV fistula value by ANOVA.
688
CIRCULATION
LABORATORY INVESTIGATION-PHARMACOLOGY
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LVEDP
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FIGURE 3. Analog recordings obtained at control
and during steady-state equihypotensive infusions of
diltiazem and nitroprusside in a single dog before and
after aortocaval fistula. Diltiazem reduces left ventricular dP/dt only after CVO, and nitroprusside has
no effect on dP/dt but decreases left ventricular enddiastolic minor diameter and pressure before and
after AV fistula.
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60LV
Minor
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Dit
200
sW
W\bgwo
before aortocaval fistula (control = 72 + 7 beats/min,
10 min = 94 ± 4 beats/min; p < .001) but had no
significant effect in the postaortocaval fistula state
(control = 133 ± 6beats/min, 10min = 118 ± 13
Effects of Diltiazem and Nitroprusside
on Mean Aortic Pressure Pre and Post-AV Fistula
901
E
80-
E
0~
-6
70*
0)
.c
ClC-
4)
------
Pre-AV Fistulo
Post-AV Fistula
60 ,
A Diltiazem
o Nitroprusside
N=6
0.
01/2
3
I0
Time (min)
FIGURE 4. The administered dosage of diltiazem produced significant
declines in mean aortic pressure both before and after volume overload.
These declines were matched with the nitroprusside infusion.
Vol. 68, No. 3, September 1983
beats/min; p = NS). Mean arterial pressure declined
during diltiazem infusion before and after volume
overload (before aortocaval fistula: control = 84 + 2
mm Hg, diltiazem = 78 + 3 mm Hg; p < .001; after
aortocaval fistula: control = 75
4 mm Hg, diltiazem = 66 + 6 mm Hg; p < .001). The reductions in
mean arterial pressure produced by diltiazem were
equivalent to those observed with nitroprusside before
and after volume overload by experimental design (table 1 and figure 4). However, in contrast to nitroprusside, diltiazem produced no significant change from
control in LVEDD or LVEDP (figure 5) either before
or after aortocaval fistula (before aortocaval fistula:
control = 8 + 1 mm Hg, diltiazem = 7 + 2 mm Hg,
p = NS; after aortocaval fistula: control = 14 + 2
mm Hg, diltiazem = 15 + 2 mm Hg, p = NS).
Diltiazem had no significant effect on dP/dtmx in the
animals before aortocaval fistula (control = 2601 +
276 mm Hg/sec, diltiazem = 2430 251 mm Hg/sec;
p = NS); however, after aortocaval fistula-induced
CVO, the calcium-channel blocker produced a prompt
sustained decline in dP/dtm,, (control = 3493
274
mm Hg/sec, 10 min = 2773 + 344 mm Hg/sec; p <
.001) (figure 6). This 21% reduction in dP/dtmax produced by diltiazem is in marked contrast to the slight
increase in dP/dtmax that had been observed with an
equihypotensive dose of nitroprusside (control =
3546 344 mm Hg, 10 min = 3759 336 mm Hg; p
= NS) in the same animals. Despite the substantial
689
PORTER et al.
Effects of Diltiazem and Nitroprusside
on LVEDP Pre and Post-AV Fistula
15-
EI
10 1$-1~
+
A
0
FIGURE 5. Significant declines in LVEDP were
observed during nitroprusside but not diltiazem both
before and after volume overload produced by AV
fistula. Similar directional changes occurred in
LVEDD (see table 1).
Pre-AV Fistula
Post-AV Fistula
A Diltiazem
0 Nitroprusside
------
N=6
5
T=SE
*-p<.OI
vs Control by ANOVA
O
01/2
3
lo
Time (min)
Downloaded from http://circ.ahajournals.org/ by guest on June 16, 2017
reduction in dP/dtm. produced by diltiazem after CVO,
the percent shortening of the minor diameter signal
was unchanged by the drug in both circulatory states
(19 + 1% before and after diltiazem before aortocaval
fistula; 23 2% before and after the drug after aortocaval fistula).
Discussion
The results of this investigation confirm the hypothesis that the net hemodynamic effect of calcium-channel blockade on left ventricular performance depends
on the circulatory state in which it is used.
Our data indicate that diltiazem, the calcium blocker
Effects of Diltiazem and Nitroprusside
LV dP/dt Pre and Post-AV Fistula
on
40001
0 3000N
(I
E
E
%
2000-
a-
&
Pre-AV Fistula
Post-AV Fistul
Diltiozem
o Nitroprusside
N-6
0-
I
01/2
3
Time (min)
FIGURE 6. Left ventricular dP/dt was unchanged during nitroprusside
before or after AV fistula. By contrast, diltiazem produced no change
before but a marked decline (20%) in dP/dt in the same animals after
Cvo.
690
that has been shown in vivo6 and in vitro'3-15 to possess
the least negative inotropic effects of the available
drugs, is capable of producing substantial reductions in
dP/dtmax when given parenterally to the conscious
preinstrumented dog during CVO effected by the creation of an aortocaval fistula. Despite significant depression of dP/dtm~, the extent of myocardial fiber
shortening as reflected by percent shortening of the
ultrasonic left ventricular minor diameter crystals
(%AD) was unaffected by the amount of diltiazem used
in this study. The absence of a significant decline in
percent of minor diameter shortening despite a substantial reduction in dP/dtm. in response to diltiazem
after AV fistula may be explained by the increased
sensitivity to changes in inotropic state and relative
independence of loading conditions of isovolumetric
(dP/dt) as compared with ejection phase indices
(%AD) previously observed in the conscious preinstrumented animal2l1 22 and in man.23 Specifically, the calcium blocker-induced reduction in systemic arterial
pressure may have offset the direct effects of the drug
on extent of shortening. By contrast, the same dose of
diltiazem given to the same animals before the circulatory congestion imposed by volume overload was
without discernible effect on either isovolumetric or
ejection phase measures of left ventricular function.
The diltiazem-induced reduction in dP/dtmax was not
observed before or after CVO when nitroprusside, a
vasodilator without direct myocardial effects,"6 was
used in the same animals to produce decreases in systemic arterial pressure equal to those obtained with the
calcium blocker. In addition, the calcium-channel
blocker produced no discernible effect upon left ventricular preload before of after AV fistula, whereas
equihypotensive infusions of nitroprusside significantly reduced transverse LVEDD and LVEDP before and
CIRCULATION
LABORATORY INVESTIGATION-PHARMACOLOGY
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after CVO. These results suggest that relative to nitroprusside, diltiazem is primarily a systemic arteriolar
vasodilator without important effects upon venous capacitance. Nitroprusside was given a minimum of 30
min after diltiazem by study design to precisely match
the calcium entry blocker-mediated systemic arterial
vasodilation. Although the elimination of half-life of
diltiazem is 2.24 hr in the dog,30 it is unlikely that
possible residual plasma or tissue levels of this drug
affected the observed changes produced by nitroprusside since all hemodynamic parameters had returned to
control levels before conventional vasodilation, and
we are unaware of any pharmacodynamic interaction
between the two drugs.
The previous hemodynamic characterizations of this
animal model of CVO suggests several potential explanations for the discrepant effects of diltiazem on left
ventricular function observed before and after creation
of the aortocaval fistula.2427 During the first few weeks
after AV fistula formation, circulatory congestion is
shown by pulmonary rales, ascites, and peripheral edema. The hemodynamic basis for these changes observed in this study included significant increases in
heart rate and in left ventricular diameter and pressure
(table 2). Previous investigators have noted reduced
systemic vascular resistance due to a threefold increase
in cardiac output of which 55% is shunted from left to
right at the level of the aortocaval fistula.25 Thus, this
preparation constitutes a model of high-output congestive heart failure. Myocardial performance is known to
be normal to enhanced in these dogs as indicated by the
22% increase in percent of left ventricular minor diameter shortening that we observed (table 2). Others have
noted augmented ejection fractions, contractile element velocities, and mean velocities of circumferential
fiber shortening for at least 6 weeks after aortocaval
fistula.26 Le Winter et al.28 have demonstrated that part
of this increased myocardial function is related to increased sympathetic activity. More recently Crozatier
et al.29 noted a nonadrenergically mediated increase in
inotropic state within 48 hr of volume overload produced by aortic insufficiency in the awake preinstrumented dog. This phenomenon may have been produced by an increase in calcium availability for
excitation contraction coupling.
Several potential mechanisms may be evoked to explain the myocardial depression produced by diltiazem
after CVO given the aforementioned direct and reflex
circulatory adjustments that occur in this model.
First, the high resting level of sympathetic tone and
low peripheral vascular resistance after AV fistula may
have prevented short-term reflex adaptation to calVol. 68, No. 3, September 1983
cium-channel blockade and hence unmasked the direct
myocardial depressant effect shared by these compounds. Similarly, the absence of a significant reflex
increase in heart rate after systemic vasodilation by
diltiazem and nitroprusside after AV fistula in contrast
to the reflex tachycardia evoked by both drugs before
AV fistula, may be a consequence of the elevated basal
sympathetic tone produced by CVO. Indeed, heart rate
actually declined (133 + 6 beats/min to 118 + 13
beats/min; p NS) with diltiazem after AV fistula.
It is possible that the direct negative chronotropic effect of calcium-entry blockade predominated in this
setting.
Second, if increased availability of calcium to the
contractile apparatus is partially responsible for the
normal to enhanced left ventricular function observed
in CVO, the myocardium may be more sensitive to
calcium blockade in this condition. Finally, hepatic
congestion may have increased bioavailability by reduced hepatic drug deacetylation, the major route for
elimination of diltiazem,30 and resulted in higher plasma levels in the post-AV fistula state.
Clinical implications. In this study, vasodilation with
nitroprusside infusion failed to increase the extent of
left ventricular shortening before or after CVO, and
vasodilation with equihypotensive calcium blockade
produced significant myocardial depression (table 1).
Caution must be exercised with the extrapolation of
these data to the management of patients with congestive heart failure of diverse causes. Most forms of lowoutput heart failure are associated with variably elevated systolic impedance and wall stress and diminished
left ventricular function. In this setting, arterial vasodilation by calcium-channel blockade or other direct or
receptor-dependent afterload-reducing drugs may permit more effective shortening during ventricular systole. For example, we have recently demonstrated improved left ventricular performance in response to
intravenous and oral diltiazem in a group of patients
with severe congestive heart failure due to myocardial
depression.3' By contrast, patients with heart failure
characterized by normal or enhanced left ventricular
performance may have reached the limit at which systolic ejection can increase in response to peripheral
arterial vasodilation. Such conditions might occur in
heart failure due to left-sided valvular regurgitation,
central left-to-right shunts, arteriovenous fistulae, or
any high cardiac output state. Further arteriolar vasodilation may merely lower systemic arterial pressure
without improvement in cardiac performance. Calcium-channel blockade has the additional potential
risk of producing frank myocardial depression due to
=
691
PORTER et al.
unmasking of direct negative inotropic effects, a property not shared by conventional pure vasodilators.
We appreciate the technical assistance of Danny Escobedo,
Richard Miller, and Don Watkins, and the secretarial assistance
of Julia E. Wells.
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CIRCULATION
Differential effects of diltiazem and nitroprusside on left ventricular function in
experimental chronic volume overload.
C B Porter, R A Walsh, F R Badke and R A O'Rourke
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Circulation. 1983;68:685-692
doi: 10.1161/01.CIR.68.3.685
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