Download Systemic vascular resistance: an unreliable index of left

LABORATORY INVESTIGATION
VENTRICULAR PERFORMANCE
Systemic vascular resistance:
left ventricular afterload
an
unreliable index of
ROBERTO M. LANG, M.D., KENNETH M. BOROW, M.D., ALEX NEUMANN, B.S., AND DINA JANZEN
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ABSTRACT Systemic vascular resistance (SVR) is a frequently used clinical index of left ventricular
afterload. However, SVR may not adequately assess left ventricular afterload (i.e., ventricular internal
fiber load during systole) since it reflects only peripheral vasomotor tone. In contrast, left ventricular
end-systolic wall stress (ces) reflects the combined effects of peripheral loading conditions and left
ventricular chamber pressure, dimension, and wall thickness. To determine the relationship between
SVR and cyes, left ventricular afterload and contractility were pharmacologically altered in eight dogs
instrumented with central aortic microtip and Swan-Ganz thermodilution catheters. Left ventricular
wall thicknesses and dimensions were measured from two-dimensionally targeted M mode echocardiograms. Aortic, right atrial, and left ventricular end-systolic pressures as well as cardiac output were
recorded. SVR and aes were determined under control conditions as well as during infusions of
nitroprusside, methoxamine, dobutamine, and norepinephrine. Control data acquired before each drug
infusion were similar. When compared with baseline values, SVR underestimated the magnitude of
change in left ventricular Cyes by (1) 22% when afterload alone was decreased (nitroprusside), (2) 54%
when afterload alone was increased (methoxamine), and (3) 50% when afterload was decreased and
contractility was augmented (dobutamine). Most importantly, when afterload was minimally decreased
in association with augmented contractility (norepinephrine), SVR increased by 21% while ,es fell by
9%. Thus, discordant changes in left ventricular afterload (i.e., a,) and SVR can occur during
pharmacologic interventions. SVR is an unreliable index of left ventricular afterload, reflecting only
peripheral arteriolar tone rather than left ventricular systolic wall force. This emphasizes the fact that a
true measure of left ventricular afterload must consider the interaction of factors internal and external to
the myocardium.
Circulation 74, No. 5, 1114-1123, 1986.
OVERALL left ventricular systolic performance is inversely related to the force opposing ventricular fiber
shortening (i.e., afterload). This fundamental property
of the myocardium becomes critically important in
interpreting variables of left ventricular shortening in
patients suspected of having contractile abnormalities. 1-3 In the clinical setting, the most commonly used
measure of ventricular afterload is systemic vascular
resistance (SVR). However, SVR is a measure of vasomotor tone that reflects only the nonpulsatile component of peripheral load.1-2, 4,5 In contrast, left ventricular systolic wall stress reflects the combined effects of
peripheral loading conditions and factors internal to
the heart.6' 7 Recently, the wall stress at end-systole
(Ges) has been shown to be directly related to endFrom the University of Chicago.
Supported in part by a grant from the American Heart Association,
Chicago Affiliate.
Address for correspondence: Kenneth M. Borow, M.D., Director,
Cardiac Noninvasive Imaging Lab, University of Chicago Hospitals and
Clinics, 950 E. 59th Street, Box 44, Chicago, IL 60637.
Received April 9, 1986; revision accepted Aug. 7, 1986.
1114
systolic dimension and volume.7 8 As such, aes is a
major determinant of overall left ventricular performance and can be considered the afterload that limits
ventricular fiber shortening at end-ejection.2 7-9
To determine the relationship between total left ventricular muscle load (i.e., wall stress) and SVR, an
instrumented canine preparation was studied during
alterations in left ventricular afterload alone (with nitroprusside and methoxamine) and during combined
changes in left ventricular afterload and contractile
state (with dobutamine and norepinephrine).
Methods
Animal preparation and instrumentation. Eight closedchest mongrel dogs (18.5 to 35 kg) were premedicated with
subcutaneous morphine (5 mg/kg) followed by anesthesia with
intravenous a-chloralose (100 mg/kg). After endotracheal intubation, room air ventilation was maintained with a Harvard
volume respirator. Arterial blood gases (Coming 165.2 Analyzer) were measured to ensure physiologic respiratory support. A
No. 8F Swan-Ganz catheter connected to a Statham P231D
transducer was advanced via the right external jugular vein into
CIRCULATION
LABORATORY INVESTIGATION-VENTRICULAR PERFORMANCE
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the pulmonary artery for measurements of thermodilution cardiac output (Columbus Instruments) and of pulmonary arterial and
pulmonary capillary wedge pressures. A second catheter was
advanced from the external jugular vein into the right atrium for
measurement of right atrial pressure and for injection of the iced
saline boluses required for determinations of cardiac output. A
high-fidelity micromanometer-tipped catheter (Millar, Texas)
was advanced via the left femoral artery and positioned in the
ascending aorta just above the aortic valve. Central aortic pressure tracings were obtained and used for measurements of left
ventricular ejection time and end-systolic pressure (Pes). The
femoral vein was cannulated with a large-bore catheter that was
used for infusion of intravenous drugs and fluids. The electrocardiogram, core body temperature, and central aortic pressures
were monitored throughout the experiment. The micromanometer-tipped catheter was electronically zeroed in a 370 C water
bath and calibrated with a mercury manometer before insertion.
All other pressure measurements were made with fluid-filled
catheters with the transducer zeroed to midchest level. The total
preparation time before initial measurements were obtained was
approximately 90 min.
Experimental design. Each animal was premedicated with
intravenous atropine (0.010 to 0.015 mg/kg body weight) to
abolish the vagally mediated bradycardia commonly associated
with morphine-chloralose anesthesia. Ultrasound imaging
(Hewlett-Packard, Andover, MA) was performed with a S MHz
ultrasound transducer with the beam directed just off the tip of
the anterior leaflet of the mitral valve. Recordings were obtained at end-expiration with the dogs in a right lateral position.
Animals with narrow chests were used to facilitate ease of
echocardiographic imaging. Simultaneous left ventricular twodimensional and targeted M mode echocardiograms, electrocardiogram, and mean right atrial and high-fidelity central aortic
pressures were recorded under baseline conditions. Thermodilution cardiac outputs were obtained in triplicate at the time of
echocardiographic and pressure recordings.
Afterload manipulation without alteration of contractile
state. Once baseline recordings were obtained, afterload manipulation without alteration in contractile state was accomplished
with infusions of either the a,-specific agonist methoxamine or
with the vasodilator nitroprusside. Methoxamine (infusion rate
= 15 ,g/kg/min) was used when baseline mean aortic pressure
was 125 mm Hg or less. This protocol was followed for four
dogs. At this dose, methoxamine caused a 2 to 4 mm Hg/min
increase in left ventricular systolic pressure. The left ventricular
response to the pressor challenge was assessed with recordings
obtained every 1 to 2 min until peak systolic pressure increased
30 to 60 mm Hg above baseline. At that time the infusion of
methoxamine was discontinued; the peak pressor effect lasted 2
to 5 min. Nitroprusside (initial dose 0.25 ,ug/kg/min) was given
when baseline mean aortic pressure was greater than 125 mm
Hg. Four dogs were studied with this drug. Recordings were
made 5 min after initiation of the drug infusion. The infusion
rate was titrated until mean arterial pressure fell by 20% to 30%
of the baseline value in association with a change in heart rate of
less than 10 beats/min. At this point, the infusion of nitroprusside was discontinued. Multiple data points were collected during the nitroprusside titration phase.
Alteration ofcontractile state. After baseline hemodynamics
were reestablished, all eight dogs received sequential intravenous infusions of dobutamine and norepinephrine. Dobutamine,
which has a half-life of 2 to 3 min, was infused at 5 ,ug/kg/min
for 8 min to allow establishment of steady-state pharmacokinetics. Pressures, cardiac outputs, and echocardiographic recordings were then obtained. Thirty minutes after completion of the
infusion of dobutamine a new set of baseline data was recorded.
This was followed by an infusion of 0.15 ,ug/kg/min of norepi-
Vol. 74, No. 5, November 1986
nephrine. After 8 min, simultaneous pressures, cardiac outputs,
and echocardiographic recordings were obtained.
Data analysis. The peak of the R wave of the electrocardiogram and the dicrotic notch of the high-fidelity central aortic
pressure tracing were used to designate end-diastole and endsystole, respectively. Left ventricular end-systolic and end-diastolic dimensions (Des and Ded) and wall thicknesses (hes and hed)
were measured from the echocardiographic recordings as the
mean value of three to five cardiac cycles. The left ventricular
percent fractional shortening (%A&D) was calculated as Ded minus Des divided by Ded. The left ventricular Pes and ejection time
were measured from the high-fidelity central aortic pressure
tracings in the standard fashion and taken as the average of 5
beats. Left ventricular ejection time (LVET) was corrected to a
heart rate of 60 beats/min by dividing by the square root of the
preceding RR interval. The rate-corrected left ventricular mean
velocity of fiber shortening (VcfM)10 was calculated as:
Wall stress = [pressure] [geometric factor]
%AD
%AD
= (
)( -R)
Vcf =
LVET
LVET
Left ventricular aes was calculated as the product of Pes and a
geometric factor that includes Des and he,. The following angiographically validated formula"1 was used:
aes
=
Des
(Pes)
(hes)(1
+
(0.34)
)
Des
where aes is in g/cm2, Pes is in mm Hg, Des and hes are in cm, and
0.34 is a factor to convert Pes from mm Hg to g/cm2. SVR was
calculated as the mean aortic minus mean right atrial pressure
times the conversion factor 80 dyne-cm- 2/mm Hg divided by
the thermodilution-determined cardiac output.'2
In all dogs, the same micromanometer-tipped catheter and
recording system were used. In six of the eight dogs studied,
comparisons were made between initial and end-of-study data
for zero position and overall gain. In five of the six animals, no
differences were noted. In the remaining dog, a 2 mm Hg shift
in the zero position without a change in overall gain was
present.
Statistical analysis. Each dog served as his own control. The
paired t test was used to assess the hemodynamic changes induced by each drug relative to their respective control values.
Left ventricular contractile state was measured with the use of
the load-independent relationship between cyes and Vcfc (caesVcfM).10 For each animal this relationship was determined by
linear regression analysis (least squares method) with a minimum of four data points acquired under baseline contractility
conditions over a wide range of afterload (Ces) generated by
either methoxamine or nitroprusside. In addition, all 44 data
points obtained in the eight dogs under baseline contractility
conditions were used to construct the mean regression line and
95% confidence limits for the aes-Vcfc relation. For any individual cres-vcfc point acquired during either dobutamine or norepinephrine infusion, the vertical distance above or below this
mean regression line was used as an estimate of contractile
state.9'13 This allowed comparisons to be performed at the same
level of afterload (i.e., cyes) for control Cyes-Vcfc points and data
acquired during dobutamine or norepinephrine infusion.
Interobserver and intraobserver coefficients of variation were
lllS
LANG et al.
TABLE 1
Hemodynamics during afterload manipulation without altered left ventricular contractility
Percent
change
from
Percent
change CNP VS
from CMETH
CNP
HR (beats/min)
P. (mm Hg)
Ps (mm Hg)
G
CO (1/min)
Vcf (circ/sec)
SVR (dyne-sec-cm-5)
CNP
vs NP vs
CMETH to
(p
(p
(p
CNP
NP
to NP
CMETH
METH
METH
value)
value)
value)
95 ± 11
143 ±18
154± 13
1.53 ±0.18
-6
-28
-26
- 25
+13
+ 18
44± 13
<.01
<.01
<.01
<.001
80±16
-35
-45
-4
+44
+41
+ 32
2
- 24
+48
+86
<.001
<.001
<.01
1379+132
94 ± 12
164±8
176±9
2.16 ± 0.06
5.0±0.5
0.80 ±0.09
2521±265
<.01
<.01
<.01
2126+331
98 ± 20
114±8
125±10
1.64 ±0.07
5.1±0.5
1.05 ±0.09
1710±93
69±9
<.05
<.05
1.07 ± 0.09
89 ± 16
103±7
114± 14
1.15 ±0.21
6.0±0.9
1.26±0.10
5.3+1.1
ces (g/cm2)
128+7
<.05
NP = nitroprusside; METH = methoxamine; CNP prenitroprusside control; CMETH = premethoxamine control; HR
aortic pressure; G = end-systolic geometric factor (for equation see text); CO = cardiac output.
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computed for both the Vcfc and
ies
(d )2
~e
%CV
n =
=
(100)(
-)
number of observations; di
<.001
<.001
<.001
<.05
<.001
<.001
<.001
<.01
<.001
heart rate;
P.
= mean
are
In
| E
=
NP vs
METH
listed in table 2. Representative two-dimensional
and targeted M mode echocardiographic images are
shown in figure 1.
Control data. The four dogs with control aortic mean
pressures of 125 mm Hg or less received methoxamine
while the other four dogs (i.e., those with aortic mean
pressures > 125 mm Hg) received nitroprusside. As
expected, aortic mean pressure, left ventricular endsystolic pressure, and SVR were higher for the dogs
subsequently given nitroprusside. There were no differences between the nitroprusside and methoxamine
groups with respect to heart rate, cardiac output, Vcfc,
or the geometric factor found in the fornula for
with the following formulas:
r
where
CMETH
METH
difference between
measurements: %CV = coefficient of variation (percent); x =
average of all measurements. The intraobserver coefficients of
variation were 3.9% and 3.8% for Vcf, and aes, respectively.
The interobserver coefficients of variation were 7.3% for Vcf,
and 7.6% for ces,
es
Results
The hemodynamic data obtained under baseline
contractility conditions before and during afterload
manipulation with nitroprusside or methoxamine are
summarized in table 1. Similar data recorded before
and during dobutamine and norepinephrine infusions
Ces-
The hemodynamic data acquired from the eight dogs
similar under control conditions before dobutamine and before norepinephrine. For a given animal,
the ces-Vcfc points obtained under these two control
conditions fell on the linear regression line generated
were
TABLE 2
Hemodynamics during augmentation of left ventricular contractility
Percent
change
from
Percent
change
from
CDB
CDB
DB
to DB
+ 14
+ 18
+21
-38
+38
+43
-13
-26
HR (beats/min)
P. (mm Hg)
97± 18
111 + 15
130±22
154±32
Pes (mm Hg)
141±22
171±32
1.01 ±0.07
G
CO (1/min)
Vcf (circlsec)
SVR (dyne-sec-cm -5)
aes (g/cm2)
DB
1116
=
dobutamine; NE
1.63±0.09
5.3±0.8
1.05 ± 0.11
1895+285
80+25
=
7.3±0.9
1.50±+ 0.21
1652+348
59± 18
norepinephrine; CDB
=
CNE to
CNE
100±22
CDB vs
CNE
CDB
vs DB
CNE
vs NE
DB
vs NE
(p
(P
value) value)
(p
value)
value
NE
NE
100± 15
177±29
<.05
-
143±24
189±29
0
+35
+32
-
131 ± 18
1.58±0.08
5.9+1.7
1.06 0.11
1.09±0.09
-31
-
<.001
<.01
<.01
6.4± 1.4
1.41 ± 0.17
<.001
1834±540
2228±493
< .001
<.001
77 16
70± 15
+8
+ 34
+21
-9
<.05
<.01
<.01
<.001
predobutamine control; CNE
=
<.01
<.01
(p
<.01
<.05
<.05
<.01
<.05
prenorepinephrine control; other abbreviations are as in table 1.
CIRCULATION
LABORATORY INVESTIGATION-VENTRICULAR PERFORMANCE
by "pure" afterload manipulation with nitroprusside or
methoxamine. This established the fact that left ventricular contractility had returned to a baseline level
before dobutamine and norepinephrine infusions. This
is illustrated for a representative dog in figure 2.
Data acquired during pharmacologic manipulations
Physiologic determinants of SVR. Figure 3 shows percent
change from control for mean aortic pressure, cardiac
Downloaded from http://circ.ahajournals.org/ by guest on April 29, 2017
ECG
'vs
AOP
LVPW
A
ECG
S,O,_ K
~~~~~~
-.
~~~~200
,
Ivs
output, and SVR. Nitroprusside decreased mean aortic
pressure by 28% (p < .01) without associated changes
in cardiac output or heart rate. This resulted in a 35%
decrease in SVR (2126 ± 331 to 1379 ± 132 dynesec-cm- 5, p < .01). Methoxamine increased mean
aortic pressure by 44% (p < .001), while cardiac output and heart rate remained unchanged. This resulted
ina48% rise in SVR (1710 + 93 to 2521 + 265 dynesec-cm -5, p < .001). Dobutamine increased mean aortic pressure by 18% (p < .05) and cardiac output by
38% (p < .001). The rise in cardiac output was predominant and in part reflected a 14% increase in heart
rate (p < .05). SVR fell by 13% (1895 + 285 to 1652
± 348 dyne-sec-cm- , p < .01). Finally, norepinephrine increased SVR by 21% (1834 ± 540 to 2228 ±
493 dyne-sec-cm-5, p < .001), reflecting a 35% rise in
mean aortic pressure (p < .001) without significant
changes in cardiac output or heart rate.
Physiologic determinants of (Yes, Figure 4 shows percent
change from control in Pe, the left ventricular geometric factor, and cys Nitroprusside decreased Pes by 26%
(p < .01) in conjunction with a 25% fall in the left
ventricular geometric factor (p < .01). This resulted in
a 45% decline incoes (80 ± 16 to 44 + 13 g/cm2, p <
.01). Methoxamine increased all of these variables,
with a 41% rise in Pes (p < .001) and a 32% rise in the
left ventricular geometric factor (p < .01). The net
result was an 86% increase in ces (69 ± 9 to 128 + 7
g/cm2, p < .001). In contrast, when contractility was
augmented with dobutamine, P.S increased by 21% (p
< .01) while the left ventricular geometric factor decreased by 38% (p < .01). This resulted in a 26%
decline in cy,, (80 + 25 to 59 + 18 g/cm2, p < .01).
Finally, norepinephrine increased P.S by 32% (p < .01)
and decreased the left ventricular geometric factor by
31% (p < .01), leading to a 9% fall in aes (77 ± 16to
70 ± 15 g/cm2, p < .12).
Relationship between changes in SVR and
-100
AO
'Pressure
immnwH
LVP
FIGURE 1. Two-dimensional echocardiogram (top of A) and targeted
M mode echocardiograms (bottom of A and B) obtained from a dog in
the current study. Panel A was taken from a videotape still frame while
panel B came from hardcopy. ECG = electrocardiogram; IVS = interventricular septum; AOP
=
aortic pressure; LVPW
posterior wall.
Vol. 74, No. 5, November 1986
=
left ventricular
Ge,.
Figure 5
shows a side-by-side comparison of the mean changes
in SVR and cGes after each of the four drugs. With
peripheral vasodilation produced by nitroprusside,
SVR underestimated the magnitude of change in left
ventricular afterload by 22% (p < .05). When vasoconstriction was induced by methoxamine, SVR again
underestimated the change in ,es (this time by 54%, p
< .05). When afterload was decreased and contractility was augmented with dobutamine, a 50% disparity
in the change in SVR and c(YS was evident (p < .01).
Most importantly, norepinephrine, which minimally
decreased afterload while augmenting contractility, resulted in changes in SVR and Ges that were different in
magnitude and discordant in direction (p < .001).
1117
LANG et al.
z
hW
cu
1.30
-
1.20
-
0
z
to
IL
CNE
EMMETH
0
CDOB\
v-0 :
o
1.10
-
-,
.
W
-
1.001
METH
TH2
METH1
~
MTH
0
W
L)
Lu
0.90 -
W-
T
40
60
80
1
00
12
14
40
60
80
100
1 20
1 40
LV END-SYSTOLIC WALL STRESS (g/cm2)
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FIGURE 2. Data from a representative dog showing left ventricular
(LV) CSes plotted against Vcf.. The linear regression lines generated
under control conditions (CMETH) and during methoxamine (METH1 2 3)
infusion are shown. Points obtained under predobutamine control
(CDOB) and prenorepinephrine control (CNE) conditions fell on the line
generated by "pure" afterload manipulation. This established the fact
that LV contractility had retumed to the baseline level before dobutamine and norepinephrine infusions.
Effects on left ventricularforce-velocity-shortening relations
OVERALL LEFr VENTRICULAR PERFORMANCE. Figure 6
shows the maximal effect of each drug intervention on
overall left ventricular performance as measured by
Vcf,. Vcfc decreased with methoxamine (p < .01) and
-J
0
c-
z
0
increased with nitroprusside (p < .01), dobutamine (p
< .001), and norepinephrne (p < .001).
LEFT VENTRICULAR CONTRACTILE STATE. Figure 7 shows
the relationship between aes and Vcf, for the entire
study group under control conditions. The diagonal
solid line shows the mean value for this relation generated over a wide range of (yes values obtained under
baseline control conditions as well as during methoxamine or nitroprusside infusion. The curved lines are
the 95% confidence limits for this relation. Data points
above these limits indicate increased contractility
while points below indicate decreased contractility.
For any aes -Vcfc data point, the vertical distance to
the mean regression line represents the deviation in
Vcf, units at a given level of afterload (i.e., re,). Since
Vcf, incorporates heart rate and is preload independent, comparisons of the deviations of Vcfc from
the mean regression line can be used to assess left
ventricular contractility independent of changes in
loading conditions induced by various pharmacologic
interventions.9' 10, 13 With these concepts as a framework, figure 8 shows the individual and average GesVcfc data points obtained with dobutamine and norepinephrine. All points are above the 95% confidence
limits for the mean cYes-Vcfc relation, indicating a significant positive inotropic effect of both drugs. The
vertical distance, measured in Vcf, units, to the mean
regression line for the average aes-Vcfc point obtained
during dobutamine (open square) and norepinephrine
80
60
SVR
** *
r
0
LL
0
40
* **
20
z
I
0
**
C.)
z -20
LU
0.) -40
NP
METH
DOB
NOREPI
FIGURE 3. Plot of the major physiologic determinants of SVR. Values are shown as percent change from control. Pm aortic
mean pressure; CO = cardiac output; NP = nitroprusside; METH = methoxamine; DOB = dobutamine; NOREPI =
norepinephrine; *p < .05; **p < .01; ***p < .001.
1118
CIRCULATION
LABORATORY INVESTIGATION-VENTRICULAR PERFORMANCE
-J
80
c-z
60
0
0
2
*
U-
Ces
* *
*E*l
p < 0.01 vs control
p< 0.001 vs control
40
0
LU
C,
Pes
G
**
**
20
zI
0
z
I- -20
z
Downloaded from http://circ.ahajournals.org/ by guest on April 29, 2017
**
-40
CL
**
NP
DOB
METH
NOREPI
FIGURE 4. Plot of the mean percent change from control values for left ventricular Pes' end-systolic geometric factor (G), and
a es Other abbreviations as in figure 2.
(open circle) was similar (0.34 ± 0.13 vs 0.27 ±
0.11). Thus, at the infusion rates used in this study and
when load was factored out as a confounding variable,
dobutamine and norepinephrine had similar positive
inotropic effects.
by SVR. To understand why SVR is an unreliable
measure of left ventricular afterload, it is necessary to
examine the concept of afterload itself.
Left ventricular afterload as measured by systolic wall
stress. Afterload is defined as the force opposing ventricular fiber shortening during left ventricular ejection. 1 2,'7 It is not synonymous with peripheral arterial
pressure, peripheral vasomotor tone, or SVR. Rather,
it can be more appropriately thought of as left ventricu-
Discussion
Our results demonstrate that alterations in left ventricular afterload (i.e., (aes) are not adequately reflected
80
SVR
-J
0
c-z
El
60
0
0
aes
*
**
**W
40
p<0.05 VS aes
p<.01
p
1
<c 0.001
-
C)
C.)
VS °es
FIGURE 5. Comparison of the mean percent change
from control values for SVR and ces during nitroprusside (NP), methoxamine (METH), dobutamine
(DOB), and norepinephrine (NOREPI) infusions.
Note the discordant changes with norepinephrine.
20
z
c
z
vs °es
0
-20
-40
CL
-60
-J
NP
lr
MFTU
._.- . .
Vol. 74, No. 5, November 1986
DOB
NOREPI
1119
LANG et al.
CD
-J
z
40
0
I- c0 z
z 0
Uo C-)
30
0
20
LL
0
I-
U-
0
1W
0
cc
cc
0
FIGURE 6. Effects of the four drug interventions on
w
overall left ventricular
z
-
* *
z
-10
cc)
-20
performance
as
measured
by
Vcf.. Abbreviations as in figure 2.
0
***
W
CL)
W
I-c
10
0.05 vs control
p
<
p
<0,01
p
<
vs
control
0.001 vs control
0a
Downloaded from http://circ.ahajournals.org/ by guest on April 29, 2017
cc
NP
DOB
METH
NOREPI
lar wall stress during ejection. It includes factors both
internal and external to the myocardium. According to
La Place's principle, left ventricular wall stress is directly related to chamber dimension and pressure and
inversely related to wall thickness.' 1- 11 During the
ejection phase of the cardiac cycle, the left ventricular
dimension decreases while ventricular pressure and
wall thickness increase. Normally, left ventricular afterload (i.e., wall stress) reaches its peak within the
first one-third of ventricular ejection and then declines
throughout the remainder of systole.6 8 9 11 This occurs
despite rising ventricular pressure throughout most of
the ejection period, and emphasizes the importance of
the decline in left ventricular size and increase in wall
1.8
1.6
0
F
1.4
~0
1.2 [
&a
h.
0
0
1.0
0.8
.
[
195%
Limits
0.8
0
20
40
60
80
100
120
140
LV End-Systolic Wall Stress (g/cm2)
FIGURE 7. Relationship between left ventricular (LV) c,s and Vcf. for the entire study group under control conditions. See text
for detailed description.
1120
CIRCULATION
LABORATORY INVESTIGATION-VENTRICULAR PERFORMANCE
a
1.8k
rf
U Dobutamine
1.61=
® Norepinephrine
0
1.4
0
U
0
U
1.2
a
C.
h.
1.0
0.8 F
95%
Confidence
Limits
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0.6 F
0
20
40
60
80
100
120
140
LV End-Systolic Wall Stress (g/cm2)
FIGURE 8. Effects of dobutamine and norepinephrine on left ventricular (LV) contractile state. Individual and mean data are
superimposed on the graph shown in figure 6. All points are above the 95% confidence limits for the mean LV es-Vcf relation,
indicating a significant and equal positive inotropic effect for both drugs.
a
thickness (i.e., geometric factors) as determinants of
instantaneous systolic wall stress. By end-ejection,
wall stress is generally less than 50% of its peak value.8' 9 Left ventricular systolic wall stress can be divided into several components, each of which has specific
physiologic significance. These include: (1) peak systolic wall stress, which is one of the most important
stimuli for left ventricular hypertrophy in chronic pressure overload states such as systemic hypertension,
valvular aortic stenosis, or coarctation of the aorta,6' 11, 1416 (2) integral of left ventricular systolic wall
stress over time, which along with heart rate and contractile state is a major determinant of myocardial oxygen requirements,'17 18 (3) aes which defines the limiting force to left ventricular fiber shortening. This is
demonstrated by the fact that ventricular ejection ends
when instantaneous myocardial force reaches the
maximal or isometric value for the existing chamber
size, thickness, and pressure.7'8 10 19-22 The (yes is a
measure of this load. For a given level of contractility,
it is the wall stress at end-systole rather than the load
throughout the course of ventricular ejection that is
inversely related to the overall extent and mean velocity of fiber shortening. Accordingly, absolute values
for peak, mean, and integral of left ventricular systolic
Vol. 74, No. 5, November 1986
force (i.e., wall stress) can vary without altering events
at end-systole.7'20
In this study, the physiologic determinants of aes
(i.e., end-systolic pressure and the left ventricular geometric factor) decreased when afterload was reduced
with nitroprusside and increased when afterload was
augmented with methoxamine (figure 4). This reflects
the direct linear relationship between Pes and Des when
contractile state is maintained constant over a wide
range of afterload.23 25 In contrast, when contractility
was augmented with either dobutamine or norepinephrine, Pes increased (+21% and +32%, respectively)
while the left ventricular geometric factor decreased
(-38% and -31%, respectively). These discordant
changes between pes and the left ventricular geometric
factor reflect the increased slope and leftward shift in
the Pes-Des relation that occur with a positive inotropic
intervention.24' 25 This means that relative to control
values, Des is smaller for any pes. Since there is conservation of left ventricular mass, the decrease in Des is
associated with an increase in end-systolic wall thickness. The net result is a decline in the left ventricular
geometric factor that more than counterbalances the
rise in Pes' leading to a 26% fall in Ces with dobutamine
and a 9% fall with norepinephrine (figure 4).
1121
LANG et al.
Left ventricular afterload as measured by SVR. For
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years SVR has been used as a measure of ventricular
afterload. It is defined by analogy to Ohm's law as the
ratio of mean pressure drop to total flow across the
systemic vascular bed. This assumes that the cardiovascular system is a "'DC" circuit that generates constant pressure and flow throughout systole and diastole. However, the left ventricular is a pulsatile rather
than steady-state pump that works against an internal
load consisting of pressure and geometric factors plus
an external load consisting of pulsatile and nonpulsatile components.4 9. 26-28 The relative importance of
each of these components depends on multiple factors,
including the inertial properties of blood, the elasticity, viscosity, and geometry of arteries and the viscous
properties of blood in small vessels. Since SVR incompletely assesses the ventricle's internal and external
loads, it is not surprising that conditions exist in which
SVR is an unreliable measure of left ventricular afterload. Results from the current study confirm this fact
by showing that SVR underestimates the magnitude of
change in afterload (1) by 22% when afterload alone is
decreased (nitroprusside), (2) by 54% when afterload
alone is increased (methoxamine), and (3) by 50%
when afterload is decreased and contractility is augmented (dobutamine). Most importantly, when afterload is minimally decreased in association with augmented contractility (with norepinephrine), SVR fails
to accurately predict either the magnitude or direction
of change.
Effects of dobutamine and norepinephrine on left ventricular contractility. The relationship between left ventricular ces and the Vcf, is a sensitive measure of contractility that incorporates heart rate and afterload
while being preload independent. 1 This overcomes the
load- and rate-dependent limitations of traditional indexes of left ventricular systolic performance such as
ejection fraction, percent fractional shortening, and
mean velocity of fiber shortening. In our study, dobutamine increased Vcf, by 43%, while norepinephrine
increased it by 34% (figure 5). These changes in overall performance were associated with a greater afterload-reducing effect for dobutamine than for norepinephrine (-34% vs- 9%, p < .05). When changes in
left ventricular afterload were incorporated into the
data analysis, both sympathomimetic drugs were
shown to be equipotent positive inotropes (figure 8).
Thus, assessment of left ventricular mechanics by the
approach outlined in this investigation allowed separation and quantitation of the multiple hemodynamic
effects of each of the cardioactive agents studied.9 29-31
Methodologic considerations. A detailed discussion of
1122
the methods used in this study has been presented
previously.8-1010 However, several issues specific to
the current investigation should be addressed. First, all
animals studied had symmetrically contracting left
ventricles without evidence of regional wall motion
abnormalities on two-dimensional echocardiographic
imaging. It was therefore assumed that the targeted M
mode echocardiograms were representative of global
left ventricular performance. Second, it was assumed
that the alterations in left ventricular afterload induced
by nitroprusside and methoxamine occurred without
associated changes in ventricular contractility. This
seems reasonable since heart rate remained unchanged
with both drugs, suggesting that a large outflow of
catecholamines did not occur. Finally, left ventricular
meridional rather than circumferential wall stress was
used to measure ventricular afterload. In normally
shaped hearts, both of these components of total wall
force are important determinants of ventricular shortening characteristics. Although their absolute values
may differ in magnitude, their usefulness as measures
of left ventricular afterload are comparable.6 15 A2 In
accordance with this concept are the results of the
animal study by Little et al.33 in which ultrasonic crystals and a left ventricular micromanometer catheter
were used to assess left ventricular mechanics before
and after infusion of 10 ,ug/kg/min dobutamine. For
comparable changes in left ventricular pressure, proportionally similar changes in left ventricular long- and
short-axis dimensions were noted. This suggests that
meridional and circumferential wall stresses also
changed in a proportionally similar manner with a catecholamine challenge. Thus, it appears that either analysis of wall stress would have resulted in similar findings in our study.
Clinical implications. SVR is an unreliable measure of
left ventricular afterload, as demonstrated by its inability to accurately assess afterload changes associated
with pharmacologic interventions. In the clinical setting, changes in SVR do not necessarily reflect left
ventricular loading conditions since the true measure
of ventricular afterload must consider the interaction of
factors internal and external to the myocardium.
We thank David P. James for his expert graphic art and
secretarial skills and Drs. Paul T. Schumacker and Keith Walley
for their technical support in the animal laboratory.
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Systemic vascular resistance: an unreliable index of left ventricular afterload.
R M Lang, K M Borow, A Neumann and D Janzen
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Circulation. 1986;74:1114-1123
doi: 10.1161/01.CIR.74.5.1114
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