© 1996 American Heart Association, Inc.
Articles |
Tumor Necrosis Factor-
Induces a Biphasic Effect on Myocardial Contractility in Conscious Dogs
From the Department of Medicine, University of Texas Health Science Center at San Antonio, and the Audie L. Murphy Memorial Veterans Hospital, San Antonio, Tex.
Correspondence to David R. Murray, MD, Medicine/Cardiology, 7703 Floyd Curl Dr, San Antonio, TX 78284.
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Abstract |
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 Top Abstract IntroductionMaterials and Methods Results Discussion References |
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Abstract Tumor necrosis factor-
(TNF-) likely plays a
role in the pathophysiology of myocardial depression observed in septic
shock. To evaluate the hemodynamic effects of TNF-
in vivo while eliminating the influence of altered sympathetic tone,
eight conscious chronically instrumented dogs were studied after
pretreatment with propranolol (2 mg/kg) and atropine (2
mg). Using three sets of piezoelectric crystals to measure left
ventricular (LV) volume and LV manometers to measure
pressure, we determined load-independent parameters of
LV systolic performance before, during, and after
infusion of recombinant human TNF- (rhTNF-, 40 µg/kg for 1
hour). Plasma was analyzed for epinephrine and
norepinephrine. Between 1 and 7 hours of exposure,
rhTNF- induced significant increases in circulating
catecholamines. Norepinephrine rose from
268.6±47.2 to 426.2±87.0 pg/mL (P<.05) at 1 hour and
peaked at 921.2±156.8 pg/mL (P<.001) at 4 hours after
initiating rhTNF- treatment. Similarly, epinephrine
increased from 130.2±30.9 to 884.5±210.2 pg/mL
(P<.05) at
1 hour and peaked at 3195.3±476 pg/mL (P<.001) at 4 hours.
Before the surge of circulating catecholamines and despite
complete ß-adrenergic blockade, rhTNF- induced a 7% to 40%
increase in LV contractile performance during the 60-minute
infusion. After this initial positive inotropic effect, rhTNF-
treatment led to precipitous systolic dysfunction between 2 and
7 hours of exposure; this myocardial depressant effect persisted at 25
hours. LV systolic performance declined to 19% to 35%
of baseline values, depending on the specific contractile
parameter evaluated. We conclude that rhTNF- affects LV
systolic function in a time-dependent biphasic manner.
Increases in circulating catecholamines after rhTNF-
infusion cannot account for the early improvement in LV
systolic performance.
Key Words: cytokine • left ventricular function • septic shock • norepinephrine • epinephrine
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Introduction |
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TopAbstractIntroductionMaterials and Methods Results Discussion References |
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The specific mechanisms by which sepsis leads to hemodynamic disturbance and organ failure are not understood, although substantial evidence points to the role of TNF-
, a pleiotropic
cytokine.1 Infusions of rhTNF- in
humans2 and animals3 4 5
have produced fever,
hypotension, metabolic acidosis, hemoconcentration,
capillary leak, and even death. Moreover, baboons pretreated with
neutralizing monoclonal anti–TNF- antibody fragments have been
afforded complete protection from the hemodynamic
collapse seen in endotoxic shock.6 More recently, TNF-
has been shown to play an adverse role in acute hypovolemic
hemorrhagic shock, perhaps as a consequence of vascular hyporeactivity
to -adrenergic stimulation.7
In addition to its vasodilating effect, TNF- appears to induce
reversible myocardial dysfunction. Earlier studies have revealed that
sepsis is associated with LV contractile
impairment,8 9
attributable to a circulating myocardial depressant
substance.10 Humans with septic shock have elevated
TNF- levels,11 and volunteers challenged with endotoxin
develop increases in circulating TNF- followed by LV dilation and a
reduced ejection fraction.12 13 In vitro studies
using
isolated feline LV and cardiomyocytes14 and
Syrian hamster papillary muscles15 have confirmed that
TNF- exerts a transient myocardial depressant effect, which occurs
within minutes. Recent investigations have delineated the time course
and dose dependence of rhTNF-–induced myocardial dysfunction in
conscious autonomically intact dogs.16 17 Unlike the
in
vitro studies, which have characterized an immediate negative inotropic
influence, Pagani et al16 did not observe deterioration of
myocardial performance until 24 hours after rhTNF-
treatment. In another canine study, however, LV ejection fraction was
noted to initially decline 2 hours after rhTNF-.17
Neither canine study has addressed potential TNF- effects on the
myocardium within the first 2 hours of exposure or the
potentially confounding influences of altered sympathetic tone in the
face of TNF-–mediated vasodilation.
The objective of the present study was to define the kinetics of
TNF-–induced myocardial depression in vivo while neutralizing
the changes that might occur in endogenous sympathetic
tone. Accordingly, we studied the hemodynamic effects
of rhTNF- in conscious chronically instrumented dogs pretreated with
a combination of propranolol and atropine. Our results will
demonstrate that rhTNF- induces a biphasic myocardial response,
characterized by an early increase in LV contractility,
followed by precipitous and sustained myodepression.
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Materials and Methods |
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TopAbstractIntroductionMaterials and Methods Results Discussion References |
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Instrumentation
All animal studies were performed in accordance with the "Guide for Care and Use of Laboratory Animals" (Department of Health and Human Services publication No. [NIH] 85-23, revised 1985); eight adult mongrel dogs (22 to 30 kg) of either sex were used. The surgical preparation has been described in detail previously.18 In brief, after intravenous sedation with 2.5% sodium pentothal (6 to 10 mL) and acepromazine (0.25 mg/kg), the animals were intubated and anesthetized with 1% to 2% isofluorane. Under sterile conditions, a left thoracotomy was performed. Three sets of piezoelectric crystals were implanted in the endocardium of the LV, oriented orthogonally, to allow for continuous assessment of the DAP, DSL, and DLA. A micromanometer-tipped catheter (Konigsberg Instruments) and a fluid-filled polyvinyl catheter (1.1-mm internal diameter) were placed through the LV apex and held in place by a purse-string suture. A second fluid-filled catheter was positioned in the left atrium for infusion of drugs and saline; a third fluid-filled catheter was inserted into the aortic arch to measure arterial pressure and to collect blood samples. Pacing electrodes were sutured to the left atrium, and balloon occluder cuffs were positioned around the inferior vena cava to permit alteration of LV loading during the experiments. All leads, catheters, and occluders were exteriorized dorsal to the thoracotomy incision, and the chest was closed. After surgery, the animals received trimethoprim/sulfadiazine (960 mg daily for 7 days).
Data Collection
The dogs were studied after full recovery
from surgery, a period
of at least 10 days, during which time they were trained to lie quietly
in a sling. Data were collected with the animals awake and unsedated.
The LV catheter was connected to a Statham P23 dB pressure gauge
calibrated against a mercury manometer. The signal from the
manometer-tipped catheter was matched with the fluid-filled
catheter in the LV apex. Lead II of the surface ECG was recorded.
LV dimensions were obtained from the three sets of piezoelectric
crystals coupled to a sonomicrometer (Triton
Technology).
Analog recordings were made on an eight-channel forced-ink oscillograph (Beckman Instruments) at a paper speed of 25 mm/s. The following variables were measured: PLV, the first derivative of PLV with respect to time (dP/dt), ECG, the three diameters, and aortic pressure. These variables were simultaneously converted to digital form at a rate of 500 Hz and stored on floppy disks. Digital data were recorded for 12-second periods under control conditions and after caval occlusions.
Whole Animal Studies
After surgery, the dogs'
temperatures, body weights, and
overall conditions were monitored daily. Systemic infection was ruled
out with blood cultures. The studies were conducted after pretreatment
with propranolol (2 mg/kg) and atropine (2 mg). To ensure
the adequacy of ß-adrenergic blockade, we evaluated the
hemodynamic performance and heart rate in five
dogs on an hourly basis before and after brief infusions of
dobutamine at 5 µg/kg per minute, a dose that typically
increases LV contractility 
50% to 75% in this
model. After treatment with propranolol and atropine as
described above, dobutamine had no effect on LV
systolic function and heart rate, a finding that persisted for
7 hours.
We proceeded to study the hemodynamic
performance in eight dogs before and after rhTNF-.
Approximately 10 minutes after the infusion of propranolol
and atropine, blood was obtained for catecholamine
analysis, followed by acquisition of baseline
hemodynamic data. After steady state recordings
were made, vena caval occlusions were performed to define LV function
over a range of loading conditions. Immediately after the
recording period, the vena caval occlusion was released. All
studies were performed at a paced rate of 160 bpm.
After acquisition of
baseline data, the animals received 40 µg/kg of
rhTNF- (lot EB6011) kindly supplied by Knoll Pharmaceutical, Inc.
This dose was selected because it has been shown to impact on LV
function in a previously published study of intact animals. Specific
activity was 1x107 U/mg protein, and the
lipopolysaccharide content was <0.5 ng/mg protein
(manufacturer's data). Individual doses of active rhTNF- were
reconstituted in 20 mL of saline and administered over 1 hour into the
left atrium via a calibrated infusion pump. Before rhTNF- infusion,
the tubing and syringes were treated with 3 mL of canine plasma.
Hemodynamic recordings before and during caval
occlusions were obtained 5, 15, 30, and 60 minutes into the rhTNF-
infusion as well as 2, 3, 4, 7, and 25 hours after starting the
rhTNF- infusion. Dogs received a repeated dose of
propranolol (2 mg/kg) and atropine (2 mg) before the
25-hour study. Two milliliters of blood was obtained at each time
point, after propranolol/atropine infusion and before vena
caval occlusions, for catecholamine analysis.
Of the eight dogs that
underwent the rhTNF- protocol after
pretreatment with propranolol/atropine, six dogs survived
the study. One of the survivors developed pulsus alternans with
inferior vena caval occlusion at 4 hours, precluding the
ability to evaluate contractility 4,7, and 25 hours
after rhTNF- exposure. Two dogs developed status epilepticus and
died 5 hours into the study. The hemodynamic data
from the nonsurvivors were included in the analysis.
At the end of the studies, the animals were killed by lethal injection of pentobarbital sodium and potassium chloride. The hearts were excised and dissected to confirm proper positioning of the instruments and the absence of heart worms.
Plasma Catecholamine Measurement
Sample Preparation
Plasma samples were obtained from blood samples collected into
chilled syringes containing 0.025 mL of ethylene glycol tetraacetic
acid (95 mg/mL) and reduced glutathione (60 mg/mL) per 1 mL blood.
Radioenzymatic Assay
Catecholamine determinations
were carried out by
following the technique of Peuler and Johnson.19
Endogenous catecholamines were converted to
radiolabeled O-methylcatecholamine
derivatives by incubating plasma samples with
catechol-O-methyltransferase isolated from rat liver and a
tritiated methyl group donor,
S-adenosyl-L-methionine. The 3H
derivatives were then extracted and separated by thin-layer
chromatography. Zones containing
[3H]metanephrine and
[3H]normetanephrine
were scraped into separate scintillation vials and converted to
[3H]vanillin by oxidation with sodium periodate. Tritium
(in counts per minute) was measured by the addition of a
toluene-based scintillation fluid and counted with a window setting
appropriate for tritium. This method has a minimum sensitivity of 20
pg/mL, with an interassay coefficient of variation of 6% and a
between-assay coefficient of variation of 10%.
Data Analysis
The digitized data were analyzed by using
software
developed in our laboratory. Pressure and diameter data were
analyzed without the use of digital filters. VLV
was calculated from the three orthogonal dimensions by using the
following equation:
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We have previously demonstrated that this method gives a consistent measure of LV stroke volume despite marked changes in LV size, configuration, and heart rate.18 20 21 22
End diastole was defined as the time of the peak of the QRS complex of the surface ECG. Under control conditions, end systole was defined as the peak ratio of PLV to VLV23 ; for caval occlusion data, end systole was defined by using the iterative approach of Kono et al.24 dP/dt was calculated by using a running five-point Lagrangian fit of the instantaneous PLV data. For each dog, beats were chosen from the caval occlusion runs that had a common Ved to allow comparison of dP/dtmax independent of Ved. SW was calculated as the integral of PLV and VLV over each cardiac cycle as described by the following equation:
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The period of isovolumic relaxation was defined as occurring between the time of peak negative dP/dt and the time when pressure fell to 5 mm Hg above the end-diastolic pressure for that beat. The time constant of isovolumic relaxation was determined by nonlinear regression analysis of the pressure and time data during isovolumic relaxation by using a monoexponential function of the following form:
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where
P0 was an estimate of the pressure at peak
negative dP/dt, t was the time (in milliseconds), 
was the time
constant of LV relaxation, and Pb was the floating pressure
asymptote as t approached infinity. To solve for , we used a
computer algorithm based on the method described by
Hartley.25 For all of these parameters, the
values for 20 to 25 consecutive beats, spanning two to three
respiratory cycles, were averaged to yield a single result.
The slope and volume intercepts of the Pes-Ves relation,26 the SW-EDV relation,27 and thed P/dtmax-EDV relation28 were each determined by using a linear least-squares algorithm. For the Pes-Ves relation, end-systolic data were fit to the following equation:
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where Ees was the slope of the relation and V0 was its volume-axis intercept. To evaluate the position of the relation in the physiological pressure range, VLV at Pes of 100 mm Hg was calculated and termed V100. For the SW-EDV relation, the data were fit to the following equation:
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where Mw was the slope of the relation and Vw was its volume-axis intercept. For the dP/dtmax-EDV relation, the data were fit to the following equation:
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where dE/dtmax was the slope of the relation and EDV0 was its volume-axis intercept. For analysis of these constructs, only caval occlusions that caused a reduction in Pes of at least 20 mm Hg were accepted.
Statistical Analysis
Data are presented as mean±1 SEM.
Measurements over
various time points were compared against the corresponding
pre–rhTNF- value to determine their statistical significance.
In these intragroup comparisons, an ANOVA of repeated measurements,
based on the least-squares means to correct for missing values, was
performed. In addition, certain values (Ees,
Mw, dE/dtmax,
dP/dtmax at a common Ved, and
V100) were expressed as ratios (parameter at
time n/parameter at time 0) and then compared versus 1 in a
t test. A value of P<.05 was considered
significant.
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Results |
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TopAbstractIntroductionMaterials and Methods Results Discussion References |
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Effect of rhTNF-
on Circulating Norepinephrine
and Epinephrine Pretreatment with propranolol/atropine did not affect baseline levels of circulating catecholamines. Between 1 and 7 hours of exposure, rhTNF-
induced precipitous increases in
circulating catecholamines (Fig 1
). After
pretreatment with propranolol/atropine,
norepinephrine rose from 268.6±47.2 to 426.2±87.0 pg/mL
(P<.05) at completion of the 1-hour rhTNF- infusion,
peaking at 921.2±156.8 pg/mL (P<.001) at 4 hours.
Similarly, epinephrine increased from 130.2±30.9 to
884.5±210.2 pg/mL (P<.05) at 1 hour and peaked at
3195.3±476.0 pg/mL (P<.001) at 4 hours.
Catecholamine levels remained elevated at 7 hours but
normalized by 25 hours.
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P<.01, and
P<.001.
Effect of rhTNF- on LV Function in
Propranolol/Atropine-Pretreated Dogs
LV systolic function
significantly improved as early as 5
minutes into rhTNF- infusion, persisting for the first hour
following treatment when defined by Ees. Similar trends
were observed for Mw and dE/dtmax (Table
1). Normalization of contractile
parameters to respective baseline values revealed
additional significant increases in systolic
performance, especially during the first 60 minutes of
rhTNF- exposure: Ees (18% to 40% increase during the
first 120 minutes), Mw (3% to 7% increase over the first
60 minutes), and dE/dtmax (15% to 24% increase
during the first 60 minutes). rhTNF- also induced an increase in
dP/dtmax when evaluated at steady state (Table 2) as
well as at a common Ved (peak value,
109.1±3.4% of baseline at 15 minutes; Fig 2) during
the initial 30 minutes of infusion.
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Early enhanced LV systolic function
was accompanied by a
statistically significant 6% to 8% decline in V100 (Fig
3) and by decreases in (Table 2
). This
reduction in
occurred despite increases in afterload. Pes increased
as early as 5 minutes into rhTNF- infusion, persisting up to 2 hours
after infusion (P<.05 at 30 minutes and 1 hour after
infusion). This initial increase in Pes was likely
secondary to an rhTNF-–induced surge in
catecholamines, resulting in vascular -receptor
stimulation (Fig 1). Neither Ped nor SW changed
during the
phase of improved LV contractility.
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LV systolic performance eventually
deteriorated after
rhTNF- infusion. Regardless of the contractile parameter
evaluated, myocardial depression was evident at 25 hours (Table
1, Fig 2). The time of onset of LV systolic
dysfunction differed,
depending on which contractile parameter was assessed.
dP/dtmax, measured at a common
Ved, declined significantly as early as 2 hours,
persisting to 25 hours (nadir, 65.1±5.9% of baseline value at 4
hours; Fig 2). Although derived indexes of LV contractile
function
(Ees, Mw, and
dE/dtmax) tended to show initial evidence of
LV systolic impairment between 3 and 7 hours, significant
reductions did not occur until 7 hours
(dE/dtmax) and 25 hours (Ees and
Mw) after onset of rhTNF- (Table 1). Between 4
and 25
hours, Mw decreased 9% to 19%,
dE/dtmax decreased 14% to 29%, and
dP/dtmax at a common Ved decreased 28%
to 35% from baseline values. End-systolic elastance
diminished 10% at 7 hours and 31% at 25 hours.
The onset of myocardial
depression was accompanied by LV dilation, by
reduced steady state dP/dtmax, by diminished
SW, and shortly thereafter by slowed LV relaxation. These changes
persisted at 25 hours (Table 2). The increase in
V100
mirrored the deterioration in dP/dtmax at a common
Ved (16% to 31% increase between 3 and 25 hours, Fig
3).
The decrease in SW occurred as a consequence of decreases in stroke
volume. Despite deterioration of LV contractile function,
Ped did not change (Table 2).
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Discussion |
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TopAbstractIntroductionMaterials and Methods Results Discussion References |
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Our data show for the first time that rhTNF-
induces a biphasic
myocardial response in conscious dogs, characterized by an early
increase in contractility and a delayed sustained
myodepression. Catecholamines are not responsible for the
early positive inotropic effect of rhTNF-; the initial enhancement
of LV performance precedes a surge in epinephrine and
norepinephrine and occurs despite complete
ß-adrenergic blockade. These data confirm the known negative
inotropic effects of rhTNF- while suggesting a complex
multifactorial mechanism in the intact animal.
Our results differ from those of previous in vitro
investigations. Studies performed using Syrian hamster papillary
muscles and isolated intact feline LVs or cardiomyocytes
have shown that TNF- causes myocardial depression within 15 to 20
minutes of exposure.14 15 In juvenile or adult rat
cardiomyocytes, TNF- has been observed to have no
immediate effect on baseline
contractility.29 30 Contrary to these in
vitro studies, we have found an increase in LV systolic
performance during the first 60 to 120 minutes of rhTNF-
exposure in an in vivo model. Since our dogs are conscious and
physiologically intact, preserved paracrine,
endocrine, hematologic, and neurological influences may account for
these differences.
The mechanism responsible for enhanced LV systolic function in
the initial hours of rhTNF- treatment is uncertain. However, we have
shown that sympathoadrenal activation is not responsible for the
initial positive inotropic influence of rhTNF-. Given that our dogs
were pretreated with propranolol at doses that provided
complete ß-adrenergic blockade, the precipitous increases in
circulating catecholamines after rhTNF- infusion cannot
account for the early improvement in LV systolic
performance. The relatively rapid improvement in LV
systolic function after rhTNF- treatment (as early as 5 to
15 minutes) suggests a direct influence on the myocardium
or the release of a secondary mediator not requiring protein synthesis.
Further studies will be required to define the mechanism of this
effect.
LV systolic performance deteriorated 2 to 7 hours
(depending on the contractile parameter evaluated) after
completing rhTNF- infusion, at the time when peak
epinephrine levels were recorded. In this regard, our
results are similar to those reported by Eichenholz et
al.17 These investigators found a dose-dependent
decrease in LV ejection fraction as early as 2 hours after completion
of rhTNF- treatment in autonomically intact conscious dogs, an
effect that later became independent of dose and most pronounced at 8
hours. In our model, LV systolic performance was
preserved at 2 hours after rhTNF- infusion (with the exception of
dP/dtmax at a common Ved) but began to
deteriorate 1 hour later. These subtle differences may be attributed to
the influence of loading conditions on LV ejection fraction; we avoided
this problem by evaluating LV systolic function with relatively
load-independent parameters of contractile
performance.
Our data differ from those of Pagani et al,16 who did not
find evidence of impaired myocardial performance in chronically
instrumented dogs until 24 hours after rhTNF- infusion. This
difference may result from differences in instrumentation; we used
three endocardial dimension signals to calculate LV volume, but they
used a single epicardial dimension, an approach that is less accurate
if changes occur in LV shape or wall thickness (secondary to
edema).31 In addition, data in our study were acquired at
a single paced heart rate, whereas in their study heart rate was
allowed to vary. Since contractile performance is dependent on
heart rate,20 coexistent
tachycardia may have masked the negative effects of
rhTNF-. Furthermore, Pagani et al relied on the
SW–end-diastolic dimension relation to assess LV
contractility. This parameter may be
relatively insensitive for detecting alterations in systolic
function. Deviation of contractility from baseline
values in our study was more prominently shown with Ees and
dE/dtmax than with Mw, a measure
similar to that used by Pagani et al. Finally, Pagani et al performed
their investigations in autonomically intact dogs; a pronounced
endogenous sympathoadrenal response may
have obscured an earlier negative impact of rhTNF- on LV
systolic function.
rhTNF- appears to affect diastolic as well as
systolic LV performance. One such manifestation was a
prolongation of , a finding that occurred in the absence of changes
in loading conditions. Lengthening of was coupled to
systolic dysfunction and likely reflects one aspect of a
pattern of abnormal intracellular calcium handling that may be
present in cardiac depression. In addition, LV dilation occurred
without a change in end-diastolic pressure, suggesting
rhTNF- induced myocardial creep. Because we studied the dogs while
they were conscious and spontaneously breathing, significant changes in
intrathoracic pressure precluded a precise definition of the entire
diastolic pressure-volume relation. Nonetheless, the
finding of creep would confirm the prior results of Pagani et
al,16 who made similar observations in intact dogs.
Possible etiologies of myocardial creep include myocardial edema,
disruption of the collagen supportive framework, and elongation of
myocardial fibers.
Although the precise mechanism by which rhTNF- leads to impaired
contractile performance remains undefined, the temporal
sequence we describe may provide helpful clues to its nature. As noted
both in vitro14 15 and in
vivo,3 14 15 16 17
the
detrimental effects of TNF- on myocardial function are fully
reversible, similar to those seen with myocardial stunning, where
oxygen-derived free radicals have been shown to play a major
role.32 TNF- is known to stimulate neutrophil
migration33 and phagocytosis,34 adherence to
endothelial cells35 and
myocytes,36 and superoxide anion37 and
hydrogen peroxide release.38 Thus, the delay in the onset
of mechanical dysfunction observed in the present study may have
been related to the time necessary for recruitment and activation of
neutrophils in the coronary microcirculation.
Whether NO, a ubiquitous intracellular messenger involved in
signal transduction,39 mediates TNF-–induced
myocardial depression is controversial. Myocytes are capable of
expressing both constitutive and inducible isoforms of NO
synthase.40 Although studies in isolated Syrian hamster
papillary muscle have provided indirect evidence that
TNF-–induced contractile dysfunction results from enhanced
activity of constitutive NO synthase,15 this finding has
been refuted by subsequent investigations using feline
cardiomyocytes.14 Our inability to demonstrate
immediate contractile dysfunction would support the contention that
TNF- does not mediate its effects via constitutive NO synthase.
Brady et al41 have proposed that the loss of
contractility of cardiac myocytes in endotoxic shock is
secondary to synthesis of an inducible NO synthase and subsequent NO
generation and not activation of a constitutive NO synthase. The
kinetics of TNF-–induced mechanical dysfunction observed in the
present study are compatible with this idea.
Other mechanisms may play a role in TNF-–induced myocardial
depression. Yokoyama et al14 suggested that the immediate
negative inotropic effects of TNF- observed in isolated feline LVs
and cardiomyocytes result from alterations in intracellular
calcium homeostasis, independent of the need for de novo protein
synthesis, arachidonic acid metabolism, or
NO synthesis. As with the study by Finkel et al,15 these
in vitro studies have focused on mechanisms responsible for
TNF-–induced myocardial dysfunction in the first 5 to 20
minutes of exposure, an effect that we were unable to duplicate in
vivo. Although Yokoyama et al discount the need for de novo protein
synthesis to mediate rapid TNF- impairment of
cardiomyocyte contractility in vitro,
protein synthesis may be necessary for the induction of profound
myocardial dysfunction observed 4 hours after TNF- exposure in vivo.
Other potential causes of TNF-–induced contractile depression
include direct injury to myocardial fibers, disruption or rearrangement
of the interstitial matrix, and formation of myocardial
edema via capillary leakage. These effects may take hours to manifest.
On the basis of previous studies, neither systemic
metabolic abnormalities nor changes in coronary
blood flow are likely to be responsible.16
The present study must be interpreted in light of possible limitations. We have assumed that the three relations used for assessment of LV performance are linear. Prior studies in our preparation have shown that although the Pes-Ves relation is nonlinear, the degree of nonlinearity is consistent over a broad range of contractile states; in the physiological range, the assumption of linearity does not introduce substantial error.42 Thus, we are confident that this assumption has not affected our results. To illustrate how the hearts behaved in the physiological range of pressures, we have shown data on V100, the Ves achieved when confronted by a Pes of 100 mm Hg. Although our data have shown that significant rightward shifts of these Pes-Ves relations at 100 mm Hg occurred consistently with depressed indexes of LV performance, leftward shifts of these relations were not always seen during periods of enhanced LV contractility as defined by Ees (V100 not always significantly decreased at each time point). These observations likely result from concomitant increases in the extrapolated x intercept for each relation. This pattern has previously been seen in our laboratory in the setting of contractile augmentation by the force-frequency effect.20
In conclusion, conscious dogs exhibit a biphasic myocardial response to
a 1-hour infusion of rhTNF-. Early positive inotropic effects occur
even in the face of complete ß-adrenergic blockade, ruling out a
catecholamine-mediated phenomenon. Myocardial
depression occurs between 2 and 7 hours (depending on the contractile
parameter evaluated) after initiating rhTNF- treatment.
In addition to its effects on contractile function, rhTNF- impairs
LV diastolic relaxation and promotes LV myocardial
dilation. TNF- likely plays an integral role in myocardial
depression observed in septic shock and may be involved in the
pathophysiology of myocarditis,43 cardiac allograft
rejection,44 and congestive heart failure.45
Additional studies need to be performed in order to precisely define
the mechanisms responsible for the detrimental influence of TNF- on
myocardial function.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This study was supported in part by an institutional research grant and by an American Heart Association Grant-in-Aid (Dr Murray) and the Research Service of the Department of Veterans Affairs (Dr Freeman). The authors thank Danny Escobedo and Cindy Ramirez for technical assistance, Norma Garcia for processing the manuscript, Merardo Monzon for software development, Gabriela Helesic and Dr Robert E. Shade for catecholamine analysis, and Dr Cheng Yuan for statistical assistance. We also thank Knoll Pharmaceutical for supplying the rhTNF-
used in these studies. Received August 25, 1994; accepted October 2, 1995.
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References |
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TopAbstractIntroductionMaterials and Methods Results Discussion References |
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