From the Department of Surgery, Division of Cardiovascular and Thoracic
Surgery, Duke University Medical Center, Durham, NC.
Methods and Results—Sixteen mongrel dogs (22 to 24 kg) were used.
Animals underwent percutaneous pulmonary artery
(PA) catheterization to measure pulmonary
hemodynamics before and 8 weeks after injection of 3
mg/kg MCTP (n=8) or placebo (control, n=8). Eight weeks after
injection, all hearts were instrumented with a PA flow probe,
sonomicrometric dimension transducers, and
micromanometers. Data were collected at baseline
and after both NO and milrinone administration. Diastolic
properties were quantified by use of the end-diastolic
pressure-volume relationship and the time constant of
ventricular isovolumic relaxation. Eight weeks after
injection, significant increases in the PA pressure and
pulmonary vascular resistance were observed in MCTP dogs.
Significant worsening of RV diastolic function occurred in
association with significant increases in the ratio of RV dry weight to
LV+septal dry weight. NO and milrinone administration both led to
significant improvements in RV diastolic properties.
Conclusions—In the setting of MCTP-induced CPH, significant
worsening of RV diastolic function was observed in
association with significant increases in the ratio of RV dry weight to
LV+septal dry weight, suggesting that these changes are partially due
to RV hypertrophy. The significant improvement in RV
diastolic properties after both NO and milrinone administration
suggests that these agents may be effective forms of pharmacological
therapy for improving RV diastolic dysfunction in the
setting of CPH.
Nitric oxide is not only a selective pulmonary vasodilator
without significant hemodynamic effect on the systemic
circulation3 4 but also an important mediator of
cardiac diastolic function.5 6
Milrinone, conversely, is a phosphodiesterase inhibitor
that possesses positive inotropic and selective pulmonary
vasodilatory effects.7 In addition to these
properties, milrinone is also a positive lusitropic
agent.8 9 Such properties suggest that both these
agents may be potentially useful strategies for improving RV
diastolic dysfunction in the setting of chronically
elevated pulmonary vascular pressures. However, an appropriate
large-animal model of CPH and RV hypertrophy has not
previously been available for basic investigation of this problem. This
study was therefore designed to investigate the effects of NO and
milrinone on RV diastolic dysfunction in the setting of CPH
and RV hypertrophy by use of a canine model of MCTP-induced
CPH10 and functional assessment of RV chamber
stiffness.
Experimental animals (MCTP, n=8, 22 to 24 kg) received an injection of
3 mg/kg MCTP dissolved in N,N-dimethyl formamide
at a concentration of 40 mg/mL, and control animals (n=8, 22 to 24 kg)
received dimethyl formamide as placebo. Consequently, the volume of
injectate was dependent on the individual weight of each animal and
varied from 1.65 to 1.8 mL. MCTP was synthesized by a previously
well-established method.11
Instrumentation and Surgery
Hemispheric ultrasonic dimension transducers (1.5-mm OD, No.
1–1015-5A, Vernitron) were sewn to the epicardial surface of the heart
across the base-apex major-axis and anteroposterior minor-axis
diameters of the LV. Two additional transducers were also placed on the
epicardial surfaces of the RV and LV free walls, and another was
inserted into the interventricular septum to measure the
septal–free wall minor-axis diameters of both the RV and LV.
Experimental Protocol During Pharmacological Studies
After each incremental change in the NO concentration, the animal's
condition and hemodynamic parameters were
allowed to equilibrate for 10 minutes before any further data
collection. After data were obtained at the dose of 80 ppm, NO was
stopped, and the level in the ventilator's inspiratory circuit was
restored to 0 ppm. Pulmonary hemodynamic
parameters were allowed to return to baseline, which
usually occurred within 5 to 8 minutes of discontinuation.
Milrinone was then loaded as an initial dose of 50 µg ·
kg-1 · min-1 given
over 10 minutes and subsequently infused at rates of 0.5 µg ·
kg-1 · min-1 and
1.0 µg · kg-1 ·
min-1. As with NO, after each incremental
increase in the milrinone infusion rate, pulmonary
hemodynamic parameters were permitted to
stabilize for 10 minutes before additional data acquisition. The entire
duration of anesthesia, including instrumentation, drug
administration, and all data acquisition, was
Raw data were digitized on-line, collected, and stored on a
microprocessor (PDP 11/23, Digital Equipment Corp). All data were
analyzed on a Dell Dimension XPS P90 computer (Dell Computer
Corp) with software that has previously been well
described.12
Tissue Analysis
Calculation of Ventricular Cavitary Volumes
Assessment of Biventricular Diastolic
Properties
A parameter of myocardial stiffness was quantified
according to the following equation: myocardial
stiffness=
To assess ventricular isovolumic pressure decay, the period
of isovolumic relaxation was defined from the nadir of the
ventricular pressure derivative
(dP/dtmin) to the point at which
ventricular pressure decreased to the level of atrial
pressure.15 The time constant of isovolumic
pressure decay (
Assessment of Biventricular Systolic Function
Experimental Approval and Animal Rights
Statistical Analysis
To test for significant changes in the parameters of
diastolic function as well as systolic function
after NO inhalation within the MCTP group, a one-way ANOVA for repeated
measurements was used. Follow-up comparison of each index of
ventricular diastolic properties at the
individual levels of NO were done with paired Student's t
tests. Comparison of changes in RV diastolic function
occurring after milrinone infusion was performed in a similar fashion.
The results are expressed as mean±SEM. A difference was considered
statistically significant at P<.05.
Diastolic Properties in MCTP-Induced CPH
The monoexponential model of isovolumic pressure
decay accurately predicted (r2>.993) the
fall of ventricular pressure during isovolumic relaxation
for the RV and LV. There was no significant difference in LV
Systolic Function in MCTP-Induced CPH
Effect of NO on Diastolic Properties and Systolic
Function
Effect of Milrinone on Diastolic Properties and
Systolic Function
Milrinone infusion also led to significant improvements in RV
Tissue Analysis in the Setting of MCTP-Induced CPH
Myocardial hypertrophy is a compensatory process of the
heart that can develop in the setting of a sustained pressure overload,
such as CPH, and is perhaps one of the most important causes of
diastolic dysfunction.2 Hypertrophied
myocardium is particularly susceptible to
diastolic dysfunction as a result of structural changes
(increased LV mass) and impaired ventricular
relaxation.16 In a previous investigation, a
significant correlation was noted between myocardial
hypertrophy and diastolic dysfunction, which
later improved after regression of the
hypertrophy.17
Approximately 10 years ago, NO was identified as an important
endogenous biological mediator of vascular
tone.18 19 Since that initial discovery,
clinical3 and experimental4
investigations have shown that NO is a selective pulmonary
vasodilator without significant effect on the systemic circulation.
Recent reports have also suggested that NO is an important regulator of
cardiac diastolic function.5 6
Milrinone is a phosphodiesterase inhibitor that possesses
positive inotropic, selective pulmonary vasodilator, and
positive lusitropic effects.8 In a canine model
of embolism-induced pulmonary hypertension using autologous
muscle, milrinone increased cardiac index while improving mean
pulmonary artery pressure and pulmonary vascular
resistance.20 Clinically, in the setting of
congestive heart failure, significant improvements have been observed
in the indexes of LV diastolic performance as well
as overall global improvement of diastolic function after
administration of milrinone.9 21
Thus, NO and milrinone may both be potentially useful pharmacological
strategies for improving altered RV diastolic properties in
the setting of CPH. However, experience with these two agents in
treating RV diastolic dysfunction is currently limited.
Experimental investigation of this problem has not previously been
possible because of lack of an appropriate large-animal model of
CPH.
In this investigation, the effects of NO and milrinone on RV
diastolic and systolic mechanics were assessed in a
recently established canine model of MCTP-induced
CPH.10 MCTP-induced CPH is characterized by a
proliferative vasculitis. Pulmonary vascular injury, after the
initial injection, affects the medium and small pulmonary
arterioles. Subsequent vascular remodeling leads to
endothelial degeneration and hyperplasia, smooth muscle
hypertrophy and medial thickening, and perivascular
connective tissue proliferation.22 The
development of these microscopic changes along with the ensuing rise in
pulmonary vascular pressures is gradual. In addition, the
characteristic parenchymal features of this model are often observed in
the pulmonary vasculature of patients with pulmonary
hypertension of differing etiologies, including end-stage cardiac
disease as well as a subtype of primary pulmonary hypertension
known as plexogenic pulmonary
arteriopathy.23
MCTP-induced CPH has a significant impact on RV diastolic
properties and an insignificant effect on LV diastolic
function. RV
Ventricular chamber stiffness, as estimated by the EDP-EDV
relationship, represents a useful means for quantifying
diastolic function in an intact
heart.25 Pressure-volume relationships provide
important information regarding diastolic
function26 and have been applied in clinical and
experimental investigations.27 28 Another
technique that is often used for assessing diastolic
properties involves assessment of myocardial elasticity with
parameters of stress and strain.25 In
a previous investigation comparing patients with normal and
hypertrophied hearts, however, myocardial diastolic
stiffness, as defined by use of stress-strain relations, remained
relatively unchanged despite dramatic shifts in the passive
pressure-volume relations.29 Measurement of
pressure-volume relations may therefore be a more sensitive means to
assess myocardial diastolic properties than estimation of
stress-strain relations.30
Tissue dry weight analysis revealed that the RV was
significantly hypertrophied, whereas no significant change in LV muscle
mass occurred. There were significant elevations in the ratio of RV dry
weight to LV+septal dry weight as well as the ratio of RV dry weight to
body weight in MCTP animals compared with control animals, indicating
that a significant degree of RV hypertrophy had occurred.
These findings suggest that the alterations in RV diastolic
and systolic properties observed in this model are at least
partially due to hypertrophy. The significant augmentation
of RV systolic function associated with the significant
worsening of RV diastolic properties may provide insights
into the mechanisms of myocardial dysfunction in the setting of
CPH.
NO-mediated improvement of ventricular
diastolic properties can occur indirectly through easing of
RV loading conditions or via direct myocardial relaxation. It has
previously been shown that endogenous NO released from
coronary endothelial cells plays an important
role in the modulation of myocardial relaxation
activity.35 In other investigations using sodium
nitroprusside as an exogenous donor, NO was shown to exert a direct
myocardial relaxant effect in isolated ejecting hearts, independent of
any changes in cardiac loading,36 as well as in
isolated papillary muscles.37 Similar results
were observed in the clinical setting of Paulus and
associates,5 where significantly improved LV
diastolic properties were observed after global
intracoronary infusion of sodium nitroprusside.
In this report, however, the beneficial effects of NO appear to be
related to its well-established vasodilator activity. By improving
pulmonary hemodynamic indices, NO led to a
significant easing of RV loading conditions, which were observed in
association with significant decreases in RV diastolic
properties and LV
Although the lusitropic effects of milrinone have been clearly
demonstrated in this study in association with significant improvements
in pulmonary blood flow, the vasodilatory properties of this
agent can potentially play a key role in its total effects and may
partially account for the observed improvements in RV
Evaluation of diastolic function with in vivo models
necessitates careful measurement of the dynamic changes occurring in
ventricular pressure and volume within an intact heart.
With respect to EDP, use of transmural pressures is required for an
accurate assessment of diastolic
properties.31 Estimates of
It is acknowledged that the absolute level of pulmonary
hypertension occurring after MCTP injection may not accurately reflect
the degree of CPH observed clinically. Consequently, the amount of
hypertrophy induced in this model was much less than what
one would expect in the clinical setting. It is important to point out,
however, that the baseline pulmonary vascular pressures
observed in the dogs before drug injection were significantly lower
than normal levels found in human beings and that a twofold increase in
pulmonary hemodynamic indices was achieved.
Even at this level of pulmonary hypertension, significant
alterations in RV diastolic properties were observed, which
improved significantly after pharmacological therapy. A potential way
to achieve a higher degree of pulmonary hypertension would be
to perform multiple injections of MCTP at regular intervals to
theoretically cause repeated injury to the pulmonary vascular
bed and produce greater scarring of the pulmonary circulation.
Higher pulmonary hemodynamic indices might, in
turn, lead to more severe hypertrophy. When such a model of
CPH is used for basic investigation, however, it is reasonable to state
that the resultant pulmonary hypertension should not be so
severe that clinical right-sided heart failure would ensue and result
in a highly unstable situation.
In summary, a canine model of MCTP-induced CPH provides a useful
means to evaluate various pharmacological strategies for improving RV
diastolic dysfunction in the setting of CPH. There was a
significant worsening of RV diastolic properties, which was
significantly improved after NO and milrinone administration. These
data suggest that NO and milrinone may both be effective
pharmacological strategies in the treatment of diastolic
dysfunction in the setting of CPH.
Presented at the 69th Scientific Sessions of the American Heart Association, New Orleans, La, November 10–13, 1996, and published in abstract form (Circulation. 1997;96(suppl I):I-63).
Received September 18, 1997;
revision received October 21, 1997;
accepted November 6, 1997.
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© 1998 American Heart Association, Inc.
Basic Science Reports
Pharmacological Strategies for Improving Diastolic Dysfunction in the Setting of Chronic Pulmonary Hypertension
Abstract
Top
Abstract
Introduction
Methods
Results
Discussion
References
Background—Right
ventricular (RV) hypertrophy is an adaptive
process that occurs in the setting of chronic pulmonary
hypertension (CPH) and can lead to alterations in normal RV
diastolic properties. This study was designed to
investigate the effects of NO and milrinone on RV diastolic
dysfunction in the setting of CPH and RV hypertrophy by use
of a canine model of monocrotaline pyrrole (MCTP)–induced
CPH.
Key Words: hypertension, pulmonary • diastole • ventricles • hypertrophy
Introduction
Top
Abstract
Introduction
Methods
Results
Discussion
References
The clinical
management of diastolic dysfunction is challenging, and
despite the existence of several therapeutic options, no single
treatment is universally recommended. Contemporary clinical strategies
for improving abnormal ventricular diastolic
properties include the use of pharmacological agents that increase
ventricular relaxation and ease cardiac loading
conditions.1 2 These strategies, however, have
been applied primarily toward treating LV diastolic
dysfunction in the setting of systemic arterial
hypertension and myocardial hypertrophy. Few reports
describe the application of these measures with respect to improving RV
diastolic dysfunction associated with cardiac
hypertrophy in the setting of CPH.
Methods
Top
Abstract
Introduction
Methods
Results
Discussion
References
Hemodynamic Monitoring, Experimental Groups, and
Drug Synthesis and Injection
The anesthetic regimens, mode of ventilatory support, and all
invasive hemodynamic and metabolic
monitoring used in this investigation have previously been well
described.10 Hemodynamic
measurements were done at baseline and 8 weeks after monocrotaline
injection. MCTP or placebo was injected into the right atrium.
Eight weeks after MCTP injection, a standard median
sternotomy and an anterior pericardiotomy were performed to expose the
hearts of all animals. An ultrasonic flow probe (T208X, Transonic
Systems Inc) was placed around the main pulmonary trunk to
measure pulmonary blood flow.
Micromanometers (MPC-500, Millar Instruments Inc)
were placed into the RV and LV, right and left atrium, and
pulmonary artery for continuous recording of
intracavitary pressures.
Eight weeks after MCTP injection, baseline functional and
hemodynamic data were collected in every animal in the
control and MCTP groups after the instrumentation procedure. Control
animals did not receive any pharmacological treatment or undergo any
further data collection. In MCTP animals, inhaled NO (NO, 777 ppm and
NO2, <0.1 ppm, National Specialty Gases) was
then administered into the ventilator at levels of 40 and 80 ppm, and
data were again collected at each respective concentration. NO and
NO2 levels were measured by continuous
chemiluminescent analysis (model 42H, Thermo Environmental
Instruments, Inc). 
2.5 to 3 hours in each
MCTP animal.
After collection of hemodynamic and functional
data, all hearts were excised, and the atria were separated from the
ventricles at the atrioventricular groove. The RV free
wall was separated from the LV and septum. The RV and LV from each
animal were weighed, and wall volumes were then determined by saline
displacement. To calculate percent water, all samples were placed in a
120°C oven and dried for 24 hours. The dry weight of each tissue
sample, for both the RV and LV+septum, was measured, and these weight
ratios were compared between experimental groups. The percentage of
tissue water content was calculated from the following equation: (wet
weight-dry weightx100%)/wet weight.
LV and RV cavitary volumes were calculated by use of
well-validated models.12 13 LV cavitary volume
was calculated by representing the epicardial surface of
the LV as an ellipsoidal shell and subtracting ventricular
wall volume according to the following equation:
LVV=
b2a/6-Vwall, where
b is the minor-axis diameter, a is the major-axis
diameter, and Vwall is LV wall
volume.12 RV cavitary volume was calculated
according to the ellipsoidal shell subtraction
method,13 which assumes an ellipsoidal shape for
the LV as well as the total biventricular shell, by the
following equation:
RVVendo=BVVepi-LVVepi-FWV,
where BVVepi is the biventricular
epicardial shell volume, LVVepi is the LV
epicardial shell volume, and FWV is the volume of the RV free
wall.13
Chamber stiffness was quantified by fitting the exponential
function EDP=Axe
EDV to EDP and EDV
obtained during vena caval occlusion for both the RV and LV by use of
nonlinear least-squares regression. is defined as the change in the
logarithmic function of ventricular pressure relative to
the change in volume and represents an index of
ventricular chamber stiffness, whereas A is a
proportionality constant. Vw, where is chamber stiffness
and Vw is ventricular wall
mass.14 
) was then calculated from the following
monoexponential model:
PIVR=P0e-t/+P
,
where P0 is the initial pressure above
P during isovolumic relaxation, t is time,
P is the asymptote to which pressure
decays, and is the time required for pressure at any point on the
isovolumic curve to fall to 1/e of its original
value.14 RV/LV model parameters were
estimated by nonlinear least-squares regression.
RV and LV systolic function were assessed with
load-insensitive means. The highly linear relationship between stroke
work and end-diastolic chamber volume was calculated from
data acquired during vena cava occlusion by use of least-squares linear
regression. The slope of these linear regressions is known as the PRSW
and represents a load-independent index of systolic
function and myocardial
contractility.12
The experimental setup and procedures conformed to the
guidelines established by the American
Physiological Society and the National Institutes
of Health (Guide for the Care and Use of Laboratory Animals,
National Institutes of Health publication 86–23, revised 1985).
The experiments described in this report were approved by the Duke
University Institutional Animal Care and Use Committee (DUIACUC
Assigned Registry A621–95-9R1).
Statistical analysis was performed with commercially
available software (SigmaStat Version 2.0, Jandel Corp).
Hemodynamic data obtained before and after injection of
MCTP within the MCTP group were analyzed with standard
two-tailed paired Student's t tests. Unpaired Student's
t tests were used to compare all data between MCTP and
control.
Results
Top
Abstract
Introduction
Methods
Results
Discussion
References
There was no significant difference in the baseline
pulmonary hemodynamic indices between control
and MCTP dogs; however, 8 weeks after MCTP injection, significant
differences in these same indices were observed between the two groups
(Table 1
).
View this table:
[in a new window]
Table 1. Hemodynamic Measurements Before and
8 Weeks After MCTP or Placebo Injection
The exponential EDP-EDV model accurately represented
(r2>.92) all pressure and volume
data during transient vena cava occlusion in both groups. No
significant differences in LV were observed between control
(.021±.005) and MCTP (.024±.005). There was, however, a significant
increase in the RV of MCTP (.070±.006, P<.05) compared
with control (.046±.008). RV Vw was
significantly greater in MCTP (.724±.066) than in control (.383±.068,
P<.005), while no significant difference was observed in LV
Vw between the two groups (.560±.108 versus
.495±.105). (41±3
versus 42±3 ms) between the two experimental groups. RV was
significantly longer, however, in MCTP (84±15 ms, P<.05)
than in control (35±3 ms).
Highly linear relationships
(r2>.95) were obtained between
calculated RV and LV EDV and stroke work during vena caval occlusion in
both control and MCTP 8 weeks after MCTP injection. There was no
significant difference in LV PRSW between MCTP
(94.65±6.26x103 erg/mL) and control
(87.98±7.23x103 erg/mL). However, significant
increases in RV PRSW were observed in MCTP
(46.90±3.16x103 erg/mL, P<.0005)
compared with the control values
(24.56±3.12x103 erg/mL).
NO led to significant improvements in pulmonary
hemodynamic indices (Table 2). In addition, significant decreases
occurred in RV as well as RV Vw, whereas
no significant improvements in these same parameters were
observed in the LV (Table 3). RV and LV
were significantly shorter after NO inhalation; however, RV/LV PRSW
was not significantly different (Table 3). Although NO did not lead to
significant changes in the LV of MCTP dogs, a substantial downward
shift was observed in the LV EDP-EDV relationship of these animals (Fig 1). The changes occurring in the EDP-EDV
relationship as a result of NO inhalation for both the LV and RV are
illustrated in Figs 1 and 2,
respectively.
View this table:
[in a new window]
Table 2. Effects of NO on Hemodynamic Measurements in
MCTP-Induced Pulmonary Hypertension
View this table:
[in a new window]
Table 3. Effects of NO on Biventricular
Diastolic Properties and Systolic Function
View larger version (13K):
[in a new window]
Figure 1. Effects of NO on the LV EDP-EDV relationship, as
plotted from average values of chamber stiffness, in setting of
MCTP-induced CPH. There were no significant changes in LV chamber
stiffness after NO inhalation at either 40 or 80 ppm compared with 0
ppm, although a substantial downward shift was observed in this
relationship.
View larger version (14K):
[in a new window]
Figure 2. Effects of NO on the RV EDP-EDV
relationship, as plotted from average values of chamber stiffness, in
setting of MCTP-induced CPH. Significant improvements in RV chamber
stiffness were observed after NO inhalation at both 40 and 80 ppm
compared with 0 ppm. There was no further significant decrease in RV
chamber stiffness at 80 vs 40 ppm. *P<.05 vs 0
ppm.
Milrinone infusion caused significant decreases in the
pulmonary vascular resistance, which were associated with
significant improvements in pulmonary blood flow (Table 4). Although there were decreases in the
mean pulmonary artery pressure at 0.5 and 1.0 µg ·
kg-1 · min-1,
these differences were not statistically significant.
View this table:
[in a new window]
Table 4. Effects of Milrinone on Hemodynamic
Measurements in MCTP-Induced Pulmonary Hypertension , RV
Vw, RV/LV , and RV/LV PRSW (Table 5). There was no significant change in LV
after milrinone infusion; however, as with NO, a substantial
downshifting of the EDP-EDV relationship was also noted (Fig 3). The changes occurring in the EDP-EDV
relationship after milrinone infusion for both the LV and RV are
illustrated in Figs 3 and 4,
respectively.
View this table:
[in a new window]
Table 5. Effects of Milrinone on Biventricular
Diastolic Properties and Systolic Function
View larger version (15K):
[in a new window]
Figure 3. Effects of milrinone on the LV EDP-EDV
relationship, as plotted from average values of chamber stiffness, in
setting of MCTP-induced CPH. There were no significant changes in LV
chamber stiffness after infusion of milrinone at either 0.5 or 1.0
µg · kg-1 · min-1 vs 0
µg · kg-1 · min-1, although a
substantial downward shift was observed in this relationship.
View larger version (16K):
[in a new window]
Figure 4. Effects of milrinone on the RV EDP-EDV
relationship, as plotted from average values of chamber stiffness, in
setting of MCTP-induced CPH. Significant improvements in RV chamber
stiffness were observed after infusion of milrinone at both 0.5 and 1.0
µg · kg-1 · min-1 compared
with 0 µg · kg-1 · min-1.
There was no further significant decrease in RV chamber stiffness at
1.0 vs 0.5 µg · kg-1 · min-1.
*P<.05 vs 0 µg · kg-1 ·
min-1.
There was a significant increase in the RV dry weight of MCTP dogs
(10.29±0.55 g, P<.05) compared with control animals
(8.40±0.51 g). Both the ratio of RV dry weight to LV+septal dry weight
(0.45±0.02 versus 0.37±0.01, P<.05) and the ratio of RV
dry weight to body weight (0.43±0.02 versus 0.36±0.02 g RV/kg body
wt, P<.05) were also significantly elevated in MCTP animals
compared with the control group. No significant differences were
observed in the LV dry weights (23.3±1.4 versus 23.3±1.3 g) or in the
RV (79.6±0.4% versus 78.6±0.4%) and LV (79.0±0.4% versus
78.4±0.3%) water contents between the two experimental groups.
Discussion
Top
Abstract
Introduction
Methods
Results
Discussion
References
CPH represents an important clinical sequela that
commonly occurs as a result of chronic obstructive pulmonary
disease. It is also associated with a number of other pathological
processes, including long-standing congestive heart failure, mitral
valve disease, congenital heart defects, and chronic pulmonary
embolism; alternatively, CPH may exist as a primary process. This state
of chronically elevated pulmonary vascular pressures can lead
to adaptive mechanisms in the RV and eventually result in altered
systolic and diastolic mechanics. and RV Vw were significantly
elevated in animals with MCTP-induced CPH, whereas no significant
differences were observed in LV or Vw. The
significant increase in RV should be interpreted with caution,
because it may have been due to collagen recruitment. It is unlikely,
however, that these changes were the result of MCTP-induced myocardial
damage, because previous morphological analysis using light and
electron microscopy suggests that monocrotaline itself has no
direct toxic effect on myocardial tissue.24 represents another useful index frequently used for
assessing diastolic properties that has been shown to be
independent of any changes in loading
conditions15 31 and is relatively insensitive to
heart rate.32 33 34 RV was significantly longer
in the setting of MCTP-induced CPH. However, no significant differences
were observed in LV between the two experimental groups. . Although the use of sodium nitroprusside as an
exogenous NO donor might be equally effective in decreasing RV and
RV in this model, such conclusions are not possible on the basis of
the data presented in this study. Future studies should examine
whether sodium nitroprusside would be as effective as inhaled NO for
improving RV diastolic properties in MCTP-induced CPH. , RV , and
overall hemodynamic status in this model. In a previous
report by Monrad and associates,9 the relative
ratio of the lusitropic and vasodilator actions of milrinone was
examined in patients with advanced congestive heart failure. In that
investigation, significant improvement of LV diastolic
function was observed in association with relatively small decreases in
mean arterial pressure, suggesting that the influence of
milrinone on cardiac relaxation at the level of the individual myocyte
plays a more fundamental role in its overall effects than its
vasodilator actions. In the present report, significant
improvements in RV diastolic properties as well as LV
occurred in association with slight decreases in mean pulmonary
artery pressure after milrinone infusion, which would appear to be
consistent with the findings of Monrad and associates. Further
investigation should attempt to elucidate the relative contributions of
the lusitropic and vasodilatory effects of milrinone in MCTP-induced
CPH. from EDP-EDV
relationships, however, generally ignore any possible restrictive
effect of the pericardium and assume that no external forces are
imposed on the heart when intraventricular pressure
is elevated.38 When the pericardium is left
intact, the possibility exists that pericardial pressures might exceed
zero and violate these assumptions. Previous investigations have
demonstrated that in the setting of pressure or volume overload, an
intact pericardium contributes significantly to increases in EDP and
may affect the EDP-EDV relationship independently of changes in
ventricular diastolic
properties.39 40 Admittedly, use of an
open-chest, open-pericardium model could potentially introduce a degree
of experimental artifact and might be considered a study limitation. It
should be noted, however, that this type of experimental preparation
allows one to obtain true transmural pressures, which, as previously
discussed, are requisite for accurate assessment of
ventricular diastolic properties.
Selected Abbreviations and Acronyms
CPH
=
chronic pulmonary hypertension
EDP
=
end-diastolic pressure
EDV
=
end-diastolic volume
LV
=
left ventricular, left ventricle
MCTP
=
monocrotaline pyrrole
PRSW
=
preload recruitable stroke work
RV
=
right ventricular, right ventricle
Acknowledgments
Dr Chen is a recipient of a National Research Service Award,
fellowship HL-09489.
Footnotes
Reprint requests to Edward P. Chen, MD, Department of Surgery, S-343, University of California San Francisco, 505 Parnassus Ave, San Francisco, CA 94143.
References
Top
Abstract
Introduction
Methods
Results
Discussion
References
1.
Modersohn D, Walde T, Bruch L.
Diastolic heart function: pathophysiology,
characterization, and therapeutic approaches. Clin
Cardiol. 1993;16:850–858.[Medline]
[Order article via Infotrieve]) on pericardial
pressure. Circulation. 1990;81:1071–1080.
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