Download Impairment of left ventricular function by acute cardiac lymphatic

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Research
Cardiovascular Research 33 (1997) 164-171
Impairment of left ventricular function by acute cardiac lymphatic
obstruction
L.L. Ludwig a, E.R. Schertel a“, J.W. Pratt c, D.E. McClure b,A.J. Ying a, C.F. Heck a,
P.D. Myerowitz a
a Division of Thoracic and Cardiovascular Surgery, Department of Surgery, The Ohio State UniuersiQ, Columbus, OH 43210, USA
b Department of Veterinary Preuenti.e Medicine, The Ohio State University, Columbus, OH 43210, USA
‘ Department of Surgery, Wi~ord Hall Medical Center, 59th Medical Wing/PSSG LacklandAFB, TX 78236, USA
Received 22 March 1996; accepted 16 July 1996
Abstract
Objectives:We performed the following study to define the effects of acute cardiac lymphatic obstruction on left ventricular (LV)
systolic and diastolic function. Methods:Cardiac lymphatic obstruction was created in 8 pentobarbital-anesthetized dogs by identifying
(Evans blue) and ligatingthe right and left epicardial lymphatic, the afferent and efferent lymphatic associated with the pretrachael and
cardiac lymph nodes, and the thoracic duct. Left ventricular function was assessed by analysis of micromanometer-conductance
catheter-derived LV pressure–volume relationships. Contractility was assessed by preload recruitable stroke work (PRSW). The active
and passive phases of LV relaxation were assessed by the time constant of isovolumic relaxation (~) and the end-diastolic pressure–volume
relationship (stiffness), respectively. Results:PRSW decreased significantly and r increased significantly from baseline at 1, 2, and 3 h
after cardiac lymphatic obstruction (n = 8), but stiffness did not change. Cardiac lymphatic obstruction had similar effects on LV function
in a group of autonomically blocked dogs (n = 5). Left ventricular function did not change in sham treated controls (n = 8). Cardiac
lymphatic obstruction induced a significant increase in LV wet/dry weight ratios (3.58 + 0.01) when comparedto the control group
(3.53f 0.02). Histopathology of the myocardium in the lymphatic obstruction groups revealed significant lymphangiectasis and increased
interstitial spacing when compared to controls. Conclusions: Acute cardiac Iymphatic obstruction depresses contractility and active
relaxation and causes mild LV myocardial edema, but does not alter diastolic stiffness.
Keywords: Ventricular function; Lymph flow; Edema; Dog, anesthetized
1. Introduction
Interstitial myocardial edema occurs in numerous clinical conditions and is commonly associated with ventrictrhtr
dysfunction. However, only recently has adequate evidence been obtained to support the concept of a causal
relationship between interstitial myocardial edema and left
ventricular dysfunction. In those studies, lowered colloid
osmotic pressure [1–3], continuous warm blood cardioplegia [4], and increased coronary microvascular pressure
[5,6] were each found to induce predominantly interstitial
myocardial edema and to depress left ventricular contrac-
“ Corresponding author. N-816 Doan Hall, Department of Surgery, 410
West IOth Avenue, Columbus, OH 43210, USA. Tel, + 1614 293-4558;
Fax + 1614293-4726.
tility. Diastolic function was also found to be depressed by
these methods of creating interstitial edema [2,3,6]. The
demonstration by these studies that different methods of
inducing interstitial myocardial edema produce similar
changes in ventricular function strengthens the concept of
a causal relationship between interstitial myocardial edema
and ventricular dysfunction. In this context, acute cardiac
lymphatic obstruction has been found to produce
histopathologic evidence of interstitial edema [7], but its
effects on ventricular function and myocm-dial water content, as measured by gravimetric means, have not been
investigated. Chronic obstruction of cardiac lymph flow
results in histopathologic changes in the myocardium and
Timefor primaryreview21 days.
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L.L. Ludwig et al, / Cardio,asc’ukzrResearch 33 (1997) 164–171
atrioventricular valves consistent with interstitial edema
[8,9], electrocardiographic changes [10,1I], and decreases
in developed pressure and the rate of change of pressure
[12, 13]. However, detailed examination of the effects of
chronic lymphatic obstruction on contractility and diastolic
function have not been performed. Cardiac lymphatic obstruction induces interstitial edema by a mechanism that is
distinctly different from methods previously utilized and,
therefore, establishing its effects on ventricular function
may further validate the concept of a causal relationship
between interstitial myocardial edema and ventricular dysfunction.
The purpose of our study was to test the hypothesis that
acute cardiac lymphatic obstruction induces interstitial myocardial edema and ventricular dysfunction, specifically
causing a decrease in contractility and increases in diastolic stiffness and the time constant of isovolumic relaxation (~). We utilized the load-independent index, preload
recruitable stroke work (PRSW), to assess contractility, ~
to evaluate active relaxation, and the slope of the end-diastolic pressure volume relationship to assess diastolic
stiffness. We controlled for the influences of time, experimental preparation, and the autonomic nervous system on
our results by utilizing appropriate control groups.
2. Methods
2.1. Experimental preparation
Twenty-one mature male, heartworm-free, semi-conditioned dogs (weight range 20.5–25.5 kg) were anesthetized
by an intravenous dose of sodium pentobarbital (25-35
mg ~kg-’ ) followed by continuous administration (5 mg.
kg- I . h-1) The investigation conformed with the Guide
for the Care and Use of Laboratory Animals published by
the National Institutes of Health (NIH publication No.
85-23, revised 1985). The dogs were intubated and ventilated with IOO~c Oz using a volume-cycled ventilator
(Model 613, Harvard Apparatus Co., Inc., Minis, MA) at a
tidal volume of 15 to 20 ml . kg- and a respiratory rate of
8–15 breaths . rein-. The dogs were paralyzed by intravenous administration of pipecuronium (70 pg “kg-),
followed by additional hourly doses (35 Kg . kg-). Maintenance fluids were given as continuous infusion of 0.9%
PH, PC02,
NaCl at a rate of 10 ml ~kgh-. Arterial
and P02 were measured periodically (ABL 30, Radiometer, Denmark) during instrumentation and maintained
within normal limits by adjusting tidal volume and ventilator rate, and by intravenous administration of sodium
bicarbonate. The left femoral artery was cannulated for
sampling arterial blood. The left femoral vein was cannulated for drug and maintenance fluid administration. A
tracheotomy was then performed and a tracheal cannula
was inserted and secured. The chest was opened by a
median sternotomy and the internal thoracic vessels were
I65
ligated and divided when necessary. The heart was cradled
in the incised pericardium. Cardiac lymphatic channels
were identified by injections of approximately O.I ml of
Evans blue (0.5% aqueous solution) into the epicardium of
the right and left ventricles. Once visualized, the right and
left epicardial lymphatic, afferent and efferent Iymphatics
of the pretracheal and cardiac lymph nodes, and the thoracic duct were isolated and encircled with 5-Oligatures. A
7.5-F thermodilution catheter was introduced via the right
femoral vein and advanced into the pulmonary artery for
measuring pulmonary artery pressure. Sodium heparin was
administered as an intravenous bolus of 400 U followed by
200 U . h-’. An elastic vessel loop was positioned around
the caudal thoracic vena cava as a means of altering
loading conditions in the LV.
2.2. Left uentricularfuncticm and hemodynamic parameter
assessment
Left ventricular contractility was evaluated utilizing
preload recruitable stroke work (PRSW) derived from the
stroke work-end diastolic volume relationship (SWEDVR)
[14]. Left ventricular volume was assessed by determining
the electrical conductance of the time-varying quantity of
blood in the LV using a 7-F, 12-electrode conductance
catheter (Webster Laboratories, Baldwin Park, CA) and
stimulator/signal processor (Sigma-5-DF, Leycom, The
Netherlands) [15,16]. The conductance catheter was introduced through the left carotid artery, inserted in the LV
and positioned along the long axis of the ventricle such
that a maximum number of electrodes were within the LV.
Position was verified by evaluating the relationship of
segmental volume signals to the electrocardiogram. A 7-F
micromanometer catheter (Millar Instruments, Houston,
TX) was advanced through the right femoral artery and
positioned in the LV for pressure determination. The position of the micromanometer was verified by pressure
tracings.
The outermost of the 12 electrodes of the conductance
catheter were used to apply 2 opposite-polarity, low-amplitude, high-frequency electrical fields. The remaining electrodes positioned within the LV measured interelectrode
segmental voltage differences. Segmental conductance
(Gi) were calculated from the segmental voltage differences. The volume of each segment was calculated as:
Vi(t) = ( 1\ai)(L~/sb)(Gi(
t) – Gpi)
where subscript i refers to segment i; Vi(t), the time
varying (intravent.ricular) segmental volume; ai, the dimensionless slope factor which is assumed to be 1.0; Li,
the interelectrode distance; sb, the specific conductivity of
blood; Gi(t), the time varying segmental conductance; and
Gpi the parallel conductance. These segmental conductance signals were calibrated into time-varying segmental
volumes and the total LV volume was calculated as the
sum of the 5 segmental volumes. The specific conductivity
166
L.L. Ludwig et al./Cardiouascular Research 33 (1997) 164-171
of a known volume of blood (sJ was determined by
withdrawing 4 ml of arterial blood directly into a blood
conductivity test chamber. The parallel conductance of
structures surrounding the blood in the LV (Gpi) was
accounted for by transiently changing blood conductivity
in the LV by injecting 3 ml of 770 NaCl into the pulmonary artery. Cardiac output was measured by the thermodilution technique using a cardiac output computer
(SAT-1, American Edwards Laboratories, Santa Ana, CA).
Stroke volume of the conductance catheter system was
calibrated utilizing the average value calculated from 3–5
thermodilution measurements of cardiac output and heart
rate determined from the LV pressure trace. These latter
procedures constituted catheter calibration and were performed prior to each assessment of cardiac function. A
complete description of the principles and use of the
conductance catheter technique appears elsewhere [15,17].
Left ventricular function and hemodynamic data were
recorded at end-expiration with the ventilator turned off
(< 15 s). The left ventricular pressure, electrocardiogram
and segmental volume signals were digitized at 200 Hz
(CONDUCT-PC software, Leycom, The Netherlands) on a
486, 50 MHz microcomputer and stored on hard disc for
later analysis. The SWEDVR was obtained by transiently
occluding venous return for approximately 10 s and analyzing 8–15 consecutive beats, starting from the point of
reduction of LV pressure. A minimum of 3 venous occlusions were performed at each experimental period. Extrasystolic beats and beats where end-systolic pressure
decreased below 70 mmHg were excluded from analysis.
Stroke work (SW) was calculated as the integral of LV
transmural pressure and volume over each cardiac cycle
from:
SW= ~PdV
PRSW was determined from the slope of the linear regression analysis of the SWEDVR:
Sw = Sp,,w(ved
– Vosw)
where SP,,Wis the slope of the linear SWEDVR, V.~ is the
end-diastolic volume and VO,Wis the volume axis intercept.
The calculated PRSW values with correlation coefficients
greater than 0.75 were averaged for each experimental
period.
The time constant of isovolumic relaxation was derived
from the following relationship by plotting left ventricular
dP/dt against pressure [18].
of the linear regression analysis of the end-diastolic pressure–volume relationship (EDPVR) for the same beats as
the SWEDVR such that:
‘ed =‘(ved–‘od)
where P~dis the end-diastolic pressure, V~dis the end-diastolic volume, and VO~is the volume intercept.
The amplified analog signals of the LV, aortic, pulmonary arterial and right atrial pressure transducers were
digitized and acquired by a 16-channel data acquisitionanalysis system (PO-NE-MAH, Inc., CT) at 250 Hz for
each channel. In addition, the moving average of all
derived data was recorded every 5 s for the duration of
each experiment. Left ventricular end-diastolic pressure
was determined using the LV pressure computer algorithm
(PO-NE-MAH, Inc., CT). Mean pressures were derived for
the aortic (MAP), pulmonary arterial (Pp~) and right atrial
(P~A) pressures as calculated over a 1 min recording
period.
2.3. Protocol
All dogs were allowed to stabilize for 30 min prior to
each experiment and assigned to one of 3 groups: lymphatic obstruction (LO; n = 8), lymphatic obstruction with
autonomic nervous system blockade (LO/AX; n = 5), and
a control group (n = 8). Autonomic nervous system blockade was performed 20 min prior to baseline measurements
by intravenous administration of atropine sulfate (0.2 mg .
kg-l then 0.1 mg . kg-1 . hand propranolol HC1 (0.5
mg . kg-1 then 0.25 mg . kg- . h– 1). Baseline LV function, hemodynamic parameter and blood gas measurements
were performed in all dogs at O and 30 min. After baseline
measurements, lymphatic obstruction was accomplished in
the LO and LO/AX groups by tightening the ligatures
encircling the lymphatic vessels. Lymphatic obstruction
was confirmed with injections of Evans blue after ligation.
Left ventricular function, hemodynamic parameter and
blood gas measurements were performed at 1, 2 and 3 h.
In the control group, left ventricular function, hemodynamic parameter and blood gas measurements were performed as in the other groups, except that the ligatures
placed during the preparation period were removed. After
all data were recorded, 7 ml of saturated KC1 was injected
into the peripheral catheter and the heart was rapidly
excised. Samples of the LV were taken for wet/dry weight
ratio analysis and histopathology.
dP( t)/dt = AP( t) – APu,,J,~
The least square linear regression of the dP/dt and pressure data for the isovolumic period of relaxation yielded a
slope (A) equal to – l/~ and a P-axis intercept of P,,Y~.
The value for ~ reported for each experimental period
represents an average of the values calculated from each
cardiac cycle over a 1 min recording.
Left ventricular compliance was assessed by the slope
2.4. Wet/dry weight ratio analysis
The LV samples taken at the end of each experiment
were immediately weighed (wet weight). The samples
were then scored with a scalpel, to increase surface area
for drying, and placed in a 70°C oven where they were
kept until a constant weight was reached (dry weight). The
L.L, Ludwig et al, / Curdio[ascular Rehearch 3.3(1997) 164–171
wet/dry
weight ratio was determined
as wet minus dry
167
Histopathologic index scores of the LO and control group
hearts were compared using a Mann-Whitney Rank Sum
test.
weight divided by dry weight.
2.5. Light microscopy
Full-thickness tissue samples were obtained from the
LV of animals in the control and LO groups for 1ight-microscopic histologic examination. The samples were colIected and fixed in IO$ZObuffered formalin before they
were sectioned, mounted, and stained with hematoxylin
and eosin. All s] ides were evaluated in a blinded fashion.
Each of 5 histopathologic indices was graded on the basis
of a scale of normal, mild, moderate, and severe. A
numerical grade of O was given if the lesion was not
present (normal), I if the lesion was present and of mild
severity, 2 if the lesion was of moderate severily, and 3 if
the lesion was of marked severity. The histopathologic
indices that were semi-quantitatively evaluated were
perivascular interstitial spacing, perivascular and interstitial hemorrhage, lymphangiectasis, inflammation, and fibrin deposition. Endomyocardial and epimyocardial regions
were evaluated and the highest score used for analysis.
2.6. Statistical analy.$i.s
3. Results
3.I. Hemadynamic parameters (Table 1)
The baseline heart rate of the LO/AX group was
significantly less than that of the LO group, but did not
differ from that of”the control group. Heart rate decreased
significantly after lymphatic obstruction in the LO group,
but remained stable thereafter. Heart rate did not change in
the control or LO,/AX groups over the course of the study.
Mean arterial pressure did not change during the study in
any of the groups and did not differ between groups.
Cardiac output declined similarly in all groups over the
course of the study, but only significantly in the control
and LO groups at 3 h. There were no differences in cardiac
output between groups. Pulmonary artery pressure increased significantly from baseline in the control group at
3 h and in the LO group at 2 and 3 h after lymphatic
obstruction, but there were no significant differences between groups. Right atrial pressure did not change during
the study nor were there differences between groups.
Data are presented as the mean and the standard error of
the mean. Comparisons within and between groups were
made using a two-way repeated measures analysis of
3.2. C{jntractile,fi~ncti(jn(Fig. 1)
variance. Student-Neumann-Kettls multiple comparison
tests were performed when significant variation occurred
within or between groups ( P < 0.05). Wet/dry weight
ratios were compared between groups with t-tests.
Preload recruitable stroke work values decreased significantly at 1, 2 and 3 h after lymphatic obstruction in both
the LO and LO,IAX groups. Preload recruitable stroke
Table 1
Hem-tmtc (HR), pulmonary artery pressure (PP.), right atrial pressure (P,.), mean arterial pressure (MAP) and cardiac output (CO) responses k) cardiac
lymphatic obstruction in control, lymphatic obstruction (LO), and lymphatic obstruction\ autonomically blocked (LO/AX) groups
Parameter
Group
Baseline
Ih
2h
3 hr
HR (beats rein- )
Control
LO
LO/AX
143+ 10
161+7
I 17+4$
143*9
148+ 3 *
121+4
147* 9
148+ 3
120+4
151*7
149+4‘
I I5 *4”
PP,,(mmHg)
Control
LO
LO/AX
1I.5 * 0.4
1I.O~O.6
12.9~0.9
12.4+0.6
[2.4 ~0.84
13.6+0,9
12,8+ 0.6
13.0+ 1.I ‘
13.5+ I,2
12.6+ 0.6 “
13.1+ 1.113.5* I.3
P,,l(mmHg)
Control
LO
LO/AX
0.55 ~0.29
0.91 i 0.4
0.58 kO.5
0.56+ 0.25
0,710.51
1.2* 0.45
0.46 +0.3 1
0.56+0.45
0.62 +0.37
0.56 + 0.42
0.53 +0.42
0.76 i0.43
MAP (mmHg)
Control
LO
LO/AX
125+9
115+8
111+6
125+ 10
I 17f9
110+5
127+9
115+7
106~ 5
124+9
I I 1*7
96A5
CO (1 rein- )
Control
LO
LO/AX
2.47 ~0. 16
2.92 &0,31
2.68 i 0.12
2.27 +0.19
2.61 +0.32
2,37 +0.1 8
2.2 *O. 19
2.62 ~0.38
2.22 +0.2
1,87+0.13 ‘
2.36+ 0.4 ‘
2.16 +0. 17
‘ P <0.05 fnr difference from baseline pcrind.
“lP<0.05 for difference from control group.
‘P <0.05 for difference between LO and LO/AX groups.
168
L.L. Ludwig et al. /Cardiovascular Research 33 (1997) 164-171
work did not change over the course of the study in the
control group. There were no significant differences in
PRSW between groups. The VO,Wof the SWEDVR did not
differ between groups or change during the study.
3.3. Isouolumic relaxation (Fig. 1)
3.4. End-diastolic pressure–volume relationship (Table 2)
There were no significant within or between group
differences in LV P.~ or V.~during the study. Stiffness, the
slope of the EDPVR, did not change in response to
lymphatic obstruction.
3.5. Wet/dry weight ratios
The ~-values increased significantly from baseline after
3 h of lymphatic obstruction in the LO group and 2 and 3
h in the LO/AX group. The ~-values did not change in the
control group during the study.
The wet/dry weight ratios of the LV specimens in the
LO (3.58 + 0.01) and LO/AX (3.58 + 0.01) groups were
significantly greater than those of the control group (3.53
* 0.02).
3.6.Histopathology
9585-: 75~
65-
“0
z
55-
*3
u
n
___
~..+!k~
,5
..
r
L
45-
*
“’”’’..., *
*
-.-.-,-.-, *
*
.-..,-, --- *
t~
35T
2515
1
0
1
1
I
I
2
3
3020-
The median scores of the interstitial spacing and lymphangiectasis were 2.0 and 3.0, respectively, in the LO
group. These values were significantly greater than their
respective values in the control group (1.0 and 1.0). The
median scores for perivascular hemorrhage (2.0), inflammation (2.0), and fibrin deposition (0) in the LO group did
not differ significantly from their respective control group
values (1.5, 1.5, and 0.0). The histopathologic changes of
the control animals were found only in the epicardium and
were likely due to the handling necessary for surgical
preparation.
3.7. Blood gas/acid
base values
,&-__&
10
/
g
/
‘\
‘\
...
‘......
?O
&
-- .-.-,-,
-.-.-.-,-,-
>
T
-10
~D•Œ
%
-20
.30J
ti
1
2
3
70-
I
60-
=
50-
1
~
40-
30-
20J
The Paoz values did not differ between groups and the
average values were above 270 torr in all groups throughout the study. The pH values did not differ between or
within groups, and the average values ranged between 7.37
and 7.45 over the course of the study. The Paco2 values
did not differ between or within groups, and the average
values ranged between 29 and 36 tom over the course of
the study.
,.A*
.--...-
1
*
*.
,
1
o
1
1
(
2
3
Time (hr)
Fig. 1. Preload recruitable stroke work (PRSW), volume axis intercept of
the stroke work–end-diastolic volume relationship (VO,W)and time constant of isovolumic pressure decline (t) responses to cardiac lymphatic
obstruction in control (open square), lymphatic obstruction (closed circle),
and lymphatic obstrrrctiorr/autonomically blocked (closed triangle)
groups. *P <0.05 for difference from baseline period; ‘P <0.05 for
difference from control group *P <0.05 for difference between LO and
LO/AX groups.
4. Discussion
Cardiac lymphatic obstruction (CLO) resulted in a progressive decrease in left ventricular contractility and prolongation of isovolumic relaxation, reflecting impairment
of the active processes of contraction and relaxation. However, CLO did not significantly affect diastolic stiffness.
Cardiac lymphatic obstruction had little influence on the
hemodynarnic parameters measured. The slight, but progressive decline in cardiac output and increase in pulmonary artery pressure occurred in all groups and was
therefore not likely to be the result of CLO or the cause of
the function changes in the CLO groups.
Autonomic nervous system mechanisms were not responsible for the changes in systolic and diastolic function,
since CLO had similar effects in dogs with (3-adrenergic
L.L. Ludwig et al. / Cardiovascular Rexearch 33 (1997) 164–171
169
Table 2
Left ventricular end-diastolic pressure (P,<(), end-diastolic volume (Vcd), and stiffness responses to cardiac lymphatic obstruction in control, lymphatic
obstruction (LO), and lymphatic obstruction\ autonomicallyblocked (LO\ AX) groups
Parameter
Group
Baseline
Ih
2h
3h
P,d (mmHg)
Control
LO
LO/AX
4.5 i 0.5
3.4+ 0.8
5.9+ 0.6
4.5 +0,61
5.6+ 1.1
6.7 *0,7
4.1 *0.5
5.8 i 1.4
6.2 +0.4
3.3 +0.7
5.2+ 1.2
5.6Y0.2
V,d(ml)
Control
LO
LO/AX
35+-5
39+ 6
47*4
46 k 5
37 ~ 6
42 ~ 7
41 * 11
41 *8
47+ 11
37* 5
36* 8
51 +8
Stiffness (mmHg. ml- )
Control
LO
LO/AX
0.2 +0,02
0.32 + 0.07
0.38 i 0.12
0.17 +0.02
().25+0,04
0.41 +0, I 1
0.19 +0,02
0.23 + 0.04
0.36 + 0.09
0.26+0.03
0.26 + 0.05
0.29 i 0.08
‘ f <0.05 for difference from baseline period.
“’”P<0,05 for difference from control group.
1P <005 fol. difference between LO and LO}AxgrOuPs
and cholinergic receptor blockade. Left ventricular systolic
and diastolic function remained unchanged in dogs of the
control group, indicating that the experimental preparation
had no effect on these parameters. We did not perform
experiments to control for the effects of autonomic nervous system blockade in this study, but have previously
performed such experiments using the same autonomic
blockade protocol [19]. In that previous study, neither
ventricular function nor hemodynamic parameters changed
over time in the autonomically blocked control group.
Further, autonomic blockade affected heart rate and ~ in a
manner similar to what was observed in the current study.
While the effects of acute CLO on ventricular function
have not been previously reported, there are several reports
of the effects of chronic CLO on ventricular function. Ullal
and colleagues [13] and Symbas and co-workers [12] have
demonstrated in dogs that CLO for 1–30 weeks resulted in
a decrease in cardiac output and dP/dt. These studies,
however, did not control for autonomic reflexes or evaluate the effects of CLO on diastolic function. Furthermore,
the indices used to assess systolic function were load-dependent and limited interpretation of the results. Thus, our
study extends previous findings by defining the effects of
acute CLO on the major determinants of systolic and
diastolic function—contractility, the rate of isovolumic
relaxation, and diastolic stiffness.
Acute cardiac lymphatic obstruction produced gravimetric and histopathologic evidence of myocardial edema
when compared to a control group. These findings are
consistent with the histopathologic evidence of previous
studies [7,12,13]. However, there have been no previous
reports of gravimetric measurement of CLO-induced
changes in myocardial water content. The increase in
wet/dry weight ratio brought about by CLO (1.4970)was
less than what we observed previously (690) when interstitial myocardial edema was created in dogs by acute coronary venous hypertension [6]. Despite the differing degrees
of edema produced by CLO and coronary venous hyper-
tension, contractility decreased and ~ increased by similar
amounts. A major difference between the results of the two
studies was that CLO did not cause an increase in diastolic
stiffness. These disparate responses may merely reflect a
difference in the degree of edema. Assuming that the
edema induced by CLO and coronary venous hypertension
was responsible for the LV dysfunction, contractility and ~
may be more sensitive to water content changes than
stiffness. Thus, the minor increase in water content with
CLO may not have been adequate to increase stiffness.
Alternatively, CLO may alter ventricular function by a
mechanism that differs from that of coronary venous
hypertension.
Cardiac lymphatic obstruction may induce LV dysfunction through several possible mechanisms. For the sake of
discussion the mechanisms may be divided into those that
are and those that are not related to edema. A mechanism
which may cause dysfunction that is not necessarily related
to edema formation is: acute lymphatic obstruction may
cause an increase in interstitial concentration of a metaboIite(s) that has negative inotropic effects, but is normally
cleared by lymph. The exact nature of the substance can
only be speculated, but accumulation of such a substance
may occur without a significant increase in water content.
There are several previously proposed mechanisms by
which the edema induced by CLO may have caused
ventricular dysfunction. Rusznyak [20] and other investigators [10,21] reported significant electrocardiographic (ECG)
changes after CLO that included ST segment changes and
alterations in T-wave morphology consistent with “hypoxaemia ”. Alternative methods of inducing interstitial myocardial edema, such as coronary sinus occlusion, have
also caused ECG changes that included ST segment elevation and altered T-wave morphology [22]. These conduction disturbances may explain the deterioration in systolic
function and perhaps active relaxation, but do not as
clearly explain edema-related changes in stiffness. We did
not petform a detailed analysis of the ECG in our study,
170
L.L. Ludwig et al./ Cardiovascular Research 33 (1997) 164–171
but did note occasional premature ventricular contractions.
These arrhythmias were seen in dogs of all groups with
approximately equal frequency and may have been the
result of the catheters in the LV.
A second mechanism by which CLO-induced interstitial
myocardial edema may have caused LV dysfunction is by
causing oxygen supply limitation and ischemia. Myocardial edema may result in increased coronary vascular
resistance and oxygen diffusion distance that limit oxygen
delivery and result in ischemia. Recently, Rubboli and
colleagues [1] demonstrated that myocardial edema, induced by altering coronary perfusion pressure in the isolated rat heart, resulted in an increase in coronary vascular
resistance, a decrease in coronary blood flow, and a decrease in developed pressure. However, the increase in
water content in that study was markedly greater than what
we observed with CLO in the current study or with
coronary venous hypertension [6]. Acute CLO has been
demonstrated by Pick and co-workers [23] to create
histopathologic evidence of ischemic injury, as assessed by
a hematoxylin–basic fuchsin–picric acid stain. Other investigators have demonstrated that obstruction of cardiac
lymphatic results in coronary microvasculature injury [24].
Furthermore, in an experiment in which the coronary sinus
was occluded in combination with lymphatic obstruction in
dogs, there were ECG changes consistent with myocardial
infarction, evidence of cardiac muscle necrosis, and an
increase in mortality over dogs with either coronary sinus
occlusion or CLO alone [25]. Thus, CLO may induce
adequate edema over time to cause the changes described
above and ischemic injury. In a contrasting study carried
out in vivo in dogs using 31P-nuclear magnetic resonance
spectroscopy [26], we found that acute coronary venous
hypertension and the associated interstitial myocardial
edema did not diminish the LV creatine phosphate/ adenosine triphosphate concentration ratio. The results suggest
that no significant oxygen supply limitation was created by
either the altered coronary perfusion pressure or the interstitial edema produced by coronary venous hypertension.
Since the increase in myocardial water content in our
previous study was approximately 4 times that observed in
the present study, it is doubtful that oxygen supply limitation played an important role in the CLO-induced LV
dysfunction.
Interstitial myocardial edema also may interfere with
systolic and diastolic function by altering the viscoelastic
properties of the myocardium. This mechanism may include disruption or acute remodeling of the myocardial
extracelh.dar protein matrix [27]. Several studies have
demonstrated that interstitial myocardial edema causes an
increase in diastolic stiffness [3,6]. However, little direct
evidence is available to support involvement of this mechanism in the decline of systolic function.
In conclusion, acute cardiac lymphatic obstruction resulted in a decrease in contractility and prolongation of
active relaxation, but did not affect diastolic stiffness.
These changes were associated with the formation of
interstitial myocardial edema as demonstrated by gravimetric and histopathologic means. The autonomic nervous
system was not involved in the effects of lymphatic obstruction. The role of interstitial edema as a mechanism of
the ventricular dysfunction induced by lymphatic obstruction was not clarified by this study. However, this study
adds to the evidence supporting a causal association between interstitial myocardial edema and ventricular dysfunction.
Acknowledgements
We thank Angela Phillips, Kim Watson, and Brian
Mitchell for their technical assistance. We appreciate the
help of Dr. Steven Weisbrode in performing the
histopathology. This study was supported by the Depatl
ment of Surgery Medical Research Development Fund and
Surgical Research Incorporated, Columbus, Ohio.
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