Intracardiac flow separation in an in situ perfused heart from Burmese python Python molurus
1 Department of Zoophysiology, University of Aarhus, 8000 Aarhus C,
Denmark
2 Department of Zoophysiology, University of Gothenburg, Sweden
* Author for correspondence (e-mail: tobias.wang{at}biology.au.dk)
Accepted 6 June 2002
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Summary |
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Here we characterise cardiac performance and flow dynamics in the Burmese python (Python molurus) using an in situ perfused heart preparation. The pericardium remained intact and the two atria were perfused separately (Ringer solution), and the two systemic and the pulmonary outflows were independently cannulated. Right and left atrial filling pressures and ventricular outflow pressures of the pulmonary and systemic vessels could be manipulated independently, permitting the establishment of large experimental intraventricular pressure gradients across the muscular ridge. The maximal power output generated by the systemic side of the ventricle exceeded the maximal power output that was generated by the cavum pulmonale that perfuse the pulmonary circulation. Furthermore, systemic flow could be generated against a higher outflow pressure than pulmonary flow. Perfusate entering the right atrium was preferentially distributed into the pulmonary circulation, whereas perfusate into the left atrium was distributed to the systemic circulation.
Our study indicates that the well-developed muscular ridge can separate the cavum systemic and pulmonary sides of the heart to prevent mixing of systemic and pulmonary flows. Therefore, the heart of Python appears to exhibit a large degree of ventricular flow separation as previously described for varanid lizards. We speculate that the ventricular separation has evolved in response to the need of maintaining high oxygen delivery while protecting the pulmonary circulation from oedema as result of high vascular pressures.
Key words: reptile, snake, python, Python molurus, cardiovascular, perfused heart, blood flow, filling pressure, Starling curve, power curve, cardiac shunting
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Introduction |
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Wash-out and pressure shunts can occur simultaneously in a given species
(e.g. Hicks et al., 1996;
Hicks, 1998
), but their
relative contribution may depend on the size of the muscular ridge, cardiac
contractility and the size of the CV
(Heisler and Glass, 1985
).
Turtles can exhibit large cardiac shunts, which correlate with a small
muscular ridge that is unable to separate pressures between the ventricular
chambers (e.g. Shelton and Burggren,
1976
). Thus, a pressure shunt is probably the most important
mechanism (Shelton and Burggren,
1976
; Hicks et al.,
1996
). In contrast, the CV of varanid lizards is greatly reduced
and they possess a very well developed muscular ridge (e.g.
Webb, 1979
). The large
muscular ridge separates the CP from the CA early in ventricular systole and
allows for much higher pressures in CA compared with CP, as well as an
effective separation of intraventricular blood flows
(Burggren and Johansen, 1982
;
Heisler et al., 1983
). Varanid
lizards sustain the highest metabolic rates of any reptile during exercise and
it has been suggested that there is a correlation between the ability to
separate ventricular blood flows and the metabolic rate (see
Wang and Hicks, 1996
;
Wang et al., 2001c
).
Ventricular shunt patterns have not been thoroughly investigated in many
species of non-crocodilian reptiles, so the extent to which different species
can separate blood flows is not well known (e.g.
Hicks, 1998). Several
anatomical descriptions of Python have shown a very well developed
muscular ridge as well as a reduced CV, and the cardiac anatomy of pythons
resembles that of varanid lizards (Webb,
1979
; van Mierop and Kutsche,
1985
; Farrell et al.,
1998
). It seems likely, therefore, that the heart of
Python can exert considerable flow separation. Consistent with this
possibility, pythons can sustain high rates of oxygen consumption over several
days when they digest large meals (e.g.
Secor and Diamond, 1995
).
Therefore, we decided to investigate cardiac performance and flow dynamics in
the Burmese python, Python molurus. For this purpose, we used an
in situ perfused heart, which allowed for separate control of the
input and output pressures (preload and afterload, respectively).
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Materials and methods |
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Experimental animals
The study was conducted on seven specimens of Burmese pythons (Python
molurus, L.) with a body mass of 1.5-3.3 kg (2.2±0.2 kg, mean
± S.E.M.). These snakes were bred in captivity and were transported to
Gothenburg 1 week before the experiments began. Here they were kept in
individual chambers at 30 °C with free access to water and a 12 h: 12 h
L:D cycle.
Surgery and instrumentation for the perfused heart preparation
The snakes were anaesthetised with an intraperitoneal injection of 15-20 mg
kg-1 sodium pentobarbital and the surgery was started as soon as
the responses to pinching of the skin had ceased. The lungs were artificially
ventilated (97 % O2, 3 % CO2) during instrumentation to
maintain oxygenation of the heart, and blood coagulation was prevented by a
systemic injection of heparin (2000 IU kg-1).
To cannulate the central blood vessels, the abdomen was opened by a ventral
incision. The left atrium was accessed through the common pulmonary vein that
drains both lungs, whereas the right atrium was accessed through the hepatic
vein; all other systemic veins were ligated. Both the right aortic arch (RAo)
and the left aortic arch (LAo) were cannulated, and these outflows were joined
by a T-piece so that total systemic outflow could be measured in one common
outflow. The carotid and vertebral arteries were ligated. The pulmonary
outflow was collected from the larger right pulmonary artery, whereas the left
pulmonary artery was ligated. When all the catheters were in place, the head
and the rostral portion of the snake was cut and the in situ perfused
heart was placed in a thermostat-controlled bath, maintained at 30 °C,
containing a Ringer solution that resembles normal plasma composition
(Overgaard et al., 1999). The
Ringer had the following composition (in mmol l-1): NaCl, 115; KCl,
2.5; MgSO4. 7H2O, 1; CaCl2.2H2O,
2.5; NaHCO3, 24.8; NaH2PO4, 1.2; Hepes, 10;
glucose, 5; and pyruvate, 5. Polyvinylpyrrolidone (PVP; 3 %) was added as a
volume expander. The solution was adjusted to pH 7.5 with NaOH at a
PCO2 of 3 kPa. The perfusion of the heart was
started immediately after completing the surgery and the preparation was
allowed to stabilise for 20 min.
All cannulations were performed with double-bore stainless steel cannulae
(see Franklin and Axelsson,
1994), so pressures could be measured at the tip of insertion. The
in- and outflow pressures were measured with four DPT-6100 (Peter von Berg)
pressure transducers, that were calibrated daily against static water columns.
The systemic and pulmonary outflows (Qsys and Qpul, respectively) were
measured by two 4NRB flow probes (Transonic System, Ithaca, NY, USA) placed in
the outflow tracts and connected to a Transonic T206 flow meter. The pressure
transducers and the flow meter were connected to a Grass 7G Polygraph for
appropriate amplification and filtering. Heart rate was derived from the
pulsatile pressures using a Grass tachograph (Model 7P44D) and all signals
were recorded on-line by a LabView 5.1 (National Instrument) data-acquisition
system.
Experimental protocols
The outflow pressures in both the systemic and pulmonary circulations were
set at 6.5 kPa to mimic the systemic blood pressure in the closely related
Boa constrictor (Wang et al.,
2001b) and anaesthetised pythons
(Wang et al., 2000
)
(Psys and Ppul have not been
previously reported for unanaesthetised pythons). The filling pressures were
then adjusted to attain a total cardiac output (i.e.
sys+
pul) of approximately 25 ml
min-1 kg-1 that was distributed evenly between the two
circuits (Table 1). This
resulted in a
sys of 12 ml
min-1 kg-1, which is lower than the systemic blood flow
of 19 ml min-1 kg-1 that has been measured in
vivo during resting conditions in P. molurus
(Secor et al., 2000
). Having
adjusted the filling pressures and allowed the flows to stabilise, three
experimental protocols were performed in the following order:
|
(1) Effects of altering filling pressures: Starling curves
To quantify the influence of filling pressure on stroke volume and cardiac
output, the input pressure was varied at constant output pressures (6.5 kPa).
The filling pressures of the left and right atria were manipulated
independently. The experiments were started by lowering the left atrial
filling pressure until systemic flow had decreased to around 25 % of the
control condition. Then, filling pressure was increased in steps of
approximately 0.05 kPa to a maximum value of approximately 0.7 kPa. Flows and
pressures stabilised within 15 s at each level and a subsequent 15 s recording
was used for data analysis. After completion of the Starling curve from the
left atrium, filling pressure to the right atrium was lowered until pulmonary
flow decreased to approximately 25 % of the control value. Preload to the
right atrium was then increased in steps of 0.05 kPa until a maximum pressure
of 0.4 kPa was reached.
(2) Effects of altering output pressures
Filling pressures were readjusted to attain control level flows at output
pressures of 6.5 kPa. Then, output pressure of the systemic or the pulmonary
circulation was reduced abruptly to 1 kPa followed by stepwise increases (1
kPa for each step) until an outflow pressure of 13 kPa was reached for the
systemic side. Because flow in the pulmonary side was more sensitive to
increases in outflow pressure, it was only increased to 9 kPa on this side.
During these experiments the output pressure in the other circuit remained
constant at 6.5 kPa.
(3) Effects of atrial input occlusion and output pressures
To test for intracardiac pressure and flow separation the outflow pressure
of the pulmonary and systemic side of the heart were altered simultaneously
and independently. During these manipulations, constant input pressures were
maintained. In the control situation the output pressures of the systemic and
pulmonary circuits were independently varied to levels of 3.0, 6.5 and 8.0 kPa
in randomly chosen combinations. Following this protocol, we repeated these
manipulations after having clamped one of the two atrial inflows. Thus, when
standard flow conditions were achieved, the inflow to one atrium was clamped
by a haemostat on the inflow cannula, and flows were allowed to stabilise.
Then the output pressures of the systemic and pulmonary circuits were varied
as described for the control experiments above. Finally, the inflow to the
other atrium was clamped and the changes in outflow pressure were repeated.
Flows and pressures stabilised within 15 s at each combination of outflow
pressures and the steady flows occurring over the subsequent 15 s period were
used for data analysis.
Calculation of haemodynamic variables, cardiac work and
statistics
Heart rate (fH) was derived from the pulsatile flow signal, and
stroke volumes (VS) were calculated for the systemic (left
and right aortic outflow combined) and pulmonary outflow separately as
flow/fH. Flows and stroke volumes were normalised per gram ventricle.
Flows from the left and right aortic arches
(LAo and
Rao, respectively) were
combined to give total systemic flow
(i.e.
sys=
LAo+
RAo).
Cardiac power output (mW) was also calculated separately for the systemic and
pulmonary output using the following equations:
![]() | (1) |
![]() | (2) |
![]() | (3) |
Total cardiac power output for the whole heart was normalised to heart mass. However, it was not possible to estimate the mass of the subcompartments in the undivided ventricle and power output for the systemic and pulmonary outflow were, therefore, normalised to body mass. For each individual animal, flow and power were fitted to filling pressure and output pressure using a third-order polynomial function. The individual polynomial equations were used to generate data at set pressure (input or output) intervals, so that pre-load data points could be generated in 0.05 kPa steps, whereas afterload curves were generated for each 0.5 kPa step. Finally, these individual fits were combined to produce composite graphs consisting of means of all animals.
All data are presented as means ± S.E.M. (N=7). A
Wilcoxon's sign rank test for matched pairs was used to test for significant
changes. For protocols 1 and 2 we tested for significant differences between
sys and
pul or Power from the
systemic side and Power from the pulmonary side. This was done only at three
points in the curves, the lowest and the highest pressures tested and an
intermediate pressure. For protocol 3 we tested for differences in
sys before and after
clamping. Statistical significance was set at P<0.05.
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Results |
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The effects of independently altering the filling pressures to the two
atria on flow and power development are presented as Starling curves in
Fig. 1. Filling of the left
atrium, which receives pulmonary venous blood in vivo, markedly
increased sys, whereas
pul decreased
(Fig. 1A). Although left atrial
filling pressure was elevated to 0.7 kPa,
sys did not appear to reach
a plateau during the experiments. Filling of the right atrium, which receives
systemic oxygen-poor blood in vivo, resulted in maximal
pul and power development
at values between 0.2 and 0.3 kPa. Increasing filling pressure of the right
atrium led to a small decrease in
sys. Because output
pressure was kept constant, the power output during filling of the left or the
right atrium mirrored the changes in flows
(Fig. 1B,D).
|
Fig. 2 depicts the effects
of increasing outflow pressure, at constant inflow pressure, on flow and power
output. In these experiments, outflow pressure was either altered in the
systemic or pulmonary circulation (Fig.
2A,B and C,D, respectively). For both the systemic and pulmonary
circulation, increased outflow pressure caused a progressive decline in flow
to that side of the circulation (Fig.
2A,C). Flow in the other side of the heart was also affected, but
the absolute changes were smaller. Increased outflow pressure in the systemic
arches (Psys) caused a small increase in
pul from 8.6±2.0 to
12.2±0.5 ml kg-1 min-1, but further increase
above 6 kPa caused a decline in
pul to a value of around
5.4±1.5 ml kg-1 min-1
(Fig. 2A). Increasing the
outflow pressures in the pulmonary circulation from 1 to 9 kPa, caused a
decline of
pul from
31.5±4.4 to 0 ml kg-1 min-1 and was associated
with a reduction in
sys
from 23.0±3.2 to 10.2±1.6 ml min-1 kg-1.
As noted for the Starling curves, there were substantial differences between
the systemic and pulmonary circulation. Most strikingly, an increase in the
outflow pressure to 9 kPa completely abated
pul, whereas
sys was 8 ml
kg-1 min-1 (a reduction of two-thirds compared with the
lowest outflow resistance) at a similar Psys. Furthermore,
sys persisted even at the
maximal tested outflow pressure of 13 kPa.
|
The changes in systemic and pulmonary flows from experimental protocol 3
are presented in Table 2. Flows
are expressed relative to total cardiac output (i.e.
pul+
sys)
in Figs 3 and
4, where the left-hand panels
show the data obtained when only outflow pressures were manipulated, while the
right-hand panels show the flows measured with alteration of output pressures
following occlusion of the input to one of the atria. The effects of
manipulating one of outflow pressures (Psys or
Ppul; see Table
2) were similar to the data presented in
Fig. 2. Thus,
sys gradually decreased
when Psys was increased, while only small changes occurred
in
pul
(Table 2). By contrast, changes
in Psys predominantly affected
pul
(Table 2). These findings
indicate that the flows entering the heart from the two atria are functionally
separated. This was investigated further by clamping the inflow to one of the
atria and repeating the changes in outflow pressures (right-hand panels in
Figs 3,
4;
Table 2). When the systemic
vein was clamped at baseline conditions
(Table 1),
pul decreased from
11.1±0.7 ml min-1 kg-1 to 0.6±0.4 ml
min-1 kg-1 (Fig.
3; Table 2).
Similarly, when the pulmonary vein was clamped, there was a large reduction in
sys (from 11.4±1.2
ml min-1 kg-1 to 2.7±1.0 ml min-1
kg-1) (Fig. 4;
Table 2). These patterns
applied to all combinations of outflow pressures, and flow distributions were
invariably affected by clamping one of the inflow to the atria (Figs
2,
4). However, the pulmonary
circulation was less affected by atrial clamping than the systemic
circulation. In both cases, the amount of perfusate that was shunted to the
other circulatory system increased with the difference between outflow
pressures. During clamping of the systemic vein, the maximal amount of shunted
perfusate was 17±4 % and occurred at
Ppul/Psys of 3 kPa/8 kPa
(Fig. 3), whereas the maximal
shunt during clamping of the pulmonary vein was 83±8 % and occurred at
a Ppul/Psys of 8 kPa/3 kPa
(Fig. 4).
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Discussion |
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Differential power and Starling curves for the cavum arteriosum and
the cavum pulmonale
Stroke volume was very sensitive to filling pressure and the in
situ perfused P. molurus heart exhibited a marked
FrankStarling response as previously shown for turtles, crocodiles and
other vertebrates (Reeves,
1963; Strobeck and
Sonnenblick, 1986
; Farrell et
al., 1992
; Farrell et al.,
1994
; Franklin,
1994
; Franklin and Axelsson,
1994
). There was no effect of increased filling pressure on heart
rate (data not shown). This is also the case in turtles
(Farrell et al., 1994
;
Franklin, 1994
), whereas
filling of the right atrium exerts a chronotropic effect in crocodiles
(Franklin and Axelsson, 1994
).
This response can probably be ascribed to excitement of the sinoatrial
pacemaker by stretch of the atrial wall. In mammals, approximately 15% of the
increased heart rate following increased atrial pressure is due to stretch of
the S-A node, and the rest to the Bainbridge effect
(Guyton, 1986
). Our data
suggest that atrial stretch receptors are of little importance in modulating
the pacemaker in P. molurus.
Our experiments show that the systemic and pulmonary sides of the P.
molurus heart exhibit very different quantitative responses to changes in
filling and outflow pressures. Thus, the maximal power output from the cavum
arteriosum, which perfuses the systemic circulation in vivo, is at
least threefold higher than the power output from the cavum pulmonale, which
perfuses the pulmonary circulation (Figs
1,
2). This indicates that the
strength of contraction in the cavum arteriosum greatly exceed that in the
cavum pulmonale. The differences in power development between the two sides of
the ventricle are reflected in the ability to generate flows against elevated
resistance in the outflow tracts.
pul ceased when outflow
pressure in the pulmonary artery was increased to approximately 9 kPa, while
the systemic side of the heart was able to deliver a flow against no less than
13 kPa (Fig. 2). Thus, the
cavum arteriosum was able to maintain systemic flow in the face of increased
systemic outflow pressure to a larger degree than the cavum pulmonale.
Differences in the contractile properties of the cavum arteriosum versus the
cavum pulmonale have been previously proposed by Farrell et al.
(1998
), who noted that the
ventricular wall surrounding the CA is much thicker than the wall surrounding
the CP (Farrell et al.,
1998
).
The larger power generating ability of the CA compared with the CP of the
perfused P. molurus heart indicates that systemic blood pressure can
greatly exceed pulmonary pressures in vivo. Systemic blood pressure
can indeed exceed 20 kPa during forced activity in Boa constrictor
(Wang et al., 2001a) and
immediately following induction of anaesthesia in P. regius (T. W.
and M. A., unpublished), but pulmonary blood pressures have not been reported.
Ventricular pressure separation has not been demonstrated in other snakes.
Vipera berus and Natrix natrix exhibit identical systolic
pressures in systemic and pulmonary arteries and ventricular pressures showed
no indication of pressure separation
(Johansen, 1959
). In
Thamnophis spp., the pressures in the pulmonary artery are lower than
systemic pressures, but there were no intraventricular pressure differences
and the lower pulmonary pressure can be explained by constriction of a muscle
surrounding the base of the pulmonary artery
(Burggren, 1977
). Clearly,
intraventricular pressures need to be measured in P. molurus to
investigate whether their heart differs from the other snakes. Within
non-crocodilian reptiles, a clear pressure separation between the pulmonary
and systemic circulations has so far been established only for varanid lizards
(e.g. Millard and Johansen,
1974
; Heisler et al.,
1983
) and may be related to the ability of these lizards to
maintain high aerobic metabolism during exercise
(Wang and Hicks, 1996
).
Separation of blood flows and ventricular shunts in the perfused P.
molurus heart
The different power relationships of the CP and CA were associated with an
apparent ability to separate flows entering the ventricle from the two atria.
Thus, increased filling of the right atrium preferentially affected
pul, and
sys was only marginally
affected when the outflow pressure was elevated in the pulmonary artery. A
reciprocal relationship was observed for the other side of the heart (Figs
3,
4). Therefore, it appears that
perfusate entering the in situ perfused heart from the two atria are
well separated during both ventricular diastole and systole. The separation of
flows during diastole is likely to be caused by the atrioventricular
valves that direct right atrial inflow across the muscular ridge to the PA,
while the other valve directs left atrial perfusate into the base of the CA
(see White, 1968
;
Webb, 1979
). Early in
ventricular systole, the flow separation between the CA and CP is probably
accomplished by the well-developed muscular ridge in P. molurus
(Farrell et al., 1998
). If the
muscular ridge does indeed separate the CA and CP during systole, this would
allow for differential pressures within the chambers, as observed in
Varanus exanthematicus (Burggren
and Johansen, 1982
).
The apparent separation of flows within the ventricle was further
substantiated from the experiments where atrial inflows were clamped (Figs
3,
4). Clamping of the right
atrium virtually abolished
pul even when
Ppul was set much lower than Psys
(Fig. 3). These experiments
show that virtually all the perfusate delivered to the caudal portion of the
CA from the left atrium remains there during the entire diastolic phase and is
virtually incapable of crossing the muscular ridge to enter the CP. This
separation persisted when Ppul was reduced substantially
compared to Psys. Thus, the extent to which
intraventricular pressure differences can affect LR shunt
(recirculation of pulmonary venous blood to the lungs) appears to be very
small.
Clamping the left atrium caused substantial reduction in
sys, but some of the
perfusate entering the right atrium was ejected through the systemic arches
when Ppul was set high. Under these circumstances, some of
the perfusate that enters the CV during diastole does not cross the muscular
ridge, and instead enters the CA and is ejected through the systemic arteries
(equivalent of RL shunt). Furthermore, because the CP is weaker than
the CA, contraction of the CP may be unable to overcome high pulmonary
pressures and end-systolic volume of the CP is likely to be high during these
conditions. In comparison to right atrial clamping, the RL shunt flows
were higher than the LR shunt flows. Thus, because the muscular ridge
may act as a barrier for right atrial inflow and because the CP is weaker than
the CA, it seems that RL shunts are more likely to occur than LR
shunts.
The in situ perfused heart preparation allows for exquisite
experimental control of haemodynamics variables that are difficult to
manipulate in vivo (Perry and
Farrell, 1989). However, in spite of these advantages, the in
situ perfusion differs from in vivo conditions. First, outflow
pressures are static and the steady decline in central vascular blood
pressures that normally occur during diastole does not take place. Therefore,
the ventricular valves of the in situ perfused heart open later in
systole than they would in vivo. This is particularly relevant to the
pulmonary circulation because diastolic pressure in the pulmonary artery is
lower than the systemic arteries, which, even at homogeneous intraventricular
pressures causes an earlier opening of the pulmonary arterial valves compared
with the systemic valves (e.g. Johansen,
1959
). Second, the flows into the left and right atria do not
necessarily match
pul and
sys in the perfused heart,
as they would do in vivo. Thus, until in vivo measurements
of flow and pressure relationships are conducted, predictions of in
vivo shunt patterns of Python remain speculative. However, it is
unlikely that Ppul ever exceed Psys to
the extent that was manipulated in the present study and therefore the
RL shunt is likely to be relatively small.
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Conclusions and perspectives |
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Acknowledgments |
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References |
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