Vol. 277, Issue 2, H756-H762, August 1999
Effects of long-term, high-altitude hypoxia on the capillarity
of the ovine fetal heart
A. M.
Lewis1,
O.
Mathieu-Costello2,
P. J.
McMillan1, and
R. D.
Gilbert1
1 Center for Perinatal Biology,
Loma Linda University, Loma Linda 92350; and
2 Department of Physiology,
School of Medicine, University of California, San Diego, La Jolla,
California 92093
 |
ABSTRACT |
To determine the effect of chronic hypoxia on
myocardial capillarity, we exposed pregnant ewes to an altitude of
3,820 m from day 30 to
day 139 of gestation and compared the
fetus to low-altitude (~300 m) controls. We hypothesized that
capillarity would increase in the hypoxic myocardium to optimize oxygen
and metabolite flux to hypoxic tissues. Fetal hearts were fixed by
retrograde aortic perfusion and processed for microscopy and
stereological evaluation. Fiber cross-sectional area and capillary
density were measured and standardized to sarcomere length. Capillary
volume density and capillary diameter were measured, capillary-to-fiber
ratio and capillary length density were calculated, and the capillary anisotropy coefficient was obtained from a table of known values. Capillary-to-fiber ratio, capillary volume density, and the capillary anisotropy coefficient were not different between hypoxia and control
groups. Capillary diameter was significantly larger in the right
compared with the left ventricle of hypoxic but not control hearts;
fiber cross-sectional area tended to be larger in the right ventricle
of both groups, but this was not significant. As a result of larger
fiber size, capillary density and capillary length density were
significantly smaller in the right ventricle of hypoxic but not control
fetal hearts. Contrary to our hypothesis, the ovine fetus does not show
morphological adaptation in the myocardium after ~109 days of
high-altitude hypoxic stress.
light microscopy; morphometry; angiogenesis
| |
INTRODUCTION |
PREGNANCY COMPLICATED WITH high-altitude hypoxemic
stress has been shown to elevate risk for preeclampsia and low maternal blood volume (34) and contribute to low birth weight and increased fetal mortality rates (21, 22, 32). In previous
experiments, our laboratory examined the effects of long-term,
high-altitude hypoxemia (3,820 m) on ovine fetal cardiac output and
reported a 34 and 38% decrease in right and left ventricular outputs,
respectively, after 14 days of hypoxia (12). After 90 days of fetal
hypoxia, a substantial reduction in right and combined ventricular
outputs were found with no significant difference in left ventricular output (11). Despite this profound deficit in flow, a redistribution of
blood flow was observed to favor the heart and brain (10), at the
expense of the rest of the tissues, maintaining physiological oxygen
delivery to these vital organs.
We also found that chronic hypoxia significantly reduced the inotropic
response to calcium (4) in ovine fetal papillary muscles, and it
elevated cardiac enzymes such as citrate synthase and lactate
dehydrogenase (23). Left and right ventricular function was
significantly depressed with prolonged hypoxemia (1, 11, 12).
In addition to potential hypoxic influences on myocyte function, we
hypothesized that morphological adaptations may have occurred that
altered cardiac function. It is well known that substantial right
ventricular hypertrophy occurs at moderate elevations after only a few
days in the adult. Significant right and left ventricular hypertrophy
is seen in fetal and young rats (7, 25, 30), young guinea pigs (13),
calves (15), pigs (8), and human children (2), whereas myocardial
hypotrophy has been found in developing chick hearts (14) exposed to
gestational hypoxia. It has been speculated that, in the face of
myocyte hypertrophy, tissue oxygenation is threatened, and compensatory
angiogenesis has been found to occur in the right or in both ventricles
of rats (7, 30), guinea pigs (13, 33), calves (15), and puppies (3)
born at moderate to high altitudes.
To our knowledge there has been no comprehensive morphological study
quantitating the cardiac adaptations to gestational hypoxia in the
near-term sheep fetus. We therefore sought to identify the changes in
microvasculature and myocyte structure of the developing ovine
myocardium after prolonged gestational high-altitude hypoxia using
light microscopy and stereological analysis. We hypothesized that
capillary proliferation would occur to offset probable fiber hypertrophy and, therefore, maintain proper oxygenation in an hypoxic environment.
| |
METHODS |
Isolation of fetal sheep heart.
Time-dated pregnant ewes of a homogeneous-mixed Western breed were
obtained from a single supplier (Nebeker Ranch, Lancaster, CA) and
randomly allocated to long-term hypoxic or control groups. The control
group (n = 5) remained at Nebeker
Ranch, altitude ~300 m, until ~138 days of gestation. At 30 days of
gestation, we transported the long-term hypoxic group
(n = 6) to the Barcroft Laboratory
(White Mountain Research Station, Bishop, CA; altitude 3,820 m), where
they remained until ~138 days of gestation. In a previous study we
reported that arterial PO2 was 102 ± 2 mmHg at Nebeker Ranch and 64 ± 2 mmHg at the White Mountain Research Station (barometric pressure ~480 Torr) (24). Both high- and
low-altitude ewes were kept in a sheltered pen and provided with
alfalfa pellets, mineral supplements, and clean water ad libitum. We
transported animals (~7-h trip) from either location to our
laboratory at Loma Linda University, where they either underwent
immediate study or, in the case of hypoxic ewes awaiting study, were
surgically implanted with a nonocclusive tracheal catheter (6) for
nitrogen gas administration to reestablish hypoxemia immediately after
arrival at our laboratory. On the experimental day, animals ranged from
139 to 142 days of gestation (control: 139.3 ± 0.2 days; hypoxic:
140.4 ± 0.7 days). The ewes were sedated intravenously with
thiamylal (10 mg/kg), intubated, and kept under surgical anesthesia
(halothane 5% in oxygen) while we delivered the fetuses through a
midline laparotomy. After fetal weights were recorded, the fetal heart
was quickly removed via a midline thoracotomy and immersed in
heparinized saline.
Tissue preparation.
Within 1 min of removal of the heart, the aorta was secured to a
cannula, which was connected to a perfusion pump. The heart was
immediately flushed with heparinized saline and 0.1% sodium nitrite at
a nonpulsatile flow rate of 50 ml/min until the exudate was clear of
red blood cells (~90 s). The apex of the left ventricle (LV) was
pierced for outflow. Retrograde aortic perfusion was then switched to
6.25% glutaraldehyde in 0.1 M sodium cacodylate buffer, pH 7.4, 1,125 mosmol, for 20 min at continuous flow rate. The physiological flow rate
was calculated to be 50-55 ml/min for these fetuses. A pressure
transducer was calibrated before each experiment and connected to the
perfusion line to measure changes in perfusion pressure. Hearts were
dissected free of the great vessels and weighed. Right ventricle (RV)
and LV plus septum (LV + S) weights were also obtained. RV and LV
samples were taken from the entire thickness of the central portion of
the ventricle free wall, 50% of the distance from apex to base. From
the same area the wall thickness of both ventricles was measured under a dissecting microscope. Tissue from each ventricle was subsampled into
subepicardium and subendocardium portions of equal size, and the
midwall section was discarded. Subepicardium and subendocardium were
subsequently cut into 1 × 1 × 3 mm blocks and
immersed in glutaraldehyde fixative for at least 1 day. Blocks were
rinsed in 0.1 M sodium cacodylate buffer, postfixed for 2 h in 1%
osmium tetroxide solution in cacodylate buffer, dehydrated in
increasing concentrations (70-100%) of ethanol, rinsed in
propylene oxide, and embedded in Araldite.
Tissue sectioning.
Sections 1 µm in thickness were cut using an LKB Ultrotome III and
stained with aqueous 0.1% toluidine blue solution. For each subsample,
24 blocks were embedded, and from those, 4 transverse and 4 longitudinal blocks were randomly selected from each subepicardial and
subendocardial sample. Transverse sections were cut (1 µm) with the
muscle fiber axis at an orientation perpendicular to the microtome
knife. As sections were cut and examined under the light microscope,
they were determined to be transverse when changing the sectioning
angle by 5° in either direction produced smaller A-band spacing
within the fiber sections. For longitudinal sections, at least three
sections were obtained, after the sectioning angle was changed by
1°, with muscle fibers parallel to the microtome knife, and
sarcomere length was measured (mean of 10 measurements) in each
section. Longitudinal sections were identified as those with the
shortest sarcomere length compared with that in sections obtained at a
sectioning angle altered by 1° in either direction. Because of the
interwoven network of myocytes characteristic of the heart, sections
often contained areas of longitudinally as well as obliquely or
transversely oriented fibers. In these cases, a specific area was
chosen as nearly longitudinal, and the above procedure of
systematically altering the section angle was performed until a
longitudinal subsample was obtained.
Morphometric analysis.
Morphometric data were collected from the 1-µm sections of
subepicardium and subendocardium from the LV and RV. Mean fiber cross-sectional area
[
(f)], mean
fiber cross-sectional perimeter
[
(f)], and
mean number of capillaries around a fiber
(NCAF) were
measured with an image analyzer (Videometric 150, American Innovision,
San Diego, CA) on transverse sections. An average of 167 fibers were
measured per subsample at ×400 magnification. Capillary diameter
![[<OVL><IT>d</IT></OVL>(c)]](/content/vol277/issue2/fulltext/H756/img003.gif)
was measured on
transverse sections using image analysis (560 capillaries/subsample) by
identifying circular profiles on transverse sections with a diameter
8 µm and a difference between the shortest and longest diameters
not exceeding 15%. This excluded small venules of ~10 µm in diameter.
Capillary numerical density was determined on transverse
[QA(0)] and
longitudinal
[QA(
/2)] sections
(4 blocks each, ×400 magnification) with an average of three and
six fields sampled per section, respectively. Because of the effect of
sarcomere length on fiber cross-sectional area, we normalized fiber
cross-sectional area and capillary density to a 1.9-µm sarcomere
length, a value close to the mean of each group. Points were collected
and stored on an Apple computer (17). Capillary-to-fiber ratio
[NN(c, f)], was calculated as the product of capillary number per fiber area in
transverse section and fiber cross-sectional area. The
number of fibers sharing one capillary (SF) was calculated as
NCAF/NN(c, f).
Capillary length density
[JV(c, f)],
the capillary orientation parameter
(K), and its coefficient
[c(K, 0)],
which represents the contribution of tortuosity and branching to
capillary length, were estimated using the method developed by Mathieu
et al. (16). Briefly, it was demonstrated that the Fisher axial
distribution model is suitable for estimation of capillary anisotropy
in rat heart muscle (26). Thus the capillary length density is related to capillary numerical density in transverse and longitudinal sections
by the following equations
|
(1)
|
and
|
(2)
|
where
c(K, 0) and
c(K, /2) are capillary
anisotropy coefficients for transverse and longitudinal sections,
respectively. Combining and rearranging Eqs.
1 and 2 gives the
relationship between capillary densities and the anisotropy coefficient
for transverse and longitudinal sections
|
(3)
|
In
the Fisher axial distribution model, the ratio
c(K, /2)/c(K, 0)
is a uniform and monotonic function of
K and thus can be used to estimate
K and
c(K, 0)
from a table of known coefficients (16).
JV(c, f) is then
estimated from Eq. 1 or
2.
When capillaries are anisotropic (straight and parallel) with respect
to muscle fibers, K = 
and
c(K, 0) = 1. For isotropic (randomly oriented) capillaries,
K = 0 and
c(K, 0) = 2. Estimates of capillarity in each sample were expressed per unit of
muscle fiber area as reference space. This prevents error due to
fixation influences on extracellular space (17). Capillary volume
density [VV(c, f)]
was estimated using a standard point-counting procedure on transverse sections.
Statistical analysis.
Differences between subepicardium and subendocardium, LV and RV, and
hypoxic and control hearts were assessed using three-way ANOVA and
Duncan's multiple-range test for post hoc differences. When
differences between subendocardium and subepicardium were absent, the
data were pooled. Subsequently, when further comparison of RV and LV
showed no statistical significance, these data were also pooled.
Student's t-test was used for
comparison between control and hypoxic hearts. Results are presented as
means ± SE, and significance was accepted at
P < 0.05.
| |
RESULTS |
Gross morphology.
Representative low-power light micrographs of transverse and
longitudinal sections of heart muscle are shown in Fig.
1. Retrograde aortic perfusion provided
optimum preservation of myocardial ultrastructure with no contracture.
Pressure transducer recordings indicated no changes in perfusion
pressure of any animals, as indicated by the flow rate (50-55
ml/min), other than the negligible rise in pressure observed caused by
gradual hardening of the tissue with fixation.
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Fig. 1.
Light micrographs of portions of myocardium in transverse
(A and
C) and longitudinal
(B and
D) sections from control
(A and
B) and hypoxic
(C and
D) fetal heart. Bar, 20 µm.
|
|
Fetal weight in the hypoxic group was not statistically different from
that in the control group (Table 1). There
were no significant differences in heart weight, LV + S weight, and RV weight between hypoxic and control fetuses (Table 1). Sarcomere length
in the hypoxic animals was not statistically different from that in
controls (Table 2), and it is therefore
assumed that animals were perfusion fixed at comparable levels of
diastole. Wall thickness in the LV and RV (Table 1) was not
significantly different in hypoxic myocardium compared with those in
controls.
Light microscopy.
Mean sarcomere length varied from 1.90 to 1.99 µm and from 1.89 to
1.93 µm (Table 2) in subendocardial and subepicardial regions of
control and hypoxia, respectively, and there was no significant
difference between regions. No systematic differences were found
between control and hypoxic groups in capillary-to-fiber ratio, number
of capillaries around a fiber, capillary anisotropy coefficient, number
of fibers sharing one capillary, mean fiber cross-sectional area, and
capillary volume density (Table 2).
Although capillary diameter was not significantly different between
control and hypoxia, it was significantly greater in the RV (4.81 ± 0.08 µm) than in the LV of hypoxic fetuses (4.46 ± 0.06 µm, P < 0.05) (Fig.
2) but not in controls (RV, 4.71 ± 0.16 µm; LV, 4.44 ± 0.12 µm). Similarly, capillary numerical density did not differ between control and hypoxia, whereas it was
significantly lower in the RV (5,867 ± 167 capillaries/mm2) than in the LV
of hypoxic animals (7,144 ± 355 capillaries/mm2,
P < 0.05) (Fig.
3). This is consistent with the tendency
for fiber cross-sectional area to be greater in the RV (control, 42.5 ± 3.6 µm; hypoxic, 47.3 ± 3.8 µm) than in the LV
(control, 35.5 ± 1.9 µm; hypoxic, 37.3 ± 4.0 µm;
P = not significant). Capillary numerical density was not significantly different between control ventricles (RV, 6,358 ± 423 capillaries/mm2; LV, 7,427 ± 626 capillaries/mm2)
(Fig. 3).
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Fig. 2.
Comparison of capillary diameter
[ (c)]
in right (open bars) and left ventricle (filled bars) of control
(n = 5) and high-altitude
(n = 6) fetal hearts.
* Significantly different (P < 0.05) from right ventricle.
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Fig. 3.
Comparison of capillary number per fiber cross-sectional area between
right (open bars) and left ventricle (filled bars) of control
(n = 5) and hypoxic
(n = 6) fetal myocardium.
* Significantly different (P < 0.05) from left ventricle.
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|
Capillary length density was not significantly different between
hypoxic and control animals (Fig. 4). It
was significantly smaller in hypoxic RV (6,339 ± 288 mm
2) than hypoxic LV
(7,477 ± 362 mm2;
P < 0.05) (Fig. 4), consistent with
the decreased capillary density and unchanged anisotropy coefficient in
the hypoxic RV. Capillary length density was not significantly
different in control hearts (RV, 7,046 ± 400 mm2; LV, 7,969 ± 546 mm2). Capillary volume
density was not significantly different between hypoxic and control
animals (Table 2).
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Fig. 4.
Comparison of capillary length density
[JV(c, f)] in
right (open bars) and left ventricle (filled bars) of control
(n = 5) and hypoxic
(n = 6) ovine fetal myocardium.
* Significantly different (P < 0.05) from left ventricle.
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| |
DISCUSSION |
Blood gases and pH.
Blood gases were not measured in fetuses for this study because of the
immediate, rapid removal of the heart. However, in a previous study
(11), arterial PO2 averaged 23.3 ± 0.5 Torr in controls compared with 19.3 ± 0.8 Torr
(P < 0.01) in high-altitude animals.
Similarly, PCO2 was reduced from 48.9 ± 1.2 Torr in controls to 39.9 ± 0.9 Torr
(P < 0.01) in hypoxic fetuses.
However, pH remained unchanged between hypoxic (7.35 ± 0.01) and
control animals (7.33 ± 0.01), and fetal lactate was also
unchanged. Oxyhemoglobin concentration was significantly reduced from
59.2 ± 1.7% in controls to 49.8 ± 3.6%
(P < 0.05) in the hypoxic group.
However, because of the elevated hemoglobin concentration with hypoxia,
oxygen content did not differ significantly between the two groups
(11).
Gross weights.
The sheep fetuses in this study do not exhibit low birth weight after
~109 days of development at 3,820 m. We report comparable birth
weights for control and high-altitude sheep fetuses (Table 1). Growth
retardation in high-altitude native human infants was reported after
development at an altitude range of 2,740-3,100 m (22), and in
another study, trends toward low birth weights were reported at 3,100 m
(34). Despite the higher altitude in our study (3,820 m), we may
speculate that the influence of hypoxic stress on birth weight is
attenuated in the sheep, representing a unique adaptive characteristic.
In addition, Jacobs et al. (9) reported significant growth retardation
in the ovine fetus exposed to 4,572 m from day
30 to day 135 of
gestation. It is possible that, despite profound physiological
adaptation in our model at 3,820 m, the critical stimulus for
morphological adjustments to hypoxia in the ovine model occurs
somewhere between our altitude of 3,820 m and that of 4,572 m reported
by Jacobs et al. (9).
Gross measurements of whole heart weights, ventricular weights, and
wall thicknesses were similar for control and hypoxic fetuses (Table
1), indicating a lack of the hypertrophy commonly seen in developing
hearts after altitude exposure (2, 8, 13, 15, 25). These data are
supported further by the unchanged fiber cross-sectional area in
hypoxic compared with control myocardium (Table 2). Fiber
cross-sectional area tended to be greater in the RV than LV in control
and hypoxic myocardium. This might suggest that the fetal heart is in
early stages of anatomic acclimatization at 3,820 m. Because extreme RV
hypertrophy and capillary proliferation were reported in several animal
models after equivalent high-altitude exposure, and because we did not
find significant changes in capillarity, we speculate that fetal sheep
offer a suitable model for altitude tolerance.
Capillarity.
Contrary to our hypothesis, this level of hypoxic stress was
insufficient to stimulate angiogenesis (Table 2 and Fig. 3) and/or
fiber hypertrophy (Tables 1 and 2) in the developing ovine fetal heart.
Arias-Stella and Recavarren (2) found substantial RV hypertrophy in
human infants and children born at altitudes ranging from 3,107 to
4,360 m as well as a retardation in the shift from RV to LV dominance
commonly observed in the human heart after birth. In rats born at 3,500 (7) and 5,000 m (30), profound RV and LV hypertrophy has been seen with
concomitant angiogenesis. RV hypertrophy and capillary growth has also
been observed in young guinea pigs after simulated altitude exposure (fractional inspired oxygen 10%) (13). Because these models (7, 13,
30) exhibit angiogenesis accompanied by fiber hypertrophy, it may be
that the lack of ventricular fiber hypertrophy in our model removes an
essential angiogenic stimulus. If this is true, then we may predict
that a direct angiogenic stimulus may also originate from surrounding
tissue made hypoxic by the hypertrophic adaptive response to altitude
and not directly from low arterial PO2. Furthermore, morphological
adaptation could occur subsequent to the physiological changes
associated with birth.
Elevated arterial pressure (afterload) and/or increased workload are
speculated to be causative agents for ventricular fiber hypertrophy
rather a than direct hypoxic influence. In a previous study from our
laboratory (11), hypoxic fetal sheep were shown to exhibit a 17% rise
in arterial pressure, a potentially strong hypertrophic stimulus.
However, our previous data (11, 12) showed that this level of arterial
pressure increase plus hypoxia is not an effective hypertrophic
influence and that the hypoxic fetal heart is less sensitive to
increased arterial pressure. Thus the sheep fetus compensates for the
higher systemic pressure at altitude, possibly preventing hypertrophy.
In large mammals such as calves (19-21 wk), altitude exposure
(3,500 m) for 53 days produced RV hypertrophy as well as capillary growth (15). These calves exhibited an elevated arterial pressure and
reduced oxygen content. The oxygen content for our sheep was not
different from that for controls (11). Oxygen delivery to the
myocardium of our fetal sheep could have remained within a physiological range because of the favorable redistribution of blood
flow and maintenance of oxygen content. Also, the reduction in
ventricular arterial pressure sensitivity prevents the fetal heart from
expending additional energy in the face of higher arterial pressure at
altitude. Thus physiological adjustments could occur without
morphological adaptation at this altitude.
In an acute hypoxic model, in the 122-day ovine fetus, Fisher et al.
(5) reported that myocardial blood flow was 160% of control after 15 min of hypoxia (PO2 14 ± 1 Torr),
and Reller et al. (28) reported that blood flows were 154% of control in 128-day fetuses after 5-8 days of hypoxia
(PO2 <18 Torr). Both authors
suggested that remodeling of the ovine fetal coronary vascular tree
occurred to accommodate these increased flows. Because we found no
evidence of capillary growth (Table 2), we may speculate that
recruitment, rather than growth of new vessels, accommodated the
enhanced coronary flow observed at altitude. It has also been shown
(29) that a threefold coronary flow reserve exists at physiological
arterial pressure in late-gestation fetal sheep. This large reserve
capacity would be sufficient to accommodate the flow increases reported
by Fisher et al. (5) and Reller et al. (28) as well as our own results
(10). However, Reller et al. (28) showed higher maximal myocardial
blood flows with adenosine infusion (induced maximal vasodilatation)
after 5-8 days of hypoxia (PO2
<18 Torr) in the ovine fetus compared with controls, suggesting some
degree of capillary proliferation.
Capillary diameter in hypoxia was significantly larger in the RV
compared with that in the LV (Fig. 2), and the same trend was seen in
controls. The reverse was seen for capillary density (Fig. 3). As
reported previously by Smolich et al. (31), these characteristics of
the sheep fetus are similar to those of humans, for whom the fetal RV
is dominant (27) and is matched by larger capillaries and a smaller
capillary density. With normal growth after birth, the LV assumes the
dominant role, and the capillary size and density relationships are
reversed. These findings suggested that the hypoxic myocardium exhibits
normal growth patterns despite high-altitude stress.
In addition to angiogenesis, the contribution of capillary tortuosity
and branching to capillary length may have been enhanced with altitude
exposure to increase capillary and fiber surface contact and,
therefore, oxygen delivery. We found the anisotropy coefficient
c(K, 0)
to be similar in both hypoxic and control fetal myocardium, and thus
there was no evidence of increased tortuosity and branching. In
hindlimb muscles of deer mice living at 3,820 m, Mathieu-Costello (18)
reported no change in capillary number or capillary tortuosity and
branching, whereas the intensely aerobic flight muscle of birds showed
increased capillary number and altered capillary tortuosity and
branching with adaptation to the same altitude (19, 20).
In conclusion, these studies demonstrated that, after ~109 days of
high-altitude (3,820 m) hypoxemia, myofiber hypertrophy and capillary
growth did not occur in the ovine fetal myocardium. This is
demonstrated by the lack of changes in capillary-to-fiber ratio, fiber
cross-sectional area, capillary diameter, and capillary density between
hypoxic and control fetuses. Similarly, capillary length and volume
density remained unchanged between the two groups. The degree of
capillary tortuosity and branching was not affected by high altitude.
Thus reduced ventricular contractility and cardiac output observed in
ovine fetuses at 3,820 m cannot be explained by morphological changes
in either fiber size or capillarization.
| |
ACKNOWLEDGEMENTS |
We thank Virginia Stiffel, Thomas Smith, Larnele Hazelwood, Peter
Agey, and Ernest Whitter for technical support.
| |
FOOTNOTES |
This work was supported by National Institutes of Health Grants
HD-31226 and 5P0-HL-17731.
The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Address for reprint requests and other correspondence: A. M. Lewis,
Center for Perinatal Biology, Loma Linda University, Loma Linda, CA
92350 (E-mail: dmlewis{at}budgetblinds.com).
Received 24 December 1998; accepted in final form 23 March 1999.
| |
REFERENCES |
1.
Alonso, J. G.,
T. Okai,
L. D. Longo,
and
R. D. Gilbert.
Cardiac function during long-term hypoxemia in fetal sheep.
Am. J. Physiol.
257 (Heart Circ. Physiol. 26):
H581-H589,
1989[Abstract/Free Full Text].
2.
Arias-Stella, J.,
and
S. Recavarren.
Right ventricular hypertrophy in native children living at high altitude.
Am. J. Pathol.
41:
55-64,
1962.
3.
Becker, E. L.,
R. G. Cooper,
and
G. D. Hataway.
Capillary vascularization in puppies born at a simulated altitude of 20,000 feet.
J. Appl. Physiol.
8:
166-168,
1955[Free Full Text].
4.
Browne, V. A.,
V. M. Stiffel,
W. J. Pearce,
L. D. Longo,
and
R. D. Gilbert.
Activator calcium and myocardial contractility in fetal sheep exposed to long-term high-altitude hypoxia.
Am. J. Physiol.
272 (Heart Circ. Physiol. 41):
H1196-H1204,
1997[Abstract/Free Full Text].
5.
Fisher, D. J.,
M. A. Heymann,
and
A. M. Rudolph.
Fetal myocardial oxygen and carbohydrate consumption during acutely induced hypoxemia.
Am. J. Physiol.
242 (Heart Circ. Physiol. 11):
H657-H661,
1982.
6.
Gleed, R. D.,
E. R. Poore,
J. P. Figueroa,
and
P. W. Nathanielsz.
Modification of maternal and fetal oxygenation with the use of tracheal gas infusion.
Am. J. Obstet. Gynecol.
155:
429-435,
1986[Medline].
7.
Grandtner, M.,
Z. Turek,
and
F. Kreuzer.
Cardiac hypertrophy in the first generation of rats native to simulated high altitude. Muscle fiber diameter and diffusion distance in the right and left ventricle.
Pflügers Arch.
350:
241-248,
1974[Medline].
8.
Haworth, S. G.,
and
A. A. Hislop.
Effect of hypoxia on adaptation of the pulmonary circulation to extra-uterine life in the pig.
Cardiovasc. Res.
16:
293-303,
1982[Medline].
9.
Jacobs, R.,
J. S. Robinson,
J. A. Owens,
J. Falconer,
and
M. E. D. Webster.
The effect of prolonged hypobaric hypoxia on growth of fetal sheep.
J. Dev. Physiol.
10:
97-112,
1988[Medline].
10.
Kamitomo, M.,
J. G. Alonso,
T. Okai,
L. D. Longo,
and
R. D. Gilbert.
Effects of long-term, high-altitude hypoxemia on ovine fetal cardiac output and blood flow distribution.
Am. J. Obstet. Gynecol.
169:
701-707,
1993[Medline].
11.
Kamitomo, M.,
L. D. Longo,
and
R. D. Gilbert.
Right and left ventricular function in fetal sheep exposed to long-term high-altitude hypoxemia.
Am. J. Physiol.
262 (Heart Circ. Physiol. 31):
H399-H405,
1992[Abstract/Free Full Text].
12.
Kamitomo, M.,
L. D. Longo,
and
R. D. Gilbert.
Cardiac function in fetal sheep during two weeks of hypoxemia.
Am. J. Physiol.
266 (Regulatory Integrative Comp. Physiol. 35):
R1778-R1785,
1994[Abstract/Free Full Text].
13.
Kayar, S. R.,
and
N. Banchero.
Myocardial capillarity in acclimation to hypoxia.
Pflügers Arch.
404:
319-325,
1985[Medline].
14.
Mancini, L.,
M. Bertossi,
D. Ribatti,
F. Bartoli,
B. Nico,
E. Lozupone,
and
L. Roncali.
The effects of long-term hypoxia on epicardium and myocardium in developing chick embryo hearts.
Int. J. Microcirc. Clin. Exp.
10:
359-371,
1991[Medline].
15.
Manohar, M.,
C. M. Parks,
M. A. Busch,
and
G. E. Bisgard.
Transmural coronary vasodilator reserve and flow distribution in unanesthetized calves sojourning at 3500 m.
J. Surg. Res.
39:
499-509,
1985[Medline].
16.
Mathieu, O.,
L. M. Cruz Orive,
H. Hoppeler,
and
E. R. Weibel.
Estimating length density and quantifying anisotropy in skeletal muscle capillaries.
J. Microsc.
131:
131-146,
1983[Medline].
17.
Mathieu, Costello, O
Capillary tortuosity and degree of contraction or extension of skeletal muscles.
Microvasc. Res.
33:
98-117,
1987[Medline].
18.
Mathieu, Costello, O
Muscle capillary tortuosity in high altitude mice depends on sarcomere length.
Respir. Physiol.
76:
289-302,
1989[Medline].
19.
Mathieu, Costello, O.,
and
P. J. Agey.
Chronic hypoxia affects capillary density and geometry in pigeon pectoralis muscle.
Respir. Physiol.
109:
39-52,
1997[Medline].
20.
Mathieu-Costello, O.,
P. J. Agey,
L. Wu,
J. M. Szewczak,
and
R. E. MacMillen.
Increased fiber capillarization in flight muscle of finch at altitude.
Respir. Physiol.
111:
189-199,
1998[Medline].
21.
Mazess, R. B.
Neonatal mortality and altitude in Peru.
Am. J. Phys. Anthropol.
23:
209-213,
1965[Medline].
22.
McCullough, R. E.,
and
J. T. Reeves.
Fetal growth retardation and increased infant mortality at high altitude.
Arch. Environ. Health
32:
36-39,
1977[Medline].
23.
Ohtsuka, T.,
and
R. D. Gilbert.
Cardiac enzyme activities in fetal and adult pregnant and nonpregnant sheep exposed to high-altitude hypoxemia.
J. Appl. Physiol.
79:
1286-1289,
1995[Abstract/Free Full Text].
24.
Penninga, L.,
and
L. D. Longo.
Ovine placentome morphology: effect of high altitude, long-term hypoxia.
Placenta
19:
187-193,
1998[Medline].
25.
Pietschmann, M.,
and
H. Bartels.
Cellular hyperplasia and hypertrophy, capillary proliferation and myoglobin concentration in the heart of newborn and adult rats at high altitude.
Respir. Physiol.
59:
347-360,
1985[Medline].
26.
Poole, D. C.,
and
O. Mathieu-Costello.
Analysis of capillary geometry in rat subepicardium and subendocardium.
Am. J. Physiol.
259 (Heart Circ. Physiol. 28):
H204-H210,
1990[Abstract/Free Full Text].
27.
Reed, K. L.,
E. J. Meijboom,
D. J. Sahn,
S. A. Scagnelli,
L. M. Valdes-Cruz,
and
L. Shenker.
Cardiac Doppler flow velocities in human fetuses.
Circulation
73:
41-46,
1986[Abstract/Free Full Text].
28.
Reller, M. D.,
M. J. Morton,
G. D. Giraud,
D. E. Wu,
and
K. L. Thornburg.
Maximal myocardial blood flow is enhanced by chronic hypoxemia in late gestation fetal sheep.
Am. J. Physiol.
263 (Heart Circ. Physiol. 32):
H1327-H1329,
1992[Abstract/Free Full Text].
29.
Reller, M. D.,
M. J. Morton,
G. D. Giraud,
D. E. Wu,
and
K. L. Thornburg.
Severe right ventricular pressure loading in fetal sheep augments global myocardial blood flow to submaximal levels.
Circulation
86:
581-588,
1992[Abstract/Free Full Text].
30.
Smith, P.,
and
D. R. Clark.
Myocardial capillary density and muscle fibre size in rats born and raised at simulated high altitude.
Br. J. Exp. Pathol.
60:
225-230,
1979[Medline].
31.
Smolich, J. J.,
A. M. Walker,
G. R. Campbell,
and
T. M. Adamson.
Left and right ventricular myocardial morphometry in fetal, neonatal, and adult sheep.
Am. J. Physiol.
257 (Heart Circ. Physiol. 26):
H1-H9,
1989[Abstract/Free Full Text].
32.
Unger, C.,
J. K. Weiser,
R. E. McCullough,
S. Keefer,
and
L. G. Moore.
Altitude, low birth weight, and infant mortality in Colorado.
JAMA
259:
3427-3432,
1988[Abstract].
33.
Valdivia, E.
Total capillary bed of the myocardium in chronic hypoxia.
Federation Proc.
21:
221,
1962.
34.
Zamudio, S.,
S. K. Palmer,
T. E. Dahms,
J. C. Berman,
R. G. McCullough,
R. E. McCullough,
and
L. G. Moore.
Blood volume expansion, preeclampsia, and infant birth weight at high altitude.
J. Appl. Physiol.
75:
1566-1573,
1993[Abstract/Free Full Text].
Am J Physiol Heart Circ Physiol 277(2):H756-H762
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INTRODUCTION
