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Direct demonstration of 25- and 50- m arteriovenous pathways in healthy human and baboon lungs

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Abstract

Postmortem microsphere studies in adult human lungs have demonstrated the existence of intrapulmonary arteriovenous pathways using nonphysiological conditions. The aim of the current study was to determine whether large diameter (>25 and 50 microm) intrapulmonary arteriovenous pathways are functional in human and baboon lungs under physiological perfusion and ventilation pressures. We used fresh healthy human donor lungs obtained for transplantation and fresh lungs from baboons (Papio c. anubis). Lungs were ventilated with room air by using a peak inflation pressure of 15 cm H(2)O and a positive end-expiratory pressure of 5 cm H(2)O. Lungs were perfused between 10 and 20 cm H(2)O by using a phosphate-buffered saline solution with 5% albumin. We infused a mixture of 25- and 50-microm microspheres (0.5 and 1 million total for baboons and human studies, respectively) into the pulmonary artery and collected the entire pulmonary venous outflow. Under these conditions, evidence of intrapulmonary arteriovenous anastomoses was found in baboon (n = 3/4) and human (n = 4/6) lungs. In those lungs showing evidence of arteriovenous pathways, 50-microm microspheres were always able to traverse the pulmonary circulation, and the fraction of transpulmonary passage ranged from 0.0003 to 0.42%. These data show that intrapulmonary arteriovenous pathways >50 microm in diameter are functional under physiological ventilation and perfusion pressures in the isolated lung. These pathways provide an alternative conduit for pulmonary blood flow that likely bypasses the areas of gas exchange at the capillary-alveolar interface that could compromise both gas exchange and the ability of the lung to filter out microemboli.
Direct demonstration of 25- and 50-m arteriovenous pathways in healthy
human and baboon lungs
Andrew T. Lovering,
1,2
Michael K. Stickland,
1
Amy J. Kelso,
2
and Marlowe W. Eldridge
1,2,3
1
John Rankin Laboratory of Pulmonary Medicine; and
2
Departments of Pediatrics, and
3
Biomedical
Engineering, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
Submitted 19 September 2006; accepted in final form 27 November 2006
Lovering AT, Stickland MK, Kelso AJ, Eldridge MW. Direct
demonstration of 25- and 50-m arteriovenous pathways in
healthy human and baboon lungs. Am J Physiol Heart Circ Physiol
292: H1777–H1781, 2007. First published December 1, 2006;
doi:10.1152/ajpheart.01024.2006.—Postmortem microsphere studies
in adult human lungs have demonstrated the existence of intrapulmo-
nary arteriovenous pathways using nonphysiological conditions. The
aim of the current study was to determine whether large diameter
(25 and 50 m) intrapulmonary arteriovenous pathways are func-
tional in human and baboon lungs under physiological perfusion and
ventilation pressures. We used fresh healthy human donor lungs
obtained for transplantion and fresh lungs from baboons (Papio c.
anubis). Lungs were ventilated with room air by using a peak inflation
pressure of 15 cmH
2
O and a positive end-expiratory pressure of 5
cmH
2
O. Lungs were perfused between 10 and 20 cmH
2
O by using a
phosphate-buffered saline solution with 5% albumin. We infused a
mixture of 25- and 50-m microspheres (0.5 and 1 million total for
baboons and human studies, respectively) into the pulmonary artery
and collected the entire pulmonary venous outflow. Under these
conditions, evidence of intrapulmonary arteriovenous anastomoses
was found in baboon (n3/4) and human (n4/6) lungs. In those
lungs showing evidence of arteriovenous pathways, 50-m micro-
spheres were always able to traverse the pulmonary circulation, and
the fraction of transpulmonary passage ranged from 0.0003 to 0.42%.
These data show that intrapulmonary arteriovenous pathways 50
m in diameter are functional under physiological ventilation and
perfusion pressures in the isolated lung. These pathways provide an
alternative conduit for pulmonary blood flow that likely bypasses the
areas of gas exchange at the capillary-alveolar interface that could
compromise both gas exchange and the ability of the lung to filter out
microemboli.
intrapulmonary arteriovenous anastomoses; shunt; baboon; pulmo-
nary circulation
RECENT WORK has demonstrated the transpulmonary passage of
saline contrast microbubbles during exercise, but not at rest, in
healthy adult human subjects without cardiac anomalies, sug-
gesting that intrapulmonary arteriovenous pathways are re-
cruited during hyperdynamic conditions (5, 14, 22). Although
the actual size of the saline contrast microbubbles is not
known, theoretical and experimental data have estimated that
the size distribution of microbubbles that survive to enter the
pulmonary microcirculation to be 60 to 90 m in diameter (8,
10, 16, 31, 32). These estimates prompted Eldridge et al. (5) to
suggest that these inducible intrapulmonary arteriovenous
pathways must be at least 60 m in diameter. Postmortem
studies in adult human lungs have documented the existence of
intrapulmonary arteriovenous pathways for more than 100
years (20). More recent studies using microspheres have dem-
onstrated that these vessels are functional under various con-
ditions. For example, Tobin and Zariquiey (25) demonstrated
that arteriovenous anastomoses were functional in atelectatic,
fresh human lungs with perfusion pressures ranging from 50 to
300 mmHg. The authors poured “several hundred” glass mi-
crospheres ranging from 10 to 750 m in diameter into the
perfusate and found that an average of 38 glass microspheres
with diameters up to 500 m traversed the pulmonary circu-
lation in 45% (9/20) of the lungs (25). In a subsequent study,
Tobin (24) studied 10 human lungs that were previously
frozen. These atelectatic lungs were perfused with 2,000
5,000 glass microspheres 200 25 m in diameter at an
unreported perfusion pressure. The microsphere injection was
followed by a perfusion of a radiopaque formalin with visual-
ization of microspheres in the pulmonary veins (24). Although
these studies demonstrate the existence of intrapulmonary
arteriovenous pathways, the experimental perfusion and infla-
tion pressures were either not reported or nonphysiological.
Thus it is not known if these anastomoses are functional under
physiological conditions. Furthermore, because the authors did
not report the amount of microspheres able to traverse the
pulmonary circulation relative to the total number of each size
infused, the relative number of the intrapulmonary arterio-
venous pathways cannot be determined. Accordingly, the aim
of the current study was to determine whether or not large-
diameter (50 m) intrapulmonary arteriovenous pathways
are functional in isolated human and non-human primate lungs
under physiological ventilation and perfusion pressures and to
determine the percentage of microspheres able to traverse the
pulmonary circulation under these conditions.
METHODS
All procedures involving animals were approved by the University
of Wisconsin Animal Care and Use Committee. The human lungs
were originally procured for organ donation and key identifiers were
not obtained; therefore, the human lung studies received an exemption
from the University of Wisconsin Health Sciences Institutional Re-
view Board.
Animal lung preparation. Non-human primate lungs were har-
vested from baboons (Papio c. anubis)(n4, 12.6 –15.6 kg body wt,
all male). All animals were anesthetized and subsequently heparinized
and euthanized by exsanguination. Lungs were gravity flushed in situ
via a peripheral vein with 2 liters of lactated Ringer. The trachea was
cannulated with a cuffed endotracheal tube, the trachea was clamped
Address for reprint requests and other correspondence: A. T. Lovering, John
Rankin Laboratory of Pulmonary Medicine, Dept. of Pediatrics and Population
Health Sciences, Univ. of Wisconsin School of Medicine and Public Health,
Rm. 4245 MSC, 1300 Univ. Ave., Madison, WI 53706-1532 (E-mail:
atlovering@wisc.edu).
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. Section 1734 solely to indicate this fact.
Am J Physiol Heart Circ Physiol 292: H1777–H1781, 2007.
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to maintain the lungs at functional residual capacity, and the lungs and
heart were removed intact from the animal and immediately prepared
for ventilation and perfusion studies.
The lungs were placed on a Styrofoam platform, and the pulmonary
artery and the left atrium were cannulated in two baboons (baboons 3
and 4). The left atrium was cannulated, and the right and left branches
of the pulmonary artery were cannulated in two baboons (baboons 1
and 2) such that the left and right lobes could be perfused indepen-
dently. After vascular cannulations, the lungs were ventilated via the
endotracheal tube to a peak inflation pressure of 15 cmH
2
O, with 5
cmH
2
O positive end-expiratory pressure at 20 –25 breaths/min with an
inspiratory duration-to-total breath duration ratio of 0.5. Airflow
pressures were measured using a Grass PT5 pressure transducer.
Lungs were perfused using a nonpulsatile, reservoir system similar
to that detailed by Conhaim et al. (2, 3). The reservoir had an overflow
outlet so that the perfusion pressure could be held constant using a
pump to deliver the perfusate to the reservoir. The pressure was
measured using a Gould-Statham P23 D6 pressure transducer, which
was set to level with the pulmonary artery. Pulmonary artery perfusion
pressure was manipulated by adjusting the height of the reservoir
above the heart. The venous outflow from the left atrial cannula was
level with the heart (or pulmonary veins) so that left atrial pressure
was atmospheric, or 0 cmH
2
O. Flow rate was determined using a
graduated cylinder. Before microsphere infusion began, the lungs
were perfused at 10 –15 cmH
2
O for 5–10 min until flows were stable.
All lungs were kept at room temperature to minimize edema forma-
tion.
Human lung procurement and preparation. Healthy human lungs
(n6, one female) were procured by the University of Wisconsin
Organ Procurement Team. Lungs were procured from donors who
died from either a cerebrovascular accident, cerebral anoxia, or head
trauma. All of the human lungs used in this study were appropriate for
transplantation. Most often the recipient patient condition dictated
whether a bilateral or single lobe transplant could be done safely. If a
single lobe transplant was necessary, then the surgeon would choose
the lobe in the best condition. If both lobes were in optimal condition,
then the surgeon would typically prefer to transplant the larger (right)
lung. Alternately, the lungs were split at procurement and the patient
condition did not allow for transplant. Because of our IRB waiver, we
were only provided with the donor’s age, weight, and cause of death
and were not provided with the exact reasons for nontransplantation.
The average donor age was 29 12 y (range 13– 42 y). Lungs were
gravity flushed in situ with 4 liters of University of Wisconsin (UW)
solution (ViaSpanTM, DuPont Pharmaceuticals) with 10 mg of phen-
tolamine injected into the pulmonary artery before aortic cross clamp.
Lungs were inflated and removed, and the trachea was stapled closed.
This was followed by a 2-liter gravity flush using UW solution (5 mg
phentolamine/l). The lungs were then stored in UW solution refrig-
erated on ice, and all lungs were studied within 24 h of procurement.
We received either the right or left lung (see Table 2). As detailed
above, the lungs were placed on a Styrofoam platform, the airway,
pulmonary artery, and pulmonary veins were cannulated, and the
lungs were ventilated and perfused. Edema formation during experi-
mentation was determined by visual inspection, and lungs 4 and 5
appeared to become edematous during the experimentation.
Microsphere studies. The perfusate for all studies was phosphate-
buffered saline (PBS) with 5% albumin to prevent alveolar edema. All
lungs were ventilated with a peak inflation pressure of 15 cmH
2
O and
perfused at 20 cmH
2
O except for the left lungs of baboons 1 and 2,
which were perfused at 10 cmH
2
O. We used 25 2.5 and 50 4m
(means SD) fluorescent-labeled (red and green, respectively) mi-
crospheres (Duke Scientific), which were combined in solution and
injected together. The number of dry microspheres per gram for a
given vial of microspheres was provided by Duke scientific. A stock
solution of 1 million microspheres/ml (10 ml of PBS total volume, 1%
albumin) was prepared so that the required amount of microspheres
could then be withdrawn from the stock solution. Five hundred
thousand total microspheres were used for baboon studies (250 K of
each size), and one million microspheres (500 K of each size) were
used for human studies. The solution of microspheres (5 ml total
volume of PBS, 1% albumin to prevent microspheres from adhering
to each other) was infused at 1 ml/min into the pulmonary artery
cannula using a constant infusion pump via an infusion plug. The
microsphere solution was continuously agitated during the infusion to
maintain an even distribution within the solution. Venous outflow was
collected beginning at infusion and continuing for 1 min following the
termination of the infusion for 6 min total. Venous outflow rates (i.e.,
pulmonary blood flow) at a given perfusion pressure were obtained
pre- and postmicrosphere injection to estimate the degree of emboli-
zation (i.e., percent change on venous outflow) caused by the micro-
spheres. Paired t-test was used to determine whether changes in flow
rates were significant and significance was set at P0.05.
Microspheres analysis. The vials containing the venous outflow
samples were gently agitated to ensure a uniform distribution of
microspheres and then were immediately vacuum filtered using a
42-mm total diameter, 36-mm functional diameter, 0.45-m pore
filter (Millipore). Filters were imaged using fluorescent microscopy
(Nikon Eclipse 50i, EXFO X-Cite 120 fluorescent illumination sys-
tem; Spot Camera v7.4 slider, Spot Advanced software v4.1) to
determine the number and sizes of microspheres not trapped in the
lung. Microspheres were counted manually on a given filter. If 500
microspheres of a given size were found on a filter, then microspheres
from those filters were resuspended in PBS (1% albumin), and
refiltered in aliquots so that there would be 500 microspheres on a
given filter. Resuspension was necessary for human lung 1.
RESULTS
Pressure-flow relationships pre- and postmicrosphere injec-
tion and the percentages of microspheres that traversed the
lungs are listed in Tables 1 (baboon) and 2 (human).
Baboon lungs. The left and right lung from baboons 1 and 2
were perfused individually. The percentages of 25- and 50-m
microspheres that traversed these lungs ranged from 0.003% to
0.2% (Table 1). Lungs from baboons 3 and 4were perfused as
a pair. The percentages of 25- and 50-m microspheres that
traversed these lungs ranged from 0 to 0.01% (Table 1). Pre-
and postmicrosphere injection venous outflow rates revealed
variable changes in individual and paired lobe perfusions, but
the changes in flow were not significant.
Human lungs. Left lung shunt fractions ranged from 0 to
0.29% for 25-m microspheres and 0 to 0.42% for 50-m
microspheres (Table 2). Right lung shunt fractions ranged from
0.0005 to 0.01% for 25-m microspheres and 0.0003 to 0.02%
for 50-m microspheres (Table 2). Venous outflow rates re-
vealed that flow was reduced on average after microsphere
injection (Table 2), but these reductions were not significant.
Lungs 4 and 5became slightly edematous during the experi-
ment, despite the use of identical conditions for previous lungs,
which did not become edematous.
Across species, there was no significant relationship be-
tween the percent change in venous outflow and the percentage
of microspheres that were able to traverse the pulmonary
circulation (r⫽⫺0.18 and 0.16 for 25- and 50-m micro-
spheres, respectively). Thus lungs with greater reductions in
venous outflow (i.e., a greater degree of embolization) did not
consistently demonstrate more transpulmonary passage of mi-
crospheres.
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DISCUSSION
Our findings directly demonstrated that intrapulmonary ar-
teriovenous pathways 25 and 50 m are functional under
physiological perfusion and ventilation pressures in human and
baboon lungs.
Transpulmonary passage via arteriovenous anastomoses or
distended capillaries? Under physiological perfusion pres-
sures, microspheres 7–10 m should be filtered by the
capillaries and other vessels and are therefore unable to tra-
verse the pulmonary circulation in the absence of arteriovenous
anastomoses. However, overembolization due to extensive
microsphere occlusion of the pulmonary vasculature may cause
excessive regional pulmonary pressures resulting in either the
opening of an arteriovenous anastomoses or microspheres
being forced through a grossly distended capillary. In the
current study we attempted to minimize the degree of overem-
bolization. Nevertheless, there were instances where pulmo-
nary venous outflow was reduced as much as 30% following
microspheres infusion. Importantly, our perfusion system
maintained a constant pressure so that when embolization
occurred, flow was reduced and an excessively elevated per-
fusion pressure was prevented. The extent of capillary disten-
tion is unknown in humans. Estimates from animal studies
have demonstrated in horses, dogs, and rabbits that averages of
pulmonary capillary radii at high pressures are between 3.2 and
3.6 m (1, 29), and therefore it is extremely unlikely that
capillaries would distend to 25–50 m. Furthermore, we found
that there was no correlation between the degree of emboliza-
tion, measured by change in pulmonary venous outflow, and
the percentage of microspheres able to traverse the pulmonary
circulation. Thus it seems highly unlikely that microspheres
were either traveling through arteriovenous anastomoses
opened by nonphysiological pressures or through abnormally
distended capillaries.
Intrapulmonary arteriovenous pathways in primates. We
chose to examine lungs from humans and baboons because of
the difficulty in obtaining fresh healthy human lungs. Both
humans and baboons have a common evolutionary ancestry
with the hominoid lineage (humans, gorillas, chimpanzees,
etc.) and the Old World monkeys (macaques, baboons, etc.)
diverging 25 to 30 million years ago (7, 17, 21). Because of
this common ancestry, we hypothesized that lungs from both
species would have intrapulmonary arteriovenous anastomoses
50 m. Our data clearly support the idea that other hominids
as well as other Old World monkeys could potentially have
intrapulmonary arteriovenous conduits.
Why is there a disparity between reports of intrapulmonary
arteriovenous anastomoses in humans? Despite our current
findings and the findings of others (24 –26, 28), there are
reports that suggest these vessels do not exist in humans (12,
27). Based on our findings in exercising humans, these path-
ways appear to be recruitable since they are not open at rest but
Table 1. Pressure-flow relationships before and after microsphere injection and percent
microsphere passage in baboon lungs
Body
Weight, kg
Premicrosphere Injection Postmicrosphere Injection
Microsphere
Passage, %
P, cmH
2
OQ, ml/min R (P/Q) P, cmH
2
OQ, ml/min R (P/Q) Q (%) 25 m50m
Baboon 1
Right lung 15.6 20 68 0.29 20 ND ND ND 0.02 0.02
Left lung 10 36 0.28 10 38 0.26 6 0.1 0.2
Baboon 2
Right lung 13.4 20 72 0.28 20 72 0.28 0 0 0
Left lung 10 41 0.24 10 28 0.36 32 0 0.003
Baboon 3 14.2 20 184 0.11 20 148 0.14 20 0 0
Baboon 4 12.6 20 156 0.13 20 ND ND ND 0.01 0.01
Ind avg @ 10 cmH
2
O14.5 10 39 0.26 10 33 0.31 13 0.05 0.10
Ind avg @ 20 cmH
2
O14.5 20 70 0.29 20 72 0.28 0 0.01 0.01
Pr avg @ 20 cmH
2
O13.4 20 170 0.12 20 148 0.14 20 0.01 0.01
P, pressure; Q, flow; R, ratio of P to Q; Q, change in flow; Ind Avg, Individual lobe perfusion average; Pr Avg, paired lobe perfusion average; ND, no data
obtained.
Table 2. Pressure-flow relationships before and after microsphere injection and percent
microsphere passage in human lungs
Premicrosphere Injection Postmicrosphere Injection
Microsphere
Passage, %
P, cmH
2
OQ, ml/min R (P/Q) P, cmH
2
OQ, ml/min R (P/Q) Q (%) 25 m50m
Human 1 Left lung 20 375 0.05 20 267 0.07 29 0.29 0.42
Human 2 Right lung 20 326 0.06 20 215 0.09 34 0.01 0.002
Human 3 Right lung 20 136 0.15 20 148 0.14 9 0.0005 0.02
Human 4 Left lung 20 126 0.16 20 92 0.22 27 0 0
Human 5 Left lung 20 90 0.22 20 104 0.19 16 * 0
Human 6 Right lung 20 116 0.17 20 116 0.17 0 0 0.0003
Average 20 195 0.14 20 157 0.15 11 0.06 0.07
Abbreviations same as in Table 1. *No 25-m microspheres used.
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become functional during exercise (5, 14, 22). Furthermore,
these pathways are likely small in number, as suggested by our
findings of small shunt fractions. Indeed, these inducible path-
ways may be very difficult to identify with histological meth-
ods, particularly when the conditions required to open them are
essentially unknown. Our findings provide strong, compelling
evidence that pulmonary arteriovenous pathways (at least 50
m in diameter) are functional in healthy human lungs under
physiological ventilation and perfusion pressures.
Significance of intrapulmonary arteriovenous pathways in
human and baboon lungs. We have previously shown that
microbubbles do not traverse the pulmonary circulation at rest
but are able to traverse the pulmonary circulation during
exercise in the majority of healthy humans (5, 22). Eldridge
and colleagues (5) hypothesized that these bubbles were trav-
eling through exercise-inducible arteriovenous anastomoses
that were between 60 and 90 m in diameter. Their estimate of
the diameter of these vessels was based on the size of micro-
bubble that would have a survival time sufficient to traverse the
pulmonary circulation under high pressure and high flow con-
ditions (15, 30 –32). The current study supports our previous
hypothesis by directly demonstrating that there are intrapul-
monary arteriovenous vessels with functional diameters 50
m in both healthy human lungs and baboons. Most likely, our
estimate of the percentage of microspheres able to traverse the
pulmonary circulation represents a minimum shunt fraction.
Indeed, with the increased pulmonary pressures and flows
associated with exercise, it is likely that more, and potentially
larger, intrapulmonary arteriovenous pathways would be re-
cruited.
We have previously hypothesized that blood traveling
through intrapulmonary arteriovenous anastomoses during ex-
ercise would add to the venous admixture and negatively
impact gas exchange inefficiency (5, 13, 22). Stickland et al.
(22) demonstrated a good correlation between the alveolar-to-
arterial oxygen difference and the onset of intrapulmonary
shunt as detected by saline contrast echocardiography. Indeed,
during heavy exercise, a shunt percentage as small as 1–2% of
cardiac output would have a significant effect on gas exchange
(5, 6, 13). In the current study, the amount of microspheres
passing through the isolated lung was 1%. Importantly, the
experimental conditions we used for our isolated ventilated and
perfused lung studies are significantly different from the con-
ditions the lung endures during exercise. Our data demonstrate
that pressures and flows obtained in the isolated, ventilated,
and perfused lung, which mimic zone I and II conditions at
peak inspiration, are sufficient to open some of these pathways.
It is likely that the greater pulmonary pressures and flows
achieved during whole body exercise would create conditions
that would recruit more of these pathways, because their
patency is likely flow and/or pressure dependent (22).
Non-gas exchange consequences of arteriovenous anasto-
moses. In addition to contributing negatively to pulmonary gas
exchange, these pathways would impact the lung’s role as a
biological filter. The importance of the lung’s role as a biolog-
ical filter becomes apparent when this filter is bypassed, as in
the case of an intracardiac shunt (patent foramen ovale, PFO),
or when the filter becomes compromised, as in the case of
intrapulmonary shunting caused by a disease process such as
hereditary hemorrhagic telangiectasia (HHT). For example, it
is well known that patients with either a PFO or HHT are more
susceptible to embolic stroke and neurological symptoms (4, 9,
11, 18). Furthermore, recent work has linked intrapulmonary
shunting and migraine headaches (23). Although the vessels
described in this report can only be estimated at slightly 50
m in functional diameter and therefore may not be able to
pass millimeter-sized emboli, recent studies in the rat demon-
strate neurological impairment from microemboli less than 100
m (19).
To summarize, we have demonstrated here that intrapulmo-
nary arteriovenous pathways exist in healthy human and ba-
boon lungs under physiological conditions. These pathways
were found to have a functional diameter 50 m in diameter,
indicating that these vessels are not capillaries. If blood flow-
ing through these conduits did not participate in gas exchange
and was 1–3% of cardiac output, the efficiency of pulmonary
gas exchange would be reduced, particularly under conditions
such as exercise. These vessels were functional under physio-
logical perfusion and ventilation pressures, but clearly, the
conditions required to open these pathways have yet to be fully
elucidated.
ACKNOWLEDGMENTS
We thank Dr. Rob Conhaim and Kal Watson for help setting up the
perfusion system in our lab. We also thank Dr. Rudolf Braun, Dr. Robert Love,
and Dr. Takushi Kohmoto for invaluable assistance.
GRANTS
Support for this project was provided by National Heart, Lung, and Blood
Institute (NHLBI) Grant HL-15469, a Grant-in-Aid from the American Heart
Association 0550176Z, and the Department of Pediatrics, University of Wis-
consin Medical School. A. T. Lovering was supported by a NHLBI Training
Grant T32 HL-07654.
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H1781INTRAPULMONARY ARTERIOVENOUS ANASTOMOSES IN HEALTHY LUNGS
AJP-Heart Circ Physiol VOL 292 APRIL 2007 www.ajpheart.org
by 10.220.33.4 on September 2, 2017http://ajpheart.physiology.org/Downloaded from
... The previous literature reports shown, transpulmonary passage of small and moderate contrast bubbles may be traveling through larger-diameter vessels. There is direct evidence that these larger-diameter (>25-50µm) intrapulmonary arteriovenous anastomoses exist in healthy human, baboon, and dog lungs (34). Furthermore, Stickland et al. have directly demonstrated that these pathways are dormant at rest in healthy dogs but open up during exercise. ...
Article
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Objective Traditional metal alloy occluders for the closure of patent foramen ovale (PFO) may be associated with some potential complications, and may restrict the trans-septal access to the left atrium for future treatment of left-sided heart disease. Increasing attention has been paid to novel biodegradable occluders (NBOs) to achieve PFO closure. We aimed to evaluate the role of transesophageal echocardiography (TEE) in the diagnostic and anatomical evaluation of PFO, as well as in the Post-procedural assessment after transcatheter closure with a NBO.Methods We conducted a prospective, single-center clinical study of 44 patients who were diagnosed with PFO by contrast transthoracic echocardiography (c-TTE) and TEE from June 2019 to June 2020. All patients underwent PFO occlusion with NBO under TTE guidance. Follow-up was performed at 2 days and 3 months after the procedure with TTE, and at 6 months and 1 year after the procedure with c-TTE, TTE, and TEE.ResultsInterventional treatment was successfully performed in all patients. The left and right sides of the occluder device disc were significantly reduced at 3, 6, and 12 months compared to 2 days after the procedure (all P < 0.01), and decreased gradually. The thickness was significantly reduced at 12 months compared to the first three time points (all P < 0.01). Thrombus was found on the surface of the occluder device in three patients (6.4%) at 3 and 6 months after occlusion. At 6 months after procedure, there were 3 (6.8%) cases of extensive residual right-to-left shunt (RLS), 2 (4.5%) cases of moderate shunt, and 7 (15.9%) cases of small shunts. One year after procedure, 2 (4.5%) cases had a extensive residual shunt, 6 (13.6%) cases of small shunts were confirmed to originate from pulmonary veins by TEE, and the PFO-RLS occlusion rate reached 95.5%.Conclusion This study demonstrates the feasibility, safety, and effectiveness of NBO for the closure of PFO in humans, with a high rate of complete shunt closure. Accurate TEE assessment of the PFO anatomy before closure with NBO is important to ensure that the procedure remains safe and effective. Furthermore, TEE plays a crucial role in the Post-procedure follow-up.
... Mais il existe également des shunts intra-pulmonaires qui s'ouvrent parfois uniquement à l'effort, et dans ce cas, le lit capillaire est directement court-circuité par une communication entre artère et veine pulmonaire. L'existence d'un tel phénomène a été montré chez l'Homme (Tobin 1966;Lovering et al. 2007). En revanche, le débat concernant l'implication des shunts dans le trouble des échanges gazeux est toujours d'actualité et aucun consensus n'a été établi (Hopkins et al. 2009a(Hopkins et al. , 2009bLovering et al. 2009aLovering et al. , 2009bJones 2009). ...
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L’hypoxémie induite à l’exercice (HIE) est un phénomène qui est caractérisé par une chute de pression et de saturation artérielle en oxygène. La HIE touche les athlètes d'endurance. A force d’entrainement, les limites des systèmes cardiaque et musculaire sont repoussées et celles du système pulmonaire apparaissent. La prévalence de la HIE est de plus de 70% chez les athlètes lors d’un effort de course à pied. Or, les athlètes d’endurance sont les plus susceptibles de performer en altitude que ce soit dans le cadre d’une compétition, d’une préparation ou d’un stage d’entrainement. La chute de la pression atmosphérique rencontrée lors de l’élévation de l’altitude entraine une diminution de la quantité d’oxygène dans l’organisme qui constitue un vrai stress, le stress hypoxique. Pour faire face à ce dernier, l’organisme met en place une série d’adaptations visant à maintenir un apport en oxygène suffisant pour les organes. Lors d’un exercice au niveau de la mer les athlètes HIE atteignent les mêmes consommations maximales d’oxygène que les non-HIE, en revanche l’environnement délétère pour la performance que représente l’altitude, pourrait avoir de plus lourdes conséquences sur les athlètes HIE. Les effets de la HIE et de l’altitude pourraient se potentialiser et accroitre la réduction de la disponibilité de l’oxygène dans l’organisme. L’objectif de ce projet est de tester l’hypothèse que les réponses à l’exercice au niveau de la mer et en altitude sont différentes entre des athlètes HIE et non-HIE. Pour cela nous avons étudié les réponses à l’exercice en normoxie et après une exposition à l’altitude modérée aiguë (de quelques minutes à quelques heures) et prolongée (après 5 jours). La première étude montre une augmentation de la désoxygénation cérébrale et une diminution de l’oxygénation musculaire lors de l’exercice en normoxie, ainsi qu’une inadaptation lors de l’effort en hypoxie aiguë aux niveaux musculaire et cérébral. Les études 2 et 3 rapportent des réponses spécifiques à l’exercice, mais également au repos, lors des cinq premiers jours d’exposition en altitude. En effet, dès le repos les athlètes HIE ont des saturations en oxygène plus basses que les athlètes contrôles. Malgré la persistance de la HIE, des mécanismes compensatoires semblent être mis en place aux niveaux cérébral et cardiaque, éventuellement médiés par une balance pro-antioxydant différente. Ces derniers permettent l’atteinte de performances similaires au groupe contrôle après 1 et 5 jours d’exposition. L’étude 4 montre que la viscosité sanguine et l’hémodynamique pulmonaire ne sont pas impliquées dans la chute de saturation de repos plus prononcée des athlètes EIH au cours de l’exposition en altitude. L’étude 5 semble indiquer une réponse vasodilatatrice spécifique chez les athlètes HIE au niveau de la mer et après 5 jours en altitude. Il ressort de ce travail de thèse que la HIE réduit la performance en hypoxie aiguë et entraine des réponses spécifiques à l’exercice en normoxie et en hypoxie, sans doute dans le but de contrebalancer la chute de saturation en oxygène. Il est donc primordial de prendre en compte ce phénomène pour la performance en hypoxie, et d’étudier et comprendre ses interactions avec les différentes modalités d’entrainement, notamment en altitude.
... The vascular endothelial cells (arrowheads) express a strong reactivity to 5-HT anastomotic vascular devices have been demonstrated in various systemic vascular beds (Mokthar and Abd-Elhafez 2015; Fath-Elbab and Abou-Elhamd 2016; Hussein and Hassan 2018). Intrapulmonary AVAs have been recognized in fetal and adult human lungs since many years ago (Tobin 1966;Lovering et al. 2007aLovering et al. , 2007b as well as in the lungs of animals (Stickland et al. 2007;Mohammaden 2009). AVAs included simple bridge-like anastomotic vessels (direct arteriovenous shunts) and glomus organs of typical structure. ...
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The present study intended to describe in detail the several blood vessels harboring special regulatory devices in rabbit's pulmonary tissue using light and electron microscopy and immuno-histochemistry. Numerous throttle arteries were recorded within the adventitia of the segmental and sub-segmental bronchi and within pulmonary pleura. These arteries showed characteristic narrow or obliterated lumens and some of them bear longitudinal muscular intimal bolsters. For the first time, TEM revealed some structural modifications of the vascular endothelial cells of these arteries indicating that they become more activated to perform some additional functions. Arteriovenous anastomoses (AVAs) including direct shunt vessels and glomus organs were also recognized. Direct arteriovenous shunts appeared as small connecting devices communicating between small arteries and small veins while glomus organs consisted of the tortuous glomus vessels and the related afferent and efferent vessels. Several arteries and veins showing unique unusual structural characteristics were also described. For the first time, serotonin (5-HT) was strongly expressed in the vascular endothelium and muscle fibers of throttle arteries, in glomus cells of the glomus vessels, and in vascular endothelium of some veins and venules of special structure. The exact role of 5-HT is still unknown and further investigations are required to determine the types and distribution of 5-HT receptors present in these vascular devices. We concluded that these special vascular devices can play a critical role in controlling blood flow and pressure in the peripheral pulmonary circulation; however, the exact physiological mechanisms by which they work or are controlled remain unknown providing a ripe area for further investigation.
... The IPAVAs are dynamic preformed vascular conduits that have the function of avoiding excessive flow and pressure increases in the pulmonary microcirculation during exercise [30], following acute pulmonary embolism [31] and in response to hypoxia [32] in order to minimize the negative effects of PH on the capillary bed and reduce RV afterload [16]. Large diameter IPAVAs are known to exist in many species including humans [33,34] and dogs [15,16,31]. The presence of IPAVAs can be demonstrated by the SCE test [15,16,34,35]. ...
... The IPAVAs are dynamic preformed vascular conduits that have the function of avoiding excessive flow and pressure increases in the pulmonary microcirculation during exercise [30], following acute pulmonary embolism [31] and in response to hypoxia [32] in order to minimize the negative effects of PH on the capillary bed and reduce RV afterload [16]. Large diameter IPAVAs are known to exist in many species including humans [33,34] and dogs [15,16,31]. The presence of IPAVAs can be demonstrated by the SCE test [15,16,34,35]. ...
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Background Angiostrongylus vasorum is a nematode living in the pulmonary arteries of canids. Infected dogs develop severe pulmonary lesions which can potentially lead to pulmonary hypertension (PH). However, reports of PH in natural infected dogs are scant. One of the possible causes of the low prevalence of PH in A. vasorum-infected dogs could be the establishment of large diameter intrapulmonary arteriovenous anastomoses (IPAVAs), which attenuate pulmonary vascular resistance, thus reducing the pulmonary arterial pressure. The present report describes the pulmonary arterial pressure (PAP) response to A. vasorum natural infection in two dogs, assessed by echocardiography and by the saline contrast echocardiographic test (SCE). Results Both dogs showed clinical signs of respiratory disease. At presentation, case 1 did not show echocardiographic signs of PH and the SCE test was positive proving the presence of IPAVAs. However, at the follow-up visit, despite A. vasorum infection resolution, the same dog showed PH and the SCE test resulted negative, which ruled out the presence of IPAVAs. Case 2 suffered from severe pulmonary arterial hypertension and right-side congestive heart failure since the day of presentation. Saline contrast echocardiography was negative both at the time of presentation and at the follow-up visit. Conclusions In the two cases described above, the PH was not associated with IPAVAs. During A. vasorum infection, IPAVAs recruitment mechanism is able to contrast the rise of PAP until a certain level. It probably represents an initial escape mechanism of PH that, over time, exhausts its compensatory capacities allowing PAP to rise and to be detectable on echocardiography.
... Presence of right and left SVC is marked R and L, and bridging veins are denoted by the white arrow (D). Shah et al.Although the actual size of saline contrast microbubbles is not known, they are suspected to be in the range of 60 to 90 mm in diameter(22), whereas the pulmonary capillaries measure 8 to 9 mm at rest(23).Experiments using 25-to 50-mm microspheres injected in healthy human donor lungs without known PAVM demonstrated the availability of arteriovenous pathways >50 mm in two-thirds of the lungs (22), adequate enough to result in mildly positive results on ASCI (<10 bubbles). Normal human lungs are also reported to have larger caliber pulmonary arteriovenous anastomoses that bypass pulmonary capillaries (24). ...
Article
Objectives: The aim of this study was to assess the incidence of persistently positive results on agitated saline contrast injection after patent foramen ovale (PFO) closure, the underlying mechanism, and management. Background: Transcatheter intervention to close a PFO is reasonable in highly selected patients younger than 60 years, after a thorough cardioneurological investigation following a cryptogenic stroke, particularly in the presence of thromboembolic disease or in patients at high risk for venous thrombosis. The U.S. Food and Drug Administration approved the Amplatzer PFO Occluder in October 2016 for such an indication. Confirmation of PFO closure is usually verified by an agitated saline contrast injection during an echocardiographic examination. The appearance of bubbles in the left atrium raises the concern of incomplete closure or other sources of shunting. Methods: The medical records and echocardiograms of patients who were treated with transcatheter closure of a PFO for cryptogenic stroke were reviewed. Results: From January 1998 through December 2015, 880 patients were taken to the catheter laboratory for PFO closure, of whom 568 patients, 320 men (56.3%), underwent transcatheter closure of a PFO using an Amplatzer PFO Occluder, at a mean age of 48.1 ± 12.9 years. The incidence of right-to-left shunting (RLS) was 19.5% at a mean of 4 months' follow-up, which reduced to 8.4% at 11 ± 2 months. Sources of RLS were identified in 10 (1.8%); pulmonary arteriovenous malformation (n = 4) was the most common etiology, followed by leak through the device (n = 3). All patients with additional sources of RLS were treated percutaneously. At 2-year follow-up, 16 patients (2.8%) persisted with only mildly positive results on agitated saline contrast injection, without an apparent additional source of shunting. Conclusions: Coexistence of a PFO and an additional lesion responsible for RLS is uncommon, but not rare; the majority are amenable to transcatheter or surgical intervention.
Article
Background: Right-to-left shunts (RLS) are prevalent in patients with chronic obstructive pulmonary disease (COPD) and might exaggerate oxygen desaturation, especially at altitude. Aim: To study the prevalence of RLS in patients with COPD traveling to altitude and the effect of preventive dexamethasone. Methods: Lowlanders with COPD, GOLD 1-2, oxygen saturation (SpO2) >92%, were randomized to dexamethasone (4 mg, bid) or placebo, starting 24 h before ascent from 760 m and while staying at 3,100 m for 48 h. Saline contrast echocardiography was performed at 760 m and after the first night at altitude. Results: Of 87 patients (81 men, mean ±SD age 57 ±9 y, FEV1 89 ±22 % pred, SpO2 95 ±2 %) 39 were assigned to placebo, 48 to dexamethasone. In the placebo group, 19 patients (49%) had RLS, of which 13 intracardiac. In the dexamethasone group 23 patients (48%) had RLS, of which 11 intracardiac (p=1.0 vs. dexamethasone). 11 patients receiving placebo and 13 dexamethasone developed new RLS at altitude (p=0.011 both changes, p=0.411 between groups). RLS prevalence at 3,100 m was 30 (77%) in the placebo and 36 (75%) in the dexamethasone group (p=ns). Development of RLS at altitude could be predicted at lowland by a higher resting pulmonary artery pressure, a lower paO2 and a greater oxygen desaturation during exercise but not by treatment allocation. Conclusion: Almost half of lowlanders with COPD revealed RLS near sea level and this proportion significantly increased to about 3/4 when traveling to 3,100 m irrespective of dexamethasone prophylaxis.
Article
Background: Perfusion of intrapulmonary arteriovenous anastomoses (IPAVA) is increased during exercise and in hypoxia and is associated with variations in oxygen saturation (SPO2), resulting in blood bypassing the pulmonary microcirculation. Sildenafil is a pulmonary vasodilator that improves SPO2 and endurance performance in hypoxia. The purpose of this study was to determine if 50 mg sildenafil would reduce IPAVA perfusion (QIPAVA) and if the decrement in maximal exercise capacity (VO2max) in hypoxia is related to QIPAVA. We hypothesized that during progressive levels of hypoxia at rest (FIO2 = 0.21, 0.14, 0.12), sildenafil would increase SPO2 and reduce bubble score (estimate of QIPAVA) compared to placebo, and that the decrement in VO2max in hypoxia would be positively correlated with bubble score at rest in hypoxia. Materials and Methods: Fourteen endurance-trained men performed a graded maximal exercise test at sea level and at a simulated altitude of 3000 m, followed by two experimental visits where, after randomly ingesting sildenafil or placebo, they underwent agitated saline contrast echocardiography during progressive levels of hypoxia at rest. Results: All participants experienced a decrement in power output in hypoxia that ranged from 9% to 19% lower than sea level values. Compared to normoxia, bubble score increased significantly in hypoxia (p < 0.001) with no effect of sildenafil (p = 0.580). There was a negative correlation between SPO2 and bubble score (p < 0.001). The decrement in peak power output at VO2max in hypoxia was unrelated to IPAVA perfusion in resting hypoxia (p = 0.32). Several participants demonstrated QIPAVA greater than zero in room air, indicating that arterial hypoxemia may not be the sole mechanism for QIPAVA. Conclusion: These results indicate that the VO2max decrement caused by hypoxia is not related to QIPAVA and that sildenafil does not improve VO2max in hypoxia through modulation of QIPAVA.
Chapter
Pulmonary endothelial cells metabolize endogenous substances and xenobiotics via ectoenzymes on their luminal surface and caveolae as well as enzyme systems within the cytosol. Pulmonary metabolism results in the activation of several endogenous substances and medications of importance to the anesthesiologist. Pulmonary uptake is often not associated with metabolism, but still markedly affects pharmacokinetics by initially attenuating peak concentrations before ultimately returning the unchanged substance to the circulation. The lung’s ability to serve as a vascular reservoir is directly related to the capacitance of the pulmonary vessels. The lung serves as a physical filter, but this function may be compromised with high cardiac output and in several disease states. The respiratory epithelium’s functions include humidification and trapping of particles and pathogens. The airway surface film has antimicrobial capacity beyond its mechanical removal of debris from the airway.
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Exercise-induced arterial hypoxemia (EIAH) is characterized by the decrease in arterial oxygen tension and oxyhemoglobin saturation during dynamic aerobic exercise. Since the time of the initial observations, our knowledge and understanding of EIAH has grown, but many unknowns remain. The purpose of this review is to provide an update on recent findings, highlight areas of disagreement, and identify where information is lacking. Specifically, this review will place emphasis on (i) the occurrence of EIAH during submaximal exercise, (ii) whether there are sex differences in the development and severity of EIAH, and (iii) unresolved questions and future directions.
Chapter
Other segments of this text report on the development and manifold applications of contrast echocardiography. In view of recent emphasis on quantitation, this chapter will review a number of mechanisms believed to be associated with observed echo-contrast effects. Emphasis will be on miscellaneous illustrative theoretical and experimental studies of gaseous microbubble dynamics in fluids and interactions of such bubbles with an ultrasound field.
Chapter
MucusCartilageMuscleBronchiole-alveolar communicationsThe respiratory surfaceThe “senile lung”Blood vesselsAnastomosesLymphaticsReceptorsPostscript
Article
1. Anhand von 181 lckenlosen Schnittserien durch Lungenstcke gesunder Menschen wurden die Blutgefverhltnisse der menschlichen Lunge untersucht. Korrosionsprparate wurden ebenfalls beigezogen. 2. In der menschlichen Lunge kommen folgende Blutgefanastomosen vor:a) Zahlreiche arterio-arterielle bronchiale Anastomosen verbinden die parallel verlaufenden ste der A. bronchialis. b) Veno-vense bronchiale Anastomosen verbinden die greren Bronchialvenen zum Plexus venosus peribronchialis. c) Vereinzelte arterio-vense bronchiale Anastomosen ermglichen einen Kurzschlukreislauf von der A. zur V. bronchialis. d) Arterio-arterielle bronchopulmonale Anastomosen leiten Blut aus der A. bronchialis in die ste der A. pulmonalis. 22 solche Anastomosen fanden sich im Bereich kleiner peripherer Bronchen, whrend zwei weitere in der Pleura lokalisiert waren. Gre, Wandbau, Lnge und Verlauf dieser Anastomosen variieren auerordentlich stark. In bezug auf ihre Hufigkeit lt sich nichts Endgltiges aussagen. Auf Grund verschiedener Kriterien ist anzunehmen, da die bronchopulmonale Stromrichtung gegenber der pulmobronchialen den Vorzug hat. e) Veno-vense bronchopulmonale Anastomosen leiten das Blut aus dem Plexus venosus peribronchialis, der keine eigenen greren Sammelgefe besitzt, in die V. pulmonalis ab. Diese Anastomosen stellen eine Manahme im Sinne der konomie der Strombahn dar und sind wenigstens zum Teil fr das Zustandekommen des Sttigungsdefizits des Arterienblutes verantwortlich. f) Anderseits mnden zahlreiche Venulae pulmonales als veno-vense pulmobronchiale Anastomosen in den Plexus venosus peribronchialis ein. 3. Die Aa. pulmonales sind Endarterien, die Vv. pulmonales Endvenen; es besteht keine Mglichkeit fr die Ausbildung eines Kollateralkreislaufs. Auerdem knnen keine prkapillren arterio-vensen pulmonalen Anastomosen nachgewiesen werden, welche zur Umgehung des Alveolarkapillarnetzes in Frage kmen. 4. Im Bereich der Bronchiolen lassen sich die verschiedenen Lungengeftypen nicht voneinander abgrenzen. Wir finden ein undifferenziertes Gefgeflecht, welches stark an die Verhltnisse whrend der Entwicklung der Lungengefe aus einem einheitlichen Gefgeflecht erinnert. 5. Die physiologische, pathologische und pathophysiologische Bedeutung der nachgewiesenen Blutgefanastomosen der Lunge werden diskutiert.
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A highly resolved primate cladogram based on DNA evidence is congruent with extant and fossil osteological evidence. A provisional primate classification based on this cladogram and the time scale provided by fossils and the model of local molecular clocks has all named taxa represent clades and assigns the same taxonomic rank to those clades of roughly equivalent age. Order Primates divides into Strepsirhini and Haplorhini. Strepsirhines divide into Lemuriformes and Loriformes, whereas haplorhines divide into Tarsiiformes and Anthropoidea. Within Anthropoidea when equivalent ranks are used for divisions within Platyrrhini and Catarrhini, Homininae divides into Hylobatini (common and siamang gibbon) and Hominini, and the latter divides into Pongina forPongo(orangutans) and Hominina forGorillaandHomo. Homoitself divides into the subgeneraH.(Homo) for humans andH.(Pan) for chimpanzees and bonobos. The differences between this provisional age related phylogenetic classification and current primate taxonomies are discussed.
Article
To determine and compare the prevalence of patent foramen ovale in patients with stroke of undetermined origin (cryptogenic) and in patients with stroke of determined origin to assess the possible role of patent foramen ovale as a risk factor for cryptogenic stroke. Cross-sectional study with nested case-control analysis. A total of 146 patients (73 men, 73 women) with acute ischemic stroke referred to the echocardiography laboratory for evaluation. Neurovascular Unit and Echocardiography Laboratory, Columbia-Presbyterian Medical Center, New York, New York. Patients were considered to have strokes of determined origin or cryptogenic strokes according to National Institute of Neurological Disorders and Stroke (NINDS) Stroke Data Bank criteria. The presence of patent foramen ovale was assessed by contrast echocardiography, performed blinded for type of stroke. The association between patent foramen ovale and type of stroke was tested after correcting for patients' demographic variables and stroke risk factors. The overall prevalence of patent foramen ovale was 26 of 146 patients (18%; 95% Cl, 11.4% to 24.6%). Patients with cryptogenic stroke (31%) had a significantly higher prevalence of patent foramen ovale than did patients with an identifiable cause of stroke (69%) in both the younger (less than 55 years; 48% compared with 4%; P less than 0.001) and the older (greater than or equal to 55 years; 38% compared with 8%; P less than 0.001) age groups. Multiple logistic regression analysis was used to identify the presence of a patent foramen ovale as strongly associated with the diagnosis of cryptogenic stroke (odds ratio, 7.2; Cl, 2.4 to 21.7), irrespective of patient age and other stroke risk factors. Patients with cryptogenic stroke have a higher prevalence of patent foramen ovale than patients with stroke of determined cause in all age groups, even after correcting for the presence of recognized stroke risk factors. This identifies patent foramen ovale as a risk factor for cryptogenic stroke. Regardless of patient age, contrast echocardiography should be considered when the cause of stroke is unknown.
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This article has summarized the liver-lung relationships from a clinical perspective. The physiology, biochemistry, and molecular biology that link the two organs are of great importance in that many disorders described affect young patients. Indeed, pulmonary abnormalities in patients with hepatic disorders are frequent, and both the pulmonary and hepatic problems may be reversible in the current era of organ transplantation.
Article
The cause of ischemic stroke in younger adults is undefined in as many as 35 percent of patients. We studied the prevalence of patent foramen ovale as detected by contrast echocardiography in a population of 60 adults under 55 years old with ischemic stroke and a normal cardiac examination. We compared the results with those in a control group of 100 patients. The prevalence of patent foramen ovale was significantly higher in the patients with stroke (40 percent) than in the control group (10 percent, P less than 0.001). Among the patients with stroke, the prevalence of patent foramen ovale was 21 percent in 19 patients with an identifiable cause of their stroke, 40 percent in 15 patients with no identifiable cause but a risk factor for stroke, such as mitral valve prolapse, migraine, or use of contraceptive agents, and 54 percent in 26 patients with no identifiable cause (P less than 0.10). These results suggest that because of the high prevalence of clinically latent venous thrombosis, paradoxical embolism through a patent foramen ovale may be responsible for stroke more often than is usually suspected.