(Stroke. 1998;29:1014-1019.)
© 1998 American Heart Association, Inc.
Anticardiolipin Antibody Aggravates Cerebral Vasospasm After Subarachnoid Hemorrhage in Rabbits
Hiroaki Nomura, MD;
Yutaka Hirashima, MD;
Shunro Endo, MD;
Akira Takaku, MD
From the Department of Neurosurgery, Toyama Medical and Pharmaceutical
University, Toyama, Japan.
Correspondence to Hiroaki Nomura, MD, Department of Neurosurgery, Toyama Medical and Pharmaceutical University, Sugitani 2630, Toyama, Toyama 930–01, Japan.
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Abstract
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Background and Purpose—We previously
reported that patients with antiphospholipid antibodies (aPLs)
frequently demonstrate cerebral infarction due to cerebral vasospasm
after subarachnoid hemorrhage (SAH). To examine the
participation of aPLs in the pathogenesis of vasospasm after SAH, we
studied the relationships of aPLs and SAH in an animal model.
Methods—SAH was produced in 34 rabbits that received two
subarachnoid injections of autologous arterial
blood. The animals were divided into four experimental groups: SAH was
induced in group A (n=9), intracutaneous injection of cardiolipin (CL)
was performed before the induction of SAH in group B (n=5),
intravenous injection of CL was performed before SAH in
group C (n=12), and cyclosporin A was infused intravenously
after the intravenous injection of CL and induction of SAH
in group D (n=8). Enzyme-linked immunosorbent assay identifying the
titer of IgG CL antibodies, neurological evaluation, cerebral
angiography, and histological examination were
performed in all four groups.
Results—A significant elevation of anti-CL antibodies,
aggravation of neurological deficit, and reduction of caliber of the
basilar artery were observed in rabbits that received the
intravenous immunization of CL (group C). The
administration of cyclosporin A reduced the titer of anti-CL antibody,
aggravation of neurological deficit, constriction of basilar artery,
and the incidence of cerebral infarction (group D).
Conclusions—Anti-CL antibodies may therefore be involved in the
deterioration of cerebral vasospasm after SAH.
Key Words: antibodies, anticardiolipin • cyclosporin • cerebral ischemia, transient • subarachnoid hemorrhage • rabbits
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Introduction
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The pathogenesis of
cerebral vasospasm after SAH is not fully understood, but attention has
been focused on the roles of inflammation and immunologic
reaction.1 2 3 Severe inflammation and
vasoconstriction were observed after the subarachnoid injection
of latex beads3 or talc4 in
experimental models. The activation of complement components C3a and
C4a in cerebrospinal fluid and plasma5 and
deposition of IgG in the arterial
wall6 have been reported in respect to the
relationship between humoral immunity and cerebral vasospasm. Neopterin
concentrations that reflect T-cell macrophage activation were
observed to be elevated in cerebrospinal fluid, which supports a
relationship between cellular immunity and cerebral
vasospasm.7 Experimental and clinical studies
have thus been performed to evaluate the efficacy of immunosuppressive
agents such as steroids8 9 10 11 and cyclosporin
A12 13 in preventing cerebral vasospasm after
SAH.
aPLs, including the biologic false-positive serologic test for
syphilis (BFP-STS), LA, aCLs,14 15 and others,
often cause thrombotic events.16 17 18 19 The
mechanism of thrombotic events caused by aPLs remains obscure. It is
suspected that they interfere with the production or release of
prostaglandin I2 by vessel wall
endothelial cells. Such an inhibition of
prostaglandin I2 production
and release could explain the recurrent thrombotic events seen in patients who have
received LA.20 LA may also reduce the
activation of protein C on the endothelial surface
by interfering with the thrombin-thrombomodulin
complex.21 22 This could also result in the loss
of regulation in the procoagulant-anticoagulant system. Recurrent
thromboembolism could also be due to the inhibitory
activity of LA on prekallikrein and antithrombin
III.23 24
We recently reported that patients who suffered cerebral
infarction due to vasospasm after SAH demonstrated the presence of aPLs
in the period of vasospasm.25 26 To investigate
the association between aPLs and cerebral vasospasm, we introduced
experimental SAH using rabbits that were immunized by CL, and we then
evaluated their neurological symptoms, cerebral angiography, and
histology. We attempted to evaluate the effect of immunosuppressive
agents that restrain the production of antibodies on the
occurrence of vasospasm after SAH.
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Materials and Methods
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Animal Preparation
Female rabbits weighing 2.5 to 3.0 kg each were used in this
study. All surgical and angiographic procedures were performed with
anesthesia induced intramuscularly with ketamine
hydrochloride (50 mg/kg). All protocols were approved by the Animal
Ethics Committee of the Toyama Medical and Pharmaceutical University.
Five weeks before the planned induction of SAH, each rabbit was placed
in the supine position with the head fixed so that the orbitomeatal
line was horizontal. With a sterile technique, a midline cervical
incision was made, the bilateral carotid arteries were isolated, and
the common carotid arteries were ligated at the carotid artery
bifurcation. Only rabbits that were asymptomatic 2 weeks
after this carotid artery ligation were subjected to experimental SAH.
Aortovertebral angiography was performed by manual injection of 7 mL
ioxaglate (Hexabrix) into a catheter inserted retrogradely through the
carotid stump into the aortic arch. An anteroposterior film obtained
during the arterial phase 5 weeks after the carotid artery
ligation and before the first SAH was used as a baseline. Repeated
angiographic procedures were performed on day 4, ie, 2 days after the
second SAH, and on days 7 and 14.
Preparation of Immunizing Antigen
CL antigen suspension, consisting of CL (Sigma Chemical Co),
lecithin (Sigma), and cholesterol (Wako Pure Chemical
Industries, Ltd) in the ratio of 1:10:30 (wt/wt/wt), was prepared
according to the Venereal Disease Research Laboratory microflocculation
technique.27 Ten milliliters of this suspension
was mixed with 30 mL of 0.1% methylated BSA (Sigma) and allowed to
stand at 4°C overnight. The mixture was centrifuged at
13 300g (0°C) for 1 hour and washed twice with cold
saline, suspended in 2 mL of saline, and injected into animals. The CL
antigen suspension described above was centrifuged before it
was mixed with the methylated BSA solution. The CL antigen precipitate
thus obtained was resuspended in methylated BSA solution, stored
overnight at 4°C, and then used for
injection.28
Experimental Groups
The animals were divided into four experimental groups. In group
A (n=9), SAH was induced 5 weeks after the carotid artery ligation. In
group B (n=8), a freshly prepared suspension of antigens with Freund's
adjuvant was injected into rabbits intracutaneously once a week for 3
weeks before the induction of SAH, with each rabbit receiving a total
of 0.9 to 1.8 mg CL. In group C (n=12), a freshly prepared suspension
of antigens was injected into rabbits intravenously every
other day for 3 weeks until the day before the induction of SAH, with
each rabbit receiving a total of 3 to 6 mg CL. In group D (n=8), after
the intravenous injection of antigens and the induction of
SAH, 6.0 mg/kg cyclosporin A (Sandimmune IV, Sandoz Inc) with 0.3 mg/kg
dexamethasone sodium phosphate as an adjunct low-dose
steroid was infused intravenously from 14 hours before the
second experimental SAH to day 7, according to the therapeutic regimen
described by Peterson et al.13
Method of Subarachnoid Injection
The animals were operated on in random order. They were placed
in the prone position with the head down. With a sterile technique, a
1.5-cm vertical suboccipital incision was made to expose the
craniospinal junction. Each rabbit received two subarachnoid
injections 48 hours apart, ie, the first injection on day 0 and the
second on day 2. A No. 26 needle inserted into the cisterna magna was
used for the injection of autologous arterial blood. Manual
injection was performed over a 2-minute period, with 0.5 mL/kg of blood
used for the first and second SAH. During this procedure spontaneous
respiration was maintained, and both
PaCO2 and blood pressure were
monitored. The PaCO2 was 35 to
45 mm Hg, and the mean arterial blood pressure before
the induced SAH was 85 to 105 mm Hg in all animals. After the
subarachnoid injection, a dramatic increase in systemic blood
pressure occurred. Within 5 minutes, however, the blood pressure
gradually returned to the preinjection level.
aCL-IgG
aCLs were identified by means of a sandwich-type enzyme-linked
immunosorbent assay that identifies IgG CL antibodies. Polystyrene
microtiter plates (96-well plates, Immulon-2; Dynatech Laboratories)
were coated with 50 µL (10 µg/mL) CL. Serum samples diluted 1:320
in 0.1% egg albumin in PBS were added to the wells for 2 hours
at room temperature. The plates were washed with 0.1% egg
albumin in PBS three times and incubated for 2 hours with a
1:1000 anti-rabbit IgG antibody that conjugated with alkaliphosphatase
(Vector Laboratories Inc) at room temperature. After six washes in
0.1% egg albumin in PBS, 100 µL of p-nitrophenyl
phosphate (1 mg/mL in 10% diethanolamine) was added to each well,
followed by incubation for 1.5 hours at room temperature. After
termination of the reaction by addition of 3N NaOH, optimal density at
405 nm (OD405) was measured with an enzyme-linked
immunosorbent assay microtiter reader. The OD405
of the sera of 20 untreated rabbits was measured, and mean+3 SD was
determined as the normal range.
In this study polyclonal antibodies were produced by injecting CL. Two
different types of aCLs have been
established29,30: one is induced by the aPL
syndrome and another by infectious diseases. To determine which type of
antibody was mainly produced in our study, the titers of aCLs were
measured in the presence of
ß2-glycoprotein 1. Wells to which
sera of day 4 in group C were added were incubated with 50 µL of
0.1% egg albumin containing 12.5 µg/mL human
ß2-glycoprotein 1 (Serbio
Laboratory) for 2 hours at room temperature, and the change of the
titer of antibody was estimated.
Neurological Examination
Neurological examination was performed before SAH and daily
thereafter until the animals were killed. Rabbits were observed on a
flat surface, and neurological status was graded according to a
four-point system reported previously31: grade 1
denotes no neurological deficit (normal); grade 2, minimal or suspected
neurological deficit; grade 3, mild neurological deficit without
abnormal movements; and grade 4, severe neurological deficit with
abnormal movements.
Evaluation of Caliber of Cerebral Arteries
The diameter of the basilar artery was measured blindly from the
angiograms with a technique similar to that described
previously.31 The average of three measurements
was expressed as the percent reduction from the baseline diameter.
Histological Examination
The rabbits were killed on day 14 for
histological examination of the brain. The brains,
including five of the animals of group C that died between days 4 and
6, were fixed by perfusion with 4% paraformaldehyde in
0.1 mol/L phosphate buffer (pH 7.4). The brains were cut into coronal
slices and stained with hematoxylin and eosin. Ischemic lesions
were evaluated in a blinded manner with light microscopy.
Statistical Examination
The findings are reported as mean±SD. Data were
analyzed with the use of Student's t test or 1-way
ANOVA followed by Fisher's protected least-squares difference test for
multiple comparisons to compare the titer of aCL-IgG and the diameter
of basilar arteries. We also used Wilcoxon's U test
to compare the neurological grades and the 
2
test to compare the occurrence of cerebral infarction among these four
groups. A value of P<0.05 was accepted as significant.
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Results
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aCL-IgG
No difference of serum levels (OD405) of
aCL-IgG before the carotid artery ligation was observed among the four
groups (Fisher's test) (Table 1
). When
the normal range was determined as less than mean+3 SD, two animals
(6%) demonstrated an elevation of serum aCL-IgG without any
experimental stimulation. The aCL-IgG level of rabbits with carotid
ligation was not different from that of rabbits without (data not
shown). No significant elevation of the titer of the antibody was
observed for 14 days after only SAH (group A) compared with the value
before carotid ligation (Table 1). The immunization by intracutaneous
injection also induced no elevation of the antibody levels (group B),
but a significant elevation of the antibody was observed by
intravenous immunization on days 4 and 7 after SAH (group
C) (P<0.01, Fisher's test) (Table 1). However, the
intravenous immunization performed in this study could not
maintain the elevation of the antibody until day 14 (Table 1). The
administration of cyclosporin A reduced the intravenous
immunized aCL-IgG levels (groups C and D) (P<0.05,
Fisher's test) (Table 1). In group C animals that were immunized
intravenously, the serum level
(OD405) of aCL-IgG before the addition of
ß2-glycoprotein 1 was 0.22±0.33
(mean±SD), and that of aCL-IgG after the addition of
ß2-glycoprotein 1 was 0.42±0.42. A
significant elevation of OD405 was observed after
the addition of ß2-glycoprotein 1
(P<0.01, Student's t test).
Neurological Examination
A significant aggravation of neurological deficits was observed on
day 4 in animals that were immunized intravenously (group
C) compared with animals without immunization (group A)
(P<0.05, Wilcoxon's U test), although
no significant difference was observed between animals that were
immunized intracutaneously (group B) and group A (Table 2). Moreover, five rabbits in group C
died between days 4 and 6. The administration of cyclosporin A improved
the neurological deficit grade of animals that were immunized
intravenously (groups C and D) (P<0.05,
Wilcoxon's U test) (Table 2). There was no
difference of neurological deficit grade among the four groups on days
7 and 14 (data not shown). In the course of this study, three rabbits
of group B were dead before the induction of SAH because of infection
and pain.
Evaluation of Caliber of Cerebral Arteries
The mean basilar artery constriction rate on day 4 was
20.4±10.0% (mean±SD) (n=9) in animals without immunization (group
A), 23.3±10.4% (n=5) in animals with intracutaneous immunization
(group B), 31.7±8.9% (n=12) in animals with intravenous
immunization (group C), and 19.3±9.0% (n=8) in animals with the
administration of cyclosporin A after intravenous
immunization (group D). Significant differences between groups A and C
were noted (P<0.01, Fisher's test) as well as between
groups C and D (P<0.001, Fisher's test).
Intravenous immunization induced significant
vasoconstriction of the basilar artery on day 4, and this
vasoconstriction was prevented by the administration of cyclosporin A.
There was no significant difference among the four groups on days 7 and
14 (Figure).
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Figure 1. Reduction in the diameter of basilar artery. Significant
reduction in the basilar artery was observed in group C
(**P<0.01) compared with group A. Significant
improvement was observed in group D
(###P<0.001) compared with group C (1-way
ANOVA followed by Fisher's protected least-squares difference test).
Group A had only SAH; group B, intracutaneous immunization and SAH;
group C, intravenous immunization and SAH; and group D,
administration of cyclosporin A after intravenous
immunization and SAH.
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Histological Examination
In light microscopic examination, cerebral infarctions were
observed in 3 of the 9 rabbits in group A, 1 of the 5 in group B, and 8
of the 12 in group C. Animals with intravenous immunization
(group C) showed a somewhat higher incidence of cerebral infarction
than animals without immunization (group A); a significant difference
was not observed (Table 3). However, the
administration of cyclosporin A (group D) clearly reduced the incidence
of cerebral lesions that were induced by intravenous
immunization of CL (P<0.01, 2
test) (Table 3).
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Discussion
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Clinical and experimental findings have suggested a role of
immunologic reaction in the development of cerebral
vasospasm.1 2 3 We recently reported that the
outcome of symptomatic vasospasm patients was much worse in
the aPL-positive groups, ie, the LA and aCL-IgG patients, than in the
aPL-negative group, and we speculated that once symptomatic
vasospasm occurred, patients with aPLs frequently demonstrated cerebral
infarction, and their outcome was therefore
worse.25 To elucidate the
pathophysiological mechanism, we attempted to
establish a rabbit model with aCLs.
Although the OD405 did not increase in animals
with only SAH (group A) and those with intracutaneous immunization of
aCLs (group B), a significant elevation of OD405
was observed in rabbits with intravenous immunization
(group C) compared with group A. Rabbits with intravenous
immunization showed significant neurological aggravation and basilar
artery constriction on day 4 after SAH. Histologically,
ischemic changes were often observed in group C. Moreover, the
administration of cyclosporin A reduced the constriction rate of
basilar artery and the incidence of cerebral infarction. Cyclosporin A
is known to inhibit both humoral and cell-mediated
immunity,32 33 34 and it thus may have contributed
to the restraint of the production of the aCLs in the
present experiment. These results suggest that aCLs may play a role
in the pathogenesis of cerebral vasospasm.
The association of aPLs with thrombosis is well recognized. Although
the mechanism is not well understood, it may involve interference with
the procoagulant-anticoagulant system. LA also reacts with platelet
phospholipids.35 Platelets may be
activated and release vasoactive substances.
Endothelial damage and platelet activation may thus
be induced by aPLs. Therefore, the changes in the vessel wall
endothelium and in platelets during vasospasm may
be caused by aPLs. We reported previously that a reduction in
platelet count, increased platelet aggregability, and an
increased plasma PF4 concentration were observed in aPL-positive
patients with symptomatic
vasospasm.24
We were not able to determine whether the mechanism for vasospasm after
SAH might be related to aCLs. However, aCL-associated neurological
worsening after SAH may be due not only to arterial
constriction but also to impairment of microcirculation.
Microcirculation may be disturbed through the interaction of aPLs and
blood cells, including platelets. Increased aPLs in patients with
SAH may involve the same type of antibody as those of patients with aPL
syndrome. The processes or mechanisms of increased antibodies are still
unknown in patients with aPL syndrome, and elucidation will be helpful.
Experimental SAH in the present study did not introduce the
production of aCLs, and therefore we could not elucidate the
mechanism of the production of aCLs. However, aggravation of
neurological deficit and a reduction of the caliber of basilar artery
were observed in the presence of this antibody, and it is therefore
possible that aCLs are involved in the deterioration of cerebral
vasospasm.
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Selected Abbreviations and Acronyms
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| aCL |
= |
anticardiolipin antibody |
| aPL |
= |
antiphospholipid antibody |
| CL |
= |
cardiolipin |
| LA |
= |
lupus anticoagulant |
| OD405 |
= |
optimal density at 405 nm |
| SAH |
= |
subarachnoid hemorrhage |
|
Received May 19, 1997;
revision received February 17, 1998;
accepted February 19, 1998.
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Editorial Comment
R. Loch Macdonald, MD, PhD, Guest Editor
Section
of Neurosurgery,
University of Chicago Medical Center,
Chicago, Illinois
|
Introduction
|
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The aPL syndrome is a relatively common cause of an acquired
hypercoagulable state associated with cerebral ischemia and
infarction.1 aPLs are antibodies directed at phospholipids
and usually a protein cofactor. They include LA and aCLs. The latter
were found and were suggested to be the cause of ischemic
stroke in 10% of patients with first ischemic
stroke.1 Hirashima et al2 previously reported
that the presence of aPLs in patients with ruptured aneurysms
is an adverse prognostic factor for good outcome. Eleven (34%) of 32
patients with SAH tested positive for these antibodies, a rate that is
higher than would be expected in a random sample of the population or
of ischemic stroke patients and suggests that SAH caused or was
previously associated with aPLs. The antibodies disappeared 7 to 13
days after hemorrhage in some patients who first tested
positively for antibodies. Patients with aPLs were more likely to
develop cerebral ischemia and to have poor outcome.
In this experimental study, Nomura and colleagues raised aPLs in
rabbits and then subjected the animals to SAH by two injections of
blood into the cisterna magna. The vasospasm produced in this model
does not usually cause neurological deficit, but both cervical common
carotid arteries were ligated 5 weeks before the hemorrhage.
This would be expected to make brain blood supply more dependent on the
basilar artery that develops the most spasm in this model. It was found
that SAH itself did not induce the formation of aPLs. When such
antibodies were increased by immunization, however, the rabbits
developed more severe vasospasm and worsened neurological condition 4
days after SAH. There were no differences by 7 days after
hemorrhage. The findings are interesting and potentially
clinically relevant but must be regarded as preliminary at this point.
The blood injection models of SAH probably produce arterial
narrowing by the same set of common mechanisms that occur after clot
placement in other models or after SAH in humans, although it is the
opinion (albiet speculative) of this reviewer that the relative
importance of various mechanisms differs between models and that
inflammation may be relatively more important in rabbits and dogs than
in humans. The differences between groups were analyzed by
pairwise comparisons between multiple groups where analysis of
variance might have been more appropriate. The mechanism of the
beneficial effect of cyclosporin A and dexamethasone is not
worked out in these studies nor is the mechanism by which aPLs worsen
vasospasm. Dexamethasone could decrease vasospasm and
neurological deficits on the basis of an anti-inflammatory action in
this model.3 Cyclosporin A theoretically could worsen
vasospasm on the basis of its action as an inhibitor of
endothelium-dependent relaxation.4
Unfortunately, the studies of anti-inflammatory and immunosuppressive
agents in humans with SAH have been marred by high complication rates
and lack of demonstrated efficacy.5 One might have
expected that aPLs would worsen neurological condition in the rabbits
without affecting vasospasm, because they might be more likely to cause
arterial thromboses in narrowed vasospastic arteries. But
why would they increase the vasospasm? Furthermore, the 30% average
basilar artery diameter reduction that was seen in the group with SAH
and aPLs would not usually be associated with enough reduction in flow
to cause cerebral ischemia.
Treatments for patients with aPLs include antiplatelet and
anticoagulant drugs. The observation that patients who were taking
aspirin before SAH were less likely to develop cerebral infarcts might
support the hypothesis of these investigators.6 Certainly
other explanations are possible. In any case, the test to detect the
antibodies is simple, and the treatment probably carries little
risk. More studies should be performed to confirm the hypothesis.
|
Selected Abbreviations and Acronyms
|
|---|
| aCL |
= |
anticardiolipin antibody |
| aPL |
= |
antiphospholipid antibody |
| CL |
= |
cardiolipin |
| LA |
= |
lupus anticoagulant |
| OD405 |
= |
optimal density at 405 nm |
| SAH |
= |
subarachnoid hemorrhage |
|
Received May 19, 1997;
revision received February 17, 1998;
accepted February 19, 1998.
|
References
|
|---|
1.
Levine SR. Antiphospholipid antibody
syndrome. In: Welch KMA, Caplan L, Reis D, Weir B, Siesjo B,
eds. Primer on Cerebrovascular Diseases. San Diego, Calif:
Academic Press; 1997:381–384.
2.
Hirashima Y, Kurimoto M, Tsukamoto E, Endo S, Takaku A.
Anti-phospholipid antibodies and cerebral vasospasm following
subarachnoid hemorrhage. Acta Neurochir
(Wien).. 1995;135:191–197.
3.
Chyatte D, Fode NC, Nichols DA, Sundt TM Jr.
Preliminary report: effects of high dose methylprednisolone on
delayed cerebral ischemia in patients at high risk for
vasospasm after subarachnoid hemorrhage.
Neurosurgery. 1987;21:157–160.
4.
Gellego MJ, Garcia Villalón AL, López
Farre AJ, García JL, Garrón MP, Casado S, Hernando L,
Caramelo CA. Mechanisms of the endothelial
toxicity of cyclosporin A: role of nitric oxide, cGMP, and
Ca2+. Circ Res.. 1994;74:477–484.[Abstract/Free Full Text]
5.
Manno EM, Gress DR, Ogilvy CS, Stone CM, Zervas NT.
The safety and efficacy of cyclosporine A in the
prevention of vasospasm in patients with Fisher grade 3
subarachnoid hemorrhages: a pilot study.
Neurosurgery. 1997;40:289–293.[Medline]
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6.
Juvela S. Aspirin and delayed cerebral
ischemia after aneurysmal subarachnoid
hemorrhage. J Neurosurg.. 1995;82:945–952.[Medline]
[Order article via Infotrieve]
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Abstract
Introduction
