From the First Department of Medicine (T.M., M.K., H.A., T. Kuzuya, T.
Kurotobi, M.H.), Osaka University School of Medicine, Suita, Japan; Division
of Cardiology (S.S., M.F., N.H.), Osaka Prefectural Hospital, Osaka, Japan;
and Division of Cardiology (Y.K.), Osaka National Hospital, Osaka, Japan.
Correspondence to Masafumi Kitakaze, MD, The First Department of Medicine, Osaka University School of Medicine, 2-2, Yamadaoka, Suita, Osaka 565, Japan. E-mail kitakaze{at}medone.med.osaka-u.ac.jp
Methods and Results—AF was induced by rapid atrial pacing
in the canine model of AF. Plasma NOx levels were significantly
decreased and the levels of P-selectin on platelets and of
neutrophil/platelet conjugates were significantly increased after
the onset of AF in this model. The in vitro experiments demonstrated
that the inhibition of NO synthesis increased the expression of
P-selectin on platelets. Plasma NOx levels (19.7±2.4 versus
27.5±2.8 µmol/L) were significantly lower in 25 patients with
AF compared with age- (±2 years) and sex-matched control subjects.
Conversely, the levels of P-selectin on platelets (7.6±0.8%
versus 4.8±0.7%) and of neutrophil/platelet conjugates
(14.8±0.9% versus 8.1±0.6%) were significantly higher in patients
with AF. Multiple regression analysis revealed that increased
P-selectin on platelets and advanced age were associated with the
number of foci of silent cerebral infarction.
Conclusions—An irregular heart rate that is characteristic of AF
appeared to blunt NO synthesis. The increased expression of P-selectin
on platelets associated with the reduced NO levels was a risk
factor for silent cerebral infarction in patients with AF.
P-selectin, an important adhesion molecule found in the secretory
granules of platelets and the Weibel-Palade bodies of
endothelial cells, is mobilized to the plasma membrane
on activation.13 P-selectin mediates
neutrophil/platelet interactions as well as
neutrophil/endothelial cell
interactions.13 Because the development of
thromboli in vivo may involve platelet activation and the formation
of neutrophil/platelet conjugates,14
P-selectin expressed on platelets may be important in the formation
of thromboemboli. Recently, the reduced bioavailability of NO has been
suggested to cause thrombotic disorders associated with the increased
expression of P-selectin on platelets in
humans.15 Therefore, we hypothesized that the
increased expression of P-selectin on platelets due to reduced NO
levels under turbulent flow conditions contributes to the formation of
thromboemboli in patients with AF. To test this idea, we examined the
time-course changes of nitrite and nitrate (NOx), the expression of
P-selectin on platelets, and the levels of neutrophil/platelet
conjugates in a canine model of AF. Next, we determined the effect of
the inhibition of NO synthesis on the expression of P-selectin on
platelets in vitro. In patients with AF, we measured plasma NOx
levels, the expression of P-selectin on platelets, and the levels
of neutrophil/platelet conjugates compared with those in age- and
sex-matched control subjects with sinus rhythm. Finally, we evaluated
the clinical and hemodynamic parameters
measured in the present study as potential risk factors for SCI in
patients with AF.
Protocol 1: Serial Changes in Plasma NOx Levels, Expression of
P-Selectin on Platelets, and Levels of Neutrophil/Platelet
Conjugates in the Canine Model of AF
Samples were analyzed on a FACScan flow cytometer with Cell
Quest software (Becton Dickinson). A gate was set around the
platelets, and a total of 5000 platelets were counted in each
sample. The percentage of platelets that were positive for
P-selectin was determined by the number that had FITC
fluorescence of >99% of the platelets incubated with the
nonspecific antibody.20 The percentage of
neutrophils bound to platelets was determined as described
previously.16
Protocol 2: Effects of L-NAME on Expression of P-Selectin on
Platelets In Vitro
Protocol 3: Plasma Levels of NOx, Expression of P-Selectin on
Platelets, and Levels of Neutrophil/Platelet Conjugates in
Patients With AF
Protocol 4: Evaluation of SCI by MRI
Statistical Analysis
Effects of the Inhibition of NO Synthesis on the Expression of
P-Selectin on Platelets
Plasma NOx Levels, Expression of P-Selectin on Platelets, and
Levels of Neutrophil/Platelet Conjugates in Patients With
AF
Plasma NOx levels in patients with AF were lower (P<0.05)
than those in age- and sex-matched subjects with sinus rhythm
(19.7±2.4 versus 27.5±2.8 µmol/L) (Figure 5
Evaluation of SCI in Patients With AF
This is the first report, to our knowledge, that irregular heart rate
characteristic of AF induces the expression of P-selectin on
platelets, which plays an important role in the formation of
thromboemboli. NO is known to inhibit platelet
activation.7 8 25 Because NO is expected to be
produced mainly in endothelial cells in
vivo,7 it is likely that a reduction in NO
released from endothelial cells is associated with
platelet activation in AF. However, our in vitro finding that the
treatment of PRP with an inhibitor of NO synthase increases
the expression of P-selectin on platelets suggests that
endogenous NO released from platelets may modulate the
expression of P-selectin on them in an autocrine fashion. Thus, we must
consider the possible contribution of NO released from platelets,
as well as endothelial cells, to the expression of
P-selectin on platelets in AF. Other possible contributing factors
for platelet activation may include the frequent collision of
platelets and the injury to the endothelium caused
by irregular atrial wall motion.26
We observed an increase in the levels of neutrophil/platelet
conjugates in the canine model of AF. Neutrophil/platelet
interactions are mediated by fibrinogen bridges, thrombospondin
bridges, and P-selectin–mediated platelet adhesion to
neutrophils.27 Because the expression of
P-selectin on platelets was increased in this model of AF,
P-selectin–mediated platelet adhesion to neutrophils may be mainly
responsible for the increased levels of platelets. Although
the pathophysiological role of
neutrophil/platelet conjugates has not been elucidated, further
investigation is needed to clarify whether neutrophil/platelet
conjugates are the target of the treatment of thromboembolism or merely
the marker of activation of platelets, neutrophils, or both in
patients with AF.
Expression of P-Selectin on Platelet and Levels of
Neutrophil/Platelet Conjugates in Patients With AF
In the present study, 52% of the subjects with AF were taking
aspirin, which may have affected platelet activation. Although
aspirin inhibits the release of
SCI in Patients With AF
Recently, Kario et al36 demonstrated that
endothelial cell damage is a potential risk factor for
SCI in elderly Japanese with sinus rhythm, supporting the idea that
reduced NO production due to endothelial cell
damage might be involved in SCI in these subjects. Although we found
that plasma NOx levels were decreased in both patients with AF and the
canine model of AF, there was no significant relationship between
plasma NOx levels and the number of foci of SCI. Further investigation
is needed to clarify the involvement of NO in the pathophysiology of
SCI.
In conclusion, the results of the present study suggest that
the increased expression of P-selectin on platelets associated with
the reduced NO levels was a potential risk factor for SCI in patients
with AF. Therapy that increases NO production or that targets
the P-selectin on platelets may provide a new strategy for
preventing thromboembolism in patients with AF.
Received January 20, 1998;
revision received May 21, 1998;
accepted June 3, 1998.
© 1998 American Heart Association, Inc.
Clinical Investigation and Reports
Increased Expression of P-Selectin on Platelets Is a Risk Factor for Silent Cerebral Infarction in Patients With Atrial Fibrillation
Role of Nitric Oxide
Abstract
Top
Abstract
Introduction
Methods
Results
Discussion
References
Background—Platelet
activation and decreased levels of nitrite and nitrate (NOx), stable
end products of nitric oxide (NO), are reported in patients with
atrial fibrillation (AF). We examined the time-course changes in plasma
NOx levels and the expression of P-selectin on platelets after the
onset of AF in a canine model and determined whether these
parameters could be risk factors for silent cerebral
infarction in patients with AF.
Key Words: fibrillation • endothelium-derived factors • risk factors • brain • infarction
Introduction
Top
Abstract
Introduction
Methods
Results
Discussion
References
Atrial fibrillation (AF) is associated with an increased
risk of stroke and thromboembolism.1 Magnetic
resonance imaging (MRI) can reveal a high prevalence of silent cerebral
infarction (SCI) in patients with AF.2 3 Although
the precise mechanism by which thromboemboli are increased in patients
with AF has not been determined, hemostatic
abnormalities4 5 and platelet
activation6 may be contributing factors. These
abnormalities are found in patients with AF even in the absence of
organic valvular changes,4 5 6 suggesting
that an irregular heart rate and the resulting turbulent flow in the
systemic vessels may cause a prothrombotic state. Nitric oxide (NO), an
antithrombotic product of the endothelial cells,
inhibits platelet activation and prevents platelet and
leukocyte adhesion to the
endothelium.7 8 Although
endothelial NO synthase activity is stimulated by shear
stress,9 its activity is quite different under
flow conditions: NO synthase activity under turbulent flow conditions,
which are characteristic of AF, is markedly depressed compared
with that under laminar or periodic flow
conditions.10 11 We recently demonstrated that
indicators of plasma NO are decreased in patients with AF
associated with hemostatic abnormalities and platelet
activation.12
Methods
Top
Abstract
Introduction
Methods
Results
Discussion
References
Materials
NG-Nitro-L-arginine
methyl ester (L-NAME), L-arginine (L-arg),
paraformaldehyde, and sodium citrate were obtained from
Sigma Chemical Co. The monoclonal antibody (mAb) against P-selectin
(CY-1747, mouse IgG1, also known as PB1.3) was
kindly donated by Sumitomo Pharmaceuticals Co., Ltd. (Osaka,
Japan). We have previously confirmed that CY1747 recognizes P-selectin
expressed on canine platelets.16 The mAb
against CD41 (MCA 1471, mouse IgG2a), which is
commonly and specifically expressed on the surface of canine
platelets16,17; fluorescent
isothiocyanate (FITC)-conjugated goat antibody against mouse
IgG1; FITC-conjugated sheep antibody against
mouse IgG2a; mAb against human P-selectin (MCA
796 F); mAb against human CD41a (MCA 467 F); and negative isotopic mAbs
were purchased from Serotec. FACS lysing solution was purchased from
Becton Dickinson.
Ten mongrel dogs (weight, 15 to 21 kg) were anesthetized
with pentobarbital sodium (30 mg/kg), the tracheas were intubated, and
the animals were ventilated with room air supplemented with oxygen.
Catheters were inserted into the left carotid artery and vein, and
patency was maintained with heparinized saline solution. Samples of
venous blood were drawn without stasis, and coagulation was inhibited
with 3.8% sodium citrate (1:9, vol/vol; pH 7.4). The chest was opened
through the right fourth intercostal space, and the heart was suspended
in a pericardial cradle. Two bipolar Teflon-coated stainless steel clip
electrodes were inserted into the right appendage in 5 dogs (AF group).
AF was induced with bursts of rapid atrial pacing (interval, 20 Hz;
pulse width, 4.5 ms; 3 times diastolic threshold) as
described previously with minor modifications18
(Figure 1
). Pacing was continued to
induce AF again when AF was spontaneously converted to sinus rhythm
during experimental protocols. Thus, we can consider AF to be sustained
during the experimental protocol. Because our preliminary experiments
demonstrated that the mean heart rate in this AF model was 
200
beats/min, we performed right atrial pacing at 200 beats/min in 5 dogs
(control group). The standard 6-lead surface ECG was recorded.
Plasma NOx levels, the expression of P-selectin on platelets, and
the levels of neutrophil/platelet conjugates were measured in blood
samples obtained before and 1, 2, 3, and 6 hours after the onset of
atrial pacing. Plasma NOx levels were measured with the Greiss reagent
as reported previously.19 We evaluated the
expression of P-selectin on platelets and levels of
neutrophil/platelet conjugate as reported
previously.16 Isotopic mAbs were used to
determine nonspecific background fluorescence in samples
prepared in parallel.
View larger version (28K):
[in a new window]
Figure 1. Representative tracings of ECGs
and systemic arterial pressure before (A) and 6 hours after
(B) onset of cardiac pacing.
Samples of venous blood were drawn from 7 healthy volunteers (5
men and 2 women; mean age, 29 years) without stasis. Coagulation was
inhibited with 3.8% sodium citrate (1:9, vol/vol; pH 7.4).
Platelet-rich plasma (PRP) was obtained as described. To
examine the role of endogenous NO produced in
platelets,21 samples were incubated with
L-NAME (1 mmol/L) at 37°C for 10 minutes. In another set of
experiments, PRP was first incubated with L-arg (1
mmol/L) for 10 minutes. After this incubation, PRP was incubated with
L-NAME for an additional 10 minutes. The platelets were washed as
described above, treated with FITC-conjugated anti–P-selectin mAb (MCA
796F, 10 µg/mL) at 4° for 30 minutes, and then washed in
Dulbecco's PBS with 0.2% (vol/vol) bovine serum
albumin to remove excess antibody. The platelets then were
washed twice, fixed in 1% (vol/vol) paraformaldehyde,
and analyzed by flow cytometry.
Twenty-five subjects with AF (17 men and 8 women) and 25 sex-
and age- (±2 years) matched nonhospitalized control subjects with
sinus rhythm were evaluated. Patients with chronic sustained AF but
without a history of cerebrovascular accident, transient
ischemic attack, mitral stenosis, left
ventricular aneurysm, or intra-atrial and
intraventricular thrombi on 2-dimensional
echocardiography were selected for inclusion into
the study. Plasma NOx levels, the expression of P-selectin on
platelets, and the levels of neutrophil/platelet conjugates
were determined as described. Blood was drawn from the cubitus vein in
the morning after the subjects had fasted overnight.
Twenty-five patients with AF in protocol 3 underwent brain MRI.
SCI was defined as a defect on the MRI consistent with a
cerebral infarct in a neurologically normal patient. MRI was performed
using a field strength of 0.5 T (GE Yokogawa Medical System, MR Vectra)
in the orbitomedial plane with sections that were 8 mm thick in
the manner of an inversion recovery technique with a repetition time of
2500 ms, an inversion time of 400 ms, and an echo time of 17 ms to
achieve T1-weighted images. A spin-echo technique (repetition time,
2500 ms; echo time, 90 ms) was used to achieve T2-weighted images. The
matrix consisted of 256x256 pixels. Infarction was defined as a
focal area with prolonged T1 and T2 relaxation times. These lesions
were visible as low and high signal intensity areas on T1- and
T2-weighted images, respectively. Hyperintense images visible only on
T2 images were not counted as infarctions so as to exclude perivascular
space (état criblé). The number of foci of SCI
in each patient were counted in a blinded fashion.
Data are expressed as mean±SEM. The time courses of changes in
parameters measured in the canine model of AF were compared
by 2-way repeated measures ANOVA. The effects of inhibition of NO
synthesis on the expression of P-selectin on platelets were
evaluated by 1-factorial ANOVA and Bonferroni's test. Baseline
characteristics of patients with and without AF were evaluated using
Student's t test for continuous variables and the
2 test for noncontinuous variables.
Multiple linear regression analysis was used to evaluate the
possible clinical significance of plasma NOx levels, the expression of
P-selectin on platelets, neutrophil/platelet conjugates, and
clinical and hemodynamic parameters
measured in the number of foci of SCI. A level of P<0.05
was accepted as statistically significant.
Results
Top
Abstract
Introduction
Methods
Results
Discussion
References
Changes in Plasma NOx Levels, Expression of P-Selectin on
Platelets, and Levels of Neutrophil/Platelet Conjugates in the
Canine Model of AF
Successive electrical complexes in each of the recordings
varied markedly in cycle length in a canine model of AF (Figure 1
).
Mean heart rate increased after the onset of AF (166±4 versus 204±5
beats/min, P<0.05). Mean aortic blood pressure before the
onset of cardiac pacing (1124 mm Hg) did not change during the
experimental protocol. At 2 hours after the onset of AF, plasma NOx
levels decreased significantly (Figure 2A). The expression of P-selectin on
platelets increased significantly 3 hours after the onset of AF
(Figure 2B). The levels of neutrophil/platelet conjugates (Figure 2C) increased significantly after 2 hours. Neither plasma NOx levels,
the expression of P-selectin on platelets, nor the levels of
neutrophil/platelet conjugates changed in the control animals paced
at 200 beats/min during the experimental protocol (Figure 2A through 2C).
View larger version (16K):
[in a new window]
Figure 2. Time course of changes in plasma NOx levels (A),
expression of P-selectin on platelets (B), and levels of
neutrophil/platelet conjugates (C) in AF ( 
) and control (
)
canine model. Data are expressed as mean±SEM (n=5).
*P<0.05 versus baseline. 
P<0.05
versus control group.
Treatment with L-NAME significantly increased the
fluorescence intensity of P-selectin on human platelets in
vitro, as indicated by a rightward shift pattern (Figure 3). The L-NAME–induced
increase in the expression of P-selectin on human platelets was
blunted by pretreatment with L-arg (Figure 4).
View larger version (9K):
[in a new window]
Figure 3. Representative
fluorescence histograms of P-selectin on human platelets
under baseline conditions (A) and effects of inhibition of NO synthesis
on expression of P-selectin on platelets (B).
View larger version (11K):
[in a new window]
Figure 4. Effects of inhibition of NO synthesis on
expression of P-selectin on human platelets. Data are expressed as
mean±SEM (n=7). *P<0.05 versus control.
Patients with AF and the control subjects with sinus rhythm showed
no significant difference in the incidence of such clinical
characteristics as hypertension, diabetes, and
hyperlipidemia, except for the incidence of
ischemic heart disease, which was higher in the patients with
sinus rhythm (Table 1). The incidence of
patients with AF who were taking aspirin was higher than that of
control subjects with sinus rhythm (Table 1). The incident of subjects
who were taking drugs other than aspirin did not differ between the two
groups. Patients with AF did not differ from control subjects with
sinus rhythm with respect to hemodynamic or
echocardiographic parameters that were
evaluated except for the diameter of left atrium, which was larger in
the patients with AF (Table 2).
View this table:
[in a new window]
Table 1. Clinical Characteristics of Patients With Atrial
Fibrillation and Those With Sinus
Rhythm
View this table:
[in a new window]
Table 2. Hemodynamic and Echocardiographic Parameters in
Patients With Atrial Fibrillation and Those With Sinus
Rhythm ). The expression of P-selectin on
platelets (7.6±0.8% versus 4.8±0.7%) and the levels of
neutrophil/platelet conjugates (14.8±0.9% versus 8.1±0.6%) were
greater (P<0.05) in subjects with AF than in subjects
with sinus rhythm (Figure 5).
View larger version (15K):
[in a new window]
Figure 5. Plasma NOx levels (A), expression of P-selectin on
platelets (B), and levels of neutrophils/platelet conjugates
(C) in patients with AF and control subjects with sinus rhythm.
Although none of the patients with AF in the present study had
a history of cerebrovascular accident, MRI revealed the high prevalence
of SCI (92%) and numerous cerebral infarcted foci (17±4 per person;
Table 3). Multiple regression
analysis revealed that advanced age and increased expression of
P-selectin on platelets were significantly (P<0.05)
associated with the numbers of foci of SCI in patients with AF. Plasma
NOx levels, the levels of neutrophil/platelet conjugates, and the
remainder of the clinical and hemodynamic
characteristics in Tables 1 and 2 were not significantly associated
with the numbers of foci of SCI.
View this table:
[in a new window]
Table 3. Number of Foci of Silent Cerebral Infarction in
Patients With Atrial
Fibrillation
Discussion
Top
Abstract
Introduction
Methods
Results
Discussion
References
Plasma NOx Levels and P-Selectin on Platelets in the Canine
Model of AF
The results of the present study demonstrate that the
irregular heart rate characteristic of AF can induce a decrease in
plasma NOx levels. Because NO rapidly decomposes in biological
solutions to form NOx,22 decreased plasma NOx
levels may reflect a decrease in the plasma levels of NO in vivo.
Although the precise mechanism by which plasma NOx levels were
decreased in AF has not been elucidated, the decrease in NO synthase
activity10 11 and damaged
endothelium23 due to turbulent
flow appear to be involved. We must also consider that hemostatic
abnormalities due to turbulent flow impair NO
production.24
Because P-selectin on platelets is important in the formation
of thromboemboli in arterial
vessels,14 the increased expression of P-selectin
on platelets might play an important role in the thrombotic
disorders in patients with AF. There are several possible mechanisms by
which the expression of P-selectin on the platelets induces the
formation of thromboemboli. Activation of platelets may lead to
their adherence to endothelial cells, causing
leukocytes within the thrombi via the P-selectin expressed on
platelets.14 28 Another possibility is that
the adhesion of platelets to neutrophils activates those
cells.27 Activated leukocytes release
vasoactive substances29 as well as reactive
oxygen metabolites that may influence the process of the formation of
thromboemboli30 and induce the
vasoconstriction,31 thereby obstructing the small
vessels.32 A third possibility is that conjugates
of neutrophils and platelets become entrapped in the small vessels.
The size of the conjugates increases as a result of homotypical
leukocytes33 and may become sufficiently large to
obstruct the capillaries. 
-granules and dense granules from
the activated platelets, it does not affect the expression
of P-selectin on activated
platelets.34 Thus, aspirin appeared to have a
minimal effect on the levels of the expression of P-selectin on
platelets in the present study.
A high incidence of SCI is reported in patients with
AF.2 3 In the present study, we carefully
identified the foci of SCI using both T1 and T2 images to differentiate
them from the perivascular space, and we revealed the presence of SCI
in >90% patients with AF. Advanced age, hypertension, diabetes
mellitus, smoking, hypercholesterolemia, and
cardiac diseases are previously reported to be potential risk factors
of the presence of SCI.35 Although the population
of the patients with AF was very small in the present study,
multiple regression analysis indicated that advanced age and
increased expression of P-selectin on platelets were significantly
associated with the number of foci of SCI. This report is the first to
demonstrate that the adhesion molecule on platelets that plays an
important role in the formation of thrombi is a potential risk factor
for SCI. Further investigation will be needed to clarify whether the
increased expression of P-selectin on platelets is a potential
predictor of SCI, stroke, or both in subjects with sinus rhythm and
AF.
Acknowledgments
Dr Minamino is a Research Fellow of the Japan Society for the
Promotion of Science (JSPS) for Young Scientists. This study was
supported by a Grant-in-Aid for JSPS Fellows from the Japanese Ministry
of Education, Science and Culture and by Japan Heart Foundation–Pfizer
Pharmaceuticals Grant for Research on Coronary Artery Disease.
We thank Sachiyo Nomura and Kazumi Furukawa for preparing blood
samples.
References
Top
Abstract
Introduction
Methods
Results
Discussion
References
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