© 1997 American Heart Association, Inc.
Articles |
Plasma Levels of Nitrite/Nitrate and Platelet cGMP Levels Are Decreased in Patients With Atrial Fibrillation
From the First Department of Medicine, Osaka University School of Medicine, Japan.
Correspondence to Masafumi Kitakaze, MD, PhD, First Department of Medicine, Osaka University School of Medicine, 2–2 Yamadaoka, Suita 565, Osaka, Japan. E-mail kitakaze{at}medone.med.osaka-u.ac.jp
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Abstract |
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Abstract Patients with atrial fibrillation have been reported to exhibit abnormal hemostasis. Since nitric oxide (NO) exerts antithrombotic effects and attenuates platelet function, we evaluated two indicators of plasma NO levels, the plasma levels of nitrite and nitrate (NOx), and the levels of cGMP in platelets. We also examined whether indicators of plasma NO levels were associated with abnormalities in parameters related to platelet function, blood coagulation, and fibrinolysis. We evaluated 45 patients with chronic sustained atrial fibrillation (33 men and 12 women, age range 63±2 years) compared with 45 sex- and age- (±2 years) matched nonhospitalized subjects with sinus rhythm. There were no significant differences between the two groups in the incidence of risk factors for stroke except for ischemic heart disease or in echocardiographic parameters. Plasma levels of NOx measured using the Greiss reagent (mean [interquartile range]: 15.6 [9.5 to 25.7] versus 24.1 [14.2 to 40.8] µmol/L, n=45) and the platelet cGMP levels (0.33 [0.16 to 0.67] versus 0.63 [0.31 to 1.29] pmol/109 platelets, n=9) were significantly (P<.05) lower in the patients with atrial fibrillation than in the control subjects. Plasma levels of D-dimer, ß-thromboglobulin, and fibrinogen were significantly (P<.05) higher in the patients with atrial fibrillation. The two groups did not differ as to the plasma levels of tissue plasminogen activator or plasminogen activator inhibitor-1. Our findings suggest that a decrease in plasma NO levels may account for the hemostatic abnormalities observed in patients with atrial fibrillation.
Key Words: atrial fibrillation • nitrite and nitrate • platelet cGMP levels • hemostatic disorders
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Introduction |
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Atrial fibrillation is commonly associated with an increased risk of stroke and thromboembolism.1 Recent studies using transesophageal echocardiography demonstrated that left atrial thrombi are found in only 12% to 26% of patients with atrial fibrillation,2 suggesting that cardiogenic thromboemboli may not be the only source of the disorder. Patients with atrial fibrillation exhibit an irregular heart rate that may cause turbulent flow in the systemic vessels. Hemostatic abnormalities3,4 and platelet activation5 are found in patients with atrial fibrillation even without organic valvular changes. Thus, turbulent flow itself may cause a prothrombotic state that could account in part for the increased risk of thromboembolism in such individuals.1 Recent experiments show that shear stress due to blood flow can modulate the production of vasoactive mediators in the endothelial cells.6,7 Nitric oxide (NO) is produced by NO synthase in endothelial cells, but this activity is markedly depressed under conditions of turbulent flow.8 NO, an antithrombotic product of the endothelial cells, inhibits the aggregation of platelets,9 prevents the adhesion of platelets to the endothelium,9 prolongs the bleeding time,10 and reduces the plasma levels of fibrinogen.11 A reduced bioavailability of NO has been suggested to cause thrombotic disorders in humans.12 We therefore hypothesized that plasma NO levels are decreased in patients with atrial fibrillation. To test this idea, we measured two indicators of plasma NO levels in patients with atrial fibrillation and subjects with sinus rhythm: the plasma levels of nitrite and nitrate (NOx), which are stable end products of NO,13 and the levels of cGMP in platelets, a biological indicator of NO.14,15 We also examined whether indicators of plasma NO levels were associated with abnormalities in markers related to platelet function, blood coagulation, and fibrinolysis. We measured the plasma levels of ß-thromboglobulin as an indicator of platelet activation. As markers of the blood coagulation system, we measured plasma levels of fibrinogen, an essential component of blood coagulation, and of fibrin D-dimer, an index of thrombogenesis. As markers of the fibrinolytic system, we measured the plasma levels of tissue plasminogen activator, a primary mediator of intravascular fibrinolysis, and of plasminogen activator inhibitor-1, an inhibitor of tissue plasminogen activator.
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Methods |
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We evaluated 45 patients with chronic sustained atrial fibrillation (33 men and 12 women; mean age 63±2 years) and 45 sex- and age- (±2 years) matched nonhospitalized control subjects with sinus rhythm (mean age 63±2 years). All patients with atrial fibrillation who lacked mitral stenosis, left ventricular aneurysm, or intra-atrial and intraventricular thrombus on two-dimensional echocardiography were eligible. To estimate plasma NO levels in patients with atrial fibrillation, we measured two indicators of plasma NO levels: the plasma levels of NOx and the platelet cGMP levels. The plasma levels of NOx were measured with the Greiss reagent.16 The platelet cGMP levels were determined with a radioimmunoassay kit (Yamasa Shoyu).15 To evaluate hemostatic conditions, we measured plasma levels of fibrin D-dimer,17 tissue plasminogen activator,18 plasminogen activator inhibitor-1,19 and ß-thromboglobulin20 using enzyme-linked immunosorbent assays. The plasma levels of fibrinogen were determined by the enzymatic method.4 Because atrial natriuretic peptide (ANP) and NO exert their actions via a cGMP-dependent pathway14 and plasma levels of ANP are reported to be increased in patients with atrial fibrillation,19 we measured plasma levels of ANP by using a radioimmunoassay kit (Amersham).15 The plasma levels of cGMP were also determined with a radioimmunoassay kit (Yamasa Shoyu).15 Blood samples were drawn early in the morning after the subjects had fasted overnight.
Measurement of Levels of cGMP in Platelets
Samples of venous blood were drawn without stasis and
anitcoagulated with 3.8% sodium citrate (1:9, vol/vol), pH 7.4.
Platelet-rich plasma was obtained by centrifugation
at 100g for 20 minutes at room temperature. Aliquots of
platelet-rich plasma were recentrifuged at 2000g
for 10 minutes to form a platelet pellet. These platelet
pellets were washed twice with modified Tyrode's solution containing
bovine serum albumin and 5 mmol/L HEPES, pH 7.35,
and resuspended in modified Tyrode's solution to obtain a final
platelet count of 2 to 3 x106/µL. The
samples were frozen at -80°C until assayed. A volume of 0.5 mL of
trichloroacetic acid (final concentration, 6%) was added to 1 mL of
platelet samples. After centrifugation at
2500g for 20 minutes, trichloroacetic acid was extracted
three times from theupernatant with water-saturated
ether. The aqueous phase was then assayed for cGMP using a
radioimmunoassay kit (Yamasa Shoyu). Results were expressed as
picomoles per 109 platelets.
Statistical Analysis
The data of indicators of plasma NO levels and of hemostatic
parameters were expressed as mean (interquartile range).
The other data were expressed as mean±SEM. Statistical evaluation
utilized the 
2 test, the two-tailed
t test for normal distributions, and the Mann-Whitney
U test for nonparametric distributions. A level
of P<.05 was considered statistically significant.
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Results |
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The patients with atrial fibrillation (n=45) and the control subjects with sinus rhythm (n=45) demonstrated no significant difference in the incidence of such clinical characteristics as hypertension, cigarette smoking, diabetes, hyperlipidemia, or drug treatment, except for the incidence of ischemic heart disease, which was higher in the patients with sinus rhythm (Table 1
). The
patients with atrial fibrillation did not differ from those with sinus
rhythm with reference to hemodynamic or
echocardiographic parameters (Table 2).
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The plasma levels of NOx (15.6 [9.5 to 25.7] versus
24.1 [14.2 to 40.8] µmol/L, n=45; Fig 1) and the platelet cGMP levels (0.33
[0.16 to 0.67] versus 0.63 [0.31 to 1.29]
pmol/109 platelets, n=9; Fig 2) in patients with atrial fibrillation
were lower (P<.05) than those in subjects with sinus
rhythm. There was significant (P<.05) correlation between
the plasma levels of NOx and the platelet cGMP levels
(r=.76, n=18; Fig 3). The
plasma levels of NOx showed no significant correlation with the plasma
cGMP levels (r=.16, P=.14, n=90) or the plasma
ANP levels (r=.10, P=.37, n=90). The platelet
cGMP levels showed no significant correlation with the plasma cGMP
levels (r=.23, P=.36, n=18) or the plasma ANP
levels (r=.37, P=.12, n=18). The plasma cGMP
levels (5.45 [3.92 to 7.58] versus 4.74 [3.80 to 5.92]
pmol/L) and the plasma ANP levels (37.6 [20.7 to 68.3] versus
31.2 [20.3 to 48.1] ng/L) in patients with atrial fibrillation
were higher (P<.05) than those in subjects with sinus
rhythm. There was a significant (P<.05) correlation between
the plasma cGMP levels and the plasma ANP levels (n=90,
r=.82; Fig 4).
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Patients with atrial fibrillation exhibited significantly higher
(P<.05) plasma levels of fibrinogen (221 [104 to 477]
versus 166 [77 to 363] ng/mL), D-dimer (141 [69
to 289] versus 85 [53 to 137] ng/mL), and
ß-thromboglobulin (77.4 [31.1 to 192.7] versus
47.0 [20.4 to 108.5] ng/mL) compared with subjects with sinus
rhythm (Fig 5). The two groups showed no
significant difference in the plasma levels of tissue
plasminogen activator (9.6 [25.3 to 3.7]
versus 8.0 [12.5 to 5.1] ng/mL) or of plasminogen
activator inhibitor-1 (44.5 [145.9 to 13.6]
versus 46.2 [92.6 to 23.0] ng/mL). A significant
(P<.05) inverse correlation was observed between the plasma
levels of NOx and those of fibrinogen (n=72, r=-.34; Fig 6). There was no significant correlation
between the plasma levels of NOx and those of
ß-thromboglobulin (n=72, r=-.22,
P=.06), tissue plasminogen activator
(n=72, r=-.20, P=.09), or
plasminogen activator inhibitor-1
(n=72, r=.02, P=.88).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The present study demonstrated that two indicators of plasma NO levels, the plasma levels of NOx and the platelet cGMP levels, were decreased in patients with atrial fibrillation in association with the presence of abnormalities in hemostatic conditions.
NO rapidly decomposes in biological solutions to form nitrite and nitrate.13 Thus, decreased levels of plasma NOx in patients with atrial fibrillation may reflect a decrease in the plasma levels of NO in vivo. However, caution is needed in using the plasma levels of NOx as an indicator of plasma levels of NO when renal function and the extracellular volume are altered.21 Thus, we also measured another indicator of the plasma NO levels, the platelet cGMP levels, and showed that the platelet cGMP levels in patients with atrial fibrillation were decreased compared with subjects with sinus rhythm. These findings strongly support that plasma NO levels are decreased in patients with atrial fibrillation. Two possible mechanisms may be involved: (1) NO synthase activity may be decreased in patients with atrial fibrillation. A previous experimental study demonstrated that the activity of endothelial NO synthase is decreased under turbulent flow conditions that are characteristic of atrial fibrillation.8 (2) Endothelial cellular function is altered in patients with atrial fibrillation. Indeed, the plasma levels of von Willebrand factor, a marker of endothelial disorder, are increased in patients with atrial fibrillation.22
We found a significant correlation between plasma levels of NOx and platelet cGMP levels. We confirmed that plasma levels of cGMP and those of ANP were increased and that these levels were significantly correlated, as consistent with previous reports.19,23,24 However, plasma levels of NOx and platelet cGMP levels showed no significant correlation with the plasma levels of either ANP or cGMP. The conversion of guanosine triphosphate to cGMP involves at least two isoenzyme forms of guanylate cyclase, the soluble and the particle types.14 The soluble type of guanylate cyclase, which can be activated by NO, is present in platelets, suggesting that the platelet cGMP levels may reflect the plasma NOx levels. The particle type of guanylate cyclase, which is activated by agents such as ANP, but not NO, is present in most tissues.25 This finding suggests that the plasma levels of cGMP may reflect the plasma levels of ANP. Although NO and ANP activate different types of guanylate cyclase, they share a common cGMP-dependent pathway.14 Thus, an increase in plasma levels of ANP might be one of compensatory mechanisms when plasma NO levels are decreased.
The present study has shown that abnormalities in hemostatic conditions were associated with a decrease in two indicators of plasma NO levels in patients with atrial fibrillation. One may speculate that a decrease in the plasma NO levels leads to abnormalities in hemostatic conditions. The plasma levels of fibrinogen were increased in patients with atrial fibrillation, consistent with the previous study.4 A recent experimental study demonstrated that endogenous NO acts to reduce plasma levels of fibrinogen.11 The present study showed a significant inverse correlation between plasma levels of NOx and those of fibrinogen. This observation suggests that increased levels of fibrinogen indicative of an increased risk of stroke26 might be due to a decrease in the plasma NO levels. On the other hand, since the products of fibrinogen degradation impair the function of NO,27 it is possible that an increase in plasma levels of fibrinogen impairs the production of NO. Further investigation is needed to clarify the relationship between plasma levels of fibrinogen and of NO. Plasma levels of ß-thromboglobulin were increased in patients with atrial fibrillation, which suggests that the activation of platelets occurs in these individuals. Since NO attenuates platelet activation, a decrease in the plasma NO levels may cause platelet activation.9 We have confirmed that the plasma levels of D-dimer were increased in patients with atrial fibrillation, as reported previously.3,5 This substrate is an indicator of thrombus formation in which the adhesion of platelet to endothelium, platelet aggregation, and thrombin formation may be involved.28 Although the direct relationship between NO and thrombus formation remains unclear, a recent study demonstrated that a reduction in the bioavailability of NO, which fails to inhibit platelet activation, may cause a thrombotic disorder in humans.12 Although NO is also reported to modulate fibrinolytic systems,29 we observed no alterna2tion in the plasma level of either plasma tissue plasminogen activator or plasminogen activator inhibitor-1, which suggests that the fibrinolytic system may be unaffected in patients in atrial fibrillation.
In the present study, 7 patients with atrial fibrillation and 11 subjects with sinus rhythm were taking aspirin or ticlopidine, drugs that may affect the platelet activity. However, our data showed that neither of those drugs affected the plasma level of NOx, ß-thromboglobulin, or the thrombotic and fibrinolytic parameters in these subjects. Since the prevalence of ischemic heart disease in the subjects with sinus rhythm exceeded that in patients with atrial fibrillation, we could not deny the possibility that the presence of ischemic heart disease may have affected the parameters measured in this study.
In conclusion, the plasma NO levels, as reflected by the plasma levels of NOx and the platelet cGMP levels, may be decreased in patients with atrial fibrillation. Substitution of NO and preservation of endothelial cell function may provide a strategy for preventing thromboembolism in patients with atrial fibrillation.
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Acknowledgments |
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This study was supported by a grant-in-aid for Japan Society for the Promotion of Science (JSPS) Fellows and by a Japan Heart Foundation/Pfizer Pharmaceuticals Grant for Research on Coronary Artery Disease. Tetsuo Minamino is a Research Fellow of JSPS for Young Scientists. We thank Yukiyo Nomura and Kayoko Yoshida for preparing blood samples and measuring plasma nitrite and nitrate.
Received October 30, 1996; accepted June 10, 1997.
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References |
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