(Circulation. 2000;102:994.)
© 2000 American Heart Association, Inc.
Clinical Investigation and Reports |
Acute Systemic Inflammation Impairs Endothelium-Dependent Dilatation in Humans
From the Centre for Clinical Pharmacology (A.D.H., J.C., R.K.K., K.B., R.J.M., P.V.) and Wolfson Institute for Biomedical Research (M.P.), University College London; Cardiothoracic Unit, Great Ormond Street Hospital for Children NHS Trust (M.J.M., M.T., A.E.D., J.E.D.); and Division of Infectious Diseases, School of Medicine, St George’s Hospital (G.E.G.), London, UK.
Correspondence to Dr A.D. Hingorani, Centre for Clinical Pharmacology, UCL, Rayne Institute, 5 University St, London WC1E 6JJ, UK. E-mail a.hingorani{at}ucl.ac.uk
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Abstract |
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Background—We tested the hypothesis that endothelial dysfunction underlies the association between an acute inflammatory episode and the transiently increased risk of a cardiovascular event by examining the effects of an experimental inflammatory stimulus on endothelium-dependent vasodilation.
Methods and Results—Salmonella typhi vaccine was used to generate a systemic inflammatory response in healthy volunteers. In 12 subjects, dilatation of the brachial artery to flow and to sublingual nitroglycerin (NTG) was recorded (conduit vessel response), and in 6 subjects, venous occlusion plethysmography was used to measure forearm blood flow during intrabrachial infusion of the endothelium-dependent dilators acetylcholine (ACh) and bradykinin (BK) and the endothelium-independent dilators NTG and verapamil (resistance vessel response). Responses were assessed 16 hours before and 8 and 32 hours after vaccination. Vaccination resulted in elevations in white cell count and serum levels of interleukin-6 and interleukin-1 receptor antagonist. Eight hours after vaccination, resistance vessel responses to BK (P=0.0099) and ACh (P=0.0414) were markedly attenuated, and brachial artery flow-mediated dilatation was depressed. Resistance vessel responses to verapamil and NTG were unchanged, as was the conduit vessel response to NTG. Thirty-two hours after vaccination, resistance vessel responses to BK and ACh had returned to normal.
Conclusions—S typhi vaccine generates a mild inflammatory reaction associated with temporary but profound dysfunction of the arterial endothelium in both resistance and conduit vessels to both physical and pharmacological dilator stimuli. This finding might explain the association between infection and inflammation and the enhanced risk of an acute cardiovascular event.
Key Words: : endothelium • nitric oxide • coronary disease
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Introduction |
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Epidemiological and observational studies have suggested an association between infection or inflammation and risk of cardiovascular disease.1 2 3 4 5 6 7 8 Two patterns of association have emerged: a link between chronic low-grade inflammation/infection and the slow process of atherogenesis,2 3 4 and an association between an acute systemic inflammatory response and a transiently increased risk of an acute cardiovascular event.5 6 7 8 The latter may underlie the increased cardiovascular morbidity and mortality seen after respiratory tract infection,9 severe illness requiring intensive care,6 or surgery.10
Previously, we have suggested that changes in endothelial activity may underpin the link between inflammation and the risk of an acute cardiovascular event.11 Loss of the normal vasodilator, antiplatelet, and antithrombotic properties of the vascular endothelium might tip the balance in favor of vasospasm, thrombosis, and inflammation and may contribute to the transition between "stable" and "unstable" atheroma. We have shown that local administration of certain proinflammatory cytokines impairs endothelium-dependent dilatation in human veins in vivo.12 In this study, we test directly the hypothesis that a mild systemic inflammatory response (generated by the administration of a vaccine) impairs endothelium-dependent dilatation in the arterial circulation.
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Methods |
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Subjects
The protocol was approved by the University College London Hospitals Research Ethics Committee. All clinical studies were performed in a temperature-controlled laboratory (24°C to 26°C). Male and female subjects (age, 22 to 37 years) who stated that they were healthy, were not taking any medication, and had not received typhoid vaccination in the previous 6 months were included.
Generation of an Inflammatory Response
Salmonella typhi capsular polysaccharide
vaccine 0.025 mg (Typhim Vi, Pasteur Merieux MSD) was injected into the
gluteus muscle at 8 AM on the morning of day 2 of
the study. In 6 subjects, the time course of the inflammatory response
was documented by measurement of body temperature (by mercury
thermometer) and pulse and blood pressure (by an automated device;
Dinamap, Critikon Inc) immediately before and hourly for 8 hours after
administration of the vaccine. At each of these time points, blood
samples were taken for measurement of white cell and platelet
counts and of cytokines. A further sample was also taken 32
hours after vaccination.
Measurement of Cytokines
Serum, obtained by centrifugation, was placed in
aliquots and stored at -70°C for the measurement of interleukin-1ß
(IL-1ß), interleukin-6 (IL-6), tumor necrosis factor-
(TNF-),
and interleukin-1 receptor antagonist (IL-1Ra) with a
commercially available ELISA (Quantikine human IL-1ß, IL-6, TNF, and
IL-1Ra immunoassays, R&D Systems).
Assessment of Forearm Blood Flow (Resistance Vessel
Response)
Mercury-in-Silastic strain-gauge plethysmography was used to
measure forearm blood flow (mL/100 mL forearm per minute) in both arms
as described previously.13 14 For each study, the brachial
artery of the nondominant arm was cannulated with a 27-gauge needle
(Cooper’s Needle Works) inserted under local anesthesia (2
mL of 1% lignocaine). Drugs or normal saline (sodium chloride 0.9%
wt/vol) were infused continuously at 0.5 mL/min. During
recording periods, the hands were excluded from the circulation
by inflation of wrist cuffs to 200 mm Hg. Forearm blood flow
responses to intrabrachial infusions of 4 vasodilator drugs—bradykinin
(BK), acetylcholine (ACh), nitroglycerin (NTG), and
verapamil—were measured on 3 occasions at 4 PM
on 3 consecutive days: 16 hours before and 8 and 32 hours after vaccine
administration. The needle was removed at the end of each study period.
Measurement of basal blood flow was made over a 15-minute period before
drug infusion. The order of drug infusions was varied between studies,
but because of its long duration of action,15
verapamil was always infused last. Saline was infused for
15 minutes between each drug infusion, and blood flow
recordings were then made for a further 2 minutes to ensure
that flow had returned to baseline values before the next drug
infusion. The ratio of flow in the infused/noninfused (control) arm was
calculated for each measurement period. Vasodilator responses were
expressed as the percentage increase in the ratio of forearm blood flow
(infused/noninfused arm) relative to the immediately preceding baseline
flow, as described previously.13 15 In a further study of
5 control subjects, forearm blood flow responses to the 4 dilator drugs
were compared 24 hours apart (at 4 PM) to determine whether
there was a vaccine-independent change in dilator responsiveness over
time.
Measurement of Brachial Artery Dilatation in Response to Flow and
NTG (Conduit Vessel Response)
Brachial artery diameter in the nondominant arm was measured
with high-resolution external vascular ultrasound (Acuson 128XP/10 with
a 7.0-MHz linear-array transducer). The vessel was scanned in
longitudinal section, and the center was identified when the clearest
views of the anterior and posterior artery walls had been obtained.
Images were magnified with a resolution box function and gated with the
R wave of the ECG. End-diastolic images of the artery were
acquired every 3 seconds with customized data-acquisition software
(Information Integrity) and stored in digital format offline for later
analysis.16 Arterial diameter over a
1- to 2-cm segment was determined for each image with a semiautomatic
edge-detection algorithm. Blood flow velocity in the brachial artery
was recorded continuously throughout the study with pulsed-wave
Doppler. Brachial artery diameter and blood flow velocity were
measured continuously for 1 minute at baseline, during 5 minutes of
reduced blood flow (induced by inflation to 300 mm Hg of a
pneumatic cuff placed at a site distal to the segment of artery being
analyzed), and for a further 5 minutes during reactive
hyperemia after cuff release. After return to baseline, vessel
diameter was again measured continuously for 5 minutes after
administration of 50 µg of sublingual NTG. Flow-mediated dilatation
(FMD) was defined as the maximum percentage increase in vessel diameter
during reactive hyperemia; NTG-mediated dilatation was defined
as the maximum percentage increase in vessel diameter after sublingual
NTG. In 12 subjects, measurements of FMD and NTG dilation were made
serially 16 hours before and 8 hours after
vaccination.
Drug Infusions
BK was obtained from Clinalfa AG; NTG, from David Bull
Laboratories; ACh, from Sigma Chemical Co; and verapamil,
from Knoll Ltd. BK, NTG, and ACh were prepared as stock solutions that
were placed in aliquots and stored at -20°C until use. A fresh vial
of verapamil was used for each study. Cumulative
dose-response curves were constructed to BK (20, 40, and 80 pmol/min,
each dose for 3 minutes), ACh (25, 50, and 100 nmol/min, each dose for
3 minutes), NTG (4, 8, and 16 nmol/min, each dose for 3 minutes), and
verapamil (20, 40, and 80 nmol/min, each dose for 3
minutes).
Statistical Analysis
Results are expressed as mean±SEM unless otherwise stated. For
conduit vessel responses, FMD and NTG dilatation were compared at each
time point by a paired t test. For resistance vessel
studies, dose–forearm blood flow response curves were constructed for
all 4 drugs at each of the time points, and comparisons were made by
repeated-measures ANOVA or 1- or 2-way ANOVA as appropriate. The paired
t test or 1-sample t test was used for assessment
of changes in inflammatory indexes and cytokine levels.
P<0.05 was considered statistically significant.
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Results |
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Systemic Response to Vaccination
In the 8 hours after administration of capsular polysaccharide typhoid vaccine, total white cell count rose from 4.0±0.3x 109/L at baseline to 6.1±0.5x109/L at 8 hours (P<0.01) (see the Table
). There was a progressive rise in
the serum level of IL-6 from 2.1±0.4 pg/mL before vaccine to 5.8±3.2
pg/mL 8 hours after vaccine (P=0.07), and the level of
IL-1Ra rose from a baseline value of 188.0±35.9 pg/mL to peak at
593.6±198.0 pg/mL 3 hours after vaccination, a 191% increase from
baseline (P<0.05). There was no rise in the plasma level of
IL-1 or TNF- (data not shown) at the time points studied. Two
subjects experienced local discomfort at the injection site, and 2
subjects reported generalized myalgia and headache. Temperature did not
change significantly: 36.5±0.06°C at baseline and 36.7±0.05°C at
8 hours (P=NS).
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Resistance Vessel Responses
Vaccine Study
Vaccination had no effect on blood pressure or resting heart rate,
nor did it alter baseline forearm blood flow measured by venous
occlusion plethysmography. Mean baseline blood flow was 4.72±0.64
mL/100 mL forearm per minute before vaccination, 4.70±0.70 mL/100 mL
forearm per minute 8 hours after vaccination, and 4.04±0.54 mL/100 mL
forearm per minute 32 hours after vaccination (P=NS). Before
vaccination, all subjects showed a dose-dependent increase in forearm
blood flow to the endothelium-dependent vasodilators BK
and ACh (Figure 1a and 1b) and to the
endothelium-independent vasodilators NTG and
verapamil (Figure 1c and 1d). When the
dilator response was reassessed 8 hours after vaccination, there was a
selective and marked blunting of the response to BK
(P<0.0099 by repeated-measures ANOVA; Figure 1a) and
an impaired response to ACh (P=0.0414 by repeated measures
ANOVA; Figure 1b). Impairment of the ACh response was most
marked at the highest dose of ACh used (P=0.0004 by
repeated-measures ANOVA of the 100-nmol/min data). There was no
significant change in the response to NTG (Figure 1c) or to
verapamil (Figure 1d). Thirty-two hours after
vaccination, the response to BK had returned to normal (Figure
1a), and the responses to NTG (Figure 1c) and
verapamil (Figure 1d) were again unchanged. The
endothelium appeared more sensitive to the effects of
ACh at this time point, at least at the 25- and 50-nmol/min doses,
although the response to the maximum dose of ACh was similar to the
level observed before vaccination.
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Control Study
When forearm blood flow studies were performed twice (24 hours
apart) in 5 nonvaccinated subjects, the responses to BK (Figure 2a), ACh (Figure 2b), and NTG
(Figure 2c) were unchanged over the 24-hour period. There was a
significant reduction in the response to verapamil on day 2
(P=0.0093 by 2-way ANOVA; Figure 2d), although
individual dilator responses to this drug proved to be more
variable than for the other agents.
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Conduit Artery Responses
Baseline brachial artery diameter and blood flow velocity–time
index did not change during the study. However, compared with
prevaccination values, there was a significant impairment in FMD by 8
hours after vaccination (mean FMD, 6.5±0.5 before versus 5.0±0.5 at 8
hours after vaccination; P<0.05; Figure 3). In contrast, there was no difference
in the NTG response at these 2 time points (9.5±0.7 versus 9.5±0.9,
P=NS; Figure 3).
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Discussion |
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Intramuscular injection of capsular polysaccharide typhoid vaccine produced a mild systemic inflammatory response in healthy volunteers that was associated with profound, but temporary, suppression of endothelium-dependent relaxation in the forearm circulation. These findings demonstrate that even a relatively mild systemic inflammatory response is associated with significant alteration in endothelial function of a type commonly thought to be associated with increased cardiovascular risk.13 17 18 19
Inflammatory Response to Vaccination
To initiate a systemic inflammatory response, we gave an
intramuscular injection of the capsular polysaccharide typhoid
vaccine Typhim Vi.20 In the 8 hours after vaccination,
there was a mild leukocytosis but no change in blood pressure or heart
rate (see Table
). Over this time, the plasma concentration of
the proinflammatory cytokine IL-6 increased, but there was no
change in the concentration of either IL-1ß or TNF-. These results
are similar to those reported previously with the whole-cell typhoid
vaccine21 and suggest that IL-6 may be an important
cytokine contributing to the response seen after this type of
vaccination.
Although the serum concentrations of IL-1ß and TNF- did not
change, the concentration of the endogenous IL-1Ra was
elevated at 3 hours after vaccination. IL-1Ra is usually synthesized in
response to IL-1ß generation,22 and the results are
compatible with the suggestion23 that significant local
cellular or tissue generation of cytokines can occur without an
increase in circulating concentrations. Therefore, we cannot exclude
the possibility that IL-1ß and TNF- were synthesized after
vaccination or indeed that other cytokines that we did not
measure contributed to the responses seen. However, in relation to
cardiovascular risk, the elevation of IL-6 is of
particular interest because IL-6 is presumed to be an important, if not
the principal, stimulus to the synthesis of C-reactive
protein,24 and elevated C-reactive protein seems to be
predictive of risk of cardiovascular
events.2 4
The increase in IL-6 and IL-Ra levels observed in vaccinated subjects cannot be explained by diurnal changes in these cytokines. IL-1Ra shows no diurnal variation,25 and although the levels of IL-6 do vary over a 24-hour period in subjects with inflammatory disorders,26 the levels are highest in the morning and not in the afternoon, as we observed in the vaccinated subjects.
Endothelium-Dependent Responses After
Vaccination
Resistance Vessel Studies
Forearm arteriolar vasodilation was assessed in healthy volunteers
before and at various times after vaccination, with each study
performed at the same time of day. Dilator dose-response curves were
constructed to local intra-arterial infusion of agents
whose dilator action is dependent on a functional vascular
endothelium (BK and ACh) and to agents whose action is
to relax directly vascular smooth muscle (NTG and
verapamil). BK and ACh have been used widely to probe the
ability of the endothelium to generate vasodilator
factors; both agents work in part through stimulation of nitric oxide
generation in this vascular bed.27 Decreased efficacy or
potency of BK or ACh in the forearm arterial bed has been
detected in patients with a wide variety of
cardiovascular disease states, including
hypertension,13 19 diabetes,15 and
hypercholesterolemia,18 and has
been taken as an indication of endothelial dysfunction.
In the present study, responses to BK 8 hours after vaccination
were suppressed by 
65%. The response to ACh was also diminished,
particularly at the highest dose used. This finding of selective
impairment in ACh responses at doses equivalent to 
100 nmol/min has
also been noted in patients with hypertension.28
Suppression of endothelium-dependent dilation was not
seen in nonvaccinated individuals studied on consecutive days, and the
magnitude of change seen after vaccination was as at least as great as
the changes reported in the presence of classical
cardiovascular risk factors.17 18 19 The
effect of vaccination was specific for agonists working through the
endothelium, because responses to the nitric oxide
donor drug NTG and the calcium channel blocker verapamil
were unaltered. In the case of BK, the defect in
endothelium-dependent relaxation had returned to normal
by 32 hours. At this time point, the endothelium
appeared more sensitive to the lower doses of ACh, although the
response to the maximal dose of ACh was unchanged. The reason for this
difference between the 2 agonists with respect to the recovery of
endothelium dependent dilator function is not clear. It
may reflect differences in the recovery of receptor or postreceptor
signaling mechanisms or might be the result of greater interindividual
variability in the response to ACh, which has been documented
previously.29 Indeed, the data for ACh were found to be
particularly variable, and the results with this agonist should be
interpreted with caution.
In nonvaccinated subjects, the responses to BK, ACh, and NTG were unchanged over 24 hours. The dilator response to verapamil was depressed on day 2 of the study in these subjects. The more marked intersubject variability in the response to verapamil might account for this observation, but in any case, it was clear that vaccination did not suppress the dilator response to this agent. In summary, for resistance vessels, vaccination caused a clear suppression of BK dilatation without altering the response to NTG. The response to ACh was also altered, but these results should be interpreted in light of a greater individual variability in ACh response. Verapamil response was unchanged by vaccination, but again the responses to this agent are more variable.
Conduit Vessel Studies
After vaccination, the attenuation in
endothelium-dependent vasodilatation in resistance
vessels in response to pharmacological stimuli was mirrored by an
attenuation in the dilator response of a conduit vessel to a physical
stimulus (flow). This attenuation in response occurred in the absence
of any change in the response to a submaximal dilator dose of
sublingual NTG. FMD of a peripheral artery appears to be
dependent on the release of endothelium-derived nitric
oxide,30 and a reduction in brachial artery FMD has been
observed in individuals with risk factors for
atherosclerosis,31 including
hypercholesterolemia,32 and in
those with established coronary artery disease.33
Therefore, an attenuation in brachial artery FMD has also come to be
regarded as indicating the presence of endothelial
dysfunction.
The results demonstrate that vaccination with capsular polysaccharide typhoid vaccine temporarily but profoundly impairs the ability of the arterial endothelium to produce endogenous vasodilators in response to agonist and physical stimuli. The endothelium is an important transducer of physical and chemical signals from the lumen of the vessel, and experiments in animals and in vitro suggest that the changes reported here could alter vascular behavior to contribute to disruption of tissue oxygenation, increased platelet and white cell adhesion to the vessel wall,34 and a predisposition to vasospasm. Relaxation to BK was affected most, and this may be particularly important because local generation of BK plays a role in vascular homeostasis.35
Mechanisms and Clinical Implications
The mechanism(s) by which inflammation may impair
endothelium-dependent relaxation are not fully
understood. One possibility is that certain cytokines induce de
novo expression of the inducible isoform of nitric oxide synthase
(iNOS) in the vessel wall (an isoform implicated in the high-output
nitric oxide production seen in inflammation and sepsis), and
this high output of NO, coupled with the generation of superoxide,
causes endothelial damage.36 This is
unlikely to be the explanation of our findings because expression of
iNOS would be expected to cause vasodilatation and neither blood
pressure nor resting forearm flow changed significantly after
vaccination. Furthermore, although we did not test basal nitric
oxide–mediated dilatation in this study, it has been shown previously
that the conversion of 15N-arginine to
15NO3- (a
breakdown product of NO) does not increase after administration of
whole-cell typhoid vaccine to healthy volunteers.37
An alternative possibility is that the cytokines caused a decrease in the expression of the constitutive endothelial NOS (eNOS). However, this is unlikely to be the sole mechanism, because in our previous studies in human veins we found no decrease in mRNA encoding eNOS after cytokine administration38 and because, in the earlier study, the defect was not confined to nitric oxide–mediated dilatation but also included prostanoid-mediated dilatation.12 Further studies are required to elucidate the mechanisms underlying the effects seen and the extent to which the endothelium loses its capacity to respond to other chemical and physical signals after inflammation.
Systemic inflammation far more severe and long-lasting than the insult produced by vaccination occurs in a wide variety of infective disorders and after iatrogenic procedures such as abdominal surgery. There is growing evidence that acute systemic inflammation is associated with an increase in the risk of cardiovascular events that may persist for days or weeks.8 9 There is also evidence that unstable angina is associated with inflammation,5 which might precede the onset of the syndrome. The present study demonstrates that even a mild inflammatory reaction disturbs endothelial regulation of vascular tone in the arterial circulation. It is important to determine whether the changes reported here are also seen after clinical inflammatory states and whether they might be a target for therapy.
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Acknowledgments |
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This study was supported by the British Heart Foundation through Research Fellowships to Drs Bhagat and Kharbanda and the British Heart Foundation (Gerry Turner) Intermediate Fellowship to Dr Hingorani. Dr Cross is supported by UCL Hospitals Trustees. We thank Dr Derek Macallan, Division of Infectious Diseases, St George’s Hospital Medical School, for a critical reading of the manuscript.
Received October 26, 1999; revision received March 22, 2000; accepted March 27, 2000.
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K. K. Koh Effects of estrogen on the vascular wall: vasomotor function and inflammation Cardiovasc Res, September 1, 2002; 55(4): 714 - 726. [Full Text] [PDF]
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K. B. Vallbracht, P. L. Schwimmbeck, B. Seeberg, U. Kuhl, and H.-P. Schultheiss Endothelial dysfunction of peripheral arteries in patients with immunohistologically confirmed myocardial inflammation correlates with endothelial expression of human leukocyte antigens and adhesion molecules in myocardial biopsies J. Am. Coll. Cardiol., August 7, 2002; 40(3): 515 - 520. [Abstract] [Full Text] [PDF]
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J. A. Vita and J. Loscalzo Shouldering the Risk Factor Burden: Infection, Atherosclerosis, and the Vascular Endothelium Circulation, July 9, 2002; 106(2): 164 - 166. [Full Text] [PDF]
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R. K. Kharbanda, B. Walton, M. Allen, N. Klein, A. D. Hingorani, R. J. MacAllister, and P. Vallance Prevention of Inflammation-Induced Endothelial Dysfunction: A Novel Vasculo-Protective Action of Aspirin Circulation, June 4, 2002; 105(22): 2600 - 2604. [Abstract] [Full Text] [PDF]
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A.D. Pradhan and P.M. Ridker Do atherosclerosis and type 2 diabetes share a common inflammatory basis? Eur. Heart J., June 1, 2002; 23(11): 831 - 834. [Full Text] [PDF]
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N. Parchure, E. G. Zouridakis, and J. C. Kaski Effect of Azithromycin Treatment on Endothelial Function in Patients With Coronary Artery Disease and Evidence of Chlamydia pneumoniae Infection Circulation, March 19, 2002; 105(11): 1298 - 1303. [Abstract] [Full Text] [PDF]
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 C. Stollberger and J. Finsterer Role of Infectious and Immune Factors in Coronary and Cerebrovascular Arteriosclerosis Clin. Vaccine Immunol., March 1, 2002; 9(2): 207 - 215. [Full Text] [PDF]
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J. Pleiner, E. Heere-Ress, H. Langenberger, A. E. Sieder, M. Bayerle-Eder, F. Mittermayer, G. Fuchsjager-Mayrl, J. Bohm, B. Jansen, and M. Wolzt Adrenoceptor Hyporeactivity Is Responsible for Escherichia coli Endotoxin-Induced Acute Vascular Dysfunction in Humans Arterioscler Thromb Vasc Biol, January 1, 2002; 22(1): 95 - 100. [Abstract] [Full Text] [PDF]
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T. Heitzer, T. Schlinzig, K. Krohn, T. Meinertz, and T. Munzel Endothelial Dysfunction, Oxidative Stress, and Risk of Cardiovascular Events in Patients With Coronary Artery Disease Circulation, November 27, 2001; 104(22): 2673 - 2678. [Abstract] [Full Text] [PDF]
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G. J. Blake and P. M. Ridker Novel Clinical Markers of Vascular Wall Inflammation Circ. Res., October 26, 2001; 89(9): 763 - 771. [Abstract] [Full Text] [PDF]
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P. Stenvinkel Endothelial dysfunction and inflammation--is there a link? Nephrol. Dial. Transplant., October 1, 2001; 16(10): 1968 - 1971. [Full Text] [PDF]
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F. Tomai, F. Crea, A. Gaspardone, F. Versaci, A. S. Ghini, L. Chiariello, and P. A. Gioffre Unstable Angina and Elevated C-Reactive Protein Levels Predict Enhanced Vasoreactivity of the Culprit Lesion Circulation, September 25, 2001; 104(13): 1471 - 1476. [Abstract] [Full Text] [PDF]
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A. Y. M. WANG, J. WOO, M. WANG, M. M. M. SEA, R. IP, P. K. T. LI, S. F. LUI, and J. E. SANDERSON Association of Inflammation and Malnutrition with Cardiac Valve Calcification in Continuous Ambulatory Peritoneal Dialysis Patients J. Am. Soc. Nephrol., September 1, 2001; 12(9): 1927 - 1936. [Abstract] [Full Text] [PDF]
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A. D. Pradhan, J. E. Manson, N. Rifai, J. E. Buring, and P. M. Ridker C-Reactive Protein, Interleukin 6, and Risk of Developing Type 2 Diabetes Mellitus JAMA, July 18, 2001; 286(3): 327 - 334. [Abstract] [Full Text] [PDF]
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C. P. Tiefenbacher Tetrahydrobiopterin: a critical cofactor for eNOS and a strategy in the treatment of endothelial dysfunction? Am J Physiol Heart Circ Physiol, June 1, 2001; 280(6): H2484 - H2488. [Full Text] [PDF]
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J. C. Chambers, L. Fusi, I. S. Malik, D. O. Haskard, M. De Swiet, and J. S. Kooner Association of Maternal Endothelial Dysfunction With Preeclampsia JAMA, March 28, 2001; 285(12): 1607 - 1612. [Abstract] [Full Text] [PDF]
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L. Ghiadoni, A. E. Donald, M. Cropley, M. J. Mullen, G. Oakley, M. Taylor, G. O'Connor, J. Betteridge, N. Klein, A. Steptoe, et al. Mental Stress Induces Transient Endothelial Dysfunction in Humans Circulation, November 14, 2000; 102(20): 2473 - 2478. [Abstract] [Full Text] [PDF]
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D. H. McDermott, J. P.J. Halcox, W. H. Schenke, M. A. Waclawiw, M. N. Merrell, N. Epstein, A. A. Quyyumi, and P. M. Murphy Association Between Polymorphism in the Chemokine Receptor CX3CR1 and Coronary Vascular Endothelial Dysfunction and Atherosclerosis Circ. Res., August 31, 2001; 89(5): 401 - 407. [Abstract] [Full Text] [PDF]
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