(Circulation. 1999;99:1411-1415.)
© 1999 American Heart Association, Inc.
Clinical Investigation and Reports |
Endothelial Dysfunction, Impaired Endogenous Fibrinolysis, and Cigarette Smoking
A Mechanism for Arterial Thrombosis and Myocardial Infarction
From the Clinical Pharmacology Unit and Research Centre, University of Edinburgh, Western General Hospital (D.E.N., C.L., D.J.W.), and the Departments of Cardiology (D.E.N., R.A.W., C.L., K.A.A.F., N.A.B.) and Haematology (C.A.L.), University of Edinburgh, Royal Infirmary, Edinburgh, Scotland, UK. Dr Wright is now at the Department of Cardiology, The Ayr Hospital, Ayr, Scotland, UK.
Correspondence to Dr D.E. Newby, Clinical Pharmacology Unit and Research Centre, University of Edinburgh, Western General Hospital, Crewe Rd, Edinburgh EH4 2XU, Scotland, UK. E-mail d.e.newby{at}ed.ac.uk
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Abstract |
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Background—Effective endogenous fibrinolysis requires rapid release of tissue plasminogen activator (tPA) from the vascular endothelium. Smoking is a known risk factor for arterial thrombosis and myocardial infarction, and it causes endothelial dysfunction. We therefore examined the effects of cigarette smoking on substance P–induced tPA release in vivo in humans.
Methods and Results—Blood flow and plasma fibrinolytic factors were measured in both forearms of 12 smokers and 12 age- and sex-matched nonsmokers who received unilateral brachial artery infusions of substance P (2 to 8 pmol/min). In both smokers and nonsmokers, substance P caused dose-dependent increases in blood flow and local release of plasma tPA antigen and activity (P<0.001 for all) but had no effect on the local release of plasminogen activator inhibitor type 1. Compared with nonsmokers, increases in forearm blood flow (P=0.03) and release of tPA antigen (P=0.04) and activity (P<0.001) caused by substance P were reduced in smokers. The area under the curve for release of tPA antigen and activity decreased by 51% and 53%, respectively.
Conclusions—Cigarette smoking causes marked inhibition of substance P–induced tPA release in vivo in humans. This provides an important mechanism whereby endothelial dysfunction may increase the risk of atherothrombosis through a reduction in the acute fibrinolytic capacity.
Key Words: plasminogen activators • endothelium • endothelium-derived factors • blood flow
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Introduction |
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Acute rupture of a coronary atheromatous plaque and subsequent coronary artery thrombosis causes the majority of sudden cardiac deaths and myocardial infarctions.1 2 Cigarette smoking not only is strongly associated with atherosclerosis3 and ischemic heart disease4 but also is a major risk factor for acute coronary thrombosis.1 5 Indeed, 75% of sudden cardiac deaths due to acute thrombosis are in cigarette smokers.1 Smoking causes endothelial dysfunction6 and is associated with increased platelet thrombus formation.5 Small areas of denudation and thrombus deposition are a common finding on the surface of atheromatous plaques7 8 and are usually subclinical. However, in the presence of an imbalance in the coagulation or fibrinolytic systems, such microthrombi may propagate, ultimately leading to arterial occlusion.
The importance of endogenous tissue plasminogen
activator (tPA) release is exemplified by the high rate of
spontaneous reperfusion in the infarct-related artery after acute
myocardial infarction, occurring in 
30% of patients within the
first 12 hours.9 10 11 It would be anticipated that high
plasma tPA concentrations should protect against subsequent
coronary events. However, in epidemiological studies of
patients with ischemic heart disease12 13 and in a
healthy male population (US Physicians Study),14 higher
total plasma tPA (antigen) concentrations positively predict future
coronary events. This is explained by the concomitant elevation
of plasminogen activator inhibitor
type 1 (PAI-1), which forms a complex with tPA and thereby causes an
overall reduction in free tPA "activity."15 16 It is
this free and unbound tPA that is
physiologically active and leads to
endogenous fibrinolysis. However, the
capacity of endothelial cells to release tPA from
intracellular storage pools and the rapidity with which this can be
mobilized may not necessarily be reflected in the basal circulating
plasma concentrations of tPA antigen or activity.17
Using the endothelium-dependent vasodilator substance P to stimulate tPA release, we recently described an in vivo model to assess the acute fibrinolytic capacity of the human forearm.18 Moreover, we have been able to demonstrate a reduction in tPA release after inducing experimental "endothelial dysfunction" with nitric oxide synthase inhibition.19 We therefore hypothesized that cigarette smoking might impair endogenous fibrinolysis by reducing the capacity of the endothelium to release tPA acutely. The aim of the study was to compare substance P–induced tPA release from the forearm vascular bed of smokers and age- and sex-matched nonsmokers.
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Methods |
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Subjects
Twelve healthy smokers (5 to 20 cigarettes/d) and 12 age- and sex-matched nonsmokers between 25 and 55 years old participated in the study, which was undertaken with the approval of the local research ethics committee and in accordance with the Declaration of Helsinki. The written informed consent of each subject was obtained before entry into the study.
All subjects were normotensive without a history of diabetes mellitus or vascular disease. Female subjects were premenopausal and not receiving hormonal contraceptives. They were clinically well and taking no regular medications. Control subjects were lifelong nonsmokers and were not exposed to regular environmental tobacco smoke. Smokers had a history of regular daily cigarette smoking of at least 5 years' standing and maintained their normal smoking habits in the week before attendance. None of the subjects received vasoactive or nonsteroidal anti-inflammatory drugs in the week before the study, and all abstained from alcohol for 24 hours before and from food, tobacco, and caffeine-containing drinks on the day of the study. All studies were performed in a quiet, temperature-controlled room maintained at 23.5°C to 24.5°C.
Intra-Arterial Drug Administration
The brachial artery of the nondominant arm was cannulated with a
27–standard wire gauge steel needle (Cooper's Needle Works Ltd) under
local anesthesia. The cannula was attached to a 16-gauge
epidural catheter (Portex Ltd), and patency was maintained by infusion
of saline (0.9%: Baxter Health Care Ltd) via an IVAC P1000 syringe
pump (IVAC Ltd). The total rate of intra-arterial infusions
was maintained constant throughout all studies at 1 mL/min.
Pharmaceutical-grade substance P (Clinalfa AG) was administered after
dissolution in saline.
Measurements
Blood flow was measured in both forearms by venous occlusion
plethysmography as previously described.18 19 20 Blood
pressure was monitored in the noninfused arm at intervals throughout
each study with a semiautomated noninvasive oscillometric
sphygmomanometer (Takeda UA 751, Takeda Medical Inc).
Venous cannulas (17-gauge) were inserted into large subcutaneous veins of the antecubital fossae of both arms. Blood (10 mL) was withdrawn simultaneously from each arm and collected into acidified buffered citrate (Biopool Stabilyte, for tPA assays) and citrate (Monovette, for PAI-1 assays) tubes and kept on ice before being centrifuged at 2000g for 30 minutes at 4°C. Platelet-free plasma was decanted and stored at -80°C before assay. Plasma PAI-1 and tPA antigen and activities were determined as previously described18 19 with an ELISA (Coaliza PAI-1 and Coaliza tPA, Chromogenix AB) and a photometric method (Coatest PAI-1 and Coaset tPA, Chromogenix AB). Hematocrit was determined by capillary tube centrifugation at baseline and during infusion of 8 pmol/min of substance P. Plasma lipid fractions were measured by an enzymatic colorimetric method (Boehringer Mannheim GmbH Diagnostica). LDL cholesterol was derived according to the method of Friedewald et al.21
Study Design
At 9 AM, subjects attended fasted and then rested
recumbent throughout each study. Strain gauges and cuffs were applied,
and the brachial artery of the nondominant arm was cannulated. Forearm
blood flow was measured every 10 minutes. Saline was infused for the
first 30 minutes to allow time for equilibration. The final blood flow
measurement during saline infusion was taken as the basal forearm blood
flow. Thereafter, subjects received intra-arterial
substance P at 2, 4, and 8 pmol/min for 10 minutes at each dose.
Data Analysis and Statistics
This study's population size, on the basis of power
calculations derived from previous studies, gives 90% power of
detecting an 18% difference in tPA release at a significance level of
5%. Coefficients of repeatability22 for plasma
concentrations of tPA antigen and activity during substance P infusion
at 8 pmol/min are 1.6 ng/mL and 1.4 IU/mL, respectively (data on
file).
Plethysmographic data were extracted from the Chart data files, and forearm blood flows were calculated for individual venous occlusion cuff inflations by use of a template spreadsheet (Excel version 5.0; Microsoft Corp). Recordings from the first 60 seconds after wrist cuff inflation were not used because of the reflex vasoconstriction this causes.20 Usually, the last 5 flow recordings in each 3-minute measurement period were calculated and averaged for each arm. Estimated net release of tPA activity and antigen was defined previously18 as the product of the infused forearm plasma flow (based on the mean hematocrit, Hct, and the infused forearm blood flow, FBF) and the concentration difference between the infused ([tPA]Inf) and noninfused ([tPA]Noninf) arms: Estimated net tPA release=FBFx(1-Hct)x([tPA]Inf -[tPA]Noninf).
Data were examined, where appropriate, by 2-way ANOVA with repeated measures and 2-tailed Student's t test using Excel version 5.0 (Microsoft). The area under the curve was calculated for the estimated net release of tPA across the study period. All results are expressed as mean±SEM. Statistical significance was taken at the 5% level.
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Results |
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There were no significant differences in baseline characteristics, except that smokers had a slightly lower HDL concentration (Table 1
). There were no significant
changes in blood pressure, heart rate, hematocrit, or blood flow in the
noninfused forearm during the study (data on file; Table 2). In the noninfused arm, plasma tPA
antigen concentrations were higher in smokers than nonsmokers
(P=0.02; Table 2). There were no significant
differences in plasma PAI-1 antigen and activity between the
groups.
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Substance P caused dose-dependent increases in forearm blood flow in
the infused arm in both smokers and nonsmokers (Table 2
,
Figure), but the increase in blood flow
was greater in nonsmokers (P=0.03; 2-way ANOVA, nonsmokers
versus smokers). Compared with the noninfused arm (2-way ANOVA),
substance P caused dose-dependent increases in plasma concentrations of
tPA antigen (P<0.001) and activity (P<0.001) in
the infused arm of both smokers and nonsmokers (Table 2). There
were no significant changes in plasma PAI-1 antigen or activity in
either group. The increase in plasma tPA activity in the infused arm
was greater in the nonsmokers (P=0.001; 2-way ANOVA,
nonsmokers versus smokers).
|
) and nonsmokers (
).
P<0.001 (1-way ANOVA) for all responses. Two-way ANOVA
(nonsmokers vs smokers): *P<0.05;
P<0.001.
Substance P increased the net release of tPA antigen
(P=0.009) and activity (P<0.001) in smokers
(Figure). In nonsmokers, substance P increased the net release
of tPA antigen (P<0.001) and activity (P<0.001)
significantly more than in smokers (P=0.04 and
P<0.001, respectively; 2-way ANOVA, nonsmokers versus
smokers). Compared with the nonsmokers, the area under the curve for
net tPA antigen and activity release was reduced by 51% and 53%,
respectively, in the smokers.
Subgroup analysis after exclusion of female subjects did not alter the magnitude or the statistical significance of the above findings. Qualitatively, the responses in female smokers and nonsmokers were similar to those observed in the male subjects.
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Discussion |
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We have shown here, for the first time, that despite higher basal plasma tPA antigen concentrations, cigarette smokers have a markedly impaired capacity of the endothelium to release tPA acutely. This establishes an important mechanism whereby cigarette smoking can lead to arterial thrombosis and myocardial infarction.
The rapid mobilization of tPA from the endothelium is crucial if endogenous fibrinolysis within the arterial circulation is to be effective, with thrombus dissolution being much more effective if tPA is incorporated during, rather than after, thrombus formation.23 24 The increased risk of spontaneous thrombosis seen in smokers may therefore plausibly relate to the propagation of thrombus, which would otherwise undergo lysis and remain subclinical. Although cigarette smokers have a higher overall mortality from myocardial infarction than nonsmokers,25 the in-hospital mortality is lower.26 27 28 This apparent paradox can be explained by the observation that the infarct-related artery is more than twice as likely to become patent in current smokers as in nonsmokers after thrombolytic therapy for acute myocardial infarction.28 29 30 Indeed, it has been suggested30 that thrombolytic therapy should only be given to smokers and that alternative strategies such as primary angioplasty should be used in nonsmokers. These observations are consistent with the present findings because it might be anticipated that patients with impaired endothelial cell tPA release would benefit most from thrombolytic therapy, whereas those with a normal endogenous fibrinolytic capacity are more likely to have tPA-resistant thrombus, which would respond less favorably.
Our findings in smokers are consistent with the previous observational data12 13 14 that increased basal plasma concentrations of tPA antigen are associated with future coronary events. The assessment of endogenous fibrinolysis has previously relied on measurement of basal plasma tPA concentrations and the acute release of tPA in response to venous occlusion, systemic desmopressin infusion, or exercise.31 32 33 34 However, because of confounding systemic effects and the nonuniformity of the stimuli applied, these responses can be variable and give only a relatively crude measure of fibrinolytic capacity. Moreover, although it has previously been shown that systemic desmopressin infusion causes less tPA release in smokers,31 this effect may not be directly endothelium-dependent.35 In contrast, we have used locally active doses of substance P to provide a more precise pharmacological stimulus to the endothelium and to cause a substantial and dose-dependent local release of tPA.18 19 This has allowed us to demonstrate a distinct and marked inhibition of stimulated endothelial tPA release in smokers.
Although thrombin is more physiologically relevant to acute tPA release than substance P, we have used the latter because its vascular actions are endothelium-dependent,36 mediated in part through nitric oxide,37 and its administration intra-arterially is safe and well tolerated.38 Consistent with previous workers,6 39 40 we have also found an attenuation of the endothelium-dependent forearm blood flow responses in smokers. This inhibition of both the blood flow and tPA response may, in part, relate to an impairment of the L-arginine:nitric oxide pathway in smokers.19 39 Although differences exist,41 the forearm model may provide a useful surrogate for the coronary vascular bed42 43 and permits a readily accessible and reliable assessment of endothelial cell function. However, the present findings need to be confirmed in the coronary circulation.
We have studied the sustained effect of chronic smoking in a selected healthy and predominantly male population at a single time point. Although total and LDL cholesterol concentrations were similar in smokers and nonsmokers, HDL cholesterol concentrations were slightly lower in smokers. This is not unexpected, because cigarette smoking is known to be associated with a selective reduction in HDL cholesterol concentrations.44 45 However, the application of this model to other conditions associated with endothelial dysfunction, such as dyslipidemia, is warranted. Finally, because hormonal status influences fibrinolytic parameters,46 the assessment of the acute fibrinolytic capacity in premenopausal and postmenopausal women and the modulating effect of hormonal therapy will also be of particular interest.
In conclusion, we have demonstrated a major impairment of tPA release from the vascular endothelium of smokers. Our findings suggest that the fundamental mechanism whereby cigarette smoking causes arterial thrombosis and myocardial infarction relates, at least in part, to impairment of the acute endogenous fibrinolytic capacity.
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Acknowledgments |
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This work was supported by a grant from the British Heart Foundation (PG/96149). Drs Newby and Labinjoh are the recipients of British Heart Foundation Junior Research Fellowships (FS/95009 and FS/97007, respectively). Prof Webb is supported by a Research Leave Fellowship from the Wellcome Trust (WT 0526330). We would like to thank Laura Flint and Pamela Dawson for their assistance with this study.
Received September 18, 1998; revision received December 1, 1998; accepted December 18, 1998.
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 M D Cross, N L Mills, M Al-Abri, R Riha, M Vennelle, T W Mackay, D E Newby, and N J Douglas Continuous positive airway pressure improves vascular function in obstructive sleep apnoea/hypopnoea syndrome: a randomised controlled trial Thorax, July 1, 2008; 63(7): 578 - 583. [Abstract] [Full Text] [PDF]
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I. J. Guthmundsdottir, N. N. Lang, N. A. Boon, C. A. Ludlam, D. J. Webb, K. A. Fox, and D. E. Newby Role of the Endothelium in the Vascular Effects of the Thrombin Receptor (Protease-Activated Receptor Type 1) in Humans J. Am. Coll. Cardiol., May 6, 2008; 51(18): 1749 - 1756. [Abstract] [Full Text] [PDF]
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N L Mills, J J Miller, A Anand, S D Robinson, G A Frazer, D Anderson, L Breen, I B Wilkinson, C M McEniery, K Donaldson, et al. Increased arterial stiffness in patients with chronic obstructive pulmonary disease: a mechanism for increased cardiovascular risk Thorax, April 1, 2008; 63(4): 306 - 311. [Abstract] [Full Text] [PDF]
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 G. P. Van Guilder, B. L. Stauffer, J. J. Greiner, and C. A. DeSouza Impaired endothelium-dependent vasodilation in overweight and obese adult humans is not limited to muscarinic receptor agonists Am J Physiol Heart Circ Physiol, April 1, 2008; 294(4): H1685 - H1692. [Abstract] [Full Text] [PDF]
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E. V. Brauner, L. Forchhammer, P. Moller, L. Barregard, L. Gunnarsen, A. Afshari, P. Wahlin, M. Glasius, L. O. Dragsted, S. Basu, et al. Indoor Particles Affect Vascular Function in the Aged: An Air Filtration-based Intervention Study Am. J. Respir. Crit. Care Med., February 15, 2008; 177(4): 419 - 425. [Abstract] [Full Text] [PDF]
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 G. P. Van Guilder, G. L. Hoetzer, J. J. Greiner, B. L. Stauffer, and C. A. DeSouza Metabolic syndrome and endothelial fibrinolytic capacity in obese adults Am J Physiol Regulatory Integrative Comp Physiol, January 1, 2008; 294(1): R39 - R44. [Abstract] [Full Text] [PDF]
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 N. L. Mills, H. Tornqvist, M. C. Gonzalez, E. Vink, S. D. Robinson, S. Soderberg, N. A. Boon, K. Donaldson, T. Sandstrom, A. Blomberg, et al. Ischemic and Thrombotic Effects of Dilute Diesel-Exhaust Inhalation in Men with Coronary Heart Disease N. Engl. J. Med., September 13, 2007; 357(11): 1075 - 1082. [Abstract] [Full Text] [PDF]
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H. Tornqvist, N. L. Mills, M. Gonzalez, M. R. Miller, S. D. Robinson, I. L. Megson, W. MacNee, K. Donaldson, S. Soderberg, D. E. Newby, et al. Persistent Endothelial Dysfunction in Humans after Diesel Exhaust Inhalation Am. J. Respir. Crit. Care Med., August 15, 2007; 176(4): 395 - 400. [Abstract] [Full Text] [PDF]
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 S. D. Robinson, C. A. Ludlam, N. A. Boon, and D. E. Newby Endothelial Fibrinolytic Capacity Predicts Future Adverse Cardiovascular Events in Patients With Coronary Heart Disease Arterioscler Thromb Vasc Biol, July 1, 2007; 27(7): 1651 - 1656. [Abstract] [Full Text] [PDF]
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 S. Lavi, A. Prasad, E. H. Yang, V. Mathew, R. D. Simari, C. S. Rihal, L. O. Lerman, and A. Lerman Smoking Is Associated With Epicardial Coronary Endothelial Dysfunction and Elevated White Blood Cell Count in Patients With Chest Pain and Early Coronary Artery Disease Circulation, May 22, 2007; 115(20): 2621 - 2627. [Abstract] [Full Text] [PDF]
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 D. G. Yanbaeva, M. A. Dentener, E. C. Creutzberg, G. Wesseling, and E. F. M. Wouters Systemic Effects of Smoking Chest, May 1, 2007; 131(5): 1557 - 1566. [Abstract] [Full Text] [PDF]
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I. J. Gudmundsdottir, I. L. Megson, J. S. Kell, C. A. Ludlam, K. A.A. Fox, D. J. Webb, and D. E. Newby Direct Vascular Effects of Protease-Activated Receptor Type 1 Agonism In Vivo in Humans Circulation, October 10, 2006; 114(15): 1625 - 1632. [Abstract] [Full Text] [PDF]
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T. Ohira, E. Shahar, L. E. Chambless, W. D. Rosamond, T. H. Mosley Jr, and A. R. Folsom Risk Factors for Ischemic Stroke Subtypes: The Atherosclerosis Risk in Communities Study Stroke, October 1, 2006; 37(10): 2493 - 2498. [Abstract] [Full Text] [PDF]
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 L.M. Galatz, M.J. Silva, S.Y. Rothermich, M.A. Zaegel, N. Havlioglu, and S. Thomopoulos Nicotine Delays Tendon-to-Bone Healing in a Rat Shoulder Model J. Bone Joint Surg. Am., September 1, 2006; 88(9): 2027 - 2034. [Abstract] [Full Text] [PDF]
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 S D Robinson, C A Ludlam, N A Boon, and D E Newby Phosphodiesterase type 5 inhibition does not reverse endothelial dysfunction in patients with coronary heart disease Heart, February 1, 2006; 92(2): 170 - 176. [Abstract] [Full Text] [PDF]
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N. L. Mills, H. Tornqvist, S. D. Robinson, M. Gonzalez, K. Darnley, W. MacNee, N. A. Boon, K. Donaldson, A. Blomberg, T. Sandstrom, et al. Diesel Exhaust Inhalation Causes Vascular Dysfunction and Impaired Endogenous Fibrinolysis Circulation, December 20, 2005; 112(25): 3930 - 3936. [Abstract] [Full Text] [PDF]
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J. J. Oliver, D. J. Webb, and D. E. Newby Stimulated Tissue Plasminogen Activator Release as a Marker of Endothelial Function in Humans Arterioscler Thromb Vasc Biol, December 1, 2005; 25(12): 2470 - 2479. [Abstract] [Full Text] [PDF]
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 G. P. Van Guilder, G. L. Hoetzer, D. T. Smith, H. M. Irmiger, J. J. Greiner, B. L. Stauffer, and C. A. DeSouza Endothelial t-PA release is impaired in overweight and obese adults but can be improved with regular aerobic exercise Am J Physiol Endocrinol Metab, November 1, 2005; 289(5): E807 - E813. [Abstract] [Full Text] [PDF]
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 S. G. Wannamethee, G. D.O. Lowe, A. G. Shaper, A. Rumley, L. Lennon, and P. H. Whincup Associations between cigarette smoking, pipe/cigar smoking, and smoking cessation, and haemostatic and inflammatory markers for cardiovascular disease Eur. Heart J., September 1, 2005; 26(17): 1765 - 1773. [Abstract] [Full Text] [PDF]
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P. Thanyasiri, D. S. Celermajer, and M. R. Adams Endothelial dysfunction occurs in peripheral circulation patients with acute and stable coronary artery disease Am J Physiol Heart Circ Physiol, August 1, 2005; 289(2): H513 - H517. [Abstract] [Full Text] [PDF]
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B. L. Stauffer, G. L. Hoetzer, G. P. Van Guilder, D. T. Smith, and C. A. DeSouza Gender Differences in Endothelial Tissue-Type Plasminogen Activator Release in Middle-Aged Adults J. Am. Coll. Cardiol., May 3, 2005; 45(9): 1547 - 1549. [Full Text] [PDF]
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 K. E. Freedland, R. M. Carney, and J. A. Skala Depression and Smoking in Coronary Heart Disease Psychosom Med, May 1, 2005; 67(Supplement_1): S42 - S46. [Abstract] [Full Text] [PDF]
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V. F. Tapson The Role of Smoking in Coagulation and Thromboembolism in Chronic Obstructive Pulmonary Disease Proceedings of the ATS, April 1, 2005; 2(1): 71 - 77. [Abstract] [Full Text] [PDF]
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 C. M. Johnson, L. Mureebe, and D. Silver Hypercoagulable States: A Review Vascular and Endovascular Surgery, March 1, 2005; 39(2): 123 - 133. [Abstract] [PDF]
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 H. Iso, C. Date, A. Yamamoto, H. Toyoshima, Y. Watanabe, S. Kikuchi, A. Koizumi, Y. Wada, T. Kondo, Y. Inaba, et al. Smoking Cessation and Mortality from Cardiovascular Disease among Japanese Men and Women: The JACC Study Am. J. Epidemiol., January 15, 2005; 161(2): 170 - 179. [Abstract] [Full Text] [PDF]
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 M S Mahonen, P McElduff, A J Dobson, K A Kuulasmaa, and A E Evans Current smoking and the risk of non-fatal myocardial infarction in the WHO MONICA Project populations Tob. Control, September 1, 2004; 13(3): 244 - 250. [Abstract] [Full Text] [PDF]
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 K. L. Reed, A. B. Fruin, A. C. Gower, A. F. Stucchi, S. E. Leeman, and J. M. Becker A neurokinin 1 receptor antagonist decreases postoperative peritoneal adhesion formation and increases peritoneal fibrinolytic activity PNAS, June 15, 2004; 101(24): 9115 - 9120. [Abstract] [Full Text] [PDF]
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T. Mannami, H. Iso, S. Baba, S. Sasaki, K. Okada, M. Konishi, S. Tsugane, and for the Japan Public Health Center-Based Prospecti Cigarette Smoking and Risk of Stroke and its Subtypes Among Middle-Aged Japanese Men and Women: The JPHC Study Cohort I Stroke, June 1, 2004; 35(6): 1248 - 1253. [Abstract] [Full Text] [PDF]
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J. A. Ambrose and R. S. Barua The pathophysiology of cigarette smoking and cardiovascular disease: An update J. Am. Coll. Cardiol., May 19, 2004; 43(10): 1731 - 1737. [Abstract] [Full Text] [PDF]
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M. L. Summar, J. V. Gainer, M. Pretorius, H. Malave, S. Harris, L. D. Hall, A. Weisberg, D. E. Vaughan, B. W. Christman, and N. J. Brown Relationship Between Carbamoyl-Phosphate Synthetase Genotype and Systemic Vascular Function Hypertension, February 1, 2004; 43(2): 186 - 191. [Abstract] [Full Text] [PDF]
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 K. W. Lee and G. Y. H. Lip Effects of Lifestyle on Hemostasis, Fibrinolysis, and Platelet Reactivity: A Systematic Review Arch Intern Med, October 27, 2003; 163(19): 2368 - 2392. [Abstract] [Full Text] [PDF]
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F. N. Witherow, P. Dawson, C. A. Ludlam, D. J. Webb, K. A.A. Fox, and D. E. Newby Bradykinin Receptor Antagonism and Endothelial Tissue Plasminogen Activator Release in Humans Arterioscler Thromb Vasc Biol, September 1, 2003; 23(9): 1667 - 1670. [Abstract] [Full Text] [PDF]
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J. P.S. Henriques, F. Zijlstra, A. W.J. van 't Hof, M.-J. de Boer, J.-H. E. Dambrink, M. Gosselink, J. C.A. Hoorntje, and H. Suryapranata Angiographic Assessment of Reperfusion in Acute Myocardial Infarction by Myocardial Blush Grade Circulation, April 29, 2003; 107(16): 2115 - 2119. [Abstract] [Full Text] [PDF]
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S. Chia, C. A. Ludlam, K. A. A. Fox, and D. E. Newby Acute systemic inflammation enhances endothelium-dependent tissue plasminogen activator release in men J. Am. Coll. Cardiol., January 15, 2003; 41(2): 333 - 339. [Abstract] [Full Text] [PDF]
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G. L. Hoetzer, B. L. Stauffer, J. J. Greiner, Y. Casas, D. T. Smith, and C. A. DeSouza Influence of oral contraceptive use on endothelial t-PA release in healthy premenopausal women Am J Physiol Endocrinol Metab, January 1, 2003; 284(1): E90 - E95. [Abstract] [Full Text] [PDF]
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 D. T Smith, G. L Hoetzer, J. J Greiner, B. L Stauffer, and C. A DeSouza Effects of ageing and regular aerobic exercise on endothelial fibrinolytic capacity in humans J. Physiol., January 1, 2003; 546(1): 289 - 298. [Abstract] [Full Text] [PDF]
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 F. L Ruberg and J. Loscalzo Prothrombotic determinants of coronary atherothrombosis Vascular Medicine, November 1, 2002; 7(4): 289 - 299. [Abstract] [PDF]
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F. N. Witherow, P. Dawson, C. A. Ludlam, K. A. A. Fox, and D. E. Newby Marked bradykinin-induced tissue plasminogen activator release in patients with heart failure maintained on long-term angiotensin-converting enzyme inhibitor therapy J. Am. Coll. Cardiol., September 4, 2002; 40(5): 961 - 966. [Abstract] [Full Text] [PDF]
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J. A. S. Muldowney III and D. E. Vaughan Tissue-type plasminogen activator release: New frontiers in endothelial function J. Am. Coll. Cardiol., September 4, 2002; 40(5): 967 - 969. [Full Text] [PDF]
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D. A. Rosenbaum, M. Pretorius, J. V. Gainer, D. Byrne, L. J. Murphey, C. A. Painter, D. E. Vaughan, and N. J. Brown Ethnicity Affects Vasodilation, but Not Endothelial Tissue Plasminogen Activator Release, in Response to Bradykinin Arterioscler Thromb Vasc Biol, June 1, 2002; 22(6): 1023 - 1028. [Abstract] [Full Text] [PDF]
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M. Pretorius, D. A. Rosenbaum, J. Lefebvre, D. E. Vaughan, and N. J. Brown Smoking Impairs Bradykinin-Stimulated t-PA Release Hypertension, March 1, 2002; 39(3): 767 - 771. [Abstract] [Full Text] [PDF]
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 C. Bolego, A. Poli, and R. Paoletti Smoking and gender Cardiovasc Res, February 15, 2002; 53(3): 568 - 576. [Abstract] [Full Text] [PDF]
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D E Newby, F N Witherow, R A Wright, P Bloomfield, C A Ludlam, N A Boon, K A A Fox, and D J Webb Hypercholesterolaemia and lipid lowering treatment do not affect the acute endogenous fibrinolytic capacity in vivo Heart, January 1, 2002; 87(1): 48 - 53. [Abstract] [Full Text] [PDF]
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C. Labinjoh, D. E. Newby, M. P. Pellegrini, N. R. Johnston, N. A. Boon, and D. J. Webb Potentiation of bradykinin-induced tissue plasminogen activator release by angiotensin-converting enzyme inhibition J. Am. Coll. Cardiol., November 1, 2001; 38(5): 1402 - 1408. [Abstract] [Full Text] [PDF]
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A. P. Reiner, S. M. Schwartz, M. B. Frank, W.T. Longstreth Jr, L. A. Hindorff, G. Teramura, F. R. Rosendaal, L. K. Gaur, B. M. Psaty, D. S. Siscovick, et al. Polymorphisms of Coagulation Factor XIII Subunit A and Risk of Nonfatal Hemorrhagic Stroke in Young White Women Editorial Comment Stroke, November 1, 2001; 32(11): 2580 - 2587. [Abstract] [Full Text] [PDF]
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M.P. Pellegrini, D. E Newby, S. Maxwell, and D. J Webb Short-term effects of transdermal nicotine on acute tissue plasminogen activator release in vivo in man Cardiovasc Res, November 1, 2001; 52(2): 321 - 327. [Abstract] [Full Text] [PDF]
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G.K Andrikopoulos, D.J Richter, P.E Dilaveris, A Pipilis, A Zaharoulis, J.E Gialafos, P.K Toutouzas, and E.T Chimonas In-hospital mortality of habitual cigarette smokers after acute myocardial infarction. The 'smoker's paradox' in a countrywide study Eur. Heart J., May 1, 2001; 22(9): 776 - 784. [Abstract] [PDF]
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K. Minai, T. Matsumoto, H. Horie, N. Ohira, H. Takashima, H. Yokohama, and M. Kinoshita Bradykinin stimulates the release of tissue plasminogen activator in human coronary circulation: effects of angiotensin-converting enzyme inhibitors J. Am. Coll. Cardiol., May 1, 2001; 37(6): 1565 - 1570. [Abstract] [Full Text] [PDF]
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D. E. Newby, A. L. McLeod, N. G. Uren, L. Flint, C. A. Ludlam, D. J. Webb, K. A. A. Fox, and N. A. Boon Impaired Coronary Tissue Plasminogen Activator Release Is Associated With Coronary Atherosclerosis and Cigarette Smoking : Direct Link Between Endothelial Dysfunction and Atherothrombosis Circulation, April 17, 2001; 103(15): 1936 - 1941. [Abstract] [Full Text] [PDF]
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 R. Chadarevian, E. Bruckert, L. Leenhardt, P. Giral, A. Ankri, and G. Turpin Components of the Fibrinolytic System Are Differently Altered in Moderate and Severe Hypothyroidism J. Clin. Endocrinol. Metab., February 1, 2001; 86(2): 732 - 737. [Abstract] [Full Text]
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 S. E. Porter and E. N. Hanley Jr The Musculoskeletal Effects of Smoking J. Am. Acad. Ortho. Surg., January 1, 2001; 9(1): 9 - 17. [Abstract] [Full Text] [PDF]
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C. Labinjoh, D. E. Newby, P. Dawson, N. R. Johnston, C. A. Ludlam, N. A. Boon, and D. J. Webb Fibrinolytic actions of intra-arterial angiotensin II and bradykinin in vivo in man Cardiovasc Res, September 1, 2000; 47(4): 707 - 714. [Abstract] [Full Text] [PDF]
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 D.E. Newby, N.A. Boon, I. Purcell, and M. Farrer Lower cardiac mortality in smokers following thrombolysis QJM, November 1, 1999; 92(11): 679 - 681. [Full Text] [PDF]
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N. E. R. Goodfield, D. E. Newby, C. A. Ludlam, and A. D. Flapan Effects of Acute Angiotensin II Type 1 Receptor Antagonism and Angiotensin Converting Enzyme Inhibition on Plasma Fibrinolytic Parameters in Patients With Heart Failure Circulation, June 15, 1999; 99(23): 2983 - 2985. [Abstract] [Full Text] [PDF]
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