Endothelial Fibrinolytic Capacity Predicts Future Adverse Cardiovascular Events in Patients With Coronary Heart Disease
Abstract
Objective— The endothelium-derived fibrinolytic factor tissue plasminogen activator (t-PA) is a major determinant of vessel patency after coronary plaque rupture and thrombosis. We assessed whether endothelial fibrinolytic capacity predicts atherothrombotic events in patients with coronary heart disease. Methods and Results— Plasma t-PA and plasminogen activator inhibitor (PAI)-1 concentrations were measured during intrabrachial substance P infusion in 98 patients with angiographically proven stable coronary heart disease. Forearm blood flow was measured during infusion of substance P and sodium nitroprusside. Cardiovascular events (cardiovascular death, myocardial infarction [MI], ischemic stroke [CVA], and emergency hospitalization for unstable angina) were determined during 42 months of follow-up. Patients experiencing a cardiovascular event (n=19) had similar baseline characteristics to those free of events. Substance P caused a dose-dependent increase in plasma t-PA concentrations ( P <0.001). However, net t-PA release was 72% lower in the patients who experienced death, MI, or CVA, and 48% lower in those who suffered death, MI, CVA or hospitalization for unstable angina ( P <0.05). Major adverse cardiovascular events were most frequent in those with the lowest fibrinolytic capacity ( P =0.03 for trend); patients with the lowest quartile of t-PA release had the highest rate of adverse events ( P =0.01). Conclusion— Endothelial fibrinolytic capacity, as measured by stimulated t-PA release, predicts the future risk of adverse cardiovascular events in patients with coronary heart disease. We suggest that endothelial fibrinolytic capacity is a powerful novel determinant of cardiovascular risk.
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Diminished forearm endothelial t-PA release is associated with an increased risk of cardiovascular events.
“diminished forearm endothelial t-PA release is associated with an increased risk of cardiovascular events.”
From The Vasculature in Prediabetes (2018) · cites this paper as [129]
Stimulated t-PA release in the human forearm vasculature correlates with t-PA release in the coronary vasculature.
“Stimulated t-PA release in the human forearm vasculature correlates with t-PA release in the coronary vasculature”
From The Vasculature in Prediabetes (2018) · cites this paper as [129]
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“Indeed, the fibrinolytic capacity of the endothelium predicts future adverse cardiovascular events in patients with coronary disease and may provide additional insights into endothelial function.(12) However, the primary end point in all studies to date has been the quantification of t-PA release and it is unknown whe…”
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“The possible clinical relevance of this finding is highlighted by a recent study by Robinson et al. 25 They determined forearm net release of t-PA in response substance P infusion in 98 patients with angiographically proven stable coronary heart disease.”
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“sion in one third of patients suffering transmural myocardial infarction [4], and impaired t-PA release predicts future adverse cardiovascular events in patients with coronary heart disease [5].”
BackgroundImpaired endogenous fibrinolytic capacity in prehypertensive men
Diehl, K. J., Weil, B. R., Greiner, J. J., Wright, K. P., Stauffer, B. L., & DeSouza, C. A. (2015) · Journal of Human Hypertension · doi:10.1038/jhh.2014.120 · Cited by 7 · see citing works
Boman, K., Hernestål-Boman, J., Andersson, J. S. O., Olofsson, M., & Dahlöf, B. (2009) · Clinical and Applied Thrombosis/Hemostasis · doi:10.1177/1076029609349501 · Cited by 7 · see citing works
“ischemic stroke, and emergency hospitalization for unstable angina.(19) Although b-blockers have an effect on the blood vessels and a plausible secondary effect on the fibrinolytic system, atenolol has no direct effect on the fibrinolytic system.”
BackgroundVascular PAR-1: Activity and Antagonism
Lang, N. N., Guðmundsdóttir, I. J., & Newby, D. E. (2010) · Cardiovascular Therapeutics · doi:10.1111/j.1755-5922.2010.00140.x · Cited by 6 · see citing works
Self-citationGhazalian, F., Hakemi, L., Pourkazemi, L., & Akhoond, M. R. (2014) · Europe PMC (PubMed Central) · Cited by 6 · see citing works
It is time to contend with the endothelial consequences of prehypertension
Guilder, G. P. V. (2015) · Journal of Human Hypertension · doi:10.1038/jhh.2014.122 · Cited by 6 · see citing works
Cameron, A. C., Welsh, P. I., Neves, K. B., Newby, D. E., Touyz, R. M., & Lang, N. N. (2019) · Journal of Hypertension · doi:10.1097/hjh.0000000000002230 · Cited by 6 · see citing works
“The overall balance of fibrinolysis is thus important for the prevention of intravascular thrombosis and predicts the future risk of cardiovascular events [17].”
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Matsumoto, T., Takashima, H., Nakae, I., Yamane, T., Hayashi, H., & Horie, M. (2010) · Hypertension · doi:10.1161/hypertensionaha.110.154278 · Cited by 5 · see citing works
HIKIAMI, H., Nozaki, K., Nagata, Y., Nakata, S., Nogami, T., Obi, R., Goto, H., Shibahara, N., & Shimada, Y. (2008) · doi:10.11339/jtm.25.103 · Cited by 4 · see citing works
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“Robinson et al have shown that acutely stimulated t-PA release predicts the future risk of cardiovascular events.(16) Ninian Lang et al have also shown recently in a comparison of forearm blood flow that thrombin-mediated vascular responses are impaired in smokers, with a substantial reduction in proteaseactivated rec…”
BackgroundHabibi, M., Torkaman, G., Goosheh, B., & Hedayati, M. (2009) · Cited by 2 · see citing works
Ghaediyan, S., Marefati, H., Nabipur, F., & Naghizadeh, M. M. (2012) · Pars of Jahrom University of Medical Sciences · doi:10.29252/jmj.10.2.65 · Cited by 2 · see citing works
“and myocardial infarction in this age group (10).”
BackgroundBergh, N. (2019) · doi:10.17303/jcvm.2019.5.202 · Cited by 2 · see citing works
“Similarly, genetic mutations that result in the decreased t-PA expression are associated with an increased risk of arterial thrombosis [10-12], and impaired fibrinolysis has also been shown to be predictive of future cardiovascular events [13-15].”
BackgroundResearch Progress of Novel Thrombus and Hemostatic Molecular Markers in Acute Coronary Syndrome
王, 哲. (2020) · Advances in Clinical Medicine · doi:10.12677/acm.2020.1011375 · Cited by 2 · see citing works
Ibrahim, H. A. R., Khaled, S., & Shalaby, G. (2023) · The Egyptian Journal of Hospital Medicine · doi:10.21608/ejhm.2023.291967 · Cited by 1 · see citing works
Whelan, G., & Neves, K. B. (2026) · British Journal of Pharmacology · doi:10.1111/bph.70378 · Cited by 1 · see citing works
Exploration biologique de la fonction endothéliale
Bellien, J. (2020) · Revue Francophone des Laboratoires · doi:10.1016/s1773-035x(20)30199-4 · Cited by 1 · see citing works
BLOOD PRESSURE ELEVATION: IMPACT ON CARDIOVASCULAR STRUCTURE AND ENDOGENOUS FIBRINOLYSIS
Ridderstråle, W. (2008) · Gothenburg University Publications Electronic Archive (Gothenburg University)
Larsson, P. (2011) · Gothenburg University Publications Electronic Archive (Gothenburg University)
The role of leptin in endothelial dysfunction and cardiovascular disease
García, G. M., & Cruz, M. O. (2013)
The role of the fibrinolytic system in arterial and venous thrombosis
Meltzer, M. E. (2010) · Utrecht University Repository (Utrecht University)
Diabetes Mellitus and Cardiovascular Risk : epidemiology, etiology and intervention
Rautio, A. (2016) · KTH Publication Database DiVA (KTH Royal Institute of Technology)
Din, J. N., Sarma, J., Harding, S. A., Lyall, K., Newby, D. E., & Flapan, A. D. (2016)
Self-citationWilke, T. (2019) · Journal of Cancer Research and Therapeutic Oncology · doi:10.17303/jcrto.2019.5.203
Vasomotor and fibrinolytic effects of leptin in man
Gonzalez, M. A., Robinson, S. D., Mills, N. L., Eriksson, M., Sandström, T., Newby, D. E., Olsson, T., Blomberg, A., & Söderberg, S. (2025) · Scandinavian Cardiovascular Journal · doi:10.1080/14017431.2025.2478867
“Eighty-three patients with established coronary artery disease were recruited from the cardiology outpatient clinic at the Royal Infirmary, Edinburgh, Scotland, and the characteristics of this cohort have been reported previously [20].”
Self-citation
- Authors
- Robinson, S. D., Ludlam, C. A., Boon, N. A., & Newby, D. E.
- Affiliations
- Edinburgh Royal Infirmary (GB)
- Venue
- Arteriosclerosis, Thrombosis, and Vascular Biology
- Published
- 2007-07
- Volume
- 27
- Issue
- 7
- Pages
- 1651-1656
- ISSN
- 1079-5642 (ISSN-L)
- 1524-4636
- OpenAlex
- W2102657713
- Cited by
- 62
- References
- 41
- Citations by year
- 2026: 1 · 2025: 1 · 2023: 1 · 2022: 1 · 2021: 2 · 2020: 5 · 2019: 4 · 2018: 2 · 2016: 2 · 2015: 4 · 2014: 4 · 2013: 5 · 2012: 2
- FWCI
- 4.26
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Arteriosclerosis Thrombosis and Vascular Biology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Wellcome Trust
- British Heart Foundation
- Topics
- Health Sciences › Medicine › Hematology › Blood Coagulation and Thrombosis Mechanisms
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Acute Myocardial Infarction Research
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Blood properties and coagulation
- Keywords
- tissue plasminogen activator, plasminogen activator inhibitor-1, coronary artery disease, major adverse cardiovascular events, substance P, forearm blood flow, atherothrombosis, cardiovascular risk prediction, myocardial infarction, ischemic stroke, unstable angina
- MeSH terms
- Analysis of Variance, Coronary Disease, Dose-Response Relationship, Drug, Drug Administration Schedule, Female, Follow-Up Studies, Humans, Infusions, Intra-Arterial, Male, Tissue Plasminogen Activator, Predictive Value of Tests, Probability, Prospective Studies, Severity of Illness Index, Substance P, Cohort Studies, Biomarkers, Survival Analysis, Treatment Outcome, Coronary Angiography, Plasminogen Activator Inhibitor 1
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