Endothelial Fibrinolytic Capacity Predicts Future Adverse Cardiovascular Events in Patients With Coronary Heart Disease

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.

[1]  S. Jern,et al.  Impaired Capacity for Stimulated Fibrinolysis in Primary Hypertension Is Restored by Antihypertensive Therapy , 2006, Hypertension.

[2]  D. Webb,et al.  Stimulated Tissue Plasminogen Activator Release as a Marker of Endothelial Function in Humans , 2005, Arteriosclerosis, thrombosis, and vascular biology.

[3]  D. Vaughan,et al.  Angiotensin-Converting Enzyme Inhibition Increases Basal Vascular Tissue Plasminogen Activator Release in Women But Not in Men , 2005, Arteriosclerosis, thrombosis, and vascular biology.

[4]  Greta L. Hoetzer,et al.  Gender differences in endothelial tissue-type plasminogen activator release in middle-aged adults. , 2005, Journal of the American College of Cardiology.

[5]  C. Jern,et al.  Regulation of local availability of active tissue‐type plasminogen activator in vivo in man , 2004, Journal of thrombosis and haemostasis : JTH.

[6]  D. Vaughan,et al.  Angiotensin-Converting Enzyme Inhibition Increases Human Vascular Tissue-Type Plasminogen Activator Release Through Endogenous Bradykinin , 2003, Circulation.

[7]  K. Fox,et al.  Interventional versus conservative treatment for patients with unstable angina or non-ST-elevation myocardial infarction: the British Heart Foundation RITA 3 randomised trial , 2002, The Lancet.

[8]  D. Newby,et al.  Marked bradykinin-induced tissue plasminogen activator release in patients with heart failure maintained on long-term angiotensin-converting enzyme inhibitor therapy. , 2002, Journal of the American College of Cardiology.

[9]  A. Quyyumi,et al.  Prognostic Value of Coronary Vascular Endothelial Dysfunction , 2002, Circulation.

[10]  M. Eren,et al.  Age-Dependent Spontaneous Coronary Arterial Thrombosis in Transgenic Mice That Express a Stable Form of Human Plasminogen Activator Inhibitor-1 , 2002, Circulation.

[11]  D. Vaughan,et al.  Smoking Impairs Bradykinin-Stimulated t-PA Release , 2002, Hypertension.

[12]  D. Webb,et al.  Hypercholesterolaemia and lipid lowering treatment do not affect the acute endogenous fibrinolytic capacity in vivo , 2002, Heart.

[13]  T. Meinertz,et al.  Endothelial Dysfunction, Oxidative Stress, and Risk of Cardiovascular Events in Patients With Coronary Artery Disease , 2001, Circulation.

[14]  D. Webb,et al.  Potentiation of bradykinin-induced tissue plasminogen activator release by angiotensin-converting enzyme inhibition. , 2001, Journal of the American College of Cardiology.

[15]  D. Webb,et al.  Impaired Coronary Tissue Plasminogen Activator Release Is Associated With Coronary Atherosclerosis and Cigarette Smoking: Direct Link Between Endothelial Dysfunction and Atherothrombosis , 2001, Circulation.

[16]  Grace Investigators,et al.  Rationale and design of the GRACE (Global Registry of Acute Coronary Events) Project: a multinational registry of patients hospitalized with acute coronary syndromes. , 2001, American heart journal.

[17]  M. Davies.  Glagovian remodelling, plaque composition, and stenosis generation , 2000, Heart.

[18]  Davies Mj.  Glagovian remodelling, plaque composition, and stenosis generation. , 2000 .

[19]  S. Higano,et al.  Long-term follow-up of patients with mild coronary artery disease and endothelial dysfunction. , 2000, Circulation.

[20]  M J Davies,et al.  Mechanisms of progression in native coronary artery disease: role of healed plaque disruption , 1999, Heart.

[21]  D. Vaughan,et al.  Bradykinin stimulates tissue plasminogen activator release in human vasculature. , 1999, Hypertension.

[22]  W. Aird,et al.  Vascular-bed--specific hemostasis and hypercoagulable states. , 1999, The New England journal of medicine.

[23]  D. Webb,et al.  Endothelial dysfunction, impaired endogenous fibrinolysis, and cigarette smoking: a mechanism for arterial thrombosis and myocardial infarction. , 1999, Circulation.

[24]  C. Jern,et al.  Impaired capacity for endogenous fibrinolysis in essential hypertension , 1998, The Lancet.

[25]  C. Lang,et al.  Regulation of local tissue-type plasminogen activator release by endothelium-dependent and endothelium-independent agonists in human vasculature. , 1998, Journal of the American College of Cardiology.

[26]  D. Webb,et al.  An in vivo Model for the Assessment of Acute Fibrinolytic Capacity of the Endothelium , 1997, Thrombosis and Haemostasis.

[27]  D. Witte,et al.  Plasminogen deficiency accelerates vessel wall disease in mice predisposed to atherosclerosis. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[28]  R. Virmani,et al.  Coronary risk factors and plaque morphology in men with coronary disease who died suddenly. , 1997, The New England journal of medicine.

[29]  P Vallance,et al.  Measuring forearm blood flow and interpreting the responses to drugs and mediators. , 1995, Hypertension.

[30]  C. Jern,et al.  Release of Tissue-Type Plasminogen Activator in Response to Muscarinic Receptor Stimulation in Human Forearm , 1994, Thrombosis and Haemostasis.

[31]  J. Ritter,et al.  Preserved endothelium-dependent vasodilatation in patients with essential hypertension. , 1994, The New England journal of medicine.

[32]  P. Carmeliet,et al.  Physiological consequences of loss of plasminogen activator gene function in mice , 1994, Nature.

[33]  P. Smits,et al.  Effect of chronic smoking on endothelium-dependent vascular relaxation in humans. , 1993, Clinical science.

[34]  J. Emeis.  Regulation of the Acute Release of Tissue‐type Plasminogen Activator from the Endothelium by Coagulation Activation Products , 1992, Annals of the New York Academy of Sciences.

[35]  R. Collins,et al.  Blood pressure, stroke, and coronary heart disease Part 2, short-term reductions in blood pressure: overview of randomised drug trials in their epidemiological context , 1990, The Lancet.

[36]  F. Feit,et al.  Serial angiographic assessment of coronary artery obstruction and collateral flow in acute myocardial infarction. Report from the second Mount Sinai-New York University Reperfusion Trial. , 1989, Circulation.

[37]  M Gent,et al.  Tissue plasminogen activator: Toronto (TPAT) placebo-controlled randomized trial in acute myocardial infarction. , 1989, Journal of the American College of Cardiology.

[38]  A. V. van Zonneveld,et al.  On the interaction of the finger and the kringle-2 domain of tissue-type plasminogen activator with fibrin. Inhibition of kringle-2 binding to fibrin by epsilon-amino caproic acid. , 1986, The Journal of biological chemistry.

[39]  M. Rånby,et al.  Studies on the kinetics of plasminogen activation by tissue plasminogen activator. , 1982, Biochimica et biophysica acta.

[40]  M S Golden,et al.  Prevalence of total coronary occlusion during the early hours of transmural myocardial infarction. , 1980, The New England journal of medicine.

[41]  G. D. O. Lowea,et al.  Tissue plasminogen activator antigen and coronary heart disease Prospective study and meta-analysis , 2004 .

[42]  薬袋 一夫.  Bradykinin stimulates the release of tissue plasminogen activator in human coronary circulation : effects of angiotensin-converting enzyme inhibitors , 2002 .