Impaired Coronary Tissue Plasminogen Activator Release Is Associated With Coronary Atherosclerosis and Cigarette Smoking

Newby, David E.; McLeod, Andrew L.; Uren, Neal; Flint, Laura; Ludlam, Christopher A.; Webb, David J.; Fox, Keith A.A.; Boon, Nicholas A.

doi:10.1161/01.cir.103.15.1936

Cited by 227 publications

(191 citation statements)

References 27 publications

(28 reference statements)

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“…Thus, the t-PA response is independent of changes in heart rate and in local blood flow per se. With regard to blood flow, this is in line with earlier studies showing that SNP has no effect on t-PA release in either the human forearm or in the human coronary vascular bed [8,151,[156][157][158].…”

Section: Effects Of Tachycardia and Hyperaemia On Coronary T-pa Releasupporting

confidence: 89%

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Inhibition of carboxypeptidase U (TAFIa) activity improves rt-PA induced thrombolysis in a dog model of coronary artery thrombosis

Björkman

Abrahamsson

Nerme

et al. 2005

Thrombosis Research

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The physiologically most important activator of intravascular fibrinolysis is tissue-type plasminogen activator (t-PA) released from endothelial cells. In man, sympathomimetic drugs increase the systemic concentration of t-PA. It is therefore of interest to investigate whether cardiac sympathetic activation can induce a local t-PA release, which could counteract intra-coronary clot formation.Thrombolytic therapy with recombinant t-PA (rt-PA) is effective in acute myocardial infarction, but the treatment is limited by a fairly slow reperfusion rate and frequent early reocclusions. A potential mechanism behind early reocclusions might be that active thrombin is released from the thrombus during thrombolytic therapy. Thrombin has recently been shown to activate procarboxypeptidase U, which in its active form (CPU) down-regulates endogenous fibrinolysis. Therefore, one way of improving thrombolytic efficacy may be to combine rt-PA with a lowmolecular weight direct thrombin inhibitor, which theoretically could have a pro-fibrinolytic effect, either by inhibition of fibrin-bound thrombin and/or by inhibition of CPU activation. An alternative way may be direct inhibition of CPU.In a porcine model, experimental activation of cardiac sympathetic nerves by electrical stimulation at 1 and 8 Hz induced 5-and 20-fold increase in the release of both total and active t-PA together with frequency-dependent increases in heart rate, blood pressure, and coronary blood flow. The t-PA release was independent of the heart rate and coronary flow response, but local infusion of isoprenaline suggested that part of the t-PA response was mediated by stimulation of β-adrenergic receptors. Next, we studied the combined effect of rt-PA and thrombin inhibitors (melagatran, hirudin and heparin) in a canine model of copper coil-induced coronary thrombosis. The profibrinolytic effect of rt-PA, either measured as patency rate or time-to-patency, was significantly enhanced with the low-molecular weight direct thrombin inhibitor melagatran, but to a lesser degree by hirudin and heparin. In the same model it was shown that active CPU is produced locally in the coronary vascular bed during both thrombus formation and clot lysis. Inhibition of thrombin attenuated CPU formation and improved patency. A similar effect was obtained with a direct inhibitor of CPU.In conclusion, the coronary t-PA response to sympathetic stimulation may constitute a thromboprotective defence mechanism to counteract its prothrombotic effects on the systemic level. Furthermore, direct thrombin and/or CPU inhibition may be potential targets for prevention of thrombus formation via facilitation of the endogenous fibrinolytic system.

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Section: Effects Of Tachycardia and Hyperaemia On Coronary T-pa Releasupporting

confidence: 89%

“…A reduced capacity to release t-PA has also been observed in subjects with an increased risk of myocardial infarction, i.e. smokers [7,8] and hypertensives [9,10]. It has, however, recently been shown, that the impairment in the latter group is reversible as it can be restored by anti-hypertensive therapy [11].…”

Section: Introductionmentioning

confidence: 99%

Inhibition of carboxypeptidase U (TAFIa) activity improves rt-PA induced thrombolysis in a dog model of coronary artery thrombosis

Björkman

Abrahamsson

Nerme

et al. 2005

Thrombosis Research

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“…First, although we observed significant improvement in endovascular fibrinolytic function with chronic nebivolol treatment, and endothelial t‐PA release has been inversely linked with cardiovascular disease,27, 29 we are unable to conclude that nebivolol treatment will decrease cardiovascular events in patients with elevated BP. From a clinical and public health perspective, it is important to note that the Joint National Commission 8 guidelines removed β‐blocker therapy as an initial treatment for systemic hypertension 42.…”

Section: Discussionmentioning

confidence: 71%

Nebivolol, But Not Metoprolol, Treatment Improves Endothelial Fibrinolytic Capacity in Adults With Elevated Blood Pressure

Stauffer

Dow

Diehl

et al. 2017

JAHA

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BackgroundVascular endothelial fibrinolytic function is impaired in adults with prehypertension and hypertension and plays a mechanistic role in the development of atherothrombotic events. The influence of β‐blockers on endothelial fibrinolysis is unknown. This study compared the effects of chronic nebivolol and metoprolol treatment on endothelial tissue‐type plasminogen activator (t‐PA) release in adults with elevated blood pressure (BP).Methods and ResultsForty‐four middle‐aged adults (36% women) with elevated BP completed a 3‐month, double‐blind, randomized, placebo‐controlled trial comparing nebivolol (5 mg/d), metoprolol succinate (100 mg/d), and placebo. Net endothelial t‐PA release was determined in vivo in response to intrabrachial infusions of bradykinin and sodium nitroprusside before and after each intervention. In a subset, the dose‐response curves to bradykinin and sodium nitroprusside were repeated with a coinfusion of the antioxidant vitamin C. At baseline, resting BP and endothelial t‐PA release were comparable between the 3 groups. BP decreased to a similar extent (≈10 mm Hg) in the nebivolol‐ and metoprolol‐treated groups. There was a substantial increase (≈30%; P<0.05) in the capacity of the endothelium to release t‐PA following chronic treatment with nebivolol but not metoprolol or placebo. Mitigating oxidant stress with vitamin C coinfusion potentiated t‐PA release (90%; P<0.05) at baseline in all groups. However, after the intervention, t‐PA release was unchanged by vitamin C coinfusion in the nebivolol group only.ConclusionsNebivolol but not metoprolol improves endothelial t‐PA release in adults with elevated BP. This may be an important vascular benefit of nebivolol.Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT01595516.

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“…Regular physical exercise and moderate alcohol consumption promote fibrinolysis, increasing tPA activity and decreasing PAI-1 and tPA antigen levels [157]. Fibrinolytic capacity can be seriously diminished by smoking, atherosclerosis, advancing age, heavy or binge alcohol intake and obesity [157][158][159]. BMI and waist/hip ratio correlate positively with t-PA and PAI-1 antigen values, while estrogen is inversely associated with tPA and PAI-1 antigen values [157].…”

Section: Tissue Plasminogen Activator (Tpa) Plasminogen Activator Inmentioning

confidence: 99%

Associations of Thrombotic-Hemostatic Factors with Cardiovascular Disease~!2009-10-29~!2009-12-22~!2010-04-08~!

Lioudaki¹,

Ganotakis²

2012

TOCCHEMJ

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Cardiovascular disease (CVD) remains a leading cause of global morbidity and mortality despite identification of major cardiovascular (CV) risk factors and risk reduction via appropriate interventions. During the last years several markers have been studied as potential predictors of CV events. Hemostatic and thrombotic factors such as fibrinogen, homocysteine, factor VII, von Willebrand, tissue plasminogen activator, plasminogen activator inhibitor -1, D-dimer and lipoprotein ( ) have been found to be closely related to CVD. Many epidemiological studies have indicated that raised levels of these factors are associated with higher incidence of CVD, while some others have yielded conflicting results. As a consequence, it remains obscure whether they contribute to prediction of future CV events on top of conventional risk factors. Although data suggest that most of them are somehow implicated in CVD pathophysiology, it is not clearly defined yet whether treatment of abnormal levels leads to CV risk reduction. As a result measurement and treatment of these factors are justified only in exceptional cases. Further investigation is required in order to conclude whether and which of these factors may claim a position in everyday clinical practice.

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Impaired Coronary Tissue Plasminogen Activator Release Is Associated With Coronary Atherosclerosis and Cigarette Smoking

Cited by 227 publications

References 27 publications

Inhibition of carboxypeptidase U (TAFIa) activity improves rt-PA induced thrombolysis in a dog model of coronary artery thrombosis

Inhibition of carboxypeptidase U (TAFIa) activity improves rt-PA induced thrombolysis in a dog model of coronary artery thrombosis

Nebivolol, But Not Metoprolol, Treatment Improves Endothelial Fibrinolytic Capacity in Adults With Elevated Blood Pressure

Associations of Thrombotic-Hemostatic Factors with Cardiovascular Disease~!2009-10-29~!2009-12-22~!2010-04-08~!

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