Impaired coronary tissue plasminogen activator release is associated with coronary atherosclerosis and cigarette smoking: direct link between endothelial dysfunction and atherothrombosis.
BACKGROUND
The aim of the study was to establish the influence of proximal coronary artery atheroma and smoking habit on the stimulated release of tissue plasminogen activator (tPA) from the heart.


RESULTS
After diagnostic coronary angiography in 25 patients, the left anterior descending coronary artery (LAD) was instrumented, and the proximal LAD plaque volume was determined by use of intravascular ultrasound (IVUS). Blood flow and fibrinolytic responses to selective LAD infusion of saline, substance P (10 to 40 pmol/min; endothelium-dependent), and sodium nitroprusside (5 to 20 microgram/min; endothelium-independent) were measured by intracoronary IVUS and Doppler, combined with arterial and coronary sinus blood sampling. Mean plaque burden was 5.5+/-0.8 mm(3)/mm vessel (range 0.6 to 13.7 mm(3)/mm vessel). LAD blood flow increased with both substance P and sodium nitroprusside (P<0.001), although coronary sinus plasma tPA antigen and activity concentrations increased only during substance P infusion (P<0.006 for both). There was a strong inverse correlation between the LAD plaque burden and release of active tPA (r=-0.61, P=0.003). Cigarette smoking was associated with impaired coronary release of active tPA (current smokers, 31+/-23 IU/min; ex-smokers, 50+/-33 IU/min; nonsmokers 202+/-73 IU/min; P<0.05).


CONCLUSIONS
We found that both the coronary atheromatous plaque burden and smoking habit are associated with a reduced acute local fibrinolytic capacity of the heart. These important findings provide evidence of a direct link between endogenous fibrinolysis, endothelial dysfunction, and atherothrombosis in the coronary circulation and may explain the greater efficacy of thrombolytic therapy for myocardial infarction in cigarette smokers.
Newby
D E
DE
Departments of Cardiology, University of Edinburgh, Royal Infirmary, United Kingdom. d.e.newby@ed.ac.uk
McLeod
A L
AL
Uren
N G
NG
Flint
L
L
Ludlam
C A
CA
Webb
D J
DJ
Fox
K A
KA
Boon
N A
NA
D019540:Area Under Curve; D001783:Blood Flow Velocity / Q000187:drug effects; D006328:Cardiac Catheterization; D003324:Coronary Artery Disease / Q000150:complications / Q000175:diagnosis / Q000378:metabolism* / Q000503:physiopathology; D003326:Coronary Circulation / Q000187:drug effects; D003328:Coronary Thrombosis / Q000209:etiology*; D003331:Coronary Vessels / Q000201:enzymology*; D019160:Endosonography; D004730:Endothelium, Vascular / Q000187:drug effects / Q000201:enzymology* / Q000503:physiopathology; D005260:Female; D006801:Humans; D007261:Infusions, Intra-Arterial; D008297:Male; D008875:Middle Aged; D009599:Nitroprusside / Q000008:administration & dosage; D017395:Plasminogen Activator Inhibitor 1 / Q000097:blood; D012044:Regression Analysis; D012307:Risk Factors; D012907:Smoking / Q000009:adverse effects*; D013373:Substance P / Q000008:administration & dosage; D010959:Tissue Plasminogen Activator / Q000378:metabolism*; D014665:Vasodilator Agents / Q000008:administration & dosage
D017395:Plasminogen Activator Inhibitor 1; D014665:Vasodilator Agents; D009599:Nitroprusside; D013373:Substance P; D010959:Tissue Plasminogen Activator