A dynamic thrombotic process, coronary spasm or both can be responsible for recurrent episodes of transient reduction of coronary blood flow in unstable angina. We have investigated the temporal relationship between episodic platelet activation, as detected by increased urinary excretion of 11-dehydro-TXB2, and spontaneous myocardial ischemia, assessed by continuous electrocardiographic monitoring and recording in 21 patients with unstable angina pectoris. In order to validate measurements of metabolite excretion as a reflection of intracoronary platelet activation, we have also performed repeated urine sampling from 8 patients undergoing PTCA and from 6 patients with peripheral vascular disease. The latter showed a 16% coefficient of variation in 3 consecutive 8-h urine samples. 11-dehydro-TXB2 increased significantly, by up to 15-fold, in the 2.5- to 5.0-h urine collection encompassing PTCA and decreased by > 50% during the following 2-h period. Patients with unstable angina were characterized by episodic increases (>2 SD of controls) in metabolite excretion, in successive 6-8 h specimens. Paired measurements of 11-dehydro-TXB2 and 2, 3-dinor-TXB2 in 15 urine samples did not reveal evidence of altered metabolic disposition of endogenously released TXB2. A total of 125 ECG ischemic episodes were recorded, of which 64% asymptomatic. We have compared these biochemical and ECG changes in patients randomized to i. v. low-dose aspirin or i.v. isosorbide dinitrate and oral diltiazem. Twenty-five of 56 (i.e. 45%) urine samples obtained in aspirin-free periods showed increased metabolite excretion as compared to 15 of 88 (i.e. 17%) samples collected during aspirin. Of the former, only 3 episodes of enhanced 11-dehydro-TXB2 excretion were associated with ST-segment changes, 7 with chest pain, and 15 with no ECG or clinical changes. Metabolite excretion was approximately 70% lower during aspirin administration than during coronary dilators. However, despite > 95% suppression of platelet cyclooxygenase activity, as monitored ex vivo, incomplete suppression of in vivo TXB2 biosynthesis was occasionally seen during low-dose aspirin therapy. We conclude that in unstable angina, episodic platelet activation is infrequently associated with spontaneous myocardial ischemia. Although the two events may represent functional expressions of the same coronary lesion, they are likely to be triggered by independent mechanisms through different mediators.
References
1
Blumgart IIL,
Schlcsingei MJ,
Davis D.
Studies on the relation of the clinical manifestations of angina pectoris, coronary thrombosis and myocardial infarction to the pathologic findings. Am Heart J 1940; 19: 1-91
2
Neill WA,
Ritzmann LW,
Selden R.
The pathophysiologic basis of acute coronary insufficiency: observations favouring the hypothesis of intermittent reversible coronarv obstruction. Am Heart J 1977; 94: 439-445
8
Patrono C,
Ciabattoni G,
Pinca E,
Pugliese F,
Castrucci G,
De Salvo A,
Satta MA,
Peskar BA.
Low-dose aspirin and inhibition of thromboxane B2 production in healthy subjects. Throm Res 1980; 17: 317-327
9
Patrono C,
Ciabattoni G,
Pugliese F,
Pierucci A,
FitzGerald GA.
Estimated rate of thromboxane secretion into the circulation of normal humans. J Clin Invest 1986; 77: 590-594
11
Roberts LJ II,
Sweetman BJ,
Oates JA.
Metabolism of thromboxane B2 in man. Identification of twenty urinary metabolites. J Biol Chem 1981; 256: 8384-8393
12
GAllino A,
Chierchia S,
Smith G,
Morgan M,
Marchesi C,
Maseri A.
Computer system for analysis of ST-segment changes on 24 hour Holter monitor tapes. J Am Coll Cardiol 1984; 4: 245-252
13
Morgan MJ,
Croom M,
Chiercha S,
Maseri A.
A flexible system for intelligent display of electrocardiographic, pressure and nuclear medicine data recorded over a period of several hours. In: Computer in Cardiology IEEE Computer Society; Long Beach California: 1983. pp 329-332
14
Ciabattoni G,
Maclouf J,
Catella F,
FitzGerald GA,
Patrono C.
Radioimmunoassay of 11-dehydrothromboxane B2 in human plasma and urine. Biochim Biophys Acta 1987; 918: 293-297
15
Ptrono C,
Ciabattoni G,
Remuzzi G,
Gotti E,
Bombardieri S,
Di munno O,
Tartarelli G,
Cinotti GA,
Simonetti BM,
Pierucci A.
Functional significance of renal prostacyclin and thromboxane A2 production in patients with systemic lupus erythematosus. J Clin Invest 1985; 76: 1011-1018
18
Chierchia S,
Brunelli C,
Simonetti D,
Lazzari M,
Maseri A.
Sequence of events in angina at rest: primary reduction in coronary flow. Circulation 1980; 61: 759-768
21
Gottlieb SO,
Weisfeldt ML,
Ouyang P,
Mellits ED,
Gerstenblith G.
Silent ischemia as a marker for early unfavourable outcomes in patients with unstable angina. N Engl J Med 1986; 314: 1214-1219
22
FitzGerald GA,
Pedersen AK,
Patrono C.
Analysis of prostacyclin and thromboxane biosynthesis in caidiuvasculai disease. Circulation 1983; 67: 1174-1177
23
Fitzgerald GA,
Oates JA,
Hawiger J,
Maas RL,
Roberts LJ II,
Lawson JA,
Brash AR.
Endogenous biosynthesis of prostacyclin and thromboxane and platelet function during chronic administration of aspirin in man. J Clin Invest 1983; 71: 676-688
26
Cairns JA,
Gent M,
Singer J,
Finnie KJ,
Froggatta GM,
Holder DA,
Jablonsky G,
Kostuk WJ,
Melendez LJ,
Myers MG,
Sackett DL,
Sealey BJ,
Tanser PH.
Aspirin, sulfinpyrazone, or both in unstable angina. Results of a Canadian Multicenter Trial. N Engl J Med 1985; 313: 1369-1375
27
Lewis Jr HD,
Davis JW,
Archibald DG,
Steinke WE,
Smitherman TC,
Doherty JE,
Schnaper HW,
Le Winter MM,
Linares E,
Pouget JM,
Sabharwal SC,
Chesler E,
De mots H.
Protective effects of aspirin against acute myocardial infarction and death in men with unstable angina. Results of a Veterans Administration Cooperative Study. N Engl J Med 1983; 309: 396-403
