Thromb Haemost 1990; 63(02): 163-168
DOI: 10.1055/s-0038-1645038
Original Article
Schattauer GmbH Stuttgart

Dissociation of Platelet Activation and Spontaneous Myocardial Ischemia in Unstable Angina[*]

Margarita Vejar
The Cardiovascular Research Unit, Royal Postgraduate Medical School, Hammersmith Hospital, London, United Kingdom
,
Gabriele Fragasso
The Cardiovascular Research Unit, Royal Postgraduate Medical School, Hammersmith Hospital, London, United Kingdom
,
David Hackett
The Cardiovascular Research Unit, Royal Postgraduate Medical School, Hammersmith Hospital, London, United Kingdom
,
David P Lipkin
The Cardiovascular Research Unit, Royal Postgraduate Medical School, Hammersmith Hospital, London, United Kingdom
,
Attilio Maseri
The Cardiovascular Research Unit, Royal Postgraduate Medical School, Hammersmith Hospital, London, United Kingdom
,
Gustav V R Born
1   The Department of Pharmacology, King′s College, London, United Kingdom
,
Giovanni Ciabattoni
2   The Department of Pharmacology, Catholic University School of Medicine, Rome, Italy
,
Carlo Patrono
2   The Department of Pharmacology, Catholic University School of Medicine, Rome, Italy
› Institutsangaben
Weitere Informationen

Publikationsverlauf

Received 15. September 1989

Accepted after revision 27. November 1989

Publikationsdatum:
02. Juli 2018 (online)

Summary

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
  • 3 Maseri A. Pathogenic classification of unstable angina as a guideline to individual patient management and prognosis. Am J Med 1986; 80 (04) C 48-55
  • 4 Falk E. Unstable angina with fatal outcome: dynamic coronary thrombosis leading to infarction and/or sudden death. Circulation 1985; 71: 699-708
  • 5 Davies MJ, Thomas AC, Knapman PA, Hangartner JR. Intramyocardial platelet aggregation in patients with unstable angina suffering sudden ischaemic cardiac deat. Circulation 1986; 73: 418-427
  • 6 Maseri A. The role of coronary artery spasm in symptomatic and silent ischemia. J Am Coll Cardiol 1987; 9: 249-262
  • 7 Fitzgerald DJ, Roy L, Catella F, FitzGerald GA. Platelet activation in unstable coronary disease. N Engl J Med 1986; 315: 983-989
  • 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
  • 10 Ciabattoni G, pugliese F, Davì G, Pierucci A, Simonetti BM, Patrono C. Fractional conversion of thromboxane B2 to urinary 11-dehydro-thromboxane B2 in man. Biochim Biophys Acta 1989; 992: 66-70
  • 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
  • 16 Siegel S. Nonparametric Statistics for the Behavioral Sciences. McGraw-Hill; New York: 1956: 184
  • 17 Lawson JA, Patrono C, Ciabattoni G, FitzGerald GA. Long-lived enzymatic metabolites of thromboxane B2 in the human circulation. Analyt Biochem 1986; 155: 198-205
  • 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
  • 19 Hamm CW, Lorenz RL, Bleifeld W, Kupper W, Weber W, Weber PC. Biochemical evidence of platelet activation in patients with unstable angina. J Am Coll Cardiol 1987; 10: 988-1004
  • 20 Epstein SE, Quyyumi AA, Bonow RO. Myocardial ischemia – Silent or symptomatic. N Engl J Med 1988; 318: 1038-1043
  • 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
  • 24 McBride W, Lange RA, Hillis LD. Restenosis after successful coronary angioplasty.Pathophysiology and prevention. N Engl J Med 1988; 318: 1734-1737
  • 25 Lewis Jr HD, Davis JW, Archibald DJ. Letter to the Editor. N Engl J Med 1984; 310: 122-123
  • 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