Circulation, Vol 85, 1792-1798, Copyright © 1992 by American Heart Association
G Davi, M Averna, I Catalano, C Barbagallo, A Ganci, A Notarbartolo, G Ciabattoni and C Patrono
BACKGROUND. Increased platelet thromboxane (TX)A2 production has been
described in type IIa hypercholesterolemia. To verify the relevance of
these capacity-related measurements to the actual rate of TXA2 biosynthesis
in vivo, we studied the urinary excretion of its major enzymatic
metabolites in 46 patients with type IIa hypercholesterolemia and 20
age-matched controls. METHODS AND RESULTS. Urinary 11-dehydro- TXB2 and
2,3-dinor-TXB2 were measured by previously validated radioimmunoassays. The
excretion rate of 11-dehydro-TXB2 was significantly (p less than 0.001)
higher in patients (68.7 +/- 35.1 ng/hr, mean +/- SD) than in controls
(22.4 +/- 9.4 ng/hr), with metabolite excretion greater than 2 SD of the
normal mean in 74% of the patients. Urinary 11-dehydro-TXB2 was
significantly (p less than 0.01) correlated with the threshold aggregating
concentration of collagen (r = -0.641) and arachidonate (r = -0.734) and
with agonist-induced platelet TXB2 production in vitro (r = 0.647 and
0.748, respectively). Moreover, a statistically significant correlation (r
= 0.673, p less than 0.001, n = 66) was found between 11-dehydro-TXB2
excretion and total plasma cholesterol. The enzyme
3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor simvastatin (20
mg/day for 6 months) significantly reduced cholesterol levels by 22-28% and
urinary 11- dehydro-TXB2 excretion by 32-42% in 10 patients. However, the
reduction in the latter did not correlate with the reduction in the former
and may have resulted from a nonspecific effect of simvastatin. Moreover,
selective inhibition of platelet cyclooxygenase activity by low-dose
aspirin (50 mg/day for 7 days) was associated with cumulative inhibition of
11-dehydro-TXB2 excretion by approximately 70% in six patients.
CONCLUSIONS. TXA2 biosynthesis is enhanced in the majority of patients with
type IIa hypercholesterolemia; this is, at least in part, a consequence of
abnormal cholesterol levels, as suggested by the correlation between the
two. Low-dose aspirin can largely suppress increased metabolite excretion,
thus suggesting that it reflects TXA2- dependent platelet activation in
vivo.
ARTICLES
Increased thromboxane biosynthesis in type IIa hypercholesterolemia
Department of Medicine, University of Palermo School of Medicine, Italy.
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