Increased thromboxane biosynthesis in type IIa hypercholesterolemia.
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.


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.
Davì
G
G
Department of Medicine, University of Palermo School of Medicine, Italy.
Averna
M
M
Catalano
I
I
Barbagallo
C
C
Ganci
A
A
Notarbartolo
A
A
Ciabattoni
G
G
Patrono
C
C
D000328:Adult; D000368:Aged; D000924:Anticholesteremic Agents / Q000627:therapeutic use; D001241:Aspirin / Q000008:administration & dosage / Q000627:therapeutic use; D001792:Blood Platelets / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D006937:Hypercholesterolemia / Q000097:blood / Q000378:metabolism*; D008148:Lovastatin / Q000031:analogs & derivatives / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D019821:Simvastatin; D013928:Thromboxane A2 / Q000096:biosynthesis*
D000924:Anticholesteremic Agents; D013928:Thromboxane A2; D008148:Lovastatin; D019821:Simvastatin; D001241:Aspirin