Influence of lipoprotein(a) plasma concentration on neointimal growth in a monkey model of vascular injury.
Lipoprotein(a) [Lp(a)] has been proposed as a risk factor for both restenosis and coronary heart disease. Recently, we identified Lp(a) in the arterial wall during the initial rapid neointimal growth phase that occurs after balloon injury in cynomolgus monkeys. The purpose of this study was to determine the relationship between circulating Lp(a) levels and the extent of early neointimal formation. Initially, 348 cynomolgus monkeys were screened to identify 15 monkeys that had either high or low circulating Lp(a) levels. In the 15 monkeys, circulating Lp(a) levels were confirmed by two separate measurements over 6 weeks using an immunoturbidimetric assay. Cohorts were identified with plasma Lp(a) levels that differed by four fold. Lp(a) levels expressed as total mass averaged 32 +/- 4 (N = 8) and 136 +/- 12 (N = 7) mg/dl in the low and high groups, respectively. Between the two assays absolute Lp(a) levels differed by less than 6%. Iliac arteries were harvested 14 days after injury induced by expansion of the internal vessel diameter 1.4 times its initial size with an angioplasty balloon. The neointimal area in the high Lp(a) monkeys was 16% greater (0.49 +/- 0.12 mm2, N = 8 versus 0.57 +/- 0.10 mm2, N = 7) than in the low animals; however, this difference was not statistically significant (P = 0.63). Medial areas averaged 1.27 +/- 0.11 and 1.44 +/- 0.20 mm2 (P = 0.48) in these groups, respectively. Tissue Lp(a) quantification, using a mouse monoclonal anti-Lp(a) antibody, indicated that the percent total area staining positive for Lp(a) was 1.7-fold higher in the high versus the low Lp(a) group (2.7 +/- 0.4% versus 1.6 +/- 0.4%, N = 6-8); this difference was not statistical significant (P = 0.28). In summary, a four-fold increase in circulating plasma Lp(a) levels did not result in a statistically significant enhanced neointimal formation at 14 days after balloon injury. This finding suggests that studies of longer duration may be needed to amplify the trend toward increased neointimal growth observed in this study.
Vascular and Cardiac Diseases, Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, Ann Arbor, MI 48105, USA. ryanm@aa.wl.com
M J
MJ
Ryan
L L
LL
Emig
G W
GW
Hicks
R
R
Ramharack
D W
DW
Brammer
D
D
Gordon
B J
BJ
Auerbach
J A
JA
Keiser
D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism; D002784:Cholesterol / Q000097:blood; D008076:Cholesterol, HDL / Q000097:blood; D003327:Coronary Disease / Q000209:etiology* / Q000473:pathology; D017270:Lipoprotein(a) / Q000097:blood*; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D014280:Triglycerides / Q000097:blood; D017539:Tunica Intima / Q000473:pathology*
D000911:Antibodies, Monoclonal; D008076:Cholesterol, HDL; D017270:Lipoprotein(a); D014280:Triglycerides; D002784:Cholesterol