At. Gentile et al., Characterization of cellular density and determination of neointimal extracellular matrix constituents in human lower extremity vein graft stenoses, CARDIOV SUR, 7(4), 1999, pp. 464-469
Arterial restenosis has been attributed to a hyperproliferative smooth musc
le cell response. Paradoxically, studies of human coronary atherectomy and
vein graft stenotic lesions have demonstrated a relatively low nuclear prol
iferative rate with the majority of the neointimal mass consisting of extra
cellular matrix. The purpose of the present study was to characterize the c
ellular density and determine the relative composition of the extracellular
matrix protein constituents in stenotic, human lower extremity vein-bypass
graft lesions. Methods: Duplex surveillance of 148 consecutive infrainguin
al bypass grafts identified 17 patients with 22 preocclusive autogenous vei
n graft stenoses (mean graft age 7 months). Morphological analyses of these
stenotic lesions were compared with excised samples of 20 greater saphenou
s vein segments taken at the time of graft implantation from matched contro
l patients. Intimal and medial areas were compared and cell density was det
ermined with fluorescent nuclear (Bisbenzimide) staining. Differential ligh
t microscopy with pentachrome staining was pet-formed to determine the rela
tive percent composition of intimal matrix constituents by stereological mo
rphometric (point-count) techniques. Results: The intimal areas for control
and stenotic vein segments were 1.64 x 10(6) mu m(2) and 3.85 x 10(6) mu m
(2), P < 0.0001, whereas the intimal nuclear densities (cells/unit volume)
were 1.42 x 10(3) and 1.70 x 10(3) cells/mu m(2), P = 0,03, respectively. T
he corresponding medial area and medial nuclear densities were 5.01 x 10(6)
mu m(2), 3.31 x 10(6) mu m(2): P = 0.08, and 2.27 x 10(3), 3.29 x 10(3), P
= 0.001, for control and stenotic specimens, respectively. The intima:medi
a area ratios were much greater, whereas the intimal and medial cell densit
ies were only slightly greater in the stenotic compared with control veins.
The relative composition of intimal extracellular matrix proteins of steno
tic vein graft segments consisted of 21% cellular (fibrous) material, 33% c
ollagen, and 46% glycosaminoglycan ground substance. Conclusion: The intima
l lesions responsible for lower extremity vein graft stenosis are more hype
rtrophic than hyperplastic, Therapies aimed at preventing arterial and vein
graft restenosis may thus need to inhibit matrix biosynthetic processes in
addition to cellular proliferation. (C) 1999 The International Society for
Cardiovascular Surgery. Published by Elsevier Science Ltd. All rights rese
rved.