Vascular remodeling in the internal mammary artery graft and association with in situ endothelin-1 and receptor expression

Abstract

Background - The vasoconstricting peptide endothelin-1 (ET-1) has been associated with atherosclerotic cardiovascular disease, vascular smooth muscle cell (VSMC) growth stimulation, and intimal thickening. ET-1 binds 2 receptor subtypes, endothelin A and B, and the ETA receptor mediates vasoconstriction and VSMC growth. This study aims to quantitatively assess arterial remodeling variables and compare them with changes in ET-1, ET A, and ETB expression in the internal mammary artery (IMA). Methods and Results - Specimens from 55 coronary artery disease (CAD) patients (45 men, 10 women; mean age 65 years) and 14 control IMA specimens (from 7 men and 7 women; mean age 45 years) were collected. IMA cross sections were assessed by histochemical and immunohistochemical staining methods to quantify the levels of medionecrosis, fibrosis, VSMC growth, ET-1, ET A, ETB, and macrophage infiltration. The percentage area of medionecrosis in the patients was almost double that in the controls (31.85±14.52% versus 17.10±9.96%, P=0.0006). Total and type 1 collagen was significantly increased compared with controls (65.8±18.3% versus 33.7±13.7%, P=0.07, and 14.2±10.0% versus 4.8±2.8%, P=0.01, respectively). Despite ACE and/or statin therapy, ET-1 expression and cell cycling were significantly elevated in the patient IMAs relative to the controls (46.27±18.46 versus 8.56±8.42, P=0.0001, and 37.29±12.88 versus 11.06±8.18, P=0.0001, respectively). ET A and ETB staining was elevated in the patient vessels (46.88±11.52% versus 18.58±7.65%, P=0.0001, and 42.98±7.08% versus 34.73±5.20%, P=0.0067, respectively). A mild presence of macrophages was noted in all sections. Conclusions - Elevated distribution of collagen indicative of fibrosis coupled with increased cell cycling and high levels of ET-1 and ETA expression in the absence of chronic inflammation suggests altered IMA VSMC regulation is fundamental to the remodeling process. © 2006 American Heart Association, Inc.