CHARACTERIZATION OF THE EARLY LESION OF DEGENERATIVE VALVULAR AORTIC-STENOSIS - HISTOLOGICAL AND IMMUNOHISTOCHEMICAL STUDIES

Background Nonrheumatic stenosis of trileaflet aortic valves, often te rmed senile or calcific valvular aortic stenosis, is considered a ''de generative'' process, but little is known about the cellular or molecu lar factors that mediate its development. Methods and Results To chara cterize the developing aortic valvular lesion, we performed histologic al and immunohistochemical studies on Formalin-fixed and methanol-Carn oy's-fixed paraffin-embedded aortic valve leaflets or on frozen sectio ns obtained at autopsy from 27 adults (age, 46 to 82 years) with norma l leaflets (n=6), mild macroscopic leaflet thickening (n=15), or clini cal aortic stenosis (n=6). Focal areas of thickening (''early lesions' ') were characterized by (1) subendothelial thickening on the aortic s ide of the leaflet, between the basement membrane (PAS-positive) and e lastic lamina (Verhoeff-van Gieson), (2) the presence of large amounts of intracellular and extracellular neutral lipids (oil red O) and fin e, stippled mineralization (von Kossa), and (3) disruption of the base ment membrane overlying the lesion. Regions of the fibrosa adjacent to these lesions were characterized by thickening and by protein, lipid, and calcium accumulation. Control valves showed none of these abnorma lities. Immunohistochemical studies were performed using monoclonal an tibodies directed against macrophages (anti-CD68 or HAM-56), and contr actile proteins of smooth muscle cells or myofibroblasts (anti-alpha-a ctin and HHF-35) or rabbit polyclonal antiserum against T lymphocytes (anti-CDS). In normal valves, scattered macrophages were present in th e fibrosa and ventricularis, and occasional muscle actin-positive cell s were detected in the proximal portion of the ventricularis near the leaflet base, but no T lymphocytes were found. In contrast, early lesi ons were characterized by the presence of an inflammatory infiltrate c omposed of non-foam cell and foam cell macrophages, occasional T cells , and rare alpha-actin-positive cells. In stenotic aortic valves, a si milar but more advanced lesion was seen. Conclusions The early lesion of ''degenerative'' aortic stenosis is an active inflammatory process with some similarities (lipid deposition, macrophage and T-cell infilt ration, and basement membrane disruption) and some dissimilarities (pr esence of prominent mineralization and small numbers of smooth muscle cells) to atherosclerosis.