The role of the atherosclerotic process in the pathogenesis of age-related macular degeneration.

T HE CAUSE OF AGE-RELATED MACULAR DEGENERAtion is unknown. In an editorial1 published in the November 1997 issue of the American Journal of Ophthalmology, I proposed that age-related macular degeneration is a vascular disorder, the hemodynamic sequela of atherosclerotic changes affecting the eye. New information regarding the nature and source of the lipids in Bruch membrane and in drusen prompts refinement of the hypothesis. Arteriosclerosis refers to the group of disorders that have in common thickening and loss of elasticity of the arterial wall. It is so universal as to be considered part of “normal” aging. Atherosclerosis, the most common form of arteriosclerosis, is less universal, and is influenced by genetic, dietary, and other environmental factors. It is characterized by lipid deposition (the atherotic component) and vessel stiffening (the sclerotic component).2 The deposition of lipid involves the extracellular trapping of small lipid particles enriched in cholesterol esters in the intima of large arteries.3 The resulting loss of elasticity is caused by increased lesion collagen and destruction of medial elastin. The hemodynamic model, proposed earlier,1 is revised and designated the vascular model (Figure 1), to reflect the roles proposed for both structural and hemodynamic factors in the pathogenesis of age-related macular degeneration. The vascular model proposes that age-related macular degeneration is the result of the accumulation of lipid in the sclera4 and in Bruch membrane,5,6 progressively increasing the stiffness of these tissues7,8 and increasing the postcapillary resistance9 of the choroidal vasculature, situated between the progressively noncompliant sclera and noncompressable contents of the globe. In addition to decreasing choroidal blood flow, the increase in resistance tends to elevate the hydrostatic pressure10 of the choriocapillaris, enhancing leakage and deposition of extracellular proteins and lipids, particularly in the posterior pole. These deposits take the form of basal deposits within Bruch membrane and of drusen between the inner surface of Bruch membrane and the retinal pigment epithelium. Basal deposits and large drusen can compromise the overlying retinal pigment epithelium,11,12 causing pigment clumping, and confluent drusen can cause geographic atrophy of the retinal pigment epithelium. These are the clinical signs of the non–neovascular form of age-related macular degeneration. Retinal pigment epithelium cell dysfunction is proposed to be the result of the process not its cause. The progressive deposition of lipid in Bruch membrane results in the degeneration of elastin and collagen,12 calcification,13 and the upregulation of vascular endothelial growth factor.14 Whether the upregulation of vascular endothelial growth factor is the result of ischemia, hypoxia, or nonspecific tissue damage is not clear. In either case, the vascular model proposes that it is the combination of high choriocapillary pressure, breaks in a calcified Bruch membrane, and vascular endothelial growth factor that is responsible for the growth of new vessels into the subretinal space. The model also suggests that retinal pigment epithelial detachments,15 polypoidal choroidal vasculopathy,16 and choroidal neovascularization are pathogenetic variations of the neovascular form of agerelated macular degeneration. Which variation develops may depend on the level of the intravascular pressure and the relative structural integrity, permeability, and hydraulic conductivity of Bruch membrane. If the choriocapillary pressure is relatively low, the non–neovascular form of age-related macular degeneration will result. If the pressure is elevated, but Bruch membrane is relatively intact, polypoidal choroidal vasculopathy or retinal pigment epithelial detachments may result. Choroidal neovascularization is the outcome if a calcified Bruch membrane is fragmented in the presence of an elevated intravascular pressure. The vascular model proposes that numerous, large, confluent drusen are “risk factors” for choroidal neovascularization, in the sense that they are ophthalAccepted for publication Jun 19, 2000. From the Department of Ophthalmology, Harvard Medical School Retina Service, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts. This work was supported in part by The Solman Friedman Research Fund, Boston, Massachusetts; The Harold Alfond Research Fund, Boston, Massachusetts; and The Ben Wunsch Research Fund, Boston, Massachusetts. Reprint requests to Ephraim Friedman, MD, Massachusetts Eye and Ear Infirmary, 243 Charles St, Boston, MA 02114; fax: (978) 927-3506; e-mail: efriedman@MEEI.harvard.edu