A Revised Hemodynamic Theory of Age-Related Macular Degeneration

Abstract

Age-related macular degeneration (AMD) afflicts one out of every 40 individuals worldwide, causing irreversible central blindness in millions. The transformation of various tissue layers within the macula in the retina has led to competing conceptual models of the molecular pathways, cell types, and tissues responsible for the onset and progression of AMD. A model that has persisted for over 6 decades is the hemodynamic, or vascular theory of AMD progression, which states that vascular dysfunction of the choroid underlies AMD pathogenesis. Here, we re-evaluate this hypothesis in light of recent advances on molecular, anatomic, and hemodynamic changes underlying choroidal dysfunction in AMD. We propose an updated, detailed model of hemodynamic dysfunction as a mechanism of AMD development and progression.

Figure 1. The Retina-Choroid Interface in AMD: Schematic Diagram of the Choroid and Retina in the Eye

Light entering from the right is focused on the outer retinal photoreceptors (PR). PR are supported by the retinal pigmented epithelium (RPE) and the choroidal vasculature. The innermost layer of the choroid is the choriocapillaris (CC), a thin, dense, highly anastomotic microvascular structure. Between the RPE and the CC is Bruch’s membrane (BM), a specialized multi-layered extracellular matrix that divides the ‘inside’ and ‘outside’ of the eye. The first clinical presentation of AMD is the presence of drusen, extracellular debris that most often develop basal to the RPE, in between CC lumens, and subretinal drusenoid deposits (SDD) that develop between the RPE and photoreceptor layer, and cause outer retinal degeneration. AMD progresses to either geographic atrophy (GA), the gradual atrophy of the choroid, RPE and photoreceptors, and neovascular AMD, aberrant angiogenesis of the choroid through ruptures in BM and the RPE to the PR. Leakage of blood constituents into the retina causes disorganization and swelling of the retina, frequently incompatible with vision.

Figure 2. Friedman’s Hemodynamic Theory of AMD

In 1998 Friedman formally postulated that increased stiffness of the sclera, (supportive fibrous structure that lies posterior to the choroid), and BM, promotes AMD pathogenesis. By this model, the progression towards ‘wet’ or ‘dry’ AMD depends on whether the ophthalmic artery (OA), which provides blood the retinal and choroidal circulations, or the middle cerebral artery (MCA) provides greater vascular resistance. In the case where the OA provides less resistance due to intimal constriction of the the MCA, results in elevated blood pressure in the choroidal vasculature. Because of increased scleral stiffness to the posterior, and intraocular pressure to the anterior, elevated pressure within the choroidal vasculature results in hydrostatic pressure. Friedman postulated that this elevated hydrostatic pressure prevents the clearance of debris from the RPE layer to the choroid, and that this was the cause of neovascular AMD. If, on the other hand, the OA provides more resistance due to intimal constriction of the MCA, the choroid is hypoperfused. The choroid thins or collapses between intraocular pressure and a rigid sclera. Friedman postulated that choroidal hypoperfusion caused hypoxia and was responsible for geographic atrophy.

Figure 3. Hemodynamics of the Choriocapillaris

In this diagram, light is depicted as entering the eye upwards. Blood enters the choriocapillaris through terminal arterioles that form junctions orthogonal to the capillary plane, and exit through venules in much the same manner. As blood exits the arteriole, it spreads centrifugally. This unique anatomic scenario causes a substantial drop in hemodynamic parameters from relatively high pressures, shear stresses, and radiative heat capacity at the arterial inlet, to the relatively low pressures, shear stresses and radiative capacity at the venous exist sites. These parameters therefore are predicted to vary substantially over a relatively short distance. Residence time follows an inverse pattern. The local variability in hemodynamics is reminiscent of arterial branches, where local hemodynamics exhibit strong anatomic dependence.

Key Figure, Figure 4. A Revised Hemodynamic Model of AMD

The model posits that the normal, healthy choriocapillaris consists of resistant (red) and susceptible (brown) areas, based on the local hemodynamic environment. Relevant factors in addition to those mentioned by Friedman include distance from the terminal arteriole, density of arterioles and venules, as well as choriocapillaris thickness and density. With aging, susceptible areas may eventually adopt an atrophic phenotype (beige), which alters local hemodynamics. By virtue of decreased CC density, atrophied areas lose heat-radiating capacity, thereby increasing inflammatory mediators such as complement and Alu RNA. In areas of the CC, atrophy induces elevated shear stress in adjacent capillaries, rendering the choroid ill-suited to remove retinal waste and incapable of vascular repair. This ultimately leads to GA by choroidal RPE and retinal atrophy. Other areas of the CC experience reduced shear stress, thereby promoting an ‘activated’ endothelial phenotype. The angiogenic and inflammatory influences of low shear stress and hyperthermia of the RPE conspire to produce a choroidal neovascular membrane.