Aqueous outflow regulation – 21st century concepts

Abstract

We propose an integrated model of aqueous outflow control that employs a pump-conduit system in this article. Our model exploits accepted physiologic regulatory mechanisms such as those of the arterial, venous, and lymphatic systems. Here, we also provide a framework for developing novel diagnostic and therapeutic strategies to improve glaucoma patient care. In the model, the trabecular meshwork distends and recoils in response to continuous physiologic IOP transients like the ocular pulse, blinking, and eye movement. The elasticity of the trabecular meshwork determines cyclic volume changes in Schlemm’s canal (SC). Tube-like SC inlet valves provide aqueous entry into the canal, and outlet valve leaflets at collector channels control aqueous exit from SC. Connections between the pressure-sensing trabecular meshwork and the outlet valve leaflets dynamically control flow from SC. Normal function requires regulation of the trabecular meshwork properties that determine distention and recoil. The aqueous pump-conduit provides short-term pressure control by varying stroke volume in response to pressure changes. Modulating TM constituents that regulate stroke volume provides long-term control. The aqueous outflow pump fails in glaucoma due to the loss of trabecular tissue elastance, as well as alterations in ciliary body tension. These processes lead to SC wall apposition and loss of motion. Visible evidence of pump failure includes a lack of pulsatile aqueous discharge into aqueous veins and reduced ability to reflux blood into SC. These alterations in the functional properties are challenging to monitor clinically. Phase-sensitive OCT now permits noninvasive, quantitative measurement of pulse-dependent TM motion in humans. This proposed conceptual model and related techniques offer a novel framework for understanding mechanisms, improving management, and development of therapeutic options for glaucoma.

Effects of Schlemm’s Canal Expansion: Biomechanics and MIGS Implications

“…Our study as well as prior viscoelastic studies demonstrate disruption of valvular structure traversing the SC lumen and their attachments at CC entrances. We hypothesize that disruption of connections between the TM and CC entrances reduces the ability of the CC entrances to move in response to pressure-dependent TM motion [5].…”

“…SC functions as a compressible chamber. Its morphology and behavior suggests that it is a component of a lymphatic-like pump that regulates IOP [5]. Many studies and multiple lines of evidence document that flow to the aqueous veins is pulsatile and that the origin of the aqueous inducing pulsatile flow is SC and the distal outflow channels [6,7].…”

Trabecular Meshwork Motion Profile from Pulsatile Pressure Transients: A New Platform to Simulate Transitory Responses in Humans and Nonhuman Primates

“…TM distension into SC forces aqueous into collector channels (CC) entrances and aqueous veins. As the pressure spike decays, the TM lamellae return to their original configuration with a resultant reduction of SC pressure, permitting aqueous flow into the canal [10,11].…”

“…TM biomechanics determine TM stiffness and the ability to induce pumplike pulsatile flow [11][12][13][14]. Clinical and laboratory evidence has shown that the pulsatile pattern of aqueous flow decreases and even stops in advanced glaucoma, thought to result from increased TM stiffness [10,14].…”

Inhibitory and Agonistic Autoantibodies Directed Against the β2-Adrenergic Receptor in Pseudoexfoliation Syndrome and Glaucoma

“…The immunological targeting of the β 2 -AR is the basis for the hypothesis of an involvement of β 2 -agAAbs in dysregulation of IOP (Zimmerman, 1977). The IOP is the result of production (ciliary body) and outflow (trabecular meshwork, uveosclera) of the aqueous humor (Johnstone et al, 2020;Kaufman, 2020;Sunderland and Sapra, 2021). Clinical data of patients with POAG, showing a reduced IOP after removal of all circulating IgG antibodies by immunoadsorption, support this hypothesis (Junemann et al, 2018).…”