Download 18. The role of blood flow in glaucoma

18. The role of blood flow in glaucoma
Scott Wentz1, Casey Seizys1, Giovanna Guidoboni2, Julia C. Arciero2, Katherine Hutchins1, Brent Siesky1, Alon Harris1
Eugene and Marilyn Glick Eye Institute and Indiana University School of Medicine, Indianapolis, IN USA; 2Department
of Mathematical Sciences, IUPUI, Indianapolis, IN, USA
1
1. Vasculature of the eye (Fig. 1)
The arterial supply to the eye arises primarily from
the ophthalmic artery (OA), which is the first branch of
the internal carotid artery (ICA) and is approximately
0.5 mm in diameter. The OA branches into the central
retinal artery (CRA) and one to five posterior ciliary
trunks which divide into multiple branches forming
separate groups of the main posterior ciliary arteries
(PCA). The PCA branches into arteries supplying the
outer retina, choroid, and retrobulbar tissues. The main
PCAs further divide into several short posterior ciliary
arteries (SPCA) before or after piercing the sclera. The
CRA penetrates the optic nerve approximately 15 mm
behind the eye globe, courses adjacent to the central
retinal vein (CRV), passes through the lamina cribrosa
(LC) and branches into four major arterioles supplying
the inner retinal layers.
The venous drainage of the retina, choroid and optic
nerve is mainly through the CRV and the ophthalmic
veins (OV). The CRV and OV are major tributaries to
the cavernous sinus, which ultimately drains into the
internal jugular veins (IJV) at the base of the skull.
The vascular beds supplying the eye are typically
divided into three groups: the retinal, choroidal, and
retrobulbar vascular beds. The retinal vascular bed is
supplied by the CRA, drained by the CRV, and nourishes
the inner two-thirds of the retina. The choroidal vascular
bed is supplied by the PCA, drained by the OV, and
nourishes the deep outer retinal layer. The retrobulbar
vascular bed is supplied by the PCA and branches of the
CRA, drained by the CRV, and nourishes the superficial
nerve fiber layer, the pre-laminar (or pro-laminar)
region, the laminar region, and the retrolaminar region.
1.1. Mechanisms of blood flow regulation
Vascular beds exhibit an intrinsic ability to maintain
blood flow (BF) despite changes in perfusion pressure.
This ability is known as autoregulation and has been
observed in numerous tissues in the body including
the eye. The control of blood flow is achieved by
appropriate changes in arteriolar smooth muscle tone
that cause vessels to dilate or constrict in response to
changes in factors such as intraocular pressure (IOP),
blood pressure (BP), metabolic demands, pH levels, and
neural stimuli. For example, according to the myogenic
response mechanism, an increase in arterial pressure
causes vessel constriction. An increase in wall shear
stress causes vessel dilation, most likely mediated
through the release of nitric oxide. Local and non-local
changes in tissue metabolic status also trigger vasodilation, as in conditions of hypercapnic acidosis.
Metabolic mechanisms include responses to factors
such as nitric oxide and adenosine and conducted
responses that communicate downstream tissue
status to upstream resistance vessels via an electrical
signal conducted along the vascular endothelium. In
vessels with innervations that can affect vessel tone,
stimulation of the sympathetic nervous system leads to
altered smooth muscle tone. Failure of the above-mentioned mechanisms to combine and maintain stable
blood flow to the eye may result in ischemic damage of
the ONH and/or retinal ganglion cells, which can then
lead to retinal ganglion cell (RGC) death and structural
changes of the optic nerve (ONH) head consistent with
the pathophysiology of glaucoma.
Correspondence: Scott Wentz, Eugene and Marilyn Glick Eye Institute and Indiana University School of Medicine, Indianapolis, IN 46202,
USA.
E-mail: [email protected]
Glaucoma Research and Clinical Advances: 2016 to 2018, pp. 243-260
Edited by P.A. Knepper and J.R. Samples
© 2016 Kugler Publications, Amsterdam, The Netherlands
244
S. Wentz et al.
Fig. 1. Anatomy of blood supply to the retina, choroid, and retrobulbar regions. Image taken from the Atlas of Ocular Blood Flow1
1.2. Interactions of ocular blood flow with the extracellular matrix
The vasculature is a dynamic component of the
circulatory system that has a variety of functions
including the distribution and regulation of blood (and,
subsequently, nutrient delivery and waste removal)
as well as the delivery of immune cells to protect and
defend against pathogens. Blood vessels rely on the
extracellular matrix (ECM) to maintain their shape,
to allow for diameter constriction or dilation, and
to dampen mechanical forces and energy produced
by both pulsatile flow and vasoconstriction.2 The
ophthalmic artery supplies blood to the eye and
contains several layers of smooth muscle in order to
accommodate the wide blood pressure range created
by pulsatile blood flow. Medium-to-small-sized arteries,
such as the OA, have an ECM composition that is dense
in smooth muscle cells in order to regulate blood flow
over a certain pressure range, whereas large-sized
arteries have an ECM composition that is dense in
elastic proteins in order to dampen mechanical forces
induced by pulsatile flow produced during the cardiac
cycle.3
1.3. Effects of pulsatility on ocular blood flow
One of the key functions of large arteries (e.g., the
aorta) is to store and release energy during the cardiac
cycle. Specifically, a network of elastic fibers allows
these vessels to store energy during systole and release
energy during diastole. During systole, blood is ejected
from the heart into the vasculature. This results in
an increase in pressure across the vessel wall (i.e.,
The role of blood flow in glaucoma
transmural pressure). According to the Law of Laplace (P
= T / r, where P is transmural pressure, T is wall tension,
and r is vessel radius),5 as the transmural pressure
increases, the ratio of wall tension to vessel radius must
also increase. In its native and relatively relaxed state,
the vascular ECM network is coiled, whereby uncoiling
of the fibers leads to the storage of potential energy.
The vascular ECM stores energy during systole in the
form of wall tension by the uncoiling of the vascular
elastic fiber network. Following systole, diastole begins
during which the stored energy of the vascular ECM
network exerts force on the blood volume that entered
the vessels during systole.4 Since blood is negligibly
compressible and back flow is precluded by the aortic
valve, the ECM-produced force blood to flow to the
medium-sized and small-sized arteries, arterioles, and
capillaries.
In the normal, physiologic state, the retrobulbar
vessels (e.g., the OA, CRA, and PCA), the choroidal
vessels, and the retinal vessels are able to regulate
blood flow through the range of pressures created by
pulsatility.6 This is important since a relatively constant
amount of blood needs to perfuse through a mass of
tissue in order to prevent ischemic tissue damage.
Without the ability to regulate blood flow, pulsatile
blood flow would result in variable and erratic blood
flow – thus reducing perfusion and compromising
the ocular tissues. In disease states, such as primary
open-angle glaucoma (POAG) and diabetes, poor
blood flow regulation within the ocular vasculature has
been observed to contribute to the damage of ocular
tissues.7,8 Essentially, the capacity for the vasculature to
compensate for constant blood flow throughout a wide
range of pressures becomes reduced in these disease
states.
Elevated pulsatility due to arterial aging can also lead
to poor tissue perfusion. With age, both changes in the
vascular ECM and atherosclerosis lead to hardening of
large arteries. This hardening increases the magnitude
of pulsatility, and, consequently, overwhelms the
capacity of the resistance vessels to regulate BF. Older
patients are, thus, at an increased risk of end-organ
damage (e.g., damage to the eye).9
2. Blood flow and glaucoma
POAG is an optic neuropathy characterized by
progressive RGC death, structural changes to the retina
245
and ONH, and irreversible visual field loss. Elevated IOP
has been validated as an independent risk factor for
POAG, and it is currently the only treatable risk factor.
There are many other risk factors that are involved in
glaucoma pathogenesis, as IOP is not the only risk factor
that can increase a patient’s risk for POAG. This section
mentions some of these risk factors and discusses how
blood flow is a notable player in glaucoma pathogenesis.
2.1. Glaucoma risk factors
As previously mentioned, elevated IOP is the only
treatable risk factor for POAG, even though there is
overwhelming evidence that elevated IOP is not the
only factor involved in the disease process. Other
factors that have been shown to be associated with
POAG development include cup-to-disc ratio,10,11 visual
field patterns,10 disc hemorrhages,12,13 myopia,14,15
central corneal thickness (CCT),10,11,16 ocular perfusion
pressure,17,18 intracranial pressure (ICP),19-21 trans-lamina cribrosa pressure gradient,19,22 diabetes,15 systemic
blood pressure,15,18,23,24 ocular blood flow,17 vascular
dysregulation,15,25-27 genetic factors,15,28-31 and age.10,11
Gender and ethnicity are known modifiers of the
relative risk for POAG, although, how they contribute to
an individual’s POAG risk has yet to be established.15
2.2. Blood flow as a risk factor for
glaucoma
There is significant evidence that several risk factors,
both independent of and in combination with IOP,
contribute to the development of glaucoma. In
particular, several associations between blood flow
deficits and glaucoma symptoms have been observed,
and, thus, it is necessary to understand the role of
ocular blood flow as a risk factor for glaucoma.
●● Retinal blood flow: Total retinal flow as measured
by Doppler OCT was found to be significantly
lower in POAG patients compared to healthy
controls (38.08 ± 14.4 µl/min vs. 54.3 ± 5.9 µl/min,
respectively, p = 0.048). These results were also
highly correlated with severity of visual field loss
(p = 0.003).32
●● Ocular structure: Decreased retinal capillary
perfusion was associated with increased optic
cup depth.33
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●● RNFL thickness and visual field: Blood flow
deficits have been linked to visual function.
Retrobulbar blood flow correlates positively with
RNFL thickness34 and visual field mean defect
after two years.35
2.3. Glaucoma medications that target ocular blood
flow
In 2003, Costa et al. reviewed a number of studies that
investigated the ocular hemodynamic effects of various
anti-glaucoma medications.36 Since then, additional
clinical studies have demonstrated the vasoactive
properties of various anti-glaucoma medications in
healthy and glaucoma patients. Many of these anti-glaucoma medications are formulated in topical drops and
are currently used to treat glaucoma by lowering IOP.
Here, we review several anti-glaucoma drug classes
and provide evidence that many of the medications
used to treat glaucoma via lowering IOP also affect
ocular hemodynamics. Consequently, medications
that improve OBF may protect against glaucoma in an
IOP-independent manner.
Prostaglandin analogs (PGAs): Prostaglandin analogs
including latanoprost, unoprostone, bimatoprost, and
travoprost have been shown to lower IOP and, thus,
are used to treat glaucoma. The exact means by which
these medications lower IOP is not fully understood,
but there is very convincing evidence that they enhance
uveoscleral reabsorption of aqueous humor. It is not
yet clear if these medications affect the trabecular
meshwork or other ocular structures as well.37
Generally, these medications are well-tolerated due
to a relatively benign side effect profile with the most
common side effects being conjunctival hyperemia,
pigmentation of the iris, periocular skin or eyelashes,
hypertrichosis, and ocular surface irritation.38
Latanoprost is a very widely-used PGA used for
anti-glaucoma therapy since it has the benefit of being
one of the most well-tolerated agents along in addition
to a desired efficacy in lowering IOP.39 A randomized,
double-masked, placebo-controlled crossover study
on healthy subjects showed that latanoprost has mostly
neutral effects on the ocular circulation,40 but the study
did not evaluate its effects on glaucoma patients.
Other studies have supplied additional information on
the effects of latanoprost on the ocular circulation in
both POAG and OHT patients. For example, Koz et al.
S. Wentz et al.
showed that, at a six-months follow-up assessment,
topical latanoprost significantly reduced the RI in the
OA compared to the baseline values.41
Bimatoprost, one of the most efficacious PGA agents
in terms of lowering IOP, gives mixed results when its
effects on ocular hemodynamics are evaluated.39 Koz
et al. showed that bimatoprost was hemodynamically neutral, meaning BF values were not significantly
changed in POAG or OHT patients after administering
the medication.41 BF velocities in retrobulbar vessels
were not altered in NTG patients taking bimatoprost,42
but the end-diastolic velocity in the CRA was significantly higher compared to baseline values in patients
with newly-diagnosed POAG taking bimatoprost.41
More research will further clarify the effects of
bimatoprost on OBF.
Travoprost is a widely-used anti-glaucoma
medication that has been shown to reduce IOP, increase
OPP (defined as OPP = 2/3*MAP-IOP), and reduce the
RI of the CRA in patients with either POAG or OHT.41
In a study comparing the effects of travoprost and
latanoprost on pulsatile ocular blood flow (pOBF) in
POAG patients,43 both medications caused an increase
in pOBF, but the effect of travoprost did not diminish
over time. Also, the travoprost group showed an
inverse correlation between IOP and pOBF.43 Studies in
rabbits also demonstrated that PGAs increase ONH BF
properties, even after only a single dose.44 Overall, the
ability of travoprost to increase blood flow within the
ONH and decrease IOP makes it an attractive option
for treating glaucoma.
A placebo-controlled study investigated the effects
of unoprostone on ONH blood volume, velocity, and
flow in control patients and patients with NTG. The
treated groups, both NTG patients and normal controls,
showed changes in ocular hemodynamics, while
the placebo groups did not. Specifically, the normal
controls experienced a significantly higher mean
blood flow velocity and flow at hours one and two after
administration. Blood volume was not significantly
increased in the normal controls. In NTG patients, all
three of the investigated hemodynamic parameters
(blood volume, velocity, and flow), were significantly
higher than baseline values measured before administering the medication. Of note, unoprostone administration did not result in a significant decrease in
IOP when comparing the control patients with NTG
patients.45 This is likely due to the low baseline IOP
The role of blood flow in glaucoma
values seen in both normal controls and NTG patients.
Beta-blockers (BBs): Systemic beta-blockers are used
in medicine because they are antagonists of beta-adrenergic receptors. Many tissues within the body have
beta-adrenergic receptors, including the heart, lungs,
brain, kidney, the ciliary apparatus within the eye, and
many others.46-48 In the eye, BBs lower IOP by reducing
cyclic AMP in the ciliary epithelium.49 Since BBs can
affect multiple body sites, BBs used for glaucoma
treatment (e.g., timolol, betaxolol, and levobunolol) are
topical. This allows for local antagonism of the ciliary
epithelium without blocking sites in other parts of the
body.
Timolol is one of the most widely used anti-glaucoma BBs on the market. It is available in the United
States as a sole agent or contained in a combination
eye drop (e.g., Cosopt®). A study on healthy Japanese
subjects showed that timolol was hemodynamically neutral in the ONH circulation when used as a sole
agent. However, when timolol was combined with
dorzolamide, the combination product increased ONH
BF.50 This suggests there may be a synergistic effect
on ONH BF when the combination product is used.
However, it is also possible that the size of the study (n =
15) was not sufficient to observe a statistical difference
in BF when studying the medications in isolation.
Carbonic anhydrase inhibitors (CAIs): Carbonic
anhydrase inhibitors are a relatively common
treatment modality for glaucoma. The mechanism
of action in lowering IOP for CAIs is the inhibition of
carbonic anhydrase within the ciliary apparatus of
the eye. Carbonic anhydrase normally produces both
a bicarbonate ion and hydrogen ion within the ciliary
epithelium. The production of these two ions leads to
the transport of water into the posterior chamber of
the eye, thus increasing the volume of aqueous humor.
CAIs block this process, and, as a result, lower IOP by
decreasing the volume of aqueous humor produced.51
Similar to the beta-adrenergic receptors, carbonic
anhydrase is present elsewhere in the body. Consequently, topical CAIs instead of systemic CAIs are used
to treat POAG in order to prevent systemic side effects
(e.g., metabolic acidosis, paresthesias, dysgeusia with
carbonated beverages).52 However, in the case of an
acute angle-closure glaucoma attack, acetazolamide,
a systemic CAI, is used, since the benefit of preserving
247
retinal ganglion cells outweighs the systemic side
effects of the medication.53
Dorzolamide is a common topical CAI used to treat
glaucoma. It is available in the United States as either
a sole agent or a combination product with another
drug class agent. When added to timolol, dorzolamide
has been shown to increase BF within the superficial
retinal vasculature for POAG and non-POAG patients
and within the retrobulbar vessels for POAG.54,55
Brinzolamide is another commonly used CAI that
has been shown to improve retinal blood flow in the
peripapillary retina.56 A comparative study of brinzolamide and dorzolamide suggests that brinzolamide
may be more efficacious in increasing retinal BF than
dorzolamide.55 However, brinzolamide does not seem
to affect the retrobulbar circulation while dorzolamide
does.55,57,58 This vessel selectivity exhibited by brinzolamide could be used in cases requiring increased BF
only to the retina.
Alpha2-adrenergic agonists: Brimonidine is a selective
alpha2-adrenergic receptor agonist which has been
shown to reduce IOP through both decreased aqueous
humor production and increased uveoscleral outflow.59
It is still unclear if brimonidine increases OBF since
some studies showed an increase in blood flow velocity
and pOBF60,61 while other studies showed no change in
BF in POAG and OHT patients.62-65 Despite this, there is
significant evidence to assert that brimonidine acts to
stabilize the ocular vessels by enhancing blood flow
autoregulation in POAG and NTG patients.66,67
Like brimonidine, apraclonidine is an alpha2-adrenergic receptor agonist. Apraclonidine has been shown
to lower RI and PSV in the retrobulbar circulation of
newly-diagnosed POAG patients,68 but did not affect
peripapillary retinal blood flow or ONH BF.45 It has been
proposed that topical application of apraclonidine may
cause vasoconstriction, thereby decreasing the amount
of aqueous humor.37
Cholinergic agonists: Cholinergic agonists reduce IOP
by causing the ciliary muscle to contract, resulting in
enhanced reabsorption of aqueous humor through the
trabecular meshwork. Examples of cholinergic agonists
include pilocarpine, echothiophate, and carbachol.
Pilocarpine has been shown to increase pulsatile OBF
in untreated ocular hypertension patients69 but had
no direct effect on pulsatile OBF in POAG patients.70
248
Like apraclonidine, the ability of pilocarpine to reduce
aqueous humor production may be partly due to
triggering vasoconstriction in the blood vessels
supplying the iris and ciliary processes.71 The effects
of echothiophate and carbachol on OBF have not been
well-studied which illustrates a relative need for more
research in this area. Ultimately, the side effect profile
of cholinergic agonists (e.g., miosis leading to reduced
vision due to increased light diffraction, myopia, brow
ache) makes them a poor choice for glaucoma therapy.
Systemic medications: It is important to identify the
effects of systemic medications on OBF since many
glaucoma patients have comorbidities that necessitate
treatment with systemic medications. Two examples
include patients with hypertension require treatment
with anti-hypertensive medications and patients with
idiopathic intracranial hypertension, also known as
pseudotumor cerebri, who are treated with medical
therapy (i.e., acetazolamide).72 As mentioned previously,
acetazolamide is used in glaucoma therapy for acute
angle-closure glaucoma attacks meaning it is only
used on a short-term basis for glaucoma. Knowing
how the medication affects OBF would provide useful
information.
Fortunately, a 2013 study investigated this and
showed that acetazolamide leads to the dilation of
retinal vessels, increased BF to the ONH, and decreased
para-papillary retinal BF.73 Acetazolamide also has been
shown to increase choroidal BF.74 Another systemic
medication, bisoprolol, a systemic beta-blocker,
shows evidence of unfavorably affecting OBF75 while
propranolol does not.76 Another systemic beta-blocker, nebivolol, showed accelerated BF in the small
retrobulbar vessels, possibly due to its nitric oxide-releasing properties.77 Lastly, nimodipine and nifedipine,
systemic calcium-channel blockers, have been shown to
affect OBF in a beneficial way.78,79
The list is much more extensive, but, for brevity,
the key point is that a plethora of data is available that
supports the notion that both topical and systemic
anti-glaucoma medications affect OBF. Many of these
medications affect OBF in a beneficial way by accelerating BF velocities in the ONH, choroid, and retinal vessels.
However, some affect OBF in a detrimental way by
reducing OBF in certain vascular beds. The consequences of increasing or decreasing OBF may be protection
against or increased risk for glaucoma, respectively.
S. Wentz et al.
2.4. Effects of hypertension on blood flow in glaucoma patients
Although decreases in perfusion pressure and blood
pressure have been associated with glaucomatous
damage, the association between arterial hypertension and POAG remains unknown due to inconsistent study findings. The Blue Mountain Eye Study, for
example, showed that hypertension was associated
with an increased risk of POAG, whereas the Barbados
Eye Study concluded that low systolic blood pressure is
a significant risk factor for POAG.80,81
Several studies link low OPP with glaucoma,
including the Baltimore Eye Survey, the Egna-Neumarkt Study, Proyecto VER, the Rotterdam Study, the
Los Angeles Latino Eye Study, the Singapore Malay Eye
Study, the South Indian Study, the Barbados Eye Study,
and the Early Manifest Glaucoma Trial.18,80,82-87 Since
OPP is defined as the difference between arterial blood
pressure and IOP, high IOP and low blood pressure
may also be risk factors for glaucoma. However, the
association between blood pressure and glaucoma has
been inconsistent.
The Thessaloniki Eye Studies investigated the relationship between blood pressure and glaucomatous
progression. A subgroup analysis of blood pressure
status, which takes into account whether or not a
subject uses antihypertensive medication, provided
more conclusive data.88,89 Only subjects with low
diastolic BP who were being treated with anti-hypertensive medications had an associated increase in cup
area and cup-to-disc ratio. Another study showed that
the use of calcium channel blockers was associated
with POAG.90 Grunwald et al. noted that treatment of
systemic hypertension may further decrease ocular
blood flow in glaucoma patients with hypertension.91
There are two major hypotheses for the role of antihypertensive medication in the relationship between
glaucoma and decreased systemic and ocular perfusion
pressure. The first hypothesis is that impaired vascular
regulation disrupts the natural ability of blood vessels to
maintain BF to the eye, causing ischemia or reperfusion
damage and ultimately glaucomatous progression.92
Studies have demonstrated optic nerve head autoregulation with increasing IOP but altered hemodynamic
responses in patients with hypertension.93-95 BF dysregulation may be due to chronic microvascular damage
caused by systemic hypertension, or possibly due
to the antihypertensive medications themselves, as
The role of blood flow in glaucoma
suggested by the results of the Thessaloniki Eye Studies.
The second hypothesis is that subjects treated for
systemic hypertension experience larger reductions of
nocturnal blood pressure, or ‘nocturnal overdipping’,
which may increase chances of ischemia and
reperfusion damage and thus tissue damage and glaucomatous progression.96 Several studies have investigated this theory and have provided supporting results,
showing an association of glaucomatous progression
with nocturnal overdipping and greater fluctuations in
circadian blood pressure.96-99
3. Diabetes and blood flow
Several studies have indicated that diabetic patients
with glaucoma have a stronger vascular component
to their glaucomatous progression than non-diabetic
POAG patients. Specifically, diabetes is shown to affect
structural and hemodynamics factors associated with
ocular blood flow.
3.1. Impact of diabetes on ocular structural factors
In POAG patients with diabetes, changes in inferior
retinal blood flow was significantly correlated with
changes in the ONH (e.g., rim volume, cup to disc area
ratio, rim area, cup area, cup shape, linear c/d ratio)
after four years.100,101 In addition, the change in retinal
blood flow in these patients was significantly correlated
with changes in macular thickness after four years. This
suggests that POAG patients with diabetes may have a
stronger vascular contribution to their glaucomatous
structural damage.102 It is also important to note that
changes in vascular resistance were strongly correlated
with deterioration of the RNFL and macula in POAG
patients with DM.103
3.2. Impact of diabetes on ocular hemodynamic
factors
POAG patients with diabetes may have more ocular
vascular contributions to glaucomatous progression
than non-diabetic patients. In POAG patients with
diabetes, the resistive index was found to increase in
the central retinal artery and temporal posterior ciliary
arteries.104,105 These results suggest blood flow may be
altered to the retina and ONH in POAG patients with
diabetes.106
Preliminary studies also suggest that POAG patients
with diabetes may have impaired vascular autoreg-
249
ulation compared to non-diabetic POAG patients. In
POAG patients with diabetes, changes in SBP, MAP,
SPP, OPP, and MPP correlated to changes in EDV and
RI. It was found that changes in SCPH blood flow
correlated to changes in systemic blood pressure and
ocular perfusion pressures,107 suggesting alterations
of autoregulation during BP and OPP fluctuations.
Another study demonstrated that impaired retrobulbar
vascular autoregulation may lead to passive blood flow
dynamics from the retrobulbar blood supply to the
retinal vessels.108
Furthermore, Egan et al. found that POAG patients
with diabetes had decreased areas of capillary blood
flow than non-diabetic patients, suggesting that
diabetic patients with POAG experience more capillary
dropout.109
In summary, these studies suggest that POAG
patients who also have diabetes experience many
additional changes in ocular vasculature as opposed
to POAG patients without diabetes, and these changes
may enhance glaucomatous progression.
3.3. Impact of diabetes on the extracellular matrix
Pathologic complications of diabetes that occur in
the retina are typically due to hyperglycemia-induced
changes of the microvasculature. Non-enzymatic glycation (NEG) and accumulation of extracellular
matrix (ECM) proteins in the vasculature is the primary
pathophysiologic mechanism by which these complications arise. NEG of proteins can cause modification of
protein function and gene expression.
Accumulation of ECM is caused by several factors.
An increase in laminin and type-IV collagen production
via altered oncogene expression causes thickening
of capillary basement membranes, which affects cell
migration, adhesion, and growth and may impair
vascular metabolism.110-112 Glycation of these ECM
proteins also alters the interaction between the cell
and ECM. Hyperglycemia can activate the protein
kinase C (PKC) pathway, which upregulates endothelins
(ET), causing activation of Nuclear Factor-κβ (NF-κβ)
and activating protein-1 (AP-1) to increase production
of fibronectin.113
After glycation of certain proteins, advanced glycation
end products (AGEs) can form through a series of
chemical reactions. Elevated levels of AGEs have been
found in diabetic retinal tissue and impart damage to
the retinal vasculature by increasing inflammation,
S. Wentz et al.
250
vascular permeability, oxidative damage, and cellular
apoptosis and potentially inducing a pro-coagulatory
state. By binding to their receptor (i.e., RAGE), AGEs can
induce activation of cell signaling cascades, including
Nuclear Factor-κβ (NF-κβ), that have many deleterious
effects, such as increased formation of cytokines and
free radicals; altered vasodilator response to nitric
oxide (NO); altered gene expression of thrombomodulin, tissue factor (TF), and endothelin-1 (ET-1); and
modified levels of growth factors such as vascular
endothelial growth factor (VEGF) and basic fibroblastic
growth factor (FGF).110,112,114 Current research is investigating a new target for the prevention and treatment
of microvascular diabetic complications by blocking
RAGE/AGE interaction.115
AGEs also induce cross-linking of collagen fibrils,
causing corneal stiffening. This would suggest that
diabetic patients would have an increased risk of
glaucoma, due to low corneal hysteresis (CH), i.e., low
viscous damping capacity of the cornea influenced by
its viscoelastic properties.
Hager et al. evaluated changes in the ECM of the
cornea in diabetic patients and found that CH was significantly higher in diabetic patients than in non-diabetics. Although AGE-induced cross-linking does
cause corneal stiffening, Hager et al. discussed the
hypothesis that the increase in glycosaminoglycans
from the glycation of corneal proteoglycans may play
a major role in increasing corneal hysteresis, and, thus,
protecting diabetics from glaucoma.116 Although many
studies have reported that diabetes is a risk factor for
glaucoma, several other studies reported that diabetes
has a protective effect against the progression of
glaucoma.117,118 Such studies thus show an inconclusive link between diabetes and the progression of
glaucoma.117,118
ET-1 is an essential mediator for the activity of
proteolytic enzymes that degrade ECM proteins called
matrix metalloproteinases (MMP) and is a regulator
of ECM protein production, specifically fibronectin
(FN). ET-1 is elevated in diabetes, and the levels of
fibronectin and the expression of MMP and matrix
scaffold protein genes are altered in diabetic retinal
disuse.119 Khan et al. used bosentan, an ET antagonist,
to prevent FN expression in cells exposed to high levels
of glucose, suggesting that ET may be a future target
for therapy for diabetic complications.120 FN not only
causes basement membrane thickening, but it also is
involved in cellular proliferation and VEGF expression,
which plays a key role in neovascularization in proliferative diabetic retinopathy.
3.4. Impact of diabetes on pulsatility
The effects of diabetes on the ECM of the vasculature
likely translate to changes in the pulsatility of the
vasculature within the eye. As described in Section
3.2, the RIs in diabetic, POAG patients are significantly higher than in patients with only POAG. This is
supported in other systems outside of the eye, as the
resistive indices of diabetics (calculated as peak systolic
velocity minus end diastolic velocity) measured within
intra-renal arteries are significantly higher compared to
RIs in healthy control subjects.121 Further, the pulsatility
index (PI) and RI within renal arteries are both associated
with the progression of chronic renal failure, indicating
that pathologic perfusion through aberrant pulsatile
blood flow is one of many sequelae that results from
diabetes.122 Qualitatively, the RI may be used to infer
pulsatility since the PI takes into account the mean
velocity during the cardiac cycle while the RI does not.
Resistive Index = peak systolic velocity ‒ end diastolic
velocity
Pulsatility Index = RI / mean velocity during cardiac
cycle
If the same vessels are measured at similar locations
within the body between groups, a statistical difference
in RI values between groups would likely yield a
statistical difference in PI values for the same system.
In conclusion, previous studies assessing pulsatile BF
in the kidney support the idea that aberrant pulsatility
within the eye is associated with the progression of
glaucoma in the eye. This makes sense since diabetes
is a systemic disease. There is also convincing evidence
that the ECM changes incurred from diabetes is the
keystone to the pathophysiology.
4. Summary
The involvement of vascular factors in glaucomatous
optic neuropathy was postulated as early as 1885
by Priestley Smith, who suggested involvement of
both mechanical and vascular factors in glaucoma
pathology. Over the past several decades, many pop-
The role of blood flow in glaucoma
ulation-based studies have found low OPP to be an
independent risk factor for glaucoma while numerous
small clinical studies have identified decreased retinal,
choroidal, and retrobulbar blood flow to be associated
with glaucoma prevalence and incidence. While the
relationship between OBF and glaucoma is relatively
a well-established concept, the nature of that relationship is not well understood. The reduced ocular blood
flow seen in OAG patients may be secondary to elevated
IOP, RGC death, or of primary vascular origin. Some
theorize that decreased blood flow causes ischemic
insult to the optic disc and retina, which may play a role
in the structural and functional damage that is characteristic of glaucoma. Others theorize that elevated IOP
in glaucoma leads to tissue injury, thus obviating the
need for blood flow to that region.
The more recent focus on the need for prospective
longitudinal vascular-based studies has finally begun
to produce initial pilot data showing decreased ocular
blood flow to be predictive of and/or correlated with
glaucomatous structural and functional progression.
However, these studies are small in number, often
measure only one vascular bed and require larger
longitudinal samples confirm these pilot findings.
The lack of a gold standard in measuring all relevant
vascular beds in the eye for glaucoma risk assessment
remains the largest barrier to advancement, as does
limited availability of imaging expertise in traditional
glaucoma management facilities. Future development
of improved devices for the non-invasive vascular
imaging for the eye is still paramount for the field to
advance from its current status.
Finally, individual susceptibility and personalized
risk evaluations hold the promise of improved patient
care as glaucoma is non-uniform in its disease presentation. Persons with diabetes have been shown to be at
elevated risk for vascular complications in glaucoma,
as have persons of African descent. In general, age
affects vascular compliance and autoregulation, as may
gender, obesity, medications, and overall health. So an
individual may be at a much higher risk for vascular
impairment and subsequent glaucoma risk based upon
their diabetic status, race and confounding health
issues. Therefore the long-term focus for glaucoma
management should be on identifying individualized
risk assessment, using a model, which incorporates
vascular functionality, diabetic status, race, gender,
and other health factors.
251
4.1. The role of clinical blood flow studies in understanding the pathophysiology of glaucoma
In the previous section, we outlined the need for larger,
longitudinal studies to follow up on pilot work showing
how vascular impairment is linked to glaucoma
progression. The need for more standardized and
easily accessible non-invasive blood flow evaluation
methodology is key to increasing the existing body
of evidence to a point of differentiation. Meanwhile
individualized risk assessment factoring in multiple
variables and overall health status may provide the key
for elucidating why many individuals have glaucoma
pathology while others with similar traditionally
measured variables do not experience glaucomatous
vision loss. Future studies that may greatly impact our
understanding of glaucoma will likely have several key
characteristics:
●● Studies should be longitudinal, with large patient
populations similar in size and scope to the
previously established IOP trials;
●● Due to the non-uniformity of glaucoma
pathology, studies should account for age, sex,
race, obesity, blood pressure, and medication
use, all of which may greatly affect individualized
outcomes;
●● Diabetic status, which has begun to be found
to have substantial influences on the ocular
vasculature, will need to be accounted for, as will
other vascular-impacting pathologies;
●● Other confounding variables, such as intracranial
pressure, may be highly influential in determining
how IOP and vascular perfusion are linked;
●● Mathematical and other dynamic modeling of
fluid forces and regulatory mechanisms may
be increasingly important for differentiating
outcomes for individuals who present with
different combinations of variables that a study
population may not reveal regardless of size and
scope.
Taken as a whole, there remains much work to be
done to understand how OBF and metabolism are specifically involved in the glaucomatous disease process.
However, there is little doubt that a healthy vibrant
ocular vascular system would not be protective of other
influences while the presence of an impaired vascular
system may increase susceptibility. Diabetic status, race,
252
gender, age, medication use, obesity, and many other
physiological and pathological factors are likely linked,
as are other fluid forces such as intracranial pressure,
blood pressure and IOP. What will be most impactful
will be future studies that take as many individualized
risk factors into account as possible to produce a risk
profile specific to that individual. Groups of patients are
by nature heterogeneous, and glaucoma is specifically
a multifactorial optic neuropathy. Therefore the true
advancement of glaucoma risk assessment may very
well lie in the individualized modeling approach, or at
least in advanced statistical applications which look
beyond static, traditional one-for-one paradigms and
take into account the complex, interwoven nature of
known and theorized risk factors and also the dynamic
nature of the human body.
4.2. Role of mathematical modeling in understanding relationships between blood flow and glaucoma
The evidence reviewed in the previous sections show that
several important questions concerning the relationship between blood flow and glaucoma remain open.
The following issues are among the most controversial
open questions in glaucoma research: are alterations in
ocular blood flow primary or secondary to glaucomatous damage? Is low OPP dependent or independent of
the two separate risk factors of low MAP and high IOP?
Does the answer to the previous question depend on the
ranges of MAP and IOP?123,124 Indeed, multiple population-based studies have found significant associations
between low OPP and glaucoma incidence, prevalence,
and progression,82,85,86,125 providing the strongest
evidence for vascular contributions in glaucoma.
However, several factors can affect OPP, including fluctuations in MAP and IOP,126,127 alterations of cerebrospinal fluid pressure (CSFp),19,128 and impairment of blood
flow regulation.25 The extent to which these different
factors alter OPP has not yet been assessed. Additionally, the extent to which different ocular vascular bed,
including retinal, choroidal, and ONH, are affected by
low OPP has not yet been determined.123
Mathematical modeling can help disentangling the
influence of individual factors on the behavior of a
complex system thereby creating a virtual lab where
various hypotheses can be tested and various scenarios
can be simulated as to better interpret clinical and experimental findings. Due to the complexity of the anatomy
and physiology of the human eye, the development of
S. Wentz et al.
mathematical models describing ocular blood flow,
vascular autoregulation and their relationship with
blood pressure and IOP can be extremely useful in
aiding the interpretation of clinical data. However,
the mathematical modeling of the human eye is an
extremely challenging task. As a matter of fact, this is
a fervent and active area of scientific investigation to
which our group has significantly contributed. In order
to effectively address the above-mentioned open
questions in glaucoma research, mathematical models
must combine descriptions of ocular biomechanics,
hemodynamics and oxygen transport,129 as discussed
below.
4.2.1. Ocular biomechanics
Alterations in the biomechanical response of the optic
nerve head (ONH) to changes in IOP have been identified
as a major factor in the pathogenesis of ­glaucoma.­130-133
Particular attention has been devoted to the mathematical description of the IOP-induced mechanical
stresses and strains arising within the lamina cribrosa,
which is thought to be a primary site of axonal injury
in glaucoma.134 Recent studies have utilized finite
element models of the eye to investigate IOP-induced
stresses and strains in the optic nerve head,135-139 as
well as growth and remodeling mechanisms including
adaptation of tissue anisotropy, tissue thickening/
thinning, tissue elongation/shortening and tissue
migration.140-144 Further development of these sophisticated finite element models may benefit from the
recent advances in OCT imaging aimed at providing a
more accurate characterization of the architectural
microstructure within the lamina cribrosa.145
In these modeling approaches IOP and retrolaminar tissue pressure (RLTp) are assumed to be given
values set by the user. Interestingly, mathematical
models has already been developed to investigate the
mechanisms leading to IOP elevation, with particular
focus on the relationship between ciliary blood flow
and aqueous humor production146 and the biomechanics of the Schlemm’s canal,147,148 even considering
realistic three-dimensional ocular geometries.149 It
would be extremely interesting to couple the models
for the ONH response to IOP elevation with models
actually investigating the mechanisms leading to IOP
elevation, as to provide a more complete description
of the IOP action on the ocular apparatus. The retrolaminar tissue pressure (RLTp) is another very important
The role of blood flow in glaucoma
factor influencing ONH biomechanics. RLTp has been
shown to be strongly correlated to CSFp in dogs, for
CSFp higher than four mmHg.150 Mathematical models
describing CSFp dynamics have been developed in
the context of cerebral and spinal circulation.151-153 The
extension of such models to describe the complex relationship between CSFp and RLTp in the ONH would be
very beneficial to better understand the role played by
CSFp alterations in glaucoma.
4.3.2. Ocular hemodynamics
The modeling of retinal blood flow has attracted
the attention of many investigators in the recent
­years.154-157 A few groups have pioneered the mathematical modeling of the complex relationship between
ocular blood flow, blood flow autoregulation, IOP and
RLTp and the use of such models for the interpretation
of clinical data.158-163 For example, in [158] the electric
analogy between blood flow in a vascular network and
the flow of a current in a circuit is utilized to theoretically investigate the mechanisms governing the hemodynamics in the retina and in the central retinal vessels.
Arterioles can actively adjust their vascular resistance by
dilating and constricting to attain blood flow regulation,
whereas venules can passively compress due to the IOP
action on their walls and eventually collapse (acting like
Starling resistors). The model is used to investigate how
IOP elevation (from 15 to 45 mmHg) influences total
RBF for three different scenarios, namely high, normal
and low blood pressure denoted by HBP, NBP, and LBP,
respectively, characterized by systolic/diastolic blood
pressures of 140/90 mmHg, 120/80 mmHg, and 100/70
mmHg, respectively. If IOP < 26 mmHg, the model
predicts the presence of an autoregulation plateau
for the HBP and NBP cases, but not for the LBP case.
When IOP is elevated beyond 26 mmHg, the model does
not predict any autoregulation plateau for any of the
theoretical scenarios, suggesting the loss of autoregulation capacity regardless of the blood pressure. The
model allowed to identify the progressive collapse of
retinal veins as the main mechanism responsible for the
loss in autoregulation capacity following IOP elevation.
These results are in agreement with the findings of the
clinical experiment performed by Boltz et al.,164 who
showed that inadequate autoregulation of ONH blood
flow occurs at IOP values at 26 mmHg or greater where
blood flow became independent of MAP. Contrastingly,
blood flow was always dependent on IOP throughout
253
all data values for MAP. Our model predictions are in
good agreement with these clinical data, and most
importantly, they helped explaining why these trends
are observed, namely the importance of the venous
collapse (Starling resistor).
Mathematical modeling can also be used to
investigate the relative role of blood pressure, IOP and
CSFp on ocular hemodynamics. For example, in [163]
the central retinal vessels are modeled as compliant
tubes whose walls deform under the action of an
external pressure that varies along the vessel length
to include CSFp, IOP, and the effect of mechanical
deformation of the lamina cribrosa (induced by the
translaminar pressure difference TLpD = IOP ‒ CSFp).
Retinal arterioles, capillaries and venules are modeled
as a network of resistances as described in the study by
Guidoboni et al.158 The total retinal blood flow (Q) and
the blood velocity in the CRA and CRV (Va and Vv) are
simulated and compared assuming that IOP and CSFp
vary independently and assuming that IOP and CSFp
may or may not be accompanied by changes in MAP. The
model predicts that, for a certain TLpD, the level of IOP
affects hemodynamics more than the level of CSFp. For
example, for TLpD = 33 mmHg, when IOP = 40 mmHg
and CSFp = 7 mmHg, Q is reduced of 38% from baseline,
whereas for IOP = 15 mmHg and CSFp = 48 mmHg, Q
is reduced of only 4% from baseline. The model also
predicts that a decrease in CSFp from 13.64 to 11.48
mmHg due to MAP variations induces a decrease in
Q, Va and Vv of 56.6%, 54.7%, and 56.7%, respectively. Thus, the model suggests that changes in IOP have
a stronger hemodynamic implications than changes
in CSFp, even though these changes lead to the same
TLpD. This might be due to the fact that, unlike CSFp,
IOP acts directly on the intraocular retinal vessels,
thereby altering the vascular resistance of the microcirculation. Our model suggests that the influence of CSFp
on hemodynamics might be mediated by associated
changes in arterial blood pressure.
In the study by Causin et al.,161 a mathematical model
was proposed to investigate the mechanisms governing
the perfusion of the ONH tissue and, particularly, the
lamina cribrosa. More precisely, the lamina cribrosa is
modeled as a poro-elastic material, where (1) blood
vessels are viewed as pores in a solid matrix; (2) the
vascular porosity (N) (ratio between blood volume and
tissue total volume) changes with the local state of stress
and strain; (3) tissue permeability (ability of the porous
254
material to allow fluid passing through it) is assumed
to be proportional to the square of N; and (4) the solid
matrix is assumed to behave as a non-linear elastic
material. Blood flow is driven by the difference between
the arterial pressure in the SCPAs and the venous
pressure in the CRV. The model is used to investigate the
influence on the distributions of stress, blood volume
fraction (or vascular porosity) and blood velocity
within the lamina cribrosa due to the application of
different levels of the intraocular pressure (IOP) and the
enforcement of different mechanical constraints at the
lamina’s boundary. The model simulations suggest that
the degree of fixity of the boundary constraint strongly
influences the lamina’s response to IOP elevation. Specifically, when the boundary is mechanically clamped,
IOP elevation leads to an increase in stress close to the
lamina’s boundary, making it more susceptible to tissue
damage. On the other hand, when rotations are allowed
at the boundary, the most vulnerable region appears
to be located at the lamina’s central axis, in proximity
of the eye globe, where increased stress and reduced
vascular porosity and blood velocity are predicted for
increased levels of IOP. The extension of such a model
to incorporate a more realistic description of the
structural ONH biomechanics (see Section 4.3.1) would
be very beneficial to better understand the mechanisms
governing ONH perfusion in health and disease.
4.3.3. Ocular oxygenation
Several authors have addressed the modeling of oxygen
transport and delivery within the retina. In the study
by Liu et al.,165 the Navier-Stokes equations for blood
flow and the convection-diffusion equation for oxygen
transfer were solved numerically to obtain detailed
blood flow and oxygen distribution patterns in a realistic
network of retinal arterioles. The image-based arterial
geometry is combined with a structured tree model for
the distal peripheral vessels. The intravascular oxygen
tension profiles predicted by the computational model
were in good agreement with in vivo measurements
reported in the literature, demonstrating the potential
of our model for prediction of oxygen distribution. In
S. Wentz et al.
the study by Causin et al.,166 the model was extended
to simulate oxygen transport and diffusion in the whole
retinal vascular network, from arteries to veins, and the
oxygen delivery and consumption within the layers of
the retinal tissue. The model predicted that the oxygen
tension in the RGCs is particularly sensitive to changes
in arterial blood pressure and metabolic consumption
rate. In Arciero et al.,159 oxygen transport and delivery
was also modeled along the whole retinal vascular
network. Here, the level of oxygen saturation within the
vessels was used to define a stimulus function dictating
the vasoactive response of retinal arterioles to changes
in blood pressure and/or IOP. The stimulus function
also included other regulatory mechanisms, namely
the myogenic response, the shear-stress response ,
and the response to the level of carbon dioxide. The
combined effects of the responses to changes in
oxygen and carbon dioxide levels were predicted to be
critical for achieving retinal autoregulation. It would be
extremely beneficial for glaucoma research to extend
these modeling approaches to the description of
oxygen transport, delivery and consumption within the
ONH tissue as this would help to better understand the
pathogenesis of axonal injury and RGC loss.
The reliability of the predictions of a mathematical model strongly depends on the rationality of the
assumptions on which the model is based, the precision
of the parameter values involved in the model, and the
accuracy with which the model solutions have been
obtained.129 Thus, the development of a reliable mathematical model is a truly interdisciplinary endeavor.
It requires active collaboration and continuous
interaction between groups of theoretical and applied
investigators. Mathematical modeling is certainly not a
stand-alone investigative tool; it complements and synergistically combines with laboratory experiments and
human or animal studies. Experimental and/or clinical
data are critical for obtaining parameter values in the
model. Moreover, the comparison between model
predictions and experimental/clinical data might unveil
new phenomena to be studied with future experiments.
The role of blood flow in glaucoma
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