Cardiovascular Journal of Africa: Vol 32 No 1 (JANUARY/FEBRUARY 2021)

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CARDIOVASCULAR JOURNAL OF AFRICA • Volume 32, No 1, January/February 2021 14 AFRICA
individuals, a profile of endothelial dysfunction47 emerges, which
could enable the α 1b‐adrenoceptor subtype to mediate adrenergic
vasoconstriction in retinal arteries.48 The overall reflex increases
in u-NE, and pre-FLIP α-amylase levels support the notion
of adrenergic-induced vasoconstriction. These changes have
presumably been mediated via the following catecholamine
receptors: α1a-AR, α1b-AR,desensitised α2a -ARand D2R.10,22,37,39,43,44
Such a profile compromises the integrity of the BRB33 and
increases susceptibility for ischaemic stroke risk.15,16,34
Cortisol and the retinal vasculature
Compared with SAM responses, the HPA has a particularly
high threshold for activation12,49 and facilitates the ability to cope
with, adapt to, and recover from stress.2 A homeostatic negative
feedback response occurred in u-NE tertile 3, where increases
in ACTH and decreases in cortisol levels were observed, and
which were not related to retinal vascular dysregulation. In u-NE
tertile 1, however, no increases in ACTH level occurred despite
decreases in cortisol level. This potentially reflects a positive
feedback response of HPA hypo-activity, which is indicative
of chronic uncontrollable stress.12,49 In rodent models a low
norepinephrine level10 in the central amygdala and hypothalamus
(PVN) inhibited HPA responses to neural stress stimuli such
as photic stimulation.50 This might explain attenuation of the
negative feedback exerted by glucocorticoids in u-NE tertile 1,
probably by reducing hippocampal glucocorticoid receptors and
facilitating consistently raised ACTH levels.
HPA regulation, particularly by cortisol, protects neurons
by suppressing inflammation and inhibiting microglial TNF-α
release and GCR signalling to permit the formation of
proliferating Müller glia-derived progenitor cells.12,51 Cortisol
hypo-secretion in adrenergic-driven u-NE tertile 1 might,
therefore, reduce immune function suppression and explain the
observed low-grade inflammation and retinal vein widening.
Retinal veins consist of a single layer of endothelial cells and few
smooth muscle cells.52 Retinal vein vascular tone and diameter
changes in u-NE tertile 1 may therefore affect vein drainage
resistance and upstream pressure in retinal capillaries. Indeed,
HPA dysregulation reflected lower vein vasoactivity and tone,
which delayed recovery responses upon provocation and implies
non-adaptation to stress.
In support, the observed prolonged stress responses in
hippocampal (ventral subiculum) lesions of rats were
accompanied by enhanced depletion of corticotrophic hormone
immunoreactivity over time2 and, in humans, were related to
neurodegenerative disease risk (depression and the late onset
of Alzheimer’s disease).53 In a previous study, retinal vein
widening reflected self-reported chronic depressive symptoms
and a compromised NO-synthase system in a black cohort.18
Presently, HPA dysregulation in u-NE tertile 1, independent of
race and gender, might decrease nitric oxide (NO) bioavailability
by inhibiting NO-synthase directly54 and explain compromised
vein dynamics in the retina.54 In the current low u-NE group,
retinal vein responses were not related to self-reported chronic
depression, but only to stress hormone dysregulation. This
discrepancy and the lack of association between cardiovascular
disease risk markers and self-reported chronic depression
concurs with previous observations,4,27 as well as with the most
recent findings by Levis et al.55 Applying a validated chronic
stress and stroke risk marker may prove to be superior to self-
reported chronic depression.
Stress and ischaemic stroke susceptibility
Small vessels in the brain react to hydrostatic pressure and will
regulate vascular tone to maintain a constant blood flow, or
autoregulation.34 Central control with dysregulated HPA and
downregulated HDL-C enhanced endothelial dysfunction in
u-NE tertile 1, increasing susceptibility for ischaemic stroke. 15
The greater FLIP venous dilation in u-NE tertile 1, slower
recovery to baseline and widening have now been associated with
both cortisol hypo-secretion and low HDL-C levels. This may
impede constant blood flow and autoregulation, and facilitate
ischaemic stroke susceptibility.15 Central control may indeed
override autoregulation when chronic stress is apparent.
Neuronalhyperactivitymaydriveanddominatetheseresponses
as low HDL-C level in turn influences cerebrovascular function
and breaching of the BRB.10,13-15 Intra-retinal lipid transport
depends on HDL-C, the major apolipoprotein constituent of
apolipoprotein E (ApoE).56-58 The 22% decrease (1.1–0.9 mmol/l)
observed in u-NE tertile 1 may be indicative of a high risk (<
1.04) for depression,56 retinal pathology, 58 cognitive decline59 and
ischaemic stroke.60 Low HDL-C levels reflected chronic stress51
and clinical depression,61 endorsing the prevalence of chronic
stress in u-NE tertile 1. It is important to note that certain
depression treatments may downregulate norepinephrine, such
as tricyclic antidepressants (e.g. serotonin re-uptake inhibitors).
Subsequent upregulation of norepinephrine can occur, which
will disturb neurovascular coupling62 and potentiate stroke risk.
Neural mechanism for chronic stress and stroke risk
In response to low norepinephrine levels, a reflex increase
in sympathetic activity/adrenergic drive occurred as a
compensatory mechanism to low monoamine levels. Higher
adrenergic drive may potentiate catecholamine receptor
sensitisation (potentially α1a-AR, α1b-AR, D2R) and/or chronic
α2a-AR desensitisation.10,22,37-39,43,44 Indeed, higher adrenergic
drive increased vasoconstriction and hypo-perfusion or
ischaemia in retinal arteries. Consistent high blood pressure
and vasoconstrictive signalling may exert deleterious effects on
the retinal ganglion cells.40 Concomitant HPA dysregulation,
resembling uncontrollable stress, was related to delayed venous
dilation, recovery and widening. Most prominently, the delayed
venous recovery upon provocation may indicate a prolonged
retrograde propagation of the vascular response, reflecting lower
vein vaso-activity and tone. Consistent low-grade inflammation
will further increase the risk for endothelial dysfunction, a
breach in BRB,34 as well as ischaemic stroke.4 Delayed vein
recovery responses upon provocation suggest non-adaptation to
stress, which constrained recovery and autoregulation. Indeed,
delayed retinal venous recovery predicted chronic stress and
stroke risk (OR 4.8), having large clinical significance .
Limitations
Our study is limited as the sample size was relatively small and
it should be repeated in larger longitudinal studies. However,
within a well-controlled setting, we were able to apply (1) an