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 6 AFRICA
lation attenuated retinal vein vasoactivity and tone, reflecting
delayed vein recovery responses and non-adaptation to stress.
These constrained vein recovery responses are indicative of
increased chronic stress and stroke risk.
Keywords: retina, stress, norepinephrine, HPA, hypo-perfusion,
stroke
Submitted 5/12/19, accepted 7/8/20
Published online 26/10/20
Cardiovasc J Afr 2021; 32: 5–16
DOI: 10.5830/CVJA-2020-031
The retina shares embryonic origins with the brain, with similar
anatomy and blood-barrier physiology. The retina is therefore
of particular interest as a marker of cerebrovascular1 and
neurodegenerative diseases.2 Local perfusion mechanisms are
also similar as an increase in neuronal activity within the brain
evokes local increases in blood flow or functional hyperaemia.3
Functional hyperaemia ensures that active neurons receive
sufficient oxygen and nutrients to maintain tissue functionality
in the blood–retinal barrier (BRB).4
The inner BRB is formed by specialised retinal microvessels,
surrounding pericytes and astrocyte end-feet to form a functional
neurovascular unit (coupling).4-6 Astrocyte end-feet envelope
arterioles and capillaries, covering the vascular surface, and
directly interact or communicate with vascular smooth muscle
cells and pericytes5 (Fig. 1). Retinal vessels, therefore, offer an
easily accessible view of the vasculature that responds to flicker
light-induced provocation (FLIP), and which might reflect
emotional stress pathology and stroke risk.
It is well-known that chronic stress facilitates the release
of neurotransmitters and hormones such as norepinephrine,
adrenocorticotrophin (ACTH) and cortisol via key
neuroendocrine signalling pathways, namely the sympathetic–
adrenal–medulla axis (SAM) and hypothalamic–pituitary–
adrenal axis (HPA).5-12 Dysregulation of the SAM and HPA
hormones are related to structural degeneration in the
hippocampus and prefrontal cortex, while impaired functioning
reflect cerebrovascular perfusion deficits.13 Stress, facilitating
higher sympathetic activity and metabolic demands, promotes
active transport of norepinephrine in the central nervous system
(CNS),13,14 increasing local blood flow or functional hyperaemia3
and risk for ischaemic stroke.15,16
Stress hormones released from astrocyte end-feet may,
therefore, have a direct effect on retinal vessel dilation or
constriction, as norepinephrine is an effective stimulator of
adenylate cyclase, which compromises integrity of the BRB.5
Similar cerebral neurovascular mechanisms in the brain–retina
axis may further underscore the interrelationship between
psychopathology and neurodegenerative disease.17,18 Indeed,
Alzheimer’s disease and depression as neurodegenerative diseases
have recently been associated with delayed retinal vessel dilation
upon FLIP, reflecting increased sympathetic tone.17
We have previously reported that the stroke risk markers,
retinal artery narrowing and vein widening,18 were related
to depressed heart-rate variability (HRV)19 and stroke
risk in a bi-ethnic cohort.20 It is therefore feasible to link
neurodegenerative disease and psychopathology assessments in
the BRB, as the inner neural retinal layers and cell components
express adrenergic receptors (AR) namely α1a-AR,10 α2a -AR21,22
as well as glucocorticoid receptors (GCR). 2 α1a -AR increases
norepinephrine release and vasoconstriction, whereas α2a -AR
inhibits norepinephrine release to protect ganglion cells in the
optic nerve head (Fig. 1).
Norepinephrine or adrenergic receptor-driven changes
in retinal vessel dynamics and tone may reflect neuronal
hyperactivity or adrenergic drive. The GCR protect retinal
neurons by suppressing inflammation and inhibiting microglial
cells to block the production of cytotoxic molecules. 23
Corticosteroid hormones control vascular smooth muscle tone
by their permissive effects in potentiating vasoactive responses
to catecholamines through GCR.24 Flicker provocation, as acute
mental stressor, may therefore reflect norepinephrine (SAM) and
HPA’s function on sensory processing via receptor activation or
inhibition.
We previously observed that the cardiac and retinal micro-
vasculature reflected depressed HRV and hypo-perfusion.18-20,25-27
Whether stress hormones will disturb retinal vessel responsiveness
to increase the risk for stroke has yet to be determined. The
aim of this study was therefore (1) to investigate temporal
relationships between the retinal vasculature, SAM and HPA
responses over three years and upon provocation, and (2) to
determine stress and stroke risk.
Methods
The Sympathetic activity and Ambulatory Blood Pressure in
Africans (SABPA) prospective study was conducted from late
summer until late autumn in 2008/9, and after three years, in
2011/12. A teachers’ cohort (20–65 years), having similar socio-
economic status, was included.25 Baseline exclusion criteria were
tympanum temperature ≥ 37.5°C, pregnancy and/or lactation,
α- and/or or β-blocker use, psychotropic substance use, as well
as vaccination and/or blood donation three months prior to
participation. Only participants who participated in both phases
( n = 359) were included for the current investigation. Additional
exclusions were poor-quality retinal vessel images and missing
data (n = 65), stroke (n = 1), HIV infection ( n = 19), and a user of
central nervous stimulants (n = 1). The final participant sample
comprised 273 individuals.
Participants were fully informed about the objectives and
procedures prior to recruitment and provided written, informed
consent. The study conformed to the Helsinki Declaration
(2004) and was approved by the ethics review board of the
North-West University, Potchefstroom campus (approval
number NWU-0003607S6).
During the working week, 24-hour ambulatory blood
pressure and ECG monitors (Cardiotens CE120 ®, Meditech,
Budapest, Hungary) were fitted to teachers at their school of
employment at approximately 07:00. A 24-hour standardised
diet plus 24-hour urine sampling commenced, after which
participants resumed their normal daily activities. At 15:00,
participants were transported to the North-West University for
retinal vessel imaging and an overnight stay in a relaxed, well-
controlled environment. For the remaining clinical measures
each participant received his/her own room and was informed
on the experimental set-up and sampling conditions to lessen