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OBJECTIVES Low or high sympatho-adrenal-medullary axis (SAM) and hypothalamic-pituitary-adrenal axis (HPA) dysregulation reflect chronic stress. Retinal vessel dynamics may relate to SAM, HPA activity and stroke risk. Our objectives were therefore to assess the relationships between retinal vessel, SAM and HPA responses, and to determine stroke risk. METHODS A prospective bi-ethnic gender cohort (n = 275, 45 ± 9 years) was included. Urine/serum/saliva samples for SAM [norepinephrine:creatinine ratio (u-NE)] and HPA [adrenocorticotrophic hormone (ACTH), cortisol] were obtained at baseline, three-year follow up and upon flicker light-induced provocation. Diastolic ocular perfusion pressure was measured as a marker of hypo-perfusion. Retinal arterial narrowing and venous widening calibres were quantified from digital images in the mydriatic eye. A validated stress and stroke risk score was applied. RESULTS An interaction term was fitted for venous dilation in u-NE tertiles (p ≤ 0.05) and not in u-NE median/quartiles/quintiles. Independent of race or gender, tertile 1 (low u-NE) had a 112% increase in u-NE, decreases in cortisol, and no changes in ACTH over three years (positive feedback). Tertile 3 (high u-NE) contradictorily had decreases in u-NE and cortisol, and increases in ACTH (negative feedback). In tertile 1, reduced arterial dilation, and faster arterial vasoconstriction and narrowing were related to higher SAM activity and hypo-perfusion (p ≤ 0.05), whereas delayed venous dilation, recovery and widening were related to cortisol hypo-secretion (p ≤ 0.05). In tertile 1, delayed venous recovery responses predicted stress and stroke risk [odds ratio 4.8 (1.2-19.6); p = 0.03]. These associations were not found in u-NE tertiles 2 and 3. CONCLUSIONS In response to low norepinephrine, a reflex increase in SAM activity occurred, enhancing arterial vasoconstriction and hypo-perfusion. Concomitant HPA dysregulation attenuated retinal vein vasoactivity and tone, reflecti

Type 3 diabetes (T3D) accurately reflects that dementia, e.g., Alzheimer’s disease, represents insulin resistance and neurodegeneration in the brain. Similar retinal microvascular changes were observed in Alzheimer’s and chronic stressed individuals. Hence, we aimed to show that chronic stress relates to T3D dementia signs and retinopathy, ultimately comprising a Stress syndrome prototype reflecting risk for T3D and stroke. A chronic stress and stroke risk phenotype (Stressed) score, independent of age, race or gender, was applied to stratify participants (N = 264; aged 44 ± 9 years) into high stress risk (Stressed, N = 159) and low stress risk (non-Stressed, N = 105) groups. We determined insulin resistance using the homeostatic model assessment (HOMA-IR), which is interchangeable with T3D, and dementia risk markers (cognitive executive functioning (cognitiveexe-func); telomere length; waist circumference (WC), neuronal glia injury; neuron-specific enolase/NSE, S100B). Retinopathy was determined in the mydriatic eye. The Stressed group had greater incidence of HOMA-IR in the upper quartile (≥5), larger WC, poorer cognitiveexe-func control, shorter telomeres, consistently raised neuronal glia injury, fewer retinal arteries, narrower arteries, wider veins and a larger optic cup/disc ratio (C/D) compared to the non-Stressed group. Furthermore, of the stroke risk markers, arterial narrowing was related to glaucoma risk with a greater C/D, whilst retinal vein widening was related to HOMA-IR, poor cognitiveexe-func control and neuronal glia injury (Adjusted R2 0.30; p ≤ 0.05). These associations were not evident in the non-Stressed group. Logistic regression associations between the Stressed phenotype and four dementia risk markers (cognitiveexe-func, telomere length, NSE and WC) comprised a Stress syndrome prototype (area under the curve 0.80; sensitivity/specificity 85%/58%; p ≤ 0.001). The Stress syndrome prototype reflected risk for HOMA-IR (odds ratio (OR) 7.72) and

Defensive coping (DefS), oxidative stress, inflammation, and related amino acids (phenylalanine [Phe] and tyrosine [Tyr]) have been implicated in cardiovascular disease. This study assessed whether inflammation, oxidative stress, changes in essential amino acids, and altered coping strategies are correlated with subclinical vascular changes in African (n = 82) and Caucasian (n = 100) men from the Sympathetic Activity and Ambulatory Blood Pressure in Africans (SABPA) study. The Coping Strategy Indicator questionnaire identified DefS participants. Ambulatory blood pressure (BP) was monitored for 24 h, whereas carotid intima media thickness (CIMT) and cross-sectional wall area (CSWA) were determined ultrasonically. Essential amino acids were analyzed with a liquid chromatography tandem mass spectrometry method. Oxidative-inflammatory markers were measured by spectrophotometry. African men had poorer health than Caucasian men, including higher alcohol abuse, elevated BP, abdominal obesity, physical inactivity, and elevated inflammation. Phe (p < .001) and Phe/Tyr ratio (p = .006) as well as CIMT (p = .032) were higher in African men. DefS African men had higher levels of Phe (p = .002) and Phe/Tyr (p = .009) compared to DefS Caucasian men; these differences were not observed in non-DefS men. Systolic BP and inflammation (C-reactive protein) were positively associated with left (L-) CSWA, while Phe/Tyr was negatively associated with L-CSWA in DefS African men. African males presented with elevated Phe and Phe/Tyr ratio, catecholamine precursors, worsening during DefS—possibly driven by inflammation and BP contributing to structural vascular abnormalities

"Globally most interventions focus on improving lifestyle habits and treatment regimens to combat hypertension as a non-communicable disease (NCD). However, despite these interventions and improved medical treatments, blood pressure (BP) values are still on the rise and poorly controlled in sub-Saharan Africa (SSA). Other factors contributing to hypertension prevalence, such as chronic emotional stress, might provide some insight for future health policy approaches. Currently, Hypertension Society guidelines do not mention emotional stress as a probable cause for hypertension. Recently the 2014 World Global Health reports, suggested that African governments should consider using World Health Organization hypertension data as a proxy indicator for social well-being. However, the possibility that a stressful life and taxing environmental factors might disturb central neural control of BP regulation has largely been ignored in SSA. Linking emotional stress to vascular dysregulation is therefore one way to investigate increased cardiometabolic challenges, neurotransmitter depletion and disturbed hemodynamics. Disruption of stress response pathways and subsequent changes in lifestyle habits as ways of coping with a stressful life, and as probable cause for hypertension prevalence in SSA, may be included in future preventive measures. We will provide an overview on emotional stress and central neural control of BP and will include also implications thereof for clinical practice in SSA cohorts."

Background Depression has been associated with impaired nitric oxide (NO)-mediated vasodilation and vascular dysregulation (VD). Whether depression and NO levels will disturb retinal haemodynamics is not clear. Objectives and methods Associations between the retinal vasculature, diastolic ocular perfusion pressure (DOPP) as measure of hypoperfusion, NO metabolites (NOx) and depression symptoms were assessed. Chronic VD risk markers [depression symptoms (Patient Health Questionnaire/PHQ-9 ≥ 10) and 24 h pulse pressure] were determined in a bi-ethnic cohort (n = 313; 48.6 ± 9 years; 53.9% men). At 3 year follow-up, retinal vessel calibre and retinopathy signs were quantified from digital images. Salivary NOx was obtained pre- and post-flicker light-induced provocation (FLIP). DOPP was defined as diastolic blood pressure minus intraocular pressure. Results Chronic VD risk was evident in Blacks opposed to acute risk in Whites (P < 0.05). At follow-up, retinopathy (Blacks 60.4%/Whites 39.6%), lower pre-FLIP (μM) and higher post-FLIP NOx (changes from baseline, %), arteriolar narrowing and wider venular calibre values were evident in Blacks compared to Whites, independent of confounders. A wider venular calibre, an index of stroke risk, was associated with chronic depression symptoms [cut point 248 MU: Area under the curve 0.61 (95% CI: 0.51, 0.72); 71% sensitivity; 55% specificity] as well as with hypoperfusion in the Blacks. In this group, arteriolar narrowing was associated with hypoperfusion; and attenuated arteriolar dilation with increased post-FLIP NOx responses. Conclusions Chronic depression symptoms may alter NO regulation and facilitate VD. NO-mediated vasoconstriction presumably impeded perfusion, retinal haemodynamics and –remodelling; potentiating stroke risk in Blacks

A hypercoagulable state might be one important mechanism linking obstructive sleep apnea (OSA) with incident myocardial infarction and stroke. However, previous studies on prothrombotic factors in OSA are not uniform and cross-sectional. We longitudinally studied prothrombotic factors in relation to OSA risk, adjusting for baseline levels of prothrombotic factors, demographics, metabolic parameters, aspirin use, and life style factors. The Berlin Questionnaire and/or neck circumference were used to define high OSA risk in 329 South African teachers (48.0% male, 44.6% black) at baseline and at three-year follow-up. Von Willebrand factor (VWF), fibrinogen, D-dimer, plasminogen activator inhibitor-1, clot lysis time (CLT), and soluble urokinase-type plasminogen activator receptor (suPAR) were measured in plasma. At baseline 35.7% of participants had a high risk of OSA. At follow-up, persistently high OSA risk, persistently low OSA risk, OSA risk remission, and new-onset OSA risk were present in 26.1%, 53.2%, 9.4%, and 11.3% of participants, respectively. New-onset OSA risk was associated with a significant and longitudinal increase in VWF, fibrinogen, CLT, and suPAR relative to persistently low OSA risk; in VWF, fibrinogen, and suPAR relative to remitted OSA risk; and in VWF relative to persistently high OSA risk. Persistently high OSA risk was associated with an increase in CLT and suPAR relative to persistently low OSA risk and in D-dimer relative to remitted OSA risk. Remitted OSA risk was associated with D-dimer decrease relative to persistently low OSA risk. In OSA, hypercoagulability is a dynamic process with a most prominent three-year increase in individuals with new-onset OSA risk.

Summary: Background: Low levels of testosterone in men and changes in retinal microvascular calibre are both associated with hypertension and cardiovascular disease risk. Sex hormones are also associated with blood flow in microvascular beds which might be a key intermediate mechanism in the development of hypertension. Whether a direct association between endogenous testosterone and retinal microvascular calibre exists is currently unknown. We aimed to determine "whether testosterone is independently associated with ocular perfusion via a possible association with retinal vascular calibre or whether it plays only a secondary role via its effect on blood pressure in a bi–ethnic male cohort. Probands and methods: A total of 72 black and 81 white men (28–68 years of age) from the follow–up phase of the Sympathetic activity and Ambulatory Blood Pressure in Africans (SABPA) study were included in this sub–study. Ambulatory pulse pressure and intraocular perfusion pressures were obtained, while metabolic variables and testosterone were measured from fasting venous blood samples. Retinal vascular calibre was quantified from digital photographs using standardised protocols." "Results: The black men revealed a poorer cardiometabolic profile and higher pulsatile pressure (> 50 mm Hg), intraocular" "pressure and diastolic ocular perfusion pressure than the white men (p ? 0.05). Only in the white men was free testosterone positively associated with retinal calibre, i.e. arterio–venular ratio and central retinal arterial calibre and inversely with central retinal venular calibre. These associations were not found in the black men, independent of whether pulse pressure and ocular perfusion pressure were part of the model." "Conclusions: These results suggest an independent, protective effect of testosterone on the retinal vasculature where an apparent vasodilatory response in the retinal resistance microvessels was observed in white men.

Recent work identified a high prevalence of modifiable risk factors for cardiovascular disease (CVD) among urban black South Africans. The aim was to track the progression of CVD risk factors in a multi-ethnic sample of South Africans. Participants were 173 black (aged 47.5 ± 7.8 yrs) and 186 white teachers (aged 49.6 ± 9.9 yrs) that were examined at baseline and 3 years follow-up. Blacks demonstrated a substantially higher prevalence of composite CVD burden (defined as history of physician diagnosed heart disease, use of anti-hypertensives, anti-diabetic, or statin medications at either time point) compared to whites (49.1 vs. 32.0%, p = 0.012) respectively. After controlling for baseline, the black participants demonstrated greater increases in 24 h systolic and diastolic blood pressure, total cholesterol, fasting glucose, fibrinogen, D-dimer, and waist circumference in comparison with whites. In summary, an adverse progression of CVD risk factors was observed in the whole sample, although to a larger degree in black participants. Aggressive treatment strategies for controlling risk factors in black Africans are needed to reduce the increasing burden of CVD in South Africa.

Background: Defensive coping is an established cardiovascular risk factor in Africans. Additionally, chronic, excessive or inadequate hypothalamic pituitary adrenal axis (HPAA) stress responses could either increase or decrease cortisol responses, which may relate to renal impairment. We scrutinised the relationship between urinary cortisol levels and renovascular disease risk in Africans and Caucasians utilising defensive coping. Methods: Africans (n = 168) and Caucasians (n = 207) from the SABPA (Sympathetic activity and Ambulatory Blood Pressure in Africans) study were included in our analyses, excluding HIV positive, diabetic, renal impairment, and cortisone users. The Coping Strategy Indicator questionnaire assessed preferred coping responses. Ambulatory blood pressure was recorded together with 8 h fasting blood and urine sampling. Renovascular disease risk markers included the albumin–to–creatinine ratio (ACR) and estimated glomerular filtration rate (eGFR). Results: The main findings revealed that Caucasians with high cortisol showed augmented renovascular disease risk. Conversely, Africans revealed lowcortisol levelswhilst 21.84% reported experience of severe stress, possibly depicting HPAA hypoactivity. Additionally, these Africans with low cortisol revealed increased ACR and decreased eGFR, which was further enhanced by defensive coping. Conclusions: Defensive coping enhanced renovascular risk in Africans, especially in those with lower cortisol, which may be due to HPAA dysfunction and/or adrenal fatigue.

The risk of cardiovascular disease is dramatically increasing in Africans (black). The prothrombotic stress response contributes to atherothrombotic disease and is modulated by depressive symptoms. We examined coagulation reactivity to acute mental stress and its relation to psychological well-being in Africans relative to Caucasians (white). A total of 102 African and 165 Caucasian school teachers underwent the Stroop Color-Word Conflict test. Circulating levels of von Willebrand factor (VWF) antigen, fibrinogen, and D-dimer were measured before and after the Stroop. Cardiovascular reactivity measures were also obtained. All participants completed the Patient Health Questionnaire-9 and the General Health Questionnaire-28 for the assessment of depressive symptoms and total psychological distress, respectively. After controlling for covariates, resting levels of VWF, fibrinogen, and D-dimer were higher in Africans than in Caucasians (all p-values ≤0.006). Depressive symptoms and psychological distress were not significantly associated with resting coagulation measures. Stress reactivity in VWF (p<0.001) and fibrinogen (p=0.016), but not in D-dimer (p=0.27), were decreased in Africans relative to Caucasians with Africans showing greater reactivity of total peripheral resistance (p=0.017). Depressive symptoms, but not general psychological distress, were associated with greater VWF increase (p=0.029) and greater fibrinogen decrease (p=0.030) in Africans relative to Caucasians. In conclusion, Africans showed greater hypercoagulability at rest but diminished procoagulant reactivity to acute mental stress when compared with Caucasians. Ethnic differences in the vascular adrenergic stress response might partially explain this finding. Depressive symptoms were associated with exaggerated VWF reactivity in Africans relative to Caucasians. The clinical implications of these findings for Africans need further study

Disturbances in circadian rhythm might play a central role in the neurobiology of depression. We examined the association between depressive symptoms and 24-hour ambulatory BP in a sample of 405 (197 black and 208 Caucasian) urbanized African teachers aged 25 to 60 yrs (mean 44.6 ± 9.6 yrs). Depressive symptoms were assessed using the self-administered 9-item Patient Health Questionnaire (PHQ-9). After adjusting for age, sex, and ethnicity, participants with severe depressive symptoms (PHQ-9 ≥ 15) had higher odds of hypertension defined from ambulatory BP and/or use of antihypertensive medication (odds ratio = 2.19, 95% CI, 1.00–4.90) in comparison to participants with no symptoms. Compared to Caucasians with no depressive symptoms, those with severe symptoms had blunted nocturnal systolic BP drop of 4.7mmHg (95% CI, −0.5 to 10.0, P = 0.07). In summary, depressive symptoms were associated with the circadian BP profile in black and Caucasian Africans.

Background: Defensive active coping responses (being-in-control, acceptance of the stressor as reality) have been associated with vascular hyper-responsiveness in urban Africans. However, the association between active coping responses, blood pressure (BP), and ECG-derived left-ventricular hypertrophy (LVH) responses is unknown. Objectives and methods: Associations between BP, silent ischaemia and ECG Cornell product LVH were assessed in 161 African and Caucasian men with active coping responses identified by the Amirkhan Coping Strategy Indicator. BP, ECG and silent ischaemia data were obtained from 24-h ambulatory monitoring. Beat-to-beat BP was continuously recorded during stress testing and fasting resting blood samples obtained for biochemical analyses. Results: Enhanced ß-adrenergic central cardiac responses were evident in active coping Caucasians as opposed to a predomination of α-adrenergic vascular responses in active coping Africans. Active coping African men displayed higher 24-h BP and prevalence of silent ischaemia events compared to the Caucasian men. Regression analyses revealed that α-adrenergic responses were associated with silent ischaemic events, adjusted R2 0.21 [ß 1.07, 95% confidence interval (CI) 0.29–1.85] and that ischaemic events predicted LVH in active coping Africans (adjusted R2 0.12, ß 0.35, 95% CI 0.11–0.59). Receiver-operated characteristic (ROC) analyses indicated a defensive pathway cut point of 16 in Africans as opposed to 32 in Caucasians predicting silent ischaemia with sensitivity/specificity 100/96%. Conclusions: A defensive pathway revealed disturbed vascular function showing dissociation between behavioural and physiological ß-adrenergic active coping responses in Africans. Vascular responsiveness facilitated silent ischaemia events and structural LVH changes which potentially explain the increased risk for incident ischaemic stroke in black Africans.

Background: Hypertension and increased blood glucose are associated with subclinical kidney damage, atherosclerosis and with low testosterone values. Low testosterone in men is often accompanied by increased levels of estradiol. Objectives and methods: In this study, the association between estradiol, subclinical kidney damage and atherosclerosis in African and white men in a South African cohort was investigated. Cardiovascular variables were studied by means of B-mode ultrasound and ambulatory blood pressure (BP) monitoring. The sex hormones and other biochemical values were measured from fasting venous blood and overnight urine samples. The ethnic groups were stratified into low and high testosterone groups by means of median split. Results: The low testosterone African group demonstrated a higher cardiovascular risk compared with the low testosterone white men with 91% being hypertensive and having increased albumin-to-creatinine ratio (ACR), left carotid intima–media thickness (L-CIMTf) and estradiol-to-testosterone ratio. In the low-testosterone African men, estradiol explained 33% of the variance in ACR, whereas the estradiol-to-testosterone ratio explained 22% of the variance in L-CIMTf, respectively. Estradiol-to-testosterone ratio was positively associated with ACR in the low testosterone whites. Conclusion: We conclude that increased levels of estradiol may play a role in the development of subclinical kidney damage in both African and white men as well as atherosclerosis in low-testosterone African men.

Objective Alarming increases in hypertension and type 2 diabetes among Africans accentuate the need to identify factors that could serve as targets for prevention or treatment. In Caucasian populations, asymmetric dimethylarginine (ADMA), the predominant endogenous nitric oxide synthase inhibitor, is associated with cardiovascular disease and insulin resistance (IR). ADMA's counterpart, symmetric dimethylarginine (SDMA), originally thought to be inert, was recently also linked with cardiovascular risk. Since little information regarding ADMA or SDMA is available for Africans, our aim was to explore the relationships of ADMA and SDMA with measures of arterial stiffness and IR in Africans and Caucasians from South Africa. Methods The study consisted of 235 nonsmoking, nondiabetic, nonobese, human immunodeficiency virus-uninfected Africans (n=64) and Caucasians (n=171), aged 20–70 years. We measured blood pressure, pulse wave velocity, ADMA, SDMA, and IR (homeostasis model assessment, HOMA). Results African and Caucasian men had similar ADMA and SDMA, whereas Caucasian women had higher ADMA and SDMA than African women (P<0.05). African men and Caucasian women indicated strong correlations of ADMA with arterial stiffness (r=0.47, P=0.021; r=0.26, P=0.008), confirmed in multivariate analyses. Caucasian participants showed negative associations between SDMA and HOMA, being strongest in the men (r=−0.41; P=0.002). Conclusion Our results indicate that ADMA is independently associated with vascular dysfunction in African men and Caucasian women. A strong, independent negative association of SDMA with IR was found only in Caucasian participants. The molecular explanation for this is unclear, but these findings motivate experimental studies that could shed more light on these relationships