Glial cell activity in cardiovascular diseases and risk of acute myocardial infarction.

Growing evidence indicates that the pathophysiological link between the brain and heart underlies cardiovascular diseases, specifically acute myocardial infarction (AMI). Astrocytes are the most abundant glial cells in the central nervous system and provide support/protection for neurons. Astrocytes and peripheral glial cells are emerging as key modulators of the brain-heart axis in AMI, by affecting sympathetic nervous system activity (centrally and peripherally). This review, therefore, aimed to gain an improved understanding of glial cell activity and AMI risk. This includes discussions on the potential role of contributing factors in AMI risk, i.e., autonomic nervous system dysfunction, glial-neurotrophic and ischemic risk markers [glial cell line-derived neurotrophic factor (GDNF), astrocytic S100 calcium-binding protein B (S100B), silent myocardial ischemia, and cardiac troponin T (cTnT)]. Consideration of glial cell activity and related contributing factors in certain brain-heart disorders, namely, blood-brain barrier dysfunction, myocardial ischemia, and chronic psychological stress, may improve our understanding regarding the pathological role that glial dysfunction can play in the development/onset of AMI. Here, findings demonstrated perturbations in glial cell activity and contributing factors (especially sympathetic activity). Moreover, emerging AMI risk included sympathovagal imbalance, low GDNF levels reflecting prothrombic risk, hypertension, and increased ischemia due to perfusion deficits (indicated by S100B and cTnT levels). Such perturbations impacted blood-barrier function and perfusion that were exacerbated during psychological stress. Thus, greater insights and consideration regarding such biomarkers may help drive future studies investigating brain-heart axis pathologies to gain a deeper understanding of astrocytic glial cell contributions and unlock potential novel therapies for AMI.

The chronic stress risk phenotype mirrored in the human retina as a neurodegenerative condition.

The brain is the key organ that orchestrates the stress response which translates to the retina. The retina is an extension of the brain and retinal symptoms in subjects with neurodegenerative diseases substantiated the eye as a window to the brain. The retina is used in this study to determine whether chronic stress reflects neurodegenerative signs indicative of neurodegenerative conditions. A three-year prospective cohort (n = 333; aged 46 ± 9 years) was stratified into stress-phenotype cases (n = 212) and controls (n = 121) by applying the Malan stress-phenotype index. Neurodegenerative risk markers included ischemia (astrocytic S100 calcium-binding protein B/S100B); 24-h blood pressure, proteomics; inflammation (tumor-necrosis-factor-α/TNF-α); neuronal damage (neuron-specific-enolase); anti-apoptosis of retinal-ganglion-cells (beta-nerve-growth-factor), astrocytic activity (glial-fibrillary-acidic-protein); hematocrit (viscosity) and retinal follow-up data [vessels; stress-optic-neuropathy]. Stress-optic-neuropathy risk was calculated from two indices: a newly derived diastolic-ocular-perfusion-pressure cut-point ≥68 mmHg relating to the stress-phenotype; combined with an established cup-to-disk ratio cut-point ≥0.3. Higher stress-optic-neuropathy (39% vs. 17%) and hypertension (73% vs. 16%) prevalence was observed in the stress-phenotype cases vs. controls. Elevated diastolic-ocular-perfusion-pressure, indicating hypoperfusion, was related to arterial narrowing and trend for ischemia increases in the stress-phenotype. Ischemia in the stress-phenotype at baseline, follow-up and three-year changes was related to consistent inflammation (TNF-α and cytokine-interleukin-17-receptor-A), neuron-specific-enolase increases, consistent apoptosis (chitinase-3-like protein 1, low beta-nerve-growth-factor), glial-fibrillary-acidic-protein decreases, elevated viscosity, vein widening as risk marker of endothelial dysfunction in the blood-retinal barrier, lower vein count, and elevated stress-optic-neuropathy. The stress-phenotype and related neurodegenerative signs of ongoing brain ischemia, apoptosis and endothelial dysfunction compromised blood-retinal barrier permeability and optic nerve integrity. In fact, the stress-phenotype could identify persons at high risk of neurodegeneration to indicate a neurodegenerative condition.

Relation of the renin-angiotensin-aldosterone system with potential cardiac injury and remodelling: the SABPA study.

Purpose: The renin-angiotensin-aldosterone system (RAAS) plays an important role in maintaining hemodynamic homeostasis. Ethnic disparities exist regarding RAAS activity due to sympathetic activity and sodium-water retention, however the implications thereof on cardiac damage is unknown. This study investigated the associations of cardiac troponin T (cTnT), N-terminal pro-brain natriuretic peptide (NTproBNP) and subclinical LVH with components of the RAAS (renin, aldosterone and aldosterone-to-renin ratio (ARR)) and copeptin in a black and white South African cohort.Materials and methods: The study population consisted of 305 participants (black = 139, white = 166) aged 20-62 years. Serum cTnT, NTproBNP, Cornell product, components of the RAAS (active renin, aldosterone and ARR) and copeptin were determined.Results: The black group had lower renin (p < 0.001) and higher ARR (p < 0.001), cTnT (p = 0.015) and Cornell product compared to whites (all p < 0.001). NTproBNP and copeptin were similar between the groups. After forward stepwise adjustments for multiple confounders, inverse associations of cTnT with renin (ß = -0.17, p = 0.018) and aldosterone (ß = -0.14, p = 0.048) as well as an inverse association between NTproBNP and aldosterone (ß = -0.25, p < 0.001) were observed in the white population only. In the black group cTnT associated positively with renin (ß = 0.16, p = 0.040) and copeptin (ß = 0.21, p = 0.020) and inversely with ARR (ß = -0.15, p = 0.047). Additionally, NTproBNP associated positively with copeptin (ß = 0.18, p = 0.045). No correlations were observed between the RAAS and Cornell product in any of the groups.Conclusions: Our findings suggest that RAAS, together with cardiac stress may function differently in cardiac damage and remodelling in the two ethnic groups; which may influence treatment in clinical practice.

Ethnicity-Specific Changes in Cardiac Troponin T in Response to Acute Mental Stress and Ethnicity-Specific Cutpoints for the R Wave of the aVL Lead.

Acute mental stressor-induced cardiac stress responses might contribute to excessive myocardial strain and resultant cardiovascular episode risk. We assessed ethnicity-specific acute cardiac stress (by measuring cardiac troponin T (cTnT) and N-terminal prohormone of brain natriuretic peptide) related to hemodynamic activity. The prospective Sympathetic Activity and Ambulatory Blood Pressure in Africans (SABPA) study was conducted during 2007-2008 in South Africa. In the cross-sectional phase of the SABPA study, 388 black and white participants underwent a 1-minute acute mental stressor, during which blood pressure was continuously measured. Fasting blood samples for cardiac stress markers were obtained before and 10 minutes after stress (% change). Resting 10-lead electrocardiogram measured the R wave of the aVL lead (RaVL). Black participants exhibited greater cardiac stress responses (P < 0.001), diastolic blood pressure, total peripheral resistance, and stroke volume compared with white participants, who displayed decreases in cardiac stress and increases in cardiac output. Prestress and stressor cTnT cutpoints of 4.2 pg/mL predicted 24-hour, daytime, and nighttime diastolic hypertension in black participants (P < 0.001). These cTnT cutpoints were associated with an ethnicity-specific RaVL cutpoint of 0.28 mV (odds ratio = 3.49, 95% confidence interval: 2.18, 5.83; P = 0.021). Acute mental stress elicited an α-adrenergic activation pattern and cardiac stress hyperreactivity only in black participants. Mental stress might increase the black population's risk for ischemic episodes and heart disease.

BDNF increases associated with constant troponin T levels and may protect against poor cognitive interference control: The SABPA prospective study.

BACKGROUND: Brain-derived neurotrophic factor (BDNF) modulates brain health and cognition, which can interfere with executive cognitive function. BDNF was implicated with microcirculatory ischaemia and may reflect cardiomyocyte injury. We aimed to determine whether prospective changes (%Δ) in BDNF and cardiac troponin T (cTnT) will be associated with executive cognitive function in a bi-ethnic cohort. DESIGN: A prospective investigation was conducted over a three-year period in a bi-ethnic sex cohort (N = 338; aged 20-65 years) from South Africa. Fasting serum samples for BDNF and cTnT were obtained. The STROOP-color-word conflict test (CWT) was applied to assess executive cognitive function at baseline. RESULTS: In Blacks, BDNF (P < 0.001) increased over the three-year period while cTnT did not change. In contrast, in Whites, BDNF and cTnT decreased over three years. In Black men, no change in cTnT was associated with increased ΔBDNF (ß = 0.25; 95% CI 0.05-0.45; P = 0.02). In the Black men, constant cTnT levels were inversely associated with executive cognitive function (ß = -0.33; 95% CI -0.53 to -0.12; P = 0.003). Three-year increases in BDNF increased the likelihood for chronic lower cTnT levels at a pre-established cut-point of <4.2 ng/L [OR = 2.35 (1.12-4.94), P = 0.02]. The above associations were not found in the White sex groups. CONCLUSIONS: Central neural control mechanisms may have upregulated BDNF in Black men as a way to protect against myocardial stress progression and to possibly improve processes related to cognitive interference control. High-sensitive cTnT levels may act as an early predictor of disturbed neural control mechanisms.

Coping and Cardiac Troponin T - A Risk for Hypertension and Sub-Clinical ECG Left Ventricular Hypertrophy: The SABPA Study.

BACKGROUND: Defensive coping (DefS) was associated with cardiovascular disease (CVD) susceptibility in Blacks. Whether coping strategies will associate with sub-clinical left ventricular hypertrophy (electrocardiographic-left ventricular hypertrophy [ECG-LVH] or Cornell product), cardiomyocyte injury and blood pressure (BP), is unclear. Therefore, we assessed relationships between ECG-LVH, cardiac troponin T (cTnT) and 24-hour BP in bi-ethnic groups when habitually utilising a certain coping style, and these groups when having a stress-related cTnT cut-point of 4.2ng/L. METHODS: A target population study included a Black (n=190) and White (n=204) teachers' gender cohort (20-65years) from South Africa. The Coping Strategy Indicator determined DefS, social support and avoidance coping scores. Fasting blood samples, 10-lead ECG, 24-hour BP and ECG data were obtained. RESULTS: Interaction effects showed no gender, social support and avoidance coping differences. Stratification of groups was done for ethnicity and DefS. Blacks sought more social support, used less avoidance coping and presented with higher CVD susceptibility. Hypertension prevalence and ECG-LVH levels in DefS Blacks (63%) were higher compared to DefS Whites (40%). Multivariate regression analyses showed positive associations between Cornell product, cTnT and BP [p≤0.05] in DefS Blacks only. Their 24-hour systolic blood pressure (SBP) was associated with time-domain depressed heart-rate-variability and prolonged ST-segment-depression especially when applying an established stress-related cTnT ≥ 4.2ng/L cut-point. CONCLUSIONS: Defensive coping facilitated autonomic hyperactivity, myocardial injury and subsequent compensatory BP elevations as possible homeostatic reflexes to alleviate myocardial perfusion deficits. The resulting pressure overload increased sub-clinical wall remodelling and ischaemic heart disease risk in Blacks utilising habitual defensiveness. We therefore recommend regular ECG and high sensitivity cTnT screening in asymptomatic patients with emotional stress susceptibility. Longitudinal evidence is needed to confirm causality and progression of cardiomyopathy risk.

Defensive coping facilitated a smaller cortisol-to-estradiol ratio and a higher hypertension risk: the SABPA study.

OBJECTIVES: Taxing psychosocial stress and defensive coping have been associated with hypoactivity in cortisol, a vasoconstrictive agent. Estradiol has vasodilatory properties with cardio- and neuroprotective effects. It can however also induce α1-adrenergic vasoconstrictive responsiveness. We aimed to determine whether the cortisol-to-estradiol ratio (Cort:E2) may augment α1-adrenergic responsiveness and hypertension risk when habitually using defensive coping. METHODS: African (n = 168) and Caucasian (n = 207) men and women (46 ± 9 years) were included. Preferential use of defensive coping was determined from Coping Strategy Indicator questionnaire scores. 24h Ambulatory blood pressure was obtained. Fasting serum estradiol and cortisol samples were collected before 09h00 and Cort:E2 was calculated. RESULTS: Estradiol was higher in ethnic-coping groups. Smaller Cort:E2, higher estradiol levels, self-reported emotional stress (19.05% vs. 9.66%) and 24h blood pressure reaching hypertensive status (65% vs. 24%) were evident in African compared to Caucasian men (p ≤ .05). A smaller Cort:E2 was associated with augmented 24h SBP and 24h DBP in African men [Adj R2 0.21-0.29 (p ≤ .05)], and especially when utilizing defensive coping [Adj R2 0.34-0.38 (p ≤ .001)]. CONCLUSIONS: A smaller Cort:E2 was associated with raised blood pressure in defensive coping African men. Defensive coping, possibly via highly activated α1-adrenergic vasoconstrictive responses, may facilitate neuro-endocrine dysfunction and hypertension in African men.

Emotional Stress as a Risk for Hypertension in Sub-Saharan Africans: Are We Ignoring the Odds?

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.

Depression Symptoms Facilitated Fibrinolytic Dysregulation and Future Coronary Artery Disease Risk in a Black Male Cohort: The Sympathetic Activity and Ambulatory Blood Pressure in Africans Study.

BACKGROUND: Hypercoagulation is associated with coronary artery disease (CAD). Whether depression symptoms dysregulate inflammatory and hemostatic markers in an African cohort is not known; therefore, we assessed the relationship between depressive symptoms and inflammatory and hemostatic markers as potential CAD risk markers in an African sex cohort. MATERIAL AND METHODS: We included 181 black African urban-dwelling teachers (88 men, 93 women; aged 25-60 years) from the Sympathetic Activity and Ambulatory Blood Pressure in Africans Study. The Patient Health Questionnaire was used to assess depressive symptoms. Fasting plasma concentrations of C-reactive protein, fibrinogen, D-dimer, plasminogen activator inhibitor-1 (PAI-1) and 24-hour blood pressure measures were obtained. RESULTS: Moderately severe depression symptom status was similar in the black sex groups. Both sex groups showed a mean hypertensive state and low-grade inflammation (C-reactive protein > 3 mg/L). Levels of PAI-1 were higher in depressed men, whereas D-dimer levels were lower in depressed women when considering concomitant confounders. In black men only, depressive symptoms were associated with levels of PAI-1 (adj. R = 0.12; ß = .22 [95% confidence interval, .0-.44]; P = .04) and D-dimer (adj. R = 0.12; ß = .28 [95% confidence interval, .08-.48]; P = .01), independent of confounders. CONCLUSION: In black men, depression symptoms accompanied by a mean hypertensive status may up-regulate inflammatory and thrombotic processes. Depression symptoms in black men facilitated hypercoagulation or fibrinolytic dysregulation and potentially increased their CAD risk. Early screening of fibrinolytic markers and for the presence of depressive symptoms is recommended.

Chronic depression symptoms and salivary NOx are associated with retinal vascular dysregulation: The SABPA study.

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.

Hypercoagulation and hyperkinetic blood pressure indicative of physiological loss-of-control despite behavioural control in Africans: The SABPA study.

OBJECTIVES: A dissociation between behavioural (in-control) and physiological parameters (indicating loss-of-control) is associated with cardiovascular risk in defensive coping (DefS) Africans. We evaluated relationships between DefS, sub-clinical atherosclerosis, low-grade inflammation and hypercoagulation in a bi-ethnic sex cohort. METHODS: Black (Africans) and white Africans (Caucasians) (n = 375; aged 44.6 ± 9.7 years) were included. Ambulatory BP, vascular structure (left carotid cross-sectional wall area (L-CSWA) and plaque counts), and markers of coagulation and inflammation were quantified. Ethnicity/coping style interaction was revealed only in DefS participants. RESULTS: A hypertensive state, less plaque, low-grade inflammation, and hypercoagulation were more prevalent in DefS Africans (27-84%) than DefS Caucasians (18-41%). Regression analyses demonstrated associations between L-CSWA and 24 hour systolic BP (R(2) = 0.38; ß = 0.78; p < 0.05) in DefS African men but not in DefS African women or Caucasians. No associations between L-CSWA and coagulation markers were evident. CONCLUSION: Novel findings revealed hypercoagulation, low-grade inflammation and hyperkinetic BP (physiological loss-of-control responses) in DefS African men. Coupled to a self-reported in-control DefS behavioural profile, this reflects dissociation between behaviour and physiology. It may explain changes in vascular structure, increasing cerebrovascular disease risk in a state of hyper-vigilant coping.

The defense response and alcohol intake: A coronary artery disease risk? The SABPA Study.

The behavioral defense coping response (DefS) as a measure of coping with emotional stress may increase alcohol intake (gamma glutamyl transferase (γGT)), the risk for coronary artery disease (CAD) and insulin sensitivity (homeostasis model assessment, HOMA). We assessed associations between coping and cardiometabolic risk markers in a bi-ethnic cohort (N = 390) from South Africa. Ambulatory blood pressure (BP) and ECG, fasting blood and coping scores were obtained. Africans, and mostly when utilizing DefS, showed higher 24h BP, a low-grade inflammatory state, central obesity, increased HOMA [4.07 (3.66, 4.47)] and more ST events compared to their Caucasian counterparts. ROC γ-GT analyses predicting 24-h ambulatory hypertension showed a higher γ-GT cut-point in Africans (55.4 U/l) than in Caucasians (19.5 U/l). Odds ratios (ORs) of γ-GT cut-points predicting 24-h ambulatory hypertension was evident in DefS African men [OR: 7.37 (95% CI: 6.71-8.05), p = 0.003] and in DefS Caucasians, albeit at a lower γ-GT cut-point (19.5 U/l). Higher γ-GT cut-points in DefS Africans or Caucasians were not associated with HOMA > 3. DefS accompanied by alcohol abuse in taxing emotional situations, if no social support is forthcoming, underscores a profile of reduced coronary perfusion. It may enhance vasoconstriction of the coronary arteries, with compensatory increases in BP, and induce a risk for future coronary artery disease.

Fibrosis and coronary perfusion - a cardiovascular disease risk in an African male cohort: The SABPA study.

Low-grade inflammation has been correlated with risk factors of cardiovascular diseases (CVD). Whether the pro-inflammatory and thrombotic ratio (fibrosis) may contribute to CVD is not known. We therefore aimed to assess whether Cornell Product left ventricular hypertrophy (LVH) is associated with fibrosis and coronary perfusion (silent ischemia) in a bi-ethnic male cohort from South Africa. A cross sectional study was conducted including 165 African and Caucasian men between the ages of 20-65. Fasting blood samples were obtained to measure fibrinogen, C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor (TNF-α). Ambulatory blood pressure, ECG and 12 lead ECG measures were obtained to determine silent ischemic events (ST events) and LVH, respectively. Africans revealed more silent ischemia, higher 24 h blood pressure, inflammatory, coagulation as well as fibrosis levels than Caucasians. In a low-grade inflammatory state (CRP > 3 mg/l), Africans revealed higher fibrosis (p ≤ 0.01) values, but lower IL-6 and TNF-α values than Caucasians. Linear regression analyses in several models demonstrated positive associations between silent ischemia and fibrosis [Adj. R(2) 0.23; ß 0.35 (95% CI 0.13, 0.58), p ≤ 0.01]. In a low-grade inflammatory state (CRP>3mg/l), fibrinogen predicted AV-block in African men [OR 3.38 (95% CI 2.24, 4.53); p = 0.04]. Low-grade inflammation may induce AV-block through mechanisms involving fibrosis and ischemia to increase the burden on the heart in African men.

Comparison of telomere length in black and white teachers from South Africa: the sympathetic activity and ambulatory blood pressure in Africans study.

OBJECTIVE: Telomere length is a marker of biological aging that has been linked to cardiovascular disease risk. The black South African population is witnessing a tremendous increase in the prevalence of cardiovascular disease, part of which might be explained through urbanization. We compared telomere length between black South Africans and white South Africans and examined which biological and psychosocial variables played a role in ethnic difference in telomere length. METHODS: We measured leukocyte telomere length in 161 black South African teachers and 180 white South African teachers aged 23 to 66 years without a history of atherothrombotic vascular disease. Age, sex, years having lived in the area, human immunodeficiency virus (HIV) infection, hypertension, body mass index, dyslipidemia, hemoglobin A1c, C-reactive protein, smoking, physical activity, alcohol abuse, depressive symptoms, psychological distress, and work stress were considered as covariates. RESULTS: Black participants had shorter (median, interquartile range) relative telomere length (0.79, 0.70-0.95) than did white participants (1.06, 0.87-1.21; p < .001), and this difference changed very little after adjusting for covariates. In fully adjusted models, age (p < .001), male sex (p = .011), and HIV positive status (p = .023) were associated with shorter telomere length. Ethnicity did not significantly interact with any covariates in determining telomere length, including psychosocial characteristics. CONCLUSIONS: Black South Africans showed markedly shorter telomeres than did white South African counterparts. Age, male sex, and HIV status were associated with shorter telomere length. No interactions between ethnicity and biomedical or psychosocial factors were found. Ethnic difference in telomere length might primarily be explained by genetic factors.

Prognostic significance of dipping in older hypertensive patients.

BACKGROUND AND AIMS: Arterial hypertension doubles the risk of coronary heart disease, heart and kidney failure, and peripheral arterial disease. Less variation in diurnal ambulatory blood pressure monitoring (ABPM) patterns may affect mortality outcome. Therefore, as hypertension occurs in over 95% of older subjects, the prognostic value of dipping status in older hypertensive patients will be assessed. METHOD: The retrospective study group consisted of 170 hypertensive patients, aged 75-84 years, enrolled in the years 2005 to 2007. Baseline measures included 24-h ABPM. Diurnal index and dipping status was calculated and stratified the group into dippers (40 patients, 23.5%), non-dippers (65 patients, 38.2%) and reverse-dippers (65 patients, 38.2%). RESULTS: During a 5-year observation, after baseline we have observed 69 deaths (40.9%) from the whole group of 170 patients with 23 (35.4%) being non-dippers and 36 (55.4%) reverse-dippers. There were significant differences between the groups divided according to diurnal dipping status in survival time, number of recorded deaths and night mean blood pressure. We have identified and confirmed risk factors for the all-cause mortality: age, mean systolic and diastolic blood pressure, diurnal index and dipping status (dipping, non-dipping or reverse-dipping). CONCLUSION: Reverse-dippers and non-dippers revealed worse prognosis compared with dippers.

Low serum testosterone and increased diastolic ocular perfusion pressure: a risk for retinal microvasculature.

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.

Psychosocial stress but not hypertensive status associated with angiogenesis in Africans.

AIM: Increased angiogenic factors [vascular endothelial growth factor-A (VEGF-A) and angiopoietin-2 (Ang-2)] have been associated with vascular dysfunction and hypertension. Black Africans undergoing rapid urbanization present with elevated blood pressure (BP) and we aimed to determine whether angiogenic factors are elevated in urban versus rural Africans with normal and elevated BP. METHODS AND MATERIALS: Africans (n = 272), matched for gender and age, were recruited from rural and urban communities in South Africa. Omron HEM-757 BP data were obtained and angiogenic markers in plasma and serum were determined. RESULTS: Urban African men displayed a higher (43.90%) hypertension prevalence compared with their rural counterparts (18.52%) and disturbed angiongenic factors. Adjusted VEGF-A concentrations were higher in urban men and women compared with their rural counterparts. Similar VEGF-A levels were observed in rural and urban hypertensives. Logistic regression analysis demonstrated that VEGF-A and Ang-2 levels were associated with psychosocial stress but not with hypertensive status in Africans [odds ratios 1.01-1.09 (95% CI 1.01-1.15), p ≤ 0.05]. CONCLUSION: Psychosocial stress per se was associated with disturbed VEGF-A and Ang-2. We suggest that hyperkinetic BP may act as compensatory mechanism when chronic psychosocial stress prevails, affecting vascular functioning and subsequent increased cardiovascular disease risk.

End-organ damage in urbanized Africans with low plasma renin levels: the SABPA study.

The purpose of this study was to evaluate whether active renin concentration is associated with markers of end-organ damage in urbanized Africans. This study forms part of the Sympathetic Activity and Ambulatory Blood Pressure in Africans (SABPA) study. For this study, 81 men and 74 women were divided into low- and high-renin groups. Ambulatory blood pressure measurements were conducted. A resting 12-lead ECG was determined in order to determine the gender-specific Cornell voltage. Cardiovascular variables were continuously recorded with the Finometer. Carotid-dorsalis pedis pulse wave velocity was obtained with the Complior acquisition system. The carotid intima-media thickness (CIMT) was obtained with the SonoSite MicroMaxx. Blood samples were collected; serum and plasma were stored at -80 °C for analysis. Anthropometric measurements were taken using standard methods. A general health questionnaire was also completed. The urinary creatinine was determined with a calorimetric method and albumin with a turbidimetric method. The serum sodium and potassium were determined by making use of the Konelab TM 20i Sequential Multiple Analyzer Computer (SMAC). The concentration of active renin in the plasma was analyzed by making use of a high-sensitivity radio-immunometric assay. A negative association (r=-0.29, p<0.01) exists between renal function (ACR) and plasma renin in the low-renin group (<6.18 pg/mL), which was not observed in Africans with high-renin levels. It seems evident that low renin in black South Africans may result in sub-clinical renal damage and impaired vascular function in a group of urbanized black South Africans.

Effects of acute and chronic stress on the L-arginine nitric oxide pathway in black and white South Africans: the sympathetic activity and ambulatory blood pressure in Africans study.

OBJECTIVE: This study investigated the impact of stress on effectors of the L-arginine/nitric oxide (NO) system including the endogenous inhibitor asymmetric dimethylarginine (ADMA). METHODS: Black (n = 168) and white (n = 206) South African teachers were exposed to a mental and a physical stressor for 1 minute, respectively. Serum samples for determination of l-arginine, NO metabolites, ADMA, and symmetric dimethylarginine (SDMA) were obtained at rest and during stress exposure. Perception of task stressfulness was assessed on a 7-point Likert scale, and psychological distress was estimated by the General Health Questionnaire. RESULTS: Black South Africans exhibited higher resting levels of NO metabolites (adjusted mean [standard error of the mean] = 11.3 [1.3] versus 3.9 [1.1] µmol/l, p < .001) but lower circulating ADMA (0.62 [0.02] versus 0.70 [0.02] µmol/l, p = .004) and SDMA (0.41 [0.01] versus 0.53 [0.01] µmol/l, p < .001) than did white South Africans. Ethnicity-by-psychological distress interaction was observed for resting levels of ADMA (p = .002), SDMA (p = .038), and L-arginine (p = .048). Ethnic differences in responses to experimental stress were evident for NO metabolites (blacks versus whites: 5.94 [1.55] versus -0.74 [1.25] µmol/l, p = .004) and SDMA (blacks versus whites: -0.02 [0.01] versus 0.02 [0.01] µmol/l, p = .004). Ethnicity-by-psychological distress interaction for stress responses was found for l-arginine/ADMA ratio (p = .027). CONCLUSIONS: The l-arginine/NO system is affected by psychosocial distress with higher susceptibility in black South Africans. This interaction may contribute to the higher cardiovascular disease risk in black South Africans.

Metabolic and glutathione redox markers associated with brain-derived neurotrophic factor in depressed african men and women: evidence for counterregulation?

BACKGROUND: Major depression is associated with evidence for metabolic and redox imbalance and also with reports of lower serum levels of brain-derived neurotrophic factor (BDNF). However, the relationship between these factors has not been well studied. METHODS: We studied the contribution of physiological risk factors to cardiometabolic health in 200 adult male and female black Africans, aged between 36 and 52 years, presenting with (n = 89) and without (n = 111) symptoms of depression. Specifically the association between serum BDNF and markers of basal metabolic and redox status in depressed versus nondepressed individuals were analyzed. RESULTS: BDNF and markers of redox and metabolic status were not associated with the symptoms of depression. Waist circumference, a metabolic risk factor, was positively associated with BDNF and accounts for 49% of the variance in BDNF in depressed men. Reduced and oxidized glutathione were positively and negatively correlated with BDNF in depressed women, respectively, with glutathione redox status accounting for 36-42% of the variance in BDNF. CONCLUSION: Selected metabolic and redox factors explained gender-specific variances in serum BDNF levels in depressed African men and women. Our findings suggest that changes in redox and metabolic status may represent counterregulation by BDNF or alternatively that BDNF may mediate undesirable redox and metabolic changes that are associated with the development of a mood disorder.