We conducted a phase I trial in newly diagnosed acute myeloid leukaemia (AML) to investigate the combination of two novel targeted agents, gemtuzumab ozogamicin (GO) and midostaurin, with intensive chemotherapy in FLT3-mutated AML and CBF leukaemia. Three dose levels of midostaurin and one to three sequential doses of 3 mg/m2 GO in combination with '7 + 3' induction were evaluated. Based on safety findings in 12 patients, our results show that 3 mg/m2 GO on Days 1 + 4 and 100 mg midostaurin on Days 8-21 can be safely combined with IC in newly diagnosed AML.

Abstract Background In newly diagnosed acute myeloid leukemia (AML) with FLT3 mutations (FLT3-mut), the tyrosine kinase inhibitor midostaurin (MIDO) in combination with intensive chemotherapy (IC) is considered standard of care (SoC). Subgroup analyses from the ALFA 0701 trial indicate that the addition of the conjugated CD33 antibody gemtuzumab ozogamicin (GO) to IC increases efficacy in the FLT3-ITD subgroup of patients (pts), providing a rationale for the combined use of MIDO plus GO with IC in newly diagnosed FLT3-mut AML. On the other hand, there is evidence that the subgroup of core-binding factor (CBF) AML benefits from the inhibition of the tyrosine kinase KIT with respect to survival end points. In this respect, MIDO is a more powerful KIT inhibitor as compared to dasatinib which has been applied in previous studies. While the combination of IC plus GO in induction treatment is considered SoC in patients with CBF AML the addition of MIDO to SoC seems promising to further improve treatment outcomes in the CBF subgroup. We therefore set up the clinical trial MOSAIC composed of a phase-I part to prospectively assess the feasibility of combining MIDO plus GO with IC (MODULE), followed by a randomized phase-II part evaluating the benefit of adding GO to SoC in FLT3-mut AML (MAGMA) and of adding MIDO to SoC in CBF AML (MAGNOLIA). Here, we report the results of the phase-I part (MODULE). Methods MODULE is a dose escalation phase-I trial following a 3+3 design. Eligibility criteria include newly diagnosed AML harboring either FLT3 or CBF mutations, and fitness for IC. Standard 7+3 IC using cytarabine 200 mg/m 2 continuous infusion over 7 days plus daunorubicin 60 mg/m 2 on 3 days was combined with increasing doses of MIDO and GO in three dose levels: 1 st dose level (GO 3 mg/m 2 i.v. QD on day 1+4 plus 25 mg MIDO p.o. BID days 8-21); 2 nd dose level (GO 3 mg/m 2 i.v. QD on day 1+4 plus 50 mg MIDO p.o. BID days 8-21); 3 rd dose level (GO 3 mg/m 2 i.v. QD on day 1+4+7 plus 50 mg MIDO p.o. BID days 8-21). Based on the 3+3 design, each dose cohort consisted of three but maximal six pts. The protocol predefined the maximal tolerable dose (MTD) as reached if ≤2 dose-limiting toxicity events (DLTs) would occur in maximum six evaluable pts who received ≥80% of the planned study therapy. Results From September 2020 to July 2021, 11 pts were enrolled. In the 1 st dose level, three pts completed the regular study period without DLT, whereas treatment had to be discontinued in one patient on day 6 before commencement of MIDO due to infusion related reaction CTC grade 4. This patient was subsequently replaced. In the 2 nd dose level, one of three enrolled pts experienced neutropenic colitis CTC grade 3 on day 14 of treatment, which was classified as DLT. The colitis fully recovered by day 27 after commencement of treatment. As a result of the DLT, the dose cohort was subsequently extended by three additional pts. Of those, one patient developed signs of sinusoidal obstruction syndrome (SOS) CTC grade 3 starting on day 13 of treatment. SOS was classified as DLT. The patient was treated with defibrotide and supportive care until recovery on day 28. Another patient had to discontinue treatment on day 14 due to inability of swallowing MIDO. This patient was replaced as the target dose of MIDO was not reached. As predefined in the study protocol, the occurrence of 2 DLTs in six evaluable pts precluded further dose escalation to the 3 rd dose level and defined the 2 nd dose level as safe and feasible. A total number of 5 serious adverse events (SAEs) were observed among all 11 pts who completed the DLT evaluation period: infusion related reaction, colitis, parvo-B19 infection, prolonged neutropenia CTC grade 4, and SOS. An unexpected increase in frequency of common AML adverse events was not observed. The 30-day mortality among all enrolled pts was 0%. After blood count recovery, remission assessment showed complete remission (CR) in 7 pts, CR with incomplete hematologic/platelet recovery (CRi/CRp) in 3 pts and primary refractory disease in one patient. Conclusion GO standard dose on days 1 + 4 and MIDO standard dose on days 8-21 of induction treatment is defined as MTD which can be safely combined with standard IC in newly diagnosed AML. In the phase-I cohort of the MOSAIC trial, CR/CRi/CRp rates of 91% were reached. Based on the results of this dose finding trial the MTD of combined MIDO and GO will be defined as phase-II dose for the randomized phase-II studies in CBF and FLT-mut AML. Figure 1 Figure 1. Disclosures Röllig: Jazz: Honoraria; Amgen: Honoraria; Bristol-Meyer-Squibb: Honoraria, Research Funding; Janssen: Honoraria; Pfizer: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Roche: Honoraria, Research Funding. Schliemann: Philogen S.p.A.: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Other: travel grants; Astellas: Consultancy; AstraZeneca: Consultancy; Boehringer-Ingelheim: Research Funding; BMS: Consultancy, Other: travel grants; Jazz Pharmaceuticals: Consultancy, Research Funding; Novartis: Consultancy; Roche: Consultancy; Pfizer: Consultancy. Fransecky: Novartis: Honoraria; Abbvie: Honoraria, Research Funding; Amgen: Honoraria; Takeda: Honoraria; Medac: Honoraria. Baldus: Novartis: Honoraria; Amgen: Honoraria; Celgene/BMS: Honoraria; Jazz: Honoraria. Wermke: Novartis, Roche, Pfizer, BMS: Consultancy, Honoraria, Research Funding.

Evidence from family, twin, and adoption studies indicates that there is a significant genetic contribution to major depressive disorder. However, the majority of individuals with a positive family history of depression do not develop depression. Thus, current hypotheses about the role of genes for the development of depression collectively favor the stress–diathesis theory. The latter postulates that repeated or chronic exposure of a vulnerable genotype to stressful life events may trigger the development of depression. The hypothalamic-pituitary-adrenal (HPA) axis is discussed as a missing link between genes, stress, and depression. The genetic variation of coping behavior in response to stress and the depression-related dysregulation of HPA axis confirm a strong impact of both genetic and environmental factors on the manifestation of depressive disorders. Such interactions would facilitate the manifestation of environmental effects in a depressive phenotype preferentially in the presence of a permissive genetic background.

Background Obesity-associated activation of sympathetic nervous outflow is well documented, whereas involvement of dysregulated adrenomedullary hormonal function in obesity is less clear. This study assessed relationships of sympathoadrenal function with indices of obesity and influences of circulating catecholamines on body mass. Methods Anthropometric and clinical data along with plasma and 24-h urine samples were collected from 590 volunteers and 1368 patients tested for phaeochromocytoma and paraganglioma (PPGL), among whom tumours were diagnosed in 210 individuals. Results Among patients tested for PPGL, those with tumours less often had a body mass index (BMI) above 30 kg/m 2 (12 vs. 31%) and more often a BMI under 25 kg/m 2 (56 vs. 32%) than those without tumours ( P < 0.0001). Urinary outputs of catecholamines in patients with PPGL were negatively related to BMI ( r = −0.175, P = 0.0133). Post-operative weight gain ( P < 0.0001) after resection of PPGL was positively related to presurgical tumoural catecholamine output ( r = 0.257, P = 0.0101). Higher BMI in men and women and percent body fat in women of the volunteer group were associated with lower plasma concentrations and urinary outputs of adrenaline and metanephrine, the former indicating obesity-related reduced adrenaline secretion and the latter obesity-related reduced adrenomedullary adrenaline stores. Daytime activity was associated with substantial increases in urinary adrenaline and noradrenaline excretion, with blunted responses in obese subjects. Conclusions The findings in patients with PPGL support an influence of high circulating catecholamines on body weight. Additional associations of adrenomedullary dysfunction with obesity raise the possibility of a permissive influence of the adrenal medulla on the regulation of body weight.

Objective: The performance of the Sudoscan technology for diagnosing diabetic polyneuropathy (DPN) was evaluated against the quantitative sudomotor axon reflex test (QSART). Furthermore, the association of Sudoscan with two clinical neuropathy scoring systems was evaluated. Methods: Forty-seven patients with type 2 diabetes (20 without DPN, 27 with DPN) and 16 matched controls were examined for neuropathic symptoms and for the extent of sensory deficits. Sweat latency and volume by QSART and the skin electrochemical conductance (ESC) by Sudoscan were measured. Results: The feet and hand ESC was significantly lower in patients with DPN as compared to controls. Patients with DPN had also lower hand ESC than patients without DPN. Sensitivity and specificity of feet and hand ESC for detecting DPN were 70/85% and 53/50% respectively. QSART could not differentiate between the three groups. ESC was inversely related to neuropathic symptoms and sensory impairment. ESC was significantly correlated with sensory impairment and pain. Conclusions: Sudoscan shows a good performance in detecting subjects with DPN and it correlates well with clinical signs and symptoms of neuropathy. Significance: This study provides evidence that Sudoscan has high potential to be used as screening tool for DPN and possibly also for small fiber neuropathy in diabetic patients. HIGHLIGHTS - The sudomotor function test Sudoscan shows a good performance to detect diabetes peripheral neuropathy.- Sudoscan measures significantly correlate with clinical signs and symptoms of neuropathy.- The Sudoscan technology may help to secure clinical diagnosis of small fiber neuropathy.

Objective: It is well-known that initiation of fingolimod induces a transient decrease of heart rate. However, the underlying cardiac autonomic regulation is poorly understood. We aimed to investigate the changes of autonomic activity caused by the first dose of fingolimod using a long-term multiple trigonometric spectral analysis for the first time. In addition, we sought to use the continuous Holter ECG recording to find predictors for fingolimod induced bradycardia.Methods: Seventy-eight patients with relapsing remitting multiple sclerosis (RRMS) were included. As a part of the START study (NCT01585298), continuous electrocardiogram was recorded before fingolimod initiation, and until no <6 h post medication. Time domain and frequency domain heart rate variability (HRV) parameters were computed hourly to assess cardiac autonomic regulation. A long-term multiple trigonometric regressive spectral (MTRS) analysis was applied on successive 1-h-length electrocardiogram recordings. Decision tree analysis was used to find predictors for bradycardia following fingolimod initiation.Results: Most of the HRV parameters representing parasympathetic activities began to increase since the second hour after fingolimod administration. These changes of autonomic regulations were in accordance with the decline of heart rate. Baseline heart rate was highly correlated with nadir heart rate, and was the only significant predicting factor for fingolimod induced bradycardia among various demographic, clinical and cardiovascular variables in the decision tree analysis.Conclusions: The first dose application of fingolimod enhances the cardiac parasympathetic activity during the first 6h post medication, which might be the underlying autonomic mechanism of reduced heart rate. Baseline heart rate is a powerful predictor for bradycardia caused by fingolimod.

We aimed to explore the effects of bilateral subthalamic nucleus stimulation and levodopa on cardiovascular autonomic function in Parkinson's disease. Twenty-six Parkinson's disease patients with bilateral subthalamic nucleus stimulation in a stable state were tested under stimulation off and dopaminergic medication off (OFF-OFF), stimulation on and dopaminergic medication off (ON-OFF), and stimulation on and medication (levodopa) on (ON-ON) conditions by recording continuously blood pressure, ECG, and respiration at rest, during metronomic deep breathing, and head-up tilt test. Thirteen patients were diagnosed as orthostatic hypotension by head-up tilt test. Baroreflex sensitivity and spectral analyses were performed by trigonometric regressive spectral analysis. Subthalamic nucleus stimulation and levodopa had multiple influences. (1) Systolic blood pressure during tilt-up was reduced by subthalamic nucleus stimulation, and then further by levodopa. (2) Subthalamic nucleus stimulation and levodopa had different effects on sympathetic and parasympathetic regulations in Parkinson's disease. (3) Levodopa decreased baroreflex sensitivity and RR interval only in the orthostatic hypotension group, and had opposite effects on the non-orthostatic hypotension group. These findings indicate that subthalamic nucleus stimulation and levodopa have different effects on cardiovascular autonomic function in Parkinson's disease, which are modulated by the presence of orthostatic hypotension as well.

Background High sensitivity cardiac troponin T (hs-cTnT) is a validated marker of myocardial damage and may reflect the degree of silent myocardial ischaemia (SMI) and ventricular strain. Our aim was to compare hs-cTnT levels in black and white South Africans taking SMI into consideration. We further explored the capability of hs-cTnT to predict the presence of compensatory systolic hypertension in this South African cohort.Methods A bi-ethnic sex cohort (n=404) with similar socioeconomic status (198 black participants and 206 white participants, aged 20-65 years) participated in this target population study where 24h ambulatory blood pressure, electrocardiogram and overnight fasting cardiometabolic variables were measured.Results Hypertension, higher glycated haemoglobin levels and more frequent and longer SMI events were observed more often in the black participants. Multivariate linear regression analysis showed positive associations between SMI events [Adj. R-2=0.19; 0.35 (0.08-0.62); p<0.01], SMI event maximum duration [Adj. R-2=0.17, 0.43 (0.16-0.70), p<0.01], SMI total duration [Adj. R-2=0.12; 0.37 (0.10; 0.65), p=0.05] and hs-cTnT in black males only.] A lower hs-cTnT cut-point 4.2pg/ml for 24h systolic hypertension was predicted in the black participants compared with 5.6pg/ml in the white participants (area under the curve 0.66-67 (95% CI: 0.57-0.75), p<0.001) with a respective sensitivity/specificity of 64/68% and 61/71%.Conclusions hs-cTnT may be a potential marker of SMI in the prediction of systolic blood pressure increases, as well as clusters of risk factors for cardiovascular disease. Ethnic- and possibly sex-specific references values for hs-cTnT should be considered for risk stratification.

Background and Objective: Although there is strong evidence linking obesity with increased sympathoneural activity, involvement of the adrenal medulla is less clear. We therefore investigated adrenal medullary function under fasting and feeding conditions in normal weight (NW, n =33), overweight (OW, n =28) and obese (OB, n =36) adults (59% women). Subjects and Methods: Ninety-seven healthy adults participated in a cross-sectional study with recruitment stratified according to BMI. Plasma for catecholamines and metanephrines was sampled in the fasting state, at 30-min intervals during a 120-min glucose tolerance test and during an euglycaemic-hyperinsulinaemic clamp (40 mU m −2 min − 1 insulin dose). Body composition was determined by leg-to-leg bioelectrical impedance analysis. Results: Obese subjects had the lowest fasting plasma concentrations of epinephrine (NW: 0.17, 95% confidence interval (CI): 0.14–0.20 nmol l −1 ; OW: 0.16, 95% CI: 0.12–0.19 nmol l −1 ; OB: 0.11, 95% CI: 0.08–0.13 nmol l −1 ; P =0.018) and metanephrine (NW: 0.17, 95% CI: 0.15–0.19 nmol l −1 ; OW: 0.15, 95% CI: 0.13–0.16 nmol l −1 ; OB: 0.13, 95% CI: 0.12–0.15 nmol l −1 ; P =0.022), the latter reflecting adrenal medullary store size. Fasting plasma epinephrine ( r =−0.437; P <0.001) and metanephrine ( r =−0.477; P <0.001) concentrations were additionally inversely correlated with whole-body fat percentage. Suppression of epinephrine secretion in response to carbohydrate ingestion was significantly blunted in overweight and obese subjects compared with the normal weight subjects ( P interaction =0.045). Most of the variance in basal epinephrine was related to whole-body fat percentage ( β =−0.389, 95% CI: −0.09 to −0.69; P =0.012) that explained the lower concentrations of epinephrine and metanephrine in women than men. Conclusions: We provide evidence that adrenomedullary dysfunction is a characteristic feature of obesity that involves both reduced adrenal secretion of epinephrine and size of adrenal medullary epinephrine stores.

Spontaneous BRS estimates may considerable vary according to the technique of blood pressure and heart rate assessment. To optimise and standardise BRS estimation for clinical use we evaluated possible differences between spontaneous BRS indices estimated from either finger plethysmography or radial tonometry. Forty-five healthy volunteers underwent simultaneous recordings of electrocardiogram, finger plethysmography and radial tonometry in supine position and during 60° head-up tilt. BRS was computed by spectral analysis from either R–R time series and/or arterial pressure pulse. Radial tonometry generated higher mean BRS estimates than finger plethysmography. The difference decreased upon postural change from supine to upright. In the upright position, BRS estimates based on R–R interval proved to be generally lower compared to BRS indices estimated from arterial pressure pulse. The ratio of low-to-high-frequency power of inter-systolic interval and systolic blood pressure from tonometry was lower than that from plethysmography in supine and approximated in upright position. Spectral parameters of inter-systolic interval and R–R interval did not differ in supine but diverged in upright position. Changes of spectral parameters were most pronounced in R–R interval. Arterial pressure pulse is adequate for estimation of BRS under resting conditions but it may distort BRS estimates under physical load. We, therefore, recommend using an ECG signal for BRS estimation especially in non-stationary conditions.

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.

Sympathetic system hyperactivity and depression are related to cardiac remodelling in Black men. We investigated whether sympathetic system hyperactivity and depressive symptoms are related to retinal vascular dysregulation. A total of 76 Black and 83 White men (23–68 years of age) from the SABPA study were included. Depressive symptoms, 24h pulse pressure (PP), fasting blood and 24-hour urinary catecholamine data were obtained. Retinal vascular calibre was quantified from digital photographs using standardized protocols. Black men demonstrated increased (p < 0.05) hyperpulsatile pressure (PP > 50 mmHg), hypertension (78.9 % vs 48.4%) and depression (34.2% vs. 13.3%) prevalence compared to White men. Despite lower epinephrine levels, epinephrine was associated with arteriolar narrowing and venular widening in the Black men [Adj R2 −0.37 (95% CI: −0.66, −0.09), p=0.013; Adj R2 0.35 (95% CI: 0.13, 0.57), p=0.003]. This might suggest ß-adrenergic hyporesponsivity to epinephrine, which was accompanied by hyperpulsatile blood pressure in the Black group. In the White group, depressive symptoms and norepinephrine were associated with retinal arteriolar narrowing. A profile of ß-adrenergic hyporesponsivity, indicative of a chronically challenged sympathetic system, was associated with retinal vascular remodelling in Black men. ß-adrenergic hyporesponsivity as a result of chronic stress emphasized central control of the brain on the circulatory system irrespective of the vascular bed.

Objective: Autonomic system dysfunction is associated with various changes in the retinal vasculature. Depression has recently been acknowledged as a risk factor for poor prognosis in patients with acute coronary syndrome and was associated with cardiac remodelling in Black Africans. In this study we investigated the possible association between depressive symptoms, autonomic system activity and retinal microvasculature calibre. Design and method: A total of 89 Black and 91 White men (28–68 years of age) from the follow-up phase of the Sympathetic activity and Ambulatory Blood Pressure in Africans study were included in this sub-study. Ambulatory blood pressure and depressive symptoms (PHQ-9) were obtained, while metabolic and autonomic variables were measured from fasting venous blood samples and 24-hour urine samples. Retinal vascular calibre was quantified from digital photographs using standardized protocols. Results: The Blacks had a poorer health profile than the Whites with blood pressure and glycated haemoglobin values above the cut-off for hypertension and a pre-diabetic state. They demonstrated more depressive symptoms (PHQ = 7.37, SD = 4.54), lower catecholamines and retinal arteriolar-to-venular ratio. Depressive symptoms were associated with arteriolar narrowing in the White group only. Epinephrine was positively associated with arterial narrowing and venular calibre in the Black men. Conclusions: A profile of ß-adrenergic hyporesponsivity was evident in Blacks. They revealed more depressive symptoms, a chronically challenged SNS associated with retinal vascular remodelling and possible vascular hypertrophy. Whether these changes precede or result from hyperpulsatile pressure impacting on retinal autoregulation is still debatable. A ß-adrenergic hyporesponsiveness was previously observed in this cohort emphasizing central control of the brain on the circulatory system irrespective of the vascular bed. Early ocular and mental health screening is recommended to prevent microcirculatory pathology.

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.

Objective: Depression is associated with risk of hypertension and acute coronary syndromes. High blood pressure exerts sheer stress on vessel walls and may impair carotid and retinal perfusion, contributing to early structural wall changes. We therefore aimed to assess the association between depressive symptoms, reduced perfusion pressure and remodelling of the macro- (carotid) and microvasculature (retina). Design and method: A total of 358 teachers (Blacks ∼ 48 %, aged 48.6 ± 9 years) from the Sympathetic Activity and Ambulatory Blood Pressure in Africans cohort study, were included. Cardiometabolic risk markers were assessed under fasting well-controlled conditions using standardized protocols. Depressive symptoms scores were calculated using DSM-IV criteria. Ambulatory BP, ECG and ultrasound B-mode carotid far wall thickness were obtained. Diastolic blood pressure – Intraocular pressure defined diastolic ocular perfusion pressure (DOPP). Retinal structure and retinopathy signs were quantified from externally validated digital images using standardized protocols. Responses of retinal vessels to flicker light were evaluated as marker of microvascular endothelial function. Results: Depressive symptoms predicted 24 h hypertension with an odds ratio of 2.52 (95 % CI: 2.12, 2.94; p = 0.03) in the bi-ethnic cohort, independent of cardiovascular confounders. Overall, depressive symptoms were associated with retinal vascular changes but not carotid remodelling. Retinal arteriolar narrowing was more evident in Black Africans. In that ethnic group, both depressive symptoms [Adj R2 0.26, ß = 0.31 (95% CI: 0.13, 0.49; p = 0.001) and perfusion pressure (DOPP) [Adj R2 0.26, ß = 0.16 (95% CI: 0.0, 0.32); p = 0.03] were associated with a wider venular caliber, an index of stroke risk. In Blacks, depressive symptoms were also associated with increased arteriolar responses to flicker light [Adj R2 0.22, ß = 0.17 (95% CI: 0.06, 0.38); p = 0.04]. Conclusions: Depression may trigger changes in both ocular hemodynamics and the systemic circulation. Depression, in synergy with compensatory increases in blood pressure to alleviate reduced supply, may increase stroke risk, especially in the Blacks.

Objective: Autonomic system dysfunction is associated with various changes in the retinal vasculature. Depression has recently been acknowledged as a risk factor for poor prognosis in patients with acute coronary syndrome and was associated with cardiac remodelling in Black Africans. In this study we investigated the possible association between depressive symptoms, autonomic system activity and retinal microvasculature calibre. Design and method: A total of 89 Black and 91 White men (28–68 years of age) from the follow-up phase of the Sympathetic activity and Ambulatory Blood Pressure in Africans study were included in this sub-study. Ambulatory blood pressure and depressive symptoms (PHQ-9) were obtained, while metabolic and autonomic variables were measured from fasting venous blood samples and 24-hour urine samples. Retinal vascular calibre was quantified from digital photographs using standardized protocols. Results: The Blacks had a poorer health profile than the Whites with blood pressure and glycated haemoglobin values above the cut-off for hypertension and a pre-diabetic state. They demonstrated more depressive symptoms (PHQ = 7.37, SD = 4.54), lower catecholamines and retinal arteriolar-to-venular ratio. Depressive symptoms were associated with arteriolar narrowing in the White group only. Epinephrine was positively associated with arterial narrowing and venular calibre in the Black men. Conclusions: A profile of ß-adrenergic hyporesponsivity was evident in Blacks. They revealed more depressive symptoms, a chronically challenged SNS associated with retinal vascular remodelling and possible vascular hypertrophy. Whether these changes precede or result from hyperpulsatile pressure impacting on retinal autoregulation is still debatable. A ß-adrenergic hyporesponsiveness was previously observed in this cohort emphasizing central control of the brain on the circulatory system irrespective of the vascular bed. Early ocular and mental health screening is recommended to prevent microcirculatory pathology.

Insulin may link metabolic disorders to retinal microvascular pathology. The aim of the present study was to investigate the impact of early insulin resistance on retinal microcirculation.

Background: Elevated circulating lipids and homocysteine may affect autonomic cardiovascular function by decreasing baroreflex sensitivity (BRS) and cardiovagal outflow and by increasing sympathetic drive.Methods: To test this hypothesis 25 clinically healthy men (mean age 24 +/- 2 years) received 500 ml whipping cream (30% fat) and 0.1 g/kg L-methionine, respectively, at intervals of one week apart to induce hyperlipidemia and hyperhomocysteinemia, respectively. Cardiovascular parameters and endothelial function were assessed before and 2 h after the fat load and before and 4 h after the methionine load, respectively. Cardiovascular responses to sublingual application of a nitrovasodilator and a beta-agonist were also determined.Results: Hyperlipidemia elicited a significant decline in BRS and an increase in heart rate and sympathetic drive. Reductions in BRS were associated with changes in total cholesterol but not with triglycerides or endothelial function. Autonomic and hemodynamic variables remained unaltered during transient hyperhomocysteinemia although there was a trend to lower BRS. Autonomic and hemodynamic responses to pharmacological vasodilation and beta-adrenoceptor stimulation were preserved under both conditions.Conclusions: These data provide experimental support for the concept that acute hyperlipidemia but not hyperhomocysteinemia impairs reflex regulation of the circulatory system. (C) 2015 Elsevier Ireland Ltd. All rights reserved.