A Challenged Sympathetic System Is Associated with Retinal Vascular Calibre in a Black Male Cohort: The SABPA Study

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 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

Chronic defensiveness and neuroendocrine dysfunction reflect a novel cardiac troponin T cut point: The SABPA study.

Background: Sympatho-adrenal responses are activated as an innate defense coping (DefS) mechanism during emotional stress. Whether these sympatho-adrenal responses drive cardiac troponin T (cTnT) increases are unknown. Therefore, associations between cTnT and sympatho-adrenal responses were assessed. Methods: A prospective bi-ethnic cohort, excluding atrial fibrillation, myocardial infarction and stroke cases, was followed for 3 years (N=342; 45.6±9.0 years). We obtained serum high-sensitive cTnT and outcome measures [Coping-Strategy-Indicator, depression/Patient-Health-Questionnarie-9, 24h BP, 24h heart-rate-variability (HRV) and 24h urinary catecholamines]. Results: cTnT levels of the cohort remained similar over 3 years but recovery to cTnT-negative levels was higher in Blacks. Blacks showed moderate depression (45% vs. 16%) and 24h hypertension (67% vs. 42%) prevalence compared to Whites. A receiver-operating-characteristics cTnT cut-point 4.2 ng/L predicting hypertension in Blacks was used as binary exposure measure in relation to outcome measures [AUC 0.68 (95% CI 0.60-0.76); sensitivity/specificity 63/70%; P≤0.001]. In cross-sectional analyses, elevated cTnT was related to DefS [OR 1.08 (95% CI 0.99-1.16); P=0.06]; 24h BP [OR 1.03-1.04 (95% CI 1.01-1.08); P≤0.02] and depressed HRV [OR 2.19 (95% CI 1.09-4.41); P=0.03] in Blacks, but not in Whites. At 3 year follow-up, elevated cTnT was related to attenuated urine norepinephrine:creatinine ratio in Blacks [OR 1.46 (95% CI 1.01-2.10); P=0.04]. In Whites, a cut point of 5.6 ng/L cTnT predicting hypertension was not associated with outcome measures. Conclusion: Central neural control systems exemplified a brain-heart stress pathway. Desensitization of sympatho-adrenal responses occurred with initial neural- (HRV) followed by neuroendocrine dysfunction (norepinephrine:creatinine) in relation to elevated cTnT. Chronic defensiveness may thus drive the desensitization or physiological depression, reflecting ischemic heart disease risk at a 4.2 ng/L cTnT cut-point in Blacks

Progression of cardiovascular risk factors in black Africans: 3 year follow up of the SABPA cohort study

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 multiethnic 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 ¼ 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

Delayed retinal vein recovery responses indicate both non-adaptation to stress as well as increased risk for stroke: the SABPA study

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, reflecting delayed vein recovery responses and non-adaptation to stress. These constrained vein recovery responses are indicative of increased chronic stress and stroke risk

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 hemodynamics 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 24h 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, a novel approach, 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 (%), 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 FLIP NOx responses (%). Conclusions Higher NOx increased arteriolar vasoconstriction, presumably impeded perfusion and facilitated VD. Chronic depression symptoms may trigger disturbed NOx and retinal hemodynamics in Blacks and thereby potentiate stroke ris

Complementâ induced activation of the cardiac NLRP3 inflammasome in sepsis

Cardiac dysfunction develops during sepsis in humans and rodents. In the model of polymicrobial sepsis induced by cecal ligation and puncture (CLP), we investigated the role of the NLRP3 inflammasome in the heart. Mouse heart homogenates from shamâ procedure mice contained high mRNA levels of NLRP3 and ILâ 1β. Usingthe inflamm a some protocol, exposure of cardiomyocytes (CMs) to LPS followed by ATP or nigericin caused release of mature ILâ 1β. Immuno staining of left ventricular frozen sections before and 8 h after CLP revealed the presence of NLRP3 and ILâ 1β proteins inCMs. CLP caused substantial increases in mRNAs for ILâ 1β and NLRP3 in CMs which are reduced in the absence of either C5aR1 or C5aR2. After CLP, NLRP32/2 mice showed reduced plasma levels of ILâ 1βand ILâ 6. In vitro exposure of wildâ type CMs to recombinant C5a (rC5a) cause delevations in both cytosolic and nuclear/mitochondrial reactive oxygen species (ROS), which were C5aâ receptor dependent. Use of a selective NOX2 inhibitor prevented increased cytosolic and nuclear/mitochondrial ROS levels and release of ILâ 1β. Finally, NLRP32/2 mice had reduced defects in echo/Doppler parameters in heart afterCLP. These studies establish that the NLRP3 inflammasome contributes to the cardiomyopathy of polymicrobial sepsis.â Kalbitz, M., Fattahi, F., Grailer, J. J., Jajou, L., Malan, E. A., Zetoune, F. S., Huberâ Lang, M., Russell, M. W., Ward, P. A. Complementâ induced activation of the cardiac NLRP3 inflammasome in sepsis. FASEB J. 30, 3997â 4006 (2016). www.fasebj.orgPeer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154362/1/fsb2fasebj30120728r.pd

Complementâ induced activation of MAPKs and Akt during sepsis: role in cardiac dysfunction

Polymicrobial sepsis in mice causes myocardial dysfunction after generation of the complement anaphylatoxin, complement component 5a (C5a). C5a interacts with its receptors on cardiomyocytes (CMs), resulting in redox imbalance and cardiac dysfunction that can be functionally measured and quantitated using Doppler echocardiography. In this report we have evaluated activation of MAPKs and Akt in CMs exposed to C5a in vitro and after cecal ligation and puncture (CLP) in vivo. In both cases, C5a in vitro caused activation (phosphorylation) of MAPKs and Akt in CMs, which required availability of both C5a receptors. Using immunofluorescence technology, activation of MAPKs and Akt occurred in left ventricular (LV) CMs, requiring both C5a receptors, C5aR1 and â 2. Use of a waterâ soluble p38 inhibitor curtailed activation in vivo of MAPKs and Akt in LV CMs as well as the appearance of cytokines and histones in plasma from CLP mice. When mouse macrophages were exposed in vitro to LPS, activation of MAPKs and Akt also occurred. The copresence of the p38 inhibitor blocked these activation responses. Finally, the presence of the p38 inhibitor in CLP mice reduced the development of cardiac dysfunction. These data suggest that polymicrobial sepsis causes cardiac dysfunction that appears to be linked to activation of MAPKs and Akt in heart.â Fattahi, F., Kalbitz, M., Malan, E. A., Abe, E., Jajou, L., Huberâ Lang, M. S., Bosmann, M., Russell, M. W., Zetoune, F. S., Ward, P. A. Complementâ induced activation of MAPKs and Akt during sepsis: role in cardiac dysfunction. FASEB J. 31, 4129â 4139 (2017). www.fasebj.orgâ Fattahi, Fatemeh, Kalbitz, Miriam, Malan, Elizabeth A., Abe, Elizabeth, Jajou, Lawrence, Huberâ Lang, Markus S., Bosmann, Markus, Russell, Mark W., Zetoune, Firas S., Ward, Peter A., Complementâ induced activation of MAPKs and Akt during sepsis: role in cardiac dysfunction. FASEB J. 31, 4129â 4139 (2017)Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154261/1/fsb2fj201700140r.pd

PArallel, Robust, Interface Simulator (PARIS)

Paris (PArallel, Robust, Interface Simulator) is a finite volume code for simulations of immiscible multifluid or multiphase flows. It is based on the "one-fluid" formulation of the Navier-Stokes equations where different fluids are treated as one material with variable properties, and surface tension is added as a singular interface force. The fluid equations are solved on a regular structured staggered grid using an explicit projection method with a first-order or second-order time integration scheme. The interface separating the different fluids is tracked by a Front-Tracking (FT) method, where the interface is represented by connected marker points, or by a Volume-of-Fluid (VOF) method, where the marker function is advected directly on the fixed grid. Paris is written in Fortran95/2002 and parallelized using MPI and domain decomposition. It is based on several earlier FT or VOF codes such as Ftc3D, Surfer or Gerris. These codes and similar ones, as well as Paris, have been used to simulate a wide range of multifluid and multiphase flows