Vascular dysfunction and oxidative stress caused by acute formaldehyde exposure in female adults

This study was the first to investigate the implications of acute formaldehyde (FA) exposure on adult female vascular function in the arms and legs. The main findings from this study were a decrease in conduit vessel function without any alteration to microvascular function following a 90-min FA exposure. Additionally, the oxidative stress marker malondialdehyde increased after FA exposure. Taken together, these results suggest acute FA exposure have deleterious implications for the vasculature and redox balance.

Sacubitril-Valsartan Improves Conduit Vessel Function and Functional Capacity, and Reduces Inflammation in Heart Failure with Reduced Ejection Fraction

The PARADIGM-HF trial identified a marked reduction in the risk of death and hospitalization for heart failure in patients with heart failure with reduced ejection fraction (HFrEF) treated with sacubitril-valsartan, but the physiologic processes underpinning these improvements are unclear. We tested the hypothesis that treatment with sacubitril-valsartan improves peripheral vascular function, functional capacity, and inflammation in patients with HFrEF. We prospectively studied patients with HFrEF (n=11, 10M/1F, left ventricular ejection fraction 27±8%) on optimal, guideline-directed medical treatment who were subsequently prescribed sacubitril-valsartan (open-label, uncontrolled, and unblinded). Peripheral vascular function (brachial artery flow-mediated dilation (FMD, conduit vessel function) and reactive hyperemia (RH, microvascular function)), functional capacity (six-minute walk test (6MWT) distance), and the pro-inflammatory biomarkers, tumor necrosis factor-alpha (TNF-α) and interleukin-18 (IL-18) were obtained at baseline and again at 1, 2, and 3 months of treatment. %FMD improved after 1 month of treatment, and this favorable response persisted for months 2 and 3 (baseline: 3.25±1.75%; 1mo: 5.23±2.36%; 2mo: 5.81±1.79%; 3mo: 6.35±2.77%), while RH remained unchanged. 6MWT distance increased at months 2 and 3 (baseline: 420±92 m; 1mo: 436±98 m; 2mo: 465±115 m; 3mo: 460±110 m), and there was a sustained reduction in TNF-α (baseline: 2.38±1.35 pg/mL; 1mo: 2.06±1.52 pg/mL; 2mo: 1.95±1.34 pg/mL; 3mo: 1.92±1.37 pg/mL) and a reduction in IL-18 at months 3 (baseline: 654±150 pg/mL; 1mo: 595±140 pg/mL; 2mo: 601±176 pg/mL; 3mo: 571±127 pg/mL). This study provides new evidence for the potential of this new drug class to improve conduit vessel function, functional capacity, and inflammation in patients with HFrEF.

Endothelial phenotype differs by both sex and vessel function

Endothelial cells (the cells that line our blood vessels) were once thought to be an inert cellophane-like wrapper separating flowing blood from tissue. However, as our understanding of the human body has progressed, we have come to know that the endothelium is actually an incredibly important, metabolic ally active organ. Endothelial dysfunction appears to be an early hallmark of multiple disease states, including, but not limited to, cardiovascular disease, type II diabetes, and atherosclerosis. While it is often presumed that all non-specialized endothelial cells are the same, and thus will have the same response to various pharmacological agents, disease states, and stimuli, this may not be true. Our goal is to understand if endothelial cell phenotypes (characteristics expressed by the cell) vary based on their origin (the blood vessel they come from), or by sex, and if so, to what degree. Specifically, our research focused on primary cultures of aortic (a conduit vessel) endothelial cells and of skeletal muscle microvasculature (exchange vessels) endothelial cells from both male and female rats, then compared them to one another, after being grown under identical conditions. Our results strongly suggest that endothelial cells vary in size, growth rates, and protein expression, based on their origin and their sex. The implication is that medicines could affect different parts of our bodies indifferent ways, as well as affecting males and females differently. When studying functions mediated by vascular endothelium, it is important to use cells from an anatomical/functional location that best describes the question under investigation (or multiple locations if looking systemically), AND both sexes, as both characteristics determine the phenotype.

Chronic Transfusion Therapy in Sickle Cell Disease - Effect on Macrovascular Function, Microvascular Function, and Tissue Oxygenation Decreases the Potential for Ischemia

BACKGROUND: Sickle cell disease is an inheritable hemoglobinopathy that causes increased red blood cell (RBC) stiffness due to hemoglobin polymerization at low oxygen tension. This leads to microcirculatory occlusion as well as chronic hemolysis and chronic inflammation, resulting in a diffuse vasculopathy of bothmacrovascular and microvascular beds. Chronic transfusion therapy is used for both primary and secondary prevention of ischemic stroke, amacrovascular complication; however, there is limited knowledge of its effect on microvascular function. OBJECTIVE: To determine the effects of chronic transfusion therapy on microvascular function and tissue oxygenation. DESIGN/METHODS: We utilized a forearm, arterial and venous occlusion model, commonly used for flow-mediated dilation of the brachial artery, to simultaneously assess post occlusive reactive hyperemia (PORH) in the microcirculation and post hyperemic change in tissue oxygenation. PORH was measured using laser Doppler flowmetry placed over the third finger, proximal to the nailbed. Regional tissue oxygenation (rSO2) was measured using near infrared spectroscopy (NIRS) placed on the dorsal surface of the hand. FMD was measured using a linear ultrasound probe. Transfused patients were measured before and after a single transfusion. Kruskal-Wallis was used to test between group differences. Multivariate linear regression was used to model predictors of vascular function. RESULTS: We enrolled 18 control (CTL) patients, 75 non-transfused (NTR) SCD patients, and 26 chronically transfused (TR) SCD patients. Consistent with our previously published data, FMD was improved but not normalized by chronic transfusion and it was predicted by ln[plasma hgb], age and sex. PORH was reduced in both SCD patient groups when compared to the control group while resting flow by laser Doppler was elevated in both SCD groups (figure 1). PORH was also inversely related to resting flow, suggesting that basal conditions in the microcirculation are significant predictors of their response to forearm occlusion. Percent change in rSO2 was not different between the three groups. Lower baseline rSO2 was inversely associated with percent rSO2 increase following hyperemia; and, the baseline rSO2 was significantly decreased in the non-transfused SCD patients but normalized in the transfused SCD patients (Figure 2). Resting hypoxia was best predicted by RBC deformability in the non-transfused patients, even after correction for hemoglobin level, whereas resting hemoglobin levels predicted hypoxia in the transfused and healthy patients. DISCUSSION: With the goal to better understand the mechanism by which transfusion therapy decreases the risk of stroke, we tested the response to arterial and venous occlusion, simultaneously, at three different functional levels of the vascular system: 1.Conduit artery, 2.Pre-capillary arteriolar and capillary, 3.Tissue oxygen exchange. We confirm our previous findings that conduit vessel dysfunction is highly dependent on free hemoglobin, which is consistent with the hemolysis paradigm as a mechanism for sickle cell vasculopathy. This study extends our model to the microcirculation. Resting microcirculatory flow is increased in both transfused and non-transfused SCD patients; and while the resting rSO2 is near normal in the transfused SCD patients it is significantly lower in the non-transfused subjects. This creates the potential for severe hypoxia in the setting of a limited ability to augment flow through the microcirculation during periods of high demand, as in PORH. If there is also decreased conduit vessel reactivity upstream this creates the scenario over which large areas of tissue may rapidly become ischemic. This is a novel system, with simultaneous measurements in multiple vascular beds, allowing us to evaluate supply-demand matching. CONCLUSIONS: Chronic transfusion therapy improves both brachial artery endothelial function and regional tissue oxygenation but it does not significantly improve microcirculatory function, which may be near its maximal flow at rest. Hemoglobin determines resting tissue saturation in healthy and transfused SCD patients, but high shear RBC deformability determines rSO2 in non-transfused SCD patients. Figure 1. Laser Doppler resting flow is higher but post occlusive hyperemia is lower in SCD Figure 1. Laser Doppler resting flow is higher but post occlusive hyperemia is lower in SCD Figure 2. NIRS repsonse to forearm occlusion. Figure 2. NIRS repsonse to forearm occlusion. Disclosures Wood: World Care Clinical: Consultancy; Vifor: Consultancy; AMAG: Consultancy; Ionis Pharmaceuticals: Consultancy; Biomed Informatics: Consultancy; World Care Clinical: Consultancy; Ionis Pharmaceuticals: Consultancy; Apopharma: Consultancy; Vifor: Consultancy; Apopharma: Consultancy; AMAG: Consultancy; Biomed Informatics: Consultancy; Celgene: Consultancy; Celgene: Consultancy.