Effects of aged stored autologous red blood cells on human plasma metabolome

Cold storage of blood for 5 to 6 weeks has been shown to impair endothelial function after transfusion and has been associated with measures of end-organ dysfunction. Although the products of hemolysis, such as cell-free plasma hemoglobin, arginase, heme, and iron, in part mediate these effects, a complete analysis of transfused metabolites that may affect organ function has not been evaluated to date. Blood stored for either 5 or 42 days was collected from 18 healthy autologous volunteers, prior to and after autologous transfusion into the forearm circulation, followed by metabolomics analyses. Significant metabolic changes were observed in the plasma levels of hemolytic markers, oxidized purines, plasticizers, and oxidized lipids in recipients of blood stored for 42 days, compared with 5 days. Notably, transfusion of day 42 red blood cells (RBCs) increased circulating levels of plasticizers (diethylhexyl phthalate and derivatives) by up to 18-fold. Similarly, transfusion of day 42 blood significantly increased circulating levels of proinflammatory oxylipins, including prostaglandins, hydroxyeicosatrienoic acids (HETEs), and dihydroxyoctadecenoic acids. Oxylipins were the most significantly increasing metabolites (for 9-HETE: up to ∼41-fold, P = 3.7e-06) in day 42 supernatants. Measurements of arginine metabolism confirmed an increase in arginase activity at the expense of nitric oxide synthesis capacity in the bloodstream of recipients of day 42 blood, which correlated with measurements of hemodynamics. Metabolic changes in stored RBC supernatants impact the plasma metabolome of healthy transfusion recipients, with observed increases in plasticizers, as well as vasoactive, pro-oxidative, proinflammatory, and immunomodulatory metabolites after 42 days of storage.

Preoperative Insight Into the Quality of Radial Artery Grafts

We investigated the impact of preoperative ultrasonography of the forearm circulation on radial artery conduit selection. Preoperative ultrasound of the forearm circulation was performed routinely in 536 patients planned for radial artery harvesting. The safety assessment of the harvest included the following algorithm of tests: the ultrasound, the Allen test, and pulse oximetry. The quality criteria that were used to exclude a radial artery from harvesting were small size of the artery, diffuse atherosclerosis, calcifications, and severe neointimal hyperplasia. The overall rejection rate due to safety reasons was 16.4%. Seventy-one (13.2%) radial arteries did not fulfill the conduit quality criteria and consequently these arteries were not harvested. In 13.4% of radial arteries, localized arterial wall disease was found in the distal third of the artery. The distal part of the artery was discarded and the rest was used as a conduit. Our results indicate that the ultrasound provides an accurate preoperative insight into the radial artery morphology, enabling selection of the arteries with favorable morphological features.

Ischemic preconditioning reduces hemodynamic response during metaboreflex activation

Ischemic preconditioning (IP) has been shown to improve exercise performance and to delay fatigue. However, the precise mechanisms through which IP operates remain elusive. It has been hypothesized that IP lowers the sensation of fatigue by reducing the discharge of group III and IV nerve endings, which also regulate hemodynamics during the metaboreflex. We hypothesized that IP reduces the blood pressure response during the metaboreflex. Fourteen healthy males (age between 25 and 48 yr) participated in this study. They underwent the following randomly assigned protocol: postexercise muscle ischemia (PEMI) test, during which the metaboreflex was elicited after dynamic handgrip; control exercise recovery session (CER) test; and PEMI after IP (IP-PEMI) test. IP was obtained by occluding forearm circulation for three cycles of 5 min spaced by 5 min of reperfusion. Hemodynamics were evaluated by echocardiography and impedance cardiography. The main results were that after IP the mean arterial pressure response was reduced compared with the PEMI test (means ± SD +3.37 ± 6.41 vs. +9.16 ± 7.09 mmHg, respectively). This was the consequence of an impaired venous return that impaired the stroke volume during the IP-PEMI more than during the PEMI test (−1.43 ± 15.35 vs. +10.28 ± 10.479 ml, respectively). It was concluded that during the metaboreflex, IP affects hemodynamics mainly because it impairs the capacity to augment venous return and to recruit the cardiac preload reserve. It was hypothesized that this is the consequence of an increased nitric oxide production, which reduces the possibility to constrict venous capacity vessels.

Rho-kinase inhibition improves vasodilator responsiveness during hyperinsulinemia in the metabolic syndrome

In patients with the metabolic syndrome (MetS), the facilitatory effect of insulin on forearm vasodilator responsiveness to different stimuli is impaired. Whether the RhoA/Rho kinase (ROCK) pathway is involved in this abnormality is unknown. We tested the hypotheses that, in MetS patients, ROCK inhibition with fasudil restores insulin-stimulated vasodilator reactivity and that oxidative stress plays a role in this mechanism. Endothelium-dependent and -independent forearm blood flow responses to acetylcholine (ACh) and sodium nitroprusside (SNP), respectively, were assessed in MetS patients ( n = 8) and healthy controls ( n = 5) before and after the addition of fasudil (200 μg/min) to an intra-arterial infusion of insulin (0.1 mU/kg/min). In MetS patients ( n = 5), fasudil was also infused without hyperinsulinemia. The possible involvement of oxidative stress in the effect of fasudil during hyperinsulinemia was investigated in MetS patients ( n = 5) by infusing vitamin C (25 mg/min). In MetS patients, compared with saline, fasudil enhanced endothelium-dependent and -independent vasodilator responses during insulin infusion ( P < 0.001 and P = 0.008, respectively), but not in the absence of hyperinsulinemia ( P = 0.25 and P = 0.13, respectively). By contrast, fasudil did not affect vasoreactivity to ACh and SNP during hyperinsulinemia in controls ( P = 0.11 and P = 0.56, respectively). In MetS patients, fasudil added to insulin and vitamin C did not further enhance vasodilation to ACh and SNP ( P = 0.15 and P = 0.43, respectively). In the forearm circulation of patients with the MetS, ROCK inhibition by fasudil improves endothelium-dependent and -independent vasodilator responsiveness during hyperinsulinemia; increased oxidative stress seems to be involved in the pathophysiology of this phenomenon.