oxygen species (ROS) signal vital physiological processes including cell growth, angiogenesis, contraction, and relaxation of vascular smooth muscle. Because cytochrome P-450 family 4 (CYP4)/20-hydroxyeicosatetraenoic acid (20-HETE) has been reported to enhance angiogenesis, pulmonary vascular tone, and endothelial nitric oxide synthase function, we explored the potential of this system to stimulate bovine pulmonary artery endothelial cell (BPAEC) ROS production. Our data are the first to demonstrate that 20-HETE increases ROS in BPAECs in a time-and concentration-dependent manner as detected by enhanced fluorescence of oxidation products of dihydroethidium (DHE) and dichlorofluorescein diacetate. An analog of 20-HETE elicits no increase in ROS and blocks 20-HETE-evoked increments in DHE fluorescence, supporting its function as an antagonist. Endothelial cells derived from bovine aortas exhibit enhanced ROS production to 20-HETE quantitatively similar to that of BPAECs. 20-HETE-induced ROS production in BPAECs is blunted by pretreatment with polyethylene-glycolated SOD, apocynin, inhibition of Rac1, and a peptide-based inhibitor of NADPH oxidase subunit p47 phox association with gp91. These data support 20-HETE-stimulated, NADPH oxidase-derived, and Rac1/2-dependent ROS production in BPAECs. 20-HETE promotes translocation of p47 phox and tyrosine phosphorylation of p47 phox in a time-dependent manner as well as increased activated Rac1/2, providing at least three mechanisms through which 20-HETE activates NADPH oxidase. These observations suggest that 20-HETE stimulates ROS production in BPAECs at least in part through activation of NADPH oxidase within minutes of application of the lipid. superoxide; Rac1/2; hydrogen peroxide; CYP4A; reactive oxygen species PRODUCTS OF CYTOCHROME P-450 (CYP) -hydroxylases (including CYP4 isoforms) mediate key physiological functions including autoregulation of blood flow, tubuloglomerular feedback, Na ϩ reabsorption in the kidney, and relaxation of pulmonary arterioles (29,38). Our studies have focused on the role of CYP4 and its arachidonic acid (AA) metabolite, 20-hydroxyeicosatetraenoic acid (20-HETE), in pulmonary vascular function and biology. 20-HETE is the CYP -hydroxylation product of AA cleaved from membrane phospholipid sources. Enzymes of the CYP4A, -4B, and -4F families catalyze the -hydroxylation of fatty acids, and several isoforms in these families produce 20-HETE when incubated with AA. For example, rat CYP4A1, -4A2, and -4A3 catalyze AA -and -1-hydroxylations with the highest catalytic efficiency accruing to CYP4A1 (35). Although CYP4A2 and CYP4A3 exhibit an additional arachidonate 11,12-epoxidation activity, CYP4A1 operates solely as an -hydroxylase. Most investigators suggest that CYP4 isoforms constitute the major source of 20-HETE synthesis in extrahepatic tissues, including the lung (35, 38). Accordingly, we have investigated the effects of CYP4 product, 20-HETE, in our studies of this system in pulmonary vascular biology.We have identified a unique role f...

Myocardial work is an emerging tool in echocardiography that incorporates left ventricular afterload into global longitudinal strain analysis. Myocardial work correlates with myocardial oxygen consumption, and work efficiency can also be assessed. Myocardial work has been evaluated in a variety of clinical conditions to assess the added value of myocardial work compared to left ventricular ejection fraction and global longitudinal strain. This review showcases the current use of myocardial work in adult echocardiography and its possible role in cardiac pathologies.

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BackgroundLeft ventricular (LV) mechanics are impaired in patients with severe aortic stenosis (AS). We hypothesized that there would be differences in myocardial mechanics, measured by global longitudinal strain (GLS) recovery in patients with four subtypes of severe AS after transcatheter aortic valve replacement (TAVR), stratified based upon flow and gradient.MethodsWe retrospectively evaluated 204 patients with severe AS who underwent TAVR and were followed post-TAVR at our institution for clinical outcomes. Speckle-tracking transthoracic echocardiography was performed pre- and post-TAVR. Patients were classified as: (1) normal-flow and high-gradient, (2) normal-flow and high-gradient with reduced LV ejection fraction (LVEF), (3) classical low-flow and low-gradient, or (4) paradoxical low-flow and low-gradient.ResultsBoth GLS (−13.9 ± 4.3 to −14.8 ± 4.3, P < 0.0001) and LVEF (55 ± 15 to 57 ± 14%, P = 0.0001) improved immediately post-TAVR. Patients with low-flow AS had similar improvements in LVEF (+2.6 ± 9%) and aortic valve mean gradient (−23.95 ± 8.34 mmHg) as patients with normal-flow AS. GLS was significantly improved in patients with normal-flow (−0.93 ± 3.10, P = 0.0004) compared to low-flow AS. Across all types of AS, improvement in GLS was associated with a survival benefit, with GLS recovery in alive patients (mean GLS improvement of −1.07 ± 3.10, P < 0.0001).ConclusionsLV mechanics are abnormal in all patients with subtypes of severe AS and improve immediately post-TAVR. Recovery of GLS was associated with a survival benefit. Patients with both types of low-flow AS showed significantly improved, but still impaired, GLS post-TAVR, suggesting underlying myopathy that does not correct post-TAVR.