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.

BackgroundWhile transcatheter aortic valve implantation (TAVI) has traditionally been supported intraprocedurally by transoesophageal echocardiography (TOE), transthoracic echocardiography (TTE) is increasingly being used. We evaluated echocardiographic imaging characteristics and clinical outcomes in patients who underwent TTE during TAVI (TTE-TAVI).Methods and resultsA select team of dedicated sonographers and interventional echocardiographers performed TTE-TAVI in 278 patients, all of whom underwent TAVI through transfemoral access. We implanted the Medtronic EVOLUT R valve in 258 patients (92.8%). TTE images were acquired immediately pre-procedure by a dedicated sonographer in the cardiac catheterization laboratory with the patient in the supine position. TTE was then performed post deployment of TAVI. In the procedure, TTE image quality was fair or better in 249 (89.6%) cases. Color-flow Doppler was adequate or better in 275 (98.9%) cases. In 2 cases, paravalvular regurgitation (PVL) could not be assessed confidently by echocardiography due to poor image quality; in those cases, PVL was assessed by fluoroscopy, aortic root injection and invasive hemodynamics. Both TTE and invasive hemodynamics were used in the assessment of need for post-deployment stent ballooning (n = 23, 8.3%). TTE adequately recognized new pericardial effusion in 3 cases. No case required TOE conversion for image quality. There was only 1 case of intraprocedural TTE failing to recognize moderate PVL, without clinical implication. In 99% of patients, TTE-TAVI adequately assessed PVL compared with 24-h and 1-month follow-up TTE.ConclusionsWith the current generation of TAVI, TTE-TAVI is adequate intraprocedurally when performed by specialized sonographers and dedicated cardiologists in a highly experienced TAVI center.

OBJECTIVES: Several international studies suggest that the time between symptom onset and DMARD initiation in RA patients is longer than is considered optimal. We sought to assess the health economic impact of this delay in an Australian context. METHODS: The delay in DMARD initiation was estimated from a 2005 study of 96 Australian RA patients referred to one public and four private rheumatology practices. RA-associated utilities and costs were sourced from published data. Patients not taking and taking DMARD therapy were assumed to have utilities of 0.443 and 0.543, respectively. The annual direct costs of RA, excluding DMARDs, was AUD $3780, and of DMARD therapy was $2658. It was conservatively assumed that DMARD therapy did not reduce non-DMARD RA costs. RESULTS: In the 2005 study, the mean time from symptom onset to initiation of DMARD therapy was 1.48 years. Over this time a mean of 0.65 QALYs would have been lived per patient and $5579 of direct health care costs incurred. Had DMARDs been commenced at symptom onset, 0.80 QALYs would have been lived per patient, and $9503 of direct health care costs incurred. Hence early initiation of DMARDs would have saved 0.15 QALYs at a cost of $3924 per person, equating to an incremental cost-effectiveness ratio (ICER) of $26,583 per QALY saved. An additional $3400 could be spent per patient to reduce the time to DMARD initiation before the ICER breached the arbitrary cut-off of $50,000 per QALY saved. Our analysis was conservative in it did not consider the long-term health and cost savings associated with avoidance of permanent joint damage. CONCLUSIONS: The considerable delay in the initiation of DMARD therapy among patients with RA leads to significant health loss. Reducing the time to initiation of DMARDs represents a cost-effective means of reducing the burden of RA.

Objectives: Osteoporotic fractures are common in older adults and are often associated with high morbidity and mortality. As the incidence increases with age, it is natural that osteoporotic fractures have become a major health problem worldwide. Increasing number of patients with osteoporotic fracture will have a serious economic impact on the patient themselves and the society. The objective of this study is to study the cost-effectiveness of strontium ranelate compared to alendronate for patients with post-menopausal osteoporotic fractures in Malaysia. MethOds: A Markov model was developed to project clinical and economic benefits of strontium in a hypothetical cohort of patients (N= 1,000) over a 5-year time horizon. This study was conducted from a payer perspective. Model parameters including transition probabilities and costs of treating fracture at various sites were Malaysia-specific. Drug costs were obtained from a public teaching hospital in Kuala Lumpur. Utilities were derived from previous literatures and efficacy data were derived from two pivotal trials, i. e. SOTI and TROPOS trials. Outcomes were presented as cost per quality-adjusted life year (QALY) gained. A discount rate of 3% was applied. Both 1-way and multivariate probabilistic sensitivity analyses were undertaken to evaluate robustness of results. Results: Compared to alendronate, strontium could prevent 328 wrist, 192 hip, 7 vertebra and 115 multiple fractures respectively over 5 years, which was translated into 27.9 QALYs gained. Using strontium can lead to cost reduction of MYR1,416,595 (USD442,685), MYR478,257 (USD149,455), MYR22,784 (USD7,120) and MYR61,883 (USD113,088) due to reduced episodes of fractures at wrist/hip/vertebra/multiple sites respectively. The total reduction of direct medical costs of MYR2,279,519 (USD712,349) was larger than the extra drug cost, hence making strontium a costsaving therapy. cOnclusiOns: It was shown that strontium appeared to be more cost-effective compared to alendronate and hence should be recommended in the public sector in Malaysia.