Abstract-Vascular endothelial growth factor (VEGF)-B is poorly angiogenic but prominently expressed in metabolically highly active tissues, including the heart. We produced mice expressing a cardiac-specific VEGF-B transgene via the ␣-myosin heavy chain promoter. Surprisingly, the hearts of the VEGF-B transgenic mice showed concentric cardiac hypertrophy without significant changes in heart function. The cardiac hypertrophy was attributable to an increased size of the cardiomyocytes. Blood capillary size was increased, whereas the number of blood vessels per cell nucleus remained unchanged. Despite the cardiac hypertrophy, the transgenic mice had lower heart rate and blood pressure than their littermates, and they responded similarly to angiotensin II-induced hypertension, confirming that the hypertrophy does not compromise heart function. Interestingly, the isolated transgenic hearts had less cardiomyocyte damage after ischemia. Significantly increased ceramide and decreased triglyceride levels were found in the transgenic hearts. This was associated with structural changes and eventual lysis of mitochondria, resulting in accumulation of intracellular vacuoles in cardiomyocytes and increased death of the transgenic mice, apparently because of mitochondrial lipotoxicity in the heart. These results suggest that VEGF-B regulates lipid metabolism, an unexpected function for an angiogenic growth factor. Key Words: VEGF-B Ⅲ cardiac hypertrophy Ⅲ cardiac metabolism Ⅲ fatty acids Ⅲ mitochondria M embers of the vascular endothelial growth factor (VEGF) family, currently comprising 5 mammalian proteins, are major regulators of blood and lymphatic vessel development and growth. VEGF is essential for vasculogenesis and angiogenesis, whereas VEGF-C is necessary for lymphangiogenesis. Although not required for embryonic development, placenta growth factor and VEGF-D are likely to play more subtle roles in the control of angiogenesis and lymphangiogenesis, or function under pathological conditions. 1,2 VEGF-B exists as 2 isoforms generated by alternative splicing. VEGF-B 167 has a heparin-binding carboxyl terminus, whereas VEGF-B 186 contains a hydrophobic carboxyl terminus, is O-glycosylated, and proteolytically processed. 3 Both isoforms bind to VEGF receptor (VEGFR)-1 and neuropilin-1 but not to the major mitogenic endothelial cell receptors VEGFR-2 or VEGFR-3. 4,5 VEGF-B has a wide tissue distribution, being most abundant in the myocardium, skeletal and vascular smooth muscle, as well as in brown adipose tissue. 6 Mice lacking VEGF-B are viable and fertile and display only a mild phenotype in the heart. This is manifested as an atrial conduction abnormality characterized by a prolonged PQ interval in 1 strain (C57Bl background), 7 or as a smaller heart size with impaired recovery after myocardial ischemia in another (129/SvJ or 129/SvJϫC57Bl/6J background). 8 Furthermore, VEGF-B has also been implicated in pathological vascular changes in inflammatory arthritis 9 and in protecting the brain from ischemic injury. 10 H...

IntroductionTotal knee arthroplasty is a highly effective treatment for end-stage knee osteoarthritis, and it is usually performed under spinal or general anaesthesia with or without a surgical tourniquet. Some debate about the preferred mode of anaesthesia regarding patient outcomes remains. The aim of this study, which compares general and spinal anaesthesia with and without a tourniquet on the outcomes of total knee arthroplasty, is to determine the optimal type of anaesthesia regimen and assess the effect of a tourniquet on the patient’s recovery following total knee arthroplasty.Methods and analysisThis study is a randomised, controlled, parallel-group, four-arm study comparing spinal and general anaesthesia with and without a tourniquet in 400 patients undergoing fast-track total knee arthroplasty, with a 12-month follow-up. The primary outcome is cumulative intravenous oxycodone consumption by patient-controlled analgesia during the first 24 postoperative hours. Secondary outcomes include postoperative nausea and vomiting, the length of hospital stay, the duration of the surgery, blood loss, demand for surgical unit resources, complications, readmissions, postoperative knee function, range of motion, health-related quality of life, prolonged pain and mortality.Ethics and disseminationThis study’s protocol is in accordance with the declaration of Helsinki. The results of this study will be disseminated in international peer-reviewed journals.Trial registration number NCT03364088; Pre-results.