Hyperlipidemia,tissue factor,coagulation, and simvastatin

Hyperlipidemia affects millions of people worldwide and is a major risk factor for cardiovascular disease. People with hyperlipidemia have elevated levels of serum cholesterol and an increased risk of thrombosis. Studies have suggested that oxidized lipoproteins, such as oxidized low-density lipoprotein (oxLDL), contribute to the development of a pro-thrombotic state. In this review, we discuss our recent studies demonstrating a role for hematopoietic cell-derived tissue factor (TF) expression in the activation of coagulation and increased thrombosis associated with hyperlipidemia. In addition, we investigated the effect of simvastatin on TF expression and coagulation. We found that simvastatin reduced leukocyte TF expression, TF⁺ microparticles, and coagulation. These results and earlier studies suggest that the anti-coagulant activity of statins is due, in part, to their ability to reduce monocyte TF expression in patients with cardiovascular disease.     

IFN-γ and indoleamine 2,3-dioxygenase signaling between donor dendritic cells and T cells regulates graft versus host and graft versus leukemia activity

Allogeneic hematopoietic stem cell transplantation (HSCT) can eradicate chemorefractory leukemia through the graft-versus-leukemia (GVL) activity of donor T cells. However, the clinical success of allo-HSCT is limited by the graft-versus-host disease (GVHD) activity of donor T cells. We have reported previously that donor bone marrow precursors of plasmacytoid dendritic cells (pre-pDCs) can activate donor T cells toward T-helper 1 immune polarization in murine allogeneic HSCT. To optimize the GVL activity of these activated donor T cells and limit their graft versus host activity, we engineered the cellular constituents of an allogeneic hematopoietic stem cell graft with highly purified hematopoietic stem cells, T cells, and pre-pDCs and studied their GVL and GVHD activities in a murine model of allogeneic HSCT. Transplanted donor pre-pDCs expanded in vivo for 2 weeks after transplant, and they markedly augmented the activation and GVL activity of donor T cells while attenuating their GVHD activity, leading to an improved therapeutic index. Bidirectional signaling between donor T cells and donor pDCs with IFN-γ synthesis by donor T cells inducing indoleamine 2,3-dioxygenase synthesis by donor pDCs limited GVHD by altering the balance between donor T-reg and inflammatory T cells. Manipulating the content of donor DC precursors in allogeneic HSCT is a novel method to optimize the balance between GVL and GVHD.     

Management of Infrapopliteal Peripheral Arterial Occlusive Disease

The management of infrapopliteal peripheral arterial occlusive disease (PAD) is challenging. For patients with asymptomatic disease or claudication, exercise and optimal medical management, including antiplatelet agents, blood pressure control, statin therapy and tight glucose control for patients with diabetes mellitus, are the mainstays of therapy. However, patients with isolated tibial artery occlusive disease often have diabetes mellitus or renal insufficiency and present with critical limb ischemia (CLI). CLI is advanced occlusive disease marked by the development of rest pain, ischemic ulceration, or gangrene and is associated with a high mortality rate. Limb salvage requires an intervention in cases of CLI, but careful operative planning is required as patients often have multilevel disease and limited options for revascularization. A surgical bypass with a vein graft remains the best treatment for infrapopliteal PAD, especially in patients with a life expectancy of over 2 years. Balloon angioplasty can play an important role in limb salvage, especially for patients lacking adequate vein for bypass, at high operative risk, or with a life expectancy of less than 2 years. However, a lack of rigorous trials has left unanswered questions as to the efficacy of infrapopliteal angioplasty with or without stents compared to bypass surgery. As such, endovascular therapy is currently not a proven treatment for intermittent claudication. Patients who are unable to undergo a revascularization procedure for infrapopliteal CLI have few options besides amputation or palliation. New therapies, such as drug-eluting stents, drug-coated balloons, and stem cell therapy are under development, but their efficacy and effectiveness remain unproven.