Do Prior Driveline Infections Increase the Risk of Infection in Heart Transplant Patients Treated With Rabbit Antithymocyte Globulin Induction Therapy?

BACKGROUND: The use of mechanical circulatory support devices (MCSDs) has been increasing over the past several years. Driveline infections (DLIs) are one of the most common complications seen in these patients; reportedly, up to 50% of patients with MCSDs can develop this complication. It is believed that the removal of the driveline results in treatment of the localized infection area. MCSD patients are also known to develop circulating antibodies. These circulating antibodies have been associated with poor outcomes after heart transplantation. The use of rabbit antithymocyte globulin (ATG) as induction therapy reportedly decreases the development of circulating antibodies; it is now commonly used in sensitized patients undergoing heart transplantation. It is unknown whether ATG induction therapy immediate posttransplant will increase the risk of infection of those MCSD patients with DLIs. METHODS: Between 2003 and 2013, we evaluated 57 MCSD patients who subsequently underwent heart transplantation and received ATG induction therapy. Patients were divided into those with previous MCSD DLI and those without, and they were assessed for 1-year freedom from infection (specifically, sternal wound infections). One-year survival and freedom from treated rejection, both cellular and antibody mediated, were also assessed. RESULTS: MCSD patients with DLIs who received ATG induction did not have a lower freedom from any treated infection and from sternal wound infection posttransplant compared with those MCSD patients without DLIs and not treated with ATG induction. There were also no significant differences between the 2 groups in terms of 1-year posttransplant survival and freedom from treated rejection. CONCLUSIONS: The use of ATG induction in patients with prior DLIs did not seem to increase the risk for posttransplant infection (eg, sternal wound infection). ATG induction can therefore be safely used in this population.

Injected matrix stimulates myogenesis and regeneration of mouse skeletal muscle after ischaemic injury.

Biomaterial-guided regeneration represents a novel approach for the treatment of myopathies. Revascularisation and the intramuscular extracellular matrix are important factors in stimulating myogenesis and regenerating muscle damaged by ischaemia. In this study, we used an injectable collagen matrix, enhanced with sialyl LewisX (sLeX), to guide skeletal muscle differentiation and regeneration. The elastic properties of collagen and sLeX-collagen matrices were similar to those of skeletal muscle, and culture of pluripotent mESCs on the matrices promoted their differentiation into myocyte-like cells expressing Pax3, MHC3, myogenin and Myf5. The regenerative properties of matrices were evaluated in ischaemic mouse hind-limbs. Treatment with the sLeX-matrix augmented the production of myogenic-mediated factors insulin-like growth factor (IGF)-1, and IGF binding protein-2 and -5 after 3 days. This was followed by muscle regeneration, including a greater number of regenerating myofibres and increased transcription of Six1, M-cadherin, myogenin and Myf5 after 10 days. Simultaneously, the sLeX-matrix promoted increased mobilisation and engraftment of bone marrow-derived progenitor cells, the development of larger arterioles and the restoration of tissue perfusion. Both matrix treatments tended to reduce maximal forces of ischaemic solei muscles, but sLeX-matrix lessened this loss of force and also prevented muscle fatigue. Only sLeX-matrix treatment improved mobility of mice on a treadmill. Together, these results suggest a novel approach for regenerative myogenesis, whereby treatment only with a matrix, which possesses an inherent ability to guide myogenic differentiation of pluripotent stem cells, can enhance the endogenous vascular and myogenic regeneration of skeletal muscle, thus holding promise for future clinical use.

A stromal cell-derived factor-1 releasing matrix enhances the progenitor cell response and blood vessel growth in ischaemic skeletal muscle.

Although many regenerative cell therapies are being developed to replace or regenerate ischaemic muscle, the lack of vasculature and poor persistence of the therapeutic cells represent major limiting factors to successful tissue restoration. In response to ischaemia, stromal cell-derived factor-1 (SDF-1) is up-regulated by the affected tissue to stimulate stem cell-mediated regenerative responses. Therefore, we encapsulated SDF-1 into alginate microspheres and further incorporated these into an injectable collagen-based matrix in order to improve local delivery. Microsphere-matrix impregnation reduced the time for matrix thermogelation, and also increased the viscosity reached. This double-incorporation prolonged the release of SDF-1, which maintained adhesive and migratory bioactivity, attributed to chemotaxis in response to SDF-1. In vivo, treatment of ischaemic hindlimb muscle with microsphere-matrix led to increased mobilisation of bone marrow-derived progenitor cells, and also improved recruitment of angiogenic cells expressing the SDF-1 receptor (CXCR4) from bone marrow and local tissues. Both matrix and SDF-1-releasing matrix were successful at restoring perfusion, but SDF-1 treatment appeared to play an earlier role, as evidenced by arterioles that are phenotypically older and by increased angiogenic cytokine production, stimulating the generation of a qualitative microenvironment for a rapid and therefore more efficient regeneration. These results support the release of implanted SDF-1 as a promising method for enhancing progenitor cell responses and restoring perfusion to ischaemic tissues via neovascularisation.