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Mitral regurgitation is the most common valvular lesion in the developed world, with increasing prevalence, morbidity, and mortality. The experience with surgical mitral valve repair or replacement is very well-validated. However, more than 45% of these patients get denied surgery due to an elevated risk profile and advanced disease of the left ventricle at the time of presentation, promoting the need for less invasive transcatheter options such as transcatheter repair and transcatheter mitral valve replacement (TMVR). Early available TMVR studies have shown promising results, and several dedicated devices are under clinical evaluation. However, TMVR is still in the early developmental stages and is associated with a non-negligible risk of periprocedural and post-procedural complications. In this review, we discuss the current challenges facing TMVR and the potential TMVR-related complications, offering an overview on the measures implemented to mitigate these complications, and future implications.

Objectives: The aim of this study was to evaluate the impact of edge-to-edge PMVR on short and mid-term clinical outcomes in patients with CS and severe MR.Background: Severe mitral regurgitation (MR) in the setting of cardiogenic shock (CS) is associated with three times higher risk of 1-year mortality. In refractory CS, edgeto-edge percutaneous mitral valve repair (PMVR) can be a potential therapeutic option.Methods: We retrospectively included consecutive patients with refractory CS and concomitant severe MR treated with MitraClip ® system. CS was defined according to the criteria used in the SHOCK trial and procedural success according to Mitral Valve

Natalizumab inhibits the transmigration of activated T lymphocytes into the brain and is highly efficacious in multiple sclerosis (MS). However, from a pharmacogenomic perspective, its efficacy and safety in specific patients remain unclear. Here our goal was to analyze the effects of epithelial V-like antigen (EVA) on anti-alpha4 integrin (VLA4) efficacy in a mouse model of MS, experimental autoimmune encephalomyelitis (EAE). EVA has been previously characterized in human CD4 T lymphocytes, mouse thymic development, and choroid plexus epithelial cells. Further analysis here demonstrated expression in B lymphocytes and an increase in EVA+ lymphocytes following immunization. Following active induction of EAE using the MOG35–55 active immunization model, EVA deficient mice developed more severe EAE and white matter tissue injury as compared to wild type controls. This severe EAE phenotype did not respond to anti-VLA4 treatment. In both the control antibody and anti-VLA4 conditions, these mice demonstrated persistent CNS invasion of mature B lymphocyte (CD19+, CD21+, sIgG+), increased serum autoantibody levels, and extensive complement and IgG deposition within lesions containing CD5+IgG+ cells. Wild type mice treated with control antibody also demonstrated the presence of CD19+, CD21+, sIgG+ cells within the CNS during peak EAE disease severity and detectable serum autoantibody. In contrast, wild type mice treated with anti-VLA4 demonstrated reduced serum autoantibody levels as compared to wild type controls and EVA-knockout mice. As expected, anti-VLA4 treatment in wild type mice reduced the total numbers of all CNS mononuclear cells and markedly decreased CD4 T lymphocyte invasion. Treatment also reduced the frequency of CD19+, CD21+, sIgG+ cells in the CNS. These results suggest that anti-VLA4 treatment may reduce B lymphocyte associated autoimmunity in some individuals and that EVA expression is necessary for an optimal therapeutic response. We postulate that these findings could optimize the selection of treatment responders.

Multiple sclerosis (MS) is the most common nontraumatic cause of neurologic disability in young adults. Despite treatment, progressive tissue injury leads to accumulation of disability in many patients. Here, our goal was to develop an immune-mediated strategy to promote tissue repair and clinical recovery in an MS animal model. We previously demonstrated that a variant of the voltage-gated sodium channel NaV1.5 is expressed intracellularly in human macrophages, and that it regulates cellular signaling. This channel is not expressed in mouse macrophages, which has limited the study of its functions. To overcome this obstacle, we developed a novel transgenic mouse model (C57BL6), in which the human macrophage NaV1.5 splice variant is expressed in vivo in mouse macrophages. These mice were protected from experimental autoimmune encephalomyelitis, the mouse model of MS. During active inflammatory disease, NaV1.5-positive macrophages were found in spinal cord lesions where they formed phagocytic cell clusters; they expressed markers of alternative activation during recovery. NaV1.5-positive macrophages that were adoptively transferred into wild-type recipients with established experimental autoimmune encephalomyelitis homed to lesions and promoted recovery. These results suggest that NaV1.5-positive macrophages enhance recovery from CNS inflammatory disease and could potentially be developed as a cell-based therapy for the treatment of MS.

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