The Potential of Intertwining Gene Diagnostics and Surgery for Mitral Valve Prolapse.

Mitral valve prolapse (MVP) is common among heart valve disease patients, causing severe mitral regurgitation (MR). Although complications such as cardiac arrhythmias and sudden cardiac death are rare, the high prevalence of the condition leads to a significant number of such events. Through next-generation gene sequencing approaches, predisposing genetic components have been shown to play a crucial role in the development of MVP. After the discovery of the X-linked inheritance of filamin A, autosomal inherited genes were identified. In addition, the study of sporadic MVP identified several genes, including DZIP1, TNS1, LMCD1, GLIS1, PTPRJ, FLYWCH, and MMP2. The early screening of these genetic predispositions may help to determine the patient population at risk for severe complications of MVP and impact the timing of reconstructive surgery. Surgical mitral valve repair is an effective treatment option for MVP, resulting in excellent short- and long-term outcomes. Repair rates in excess of 95% and low complication rates have been consistently reported for minimally invasive mitral valve repair performed in high-volume centers. We therefore conceptualize a potential preventive surgical strategy for the treatment of MVP in patients with genetic predisposition, which is currently not considered in guideline recommendations. Further genetic studies on MVP pathology and large prospective clinical trials will be required to support such an approach.

Pushing the boundaries of innovation: the potential of ex vivo organ perfusion from an interdisciplinary point of view.

Ex vivo machine perfusion (EVMP) is an emerging technique for preserving explanted solid organs with primary application in allogeneic organ transplantation. EVMP has been established as an alternative to the standard of care static-cold preservation, allowing for prolonged preservation and real-time monitoring of organ quality while reducing/preventing ischemia-reperfusion injury. Moreover, it has paved the way to involve expanded criteria donors, e.g., after circulatory death, thus expanding the donor organ pool. Ongoing improvements in EVMP protocols, especially expanding the duration of preservation, paved the way for its broader application, in particular for reconditioning and modification of diseased organs and tumor and infection therapies and regenerative approaches. Moreover, implementing EVMP for in vivo-like preclinical studies improving disease modeling raises significant interest, while providing an ideal interface for bioengineering and genetic manipulation. These approaches can be applied not only in an allogeneic and xenogeneic transplant setting but also in an autologous setting, where patients can be on temporary organ support while the diseased organs are treated ex vivo, followed by reimplantation of the cured organ. This review provides a comprehensive overview of the differences and similarities in abdominal (kidney and liver) and thoracic (lung and heart) EVMP, focusing on the organ-specific components and preservation techniques, specifically on the composition of perfusion solutions and their supplements and perfusion temperatures and flow conditions. Novel treatment opportunities beyond organ transplantation and limitations of abdominal and thoracic EVMP are delineated to identify complementary interdisciplinary approaches for the application and development of this technique.

Sex as a biological variable: Mechanistic insights and clinical relevance in solid organ transplantation.

Biological sex affects immunity broadly, with recognized effects on the incidence and severity of autoimmune diseases, infections, and malignancies. Consequences of sex on alloimmunity and outcomes in solid organ transplantation are less well defined. Clinical studies have shown that donor and recipient sex independently impact transplant outcomes, which are further modified by aging. Potential mechanisms have thus far not been detailed and may include hormonal, genetic, and epigenetic components. Here, we summarize relevant findings in immunity in addition to studies in clinical and experimental organ transplantation detailing the effects of biological sex on alloimmunity. Understanding both clinical impact and mechanisms is expected to provide critical insights on the complexity of alloimmune responses, with the potential to fine-tune treatment and allocation while providing a rationale to include both sexes in transplant research.

Metabolic reprogramming of myeloid-derived suppressor cells in the context of organ transplantation.

Myeloid-derived suppressor cells (MDSCs) are naturally occurring leukocytes that develop from immature myeloid cells under inflammatory conditions that were discovered initially in the context of tumor immunity. Because of their robust immune inhibitory activities, there has been growing interest in MDSC-based cellular therapies for transplant tolerance induction. Indeed, various pre-clinical studies have introduced in vivo expansion or adoptive transfer of MDSC as a promising therapeutic strategy leading to a profound extension of allograft survival due to suppression of alloreactive T cells. However, several limitations of cellular therapies using MDSCs remain to be addressed, including their heterogeneous nature and limited expansion capacity. Metabolic reprogramming plays a crucial role for differentiation, proliferation and effector function of immune cells. Notably, recent reports have focused on a distinct metabolic phenotype underlying the differentiation of MDSCs in an inflammatory microenvironment representing a regulatory target. A better understanding of the metabolic reprogramming of MDSCs may thus provide novel insights for MDSC-based treatment approaches in transplantation. In this review, we will summarize recent, interdisciplinary findings on MDSCs metabolic reprogramming, dissect the underlying molecular mechanisms and discuss the relevance for potential treatment approaches in solid-organ transplantation.

The role of ex-situ perfusion for thoracic organs.

PURPOSE OF REVIEW: Ex-situ machine perfusion for both heart (HTx) and lung transplantation (LuTx) reduces ischemia-reperfusion injury (IRI), allows for greater flexibility in geographical donor management, continuous monitoring, organ assessment for extended evaluation, and potential reconditioning of marginal organs. In this review, we will delineate the impact of machine perfusion, characterize novel opportunities, and outline potential challenges lying ahead to improve further implementation. RECENT FINDINGS: Due to the success of several randomized controlled trials (RCT), comparing cold storage to machine perfusion in HTx and LuTx, implementation and innovation continues. Indeed, it represents a promising interface for organ-specific therapies targeting IRI, allo-immune responses, and graft reconditioning. These mostly experimental efforts range from genetic approaches and nanotechnology to cellular therapies, involving mesenchymal stem cell application. Despite tremendous potential, prior to clinical transition, more data is needed. SUMMARY: Collectively, machine perfusion constitutes the vanguard in thoracic organ transplantation research with extensive potential for expanding the donor pool, enhancing transplant outcomes as well as developing novel therapy approaches.

Aging Affects the Role of Myeloid-Derived Suppressor Cells in Alloimmunity.

Myeloid-derived suppressor cells (MDSC) are defined as a group of myeloid cells with potent immunoregulatory functions that have been shown to be involved in a variety of immune-related diseases including infections, autoimmune disorders, and cancer. In organ transplantation, MDSC promote tolerance by modifying adaptive immune responses. With aging, however, substantial changes occur that affect immune functions and impact alloimmunity. Since the vast majority of transplant patients are elderly, age-specific modifications of MDSC are of relevance. Furthermore, understanding age-associated changes in MDSC may lead to improved therapeutic strategies. Here, we provide a comprehensive update on the effects of aging on MDSC and discuss potential consequences on alloimmunity.