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Background There are increasing reports of early externally mounted pericardial Trifecta bioprosthesis failure. We compared the hemodynamic performance of Trifecta and Carpentier–Edwards Perimount Magna Ease valves to determine the failure mechanism. Methods We retrospectively included 270 consecutive patients (age: 73.4 ± 8.2 years; 57.5% male; mean follow-up: 48.0 ± 20.3 months) who underwent aortic valve replacement from 2014 to 2021 at a single center and compared the Trifecta ( N = 137) and Carpentier–Edwards Perimount Magna Ease valve ( N = 133) patients. Results The prosthetic valve major aortic regurgitation incidence was higher for the Trifecta than that for the Carpentier–Edwards Perimount Magna Ease valve (6.3% vs. 0%, P Conclusions Significantly, more early failures occurred with the Trifecta valve than the Carpentier–Edwards Perimount Magna Ease valve but the Trifecta showed reasonable mean transprosthetic pressure gradient over time. Prosthetic valve aortic regurgitation and calcific structural valve deterioration synergistically contributed to Trifecta valve failure alternatively.

Transcatheter aortic valve replacement (TAVR) is the treatment of choice for aortic stenosis. However, its safety and efficacy in patients with the bicuspid aortic valve (BAV) remain controversial. Especially, whether the BAV phenotype affects outcomes following TAVR remains debated. Despite the higher ellipticity index and more calcifications of the aortic annulus in type 1 BAV, a high residual gradient was observed in type 0 anatomy. Moreover, severe calcification of the cusps rather than aortic annulus in type 0 is predisposed to asymmetrical under-expansion of the prosthesis at the edge of the native aortic cusp. We report the rare case of a patient with BAV stenosis type 0 and single coronary artery receiving TAVR, subsequently requiring surgical aortic valve replacement. The extensive non-coronary cusp calcification caused under-expansion of the prosthesis and was protruded into the left ventricular outflow tract, leading to an obstruction.

The programmed death 1/programmed death ligand 1 (PD-1/PD-L1) pathway is a potent inhibitory pathway involved in immune regulation and is a potential therapeutic target in transplantation. In this study, we show that overexpression of PD-1 on T cells (PD-1 Tg) promotes allograft tolerance in a fully MHC-mismatched cardiac transplant model when combined with costimulation blockade with CTLA-4-Ig. PD-1 overexpression on T cells also protected against chronic rejection in a single MHC II-mismatched cardiac transplant model, whereas the overexpression still allowed the generation of an effective immune response against an influenza A virus. Notably, Tregs from PD-1 Tg mice were required for tolerance induction and presented greater ICOS expression than those from WT mice. The survival benefit of PD-1 Tg recipients required ICOS signaling and donor PD-L1 expression. These results indicate that modulation of PD-1 expression, in combination with a costimulation blockade, is a promising therapeutic target to promote transplant tolerance.

A 70-year-old man with a history of lacunar stroke about a year before was incidentally found to have primary cardiac tumor during the work up for orthopedic surgery. It uniquely originated from the coumadin ridge between the left upper pulmonary vein and the left atrial appendage. He underwent tumor resection under cardiopulmonary bypass with superior transseptal approach. It allowed enough surgical exposure for en-bloc resection of the tumor with minimal risk of tumor embolisms. The pathological report confirmed that the tumor was a cardiac myxoma. The postoperative course was uneventful with no stroke nor embolism complications. We experienced a rare myxoma orginating from the coumadin ridge and successfully resected it with superior septal approach.

Background: Transplantation is the treatment of choice for many patients with end-stage organ disease. Despite advances in immunosuppression, long-term outcomes remain suboptimal, hampered by drug toxicity and immune-mediated injury, the leading cause of late graft loss. The development of therapies that promote regulation while suppressing effector immunity is imperative to improve graft survival and minimize conventional immunosuppression. Notch signaling is a highly conserved pathway pivotal to T-cell differentiation and function, rendering it a target of interest in efforts to manipulate T cell–mediated immunity. Methods: We investigated the pattern of Notch-1 expression in effector and regulatory T cells (Tregs) in both murine and human recipients of a solid-organ transplant. Using a selective human anti-Notch-1 antibody (aNotch-1), we examined the effect of Notch-1 receptor inhibition in full major histocompatibility complex–mismatch murine cardiac and lung transplant models, and in a humanized skin transplant model. On the basis of our findings, we further used a genetic approach to investigate the effect of selective Notch-1 inhibition in Tregs. Results: We observed an increased proportion of Tregs expressing surface and intracellular (activated) Notch-1 in comparison with conventional T cells, both in mice with transplants and in the peripheral blood of patients with transplants. In the murine cardiac transplant model, peritransplant administration of aNotch-1 (days 0, 2, 4, 6, 8, and 10) significantly prolonged allograft survival in comparison with immunoglobulin G–treated controls. Similarly, aNotch-1 treatment improved both histological and functional outcomes in the murine lung transplant model. The use of aNotch-1 resulted in a reduced proportion of both splenic and intragraft conventional T cells, while increasing the proportion of Tregs. Furthermore, Tregs isolated from aNotch-1–treated mice showed enhanced suppressive function on a per-cell basis, confirmed with selective Notch-1 deletion in Tregs (Foxp3 EGFPCre Notch1 fl/fl ). Notch-1 blockade inhibited the mammalian target of rapamycin pathway and increased the phosphorylation of STAT5 (signal transducer and activator of transcription 5) in murine Tregs. Notch-1 low Tregs isolated from human peripheral blood exhibited more potent suppressive capacity than Notch-1 high Tregs. Last, the combination of aNotch-1 with costimulation blockade induced long-term tolerance in a cardiac transplant model, and this tolerance was dependent on CTLA-4 (cytotoxic T-lymphocyte–associated antigen-4) signaling. Conclusions: Our data reveal a promising, clinically relevant approach for immune modulation in transplantation by selectively targeting Notch-1.

Background Perivascular adipose tissue (PVAT) is associated with metabolically driven chronic inflammation called metaflammation, which contributes to vascular function and the pathogenesis of vascular disease. The saphenous vein (SV) is commonly used as an essential conduit in coronary artery bypass grafting, but the long‐term patency of SV grafts is a crucial issue. The use of the novel “no‐touch” technique of SV harvesting together with its surrounding tissue has been reported to result in good long‑term graft patency of SV grafts. Herein, we investigated whether PVAT surrounding the SV (SV‐PVAT) has distinct phenotypes compared with other PVATs of vessels. Methods and Results Fat pads were sampled from 48 patients (male/female, 32/16; age, 72±8 years) with coronary artery disease who underwent elective coronary artery bypass grafting. Adipocyte size in SV‐PVAT was significantly larger than the sizes in PVATs surrounding the internal thoracic artery, coronary artery, and aorta. SV‐PVAT and PVAT surrounding the internal thoracic artery had smaller extents of fibrosis, decreased gene expression levels of fibrosis‐related markers, and less metaflammation, as indicated by a significantly smaller extent of cluster of differentiation 11c–positive M1 macrophage infiltration, higher gene expression level of adiponectin, and lower gene expression levels of inflammatory cytokines, than did PVATs surrounding the coronary artery and aorta. Expression patterns of adipocyte developmental and pattern‐forming genes were totally different among the PVATs of the vessels. Conclusions The phenotype of SV‐PVAT, which may result from inherent differences in adipocytes, is closer to that of PVAT surrounding the internal thoracic artery than that of PVAT surrounding the coronary artery or that of PVAT surrounding the aorta. SV‐PVAT has less metaflammation and consecutive adipose tissue remodeling, which may contribute to high long‐term patency of grafting when the no‐touch technique of SV harvesting is used.

Ischemia reperfusion injuries (IRI) are unavoidable in solid organ transplantation. IRI augments alloimmunity but the mechanisms involved are poorly understood. Herein, we examined the effect of IRI on antigen specific alloimmunity. We demonstrate that ischemia promotes alloimmune activation, leading to more severe histological features of rejection, and increased CD4+ and CD8+ T cell graft infiltration, with a predominantly CD8+ IFNγ+ infiltrate. This process is dependent on the presence of alloreactive CD4+ T cells, where depletion prevented infiltration of ischemic grafts by CD8+ IFNγ+ T cells. IL-6 is a known driver of ischemia-induced rejection. Herein, depletion of donor antigen-presenting cells reduced ischemia-induced CD8+ IFNγ+ allograft infiltration, and improved allograft outcomes. Following prolonged ischemia, accelerated rejection was observed despite treatment with CTLA4Ig, indicating that T cell costimulatory blockade failed to overcome the immune activating effect of IRI. However, despite severe ischemic injury, treatment with anti-IL-6 and CTLA4Ig blocked IRI-induced alloimmune injury and markedly improved allograft survival. We describe a novel pathway where IRI activates innate immunity, leading to upregulation of antigen specific alloimmunity, resulting in chronic allograft injury. Based on these findings, we describe a clinically relevant treatment strategy to overcome the deleterious effect of IRI, and provide superior long-term allograft outcomes.

Phosphatidylinositol-3-kinases (PI3K) γ and δ are preferentially enriched in leukocytes, and defects in these signaling pathways have been shown to impair T cell activation. The effects of PI3Kγ and PI3Kδ on alloimmunity remain underexplored. Here, we show that both PI3Kγ −/− and PI3Kδ D910A/D910A mice receiving heart allografts have suppression of alloreactive T effector cells and delayed acute rejection. However, PI3Kδ mutation also dampens regulatory T cells (Treg). After treatment with low dose CTLA4-Ig, PI3Kγ −/−, but not PI3Κδ D910A/D910A, recipients exhibit indefinite prolongation of heart allograft survival. PI3Kδ D910A/D910A Tregs have increased apoptosis and impaired survival. Selective inhibition of PI3Kγ and PI3Kδ (using PI3Kδ and dual PI3Kγδ chemical inhibitors) shows that PI3Kγ inhibition compensates for the negative effect of PI3Kδ inhibition on long-term allograft survival. These data serve as a basis for future PI3K-based immune therapies for transplantation., Phosphatidylinositol-3-kinases (PI3K) γ and δ are key regulators of T cell signaling. Here the author show, using mouse heart allograft transplantation models, that PI3Kγ or PI3Kδ deficiency prolongs graft survival, but selective inhibition of PI3Kγ or PI3Kδ reveals alternative transplant survival outcomes post CTLA4-Ig treatment.

SUMMARY Active-targeted delivery to lymph nodes represents a major advance toward more effective treatment of immune-mediated disease. The MECA79 antibody recognizes peripheral node address in molecules expressed by high endothelial venules of lymph nodes. By mimicking lymphocyte trafficking to the lymph nodes, we have engineered MECA79-coated microparticles containing an immunosuppressive medication, tacrolimus. Following intravenous administration, MECA79-bearing particles showed marked accumulation in the draining lymph nodes of transplanted animals. Using an allograft heart transplant model, we show that targeted lymph node delivery of microparticles containing tacrolimus can prolong heart allograft survival with negligible changes in tacrolimus serum level. Using MECA79 conjugation, we have demonstrated targeted delivery of tacrolimus to the lymph nodes following systemic administration, with the capacity for immune modulation in vivo., Graphical Abstract

The clonal expansion of effector T cells and subsequent generation of memory T cells are critical in determining the outcome of transplantation. While cytotoxic T lymphocytes induce direct cytolysis of target cells through secretion of Granzyme-B (GrB), they also express cytoplasmic serine protease inhibitor-6 (Spi6) to protect themselves from GrB that has leaked from granules. Here, we studied the role of GrB/Spi6 axis in determining clonal expansion of alloreactive CD8-T cells and subsequent generation of memory CD8-T cells in transplantation. CD8-T cells from Spi6(-/-) mice underwent more GrB mediated apoptosis upon alloantigen stimulation in vitro and in vivo following adoptive transfer into an allogeneic host. Interestingly, while OT1.Spi6(-/-) CD8 T cells showed significantly lower clonal expansion following skin transplants from OVA mice, there was no difference in the size of the effector memory CD8-T cells long after transplantation. Furthermore, lack of Spi6 resulted in a decrease of short-lived-effector-CD8-cells but did not impact the pool of memory-precursor-effector-CD8-cells. Similar results were found in heart transplant models. Our findings suggest that the final alloreactive CD8-memory-pool-size is independent from the initial clonal-proliferation as memory precursors express low levels of GrB and therefore are independent of Spi6 for survival. These data advance our understanding of memory T cells generation in transplantation and provide basis for Spi6 based strategies to target effector T cells.

Ischemia reperfusion injuries (IRI) are unavoidable in solid organ transplantation. IRI augments alloimmunity but the mechanisms involved are poorly understood. Herein, we examined the effect of IRI on antigen specific alloimmunity. We demonstrate that ischemia promotes alloimmune activation, leading to more severe histological features of rejection, and increased CD4+ and CD8+ T cell graft infiltration, with a predominantly CD8+ IFNγ+ infiltrate. This process is dependent on the presence of alloreactive CD4+ T cells, where depletion prevented infiltration of ischemic grafts by CD8+ IFNγ+ T cells. IL-6 is a known driver of ischemia-induced rejection. Herein, depletion of donor antigen-presenting cells reduced ischemia-induced CD8+ IFNγ+ allograft infiltration, and improved allograft outcomes. Following prolonged ischemia, accelerated rejection was observed despite treatment with CTLA4Ig, indicating that T cell costimulatory blockade failed to overcome the immune activating effect of IRI. However, despite severe ischemic injury, treatment with anti-IL-6 and CTLA4Ig blocked IRI-induced alloimmune injury and markedly improved allograft survival. We describe a novel pathway where IRI activates innate immunity, leading to upregulation of antigen specific alloimmunity, resulting in chronic allograft injury. Based on these findings, we describe a clinically relevant treatment strategy to overcome the deleterious effect of IRI, and provide superior long-term allograft outcomes.

One of the key unmet needs to improve long-term outcomes of heart transplantation is to develop accurate, noninvasive, and practical diagnostic tools to detect transplant rejection. Early intragraft inflammation and endothelial cell injuries occur prior to advanced transplant rejection. We developed a novel diagnostic imaging platform to detect early declines in microvascular perfusion (MP) of cardiac transplants using contrast-enhanced ultrasonography (CEUS). The efficacy of CEUS in detecting transplant rejection was tested in a murine model of heart transplants, a standard preclinical model of solid organ transplant. As compared to the syngeneic groups, a progressive decline in MP was demonstrated in the allografts undergoing acute transplant rejection (40%, 64%, and 92% on days 4, 6, and 8 posttransplantation, respectively) and chronic rejection (33%, 33%, and 92% on days 5, 14, and 30 posttransplantation, respectively). Our perfusion studies showed restoration of MP following antirejection therapy, highlighting its potential to help monitor efficacy of antirejection therapy. Our data suggest that early endothelial cell injury and platelet aggregation contributed to the early MP decline observed in the allografts. High-resolution MP mapping may allow for noninvasive detection of heart transplant rejection. The data presented have the potential to help in the development of next-generation imaging approaches to diagnose transplant rejection.

Regulatory T cells (Tregs) play a pivotal role in the maintenance of immune tolerance and hold great promise as cell therapy for a variety of immune-mediated diseases. However, the cellular mechanisms that regulate Treg maintenance and homeostasis have yet to be fully explored. Although Tregs express granzyme-B (GrB) to suppress effector T cells via direct killing, the mechanisms by which they protect themselves from GrB-mediated self-inflicted damage are unknown. To our knowledge, we show for the first time that both induced Tregs and natural Tregs (nTregs) increase their intracellular expression of GrB and its endogenous inhibitor, serine protease inhibitor 6 (Spi6) upon activation. Subcellular fractionation and measurement of GrB activity in the cytoplasm of Tregs show that activated Spi6−/− Tregs had significantly higher cytoplasmic GrB activity. We observed an increase in GrB-mediated apoptosis in Spi6−/− nTregs and impaired suppression of alloreactive T cells in vitro. Spi6−/− Tregs were rescued from apoptosis by the addition of a GrB inhibitor (Z-AAD-CMK) in vitro. Furthermore, adoptive transfer experiments showed that Spi6−/− nTregs were less effective than wild type nTregs in suppressing graft-versus-host disease because of their impaired survival, as shown in our in vivo bioluminescence imaging. Finally, Spi6-deficient recipients rejected MHC class II-mismatch heart allografts at a much faster rate and showed a higher rate of apoptosis among Tregs, as compared with wild type recipients. To our knowledge, our data demonstrate, for the first time, a novel role for Spi6 in Treg homeostasis by protecting activated Tregs from GrB-mediated injury. These data could have significant clinical implications for Treg-based therapy in immune-mediated diseases.

A high-salt diet (HSD) in humans is linked to a number of complications, including hypertension and cardiovascular events. Whether a HSD affects the immune response in transplantation is unknown. Using a murine transplantation model, we investigated the effect of NaCl on the alloimmune response in vitro and in vivo. Incremental NaCl concentrations in vitro augmented T cell proliferation in the settings of both polyclonal and allospecific stimulation. Feeding a HSD to C57BL/6 wild-type recipients of bm12 allografts led to accelerated cardiac allograft rejection, despite similar mean BP and serum sodium levels in HSD and normal salt diet (NSD) groups. The accelerated rejection was associated with a reduction in the proportion of CD4(+)Foxp3(+) regulatory T cells (Tregs) and a significant decrease in Treg proliferation, leading to an increased ratio of antigen-experienced CD4(+) T cells to Tregs in mice recipients of a HSD compared with mice recipients of a NSD. Because serum- and glucocorticoid-regulated kinase-1 (SGK1) has been proposed as a potential target of salt in immune cells, we fed a HSD to CD4(Cre)SGK1(fl/fl) B6-transplanted recipients and observed abrogation of the deleterious effect of a HSD in the absence of SGK1 on CD4(+) cells. In summary, we show that NaCl negatively affects the regulatory balance of T cells in transplantation and precipitates rejection in an SGK1-dependent manner.

A pedicled pericardial fat pad (PPFP) is often used in pulmonary resection to reinforce bronchial sutures. Here, we assessed the significance of PPFP by serial chest computed tomography (CT). Ten cases in which bronchial stump were covered with a PPFP in the past 6 years were reviewed. The procedures were pneumonectomy (3), lobectomy (6), and a segmentectomy. According to the CT value evaluated serially PPFP was recognized as fat tissue until 1~2 postoperative months. No cases of bronchopleural fistulae was encountered in this series. The coverage of the sutures with the PPFP was thought to contribute to the prevention of bronchial fistula by staying around bronchial stump for at least 1 to 2 months.

We report a rare case of infected aortic arch aneurysm. 70-year-old man was admitted to our hospital for persistent high fever and blood culture demonstrated Streptococcus milleri group. Computed tomography revealed an aortic aneurysm. At the take off of the brachiocepharicartery. We performed a total aortic arch replacement with omental wrapping to prevent postoperative graft infection. The operative course was uneventful and discharged on postoperative day 65 with no signs of infection.