Candidates For Repair Research Articles

Six-month and One-year Outcomes for Repair in Patients with Functional Mitral Regurgitation from the CLASP Study

Background Transcatheter mitral valve repair has emerged as a viable option for treating functional mitral regurgitation (FMR). We report results for the FMR cohort from the multicenter, prospective, single arm CLASP study with the PASCAL transcatheter valve repair system (Edwards Lifesciences, Irvine, CA). Methods Eligible patients had clinically significant and symptomatic MR ≥3+ and were deemed candidates for transcatheter repair by the local heart team. The study outcomes were evaluated by an independent clinical events committee and echocardiographic core lab. The primary safety endpoint was a composite MAE rate at 30 days of cardiovascular mortality, stroke, MI, new need for renal replacement therapy, severe bleeding, and re-intervention for study device-related complications. Results Of the 109 patients enrolled (intent to treat/ITT and roll-in), 73 (67%) had FMR as determined by the core lab. Mean age was 73 years, 55% male, 60% NYHA Class III/IV with 100% MR grade ≥3+. Successful implantation was achieved in 96% of patients. At 30 days, the MAE rate was 11.0% including one cardiovascular mortality, one stroke, and one conversion to mitral valve replacement surgery. At 30 days, 88% of patients were in NYHA Class I/II (p Conclusions This study demonstrates that the PASCAL repair system is safe and results in remarkable MR reduction in patients with FMR. 100% of patients achieved MR ≤2+, and ∼ 80% achieved MR ≤1+, sustained at one year. Results show a high survival rate, low complications, and sustained improvements in functional status, exercise capacity, and quality of life at one year.

An interleukin-4-loaded bi-layer 3D printed scaffold promotes osteochondral regeneration

Multilayer scaffolds fabricated by 3D printing or other techniques have been used to repair osteochondral defects. However, it remains a challenge to regenerate the articular cartilage and subchondral bone simultaneously with higher performance. In the present study, we enhanced the repair efficiency of osteochondral defects by developing a bi-layer scaffold: an interleukin-4 (IL-4)-loaded radially oriented gelatin methacrylate (GelMA) scaffold printed with digital light processing (DLP) in the upper layer and a porous polycaprolactone and hydroxyapatite (PCL-HA) scaffold printed with fused deposition modeling (FDM) in the lower layer. An in vitro test showed that both layers supported cell adhesion and proliferation, as the lower layer promoted osteogenic differentiation and the upper layer with IL-4 relieved the negative effects of inflammation on murine chondrocytes, which were induced by interleukin-1β (IL-1β) and M1 macrophages. In a rabbit osteochondral defect repair model, the IL-4-loaded bi-layer scaffold group obtained the highest histological score (24 ± 2) compared to the nontreated (11 ± 1) and pure bi-layer scaffold (16 ± 1) groups after 16 weeks of implantation, which showed that the IL-4-loaded bi-layer scaffold promoted regeneration of both cartilage and subchondral bone with increased formation of neocartilage and neobone tissues. Thus, the IL-4-loaded bi-layer scaffold is an attractive candidate for repair and regeneration of osteochondral defects.

A novel γ-PGA composite gellan membrane containing glycerol for guided bone regeneration

An ideal barrier membrane design should incorporate the function of a delivery vehicle for transporting drugs and osteoinductive factors to where the body is under inflammation. In the present study, a functional hydrogel-based barrier membrane is fabricated using calcium-form poly-γ-glutamic acid (γ-PGA) and glycerol blending into gellan gum. The concentration of the calcium-form poly-γ-glutamic acid (γ-PGA) and the glycerol ratio are studied for improving practicability in easy-handling and expanding the coverage area. Gellan gum-based membranes with uniformly distributed calcium aggregates are not only successfully manufactured but also providing excellent characteristics for protein adsorption, bioactivity, and bone cell maturation. Our composite gellan gum-based membranes were tested including to their morphology, mechanical properties, swelling behavior, protein adsorption, drug diffusion, and lysozyme degradation. The biocompatibility, proliferation, and osteoblastic response of membranes were examined by osteoblast-like (MG63) cells. Our results indicate that adequate physical cross-linking with γ-PGA improves the original mechanical properties and delays degradation. Growing glycerol ratio not only enhances the elongation at break and diffusion rate, but it also changes the tensile strength and the remaining weight. In vitro biocompatibility tests, an adequate ratio of γ-PGA modification significantly enhances the proliferation, the secretion of alkaline phosphatase (ALP) and mineralization. However, worth noting is the glycerol-modified membrane cannot bear a close resemblance with the non-glycerol group in the high level of osteoblastic response. In general, these tunable materials with biocompatibility, biodegradability, and positive osteoblastic responses were poised to be possible candidates for bone defect repair.

Strontium Modified Calcium Sulfate Hemihydrate Scaffold Incorporating Ginsenoside Rg1/Gelatin Microspheres for Bone Regeneration.

The aim of this study was to prepare a promising biomaterial for bone tissue repair and regeneration. The Strontium – calcium sulfate hemihydrate (Sr-α-CaS) scaffold incorporating gelatin microspheres (GMs) encapsulated with Ginsenoside Rg1 (Rg1) was designed. The scaffolds of Rg1/GMs/Sr-α-CaS showed sustained release of Rg1, good biocompatibility and ability of promoting osteogenic differentiation and angiogenesis in vitro. The scaffolds were implanted into animal model of cranial bone defect to characterize bone tissue repair and regeneration in vivo. From the images of Micro-CT, it was obvious that the most bone tissue was formed in Rg1/GMs/Sr-α-CaS group in 12 weeks. New bone structure, collagen and mineralization were analyzed with staining of HE, Masson and Safranin O-Fast green and showed good distribution. The expression of osteocalcin of Rg1/GMs/Sr-α-CaS indicated new bone formation in defect site. The results revealed that synergy of Rg1 and Sr showed the best effect of bone repair and regeneration, which provided a new candidate for bone defect repair in clinic.

Abstract 549: Characterization of Mesenchymal Stromal Cell-derived Exosomes From Patients With Improved Function Outcome After Ischemic Cardiomyopathy: A Biorepository Evaluation of the Focus-CCTRN Trial

Mesenchymal stromal cells derived from bone marrow (BM-MSCs) have been considered promisingcandidates for regenerative medicine therapies for more than 20 years, but to date cardiovascular clinicaltrials of MSC-based therapies have demonstrated only modest improvement. However, the mechanismsunderlying why some patients improve and others do not remain undefined. Although MSC survival aftertransplantation remains a challenge, several studies have reported that BM-MSC-mediated paracrineeffects and delivery of exosomes may be therapeutically relevant. We hypothesized that MSC-derivedexosomes from patients with cardiac functional improvement contain factors that promote cell survival,proliferation, and cardiac protection. Here, we compared exosomes (derived from MSCs that had beenexpanded from BM-MNCs used for autologous transplantation) from two cohorts of disease- and age-matched consented patients with ischemic cardiomyopathy enrolled in the FOCUS-CCTRN trial—thosewith improved (cohort1, n=3) or worsened (cohort2, n=3) functional outcome in three primary endpoints:left ventricular (LV) ejection fraction, LV end-systolic volume, and maximal oxygen consumption.MicroRNA-seq analysis identified 16 upregulated and 12 downregulated miRNAs in cohort 1 whencompared to cohort 2. Using DIANA-Mir Path v.3.0, we identified 3,522 experimentally validated genetargets. Gene set enrichment analysis identified enrichment for fatty acid biosynthesis and metabolism,Hippo signaling pathway, protein processing in endoplasmic reticulum, adherent junction, cell cycle,endocytosis, RNA transport and degradation, estrogen-signaling pathway, regulation of actincytoskeleton, Prolactin signaling pathway, Focal adhesion, Notch-signaling pathway, p53-signalingpathway, insulin-signaling pathway and HIF-1-signaling pathway in the targets of upregulated miRNAs.The downregulated miRNAs were related to extracellular matrix-receptor interaction, protein processingin endoplasmic reticulum, cytokine-cytokine receptor interaction and antigen processing andpresentation. Thus, the identified miRNAs differentially expressed in patients with an improved functionaloutcome that may play a role in the molecular mechanisms that underlie in cardiac repair in patients withischemic cardiac disease. Moreover, these finding indicate that not all autologous cell products may becompetent therapy candidates for cardiac repair These results warrant further investigation to confirmthe effects of the identified differences on the target genes, which could improve the prognosis and unveilnew therapeutic approaches.

Microspheres containing biosynthesized silver nanoparticles with alginate-nano hydroxyapatite for biomedical applications

Scaffolding system plays an important role in the development of artificial bone for treatment of defective or diseased bone tissue. In the present work, we have developed microspheres (COS-Ag-Alg-HA) containing chitooligosaccharide (COS) coated silver nanoparticles (Ag NPs) with alginate (Alg) and hydroxyapatite (HA) as bone graft substitutes. The developed microspheres were characterized through various analytical techniques such as UV–visible spectroscopy, Fourier transform infrared spectroscopy (FT-IR), X-ray diffraction, field emission scanning electron microscopy with EDX and evaluated the mechanical strength by using universal testing machine. In addition to this, antimicrobial activity and biocompatibility of the developed microspheres were evaluated with pathogenic microbes and osteoblast-like cells, respectively. Results suggest that microspheres are rigid, and strong chemical interactions were observed between the materials. The size of the microspheres was ranging from 1.5 ± 0.5 to 4.0 ± 0.5 mm. Significant microbial inhibition was observed against Staphylococcus aureus, and the developed microspheres are biocompatible with osteoblast-like cells. Based on the aforementioned finding results, the developed microsphere is proposed to be a potential candidate for bone tissue repair and regeneration.

β-mercaptoethanol promotes osteogenesis of human mesenchymal stem cells via sirt1-ERK pathway.

Human umbilical cord-derived mesenchymal stem cells (hUMSCs) hold strong self-renewal capacity and low immunogenicity, which have attracted attention as potential candidates for bone repair and regeneration. However, insufficient osteogenic differentiation markedly hinders the clinical applications of hUMSCs. In the present study, the effect of β-mercaptoethanol (BME), a small molecule antioxidant which has been identified to regulate cell proliferation and differentiation, on osteogenic differentiation of hUMSCs and underlying signaling mechanism were investigated. The results indicated that under osteogenic induction conditions, BME treatment increased the alkaline phosphatase (ALP) activity and promoted calcium mineralization in hUMSCs. The gene and protein expression of osteogenesis-related markers such as ALP, osteopontin (OPN), osteocalcin (OCN) and collagen type I (COLI) were also significantly up-regulated. Besides, BME promoted the protein expression of silent information regulator type 1 (sirt1) and stimulated the activation of extracellular signal-related kinase (ERK), contributing to increased Runx2 expression. Furthermore, blocking the expression of sirt1 attenuated BME-enhanced ERK phosphorylation and osteogenic differentiation of hUMSCs. These results indicated that BME accelerated osteogenic differentiation of hUMSCs by activating the sirt1-ERK signaling pathway, thereby providing insights into the development of MSCs-based bone regeneration strategies.

Surgical Valvuloplasty Versus Balloon Dilation for Congenital Aortic Stenosis in Pediatric Patients.

For children with congenital aortic stenosis (AS) who are candidates for biventricular repair, valvuloplasty can be achieved by surgical aortic valvuloplasty (SAV) or by transcatheter balloon aortic dilation (BAD). We aimed to evaluate the longer term outcomes of SAV versus BAD at our institution. We retrospectively reviewed the outcomes of 2 months to 18 years old patients who underwent SAV or BAD at our institution between January 1990 and July 2018. Baseline and follow-up characteristics were assessed by echocardiography. Long-term survival, freedom from reintervention, freedom from aortic valve replacement (AVR), and aortic regurgitation were evaluated. A total of 212 patients met inclusion criteria (SAV = 123; BAD = 89). Age, sex, aortic insufficiency (AI), and aortic valve gradient were similar between the groups. At 10 years, 27.9% (19/68) of SAV patients and 58.3% (28/48) of BAD patients had moderate or worse AI (P = .001), and reintervention occurred in 39.2% (29/74) of SAV patients and 78.6% (44/56) of BAD patients (P < .001). Kaplan-Meier analysis revealed overall survival was 96.8% (119/123) for SAV and 95.5% (85/89) for SAV (P = .87). At 10 years, 35% (23/66) of SAV patients and 54% (23/43) of BAD patients underwent AVR (P = .213). Surgical aortic valvuloplasty demonstrated greater gradient reduction, less postoperative and long-term AI, and a lower reintervention rate at 10 years than BAD. There was no difference in survival or AVR reintervention rate. Surgical aortic valvuloplasty is a durable and efficacious intervention and should continue to be considered a favorable choice for palliation of valvular AS.

Can CO2 Be a Savior for Endovascular Aneurysm Repair Candidates with Renal Dysfunction? Critical Tips for Safe CO2 Angiography.

Can CO2 Be a Savior for Endovascular Aneurysm Repair Candidates with Renal Dysfunction? Critical Tips for Safe CO2 Angiography.

Effect of Cu- and Zn-Doped Bioactive Glasses on the In Vitro Bioactivity, Mechanical and Degradation Behavior of Biodegradable PDLLA Scaffolds.

Biodegradable polymer scaffolds filled with bioactive glass particles doped with therapeutic metal ions are a novel and promising strategy to repair critical-sized bone defects. In this study, scaffolds based on a poly (D, L-lactide acid) (PDLLA) matrix filled with un-doped and Cu-, Zn- and CuZn-doped bioactive glass particles were produced by freeze-drying and a salt-leaching method. The effects of the doping and content of the glass particles (10 and 30 wt.%) on the morphology, compression properties, apatite formation, and degradation behavior of the scaffolds were evaluated. The scaffolds presented high porosity (~93%) with pores ranged from 100 to 400 μm interconnected by smaller pores and this porosity was kept after the glass particles incorporation. The glass particles reinforced the polymer scaffolds with improvements as high as 130% in elastic moduli, and further promoted the apatite formation on the scaffold surface, both properties depending on the amount and type of filler. The bioactive glass particles boosted the scaffold degradation with the PDLLA/un-doped glass scaffold showing the highest rate, but still retaining structural and dimensional integrity. Our findings show that the incorporation of un-doped and metal-doped bioactive glasses increases the mechanical strength, promotes the bioactivity and modifies the degradation profile of the resulting polymer/glass scaffolds, making them better candidates for bone repair.

Feasibility and Applicability of the Enhanced Recovery After Surgery Protocol in Aortic Surgery: A Preliminary Pilot Study

The objective was to assess the feasibility and applicability of the enhanced recovery after surgery (ERAS) protocol in patients undergoing open repair of abdominal aortic aneurysm (AAA) and to compare it with endovascular aneurysm repair (EVAR) and with standard AAA open repair in terms of perioperative outcomes in a prospective, single-center pilot study. From December 2018 to August 2019, all the patients who were candidates for open AAA repair at our department were managed with the ERAS protocol (group 1, 17 patients). In the same period, 18 patients underwent EVAR (group 2). The control group of patients treated with standard open AAA repair included 32 patients operated on in the 6 months before the study began (group 3). The three groups were compared in terms of time to discharge, postoperative pain, time to resumption of oral intake, and time to mobilization with the χ2 test. Furthermore, patient satisfaction and quality of life were compared with two dedicated tools (Flemish Patient Survey and 12-Item Short Form Health Survey). The three groups were homogeneous in term of demographics, risk factors, and comorbidities. In group 1, the ERAS protocol was successfully performed in 15 patients (88%). The mean time to discharge was 5 days in group 1, 3.5 days in group 2, and 8.4 days in group 3 (P = .02 for groups 1 and 2 vs group 3). Postoperative pain exceeded the cutoff visual analog scale/numeric rating scale score >4 in 8 patients in group 1 (47%), in 4 patients in group 2 (22%), and in 18 patients in group 3 (62%). The average time of resumption of oral intake was 1 day in groups 1 and 2 and 3.8 days in group 3 (P < .001). The recovery of gut function was achieved in 1.3 days in group 1, 1.3 days in group 2, and 2.9 days in group 3 (P = .002). The average time to regain mobilization was 1.5 days in group 1, 2 days in group 2, and 4.5 days in group 3 (P = .03). As for quality of life, the results of the 12-Item Short Form Health Survey showed a significant improvement of the mental score index after surgery in groups 1 and 2 but not in group 3. Our preliminary pilot study showed that the ERAS protocol might be effectively and safely applied to most patients undergoing open repair of AAA, providing perioperative outcomes not different from those after EVAR and presumably better than those after standard open repair.

Hydroxyapatite based biocomposite scaffold: A highly biocompatible material for bone regeneration.

The conventional approaches for treating bone defects such as autografts donor tissue shortages and allografts transmission of diseases pose many shortcomings. The objective of this study was to design a nano strontium/magnesium doped hydroxyapatite (Sr/Mg-HA) with chitosan (CTS) and multi-walled carbon nanotubes (MWCNT) (Sr/Mg-HA/MWCNT/CTS) biocomposite was created to support the growth of osteoblasts using a solvent evaporation method. To help the growth of osteoblasts, a solvent evaporation technique was used to design a nano strontium/magnesium doped hydroxyapatite with chitosan and multi-walled carbon nanotubes biocomposite. We studied the biocompatibility and efficiency in vitro of biocomposite following physicochemical analyzes. Tests of biocompatibility, cell proliferation, mineralization, and osteogenic differentiation have shown that in-vitro safety and effectiveness of biocomposite are good. The performance of biocomposite was more efficient in in-vitro as well as in vivo experiments than in Sr/Mg-HA nanoparticles. Briefly, the Sr/Mg-HA/MWCNT/CTS biocomposite is an ideal candidate for effective bone repair in clinics with excellent mechanical properties with durable multi-biofunctional antibacterial properties and osteoinductivity.

Functional variations between Mesenchymal Stem Cells of different tissue origins: A comparative gene expression profiling.

Mesenchymal Stem Cells (MSCs), regardless of the tissue sources, are considered as excellent candidates for cellular therapy as they are immune-privileged cells containing a multitude of therapeutic functions that aid in tissue regeneration and repair. For the effective application of these cells in cell therapy, it is important to understand and characterize their biological functions. The present study attempts to characterize the variations in multipotent function such as cell surface antigen levels, proliferation, differentiation and stemness (pluripotency) potential of MSCs isolated from foetal [wharton's jelly (WJ), foetal and maternal side of placenta (PF and PM)] and adult tissue sources [bone marrow (BM) and adipose tissue (AT)] using gene expression by real time PCR (qRT-PCR). Amongst the different tissue sources, PM, PF and AT-MSCs exhibited significant increase (p < 0.001, p < 0.001 and p < 0.01 respectively) in CD 73 expression and therefore could have a role in immunomodulation. WJ-MSCs exhibited superior proliferation potential based on growth curve, PCNA and Wnt gene expression. BM-MSCs were superior in exhibiting trilineage differentiation. Enhanced stemness potential (Oct 4 and Nanog) was observed for both BM and WJ-MSCs. In addition, BM and WJ-MSCs expressed high levels of CD 90 making them suitable in bone repair and regeneration. Thus to conclude, out of the five different sources tested, BM an adult source and WJ-MSCs a foetal source were superior in exhibiting most of the biological functions indicating that these sources may be suitable candidates for cell repair and regeneration studies.

CLASP Mediates Microtubule Repair by Restricting Lattice Damage and Regulating Tubulin Incorporation.

SummaryMicrotubules play a key role in cell division, motility, and intracellular trafficking. Microtubule lattices are generally regarded as stable structures that undergo turnover through dynamic instability of their ends [1]. However, recent evidence suggests that microtubules also exchange tubulin dimers at the sites of lattice defects, which can be induced by mechanical stress, severing enzymes, or occur spontaneously during polymerization [2, 3, 4, 5, 6]. Tubulin incorporation can restore microtubule integrity; moreover, “islands” of freshly incorporated GTP-tubulin can inhibit microtubule disassembly and promote rescues [3, 4, 6, 7, 8]. Microtubule repair occurs in vitro in the presence of tubulin alone [2, 3, 4, 5, 6, 9]. However, in cells, it is likely to be regulated by specific factors, the nature of which is currently unknown. CLASPs are interesting candidates for microtubule repair because they induce microtubule nucleation, stimulate rescue, and suppress catastrophes by stabilizing incomplete growing plus ends with lagging protofilaments and promoting their conversion into complete ones [10, 11, 12, 13, 14, 15, 16, 17]. Here, we used in vitro reconstitution assays combined with laser microsurgery and microfluidics to show that CLASP2α indeed stimulates microtubule lattice repair. CLASP2α promoted tubulin incorporation into damaged lattice sites, thereby restoring microtubule integrity. Furthermore, it induced the formation of complete tubes from partial protofilament assemblies and inhibited microtubule softening caused by hydrodynamic-flow-induced bending. The catastrophe-suppressing domain of CLASP2α, TOG2, combined with a microtubule-tethering region, was sufficient to stimulate microtubule repair, suggesting that catastrophe suppression and lattice repair are mechanistically similar. Our results suggest that the cellular machinery controlling microtubule nucleation and growth can also help to maintain microtubule integrity.

Automatic Detection, Validation, and Repair of Race Conditions in Interrupt-Driven Embedded Software

Interrupt-driven programs are widely deployed in safety-critical embedded systems to perform hardware and resource dependent data operation tasks. The frequent use of interrupts in these systems can cause race conditions to occur due to interactions between application tasks and interrupt handlers (or two interrupt handlers). Numerous program analysis and testing techniques have been proposed to detect races in multithreaded programs. Little work, however, has addressed race condition problems related to hardware interrupts. In this paper, we present SDRacer, an automated framework that can detect, validate and repair race conditions in interrupt-driven embedded software. It uses a combination of static analysis and symbolic execution to generate input data for exercising the potential races. It then employs virtual platforms to dynamically validate these races by forcing the interrupts to occur at the potential racing points. Finally, it provides repair candidates to eliminate the detected races. We evaluate SDRacer on nine real-world embedded programs written in C language. The results show that SDRacer can precisely detect and successfully fix race conditions.

Regenerated silk fibroin-based dressing modified with carnosine-bentonite nanosheets accelerates healing of second-degree burn wound

Regenerated silk fibroin (RSF) is a promising candidate for skin repair due to its wound healing properties. RSF films have some drawbacks such as weak mechanical property, low porosity and poor absorption which limits their application as an ideal wound healing dressing. In this study, a novel RSF-based nanohybrid bearing carnosine (Car) intercalated bentonite (CarBen) nanosheets was prepared using solvent casting method and was applied in a second-degree burn wound model. RSF bearing different amounts of CarBen nanosheets (0, 1, 3 and 5 wt%) was prepared and fully characterized. RSF having 5 wt% of the modified Ben (RSF-CarBen5) showed superior mechanical property (ultimate stress of 8.36 ± 01 MPa and ultimate strain of 1501.33 ± 1.24%), and higher absorption capacity (1653.57 ± 0.05%) with favorable porosity (80.27%). RSF-CarBen5 was employed as dressing for healing of second-degree burn wound in rats. Histological evaluation showed considerable inflammation reduction in wound sites compared to the control groups. The wound treated with the nanohybrid showed significant epithelialization and angiogenesis on day 14 post-treatment, compared to the other groups (P < 0.05). The results showed that RSF bearing CarBen nanosheets have suitable therapeutic potential and can heal burn wounds appropriately.

Palliative Care in Ruptured Aortic Aneurysm in the United States: A Retrospective Analysis of Nationwide Inpatient Sample Database.

We assessed the trend of palliative care (PC) referrals and its effect on hospitalization cost and length of stay (LOS) in ruptured aortic aneurysm (rAA). The Nationwide Inpatient Sample from 2005 to 2014 was used to identify admissions with age ≥50 and rAA. A total of 54 134 rAA admissions were identified and 5019 (9.3%) had PC referrals. During the study period, PC referral rate increased from 0.97% to 15.3% (P trend < .0001). Length of stay (1.7 vs 2.8 days, adjusted mean ratio [aMR] = 0.62, 95% confidence interval [CI]: 0.58-0.66), and cost (US$7778 vs US$13 575, aMR = 0.57, 95% CI: 0.52-0.63) were significantly lower in rAA admissions that did not undergo interventions. In the percutaneous repair group, LOS was similar but the cost was higher (US$61 759 vs US$52 260, aMR = 1.18, 95% CI: 1.05-1.30), whereas in surgical repair group, LOS was shorter (4.6 vs 5.9 days, aMR = 0.77, 95% CI: 0.73-0.82) but the cost was higher (US$59 755 vs US$52 523, aMR = 1.14, 95% CI: 1.02-1.28). Palliative care could shorten LOS and save hospitalization cost in rAA admissions not a candidate for repair. Further studies are required to investigate the variable effects of PC on rAA.

Allogeneic stem cell therapy for cardiac repair and host immune response

Bone marrow derived allogeneic (unrelated donor) mesenchymal stem cells (MSCs) and induced pluripotent stem cell‐derived cardiomyocytes (iPSC‐CMs) have been found to have a high potential as candidates for cardiac repair. Unlike embryonic stem cells, there are no ethical issues involved with these two cell types. Both can help in replacing the dead cells directly/indirectly. Even though initial pre‐clinical and clinical trials showed promise for using MSCs and iPSC‐CMs, but after transplantation, these cells were found to be rejected by the recipient immune system that led to deterioration of beneficial effects of stem cell based therapies. Therefore, we aim to decipher the mechanisms responsible for the rejection of the transplanted allogeneic MSCs and iPSC‐CMs by the host immune system. The immunoprivilige of allogeneic MSCs is preserved by absence of cell surface immune antigen, major histocompatibility complex (MHC)–II. We recently found that MHC‐II expression increased in rat and human MSCs after exposure to hypoxia or after transplantation in the infarcted rat heart. MHC‐II expression is regulated by a class II transactivator (CIITA). We found that hypoxic environment led to upregulation of ATPase subunit of 19S proteasome Sug1 and its binding to CIITA, that was associated with activation of CIITA and upregulation of MHC‐II expression. As a result, MSCs became immunogenic and were rejected by host immune system. Knocking down Sug1 in MSCs preserved immunoprivilege and prevented rejection of transplanted MSCs in the infarcted heart. In case of iPS cells, we found that after differentiation to cardiomyocytes there was a significant increase in the MHC‐II expression that was associated with upregulation of immunogenicity of iPSC‐CMs. Therefore, current study provides novel mechanisms of increase in immunogenicity of allogeneic MSCs and iPSC‐CMs. This study may help in facilitating a better planning for future MSCs or iPSC based clinical trials in cardiac patients.Support or Funding InformationCanadian Institutes of Health Research

Case Report: Percutaneous Mitral Valve Repair in a Patient with Fontan Repair for a Single Functional Ventricle

Mitral regurgitation (MR) can complicate congenital heart disease, particularly when secondary to left ventricular dysfunction and mitral annular dilation. Significant MR is associated with substantial morbidity and mortality in patients with reduced LV systolic function, with recent studies demonstrating that percutaneous mitral valve repair can significantly reduce hospitalizations and all-cause mortality. A 31 year-old man was referred to our Advanced Valve center for evaluation and management of significant MR. He was born with pulmonary atresia and was palliated by oversewing the tricuspid valve and creating Fontan physiology using an intracardiac lateral tunnel. At the age of 30 he presented with fatigue with an echo that showed an LV EF of 40-45% with severe MR. He was evaluated for transplantation at his referring facility but was not felt to be a candidate and was referred to our clinic for consideration of valvular intervention. Following TEE and CT evaluations, he was deemed to be a candidate for transcutaneous mitral valve repair, with functional etiology of his MR. Following femoral venous access, a transseptal puncture was made across the lateral tunnel of the patient's Fontan circuit. A steerable guide catheter was then introduced into the left atrium and percutaneous transcatheter mitral valve repair was performed using the MitraClip system (4 clips on A2/P2 scallops), with reduction in the MR from severe to mild. The patient tolerated the procedure well with no significant complications. After the procedure, the patient reported improvement in his symptoms of dyspnea and fatigue with sustained clinical improvement several months later (NYHA class II). Transcatheter mitral valve repair is an accepted method for the treatment of severe MR and its symptoms in patients with both functional and degenerative MR. To our knowledge, this experience represents the first case report of this new technology being used in the treatment of congenital heart disease patients with single ventricle physiology. Given the challenges of surgical repair in this population and the increasing number of patients living into adulthood with congenital heart disease, we believe that transcatheter valvular interventions will become an important tool for the care of these complex patients.

Do the instructions for use matter?

Almost since inception, endovascular aneurysm repair (EVAR) was felt to be a less invasive way to treat abdominal aortic aneurysm in higher risk patients, many of whom would not be candidates for open repair. Graft manufacturers are required to submit instructions for use (IFU) as part of the approval process. Physicians are not required to follow the IFU, but it makes sense to adhere to it as much as feasible to allow maximal benefit to the patient. The meta-analysis by Antoniou et al1 looks at 4500 patients treated with EVAR between 2006 and 2015.