Citations

While the function of many leukocytes in transplant biology has been well defined, the role of eosinophils is controversial and remains poorly explored. Conflicting data exist regarding eosinophils’ role in alloimmunity. Due to their prevalence in the lung, and their defined role in other pulmonary pathologies such as asthma, we set out to explore the role of eosinophils in the long-term maintenance of the lung allograft. We noted that depletion of eosinophils results in the generation of donor-specific antibodies. Eosinophil depletion increased memory B cell, plasma cell, and antibody-secreting cell differentiation and resulted in de novo generation of follicular germinal centers. Germinal center formation depended on the expansion of CD4 + Foxp3 – Bcl6 + CXCR5 + PD-1 + T follicular helper (Tfh) cells, which increase in number after eosinophil depletion. Mechanistically, we demonstrate that eosinophils prevent Tfh cell generation by acting as the dominant source of IFN-γ in an established lung allograft, thus facilitating Th1 rather than Tfh polarization of naive CD4 + T cells. Our data thus describe what we believe is a unique and previously unknown role for eosinophils in maintaining allograft tolerance and suggest that indiscriminate administration of eosinophil-lytic corticosteroids for treatment of acute cellular rejection may inadvertently promote humoral alloimmunity.

Abstract Background and Aims Prior reports have demonstrated a favourable safety and efficacy profile of the Micra leadless pacemaker over mid-term follow-up; however, long-term outcomes in real-world clinical practice remain unknown. Updated performance of the Micra VR leadless pacemaker through five years from the worldwide post-approval registry (PAR) was assessed. Methods All Micra PAR patients undergoing implant attempts were included. Endpoints included system- or procedure-related major complications and system revision rate for any cause through 60 months post-implant. Rates were compared through 36 months post-implant to a reference dataset of 2667 transvenous pacemaker patients using Fine–Gray competing risk models. Results 1809 patients were enrolled between July 2015 and March 2018 and underwent implant attempts from 179 centres in 23 countries with a median follow-up period of 51.1 months (IQR: 21.6–64.2). The major complication rate at 60 months was 4.5% [95% confidence interval (CI): 3.6%–5.5%] and was 4.1% at 36 months, which was significantly lower than the 8.5% rate observed for transvenous systems (HR: .47, 95% CI: .36–.61; P < .001). The all-cause system revision rate at 60 months was 4.9% (95% CI: 3.9%–6.1%). System revisions among Micra patients were mostly for device upgrades (41.2%) or elevated thresholds (30.6%). There were no Micra removals due to infection noted over the duration of follow-up. At 36 months, the system revision rate was significantly lower with Micra vs. transvenous systems (3.2% vs. 6.6%, P < .001). Conclusions Long-term outcomes with the Micra leadless pacemaker continue to demonstrate low rates of major complications and system revisions and an extremely low incidence of infection.

Background: Premature ventricular contractions (PVCs) are associated with an increased risk of implanting implantable cardioverter defibrillator (ICD). Therefore, our study aimed to predict the risk factors for implantable cardioverter defibrillator in patients with premature ventricular contractions. Methods: A total of 309 patients (male 57%, mean age 66.73±16.12) in Olmstate Countywho had premature ventricular contractions and received a 24-hour electrocardiography monitoring were included between January 1994 and September 2010 at Mayo Clinic, Rochester, Minnesota. All these patients were continuously followed o Jun 2015. Student’s t-test, Chi-square, univariate and multivariate Logistic regression models were used to estimate the relationship between the risk factors and the incidence of implanting implantable cardioverter defibrillator (ICD) in PVCs patients. Kaplan–Meier curve of survival in PVCs patients with ICD or free-ICD. Results: The average follow-up time was 9.3±3.9 years, in which 43 (13.9%) patients died and 24 (7.8%) patients had received ICD therapy. Sex, age, pulse pressure, early repolarization syndrome (ERS), heart rate, PVC coupling interval, QRS duration, left ventricular ejection fraction (LVEF), left ventricular end-diastolic dimension (LVEDD) and left ventricular end-systolic dimension (LVESD), diabetes were significantly associated with the mortality and the incidence of implanting ICD. Using a multivariate logistic regression model adjusted for potential confounders, showed that LVEF (OR=0.916, 95% CI:0.881 to 0.953, p<0.001) and pulse pressure (OR=1.032, 95% CI:1.001-1.064, p=0.045) were independent factors for ICD implant in PVCs patients. Moreover, implantation of ICD may not reduce mortality in patients with ventricular premature. Conclusions: Increased pulse pressure was associated a higher incidence of ICD in PVCs patients, among many electrocardiographic and clinical variables studied. We also showed that PVs patients with ICD were at high risk of death, and the great pulse pressure was linked with higher morality in PVCs patients.

BACKGROUND: The incidence and prognosis of right bundle branch block (RBBB) following transcatheter aortic valve replacement (TAVR) are unknown. Hence, we sought to characterize the incidence of post-TAVR RBBB and determine associated risks of permanent pacemaker (PPM) implantation and mortality. METHODS: All patients 18 years and above without preexisting RBBB or PPM who underwent TAVR at US Mayo Clinic sites and Mayo Clinic Health Systems from June 2010 to May 2021 were evaluated. Post-TAVR RBBB was defined as new-onset RBBB in the postimplantation period. The risks of PPM implantation (within 90 days) and mortality following TAVR were compared for patients with and without post-TAVR RBBB using Kaplan-Meier analysis and Cox proportional hazards modeling. The risks of PPM implantation (within 90 days) and mortality following TAVR were compared for patients with and without post-TAVR RBBB using Kaplan-Meier analysis and Cox proportional hazards modeling. RESULTS: Of 1992 patients, 15 (0.75%) experienced new RBBB post-TAVR. There was a higher degree of valve oversizing among patients with new RBBB post-TAVR versus those without (17.9% versus 10.0%; P =0.034). Ten patients (66.7%) with post-TAVR RBBB experienced high-grade atrioventricular block and underwent PPM implantation (median 1 day; Q1, 0.2 and Q3, 4), compared with 268/1977 (13.6%) without RBBB. Following propensity score adjustment for covariates (age, sex, balloon-expandable valve, annulus diameter, and valve oversizing), post-TAVR RBBB was significantly associated with PPM implantation (hazard ratio, 8.36 [95% CI, 4.19–16.7]; P <0.001). No statistically significant increase in mortality was seen with post-TAVR RBBB (hazard ratio, 0.83 [95% CI, 0.33–2.11]; P =0.69), adjusting for age and sex. CONCLUSIONS: Although infrequent, post-TAVR RBBB was associated with elevated PPM implantation risk. The mechanisms for its development and its clinical prognosis require further study.

Genetic variation at the transmembrane protein 106B gene ( TMEM106B) has been linked to risk of frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) through an unknown mechanism. We found that presence of the TMEM106B rs3173615 protective genotype was associated with longer survival after symptom onset in a postmortem FTLD-TDP cohort, suggesting a slower disease course. The seminal discovery that filaments derived from TMEM106B is a common feature in aging and, across a range of neurodegenerative disorders, suggests that genetic variants in TMEM106B could modulate disease risk and progression through modulating TMEM106B aggregation. To explore this possibility and assess the pathological relevance of TMEM106B accumulation, we generated a new antibody targeting the TMEM106B filament core sequence. Analysis of postmortem samples revealed that the TMEM106B rs3173615 risk allele was associated with higher TMEM106B core accumulation in patients with FTLD-TDP. In contrast, minimal TMEM106B core deposition was detected in carriers of the protective allele. Although the abundance of monomeric full-length TMEM106B was unchanged, carriers of the protective genotype exhibited an increase in dimeric full-length TMEM106B. Increased TMEM106B core deposition was also associated with enhanced TDP-43 dysfunction, and interactome data suggested a role for TMEM106B core filaments in impaired RNA transport, local translation, and endolysosomal function in FTLD-TDP. Overall, these findings suggest that prevention of TMEM106B core accumulation is central to the mechanism by which the TMEM106B protective haplotype reduces disease risk and slows progression.

Background: The outcomes of leadless pacemaker (LP) implantation after transvenous lead removal (TLR) of infected cardiac implantable electronic devices (CIED) are not well-established. Objective: This study sought to describe the outcomes of LP implantation following TLR of infected CIED. Method: We conducted a literature search using PubMed and Embase for a combination of term including leadless pacemaker implantation, transvenous lead extraction, transvenous lead removal , transvenous lead explant , infected cardiac implantable electronic device . The inclusion criterion was LP implantation after TLR of infected CIED. The exclusion criterion was TLR for non-infectious reason. Study end-points were procedural complications and LP infection. Result: Of 132 publications reviewed, 13 studies with a total of 253 patients (74 ± 14 years of age, 69% males) were included. Amongst, 56.8% had systemic CIED infection and 43.2% had isolated pocket infection. Staphylococcus Aureus was the most common causative organism in 33% of the reported patients. Of 253 patients included, 105 patients (41.5%) underwent concomitant LP implantation during TLR procedure, and 36 patients (14.2%) had transvenous pacing as a bridge from TLR to LP implantation. During the LP implantation, 1 patient (0.4%) had an intra-procedural complication requiring sternotomy. Post-LP implantation, 2 patients (0.8%) developed groin hematoma, 2 patients (0.8%) developed femoral arteriovenous fistula, and 1 patient (0.4%) developed pericardial effusion requiring pericardiocentesis. During a mean follow-up of 11.3 ±10.6 months, 3 patients (1.2%) developed pacemaker syndrome, 1 patient (0.4%) developed acute on chronic heart failure exacerbation, and only 1 patient (0.4%) developed LP-related infection requiring LP retrieval. Conclusion: This study suggests that LP implant is feasible and safe post-removal of infected CIED with cumulative adverse events at 4% and a reinfection rate of 0.4%.