Suppression of Ca2+ signals by EGR4 controls Th1 differentiation and anti-cancer immunity in vivo.

While the zinc finger transcription factors EGR1, EGR2, and EGR3 are recognized as critical for T-cell function, the role of EGR4 remains unstudied. Here, we show that EGR4 is rapidly upregulated upon TCR engagement, serving as a critical "brake" on T-cell activation. Hence, TCR engagement of EGR4-/- T cells leads to enhanced Ca2+ responses, driving sustained NFAT activation and hyperproliferation. This causes profound increases in IFNγ production under resting and diverse polarizing conditions that could be reversed by pharmacological attenuation of Ca2+ entry. Finally, an in vivo melanoma lung colonization assay reveals enhanced anti-tumor immunity in EGR4-/- mice, attributable to Th1 bias, Treg loss, and increased CTL generation in the tumor microenvironment. Overall, these observations reveal for the first time that EGR4 is a key regulator of T-cell differentiation and function.

Causes and Clinical Outcomes of Patients Who Failed Screening for Transcatheter Tricuspid Valve Interventions.

Transcatheter tricuspid valve intervention (TTVI) has recently emerged as a promising alternative to surgery for tricuspid regurgitation (TR). However, a significant proportion of patients fail screening for TTVI, and little is known about their characteristics and natural history. This study sought to investigate causes of screen failure and outcomes of patients declined for TTVI. This was a retrospective single-center study of 32 patients who were ineligible for participation in transcatheter tricuspid valve replacement and tricuspid transcatheter edge-to-edge repair trials. Patients were classified into 2 groups according to the therapy they received: optimized medical therapy (OMT) group or intervention group. The mean age was 82 ± 7.8 years and 68.8% were women. The most common reasons for TTVI exclusion were anatomic/procedural impediment (53.1%), inclusion criteria not met (40.6%), and multivalvular disease (6.3%). Overall, 19 patients (59.4%) did not undergo subsequent tricuspid intervention. The clinical outcomes of these patients who received OMT alone were poor, with a 1-year composite of cardiac death or heart failure readmission of 47.4%. These rates were worse than in patients who subsequently underwent an intervention, albeit not statistically significant (OMT: 47.7% vs 23.1% interventions, p = 0.3), and were significantly more pronounced in the subgroup of patients who were excluded for anatomic/procedural limitations (OMT: 70% vs 14.3% interventions, p = 0.05). In conclusion, patients ineligible for TTVI, particularly, those with anatomic/procedural limitations, and treated medically have poor outcomes. These data underscore the importance of earlier referral and support the need for further transcatheter therapy iterations.

Five-Year Outcomes of Measured and Predicted Prosthesis-Patient Mismatch following Transcatheter Aortic Valve Implantation.

Data on the long-term outcomes of prosthesis patient mismatch (PPM) after transcatheter aortic valve implantation (TAVI) remain controversial. This study aimed to investigate the incidence and clinical outcomes of measured PPM (PPMM) and predicted PPM (PPMP) in patients who underwent TAVI. This is a retrospective analysis of 3,016 patients who underwent TAVI at a large health care system between 2012 and 2021. Effective orifice area indexed to body surface area (EOAi) was measured at discharge using the continuity equation. EOAi was predicted according to the published predictive tables for each model and size of the valve. Primary end point was 5-year survival rate. Mean age was 80 years, and 55.6% were male. The mean Society of Thoracic Surgeons risk score was 4.66%. 74.9% of patients received a balloon-expandable valve (BEV), and 25.1% received a self-expanding valve (SEV). The incidence of severe PPM was markedly lower when defined by predicted versus measured EOAi (0.8% vs 6.3%, p <0.001) and when assessed in SEV versus BEV (5.3% vs 6.6%, p = 0.02). Neither severe PPMp nor severe PPMM was associated with 5-year mortality (hazard ratio 1.26, 95% confidence interval 0.96 to 1.66, p = 0.095; hazard ratio 1.03, 95% confidence interval 0.42 to 2.49, p = 0.954, respectively), irrespective of the presence of high residual pressure gradient. Neither BEV nor SEV was associated with an increased 5-year mortality, irrespective of PPM definition or severity. In this large health care system analysis, neither severe PPMP nor severe PPMM was associated with 5-year all-cause mortality. There was no difference between BEV and SEV in terms of mortality, irrespective of the definition or severity of PPM.