Citations

Senescence induced by various stresses reprograms cancer cells to acquire senescence-associated (SA) cell growth (SACG), which allows them to escape senescence-induced cell cycle arrest with enhanced growth potential. ERK5 is a dual kinase-transcription factor, containing an N-terminal kinase domain and transactivation domains in the C-terminal half. Recent data have raised questions regarding the functional role of ERK5 kinase inhibitors in cancer and inflammatory diseases. We aimed to investigate how ERK5 reprograms myeloid cells (MC) to the SA secretory phenotype (SASP) and SACG, consequently leading to atherosclerosis (AthS). AthS was inhibited in ERK5 S496A knock-in (KI) mice. Single-cell analysis of p53 and Ki67 with imaging mass cytometry revealed three groups of MCs with different p53 and Ki67 expression patterns in the plaque. One group showed that p53 and Ki67 were co-expressed lineally, suggesting that this group of cells escaped from the growth-suppression effects of p53, which is also known as a senescence marker. The % of ERK5 S496A KI cells in this group was significantly lower than in wild-type (WT). Also, we found an increase of SA β-gal (SAβ-gal) + Ki67 + and 53BP1 + Ki67 + cells in bone narrow-derived macrophage (BMDMs) isolated from hypercholesterolemia (H-chol) WT mice, suggesting H-chol-induced MC SACG. MC SACG were significantly inhibited in ERK5 S496A KI mice, supporting the role of ERK5 S496 phosphorylation on SACG. RNA sequencing analysis identified the ERK5 S496 phosphorylation-dependent AHR induction by H-chol, and AHR depletion significantly inhibited SACG. We also discovered a critical effect of ERK5 S496 phosphorylation on SUMOylation at a novel site of NRF2 (i.e., K518), which inhibited NRF2 transcriptional activity without affecting ERK5 kinase activity and antagonized oxidized LDL (oxLDL)-induced SASP. Specific ERK5 kinase inhibitors (AX15836 and XMD8-92) inhibited oxLDL-induced ERK5 S496 phosphorylation, suggesting that ERK5 S496 phosphorylation was involved at least in part of the effects of these inhibitors. We have discovered a novel mechanism in which ERK5 S496 phosphorylation directly inhibits NRF2 activity by upregulating NRF2 K518 SUMOylation and AHR induction, subsequently inducing SACG and AthS.

Background: ERK5 (extracellular signal-regulated kinase 5) is a dual kinase transcription factor containing an N-terminal kinase domain and a C-terminal transcriptional activation domain. Many ERK5 kinase inhibitors have been developed and tested to treat cancer and inflammatory diseases. However, recent data have raised questions about the role of the catalytic activity of ERK5 in proliferation and inflammation. We aimed to investigate how ERK5 reprograms myeloid cells to the proinflammatory senescent phenotype, subsequently leading to atherosclerosis. Methods: A ERK5 S496A (dephosphorylation mimic) knock in (KI) mouse model was generated using CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/clustered regularly interspaced short palindromic repeat–associated 9), and atherosclerosis was characterized by hypercholesterolemia induction. The plaque phenotyping in homozygous ERK5 S496A KI and wild type (WT) mice was studied using imaging mass cytometry. Bone marrow–derived macrophages were isolated from hypercholesterolemic mice and characterized using RNA sequencing and functional in vitro approaches, including senescence, mitochondria reactive oxygen species, and inflammation assays, as well as by metabolic extracellular flux analysis. Results: We show that atherosclerosis was inhibited in ERK5 S496A KI mice. Furthermore, ERK5 S496 phosphorylation mediates both senescence-associated secretory phenotype and senescence-associated stemness by upregulating AHR (aryl hydrocarbon receptor) in plaque and bone marrow–derived macrophages isolated from hypercholesterolemic mice. We also discovered that ERK5 S496 phosphorylation could induce NRF2 (NFE2-related factor 2) SUMOylation at a novel K518 site to inhibit NRF2 transcriptional activity without altering ERK5 catalytic activity and mediates oxidized LDL (low-density lipoprotein)–induced senescence-associated secretory phenotype. Specific ERK5 kinase inhibitors (AX15836 and XMD8-92) also inhibited ERK5 S496 phosphorylation, suggesting the involvement of ERK5 S496 phosphorylation in the anti-inflammatory effects of these ERK5 kinase inhibitors. Conclusions: We discovered a novel mechanism by which the macrophage ERK5-NRF2 axis develops a unique senescence-associated secretory phenotype/stemness phenotype by upregulating AHR to engender atherogenesis. The finding of senescence-associated stemness phenotype provides a molecular explanation to resolve the paradox of senescence in proliferative plaque by permitting myeloid cells to escape the senescence-induced cell cycle arrest during atherosclerosis formation.

Abstract Remote monitoring is beneficial for the management of patients with cardiovascular implantable electronic devices by impacting morbidity and mortality. With increasing numbers of patients using remote monitoring, keeping up with higher volume of remote monitoring transmissions creates challenges for device clinic staff. This international multidisciplinary document is intended to guide cardiac electrophysiologists, allied professionals, and hospital administrators in managing remote monitoring clinics. This includes guidance for remote monitoring clinic staffing, appropriate clinic workflows, patient education, and alert management. This expert consensus statement also addresses other topics such as communication of transmission results, use of third-party resources, manufacturer responsibilities, and programming concerns. The goal is to provide evidence-based recommendations impacting all aspects of remote monitoring services. Gaps in current knowledge and guidance for future research directions are also identified.

AbstractRemote monitoring is beneficial for the management of patients with cardiovascular implantable electronic devices by impacting morbidity and mortality. With increasing numbers of patients using remote monitoring, keeping up with higher volume of remote monitoring transmissions creates challenges for device clinic staff. This international multidisciplinary document is intended to guide cardiac electrophysiologists, allied professionals, and hospital administrators in managing remote monitoring clinics. This includes guidance for remote monitoring clinic staffing, appropriate clinic workflows, patient education, and alert management. This expert consensus statement also addresses other topics such as communication of transmission results, use of third‐party resources, manufacturer responsibilities, and programming concerns. The goal is to provide evidence‐based recommendations impacting all aspects of remote monitoring services. Gaps in current knowledge and guidance for future research directions are also identified.

Background: Overall inferior vena cava filter (IVCF) utilization has decreased in the United States since the 2010 US Food and Drug Administration (FDA) safety communication. The FDA renewed this safety warning in 2014 with additional mandates on reporting IVCF-related adverse events. We evaluated the impact of the FDA recommendations on IVCF placements for different indications from 2010 to 2019 and further assessed utilization trends by region and hospital teaching status. Methods: Inferior vena cava filter placements between 2010 and 2019 were identified in the Nationwide Inpatient Sample database using the associated International Classification of Diseases, Ninth Revision, Clinical Modification, and Tenth Revision codes. Inferior vena cava filter placements were categorized by indication for venous thromboembolism (VTE) “treatment” in patients with VTE diagnosis and contraindication to anticoagulation and “prophylaxis” in patients without VTE. Generalized linear regression was used to analyze utilization trends. Results: A total of 823 717 IVCFs were placed over the study period, of which 644 663 (78.3%) were for VTE treatment and 179 054 (21.7%) were for prophylaxis indications. The median age for both categories of patients was 68 years. The total number of IVCFs placed for all indications decreased from 129 616 in 2010 to 58 465 in 2019, with an aggregate decline rate of −8.4%. The decline rate was higher between 2014 and 2019 than between 2010 and 2014 (−11.6% vs −7.2%). From 2010 to 2019, IVCF placement for VTE treatment and prophylaxis trended downward at rates of −7.9% and −10.2%, respectively. Urban nonteaching hospitals saw the highest decline for both VTE treatment (−17.2%) and prophylactic indications (−18.0%). Hospitals located in the Northeast region had the highest decline rates for VTE treatment (−10.3%) and prophylactic indications (−12.5%). Conclusion: The higher decline rate in IVCF placements between 2014 and 2019 compared with 2010 and 2014 suggests an additional impact of the renewed 2014 FDA safety indications on national IVCF utilization. Variations in IVCF use for VTE treatment and prophylactic indications existed across hospital teaching types, locations, and regions. Clinical Impact Inferior vena cava filters (IVCF) are associated with medical complications. The 2010 and 2014 FDA safety warnings appeared to have synergistically contributed to a significant decline in IVCF utilization rates from 2010 – 2019 in the US. IVC filter placements in patients without venous thromboembolism (VTE) declined at a higher rate than VTE. However, IVCF utilization varied across hospitals and geographical locations, likely due to the absence of universally accepted clinical guidelines on IVCF indications and use. Harmonization of IVCF placement guidelines is needed to standardize clinical practice, thereby reducing the observed regional and hospital variations and potential IVC filter overutilization.

Background Although there has been a decrease in the incidence of ST‐segment–elevation myocardial infarction (STEMI) in the United States, this trend might be stagnant or increasing in young women. We assessed the trends, characteristics, and outcomes of STEMI in women aged 18 to 55 years. Methods and Results We identified 177 602 women aged 18 to 55 with the primary diagnosis of STEMI from the National Inpatient Sample during years 2008 to 2019. We performed trend analyses to assess hospitalization rates, cardiovascular disease (CVD) risk factor profile, and in‐hospital outcomes stratified by three age subgroups (18–34, 35–44, and 45–55 years). We found STEMI hospitalization rates were decreased in the overall study cohort from 52 per 100 000 hospitalizations in 2008 to 36 per 100 000 in 2019. This was driven by decreased proportion of hospitalizations in women aged 45 to 55 years (74.2% to–71.7%; P <0.001). Proportion of STEMI hospitalizationincreased in women aged 18–34 (4.7%–5.5%; P <0.001) and 35–44 years (21.2%–22.7%; P <0.001). The prevalence of traditional and non‐traditional female‐specific or female‐predominant CVD risk factors increased in all age subgroups. The adjusted odds of in‐hospital mortality in the overall study cohort and age subgroups were unchanged throughout the study period. Additionally, we observed an increase in the adjusted odds of cardiogenic shock, acute stroke, and acute kidney injury in the overall cohort over the study period. Conclusions STEMI hospitalizations are increasing among women aged <45 years, and in‐hospital mortality has not changed over the past 12 years in women aged <55 years. Future studies on the optimization of risk assessment and management of STEMI in young women are urgently needed.

IMPORTANCE: High safety-net burden hospitals (HBHs) treating large numbers of uninsured or Medicaid-insured patients have generally been linked to worse clinical outcomes. However, limited data exist on the impact of the hospitals’ safety-net burden on in-hospital cardiac arrest (IHCA) outcomes in the United States. OBJECTIVES: To compare the differences in survival to discharge, routine discharge home, and healthcare resource utilization between patients at HBH with those treated at low safety-net burden hospital (LBH). DESIGN, SETTING, AND PARTICIPANTS: Retrospective cohort study across hospitals in the United States: Hospitalized patients greater than or equal to 18 years that underwent cardiopulmonary resuscitation (CPR) between 2008 and 2018 identified from the Nationwide Inpatient Database. Data analysis was conducted in January 2022. EXPOSURE: IHCA. MAIN OUTCOMES AND MEASURES: The primary outcome is survival to hospital discharge. Other outcomes are routine discharge home among survivors, length of hospital stay, and total hospitalization cost RESULTS: From 2008 to 2018, an estimated 555,016 patients were hospitalized with IHCA, of which 19.2% occurred at LBH and 55.2% at HBH. Compared with LBH, patients at HBH were younger (62 ± 20 yr vs 67 ± 17 yr) and predominantly in the lowest median household income (< 25th percentile). In multivariate analysis, HBH was associated with lower chances of survival to hospital discharge (adjusted odds ratio [aOR], 0.88; 95% CI, 0.85–0.96) and lower odds of routine discharge (aOR, 0.6; 95% CI, 0.47–0.75), compared with LBH. In addition, IHCA patients at publicly owned hospitals and those with medium and large hospital bed size were less likely to survive to hospital discharge, while patients with median household income greater than 25th percentile had better odds of hospital survival. CONCLUSIONS AND RELEVANCE: Our study suggests that patients who experience IHCA at HBH may have lower rates and odds of in-hospital survival and are less likely to be routinely discharged home after CPR. Median household income and hospital-level characteristics appear to contribute to survival.

Abstract Background Peroral endoscopic myotomy (POEM) is effective for the management of achalasia and its variants; however, it can be ineffective in some patients. We aimed to develop and validate a risk scoring system to predict the clinical failure of POEM preoperatively. Methods Consecutive patients who underwent POEM in 14 high volume centers between 2010 and 2020 were enrolled in this study. Clinical failure was defined as an Eckardt score of ≥ 4 or retreatment. A risk scoring system to predict the short-term clinical failure of POEM was developed using multivariable logistic regression and internally validated using bootstrapping and decision curve analysis. Results Of the 2740 study patients, 112 (4.1 %) experienced clinical failure 6 months after POEM. Risk scores were assigned for three preoperative factors as follows: preoperative Eckardt score (1 point), manometric diagnosis (−4 points for type II achalasia), and a history of prior treatments (1 point for pneumatic dilation or 12 points for surgical/endoscopic myotomy). The discriminative capacity (concordance statistics 0.68, 95 %CI 0.62–0.72) and calibration (slope 1.15, 95 %CI 0.87–1.40) were shown. Decision curve analysis demonstrated its clinical usefulness. Patients were categorized into low (0–8 points; estimated risk of clinical failure < 5 %) and high risk (9–22 points; ≥ 5 %) groups. The proportions of clinical failure for the categories were stratified according to the mid-term outcomes (log-rank test, P < 0.001). Conclusions This risk scoring system can predict the clinical failure of POEM preoperatively and provide useful information when making treatment decisions.

ObjectivesPatients with esophageal motility disorders (EMDs) including achalasia after gastric surgery have not been thoroughly characterized. Furthermore, the efficacy of peroral endoscopic myotomy (POEM) in this population should be clarified.MethodsIn this retrospective multicenter study of 3707 patients with EMDs, 31 patients (0.8%) had a history of gastric surgery. Patient characteristics and POEM efficacy were compared between patients with and without previous gastric surgery.ResultsIn patients with EMD after gastric surgery, age at EMD diagnosis was higher (72.0 years), male sex was predominant (90.3%), and the American Society of Anesthesiologists physical status score was higher (≥II, 48.4%). High‐resolution manometry (HRM) findings did not reveal significant differences. In patients who underwent gastric surgery, atrophic gastritis was common (80.6%), and gastric cancer was the primary surgical indication (32.3%). Distal gastrectomy was performed in 28 patients (90.3%). POEM was effective (3.3% adverse events; 100% treatment success). The incidence rates of reflux esophagitis (RE) and symptomatic gastroesophageal reflux disease (GERD) were 60.0% and 16.7%, respectively, without significant intergroup differences, and severe RE was not observed in the long‐term follow‐up. Extended gastric myotomy was a risk factor for RE.ConclusionPatients with gastric surgery often present severe disease manifestations; the surgical indication is mainly gastric cancer. HRM findings can be similarly used for diagnosis in patients with and without gastric surgery. POEM maintains safety and efficacy with acceptable RE and symptomatic GERD rates. To prevent RE, extended myotomy should be avoided.