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Purpose: Multiple randomized clinical trials have shown superiority of drug-eluting stents (DES) over bare-metal stents (BMS) for infrapopliteal disease. However, real-world data on DES utilization and outcomes in infrapopliteal chronic limb-threatening ischemia (CLTI) patients are unknown. Materials and Methods: We utilized the Nationwide Readmission Database (NRD) from 2016 to 2017 to extract patients undergoing infrapopliteal intervention with stents (BMS and DES) for CLTI using appropriate ICD-10 codes. Multilevel logistic regression with hospital ID as random effect was used to assess DES utilization. Primary outcome was the composite of target limb major amputation (TLmajA) and target limb revascularization (TLR). Multivariate Cox-proportional hazard regression was used to adjust for confounders. Results: Our study included a total of 1817 patients. Of these patients, 1056 patients (58.1%) received DES; DES utilization was stable (relative change: +2.5%, p-trend: 0.867) between 2016 and 2017 and was higher in teaching hospitals (adjusted odds ratio [aOR] = 1.28, 95% CI = 1.03–1.61, p=0.029] and medium (aOR = 3.13, 95% CI = 2.17–4.55, p≤0.001) and large (aOR = 1.56, 95% CI = 1.14–2.17, p=0.005) bed–sized hospitals. Inter-class correlation was 0.44 suggesting ~44% variation in DES utilization between any 2 random hospitals; DES was associated with lower rate of the primary composite outcome (aHR = 0.75, 95% CI = 0.62–0.92, p=0.004) compared with BMS. Conclusion: In patients undergoing infrapopliteal intervention for CLTI, DES demonstrated significant underutilization despite supportive evidence of their superiority compared with BMS; DES was associated with improvement in the primary composite outcome compared with BMS. [ABSTRACT FROM AUTHOR]

The epithelial Na+ channel (ENaC) has a key role in the regulation of extracellular fluid volume and blood pressure. ENaC belongs to a family of ion channels that sense the external environment. These channels have large extracellular regions that are thought to interact with environmental cues, such as Na+, Cl-, protons, proteases, and shear stress, which modulate gating behavior. We sought to determine the molecular mechanism by which ENaC senses high external Na+ concentrations, resulting in an inhibition of channel activity. Both our structural model of an ENaC α subunit and the resolved structure of an acid-sensing ion channel (ASIC1) have conserved acidic pockets in the periphery of the extracellular region of the channel. We hypothesized that these acidic pockets host inhibitory allosteric Na+ binding sites. Through site-directed mutagenesis targeting the acidic pocket, we modified the inhibitory response to external Na+. Mutations at selected sites altered the cation inhibitory preference to favor Li+ or K+ rather than Na+. Channel activity was reduced in response to restraining movement within this region by cross-linking structures across the acidic pocket. Our results suggest that residues within the acidic pocket form an allosteric effector binding site for Na+. Our study supports the hypothesis that an acidic cleft is a key ligand binding locus for ENaC and perhaps other members of the ENaC/degenerin family. [ABSTRACT FROM AUTHOR]

Proteolysis plays an important role in the maturation and activation of epithelial Na+ channels (ENaCs). Non-cleaved channels are inactive at high extracellular Na+ concentrations and fully cleaved channels are constitutively active. Cleavage of the α and γ subunits at multiple sites activates the channel through the release of imbedded inhibitory tracts. Peptides derived from these released tracts are also inhibitory, likely through binding at the inhibitory tract sites. We recently reported a model of the α subunit. We have now cross-linked Cys derivatives of the inhibitory peptide to the channel, using our model to predict sites at a domain interface of the α subunit that is in proximity to the N terminus of the peptide. Furthermore, peptide inhibition was mimicked in the absence of peptide by cross-linking the channel across the domain interface. Our results suggest a dynamic domain interface that can be exploited by inhibitory peptides and provides a mechanism for peptide inhibition and proteolytic activation. [ABSTRACT FROM AUTHOR]

The epithelial Na+ channel (ENaC) mediates Na+ transport across high resistance epithelia. This channel is assembled from three homologous subunits with the majority of the protein's mass found in the extracellular domains. Acid-sensing ion channel 1 (ASIC1) is homologous to ENaC, but a key functional domain is highly divergent. Here we present molecular models of the extracellular region of α ENaC based on a large data set of mutations that attenuate inhibitory peptide binding in combination with comparative modeling based on the resolved structure of ASIC1. The models successfully rationalized the data from the peptide binding screen. We engineered new mutants that had not been tested based on the models and successfully predict sites where mutations affected peptide binding. Thus, we were able to confirm the overall general fold of our structural models. Further analysis suggested that the α subunit-derived inhibitory peptide affects channel gating by constraining motions within two major domains in the extracellular region, the thumb and finger domains. [ABSTRACT FROM AUTHOR]

Background: No studies assessed impact of atrial flutter (AFL) ablation on outcomes in patients with AFL and concurrent heart failure (HF)., Objectives: To assess the effect of AFL ablation on mortality and HF readmissions in patients with AFL and HF., Methods: This retrospective cohort study identified 15,952 patients with AFL and HF from the 2016-17 Nationwide Readmissions Database. The primary outcome was a composite of all-cause mortality and/or HF readmission at 1 year. Secondary outcomes included HF readmission, all-cause mortality, and atrial fibrillation (AF) readmission at 1 year. Propensity score match (1:2) algorithm was used to adjust for confounders. Cox proportional hazard regression was used to generate hazard ratios., Results: Of the 15,952 patients, 9889 had heart failure with reduced ejection fraction (HFrEF) and 6063 had heart failure with preserved ejection fraction (HFpEF). In the matched HFrEF cohort (n = 5421), the primary outcome was significantly lower in patients undergoing ablation (HR 0.72, 95% CI 0.61-0.85, P < .001). HF readmission (HR 0.73, 95% CI 0.61-0.89, P = .001), all-cause mortality (HR 0.62, 95% CI 0.46-0.85, P = .003), and AF readmission (HR 0.63, 95% CI 0.48-0.82, P = .001) were also significantly reduced. In the matched HFpEF cohort (n = 2439), the primary outcome was lower in the group receiving ablation but was not statistically significant (HR 0.80, 95% CI 0.63-1.01, P = .065)., Conclusion: In patients with AFL and HFrEF, AFL ablation was associated with lower mortality and HF readmissions at 1 year. Patients with AFL and HFpEF did not show a similar significant reduction in the primary outcome., (© 2020 Published by Elsevier Inc. on behalf of Heart Rhythm Society.)