Fourteen drugs have been removed from the market worldwide because they cause torsade de pointes. Most drugs that cause torsade can be identified by assessing whether they block the human ether à gogo related gene (hERG) potassium channel and prolong the QT interval on the electrocardiogram. In response, regulatory agencies require new drugs to undergo "thorough QT" studies. However, some drugs block hERG potassium channels and prolong QT with minimal torsade risk because they also block calcium and/or sodium channels. Through analysis of clinical and preclinical data from 34 studies submitted to the US Food and Drug Administration and by computer simulations, we demonstrate that by dividing the QT interval into its components of depolarization (QRS), early repolarization (J-Tpeak), and late repolarization (Tpeak-Tend), along with atrioventricular conduction delay (PR), it may be possible to determine which hERG potassium channel blockers also have calcium and/or sodium channel blocking activity. This translational regulatory science approach may enable innovative drugs that otherwise would have been labeled unsafe to come to market.

BackgroundSpartin protein is involved in degradation of epidermal growth factor receptor and turnover of lipid droplets and a lack of expression of this protein is responsible for hereditary spastic paraplegia type 20 (SPG20). Spartin is a multifunctional protein that associates with many cellular organelles, including lipid droplets. Recent studies showed that spartin interacts with E3 ubiquitin ligases that belong to the neural precursor cell-expressed developmentally downregulated gene (Nedd4) family, including atrophin-1-interacting protein 4 (AIP4/ITCH). However, the biological importance of the spartin-AIP4 interaction remains unknown.ResultsIn this study, we show that spartin is not a substrate for AIP4 activity and that spartin's binding to AIP4 significantly increases self-ubiquitination of this E3 ligase, indicating that spartin disrupts the AIP4 autoinhibitory intramolecular interaction. Correspondingly, spartin has a seven times higher binding affinity to the WW region of AIP4 than the binding of the WW region has to the catalytic homologues of the E6-associated protein C-terminus (HECT) domain, as measured by enzyme-linked immunosorbent assay. We also show that spartin recruits AIP4 to lipid droplets and promotes ubiquitination of lipid droplet-associated protein, adipophilin, which regulates turnover of lipid droplets.ConclusionsOur findings demonstrate that spartin acts as an adaptor protein that activates and recruits AIP4 E3 ubiquitin ligase to lipid droplets and by this means regulates the level of ubiquitination of adipophilin and potentially other lipid-associated proteins. We propose that this is one of the mechanisms by which spartin regulates lipid droplet turnover and might contribute to the pathology of SPG20.

Background: The optimal timing of catheter ablation for atrial fibrillation (AF) in reference to the time of diagnosis is unknown. We sought to assess the impact of the duration between first diagnosis of AF and ablation, or diagnosis-to-ablation time (DAT), on AF recurrence following catheter ablation. Methods: We conducted a systematic electronic search for observational studies reporting the outcomes associated with catheter ablation for atrial fibrillation stratified by diagnosis-to-ablation time. The primary meta-analysis using a random effects model assessed AF recurrence stratified by DAT ≤1 year versus >1 year. A secondary analysis assessed outcomes stratified by DAT ≤3 years versus >3 years. Results: Of the 632 screened studies, 6 studies met inclusion criteria for a total of 4950 participants undergoing AF ablation for symptomatic AF. A shorter DAT ≤1 year was associated with a lower relative risk of AF recurrence compared with DAT >1 year (relative risk, 0.73 [95% CI, 0.65–0.82]; P <0.001). Heterogeneity was moderate (I 2 =51%). When excluding the one study consisting of only patients with persistent AF, the heterogeneity improved substantially (I 2 =0%, Cochran’s Q P =0.55) with a similar estimate of effect (relative risk, 0.78 [95% CI, 0.71–0.85]; P <0.001). Conclusions: Shorter duration between time of first AF diagnosis and AF ablation is associated with an increased likelihood of ablation procedural success. Additional study is required to confirm these results and to explore implementation of earlier catheter AF ablation and patient outcomes within the current AF care pathway. Visual Overview A visual overview is available for this article.