Background The key pathophysiology of human acquired heart failure is impaired calcium transient, which is initiated at dyads consisting ryanodine receptors (RyR) at sarcoplasmic reticulum apposing CaV1.2 channels at t-tubules. Sympathetic tone regulates myocardial calcium transients through β-adrenergic receptor (β-AR) mediated phosphorylation of dyadic proteins. Phosphorylated-RyRs (P-RyR) have increased calcium sensitivity and open probability, amplifying calcium transient at a cost of receptor instability. Given that BIN1 (Bridging Integrator 1) organizes t-tubule microfolds and facilitates CaV1.2 delivery, we explored whether β-AR regulated RyRs are also affected by BIN1. Methods and Results Isolated adult mouse hearts or cardiomyocytes were perfused for 5 min with β-AR agonist isoproterenol (1µmol/L) or blockers CGP+ICI (baseline). Using biochemistry and super-resolution fluorescent imaging, we identified that BIN1 clusters P-RyR and CaV1.2. Acute β-AR activation increases coimmunoprecipitation between P-RyR and cardiac spliced BIN1+13+17 (with exons 13 and 17). Isoproterenol redistributes BIN1 to t-tubules, recruiting P-RyRs and improving the calcium transient. In cardiac specific Bin1 heterozygotes (Bin1 HT) mice, isoproterenol fails to concentrate BIN1 to t-tubules, impairing P-RyR recruitment. The resultant accumulation of uncoupled P-RyRs increases the incidence of spontaneous calcium release. In human hearts with end-stage ischemic cardiomyopathy, we find that BIN1 is also 50% reduced, with diminished P-RyR association with BIN1. Conclusions Upon β-AR activation, reorganization of BIN1-induced microdomains recruits P-RyR into dyads, increasing the calcium transient while preserving electrical stability. When BIN1 is reduced as in human acquired heart failure, acute stress impairs microdomain formation, limiting contractility and promoting arrhythmias.

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ObjectiveDesign a predictive risk model for minimizing iliofemoral vascular complications (IVC) in a contemporary era of transfemoral-transcatheter aortic valve replacement (TF-TAVR).BackgroundIVC remains a common complication of TF-TAVR despite the technological improvement in the new-generation transcatheter systems (NGTS) and enclosed poor outcomes and quality of life. Currently, there is no accepted tool to assess the IVC risk for calcified and tortuous vessels.MethodsWe reconstructed CT images of 516 propensity-matched TF-TAVR patients using the NGTS to design a predictive anatomical model for IVC and validated it on a new cohort of 609 patients. Age, sex, peripheral artery disease, valve size, and type were used to balance the matched cohort.ResultsIVC occurred in 214 (7.2%) patients. Sheath size (p = 0.02), the sum of angles (SOA) (p < .0001), number of curves (NOC) (p < .0001), minimal lumen diameter (MLD) (p < .001), and sheath-to-femoral artery diameter ratio (SFAR) (p = 0.012) were significant predictors for IVC. An indexed risk score (CSI) consisting of multiplying the SOA and NOC divided by the MLD showed 84.3% sensitivity and 96.8% specificity, when set to >100, in predicting IVC (C-stat 0.936, 95% CI 0.911–0.959, p < 0.001). Adding SFAR > 1.00 in a tree model increased the overall accuracy to 97.7%. In the validation cohort, the model predicted 89.5% of the IVC cases with an overall 89.5% sensitivity, 98.9% specificity, and 94.2% accuracy (C-stat 0.842, 95% CI 0.904–0.980, p < .0001).ConclusionOur CT-based validated-model is the most accurate and easy-to-use tool assessing IVC risk and should be used for calcified and tortuous vessels in preprocedural planning.