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Caveolin proteins are involved in establishing membrane microstructure, lipid raft organization, and cell signaling. In the heart, caveolin-3 (Cav3) predominates. Inherited or disease-induced Cav3 loss increases risk of sudden cardiac death (SCD). We aimed to explore connections between Cav3 loss and arrhythmogenic changes in the ventricular action potential (AP) by investigating the Cav3 dependence of ionic currents. Drugs commonly used to disrupt or remove Cav3 in cultured cells exclude any compensatory process likely to occur in vivo. This motivated us to engineer a novel conditional Cav3 knockout (Cav3-/-) mouse that survives to adulthood. We isolated ventricular cells for electrophysiological experimentation. AP duration (APD90) was prolonged from 2454 ms in WT to 9659 ms in Cav3-/-, and several currents were affected. Reduced peak: L-type Ca 2þ current (ICaL), 21%; slow K þ current, 81%; transient outward K þ current, 57%; steady state outward K þ current (Iss), 43%. Late Na þ current was enhanced~10-fold. These changes were partially offsetting -preventing a simple account for the APD90 increase. To relate changes in currents to changes in the AP, we developed a computational representation of Cav3-/-based on the Morotti et al. mouse ventricular cell model and defined by fractional change in currents. Unexpectedly, the relatively small change in relatively small Iss caused 33% of total simulated AP prolongation. Though Iss conductance was reduced, peak Iss actually increased in the dynamic setting of the simulated AP. Early in the AP, lower Iss indirectly enhanced inward currents (importantly late ICaL) by extending the plateau phase, which in turn allowed Iss to more fully activate. This Iss/ ICaL process largely accounted for the pro-arrhythmic APD90 increase following Cav3 loss and is therefore a candidate target for normalizing SCD risk.

The proportion of patients over the age of 90 years continues to grow, and the anticipated demand for total joint arthroplasty (TJA) in this population is expected to rise concomitantly. As the country shifts to alternative reimbursement models, data regarding hospital expenses is needed for accurate risk-adjusted stratification. The aim of this study was to compare total in-hospital costs following primary TJA in octogenarians and nonagenarians, and to determine the primary drivers of cost. This was a retrospective analysis from a single institution in the U.S. We used time-drive activity-based costing (TDABC) to capture granular total hospital costs for each patient. 889 TJA’s were included in the study, with 841 octogenarians and 48 nonagenarians. Nonagenarians were more likely to undergo total hip arthroplasty (THA) (70.8% vs. 42.4%; p < 0.0001), had higher ASA classification (2.6 vs. 2.4; p = 0.049), and were more often privately insured (35.4% vs. 27.8%; p = 0.0001) as compared to octogenarians. Nonagenarians were more often discharged to skilled nursing facilities (56.2% vs. 37.5%; p = 0.0011), experienced longer operating room (OR) time (142 vs. 133; p = 0.0201) and length of stay (3.7 vs. 3.1; p = 0.0003), and had higher implant and total in-hospital costs (p < 0.0001 and 0.0001). Multivariate linear regression showed implant cost (0.700; p < 0.0001), length of stay (0.546; p < 0.0001), and OR time (0.288; p < 0.0001) to be the strongest associations with overall costs. Primary TJA for nonagenarians was more expensive than octogenarians. Targeting implant costs, length of stay, and OR time can reduce costs for nonagenarians in order to provide cost-effective value-based care.

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