The goal of this work was to investigate the role of t-tubule (TT) remodeling in abnormal Ca2+ cycling in ventricular myocytes of failing dog hearts. HF was induced using rapid right ventricular pacing. Extensive changes in echocardiographic parameters-including left and right ventricular dilation and systolic dysfunction, diastolic dysfunction, elevated left ventricular filling pressures, and abnormal cardiac mechanics-indicated that severe HF developed. TT loss was extensive when measured as the density of total cell volume, derived from 3-dimensional confocal image analysis, and significantly increased the distances in the cell interior to closest cell membrane. Changes in Ca2+ transients indicated increases in heterogeneity of Ca2+ release along the cell length. When critical properties of Ca2+ release variability were plotted as a function of TT organization, there was a complex, non-linear relationship between impaired calcium release and decreasing TT organization below a certain threshold of TT organization leading to increased sensitivity in Ca2+ release below a TT density threshold of 1.5%. The loss of TTs was also associated with a greater incidence of triggered Ca2+ waves during rapid pacing. Finally, virtually all of these observations were replicated by acute detubulation by formamide treatment, indicating an important role of TT remodeling in impaired Ca2+ cycling. We conclude that TT remodeling itself is a major contributor to abnormal Ca2+ cycling in HF, reducing myocardial performance. The loss of TTs is also responsible for a greater incidence of triggered Ca2+ waves that may play a role in ventricular arrhythmias arising in HF.
e16135 Background: Cholangiocarcinomas, based on their anatomic location are prone to a myriad of local and regional complications. This study aims to explore if the outlook of patients differs based on what type of loco-regional complications they are admitted with. Methods: The National Inpatient Sample (NIS) was queried to identify adult patients with underlying cholangiocarcinoma between 2016-2018. Relative frequency and diagnosis of locoregional complications as principal diagnosis in these patients were identified and top 5 loco-regional complications were studied and compared for all-cause mortality, mean length of stay (LOS), mean total hospital charges (THC). Statistics were performed using t-test, univariate and multinomial logistic regression. Results: There were 26,410 hospitalizations in patients with cholangiocarcinoma. Upper gastrointestinal bleed (UGIB) represented the most frequent loco-regional complication (9.2%), followed by acute liver failure and cancer pain admission (6.7% each). Mortality rate of all admissions was 5.84%; all complications except failure to thrive were associated with significantly increased odds of mortality, the highest in acute liver failure (AOR- 3.72). Except admissions for cancer associated pain, all complications were associated with statistically significant increased LOS, highest in UGIB (Adjusted mean difference of 5 days). Similarly, admission with UGIB was associated with the highest THC while cancer pain admission had a much lower cost. Conclusions: Among the loco-regional complications of cholangiocarcinoma that were studied, UGIB was the most frequent, associated with longest hospital LOS (5 extra days) and highest THC. Admission with acute hepatic failure was associated with the highest odds of mortality while cancer associated pain and failure to thrive were associated with the shortest length of stay and lowest mean charges. Further efforts are needed to improve outpatient pain management to prevent these admissions and identify ways to improve outcomes in patients with UGIB. [Table: see text]
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