Citations

Background— Various dyssynchrony indexes derived from tissue velocity and strain imaging have been proposed to predict the effectiveness of cardiac resynchronization therapy (CRT). We sought to compare the effect of CRT on dyssynchrony indexes derived by tissue velocity and strain and to determine which baseline intraventricular dyssynchrony parameters correlate with improvement in left ventricular volume after CRT. Methods and Results— Echocardiography with tissue Doppler imaging was performed in 45 patients with systolic heart failure at baseline, 1 day after CRT, and a median of 6 months after CRT. We calculated septal–lateral delay and anteroseptal–posterior delay and standard deviation of time to peak systolic velocity in the 12 basal and mid-left ventricular segments (Tv-SD). The standard deviation for time to peak strain in the 12 basal and mid-left ventricular segments (Tε-SD) was calculated as a strain-derived dyssynchrony index. None of the tissue velocity–derived dyssynchrony indexes improved after CRT (septal–lateral delay, P =0.39; anteroseptal–posterior delay, P =0.46; Tv-SD, P =0.30), whereas Tε-SD decreased significantly after CRT ( P <0.001). Improvement in Tε-SD 1 day after CRT correlated with the reduction in end-systolic volume at follow-up ( r =0.66; P <0.001). Baseline Tε-SD demonstrated significant correlation with the reduction of end-systolic volume at follow-up ( r =0.57; P <0.001); however, baseline tissue velocity–derived dyssynchrony indexes failed to predict the effect of CRT. Conclusions— The strain-derived dyssynchrony index is a better measurement than the tissue velocity dyssynchrony index for monitoring changes in mechanical dyssynchrony after CRT and for predicting reduction in left ventricular volume after CRT.

In prion-infected mice, both the Notch-1 intracellular domain transcription factor (NICD) and the disease-causing prion protein (PrP Sc ) increase in the brain preceding dendritic atrophy and loss. Because the drug LY411575 inhibits the γ-secretase-catalyzed cleavage of Notch-1 that produces NICD, we asked whether this γ-secretase inhibitor (GSI) might prevent dendritic degeneration in mice with scrapie. At 50 d postinoculation with Rocky Mountain Laboratory (RML) prions, mice were given GSI orally for 43–60 d. Because we did not expect GSI to produce a reduction of PrP Sc levels in brain, we added quinacrine (Qa) to the treatment regimen. Qa inhibits PrP Sc formation in cultured cells. The combination of GSI and Qa reduced PrP Sc by ≈95% in the neocortex and hippocampus but only ≈50% in the thalamus at the site of prion inoculation. The GSI plus Qa combination prevented dendritic atrophy and loss, but GSI alone did not. Even though GSI reduced NICD levels to a greater extent than GSI plus Qa, it was unable to prevent dendritic degeneration. Whether a balance between NICD and dendrite growth-stimulating factors was achieved with GSI plus Qa but not GSI alone remains to be determined. Although the combination of GSI and Qa diminished PrP Sc in the brains of RML-infected mice, GSI toxicity prevented us from being able to assess the effect the GSI plus Qa combination on incubation times. Whether less toxic GSIs can be used in place of LY411575 to prolong survival remains to be determined.

To shorten the transplantation waiting time in the United States, federal regulations have been introduced requiring hospitals to develop policies for organ donation after cardiac (or circulatory) death (DCD). The practice of DCD is invoked based on the validity of the University of Pittsburgh Medical Center (UPMC) protocol and relies on the accuracy of the University of Wisconsin (UW) evaluation tool to appropriately identify organ donors. There is little evidence to support the position that the criteria for organ procurement adopted from the UPMC protocol complies with the dead donor rule. A high false-positive rate of the UW evaluation tool can expose many dying patients to unnecessary perimortem interventions because of donation failure. The medications and/or interventions for the sole purpose of maintaining organ viability can have unintended negative consequences on the timing and quality of end-of-life care offered to organ donors. It is essential to address and manage the evolving conflict between optimal end-of-life care and the necessary sacrifices for the procurement of transplantable organs from the terminally ill. The recipients of marginal organs recovered from DCD can also suffer higher mortality and morbidity than recipients of other types of donated organs. Finally, transparent disclosure to the public of the risks involved to both organ donors and recipients may contribute to open societal debate on the ethical acceptability of DCD.