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Aims: Biventricular (BiV) pacing was superior to right ventricular apical (RVA) pacing at extended follow-up in the Pacing to Avoid Cardiac Enlargement (PACE) trial. Early pacing-induced systolic dyssynchrony (DYS) might be related to mid-term result. However, it remains unknown whether early pacing-induced DYS can predict long-term reduction of left ventricular (LV) systolic function.Methods and Results: Patients with standard pacing indications and normal LV ejection fraction (LVEF) were randomized either to BiV (n = 89) or RVA (n = 88) pacing. Seventy-four patients in the RVA group and 72 in the BiV pacing group completed follow-up longer than 2 years. Serial echocardiography was performed with DYS assessed by tissue Doppler imaging, and the early pacing-induced DYS was defined as >33 ms by using standard deviation of the time to peak systolic velocity (Dyssynchrony Index) in a 12-segment model of LV at 1 month. There were 46 (32%) patients having early pacing-induced DYS that was more prevalent in the RVA pacing group than that in the BiV pacing group (50.7 vs. 12.3%, χ(2) = 25.1, P < 0.001) despite the similar DYS between the two groups at baseline (30 ± 13 vs. 26 ± 11 ms, P = 0.051). At a median follow-up of 4.8 years, patients developing early DYS had lower LVEF (53.2 ± 9.4 vs. 60.9 ± 8.0%, P < 0.001) and larger LV end-systolic volume (40.3 ± 23.7 vs. 29.3 ± 13.4 mL, P < 0.001) than those without DYS. Significant EF reduction (defined as ≥5%) occurred in 71.7% (33 in 46) of patients with DYS, but only in 30% (30 in 100) in those without DYS (χ(2) = 22.4, P < 0.001). Further analysis showed that both DYS at 1 month [odds ratio (OR): 3.113, P = 0.013] and RVA pacing (OR: 7.873, P < 0.001) independently predicted the deterioration of LV systolic function with pacing period of 4.8 years.Conclusion: Early pacing-induced DYS is a significant predictor of reduction of LV systolic function for long-term pacing, which could be prevented by BiV pacing at relatively long-period follow-up.Clinical Trial Registration: Centre for Clinical Trials number, CUHK_CCT00037 (URL: http://www.cct.cuhk.edu.hk/Registry/publictrialrecord.aspx?trialid=CUHK_CCT00037). [ABSTRACT FROM AUTHOR]

Lysosomal storage diseases (LSDs) comprise ~50 monogenic disorders marked by the buildup of cellular material in lysosomes, yet systematic global molecular phenotyping of proteins and lipids is lacking. We present a nanoflow-based multi-omic single-shot technology (nMOST) workflow that quantifies HeLa cell proteomes and lipidomes from over two dozen LSD mutants. Global cross-correlation analysis between lipids and proteins identified autophagy defects, notably the accumulation of ferritinophagy substrates and receptors, especially in NPC1 -/- and NPC2 -/- mutants, where lysosomes accumulate cholesterol. Autophagic and endocytic cargo delivery failures correlated with elevated lyso-phosphatidylcholine species and multi-lamellar structures visualized by cryo-electron tomography. Loss of mitochondrial cristae, MICOS-complex components, and OXPHOS components rich in iron-sulfur cluster proteins in NPC2 -/- cells was largely alleviated when iron was provided through the transferrin system. This study reveals how lysosomal dysfunction affects mitochondrial homeostasis and underscores nMOST as a valuable discovery tool for identifying molecular phenotypes across LSDs., Competing Interests: DECLARATION OF INTERESTS J.W.H. is a consultant and founder of Caraway Therapeutics (a wholly owned subsidiary of Merck & Co, Inc) and is a member of the scientific advisory board for Lyterian Therapeutics. B.A.S. is a co-founding scientific advisory board member of Interline Therapeutics and on the scientific advisory boards of Biotheryx and Proxygen. J.M.P. holds a position on the advisory board of Thermo Fisher Scientific. J.J.C. is a consultant for Thermo Fischer Scientific. Other authors declare no competing interests. S.P.G. is on the advisory board for Thermo Fisher Scientific, Cedilla Therapeutics, Casma Therapeutics, Cell Signaling Technology, and Frontier Medicines.

Aims: It has been previously demonstrated that use of appropriate frame rates coupled with minimal use of high-dose digital acquisition can limit radiation risk to patients undergoing diagnostic and therapeutic electrophysiology (EP). Imaging without the anti-scatter grid has been proposed as a means of achieving further radiation reduction. We evaluate application of a gridless imaging technique to deliver further reductions in radiation risk to both patients and personnel., Methods and Results: Radiation and clinical data for EP procedures performed for 16 months from March 2012 were monitored. The period was divided into three phases: Phase 1 (March 2012-June 2012) provided a performance baseline (radiation output modelling and procedural risk adjustment calibration), Phase 2 (July 2012-September 2012) confirmation of performance with the grid, and Phase 3 (September 2012-June 2013) gridless imaging period. Statistical process control (SPC) charts were used to monitor for changes in radiation use and clinical outcomes (procedural success). Imaging without the grid halved the levels of radiation delivered in undertaking EP procedures. Although there was a perceptible impact on image quality with the grid removed. Review of the SPC chart monitoring procedural outcomes did not identify any discernable adverse impact on success rates. Selected use of the gridless technique is recommended with re-introduction of the grid in larger patients or during aspects of the procedure where image quality is important (e.g. transeptal punctures)., Conclusion: Use of a gridless imaging technique can contribute to a significant reduction in radiation risk to both patients and operators during cardiac EP procedures., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.)