An "exacerbate-reverse" strategy in yeast identifies histone deacetylase inhibition as a correction for cholesterol and sphingolipid transport defects in human Niemann-Pick type C disease.

Niemann-Pick type C (NP-C) disease is a fatal lysosomal lipid storage disorder for which no effective therapy exists. A genome-wide, conditional synthetic lethality screen was performed using the yeast model of NP-C disease during anaerobiosis, an auxotrophic condition that requires yeast to utilize exogenous sterol. We identified 12 pathways and 13 genes as modifiers of the absence of the yeast NPC1 ortholog (NCR1) and quantified the impact of loss of these genes on sterol metabolism in ncr1Δ strains grown under viable aerobic conditions. Deletion of components of the yeast NuA4 histone acetyltransferase complex in ncr1Δ strains conferred anaerobic inviability and accumulation of multiple sterol intermediates. Thus, we hypothesize an imbalance in histone acetylation in human NP-C disease. Accordingly, we show that the majority of the 11 histone deacetylase (HDAC) genes are transcriptionally up-regulated in three genetically distinct fibroblast lines derived from patients with NP-C disease. A clinically approved HDAC inhibitor (suberoylanilide hydroxamic acid) reverses the dysregulation of the majority of the HDAC genes. Consequently, three key cellular diagnostic criteria of NP-C disease are dramatically ameliorated as follows: lysosomal accumulation of both cholesterol and sphingolipids and defective esterification of LDL-derived cholesterol. These data suggest HDAC inhibition as a candidate therapy for NP-C disease. We conclude that pathways that exacerbate lethality in a model organism can be reversed in human cells as a novel therapeutic strategy. This "exacerbate-reverse" approach can potentially be utilized in any model organism for any disease.

Pressure wire compared to microcatheter sensing for coronary fractional flow reserve: the PERFORM study.

AIMS: Among technologies used to assess FFR, a monorail, sensor-tipped micro pressure catheter (PC) may be advantageous for delivery and re-assessment. We sought to determine whether the larger cross-sectional area of the PC influences FFR measurements compared to the pressure wire. METHODS AND RESULTS: PERFORM was a single-centre, prospective study designed to determine the precision and accuracy of the PC compared with the pressure wire (PW) for measurement of FFR. Eligible patients had native coronary artery target lesions with visually estimated diameter stenosis of 40-90%. The independently adjudicated primary endpoint was the difference in hyperaemic PW-determined minimal FFR with and without the PC distal to the stenosis. Seventy-four patients (95 lesions) were prospectively analysed between December 2015 and December 2016. Median hyperaemic FFR was 0.84 (IQR 0.78, 0.89) with the PW and 0.79 (IQR 0.73, 0.85) with the PC distal to the stenosis (p<0.001). Such differences led to clinical discordance, whereby the PC decreased the hyperaemic PW-determined FFR from >0.80 to ≤0.80 in 17 of 95 measurements (19%). Median resting Pd/Pa was lower following introduction of the PC compared with the PW alone (0.93 [IQR 0.90, 0.97] versus 0.90 [IQR 0.86, 0.95], p<0.001). Median pressure drift was not different between the PW and the PC (0.01 [IQR -0.01, 0.05] versus 0.01 [IQR 0.00, 0.02], p=0.38). CONCLUSIONS: Introduction of the PC reduced both hyperaemic FFR and resting Pd/Pa compared with the PW alone, leading to re-classifying physiological significance to below the clinical threshold in one out of five assessments.

Novel radiation dose reduction fluoroscopic technology facilitates chronic total occlusion percutaneous coronary interventions.

AIMS: Radiation exposure and prolonged procedure time continue to limit the complexity of CTO-PCI procedures attempted. This study aimed to assess the impact of radiation dose-limiting equipment on radiation dosage and fluoroscopic time in chronic total occlusion (CTO) percutaneous coronary interventions (PCI). METHODS AND RESULTS: Retrospective clinical and dosimetric data from diagnostic catheterisations (DXC) and CTO-PCI procedures performed on one of three variants of interventional fluoroscopic equipment were collected. Fluoroscopic time, air kerma, kerma area product and contrast utilisation were stratified by procedure type and compared among equipment types. To standardise comparisons among equipment configurations, an efficiency index (EI) was calculated. In total, 2,947 DXC and 276 CTO-PCI procedures were studied. For DXC, radiation dose (AK) decreased by 45% (despite modest increases in fluoroscopic time [FT]) between the reference (REF) and moderately dose-optimised (ECO) machines. A further 20% decrease in AK was observed on the highly dose-optimised machine (CLA). For CTO-PCI, AK declined by almost half (48%), despite a 76% increase in FT and higher procedural success rates (69.8% versus 83.0%) between REF and CLA. • Conclusions: Novel dose-optimised fluoroscopic equipment allows longer FT with a decrease in radiation dose to both patient and operator. This should allow operators to undertake increasingly longer and more complex procedures and reduce operators' lifetime irradiation.