Quantitative flow ratio to predict long-term coronary artery bypass graft patency in patients with left main coronary artery disease.

PURPOSE: Fractional flow reserve (FFR) has been demonstrated in some studies to predict long-term coronary artery bypass graft (CABG) patency. Quantitative flow ratio (QFR) is an emerging technology which may predict FFR. In this study, we hypothesised that QFR would predict long-term CABG patency and that QFR would offer superior diagnostic performance to quantitative coronary angiography (QCA) and intravascular ultrasound (IVUS). METHODS: A prospective study was performed on patients with left main coronary artery disease who were undergoing CABG. QFR, QCA and IVUS assessment was performed. Follow-up computed tomography coronary angiography and invasive coronary angiography was undertaken to assess graft patency. RESULTS: A total of 22 patients, comprising of 65 vessels were included in the analysis. At a median follow-up of 3.6 years post CABG (interquartile range, 2.3 to 4.8 years), 12 grafts (18.4%) were occluded. QFR was not statistically significantly higher in occluded grafts (0.81 ± 0.19 vs. 0.69 ± 0.21; P = 0.08). QFR demonstrated a discriminatory power to predict graft occlusion (area under the receiver operating characteristic curve, 0.70; 95% confidence interval [CI], 0.52 to 0.88; P = 0.03). At long-term follow-up, the risk of graft occlusion was higher in vessels with a QFR > 0.80 (58.6% vs. 17.0%; hazard ratio, 3.89; 95% CI, 1.05 to 14.42; P = 0.03 by log-rank test). QCA (minimum lumen diameter, lesion length, diameter stenosis) and IVUS (minimum lumen area, minimum lumen diameter, diameter stenosis) parameters were not predictive of long-term graft patency. CONCLUSIONS: QFR may predict long-term graft patency in patients undergoing CABG.

Diagnostic performance of quantitative flow ratio, non-hyperaemic pressure indices and fractional flow reserve for the assessment of coronary lesions in severe aortic stenosis.

Background: Quantitative flow ratio (QFR) may be used to assess the functional significance of coronary lesions. Only limited validation exists for this technology in the setting of severe aortic stenosis. Methods: A prospective study was performed on patients who were being considered for transcatheter aortic valve implantation. QFR analysis was performed (Medis Medical Imaging System, Leiden, The Netherlands) and compared to invasive measurements of haemodynamic assessment [fractional flow reserve (FFR), instantaneous wave-free ratio (iFR), diastolic pressure ratio during the wave-free period (dPR) and distal arterial pressure/arterial pressure (Pd/Pa)]. Results: A total of 35 patients were included in the study. Mean age was 75.5±6.5 and mean aortic valve gradient was 44.3±11.8 mmHg. There were 57 vessels analysed. The mean FFR was 0.83±0.10 and 22 vessels (39%) had a functionally significant FFR ≤0.80. QFR demonstrated a discriminatory power to predict functionally significant FFR [area under the receiver operating characteristic curve (AUC), 0.92; 95% confidence interval (CI): 0.84 to 1.00], representing a sensitivity of 73%, specificity of 91%, positive predictive value of 84%, negative predictive value of 84% and an accuracy of 84%. QFR also demonstrated a discriminatory power to predict functionally significant iFR ≤0.89 (AUC =0.92; 95% CI: 0.85 to 0.99), dPR ≤0.89 (AUC =0.90; 95% CI: 0.83 to 0.98) and Pd/Pa ≤0.92 (AUC =0.89; 95% CI: 0.80 to 0.97). Conclusions: QFR demonstrates acceptable diagnostic performance in patients with severe aortic stenosis when both FFR and non-hyperaemic pressure indices are used as reference standards.

Pharmacological inhibition of nSMase2 reduces brain exosome release and α-synuclein pathology in a Parkinson's disease model.

AIM: We have previously reported that cambinol (DDL-112), a known inhibitor of neutral sphingomyelinase-2 (nSMase2), suppressed extracellular vesicle (EV)/exosome production in vitro in a cell model and reduced tau seed propagation. The enzyme nSMase2 is involved in the production of exosomes carrying proteopathic seeds and could contribute to cell-to-cell transmission of pathological protein aggregates implicated in neurodegenerative diseases such as Parkinson's disease (PD). Here, we performed in vivo studies to determine if DDL-112 can reduce brain EV/exosome production and proteopathic alpha synuclein (αSyn) spread in a PD mouse model. METHODS: The acute effects of single-dose treatment with DDL-112 on interleukin-1ß-induced extracellular vesicle (EV) release in brain tissue of Thy1-αSyn PD model mice and chronic effects of 5 week DDL-112 treatment on behavioral/motor function and proteinase K-resistant αSyn aggregates in the PD model were determined. RESULTS/DISCUSSION: In the acute study, pre-treatment with DDL-112 reduced EV/exosome biogenesis and in the chronic study, treatment with DDL-112 was associated with a reduction in αSyn aggregates in the substantia nigra and improvement in motor function. Inhibition of nSMase2 thus offers a new approach to therapeutic development for neurodegenerative diseases with the potential to reduce the spread of disease-specific proteopathic proteins.

Comparison of diagnostic performance between quantitative flow ratio, non-hyperemic pressure indices and fractional flow reserve.

BACKGROUND: Quantitative flow ratio (QFR) is an estimate of fractional flow reserve (FFR) and is derived from 3-dimensional quantitative coronary angiography. The DILEMMA score is an angiographic technique developed to predict FFR. Unlike other diastolic indices such as instantaneous wave-free ratio (iFR), diastolic pressure ratio (dPR) and dPR25-75, neither QFR nor DILEMMA score require pressure wires. This study sought to compare the diagnostic performance of QFR, diastolic indices and DILEMMA score to predict FFR. METHODS: Between January 2010 and December 2013, patients who underwent invasive coronary angiography and FFR assessments were retrospectively studied. iFR and dPR were derived from FFR pressure tracings. QFR was computed using commercial software. RESULTS: Eighty-five lesions (25% FFR significant) were included in this study. Median FFR was 0.88 (0.81-0.92). QFR (rs=0.801), iFR (rs=0.710), dPR (rs=0.716), dPR25-75 (rs=0.715) and DILEMMA score (rs=-0.623) significantly correlated with FFR (P<0.001). QFR ≤0.8 had a specificity, sensitivity, positive predictive value (PPV) and negative predictive value (NPV) of 95%, 86%, 86% and 95% respectively of predicting significant FFR (P<0.001). Receiver-operating characteristic (ROC) analysis revealed the AUC to predict significant FFR for QFR (0.947), iFR (0.880), dPR (0.883), dPR25-75 (0.880) and DILEMMA score (0.916) were not significantly different. However, QFR was a better predictor of FFR than iFR (0.947 vs. 0.770, P<0.01). CONCLUSIONS: QFR had excellent correlation and accuracy as measured against FFR. When compared to other diastolic indices and DILEMMA score, QFR performed at least as well as the other indices. QFR predicts FFR better than it predicts iFR. QFR is a convenient tool to assess significance of coronary stenosis and a reliable alternative to pressure-wire based indices. Prospective studies are required to investigate the performance and cost-effectiveness of QFR when independently used to guide clinical decision making.

A small molecule ApoE4-targeted therapeutic candidate that normalizes sirtuin 1 levels and improves cognition in an Alzheimer's disease mouse model.

We describe here the results from the testing of a small molecule first-in-class apolipoprotein E4 (ApoE4)-targeted sirtuin1 (SirT1) enhancer, A03, that increases the levels of the neuroprotective enzyme SirT1 while not affecting levels of neurotoxic sirtuin 2 (SirT2) in vitro in ApoE4-transfected cells. A03 was identified by high-throughput screening (HTS) and found to be orally bioavailable and brain penetrant. In vivo, A03 treatment increased SirT1 levels in the hippocampus of 5XFAD-ApoE4 (E4FAD) Alzheimer's disease (AD) model mice and elicited cognitive improvement while inducing no observed toxicity. We were able to resolve the enantiomers of A03 and show using in vitro models that the L-enantiomer was more potent than the corresponding D-enantiomer in increasing SirT1 levels. ApoE4 expression has been shown to decrease the level of the NAD-dependent deacetylase and major longevity determinant SirT1 in brain tissue and serum of AD patients as compared to normal controls. A deficiency in SirT1 level has been recently implicated in increased tau acetylation, a dominant post-translational modification and key pathological event in AD and tauopathies. Therefore, as a novel approach to therapeutic development for AD, we targeted identification of compounds that enhance and normalize brain SirT1 levels.

Deuterium-reinforced linoleic acid lowers lipid peroxidation and mitigates cognitive impairment in the Q140 knock in mouse model of Huntington's disease.

Huntington's disease (HD) is an autosomal dominant neurodegenerative disease which has no effective treatment and is characterized by psychiatric disorders, motor alterations, and dementia, with the cognitive deficits representing a devastating aspect of the disorder. Oxidative stress and elevated levels of lipid peroxidation (LPO) products are found in mouse models and patients with HD, suggesting that strategies to reduce LPO may be beneficial in HD. In contrast with traditional antioxidants, substituting hydrogen with deuterium at bis-allylic sites in polyunsaturated fatty acids (D-PUFA) decreases the rate-limiting initiation step of PUFA autoxidation, a strategy that has shown benefits in other neurodegenerative diseases. Here, we investigated the effect of D-PUFA treatment in a knock-in mouse model of HD (Q140) which presents motor deficits and neuropathology from a few months of age, and progressive cognitive decline. Q140 knock-in mice were fed a diet containing either D- or H-PUFAs for 5 months starting at 1 month of age. D-PUFA treatment significantly decreased F2 -isoprostanes in the striatum by approximately 80% as compared to H-PUFA treatment and improved performance in novel object recognition tests, without significantly changing motor deficits or huntingtin aggregation. Therefore, D-PUFA administration represents a promising new strategy to broadly reduce rates of LPO, and may be useful in improving a subset of the core deficits in HD.

Evaluation of an Allosteric BACE Inhibitor Peptide to Identify Mimetics that Can Interact with the Loop F Region of the Enzyme and Prevent APP Cleavage.

The aspartyl protease BACE1 (BACE) has emerged as an appealing target for reduction of amyloid-ß in Alzheimer's disease. The clinical fate of active-site BACE inhibitors may depend on potential side effects related to enzyme and substrate selectivity. One strategy to reduce this risk is through development of allosteric inhibitors that interact with and modulate the Loop F region unique to BACE1. Previously, a BACE-inhibiting antibody (Ab) was shown by co-crystallization to bind and induce conformational changes of Loop F, resulting in backbone perturbations at the distal S6 and S7 subsites, preventing proper binding of a long APP-like substrate to BACE and inhibiting its cleavage. In an effort to discover small Loop F-interacting molecules that mimic the Ab inhibition, we evaluated a peptide series with a YPYF(I/L)P(L/Y) motif that was reported to bind a BACE exosite. Our studies show that the most potent inhibitor from this series, peptide 65007, has a similar substrate cleavage profile to the Ab and reduces sAPPß levels in cell models and primary neurons. As our modeling indicates, it interacts with the Loop F region causing a conformational shift of the BACE protein backbone near the distal subsites. The peptide-bound enzyme adopts a conformation that closely overlays with the crystal structure (PDB: 3R1G) from Ab binding. Importantly, peptide 65007 appears to be BACE substrate and enzyme selective, showing little inhibition of NRG1, PSGL1, CHL1, or Cat D. Thus, peptide 65007 is a promising lead for discovery of Loop F-interacting small-molecule mimetics as allosteric inhibitors of BACE.

Growth hormone therapy in children after cranial/craniospinal radiation therapy: sexually dimorphic outcomes.

Radiation therapy (RT) to the craniospinal region in childhood affects final height. The use of GH treatment (GHRx) in children after cranial or craniospinal RT results in variable improvement in final height. Nineteen children (12 males and 7 females) with tumors of the head, treated with cranial or craniospinal RT and subsequently with GHRx, were assessed for final height. Two outcome measures of efficacy of GHRx were used: Y1 = final height SD score (SDS) corrected for genetic potential, using midparental sex-adjusted target height (SATH) SDS, and Y2 = change in height SDS from predicted final height SDS pre-GHRx to actual final height SDS post-GHRx. The median age at diagnosis was 5.4 yr, the median RT to the hypothalamic-pituitary axis was 40 Gy, the median spinal RT dose in 13 of 19 of the subjects treated was 36 Gy, and the median years post-RT to GHRx was 4.8 yr. Adjuvant chemotherapy was used in 12 of 19 patients. All but one (optic glioma) had a lesion anatomically distant from the suprasellar region. The effects of age at diagnosis, sex, L-T4 or GnRH agonist use, conventional vs. hyperfractionated RT, spinal RT, dose of spinal or cranial RT, chemotherapy, peak stimulated GH, dose and duration of GHRx, age at GHRx, time interval between RT and GHRx initiation, bone age, and height SDS at the start of GHRx were also assessed. Y1girls best correlated with younger age at diagnosis and im vs. sc GHRx. Y2girls best correlated with delayed bone age and younger age at diagnosis [Y1girls = -9.95 + 0.38 (age in years at diagnosis) + 3.11[GH method (1 = i.m.; 2 = s.c.)]; r2 = 0.898; P = 0.02; Y2girls = -3.54 + 1.8 (bone age - age in years) + 0.334 (age at diagnosis in years); r2= 0.956; P = 0.02]. Both Y1boys and Y2boys were strongly associated with spinal RT and younger age at diagnosis or treatment [Y1boys = -11.22 + 4.65 [spinal RT (1 = yes; 2 = no)] + 0.396 (age in years at diagnosis); r2= 0.64, P = 0.01; Y2boys = -6.32 + 0.23 (age in years at GH start) + 1.75 [spinal RT (1 = yes; 2 = no)]; r2= 0.646; P < 0.01]. This small historical cohort underscores that final stature is significantly reduced when immature bones are exposed to ionizing radiation. Intramuscular vs. sc use of GHRx is likely to be simply a surrogate marker for earlier methods of treatment. Of note, spinal RT did not significantly impact girls' final heights, whereas in boys, spinal RT strongly predicted ultimate short stature and a reduced response to GHRx. This sexually dichotomous response may be due in part to the greater percentage of spinal growth remaining for boys vs. girls throughout childhood.