Reproducibility of volumetric intravascular ultrasound radiofrequency-based analysis of coronary plaque composition in vivo

Intravascular ultrasound radiofrequency (RF-IVUS) data permit the analysis of coronary plaque composition in vivo and is used as an endpoint of ongoing pharmacological intervention trials. We assessed the reproducibility of volumetric RF-IVUS analyses in mild-to-moderately diseased atherosclerotic human coronary arteries in vivo. A total of 9,212 IVUS analyses on cross-sectional IVUS frames was performed to evaluate the reproducibility of volumetric RF-IVUS measurements in 33 coronary segments with a length of 27 ± 7 mm. For vessel, lumen, and plaque + media volume the relative measurement differences (P = NS for all) were (A = intraobserver comparison, same pullback) −0.40 ± 1.0%; −0.48 ± 1.4%; −0.35 ± 1.6%, (B = intraobserver comparison, repeated pullback) −0.42 ± 1.2%; −0.52 ± 1.8%; −0.43 ± 4.5% (C = interobserver comparison, same pullback) 0.71 ± 1.8%; 0.71 ± 2.2%, and 0.89 ± 5.0%, respectively. For fibrous, fibro-lipidic, calcium, and necrotic-core volumes the relative measurement differences (P = NS for all) were (A) 0.45 ± 2.1%; −1.12 ± 4.9%; −0.84 ± 2.1%; −0.22 ± 1.8%, (B) 1.40 ± 4.1%; 1.26 ± 6.7%; 2.66 ± 7.4%; 0.85 ± 4.4%, and (C) −1.60 ± 4.9%; 3.85 ± 8.2%; 1.66 ± 7.5%, and −1.58 ± 4.7%, respectively. Of note, necrotic-core volume showed on average the lowest measurement variability. Thus, in mild-to-moderate atherosclerotic coronary artery disease the reproducibility of volumetric compositional RF-IVUS measurements from the same pullback is relatively high, but lower than the reproducibility of geometrical IVUS measurements. Measurements from repeated pullbacks and by different observers show acceptable reproducibilities; the volumetric measurement of the necrotic-core shows on average the highest reproducibility of the compositional RF-IVUS measurement

Impact of analyzing less image frames per segment for radiofrequency-based volumetric intravascular ultrasound measurements in mild-to-moderate coronary atherosclerosis

Volumetric radiofrequency-based intravascular ultrasound (RF–IVUS) data of coronary segments are increasingly used as endpoints in serial trials of novel anti-atherosclerotic therapies. In a relatively time-consuming process, vessel and lumen contours are defined; these contours are first automatically detected, then visually checked, and finally (in most cases) manually edited to generate reliable volumetric data of vessel geometry and plaque composition. Reduction in number of cross-sectional images for volumetric analysis could save analysis time but may also increase measurement variability of volumetric data. To assess whether a 50% reduction in number of frames per segment (every second frame) alters the reproducibility of volumetric measurements, we performed repeated RF–IVUS analyses of 15 coronary segments with mild-to-moderate atherosclerosis (20.2 ± 0.2 mm-long segments with 46 ± 13% plaque burden). Volumes were calculated based on a total of 731 image frames. Reducing the number of cross-sectional image frames for volumetric measurements saved analysis time (38 ± 9 vs. 68 ± 17 min/segment; P < 0.0001) and resulted for only a few parameters in (borderline) significant but mild differences versus measurements based on all frames (fibrous volume, P < 0.05; necrotic-core volume, P = 0.07). Compared to the intra-observer variability, there was a mild increase in measurement variability for most geometrical and compositional volumetric RF–IVUS parameters. In RF–IVUS studies of mild-to-moderate coronary disease, analyzing less image frames saved analysis time, left most volumetric parameters greatly unaffected, and resulted in a no more than mild increase in measurement variability of volumetric data

AhR transcriptional activity in serum of Inuits across Greenlandic districts

<p>Abstract</p> <p>Background</p> <p>Human exposure to lipophilic persistent organic pollutants (POPs) including polychlorinated dibenzo-<it>p</it>-dioxins/furans (PCDDs/PCDFs), polychlorinated biphenyls (PCBs) and organochlorine pesticide is ubiquitous. The individual is exposed to a complex mixture of POPs being life-long beginning during critical developmental windows. Exposure to POPs elicits a number of species- and tissue-specific toxic responses, many of which involve the aryl hydrocarbon receptor (AhR). The aim of this study was to compare the actual level of integrated AhR transcriptional activity in the lipophilic serum fraction containing the actual POP mixture among Inuits from different districts in Greenland, and to evaluate whether the AhR transactivity is correlated to the bio-accumulated POPs and/or lifestyle factors.</p> <p>Methods</p> <p>The study included 357 serum samples from the Greenlandic districts: Nuuk and Sisimiut (South West Coast), Qaanaaq (North Coast) and Tasiilaq (East Coast). The bio-accumulated serum POPs were extracted by ethanol: hexane and clean-up on Florisil columns. Effects of the serum extract on the AhR transactivity was determined using the Hepa 1.12cR mouse hepatoma cell line carrying an AhR-luciferase reporter gene, and the data was evaluated for possible association to the serum levels of 14 PCB congeners, 10 organochlorine pesticide residues and/or lifestyle factors.</p> <p>Results</p> <p>In total 85% of the Inuit samples elicited agonistic AhR transactivity in a district dependent pattern. The median level of the AhR-TCDD equivalent (AhR-TEQ) of the separate genders was similar in the different districts. For the combined data the order of the median AhR-TEQ was Tasiilaq > Nuuk ≥ Sisimiut > Qaanaaq possibly being related to the different composition of POPs. In overall, the AhR transactivity was inversely correlated to the levels of sum POPs, age and/or intake of marine food.</p> <p>Conclusion</p> <p>i) We observed that the proportion of dioxin like (DL) compounds in the POP mixture was the dominating factor affecting the level of serum AhR transcriptional activity even at very high level of non DL-PCBs; ii) The inverse association between the integrated serum AhR transactivity and sum of POPs might be explained by the higher level of compounds antagonizing the AhR function probably due to selective POP bioaccumulation in the food chain.</p

Facing the Challenge of Data Transfer from Animal Models to Humans: the Case of Persistent Organohalogens

A well-documented fact for a group of persistent, bioaccumulating organohalogens contaminants, namely polychlorinated biphenyls (PCBs), is that appropriate regulation was delayed, on average, up to 50 years. Some of the delay may be attributed to the fact that the science of toxicology was in its infancy when PCBs were introduced in 1920's. Nevertheless, even following the development of modern toxicology this story repeats itself 45 years later with polybrominated diphenyl ethers (PBDEs) another compound of concern for public health. The question is why? One possible explanation may be the low coherence between experimental studies of toxic effects in animal models and human studies. To explore this further, we reviewed a total of 807 PubMed abstracts and full texts reporting studies of toxic effects of PCB and PBDE in animal models. Our analysis documents that human epidemiological studies of PBDE stand to gain little from animal studies due to the following: 1) the significant delay between the commercialisation of a substance and studies with animal models; 2) experimental exposure levels in animals are several orders of magnitude higher than exposures in the general human population; 3) the limited set of evidence-based endocrine endpoints; 4) the traditional testing sequence (adult animals – neonates – foetuses) postpones investigation of the critical developmental stages; 5) limited number of animal species with human-like toxicokinetics, physiology of development and pregnancy; 6) lack of suitable experimental outcomes for the purpose of epidemiological studies. Our comparison of published PCB and PBDE studies underscore an important shortcoming: history has, unfortunately, repeated itself. Broadening the crosstalk between the various branches of toxicology should therefore accelerate accumulation of data to enable timely and appropriate regulatory action

Optimization of coronary optical coherence tomography imaging using the attenuation-compensated technique: a validation study.

PURPOSE To optimize conventional coronary optical coherence tomography (OCT) images using the attenuation-compensated technique to improve identification of plaques and the external elastic lamina (EEL) contour. METHOD The attenuation-compensated technique was optimized via manipulating contrast exponent C, and compression exponent N, to achieve an optimal contrast and signal-to-noise ratio (SNR). This was applied to 60 human coronary lesions (38 native and 22 stented) ex vivo conventional coronary OCT images acquired from heart autopsies of 10 patients and matching histology was available as reference. Three independent reviewers assessed the conventional and attenuation-compensated OCT images blindly for plaque characteristics and EEL detection. Conventional OCT and compensated OCT assessment were compared against histology. RESULTS Using an optimized algorithm, the attenuation-compensated OCT images had a 2-fold improvement in contrast between different tissues in both stented and non-stented epicardial coronaries (P <0.05). Overall sensitivity and specificity for plaque classification increased from 84 to 89% and from 92 to 94%, respectively, with substantial agreement among the three reviewers (Fleiss' Kappa k, 0.72 and 0.71, respectively). Furthermore, operators were 2.5 times more likely to identify the EEL contour in the attenuation-compensated OCT images (k = 0.72) than in the conventional OCT images (k = 0.36). CONCLUSION The attenuation-compensated technique can be retrospectively applied to conventional OCT images and improves the detection of plaque characteristics and the EEL contour. This approach could complement conventional OCT imaging in the evaluation of plaque characteristics and quantify plaque burden in the clinical setting