Publications

Abstract Background Conventional time-to-first event analyses for composite endpoints consider only the first event, whereas win ratio analyses account for event severity and recurrence. Methods We performed a win ratio analysis of the 1-year composite endpoint in the LANDMARK trial, a multicentre, non-inferiority study that randomized patients with severe native aortic valve stenosis to receive either the Myval transcatheter heart valve (THV) series (n = 384) or contemporary THVs (n = 384), consisting of the Sapien and Evolut series (n = 192 each). The 1-year composite endpoint included the following components, ranked in hierarchical order: all-cause death, disabling stroke, non-disabling stroke, and procedure- or valve-related hospitalization. For death and stroke events, wins or losses were determined according to the time-to-first-event principle. For procedure- or valve-related hospitalizations, the total number of events was compared. Win ratio analysis was also conducted for an extended composite endpoint that also included quality-of-life outcomes. Results Among 147 456 (384 × 384) unmatched patient pairs, the win ratio for the primary composite endpoint was 1.02 (95% CI: 0.68–1.51; P = .94), with 17 870 (12.1%) wins for the Myval group and 17 599 (11.9%) for the contemporary group. For the extended composite endpoint, the win ratio was 1.13 (95% CI: 0.82–1.55; P = .45), with 27 007 (18.3%) wins for the Myval group and 23 920 (16.2%) for the contemporary group. Comparisons between the Myval and Sapien groups, and between the Myval and Evolut groups, were also not statistically significant. Conclusions Win ratio analysis did not demonstrate a significant difference between Myval and contemporary THVs, consistent with the primary time-to-first event analysis of the LANDMARK trial.

Inhibitory nonadrenergic noncholinergic (i-NANC) nerves are the only neural bronchodilator pathway in human airways. Possible candidates for the neurotransmitter include vasoactive intestinal peptide (VIP) and nitric oxide (NO) and purines such as ATP. We have investigated the potential role of these neurotransmitters. Phosphoramidon (10(-5) M) significantly potentiated relaxations to low doses of VIP with no effect on i-NANC responses. Relaxations induced by VIp were abolished with alpha-chymotrypsin (2 U/ml), but i-NANC responses were unaffected. Reactive blue 2 had no effect on i-NANC neural responses, indicating that endogenous ATP was not involved. The NO synthase inhibitor L-NG-nitroarginine methyl ester (L-NAME, 10(-4) M) produced a concentration-dependent inhibition of the i-NANC response, producing almost complete inhibition at every frequency studied (0.5-40 Hz), whereas L-NG-monomethyl arginine was effective only at low stimulation frequencies. The inhibitory effect of L-NAME was partially reversed by L- but not D-arginine, and D-NAME was without effect. These results suggest that in human tracheal segments the neural bronchodilator response is mediated by NO, and there is no functional evidence for implicating VIP in this response.

No abstract is provided for this article.

Ozone is an oxidizing environmental pollutant that contributes significantly to respiratory health. Exposure to increased levels of ozone has been associated with worsening of symptoms of patients with asthma and COPD (chronic obstructive pulmonary disease). In the present study, we investigated the acute and chronic effects of ozone exposure-induced oxidative stress-related inflammation mechanics in mouse lung. In particular, we investigated the oxidative stress-induced effects on HDAC2 (histone deacetylase 2) modification and activation of the Nrf2 (nuclear factor erythroid-related factor 2) and HIF-1α (hypoxia-inducible factor-1α) signalling pathways. Male C57BL/6 mice were exposed to ozone (3 p.p.m.) for 3 h a day, twice a week for a period of 1, 3 or 6 weeks. Control mice were exposed to normal air. After the last exposure, mice were killed for BAL (bronchoalveolar lavage) fluid and lung tissue collection. BAL total cell counts were elevated at all of the time points studied. This was associated with increased levels of chemokines and cytokines in all ozone-exposed groups, indicating the presence of a persistent inflammatory environment in the lung. Increased inflammation and Lm (mean linear intercept) scores were observed in chronic exposed mice, indicating emphysematous changes were present in lungs of chronic exposed mice. The antioxidative stress response was active (indicated by increased Nrf2 activity and protein) after 1 week of ozone exposure, but this ability was lost after 3 and 6 weeks of ozone exposure. The transcription factor HIF-1α was elevated in 3- and 6-week ozone-exposed mice and this was associated with increased gene expression levels of several HIF-1α target genes including Hdac2 (histone deacetylase 2), Vegf (vascular endothelial growth factor), Keap1 (kelch-like ECH-associated protein 1) and Mif (macrophage migration inhibitory factor). HDAC2 protein was found to be phosphorylated and carbonylated in nuclear and cytoplasm fractions, respectively, and was associated with a decrease in DNA-binding activity and protein expression of HDAC2. Decreased HDAC2 activity, most likely a direct result of protein modification, in combination with the loss of the antioxidative stress response and activation of the HIF-1α pathway, contribute to the inflammatory response and emphysema observed in ozone-exposed mice.

Aims: The feasibility of offline optical coherence tomography (OCT) guidance in bifurcation (with either two-dimensional or three-dimensional images) and its potential benefits have been demonstrated in retrospective studies; however, these have not yet been investigated prospectively. The aim of this trial is to determine the superiority of online three-dimensional optical frequency domain imaging (3D-OFDI)-guided stenting to angiography-guided percutaneous coronary intervention (PCI) in terms of incomplete stent apposition (ISA) at the bifurcation segment. Methods and results: The OPTIMUM trial is a randomised, superiority, multicentre clinical trial. The primary endpoint of this trial is the post-procedural percentage of malapposed struts assessed by OFDI in the main branch bifurcation region after final kissing balloon dilatation (FKBD). A total of 106 patients will be randomly allocated to either 3D-OFDI guidance or angiography guidance PCI. Bifurcation lesions will be treated with a provisional single-stent strategy using the Ultimaster sirolimus-eluting stent. Patients randomised to the 3D-OFDI guidance arm will undergo OFDI assessment in the main branch (MV) after rewiring into the jailed side branch following stent implantation, while in the angiography guidance arm re-crossing of a wire into the side branch will be performed using conventional fluoroscopic/angiographic guidance. In patients in the 3D-OFDI guidance arm, if the position of the wire is not located in the optimal cell, further attempts to redirect the wire to the optimal cell will be performed, with subsequent OFDI acquisitions to confirm the re-crossing position. The proximal optimisation technique and FKBD are mandatory in this trial. The study will provide a 90% power to show superiority of 3D-OFDI guidance PCI compared with angiography-guided PCI. Conclusions: The OPTIMUM trial will be the first prospective, randomised trial to evaluate the efficacy and safety of online 3D-OFDI-guided PCI in bifurcation lesions. ClinicalTrials.gov Identifier: NCT02972489

No abstract is provided for this article.

Coronary flow assessment can be useful for determining the hemodynamic severity of a stenosis and to evaluate the outcome of interventional therapy. We developed a method for measuring the transverse flow through the imaging plane of an intravascular ultrasound (IVUS) catheter. This possibility has raised great clinical interest since it permits simultaneous assessment of vessel geometry and function with the same device. Furthermore, it should give more accurate information than combination devices because lumen diameter and velocity are determined at the same location. Flow velocity is estimated based on decorrelation estimation from sequences of radiofrequency (RF) traces acquired at nearly the same position. Signal gating yields a local estimate of the velocity. Integrating the local velocity over the lumen gives the quantitative flow. This principle has been calibrated and tested through computer modeling, in vitro experiments using a flow phantom and in vivo experiments in a porcine animal model, and validated against a Doppler element containing guide wire (Flowire™) in humans. Originally the method was developed and tested for a rotating single element device. Currently the method is being developed for an array system. The great advantage of an array over the single element approach would be that the transducer has no intrinsic motion. This intrinsic motion sets a minimal threshold in the detectable velocity components. Although the principle is the same, the method needs some adaptation through the inherent different beamforming of the transducer. In this paper various aspects of the development of IVUS flow are reviewed.

This study aimed to investigate the impact of calcific (Ca) on the efficacy of coronary computed coronary angiography (CTA) in evaluating plaque burden (PB) and composition with near-infrared spectroscopy-intravascular ultrasound (NIRS-IVUS) serving as the reference standard.

We have studied the effect of the sensory neuropeptides substance P (SP), neurokinin A (NKA), neurokinin B (NKB) and calcitonin gene‐related peptide (CGRP) on microvascular permeability in guinea‐pig airways in vivo and investigated whether CGRP would potentiate the effect of SP. We used the extravasation of intravenously‐injected Evans blue dye as an index of permeability. The tachykinins SP, NKA and NKB (0.025–5.0 nmol kg −1 , i.v.) significantly ( P < 0.05) increased extravasation of dye in a dose‐related manner and with a similar pattern of distribution; they were most potent in the trachea and main bronchi, less potent in the larynx and intrapulmonary airways, and had little significant effect in the bladder. SP was significantly more potent in causing extravasation of dye than NKA or NKB with ED 50 values (nmol kg −1 ) in the range 0.04–0.1, depending on the airway level, compared with values in the range 0.3–0.7 for the neurokinins. CGRP (0.0025–2.5 nmol kg −1 , i.v.) had no significant effect on microvascular permeability and did not potentiate SP‐induced extravasation of dye. Each neuropeptide decreased mean arterial blood pressure, indicating vasodilatation, in a dose‐related manner. Co‐injection of CGRP and SP produced additive decreases in arterial pressure. We conclude that, in guinea‐pig airways, tachykinins increase microvascular permeability via tachykinin receptors of the NK‐1 sub‐type (indicated by an order of potency of SP > NKA = NKB) on endothelial cells. The response appears to be related to mechanisms in addition to vasodilatation. The relevance of the responses to the tachykinins in asthma is discussed.

Objectives : To determine the frequency and independent predictors of acute kidney injury (AKI) in addition to the prognostic implications of both AKI and periprocedural red blood cell (RBC) transfusions on 30 day and cumulative late mortality in patients undergoing transcatheter aortic valve implantation (TAVI). Background : RBC transfusions have been reported to predict AKI following TAVI. Data on the prognostic implications of both factors, however, are lacking. Methods : 126 consecutive patients underwent TAVI with the Medtronic CoreValve Revalving System. AKI was defined according to the valve academic research consortium definitions as an absolute increase in serum creatinine ≥0.3 mg dL −1 (≥26.4 μmol L −1 ) or a percentage increase ≥50% within 72 hr following TAVI. Results : Five patients on chronic haemodialysis and three intraprocedural deaths were excluded, leading to a final study population of 118 patients. AKI occurred in 19% of the patients necessitating temporary haemodialysis in 2%. Independent predictors of AKI included: previous myocardial infarction (OR: 5.72; 95% CI: 1.64–19.94), periprocedural (<24 hr) RBC transfusions (OR: 1.29; 95% CI: 1.01–1.70), postprocedural (<72 hr) leucocyte count (OR: 1.18; 95% CI: 1.02–1.37), and logistic EuroSCORE (OR: 1.08; 95% CI: 1.01–1.14). In patients with AKI, 30‐day mortality was 23% and cumulative late mortality (median: 13 months) was 55%. AKI (OR: 5.47; 95% CI: 1.23–24.21) and postprocedural leucocyte count (OR: 1.20; 95% CI: 1.03–1.38) were independent predictors of 30‐day mortality while AKI (HR: 2.79; 95% CI: 1.36–5.71) was the only independent predictor of late mortality. Conclusions : AKI following TAVI occurred in 19% of the patients. RBC transfusion was found to be an independent predictor of AKI, which in turn predicted both 30‐day and cumulative late mortality. © 2011 Wiley‐Liss, Inc.