Publications

Chronic Obstructive Pulmonary Disease (COPD) is a debilitating inflammatory respiratory condition that presents with worsening breathing difficulties and it is assumed to be progressive and incurable. As an inflammatory disease, COPD is associated with recruitment of immune cells to lung tissue and increased levels of pro-inflammatory cytokines, including TNF-α, IL-1β, IL-6, IL-8, and GM-CSF. Low-carbohydrate ketogenic diets have anti-inflammatory properties that could, in theory, improve COPD symptoms and progression. Herein, we report on a 54-year-old patient (C.A.) with COPD who adopted a ketogenic diet (70% calories from fat). Subsequently, C.A. experienced a reduction in inflammatory markers in association with a meaningful improvement in lung function. His inflammatory markers decreased into the normal range and his forced expiratory volume increased by 37.5% relative to its pre-ketogenic diet value. Future research should explore nutritional ketosis and ketogenic diets as possible therapeutic options for individuals with COPD.

Rationale Lung quantitative computed tomographic (qCT) severe asthma clusters have been reported, but their replication and underlying disease mechanisms are unknown. We identified and replicated qCT clusters of severe asthma in two independent asthma cohorts and determined their association with molecular pathways. Methods We used consensus clustering on qCT measurements of airway and lung CT scans, performed in 105 severe asthmatic adults from the U-BIOPRED cohort. The same qCT measurements were used to replicate qCT clusters in a subsample of the ATLANTIS asthma cohort (n=97). We performed integrated enrichment analysis using blood, sputum, bronchial biopsies, bronchial brushings and nasal brushings transcriptomics and blood and sputum proteomics to characterize radiomultiomic-associated clusters (RACs). Results qCT clusters and clinical features in U-BIOPRED were replicated in the matched ATLANTIS cohort. In the U-BIOPRED cohort, RAC1 (n=30) was predominantly female with elevated BMI, mild airflow limitation, normal qCT parameters and upregulation of the complement pathway. RAC2 (n=34) subjects had a lower degree of airflow limitation, airway wall thickness and dilatation, with upregulation of proliferative pathways, including neurotrophic receptor tyrosine kinase 2/tyrosine kinase receptor B (NTRK2/TRKB), and down-regulation of semaphorin pathways. RAC3 (n=41) showed increased lung attenuation area and air trapping, severe airflow limitation, hyperinflation, and upregulation of cytokine signaling and signaling by interleukin pathways, and matrix metallopeptidase 1, 2 and 9. Conclusions U-BIOPRED severe asthma qCT clusters were replicated in a matched independent asthmatic cohort and associated with specific molecular pathways. Radiomultiomics might represent anovel strategy to identify new molecular pathways in asthma pathobiology.

Inhalation of sodium metabisulphite is thought to induce bronchoconstriction by release of sulphur dioxide. We sought to establish the reproducibility of the airway response to inhaled sodium metabisulphite given in increasing doubling concentrations (0.3 to 160 mg/ml) to 13 asthmatic and five atopic non-asthmatic subjects and the contribution of cholinergic mechanisms to this response. In 15 of the 18 subjects bronchoconstriction was sufficient to allow calculation of the dose of metabisulphite causing a 20% reduction in the forced expiratory volume in one second (FEV1) from baseline values (PD20 metabisulphite). The 95% confidence limit for the difference between this and a second PD20 metabisulphite determined 2-14 days later was 2.5 doubling doses. The difference between repeat PD20 metabisulphite measurements was unrelated to the number of days between challenges or change in baseline FEV1. Ten subjects returned for a third study 3-120 days after the second challenge; variability in PD20 metabisulphite did not differ from that seen between the first and second challenges. PD20 methacholine was determined between the two metabisulphite challenges and found to correlate with PD20 metabisulphite (r = 0.71). Inhaled ipratropium bromide 200 micrograms given in a randomised, placebo controlled, crossover study to 10 subjects increased PD20 methacholine 42 fold but had no significant effect on the response to metabisulphite. A single inhalation of the PD20 metabisulphite in five subjects induced maximal bronchoconstriction 2-3 minutes after inhalation, with a plateau in FEV1 lasting a further four minutes before recovery. A further single inhalation of the same PD20 dose 43 minutes later produced a 27% (SEM 4%) smaller fall in FEV1 than the first inhalation. These results show that metabisulphite PD20 values measured over days and weeks show similar reproducibility to those reported for histamine inhalation and that PD20 metabisulphite correlates with methacholine responsiveness. Most of the bronchoconstriction is not inhibited by antimuscarinic agents; the underlying mechanisms require further investigation.

Intravascular ultrasound (IVUS) is a technology that uses an ultrasound element on the tip of a catheter. This catheter is advanced through the groin into the coronary arteries. In this way a tomographic image of the vascular wall and atherosclerotic plaques can be produced. Historically is has been used to assess the level of occlusion, the atherosclerotic plaque burden and the native size of the vessel. This information can be used to decide to treat or not and to determine the diameter and length of the stent to be used for treatment. It has also been used extensively to determine if the stent was well deployed. The composition and morphology of an atherosclerotic lesion are currently considered more important determinants of acute coronary ischemic syndromes that the degree of stenosis. When a lesion is unstable, it can rupture and cause an acute thrombotic reaction. An unstable plaque can be characterized by a lipid core that is covered by a thin fibrous cap, which has been locally weakened by inflammatory cells. The last decade serious effort has been put in developing IVUS towards identifying these unstable plaques. This lecture will focus on the development of measuring the elastic properties of the plaque as a marker for plaque instability and measuring the vascularization in the plaque, which plays an important role in the pathogenesis of unstable plaque. Furthermore the role of combined ultrasound/light catheters will be discussed. Technology development and validation will be presented as well as the role of IVUS to provide imaging biomarkers in natural history studies and trials for the development of new cardiovascular drugs.

Percutaneous therapy of coronary bifurcated lesions is associated with greater risk of acute complications and late restenosis. Numerous innovative techniques using various stent types have been proposed. We report the first clinical use of a truly bifurcated stent (Bard XT Carina). The implantation procedure, favorable medium-term angiographic and 1-year clinical follow-up of the first human use in a 43-year-old female are illustrated with angiography and intravascular ultrasound. As a single prosthesis that effectively covers the bifurcation, this stent presents appealing alternative for the treatment of coronary bifurcation lesions when compared to methods that involve multiple-stent implantation. Cathet. Cardiovasc. Intervent. 47:361–369, 1999. © 1999 Wiley-Liss, Inc.

Background There is ongoing debate on the optimal drug-eluting stent (DES) in diabetic patients with coronary artery disease. Biodegradable polymer drug-eluting stents (BP-DES) may potentially improve clinical outcomes in these high-risk patients. We sought to compare long-term outcomes in patients with diabetes treated with biodegradable polymer DES vs. durable polymer sirolimus-eluting stents (SES). Methods We pooled individual patient-level data from 3 randomized clinical trials (ISAR-TEST 3, ISAR-TEST 4 and LEADERS) comparing biodegradable polymer DES with durable polymer SES. Clinical outcomes out to 4years were assessed. The primary end point was the composite of cardiac death, myocardial infarction and target-lesion revascularization. Secondary end points were target lesion revascularization and definite or probable stent thrombosis. Results Of 1094 patients with diabetes included in the present analysis, 657 received biodegradable polymer DES and 437 durable polymer SES. At 4years, the incidence of the primary end point was similar with BP-DES versus SES (hazard ratio=0.95, 95% CI=0.74–1.21, P =0.67). Target lesion revascularization was also comparable between the groups (hazard ratio=0.89, 95% CI=0.65–1.22, P =0.47). Definite or probable stent thrombosis was significantly reduced among patients treated with BP-DES (hazard ratio=0.52, 95% CI=0.28–0.96, P =0.04), a difference driven by significantly lower stent thrombosis rates with BP-DES between 1 and 4years (hazard ratio=0.15, 95% CI=0.03–0.70, P =0.02). Conclusions In patients with diabetes, biodegradable polymer DES, compared to durable polymer SES, were associated with comparable overall clinical outcomes during follow-up to 4years. Rates of stent thrombosis were significantly lower with BP-DES.

Paclitaxel is a potent and effective inhibitor of neointimal proliferation after coronary stenting. The Conor stent loaded with Paclitaxel can be programmed with multi-parameter matrix of dose, temporal release profiles and release pathways. The aim of this study was to determine the most efficacious dose and release pattern of Paclitaxel in a porcine model and parallels the PISCES trial.32 farm pigs were implanted with Conor stents loaded with 10 or 30 microg of Paclitaxel with, 10 or 30 day and mural or bidirectional release patterns. Angiographic and histomorphometric analysis was -performed at 30 and 90 days.All doses of Paclitaxel were angiographically superior to control (P < 0.01). At 30 days, intimal thickness was similar between Pisces D4 (30 microg/10 days, bidirectional release), D5 (10 microg/30 day mural) and D6 (30 microg/30 day, mural) with D4 having the lowest intimal thickness (167+/-59 microm). There was a significant increase in the mural injury associated with D4 in comparison to all other doses (P < 0.00001). At 90 days D4 was significantly worse in comparison to Pisces D5 and D6; (P < 0.01) and Pisces D5 and D6 were similar to controls.10 day release of Paclitaxel may be too short a period to inhibit neointimal proliferation after coronary stenting, or the rapid release of Paclitaxel may induce chemical injury causing secondary insult to the artery resulting in a rebound increase in intimal thickness at 90 days. These data parallel clinical findings in the PISCES trial.

BACKGROUND: Although safety and efficacy of the beStent (Medtronic Inc., Santa Rosa, CA, USA) have been described, the long-term angiographic and clinical outcomes have yet to be investigated. The ROSE (Registry for Optimal beStent Evaluation) trial was designed to assess the procedural safety of single 15 mm beStent implantation, and the six-month angiographic and 12-month clinical outcomes of patients treated with this novel coronary stent. METHODS: Patients with angina and a single de novo lesion in a native coronary artery of >/=2.75 mm diameter were included in this multicenter, prospective, observational trial. Clinical follow-up was obtained at one, six and 12 months. Angiography was performed before and after the stent implantation and at six months. The primary end-point included major adverse cardiac events (death, myocardial infarction and target lesion revascularization), major bleeding complications, and thrombotic occlusions at one-month follow-up. Secondary end-points were major cardiac-event-free survival at six- and 12-month follow-up and angiographic restenosis at six months. A total of 120 patients (80% male, mean age 58.6 +/- 10.6 years) with stable (48%) or unstable (44%) angina pectoris were allocated. The target vessel reference diameter pre-procedure was 2.85 +/- 0.52 mm. RESULTS: Minimal lumen diameter pre/post and at follow-up was 0.97 +/- 0.28 mm, 2.53 +/- 0.40 mm and 1.86 +/- 0.63 mm, respectively. Restenosis rate according to the >50% diameter stenosis criterion at six-month follow-up was 21.5%. At 12 months, the event-free survival rate was 75% (no deaths, two Q-wave and seven non-Q-wave infarctions, five bypass surgery interventions and 16 target lesion revascularizations), whilst 87% of the patients were free of angina pectoris. CONCLUSION: Despite the relatively high percentage of small vessels, the outcome of the ROSE trial is comparable to those observed in previous stent trials, indicating that the coronary beStent is safe and effective as a primary device for the treatment of native coronary artery lesions in patients with (un)stable angina pectoris.

Peroxynitrite is a potent oxidant formed by the rapid reaction of the free radicals nitric oxide (NO) and superoxide. It causes airway hyperresponsiveness and airway epithelial damage, enhances inflammatory cell recruitment, and inhibits pulmonary surfactant. Asthma is characterized by increased airway hyperresponsiveness, airway epithelial shedding, and inflammation. We examined the production of peroxynitrite and the expression of inducible nitric oxide synthase (iNOS) in airways of asthmatic patients compared to normal control subjects. We also performed a double-blind, crossover randomized-order, placebo-controlled study on 10 asthmatic patients to study the effects of inhaled glucocorticoid treatment (Budesonide) on the formation of peroxynitrite and NO. Fiberoptic bronchial biopsies were examined by immunohistochemistry with antiserum to nitrotyrosine, a marker of protein nitration by peroxynitrite. We also examined the expression of iNOS by immunohistochemistry and in situ hybridization, and measured exhaled NO by chemiluminescence. We correlated the airway production of peroxynitrite with pulmonary functions and airway responsiveness. In airway passages of control subjects, there was weak or no nitrotyrosine immunoreactivity. In contrast, there was strong immunoreactivity for nitrotyrosine in the airway epithelium and inflammatory cells in the airways of persons with asthma. Budesonide treatment resulted in a significant reduction in nitrotyrosine immunoreactivity. Expression of iNOS was evident in the airway pithelium of controls and asthmatic patients, but was significantly more abundant in asthmatic patients. The presence of nitrotyrosine in the airway epithelium (r=-0.841, P<0.0001; r=-0.771, P=0.0004) and inflammatory cells (r=-0.727, P=0014; r=-0.681, P=0.004) correlated inversely with methacholine PC20 and forced expiratory volume in 1 s, respectively. Asthma is associated with increased peroxynitrite formation in the airways, which is reduced after Budesonide treatment. The potent oxidant peroxynitrite may contribute to airway obstruction and hyperresponsiveness and epithelial damage in asthma.