Emphysema Is Common in Lungs of Cystic Fibrosis Lung Transplantation Patients: A Histopathological and Computed Tomography Study

Background

Lung disease in cystic fibrosis (CF) involves excessive inflammation, repetitive infections and development of bronchiectasis. Recently, literature on emphysema in CF has emerged, which might become an increasingly important disease component due to the increased life expectancy. The purpose of this study was to assess the presence and extent of emphysema in endstage CF lungs.

Methods

In explanted lungs of 20 CF patients emphysema was semi-quantitatively assessed on histology specimens. Also, emphysema was automatically quantified on pre-transplantation computed tomography (CT) using the percentage of voxels below -950 Houndfield Units and was visually scored on CT. The relation between emphysema extent, pre-transplantation lung function and age was determined.

Results

All CF patients showed emphysema on histological examination: 3/20 (15%) showed mild, 15/20 (75%) moderate and 2/20 (10%) severe emphysema, defined as 0–20% emphysema, 20–50% emphysema and >50% emphysema in residual lung tissue, respectively. Visually upper lobe bullous emphysema was identified in 13/20 and more diffuse non-bullous emphysema in 18/20. Histology showed a significant correlation to quantified CT emphysema (p = 0.03) and visual emphysema score (p = 0.001). CT and visual emphysema extent were positively correlated with age (p = 0.045 and p = 0.04, respectively).

Conclusions

In conclusion, this study both pathologically and radiologically confirms that emphysema is common in end-stage CF lungs, and is age related. Emphysema might become an increasingly important disease component in the aging CF population.     

Variation of Densitometry on Computed Tomography in COPD – Influence of Different Software Tools

Objectives

Quantitative multidetector computed tomography (MDCT) as a potential biomarker is increasingly used for severity assessment of emphysema in chronic obstructive pulmonary disease (COPD). Aim of this study was to evaluate the user-independent measurement variability between five different fully-automatic densitometry software tools.

Material and Methods

MDCT and full-body plethysmography incl. forced expiratory volume in 1s and total lung capacity were available for 49 patients with advanced COPD (age = 64±9 years, forced expiratory volume in 1s = 31±6% predicted). Measurement variation regarding lung volume, emphysema volume, emphysema index, and mean lung density was evaluated for two scientific and three commercially available lung densitometry software tools designed to analyze MDCT from different scanner types.

Results

One scientific tool and one commercial tool failed to process most or all datasets, respectively, and were excluded. One scientific and another commercial tool analyzed 49, the remaining commercial tool 30 datasets. Lung volume, emphysema volume, emphysema index and mean lung density were significantly different amongst these three tools (p<0.001). Limits of agreement for lung volume were [−0.195, −0.052l], [−0.305, −0.131l], and [−0.123, −0.052l] with correlation coefficients of r = 1.00 each. Limits of agreement for emphysema index were [−6.2, 2.9%], [−27.0, 16.9%], and [−25.5, 18.8%], with r = 0.79 to 0.98. Correlation of lung volume with total lung capacity was good to excellent (r = 0.77 to 0.91, p<0.001), but segmented lung volume (6.7±1.3 – 6.8±1.3l) were significantly lower than total lung capacity (7.7±1.7l, p<0.001).

Conclusions

Technical incompatibilities hindered evaluation of two of five tools. The remaining three showed significant measurement variation for emphysema, hampering quantitative MDCT as a biomarker in COPD. Follow-up studies should currently use identical software, and standardization efforts should encompass software as well.     

Cigarette Smoke-Induced Emphysema and Pulmonary Hypertension Can Be Prevented by Phosphodiesterase 4 and 5 Inhibition in Mice

Rationale

Chronic obstructive pulmonary disease (COPD) is a widespread disease, with no curative therapies available. Recent findings suggest a key role of NO and sGC-cGMP signaling for the pathogenesis of the disease. Previous data suggest a downregulation/inactivation of the cGMP producing soluble guanylate cyclase, and sGC stimulation prevented cigarette smoke-induced emphysema and pulmonary hypertension (PH) in mice. We thus aimed to investigate if the inhibition of the cGMP degrading phosphodiesterase (PDE)5 has similar effects. Results were compared to the effects of a PDE 4 inhibitor (cAMP elevating) and a combination of both.

Methods

C57BL6/J mice were chronically exposed to cigarette smoke and in parallel either treated with Tadalafil (PDE5 inhibitor), Piclamilast (PDE4 inhibitor) or both. Functional measurements (lung compliance, hemodynamics) and structural investigations (alveolar and vascular morphometry) as well as the heart ratio were determined after 6 months of tobacco smoke exposure. In addition, the number of alveolar macrophages in the respective lungs was counted.

Results

Preventive treatment with Tadalafil, Piclamilast or a combination of both almost completely prevented the development of emphysema, the increase in lung compliance, tidal volume, structural remodeling of the lung vasculature, right ventricular systolic pressure, and right ventricular hypertrophy induced by cigarette smoke exposure. Single, but not combination treatment prevented or reduced smoke-induced increase in alveolar macrophages.

Conclusion

Cigarette smoke-induced emphysema and PH could be prevented by inhibition of the phosphodiesterases 4 and 5 in mice.     

Airway Surface Dehydration Aggravates Cigarette Smoke-Induced Hallmarks of COPD in Mice

Introduction

Airway surface dehydration, caused by an imbalance between secretion and absorption of ions and fluid across the epithelium and/or increased epithelial mucin secretion, impairs mucociliary clearance. Recent evidence suggests that this mechanism may be implicated in chronic obstructive pulmonary disease (COPD). However, the role of airway surface dehydration in the pathogenesis of cigarette smoke (CS)-induced COPD remains unknown.

Objective

We aimed to investigate in vivo the effect of airway surface dehydration on several CS-induced hallmarks of COPD in mice with airway-specific overexpression of the β-subunit of the epithelial Na⁺ channel (βENaC).

Methods

βENaC-Tg mice and wild-type (WT) littermates were exposed to air or CS for 4 or 8 weeks. Pathological hallmarks of COPD, including goblet cell metaplasia, mucin expression, pulmonary inflammation, lymphoid follicles, emphysema and airway wall remodelling were determined and lung function was measured.

Results

Airway surface dehydration in βENaC-Tg mice aggravated CS-induced airway inflammation, mucin expression and destruction of alveolar walls and accelerated the formation of pulmonary lymphoid follicles. Moreover, lung function measurements demonstrated an increased compliance and total lung capacity and a lower resistance and hysteresis in βENaC-Tg mice, compared to WT mice. CS exposure further altered lung function measurements.

Conclusions

We conclude that airway surface dehydration is a risk factor that aggravates CS-induced hallmarks of COPD.     

Intrahepatic Vascular Anatomy in Rats and Mice—Variations and Surgical Implications

Introduction

The intra-hepatic vascular anatomy in rodents, its variations and corresponding supplying and draining territories in respect to the lobar structure of the liver have not been described. We performed a detailed anatomical imaging study in rats and mice to allow for further refinement of experimental surgical approaches.

Methods

LEWIS-Rats and C57Bl/6N-Mice were subjected to ex-vivo imaging using μCT. The image data were used for semi-automated segmentation to extract the hepatic vascular tree as prerequisite for 3D visualization. The underlying vascular anatomy was reconstructed, analysed and used for determining hepatic vascular territories.

Results

The four major liver lobes have their own lobar portal supply and hepatic drainage territories. In contrast, the paracaval liver is supplied by various small branches from right and caudate portal veins and drains directly into the vena cava. Variations in hepatic vascular anatomy were observed in terms of branching pattern and distance of branches to each other. The portal vein anatomy is more variable than the hepatic vein anatomy. Surgically relevant variations were primarily observed in portal venous supply.

Conclusions

For the first time the key variations of intrahepatic vascular anatomy in mice and rats and their surgical implications were described. We showed that lobar borders of the liver do not always match vascular territorial borders. These findings are of importance for the design of new surgical procedures and for understanding eventual complications following hepatic surgery.     

Impact of Endoscopic Lung Volume Reduction on Right Ventricular Myocardial Function

Introduction

Endoscopic lung volume reduction (ELVR) provides a minimally invasive therapy for patients with severe lung emphysema. As its impact on right ventricular (R_tV) function is undefined, we examined the extent of R_tV functional changes following ELVR, as assessed by use of speckle tracking-based R_tV deformation analysis.

Methods

We enrolled 32 patients with severe emphysematous COPD scheduled for bronchoscopic LVR using endobronchial valves (Zephyr, PulmonX, Inc.), comprising 16 matched clinical responders and 16 non-responders. Echocardiography was conducted one day prior to ELVR and at an eight-week postprocedural interval.

Results

Patients were predominantly of late middle-age (65.8±8.7yrs), male (62.5%) and presented advanced COPD emphysema (means FEV1 and RV: 32.6% and 239.1% of predicted, respectively). After ELVR, R_tV apical longitudinal strain improved significantly in the total study cohort (-7.96±7.02% vs. -13.35±11.48%, p=0.04), whereas there were no significant changes in other parameters of R_tV function such as R_tV global longitudinal strain, TAPSE or pulmonary arterial systolic pressure. In responding patients, 6MWT-improvement correlated with a decrease in NT-proBNP (Pearson´s r: -0.53, p=0.03). However, clinical non-responders did not exhibit any R_tV functional improvement.

Discussion

ELVR beneficially impacts R_tV functional parameters. Speckle tracking-based R_tV apical longitudinal strain analysis allows early determination of R_tV contractile gain and identification of clinical responsiveness.     

Pulmonary Emphysema in Cystic Fibrosis Detected by Densitometry on Chest Multidetector Computed Tomography

Background

Histopathological studies on lung specimens from patients with cystic fibrosis (CF) and recent results from a mouse model indicate that emphysema may contribute to CF lung disease. However, little is known about the relevance of emphysema in patients with CF. In the present study, we used computationally generated density masks based on multidetector computed tomography (MDCT) of the chest for non-invasive characterization and quantification of emphysema in CF.

Methods

Volumetric MDCT scans were acquired in parallel to pulmonary function testing in 41 patients with CF (median age 20.1 years; range 7-66 years) and 21 non-CF controls (median age 30.4 years; range 4-68 years), and subjected to dedicated software. The lung was segmented, low attenuation volumes below a threshold of -950 Hounsfield units were assigned to emphysema volume (EV), and the emphysema index was computed (EI). Results were correlated with forced expiratory volume in 1 s percent predicted (FEV1%), residual volume (RV), and RV/total lung capacity (RV/TLC).

Results

We show that EV was increased in CF (457±530 ml) compared to non-CF controls (78±90 ml) (P<0.01). EI was also increased in CF (7.7±7.5%) compared to the control group (1.2±1.4%) (P<0.05). EI correlated inversely with FEV1% (r_s=-0.66), and directly with RV (r_s=0.69) and RV/TLC (r_s=0.47) in patients with CF (P<0.007), but not in non-CF controls. Emphysema in CF was detected from early adolescence (~13 years) and increased with age (r_s=0.67, P<0.001).

Conclusions

Our results indicate that early onset emphysema detected by densitometry on chest MDCT is a characteristic pathology that contributes to airflow limitation and may serve as a novel endpoint for monitoring lung disease in CF.     

Quantification of lung fibrosis and emphysema in mice using automated micro-computed tomography

Background

In vivo high-resolution micro-computed tomography allows for longitudinal image-based measurements in animal models of lung disease. The combination of repetitive high resolution imaging with fully automated quantitative image analysis in mouse models of lung fibrosis lung benefits preclinical research. This study aimed to develop and validate such an automated micro-computed tomography analysis algorithm for quantification of aerated lung volume in mice; an indicator of pulmonary fibrosis and emphysema severity.

Methodology

Mice received an intratracheal instillation of bleomycin (n = 8), elastase (0.25U elastase n = 9, 0.5U elastase n = 8) or saline control (n = 6 for fibrosis, n = 5 for emphysema). A subset of mice was scanned without intervention, to evaluate potential radiation-induced toxicity (n = 4). Some bleomycin-instilled mice were treated with imatinib for proof of concept (n = 8). Mice were scanned weekly, until four weeks after induction, when they underwent pulmonary function testing, lung histology and collagen quantification. Aerated lung volumes were calculated with our automated algorithm.

Principal Findings

Our automated image-based aerated lung volume quantification method is reproducible with low intra-subject variability. Bleomycin-treated mice had significantly lower scan-derived aerated lung volumes, compared to controls. Aerated lung volume correlated with the histopathological fibrosis score and total lung collagen content. Inversely, a dose-dependent increase in lung volume was observed in elastase-treated mice. Serial scanning of individual mice is feasible and visualized dynamic disease progression. No radiation-induced toxicity was observed. Three-dimensional images provided critical topographical information.

Conclusions

We report on a high resolution in vivo micro-computed tomography image analysis algorithm that runs fully automated and allows quantification of aerated lung volume in mice. This method is reproducible with low inherent measurement variability. We show that it is a reliable quantitative tool to investigate experimental lung fibrosis and emphysema in mice. Its non-invasive nature has the unique benefit to allow dynamic 4D evaluation of disease processes and therapeutic interventions.     

Prevention of elastase-induced emphysema in placenta growth factor knock-out mice

Background

Although both animal and human studies suggested the association between placenta growth factor (PlGF) and chronic obstructive pulmonary disease (COPD), especially lung emphysema, the role of PlGF in the pathogenesis of emphysema remains to be clarified. This study hypothesizes that blocking PlGF prevents the development of emphysema.

Methods

Pulmonary emphysema was induced in PlGF knock-out (KO) and wild type (WT) mice by intra-tracheal instillation of porcine pancreatic elastase (PPE). A group of KO mice was then treated with exogenous PlGF and WT mice with neutralizing anti-VEGFR1 antibody. Tumor necrosis factor alpha (TNF-α), matrix metalloproteinase-9 (MMP-9), and VEGF were quantified. Apoptosis measurement and immuno-histochemical staining for VEGF R1 and R2 were performed in emphysematous lung tissues.

Results

After 4 weeks of PPE instillation, lung airspaces enlarged more significantly in WT than in KO mice. The levels of TNF-α and MMP-9, but not VEGF, increased in the lungs of WT compared with those of KO mice. There was also increased in apoptosis of alveolar septal cells in WT mice. Instillation of exogenous PlGF in KO mice restored the emphysematous changes. The expression of both VEGF R1 and R2 decreased in the emphysematous lungs.

Conclusion

In this animal model, pulmonary emphysema is prevented by depleting PlGF. When exogenous PlGF is administered to PlGF KO mice, emphysema re-develops, implying that PlGF contributes to the pathogenesis of emphysema.     

Computed Tomography Measurement of Rib Cage Morphometry in Emphysema

Background

Factors determining the shape of the human rib cage are not completely understood. We aimed to quantify the contribution of anthropometric and COPD-related changes to rib cage variability in adult cigarette smokers.

Methods

Rib cage diameters and areas (calculated from the inner surface of the rib cage) in 816 smokers with or without COPD, were evaluated at three anatomical levels using computed tomography (CT). CTs were analyzed with software, which allows quantification of total emphysema (emphysema%). The relationship between rib cage measurements and anthropometric factors, lung function indices, and %emphysema were tested using linear regression models.

Results

A model that included gender, age, BMI, emphysema%, forced expiratory volume in one second (FEV₁)%, and forced vital capacity (FVC)% fit best with the rib cage measurements (R² = 64% for the rib cage area variation at the lower anatomical level). Gender had the biggest impact on rib cage diameter and area (105.3 cm²; 95% CI: 111.7 to 98.8 for male lower area). Emphysema% was responsible for an increase in size of upper and middle CT areas (up to 5.4 cm²; 95% CI: 3.0 to 7.8 for an emphysema increase of 5%). Lower rib cage areas decreased as FVC% decreased (5.1 cm²; 95% CI: 2.5 to 7.6 for 10 percentage points of FVC variation).

Conclusions

This study demonstrates that simple CT measurements can predict rib cage morphometric variability and also highlight relationships between rib cage morphometry and emphysema.     

Immunomodulatory strategies prevent the development of autoimmune emphysema

Background

The presence of anti-endothelial cell antibodies and pathogenic T cells may reflect an autoimmune component in the pathogenesis of emphysema. Whether immune modulatory strategies can protect against the development of emphysema is not known.

Methods

Sprague Dawley rats were immunized with human umbilical vein endothelial cells (HUVEC) to induce autoimmune emphysema and treated with intrathymic HUVEC-injection and pristane. Measurements of alveolar airspace enlargement, cytokine levels, immuno histochemical, western blot analysis, and T cell repertoire of the lung tissue were performed.

Results

The immunomodulatory strategies protected lungs against cell death as demonstrated by reduced numbers of TUNEL and active caspase-3 positive cells and reduced levels of active caspase-3, when compared with lungs from HUVEC-immunized rats. Immunomodulatory strategies also suppressed anti-endothelial antibody production and preserved CNTF, IL-1alpha and VEGF levels. The immune deviation effects of the intrathymic HUVEC-injection were associated with an expansion of CD4+CD25+Foxp3+ regulatory T cells. Pristane treatment decreased the proportion of T cells expressing receptor beta-chain, Vβ16.1 in the lung tissue.

Conclusions

Our data demonstrate that interventions classically employed to induce central T cell tolerance (thymic inoculation of antigen) or to activate innate immune responses (pristane treatment) can prevent the development of autoimmune emphysema.     

Effect of Endobronchial Valve Therapy on Pulmonary Perfusion and Ventilation Distribution

Introduction

Endoscopic lung volume reduction (ELVR) is an emerging therapy for emphysematous COPD. However, any resulting changes in lung perfusion and ventilation remain undetermined. Here, we report ELVR-mediated adaptations in lung perfusion and ventilation, as investigated by means of pulmonary scintigraphy.

Methods

In this observational study, we enrolled 26 patients (64.9±9.4 yrs, 57.7% male) with COPD heterogeneous emphysema undergoing ELVR with endobronchial valves (Zephyr, Pulmonx, Inc.). Mean baseline FEV1 and RV were 32.9% and 253.8% predicted, respectively. Lung scintigraphy was conducted prior to ELVR and eight weeks thereafter. Analyses of perfusion and ventilation shifts were performed and complemented by correlation analyses between paired zones.

Results

After ELVR, target zone perfusion showed a mean relative reduction of 43.32% (p<0.001), which was associated with a significant decrease in target zone ventilation (p<0.001). Perfusion of the contralateral untreated zone and of the contralateral total lung exhibited significant increases post-ELVR (p = 0.002 and p = 0.005, respectively); both correlated significantly with the corresponding target zone perfusion adaptations. Likewise, changes in target zone ventilation correlated significantly with ventilatory changes in the contralateral untreated zone and the total contralateral lung (Pearson’s r: −0.42, p = 0.04 and Pearson’s r: −0.42, p = 0.03, respectively). These effects were observed in case of clinical responsiveness to ELVR, as assessed by changes in the six-minute walk test distance.

Discussion

ELVR induces a relevant decrease in perfusion and ventilation of the treated zone with compensatory perfusional and ventilatory redistribution to the contralateral lung, primarily to the non-concordant, contralateral zone.     

Modeling of Longitudinal Changes in Left Ventricular Dimensions among Female Adolescent Runners

Purpose

Left ventricular (LV) enlargement has been linked to sudden cardiac death among young athletes. This study aimed to model the effect of long-term incessant endurance training on LV dimensions in female adolescent runners.

Methods

Japanese female adolescent competitive distance runners (n = 36, age: 15 years, height: 158.1 ± 4.6 cm, weight: 44.7 ± 6.1 kg, percent body fat: 17.0 ± 5.2%) underwent echocardiography and underwater weighing every 6 months for 3 years. Since the measurement occasions varied across subjects, multilevel analysis was used for curvilinear modeling of changes in running performance (velocities in 1500 m and 3000 m track race), maximal oxygen uptake (VO₂max), body composition, and LV dimensions.

Results

Initially, LV end-diastolic dimension (LVEDd) and LV mass were 47.0 ± 3.0 mm and 122.6 ± 15.7 g, respectively. Running performance and VO₂max improved along with the training duration. The trends of changes in fat-free mass (FFM) and LVEDd were similarly best described by quadratic polynomials. LVEDd did not change over time in the model including FFM as a covariate. Increases in LV wall thicknesses were minimal and independent of FFM. LV mass increased according to a quadratic polynomial trend even after adjusting for FFM.

Conclusions

FFM was an important factor determining changes in LVEDd and LV mass. Although running performance and VO₂max were improved by continued endurance training, further LV cavity enlargement hardly occurred beyond FFM gain in these adolescent female runners, who already demonstrated a large LVEDd.     

The Dose-Dependent Organ-Specific Effects of a Dipeptidyl Peptidase-4 Inhibitor on Cardiovascular Complications in a Model of Type 2 Diabetes

Objective

Although dipeptidyl peptidase-4 (DPP-4) inhibitors have been suggested to have a non-glucoregulatory protective effect in various tissues, the effects of long-term inhibition of DPP-4 on the micro- and macro-vascular complications of type 2 diabetes remain uncertain. The aim of the present study was to investigate the organ-specific protective effects of DPP-4 inhibitor in rodent model of type 2 diabetes.

Methods

Eight-week-old diabetic and obese db/db mice and controls (db/m mice) received vehicle or one of two doses of gemigliptin (0.04 and 0.4%) daily for 12 weeks. Urine albumin excretion and echocardiography measured at 20 weeks of age. Heart and kidney tissue were subjected to molecular analysis and immunohistochemical evaluation.

Results

Gemigliptin effectively suppressed plasma DPP-4 activation in db/db mice in a dose-dependent manner. The HbA1c level was normalized in the 0.4% gemigliptin, but not in the 0.04% gemigliptin group. Gemigliptin showed a dose-dependent protective effect on podocytes, anti-apoptotic and anti-oxidant effects in the diabetic kidney. However, the dose-dependent effect of gemigliptin on diabetic cardiomyopathy was ambivalent. The lower dose significantly attenuated left ventricular (LV) dysfunction, apoptosis, and cardiac fibrosis, but the higher dose could not protect the LV dysfunction and cardiac fibrosis.

Conclusion

Gemigliptin exerted non-glucoregulatory protective effects on both diabetic nephropathy and cardiomyopathy. However, high-level inhibition of DPP-4 was associated with an organ-specific effect on cardiovascular complications in type 2 diabetes.     

Socioeconomic Status and Longitudinal Lung Function of Healthy Mexican Children

Introduction

Our aim was to estimate the longitudinal effect of Socioeconomic status (SES) on lung function growth of Mexican children and adolescents.

Materials and Methods

A cohort of Mexican children in third grade of primary school was followed with spirometry twice a year for 6 years through secondary school. Multilevel mixed-effects lineal models were fitted for the spirometric variables of 2,641 respiratory-healthy Mexican children. Monthly family income (in 2002 U.S. dollars [USD]) and parents’ years completed at school were used as proxies of SES.

Results

Individuals with higher SES tended to have greater height for age, and smaller sitting height/standing height and crude lung function. For each 1-year increase of parents’ schooling, Forced expiratory volume in 1 sec (FEV₁) and Forced vital capacity (FVC) increased 8.5 (0.4%) and 10.6 mL (0.4%), respectively (p <0.05) when models were adjusted for gender. Impact of education on lung function was reduced drastically or abolished on adjusting by anthropometric variables and ozone.

Conclusions

Higher parental schooling and higher monthly family income were associated with higher lung function in healthy Mexican children, with the majority of the effect likely due to the increase in height-for-age.     

Evaluation of Left Ventricle Function by Regional Fractional Area Change (RFAC) in a Mouse Model of Myocardial Infarction Secondary to Valsartan Treatment

Aim

Left ventricle (LV) regional fractional area change (RFAC) measured by cardiac magnetic resonance (CMR) allows the non-invasive localization and quantification of the degree of myocardial infarction (MI), and could be applied to assess the effectiveness of pharmacological or regenerative therapies. Here we investigate the ability of RFAC to identify regional dysfunction and discriminate the effect of pharmacological treatment with valsartan, a selective antagonist of angiotensin II type 1 receptor, in a model of MI.

Methods and Results

C57BL/6N mice, undergoing coronary artery ligation, were divided into two groups: untreated (MI) or treated with valsartan (MI+Val). Sham-operated mice were used as a control. Cardiac dimensions and function were assessed at baseline, 24 hours, 1 and 4 weeks post surgery by CMR and echocardiography. At sacrifice histology and whole-genome gene expression profiling were performed. RFAC was able to detect significant differences between treatment groups whereas the global ejection fraction was not. RFAC showed greater loss of regional contraction in remote non-infarcted myocardium in MI group than in MI+Val group. Consistently, in the same region MI+Val mice showed reduced myocyte hypertrophy, fibroblast proliferation, and fibrosis and modulation of target genes; in addition, left atrium volumes, appendage length and duct contraction were preserved.

Conclusion

In this study, RFAC effectively estimated the degree of systolic dysfunction and discriminated the regions preserved by pharmacological treatment. RFAC index is a promising tool to monitor changes in LV contraction and to assess the effectiveness of therapeutic regimens in clinical settings.     

Disproportionate Contribution of Right Middle Lobe to Emphysema and Gas Trapping on Computed Tomography

Rationale

Given that the diagnosis of chronic obstructive pulmonary disease (COPD) relies on demonstrating airflow limitation by spirometry, which is known to be poorly sensitive to early disease, and to regional differences in emphysema, we sought to evaluate individual lobar contributions to global spirometric measures.

Methods

Subjects with COPD were compared with smokers without airflow obstruction, and non-smokers. Emphysema (% low attenuation area, LAA_insp<−950 HU, at end-inspiration) and gas trapping (%LAA_exp<−856 HU at end-expiration) on CT were quantified using density mask analyses for the whole lung and for individual lobes, and distribution across lobes and strength of correlation with spirometry were compared.

Results

The right middle lobe had the highest %LAA_insp<−950 HU in smokers and controls, and the highest %LAA_exp<−856 HU in all three groups. While RML contributed to emphysema and gas trapping disproportionately to its relatively small size, it also showed the least correlation with spirometry. There was no change in correlation of whole lung CT metrics with spirometry when the middle lobe was excluded from analyses. Similarly, RML had the highest %LAA_exp<−856 HU while having the least correlation with spirometry.

Conclusions

Because of the right middle lobe’s disproportionate contribution to CT-based emphysema measurements, and low contribution to spirometry, longitudinal studies of emphysema progression may benefit from independent analysis of the middle lobe in whole lung quantitative CT assessments. Our findings may also have implications for heterogeneity assessments and target lobe selection for lung volume reduction.

Clinical Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00608764","term_id":"NCT00608764"}}NCT00608764     

The effects of sleep hypoxia on coagulant factors and hepatic inflammation in emphysematous rats

Objectives

To develop a sleep hypoxia (SH) in emphysema (SHE) rat model and to explore whether SHE results in more severe hepatic inflammation than emphysema alone and whether the inflammation changes levels of coagulant/anticoagulant factors synthesized in the liver.

Methods

Seventy-five rats were put into 5 groups: SH control (SHCtrl), treated with sham smoke exposure (16 weeks) and SH exposure (12.5% O₂, 3 h/d, latter 8 weeks); emphysema control (ECtrl), smoke exposure and sham SH exposure (21% O₂); short SHE (SHEShort), smoke exposure and short SH exposure (1.5 h/d); mild SHE (SHEMild), smoke exposure and mild SH exposure (15% O₂); standard SHE (SHEStand), smoke exposure and SH exposure. Therefore, ECtrl, SHEShort, SHEMild and SHEStand group were among emphysematous groups. Arterial blood gas (ABG) data was obtained during preliminary tests. After exposure, hepatic inflammation (interleukin -6 [IL-6] mRNA and protein, tumor necrosis factor α [TNFα] mRNA and protein) and liver coagulant/anticoagulant factors (antithrombin [AT], fibrinogen [FIB] and Factor VIII [F VIII]) were evaluated. SPSS 11.5 software was used for statistical analysis.

Results

Characteristics of emphysema were obvious in emphysematous groups and ABGs reached SH criteria on hypoxia exposure. Hepatic inflammation parameters and coagulant factors are the lowest in SHCtrl and the highest in SHEStand while AT is the highest in SHCtrl and the lowest in SHEStand. Inflammatory cytokines of liver correlate well with coagulant factors positively and with AT negatively.

Conclusions

When SH is combined with emphysema, hepatic inflammation and coagulability enhance each other synergistically and produce a more significant liver-derivative inflammatory and prothrombotic status.     

Endobronchial Coils for Severe Emphysema Are Effective Up to 12 Months following Treatment: Medium Term and Cross-Over Results from a Randomised Controlled Trial

Background

There is a clinical need for therapeutic options to reduce hyperinflation associated with severe emphysema. Endobronchial Coils (coils) are nitinol devices implanted bronchoscopically under fluoroscopic guidance to re-tension the lung. We report the medium term effectiveness and safety of coils in a study of patients with emphysema.

Methods

Forty five subjects with severe airflow obstruction and hyperinflation received bilateral sequential treatment with coils (30 day interval between treatments) as part of a randomised controlled trial with a primary endpoint 90 days after the final treatment (Clinicaltrials.gov NCT01334307). Further assessments were made at 180 and 360 days and in this study the primary outcome was the effect of coil treatment on the St. George’s Respiratory Questionnaire (SGRQ) 360 days following treatment.

Results

At 360 days following treatment, there was an improvement in the SGRQ score of -6.1±14.0 points (p = 0.01) compared to baseline. Improvements in secondary outcomes were seen with increases in forced expiratory volume in the first second of 8.9 ±22.2% (p = 0.002) and 6-minute walking distance of 34.1±52.4m (p = 0.003). The safety profile was acceptable out to 360 days post-treatment.

Conclusions

Statistically and clinically meaningful benefits in quality of life, exercise capacity and pulmonary function in patients treated with coils are sustained twelve months after treatment.

Trial registration information

Clinicaltrials.gov NCT01334307.     

Risk Factors for Lobar and Non-Lobar Intracerebral Hemorrhage in Patients with Vascular Disease

Introduction

Lobar and non-lobar non-traumatic intracerebral hemorrhage (ICH) are presumably caused by different types of small vessel diseases. The aim of this study was to assess risk factors for ICH according to location.

Methods

In two large prospective studies, SMART (n = 9088) and ESPRIT (n = 2625), including patients with manifest cardiovascular, cerebrovascular or peripheral artery disease or with vascular risk factors, we investigated potential risk factors for ICH during follow-up according to lobar or non-lobar location by Cox proportional hazards analyses.

Results

During 65,156 patient years of follow up 19 patients had lobar ICH (incidence rate 29, 95% CI 19–42 per 100,000 person-years) and 24 non-lobar ICH (incidence rate 37, 95% CI 26–51 per 100,000 person-years). Age significantly increased the risk of lobar ICH (HR per 10 years increase 1.90; 95% CI 1.17–3.10) in the multivariable analysis, but not of non-lobar hemorrhage. Anticoagulant medication (HR 3.49; 95% CI 1.20–10.2) and male sex (HR 3.79; 95% CI 1.13–12.8) increased the risk of non-lobar but not lobar ICH.

Conclusion

This study shows an elevated risk of future ICH in patients with manifestations of, or risk factors for, cardiovascular, cerebrovascular or peripheral artery disease. Our data suggest that risk factors for ICH vary according to location, supporting the hypothesis of a differential pathophysiology of lobar and non-lobar ICH.