John D. Newell

Genome-wide association study of smoking behaviours in patients with COPD

Background Cigarette smoking is a major risk factor for chronic obstructive pulmonary disease (COPD) and COPD severity. Previous genome-wide association studies (GWAS) have identified numerous single nucleotide polymorphisms (SNPs) associated with the number of cigarettes smoked per day (CPD) and a dopamine beta-hydroxylase (DBH) locus associated with smoking cessation in multiple populations. Objective To identify SNPs associated with lifetime average and current CPD, age at smoking initiation, and smoking cessation in patients with COPD. Methods GWAS were conducted in four independent cohorts encompassing 3441 ever-smoking patients with COPD (Global Initiative for Obstructive Lung Disease stage II or higher). Untyped SNPs were imputed using the HapMap (phase II) panel. Results from all cohorts were meta-analysed. Results Several SNPs near the HLA region on chromosome 6p21 and in an intergenic region on chromosome 2q21 showed associations with age at smoking initiation, both with the lowest p=2×10−7. No SNPs were associated with lifetime average CPD, current CPD or smoking cessation with p<10−6. Nominally significant associations with candidate SNPs within cholinergic receptors, nicotinic, alpha 3/5 (CHRNA3/CHRNA5; eg, p=0.00011 for SNP rs1051730) and cytochrome P450, family 2, subfamily A, polypeptide 6 (CYP2A6; eg, p=2.78×10−5 for a non-synonymous SNP rs1801272) regions were observed for lifetime average CPD, however only CYP2A6 showed evidence of significant association with current CPD. A candidate SNP (rs3025343) in DBH was significantly (p=0.015) associated with smoking cessation. Conclusion The authors identified two candidate regions associated with age at smoking initiation in patients with COPD. Associations of CHRNA3/CHRNA5 and CYP2A6 loci with CPD and DBH with smoking cessation are also likely of importance in the smoking behaviours of patients with COPD.

CT-Definable Subtypes of Chronic Obstructive Pulmonary Disease: A Statement of the Fleischner Society

The purpose of this statement is to describe and define the phenotypic abnormalities that can be identified on visual and quantitative evaluation of computed tomographic (CT) images in subjects with chronic obstructive pulmonary disease (COPD), with the goal of contributing to a personalized approach to the treatment of patients with COPD. Quantitative CT is useful for identifying and sequentially evaluating the extent of emphysematous lung destruction, changes in airway walls, and expiratory air trapping. However, visual assessment of CT scans remains important to describe patterns of altered lung structure in COPD. The classification system proposed and illustrated in this article provides a structured approach to visual and quantitative assessment of COPD. Emphysema is classified as centrilobular (subclassified as trace, mild, moderate, confluent, and advanced destructive emphysema), panlobular, and paraseptal (subclassified as mild or substantial). Additional important visual features include airway wall thickening, inflammatory small airways disease, tracheal abnormalities, interstitial lung abnormalities, pulmonary arterial enlargement, and bronchiectasis.

The influence of hyperosmolality on left ventricular contractile state: disparate effects of nonionic and ionic solutions.

Traditional concepts hold that hyperosmolality is a major factor in the myocardial depressant effects of contrast materials. In order to test this hypothesis, the authors studied the effects of intracoronary injections of glucose, mannitol, and sodium chloride solutions varying in osmolality from 300–1800 mOsm in nine anesthetized mongrel dogs instrumented with left ventricular (LV) pressure catheters and intramyocardial ultrasonic segment crystals. The effects of hyperosmolal solutions were studied in the normal state, during beta adrenergic blockade with propanolol, and during systemic hypoxemia. In three dogs, coronary sinus effluent was sampled to determine the changes in the osmolality of the coronary circulation after injection of small amounts of hyperosmolal solutions. Injection of 5 cc of 1800 mOsm solutions of glucose caused the maximum increases in peak (dP/dt) (P < 0.01), dP/dt at an LV pressure of 50 mmHg (dP/dt)50 (P < 0.01), and velocity of contraction (dD/dt) (P < 0.01) compared with controls. The 1800 mOsm solutions of mannitol produced maximum increases in peak (dP/dt) (P < 0.01), (dP/dt)50 (P < 0.01), and (dD/dt) (P < 0.01). Lower osmolality solutions of glucose or mannitol produced smaller increases in myocardial contractile state. Injection of 900 mOsm solutions of sodium chloride caused drastic decreases in LV pressure (P < 0.01), peak (dP/dt) (P < 0.01), (dP/dt)50 (P < 0.01), and (dD/dt) (P < 0.01). In both the normal state and after beta adrenergic blockade there was no significant difference in the magnitude of the response to glucose, mannitol, or sodium chloride. During hypoxemia, the positive inotropic effect of mannitol was greatly attenuated, while the responses to glucose and sodium chloride were unchanged compared with the normal state. Thus, nonionic (molecular) and ionic (dissociating) hyperosmolal solutions have divergent influences on myocardial contraction. Nonionic, hyperosmolal solutions cause a positive, rather than a negative, inotropic effect. These findings imply that excess sodium Na + is the major factor causing the negative inotropic action of contrast media, and that hyperosmolality per se has no role in this regard.

Pulmonary emphysema subtypes on computed tomography: the MESA COPD study.

BACKGROUND Pulmonary emphysema is divided into 3 major subtypes at autopsy: centrilobular, paraseptal, and panlobular emphysema. These subtypes can be defined by visual assessment on computed tomography (CT); however, clinical characteristics of emphysema subtypes on CT are not well defined. We developed a reliable approach to visual assessment of emphysema subtypes on CT and examined if emphysema subtypes have distinct characteristics. METHODS The Multi-Ethnic Study of Atherosclerosis COPD Study recruited smokers with chronic obstructive pulmonary disease (COPD) and controls ages 50-79 years with ≥ 10 pack-years. Participants underwent CT following a standardized protocol. Definitions of centrilobular, paraseptal, and panlobular emphysema were obtained by literature review. Six-minute walk distance and pulmonary function were performed following guidelines. RESULTS Twenty-seven percent of 318 smokers had emphysema on CT. Interrater reliability of emphysema subtype was substantial (K: 0.70). Compared with participants without emphysema, individuals with centrilobular or panlobular emphysema had greater dyspnea, reduced walk distance, greater hyperinflation, and lower diffusing capacity. In contrast, individuals with paraseptal emphysema were similar to controls, except for male predominance. Centrilobular, but not panlobular or paraseptal, emphysema was associated with greater smoking history (+21 pack-years P <.001). Panlobular, but not other types of emphysema, was associated with reduced body mass index (-5 kg/m(2); P = .01). Other than for dyspnea, these findings were independent of the forced expiratory volume in 1 second. Seventeen percent of smokers without COPD on spirometry had emphysema, which was independently associated with reduced walk distance. CONCLUSIONS Emphysema subtypes on CT are common in smokers with and without COPD. Centrilobular and panlobular emphysema, but not paraseptal emphysema, have considerable symptomatic and physiological consequences.

Evaluation of myocardial ischemic damage of various ages by computerized transmission tomography. Time-dependent effects of contrast material.

The potential role of computerized transmission tomography (CTT) in the detection and quantitation of acute myocardial ischemic damage was assessed in 42 excised canine hearts at 2 hours, 8 hours, and 48 hours after coronary occlusion. The CTT scan detected myocardial damage that was 2-48 hours old each time the presence of regional ischemia was confirmed by histochemical straining or epicardial electrocardiographic mapping. Intravenous administration of contrast material enhanced the x-ray attenuation of areas of ischemic damage of 8 and 48 hours duration compared with normal myocardium, but enhanced only normal myocardium in those of 2 hours duration. Volumetric estimation of the extent of damage from the CTT scans in dogs with ischemia of 48 hours duration showed a close linear relationship with the morphometric volume in the absence of contrast material. Quantitation of the area of ischemic damage from the CTT scan after contrast administration resulted in substantial underestimation of the volume of damaged tissue.

Paired inspiratory-expiratory chest CT scans to assess for small airways disease in COPD

BackgroundGas trapping quantified on chest CT scans has been proposed as a surrogate for small airway disease in COPD. We sought to determine if measurements using paired inspiratory and expiratory CT scans may be better able to separate gas trapping due to emphysema from gas trapping due to small airway disease.MethodsSmokers with and without COPD from the COPDGene Study underwent inspiratory and expiratory chest CT scans. Emphysema was quantified by the percent of lung with attenuation < −950HU on inspiratory CT. Four gas trapping measures were defined: (1) Exp−856, the percent of lung < −856HU on expiratory imaging; (2) E/I MLA, the ratio of expiratory to inspiratory mean lung attenuation; (3) RVC856-950, the difference between expiratory and inspiratory lung volumes with attenuation between −856 and −950 HU; and (4) Residuals from the regression of Exp−856 on percent emphysema.ResultsIn 8517 subjects with complete data, Exp−856 was highly correlated with emphysema. The measures based on paired inspiratory and expiratory CT scans were less strongly correlated with emphysema. Exp−856, E/I MLA and RVC856-950 were predictive of spirometry, exercise capacity and quality of life in all subjects and in subjects without emphysema. In subjects with severe emphysema, E/I MLA and RVC856-950 showed the highest correlations with clinical variables.ConclusionsQuantitative measures based on paired inspiratory and expiratory chest CT scans can be used as markers of small airway disease in smokers with and without COPD, but this will require that future studies acquire both inspiratory and expiratory CT scans.

Direct myocardial effects of intracoronary administration of new contrast materials with lost osmolality.

The effects of LV dynamics of the intracoronary administration of three new contrast materials with reduced osmolality were compared with those of a monomeric ionic material, sodium iothalamate, and the nonionic material, metrizamide. In eight anesthetized dogs, the monacid dimer, P286, caused increases in LV dimensions and decreases in LV systolic pressure and parameters of the contractile state. The changes were less than those caused by sodium iothalamte. The alterations in LV function tended to be greater, but not significantly so, during systemic hypoxemia compared to the normal state. The nonionic materials, P297 and iopamidol, like metrizamide, caused no deleterious effects on LV dynamics in either the normal or hypoxemic state. Nonionic materials actually caused a slight increase in parameters of the LV contractile state.

Comparison of spirometric thresholds in diagnosing smoking-related airflow obstruction

Background Diagnosis of chronic obstructive pulmonary disease is based on detection of airflow obstruction on spirometry. There is no consensus regarding using a fixed threshold to define airflow obstruction versus using the lower limit of normal (LLN) adjusted for age. We compared the accuracy and discrimination of the Global Initiative for Chronic Obstructive Lung Disease (GOLD) recommended fixed ratio of forced expiratory volume in the first second/forced vital capacity<0.70 with LLN in diagnosing smoking-related airflow obstruction using CT-defined emphysema and gas trapping as the disease gold standard. Methods Data from a large multicentre study (COPDGene), which included current and former smokers (age range 45–80 years) with and without airflow obstruction, were analysed. Concordance between spirometric thresholds was measured. The accuracy of the thresholds in diagnosing emphysema and gas trapping was assessed using quantitative CT as gold standard. Results 7743 subjects were included. There was very good agreement between the two spirometric cutoffs (κ=0.85; 95% CI 0.83 to 0.86, p<0.001). 7.3% were discordant. Subjects with airflow obstruction by fixed ratio only had a greater degree of emphysema (4.1% versus 1.2%, p<0.001) and gas trapping (19.8% vs 7.5%, p<0.001) than those positive by LLN only, and also smoking controls without airflow obstruction (4.1% vs 1.9% and 19.8% vs 10.9%, respectively, p<0.001). On follow-up, the fixed ratio only group had more exacerbations than smoking controls. Conclusions Compared with the fixed ratio, the use of LLN fails to identify a number of patients with significant pulmonary pathology and respiratory morbidity.

High attenuation areas on chest computed tomography in community-dwelling adults: the MESA study

Evidence suggests that lung injury, inflammation and extracellular matrix remodelling precede lung fibrosis in interstitial lung disease (ILD). We examined whether a quantitative measure of increased lung attenuation on computed tomography (CT) detects lung injury, inflammation and extracellular matrix remodelling in community-dwelling adults sampled without regard to respiratory symptoms or smoking. We measured high attenuation areas (HAA; percentage of lung voxels between −600 and −250 Hounsfield Units) on cardiac CT scans of adults enrolled in the Multi-Ethnic Study of Atherosclerosis. HAA was associated with higher serum matrix metalloproteinase-7 (mean adjusted difference 6.3% per HAA doubling, 95% CI 1.3–11.5), higher interleukin-6 (mean adjusted difference 8.8%, 95% CI 4.8–13.0), lower forced vital capacity (FVC) (mean adjusted difference −82 mL, 95% CI −119–−44), lower 6-min walk distance (mean adjusted difference −40 m, 95% CI −1–−80), higher odds of interstitial lung abnormalities at 9.5 years (adjusted OR 1.95, 95% CI 1.43–2.65), and higher all cause-mortality rate over 12.2 years (HR 1.58, 95% CI 1.39–1.79). High attenuation areas are associated with biomarkers of inflammation and extracellular matrix remodelling, reduced lung function, interstitial lung abnormalities, and a higher risk of death among community-dwelling adults. Increased lung attenuation on CT may identify subclinical lung injury and inflammation in community-dwelling adults http://ow.ly/97k3300tvKX

Contrast enhancement of myocardial infarction: dependence on necrosis and residual blood flow and the relationship to distribution of scintigraphic imaging agents.

All or part of a myocardial infarction (MI) can be preferentially enhanced on computerized transmission tomography after i.v. administration of iodinated contrast material. To examine the relationship of this phenomenon to the presence of myocardial necrosis, the blood flow profile of the MIs and the distribution of radionuclide infarct imaging agents, collateralized infarcts were produced in six dogs (group A) and noncollateralized infarcts were produced in nine dogs (group B). After 48 hours of coronary occlusion, each dog received technetium-99m pyrophosphate (99mTc-PYP), thallium-201 (201T1), indium-111-labeled microspheres and meglumine sodium diatrizoate (Renografin-76) before sacrifice. Residual blood flow in the center of the MI was 3–27% in group A and less than 3% in group B. In group A, the iodine concentration in the center (1.33 mg/g myocardium), periphery (1.48 mg/g), and margin (1.09 mg/g) were several times higher than normal myocardium (0.45 mg/g). The distribution of 99mTc PYP was similar to that of iodine; the distribution of 201TI was roughly the inverse of that of iodine. In group B, the average iodine and 99mTc concentrations in the margin, and periphery of the MI were several times higher than that in normal myocardium, but in the center neither concentration was significantly higher than normal. However, there was no consistent relationship between iodine and 201TI, as concentrations of iodine and 201TI were low in the center of the infarct and were inversely related at other sites. The results show that contrast material has a distribution in MI similar to that of 99mTc PYP and both are markers of ischemic myocardial necrosis. Distribution of both agents in the MI depends on a threshold level of residual myocardial blood flow.