Z-alpha1-antitrypsin polymers and small airways disease: a new paradigm in alfa-1 anti-trypsin deficiency-related COPD development?

The presence of Alpha1-Antitrypsin (AAT) polymers, known to promote a sustained pro-inflammatory activity, has been previously demonstrated in bronchial biopsies of subjects with Z-AAT deficiency (AATD) suggesting a possible role in the development of COPD through a small airway disease impairment. The study aimed to assess the presence of small airways dysfunction and the potential correlation with the presence of Z-AAT polymers obtained by Exhaled Breath Condensate (EBC) collection in PiZZ subjects, as compared with matched healthy PiMM subjects. We enrolled 19 asymptomatic, never smoker subjects: 9 PiZZ and 10 PiMM as controls, without obstructive ventilatory defect (i.e., normal FEV1/VC% ratio). All subjects underwent complete pulmonary function tests (PFT). EBC was collected in all subjects. ELISA test was applied to search for Z-AAT polymers. The PiZZ subjects showed normal lung volumes and DLCO values. However, in comparison with PiMM subjects, the single breath test N2 wash-out revealed significant differences regarding the phase III slope (1.45±0.35 N2/L vs. 0.96±0.40 N2/L) (p<0.02) in the PiZZ subjects, while the closing volume/vital capacity ratio (14.3±4.5 % vs. 11.3±6.3 %) was not significantly increased. The ELISA test detected the presence of Z-AAT polymers in 44% of PiZZ patients. Asymptomatic, never smoker PiZZ subjects with normal spirometry and lung diffusion capacity showed airways impairment when compared to PiMM subjects. Although Z-AAT polymers were found only in 44% of PiZZ subjects, these findings suggest the possibility that chronic bronchiolitis can develop as a result of the long-term pro-inflammatory activity of Z-AAT polymers in subjects with Z-related AATD.

Closing volume detection by single breath gas washout and forced oscillation technique

Closing volume (CV) is commonly measured by single-breath nitrogen washout (CVSBW). A method based on the forced oscillation technique was recently introduced to detect a surrogate CV (CVFOT). As the two approaches are based on different physiological mechanisms, we aim to investigate CVFOT and CVSBW relationship at different degrees and patterns of airway obstruction. A mathematical model was developed to evaluate the CVSBW and CVFOT sensitivity to different patterns of airway obstruction, either located in a specific lung region or equally distributed throughout the lung. The two CVs were also assessed during slow vital capacity (VC) maneuvers in triplicate in 13 healthy subjects and pre and post-methacholine challenge (Mch) in 12 mild-moderate asthmatics. Model simulations suggest that CVSBW is more sensitive than CVFOT to the presence of few flow-limited or closed airways that modify the contribution of tracer-poor and tracer-rich lung regions to the overall exhaled gas. Conversely, CVFOT occurs only when at least ~65% of lung units are flow-limited or closed, regardless of their regional distribution. CVSBW did not differ between healthy subjects and asthmatics (17±9%VC vs 22±10%VC) while CVFOT did (16±5%VC vs 23±6%VC, p<0.01). In asthmatics, both CVSBW and CVFOT increased post-Mch (33±7%VC p<0.001 and 43±12%VC p<0.001, respectively). CVSBW weakly correlated with CVFOT (r=0.45, p<0.01). The closing capacities (CV+residual volume) were correlated (r=0.74, p<0.001) but the changes with Mch in both CVs and closing capacities did not correlate. CVFOT is easy to measure and provides a reproducible parameter useful for describing airway impairment in obstructive respiratory diseases.

Periostin and closing volume in combined pulmonary fibrosis and emphysema

Background Combined pulmonary fibrosis and emphysema (CPFE) is an entity characterized by the presence of emphysema in upper lobes and fibrosis in lower lobes. Due to the presence of the two diseases concomitantly, it may be difficult to diagnose. This study aims at a better understanding of this entity and proposes biological markers (functional and biochemical) that help in this characterization. Methods A prospective, observational, cross-sectional study was carried out at a reference center. Pulmonary function tests (spirometry, CO-diffusion capacity, plethysmography and single-maneuver nitrogen washout test - SBWN 2 ) and biochemical markers (periostin, mucin-16, PDGF-BB and TGF-β 1 ) were measured in groups of patients: idiopathic pulmonary fibrosis, CPFE and chronic obstructive pulmonary disease (COPD). Results Variables derived from SBWN 2 - closing volume (CV) / vital capacity (VC) (%) and closing capacity (CC) / total lung capacity (TLC) (%) - were found to be higher in the CPFE group compared to the Idiopathic pulmonary fibrosis (IPF) group (CV/VC%: 0.25 (0.12 – 11.01) and 13.05 (0.21 – 20.73); p = 0.005; CC/TLC%: 30.1 (22.4 – 37.47) and 33.69 (32.05 – 41.98); p = 0.03, respectively). Periostin was higher in the CPFE group than in the other groups [CPFE: 66.74 (45.21 – 90.5), IPF: 43.81 (31.97 – 56.18), COPD: 40.08 (20.66 – 50.81); p = 0.0002], and mucin-16 was higher in the IPF group than in the CPFE group [CPFE: 13.59 (4.16 – 28.16); IPF: 71.94 (40.46 - 164); COPD: 25.85 (9.27 – 30.29); p = 0.02]. Conclusions Findings show that CPFE presents different functional and biochemical characteristics than IPF, including higher CV/VC%, CC/TLC% and periostin, whereas mucin-16 was higher in the IPF.

Comparative quantification of primary mitral regurgitation by computer modeling and simulated echocardiography

Clinical investigations have demonstrated that mitral regurgitation (MR) quantification using echocardiography (echo) may significantly underestimate or overestimate the regurgitant volume, especially for two-dimensional (2D) echo. Computer modeling and simulated echo were conducted to evaluate the fundamental assumptions in the echo quantification of primary MR that is due to posterior mitral leaflet prolapse. The theoretical flaw of the proximal isovelocity surface area (PISA) method originates from the assumption that the MR flow rate is the product of the isovelocity surface area and aliasing velocity, which is only valid when the velocity vectors are perpendicular to the isovelocity surface. Other factors such as the Doppler angle effect, the view planes of 2D echo, and the single time instant of PISA were also analyzed. We find that the hemielliptic PISA method gives the smallest error for moderate and severe MR cases compared with other PISA methods. Compared with the PISA method, the volumetric technique (VT) is theoretically more robust. By considering correction factors that are caused by nonflat velocity profiles and the closing volume of the aortic valve, the accuracy of the VT method can be significantly improved. The corrected volumetric technique provides more accurate results compared with the PISA methods, especially for mild MR. NEW & NOTEWORTHY We evaluate the accuracy of common echocardiography techniques for the quantification of primary mitral regurgitations using computer modeling. The hemielliptic proximal isovelocity surface area (PISA) method gives the smallest error (within 15%) for moderate and severe mitral regurgitation cases compared with other PISA methods. The volumetric method is theoretically more robust than the PISA method. The accuracy of the volumetric method can be improved by a correction factor around 0.7 because of the nonflat velocity profiles and the closing volume of the aortic valve.

Influence of leaflet geometry on hydrodynamic performance of transcatheter aortic valve prostheses

The implantation of transcatheter aortic valve prostheses (TAVP) for therapy of aortic valve stenosis shows more and more clinically non-inferiority results compared to surgical valve replacement in intermediate and low risk patients. Commonly clinically used TAVP are manufactured from chemically fixed xenograft leaflet material, e.g. bovine or porcine pericardium. While the clinical use of TAVP currently extends, challenges concerning valve durability and leaflet calcification have to be addressed. In this regard, artificial leaflet materials represent a promising option for a next generation of TAVP. As a first step for the development of TAVP from polymeric nonwoven, the aim of this study was to determine the influence of leaflet geometry on hydrodynamic performance of TAVP prototypes. Based on a parametric model of the valve leaflets, we varied the curvature of the belly line forming the leaflet coaptation area from an initial, quite concave, leaflet geometry with a value of 0.5° to an almost straight geometry for the leaflets with a value 0.15°. Manufacturing of TAVP prototypes was conducted by means of electrospinning technique with a polycarbonate based silicone elastomer. Hydrodynamic characterization according to ISO 5840-3 standards was performed using a pulse duplicator system with a heart rate of 70 BPM, systolic duration of 35%, mean aortic pressure of 100 mmHg and a stroke volume of 96 ml. Cardiac output as well as mean transaortic pressure gradient, closing volume, leakage volume and regurgitation were measured to compare the different leaflet geometries. To summarize, the curvature of the leaflets’ belly has a crucial impact on TAVP hydrodynamics under physiological test conditions. In particular, the opening and closing behavior is strongly influenced by a steeper curvature leading to larger closing volumes and higher regurgitant fractions. Further studies are planned to identify an optimum with respect to leaflet material selection, leaflet geometry and hydrodynamic properties of TAVP.

Acute effects of long-acting bronchodilators on small airways detected in COPD patients by single-breath N2 test and lung P-V curve

Small airways represent the key factor of chronic obstructive pulmonary disease (COPD) pathophysiology. The effect of different classes of bronchodilators on small airways is still poorly understood and difficult to assess. Hence the acute effects of tiotropium (18 µg) and indacaterol (150 µg) on closing volume (CV) and ventilation inhomogeneity were investigated and compared in 51 stable patients (aged 70 ± 7 yr, mean ± SD; 82% men) with moderate to very severe COPD. Patients underwent body plethysmography, arterial blood gas analysis, tidal expiratory flow limitation (EFL), dyspnea assessment, and simultaneous recording of single-breath N2 test and transpulmonary pressure-volume curve (PL-V), before and 1 h after drug administration. The effects produced by indacaterol on each variable did not differ from those caused by tiotropium, independent of the severity of disease, assessed according to the Global Initiative for Chronic Obstructive Pulmonary Disease (GOLD) scale and the presence of EFL. Bronchodilators significantly decreased the slope of phase III and CV (−5 ± 4 and −2.5 ± 2.1%, respectively, both P < 0.001), with an increase in both slope and height of phase IV and of the anatomical dead space. Arterial oxygen pressure and saturation significantly improved (3 ± 3 mmHg and 2 ± 2%, respectively, both P < 0.001); their changes negatively correlated with those of phase III slope ( r = −0.659 and r = −0.454, respectively, both P < 0.01). The vital capacity (VC) increased substantially, but the PL-V/VC curve above CV was unaffected. In conclusion, bronchodilators reduce the heterogeneity of peripheral airway mechanical properties and the extent of their closure, with minor effects on critical closing pressure. This should lessen the risk of small-airway damage and positively affect gas exchange. NEW & NOTEWORTHY This is the first study investigating in stable chronic obstructive pulmonary disease patients the acute effects of two long-acting bronchodilators, a β-agonist and a muscarinic antagonist, on peripheral airways using simultaneous lung pressure-volume curve and single-breath N2 test. By lessening airway mechanical property heterogeneity, both drugs similarly reduced ventilation inhomogeneity and extent of small-airway closure, as indicated by the decrease of phase III slope, increased oxygen saturation, and fall of closing volume, often below expiratory reserve volume.