Luciano Corda

Snoring and risk of cardiovascular disease

In order to evaluate the possible role played by snoring as a risk factor for cardiovascular disease, we studied 400 patients aged 30-80 years, divided into 4 groups matched for age, sex and body mass index. The first group consisted of 100 patients who snored, having risk factors (hypertension, diabetes, obesity, smoking, high serum cholesterol level) for cardiovascular disease. The second group consisted of 100 non-snoring patients with risk factors. The third and fourth groups were formed by 100 snoring and 100 non-snoring patients without risk factors. We investigated the morbidity and the mortality from cardiovascular disease over a period of five years (1982-1987). An increase in morbidity and mortality was found for snorers with risk factors (36 and 17 respectively) compared to non-snorers with risk factors (10 and 4, P less than 0.001), and also to both snorers and non-snorers without risk factors (7 and 3, P less than 0.001; 3 and 1, P less than 0.001 respectively). No difference was noted between snorers and non-snorers without risk factors. A higher morbidity and mortality for cardiovascular disease was found in snorers with risk factors as compared with non-snorers having risk factors. Furthermore, the morbidity and mortality in patients without risk factors was found to be lower compared with that found in snorers with risk factors. In conclusion, snoring worsened the prognosis of patients with risk factors for cardiovascular disease, but did not represent an independent or predictive risk factor in itself.

Alpha-1-Antitrypsin Deficiency-Associated Cervical Artery Dissection: Report of Three Cases

The pathogenesis of cervical artery dissection is poorly understood. Deficiency of the elastase inhibitor alpha-1-antitrypsin may represent a predisposing condition. Biochemical and genetic analyses in a series of 12 consecutive patients with spontaneous dissection of the neck vessels showed 3 cases associated to alpha-1-antitrypsin deficiency, in combination with transient precipitating factors. A disequilibrium between proteolytic enzymes and protease inhibitors may contribute to the pathogenesis of cervical artery dissection leading to structural abnormalities of the extracellular matrix and increasing the susceptibility of the vessel wall to additional short-lived trigger mechanisms.

Airway distensibility and volume recruitment with lung inflation in COPD

The effects of full lung inflation on respiratory conductance (Grs) and reactance (Xrs) were measured in 15 subjects with moderate to severe chronic obstructive pulmonary disease (COPD) and 11 matched healthy control subjects. Airway distensibility was estimated from the ratio of the difference of Grs between functional residual capacity and total lung capacity to the relevant changes in lung volume (ΔGrs/ΔVl) or transpulmonary pressure (ΔGrs/ΔPtp). Similar analysis was applied to Xrs to estimate lung volume recruitment (ΔXrs/ΔVl or ΔXrs/ΔPtp). The extent of emphysema in COPD subjects was estimated from the percentage of low attenuation area (LAA) at high-resolution computed tomography. At baseline, ΔGrs/ΔVl and ΔXrs/ΔVl were significantly less in COPD than control subjects, indicating less distensibility and volume recruitment in the former. In COPD, ΔGrs/ΔPtp and ΔXrs/ΔPtp were uncorrelated with LAA but correlated with 1-s forced expiratory volume and with each other. After albuterol, both ΔGrs/ΔPtp and ΔGrs/ΔVl became significantly and negatively correlated with LAA, while ΔXrs/ΔPtp and ΔXrs/ΔVl decreased significantly independently of LAA. Moreover, ΔGrs/ΔPtp and ΔXrs/ΔPtp with lung inflation were no longer correlated with each other, suggesting that airway distensibility and volume recruitment were affected differently by airway smooth muscle tone. Assuming that Grs mainly reflects airway caliber and Xrs the number of ventilated lung units, we conclude that airway smooth muscle contributes to airway stiffness and ventilation inhomogeneities in COPD subjects with prevailing bronchitis but only to the latter in those with more emphysema. We suggest that changes of airway distensibility and volume recruitment with a bronchodilator may be useful for disease phenotyping.

Effects on small airway obstruction of long-term treatments with beclomethasone/formoterol hydrofluoroalkane (metered-dose inhaler) versus fluticasone/salmeterol (dry-powder inhaler) in asthma: a preliminary study.

New formulations of extrafine particles of long-acting beta-2 agonists plus inhaled corticosteroids (LABA + ICS) have been shown to reach peripheral regions of the lung. The aim of the study was to assess the effect on small airway obstruction of long-term treatments with two different LABA + ICS formulations in asthma. Ten subjects with moderate persistent asthma were enrolled. After a 4-week washout period they were treated in a randomized crossover design for 24 weeks with formoterol, 12 micrograms, and beclomethasone, 200 micrograms, hydrofluoroalkane (HFA; by metered-dose inhaler) b.i.d. (FB) or salmeterol, 50 micrograms, and fluticasone, 250 micrograms (by dry-powder inhaler), b.i.d. (SF). At baseline and at the end of each period subjects underwent an Asthma Control Test (ACT) and Pulmonary Function Testing. The N(2) phase III slope and closing volume (CV) during single-breath washout test and difference between the maximal expiratory flow rates with air and heliox at isovolume corresponding to 50% [Delta(heliox-air)MEF(50%)] were measured to assess changes on peripheral airways function. Two subjects dropped out and eight completed the study. After SF and FB, forced expiratory volume at 1 second (FEV(1); p < 0.01) and FEV(1)/forced vital capacity (FVC; p < 0.01 for SF and p < 0.05 for FB) increased when compared with baseline. Although both FB and SF treatments slightly increased delta(heliox-air)MEF(50% isovolume) versus baseline, only after FB the N(2) phase III slope and CV decreased from 1.61 ± 0.61%/L to 1.35 ± 0.49 N(2)%/L (p = 0.054) and from 0.98 ± 0.56 L to 0.88 ± 0.58 L (p < 0.05), respectively. ACT score raised from 19 ± 5 (baseline) to 23 ± 1 after FB (p < 0.02) and 23 ± 2 after SF (p < 0.05). When compared with baseline and in contrast to SF (50/250 micrograms b.i.d.), FB HFA (12/200 micrograms b.i.d.) significantly improved functional parameters reflecting small airway obstruction in asthmatic patients. Registered in the public trial registry at www.ClinicalTrials.gov identifier: NCT01255579.

Inhaled Corticosteroids as Additional Treatment in Alpha-1-Antitrypsin-Deficiency-Related COPD

Background: No consistent data are available regarding the effect of inhaled corticosteroids (ICS) in α1-antitrypsin-deficiency (AATD)-related COPD. Recent data report inflammatory effects of the polymers of α1-antitrypsin on the peripheral lung. Objectives: The aim of this study was to assess the effectiveness of an extra-fine ICS, hydrofluoroalkane-134a beclometasone dipropionate (HFA-BDP) with a mass median aerodynamic diameter of 1.1 µm, on lung function and exercise tolerance in COPD patients with AATD when added to long-acting bronchodilators (LABAs). Methods: After a 1-week washout, 8 steroid-naïve COPD patients with AATD (ZZ genotype), within a double-blind randomized cross-over study, were assigned to one of the following 16-week treatments: (1) HFA-BDP 400 µg b.i.d., salmeterol 50 µg b.i.d. and oxitropium bromide 200 µg t.i.d. or (2) placebo, salmeterol 50 µg b.i.d. and oxitropium bromide 200 µg t.i.d; after a 2-week washout period they received the other treatment. In weeks 1, 17, 19 and 35, patients took a spirometry assessment (breathing air and heliox) and a shuttle walking test (SWT) with dyspnea assessed by the modified Borg scale. Results: Significant differences in improvement were found in FEV1, FVC, IC, distance covered and dyspnea perceived during SWT between the 2 treatments and baseline values (p < 0.05; Friedman’s test). However, further analysis showed that only the LABAs + ICS condition showed significant increases in the FEV1, FVC, IC, ΔMEF50% and distance covered during SWT along with a reduction in maximum isostep exertional dyspnea (p < 0.05; Wilcoxon test). A greater distance was walked at the end of the SWT with LABA + ICS than LABAs alone (301 ± 105 vs. 270 ± 112 m; p < 0.05). Conclusions: In AATD-related COPD patients (ZZ genotype) the addition of extra-fine ICS to LABAs decreases airway narrowing, mostly in the small airways, further reducing dynamic hyperinflation with a marked improvement in exercise tolerance and dyspnea, suggesting that a peripheral inflammatory process contributes to airflow obstruction in these patients.

Elastic properties of the ascending aorta in patients with α1-antitrypsin deficiency (Z homozygotes)

Objective and design α1-Antitrypsin deficiency (AATD) is a genetic disorder that may be a pathogenic factor in vascular aneurysms and dissection. The aim of this study was to measure the diameters of the Valsalva sinuses (VS), sinotubular junction (STJ), ascending aorta (AA) and aortic arch (AAr) and elastic properties of the AA (distensibility, stiffness and tissue Doppler imaging (TDI strain)) in AATD subjects. Patients 33 AATD subjects (all Z-homozygous, 17 male, 16 female) were examined. Aortic elastic properties, namely, distensibility and stiffness index, were calculated from the echocardiographically-derived thoracic aortic diameters and TDI strain was measured on the wall of the AA 3 cm above the aortic valve. The results were compared with those obtained in healthy controls matched for age, sex and body mass index. Results AATD subjects had larger aortic diameters (VS: 3.5±0.5 vs 3.2±0.5 cm, p<0.05; STJ 2.7±0.4 vs 2.4±0.4 cm, p<0.01; AA 3.3±0.5 vs 2.9±0.4 cm, p<0.01; AAr 2.3±0.3 vs 2.1±0.3 cm, p=0.05); greater aortic stiffness 14.9±11.9 versus 7.4±4.4 (pure numbers, p<0.005); and less aortic distensibility 2.4±1.8 versus 4.0±2.6 10−6×cm2×dyne−1, p<0.005. Peak systolic (S) and diastolic (E and A) waves of the aortic wall TDI were similar in patients and controls (S wave: 5.4±1.6 vs 5.9± 2.3 cm/s; E wave: −4.8±2.2 vs −4.5±2.2 cm/s; A wave: −6.1±2.2 vs −6.2±2.4 cm/s) while TDI strain of the aortic wall was lesser in patients than controls (−14.7±8.0% vs −28.3±7.1%, p<0.001). Conclusions AATD subjects have a larger AA with abnormal elastic properties as compared to controls. The increase in stiffness, decrease in distensibility and abnormal strain of the aortic wall may all reflect pathological changes in its elastic tissue.

Italian Registry of Patients with Alpha-1 Antitrypsin Deficiency: General Data and Quality of Life Evaluation

Abstract Alpha1-antitrypsin Deficiency (AATD) is a rare hereditary disorder with an estimated prevalence of about 1/5000 individuals in Italy. Deficient patients are at a higher risk of developing lung emphysema and chronic liver disease. The low estimated prevalence of AATD prompted the establishment of a registry with the aim of learning more about the natural history and the quality of care of these patients. The Italian registry for AATD was established in 1996. In this study, genetic and clinical findings of Italian AATD patients are presented. Moreover, we also evaluated the changes in health-related quality of life (HRQoL) in patients with COPD and AAT deficiency over a three-year period, in relation to augmentation therapy. In a period spanning 18 years (1996–2014) a total of 422 adult subjects with severe AATD were enrolled, namely 258 PI*ZZ, 74 PI*SZ, 4 PI*SS and 86 patients with at least one rare deficient allele. The 21.3% frequency for AATD patients with at least one deficient rare variant is the highest so far recorded in national registries of AATD. The registry data allow a detailed characterization of the natural course of the disease and the level of patient care, as well as confirm the usefulness of early AATD detection.

Polymers of Z α1-antitrypsin are secreted in cell models of disease

The α1-antitrypsin (α1-AT) is a 52 kDa glycoprotein that is predominantly synthesised in the liver and secreted into the circulation, where it protects the lungs from the enzyme neutrophil elastase. α1-AT deficiency (α1-ATD) is caused by mutations in the α1-AT gene, with most cases resulting from homozygous inheritance of the Z allele (Glu342Lys). This leads to low levels of circulating α1-AT, uncontrolled elastase activity and emphysema [1]. The Z mutation destabilises the native α1-AT and causes the formation of aberrant polymers that accumulate within the endoplasmic reticulum (ER) of hepatocytes, giving rise to inclusion bodies that are the main histological feature of α1-ATD [2]. Extracellular polymers have been found in lung lavage, the skin of an individual with panniculitis and the kidney of an individual with vasculitis [1], and are also present in the circulation of all individuals homo- or heterozygous for the Z allele [3]. Circulating polymers originate in the liver, since they became undetectable in the plasma of an individual 4 days after liver transplantation [3], but it is unknown whether polymers can be secreted from hepatocytes or can form in the extracellular environment from secreted monomeric Z α1-AT. Extracellular polymers are chemotactic and stimulatory for human neutrophils [4] and may contribute to inflammatory neutrophil infiltration in the lungs, kidney and skin. It is important to understand where these polymers form in order to design effective therapies for emphysema and other pathological manifestations of α1-ATD. Here we investigated the origin of extracellular polymers by exploiting our cellular models of α1-ATD and conformer-specific and functional monoclonal antibodies (mAb) against Z α1-AT [5–8]. Pathological polymers of Z alpha1-AT can be secreted from cells through the canonical secretory pathway http://ow.ly/WHxZh

Exercise tolerance in obstructive sleep apnea-hypopnea (OSAH), before and after CPAP treatment: Effects of autonomic dysfunction improvement

BACKGROUND Obstructive sleep apnea hypopnea (OSAH) is associated with decreased exercise tolerance and autonomic abnormalities and represents a risk for cardiovascular diseases. The aim of the study was to evaluate the effects of CPAP on cardiovascular autonomic abnormalities and exercise performance in patients with OSAH without changes in lifestyle and body weight during treatment. METHODS Twelve overweight subjects with OSAH underwent anthropometric measures, autonomic cardiovascular and incremental symptom-limited cardio-respiratory exercise tests before and after two months of treatment with CPAP. RESULTS Lower frequency component of power spectrum of heart rate variability (59.5±24.2 msec2 vs 43.2±25.9 msec2; p<0.05) and improvements of maximal workload (99.3±13.5 vs 108.3±16.8%pred.; p<0.05) and peak oxygen consumption (95.3±7.6 vs 105.5±7.9%pred.; p<0.05) were observed in these patients after CPAP, being their BMI unchanged. CONCLUSIONS CPAP-induced decrease of sympathetic hyperactivity is associated with better tolerance to the effort in OSAH patients that did not change their BMI and lifestyle, suggesting that OSAH limits per se the exercise capacity.

The role of bronchial epithelial cells in the pathogenesis of COPD in Z-alpha-1 antitrypsin deficiency

BackgroundAlpha-1 antitrypsin is the main inhibitor of neutrophil elastase in the lung. Although it is principally synthesized by hepatocytes, alpha-1 antitrypsin is also secreted by bronchial epithelial cells. Gene mutations can lead to alpha-1 antitrypsin deficiency, with the Z variant being the most clinically relevant due to its propensity to polymerize. The ability of bronchial epithelial cells to produce Z-variant protein and its polymers is unknown.We investigated the expression, accumulation, and secretion of Z-alpha-1 antitrypsin and its polymers in cultures of transfected cells and in cells originating from alpha-1 antitrypsin-deficient patients.MethodsExperiments using a conformation-specific antibody were carried out on M- and Z-variant–transfected 16HBE cells and on bronchial biopsies and ex vivo bronchial epithelial cells from Z and M homozygous patients. In addition, the effect of an inflammatory stimulus on Z-variant polymer formation, elicited by Oncostatin M, was investigated. Comparisons of groups were performed using t-test or ANOVA. Non-normally distributed data were assessed by Mann–Whitney U test or the Kruskal-Wallis test, where appropriate. A P value of < 0.05 was considered to be significant.ResultsAlpha-1 antitrypsin polymers were found at a higher concentration in the culture medium of ex vivo bronchial epithelial cells from Z-variant homozygotes, compared with M-variant homozygotes (P < 0.01), and detected in the bronchial epithelial cells and submucosa of patient biopsies. Oncostatin M significantly increased the expression of alpha-1 antitrypsin mRNA and protein (P < 0.05), and the presence of Z-variant polymers in ex vivo cells (P < 0.01).ConclusionsPolymers of Z-alpha-1 antitrypsin form in bronchial epithelial cells, suggesting that these cells may be involved in the pathogenesis of lung emphysema and in bronchial epithelial cell dysfunction.