The effect of oral clarithromycin on bronchial airway inflammation in moderate-to-severe stable COPD: a randomized controlled trial.

INTRODUCTION: COPD is characterized by bronchial neutrophilic inflammation. Clarithromycin is a macrolide antibiotic that has antibacterial and anti-inflammatory properties. Macrolide antibiotics have been shown to improve airway inflammation in diffuse pan-bronchiolitis but their role in COPD is undetermined. The aim of the study was to determine if 3 months of therapy with modified-release oral clarithromycin (Klaricid XL) 500 mg/day reduced bronchial airway inflammation in patients with moderate-to-severe stable COPD compared with placebo. METHODS: A prospective, double-blind controlled trial randomized patients with moderate-to-severe stable COPD to 3 months' therapy with oral modified-release clarithromycin 500 mg/day or placebo. Patients underwent saline sputum induction before and after treatment with clarithromycin. The effects of clarithromycin on sputum total cell and neutrophil counts, supernatant interleukin-8 (IL-8), leukotriene B(4) (LTB(4)), tumor necrosis factor (TNF)-alpha, neutrophil elastase (NE), and neutrophil chemotaxis were assessed in comparison with placebo. RESULTS: Of a total of 67 patients included in the trial, 31 were treated with clarithromycin and 36 with placebo. The groups were similar in age, body mass index, history of smoking, and spirometry. Of 60 evaluable patients, 26 and 34 completed 3 months' therapy with clarithromycin and placebo, respectively. Clarithromycin had no significant effect on sputum total cell count, neutrophil count, IL-8, LTB(4), TNFalpha levels or neutrophil elastase. However, clarithromycin did cause a small reduction in the neutrophil differential (p = 0.04 relative to placebo) and neutrophil chemotaxis (p = 0.058 relative to placebo). CONCLUSIONS: Oral clarithromycin 500 mg/day administered for 3 months had no significant effect on sputum neutrophil numbers or cytokine levels in patients with moderate-to-severe stable COPD. However, clarithromycin did cause a small reduction in the neutrophil differential and neutrophil chemotaxis. Further studies may be warranted to determine the clinical significance of these findings.

Ventricular-arterial coupling in obstructive sleep apnea.

Arterial elastance (Ea) and systolic elastance are important parameters determining effective functional interaction of heart and vessels. The aims of this study were to (1) compare arterial (arterial elastance index [EaI]) and ventricular (end-systolic elastance [Ees] and end-diastolic elastance [Eed]) elastance in subjects with obstructive sleep apnea (OSA) and patients with treated 'high-risk' hypertension (HHT) and (2) test whether these parameters in OSA patients can be improved by continuous positive airway pressure (CPAP) therapy. Echocardiographic parameters of cardiac and vascular stiffness (EaI, Ees, and Eed) were quantified in 28 patients with OSA (mean [standard deviation], age 51 [11] years; 79% male) and 28 treated subjects with HHT (mean [standard deviation], age 48 [12] years; 61% male). Twenty-three OSA patients were treated with CPAP for median of 26 weeks. Ea was calculated from stroke volume and systolic BP and adjusted by body area (EaI). Both study groups had preserved and comparable left ventricle contractility. There was no significant differences in EaI (P = .94), Ees (P = .5), Eed (P = .63), and arterial-ventricular interaction (P = .62) between OSA and HHT groups. After CPAP therapy, there was a significant reduction in EaI (paired t test, P = .013) and arterial-ventricular interaction (paired t test, P = .004). Ees (P = .17) and Eed (P = .66) parameters did not change significantly. OSA and HHT patients have similar parameters of elastance and ventricular-arterial coupling. CPAP treatment in OSA patients significantly improved ventricular-arterial coupling.

Left ventricular systolic and diastolic function in obstructive sleep apnea: impact of continuous positive airway pressure therapy.

BACKGROUND: Previous studies in obstructive sleep apnea (OSA) were limited by study cohorts with comorbidities that confound assessment of left ventricular (LV) systolic and diastolic function. We comprehensively evaluated LV function using 2-dimensional echocardiography (2DE), tissue Doppler imaging (TDI), and 3-dimensional echocardiography (3DE) in subjects moderate-severe OSA, who were compared with disease (patients with hypertension, no OSA) and healthy control subjects. METHODS AND RESULTS: A total of 120 subjects (n=40 each of matched OSA, hypertension and healthy cohorts) underwent echocardiographic examination for the assessment of septal and posterior wall thickness, LV mass index, LV volumes and ejection fraction, mitral valve inflow indices (E, A), mitral annular velocity (S, E'), and left atrial volume index (LAVI). OSA subjects were treated with continuous positive airway pressure (mean duration of 26 weeks), after which the echocardiographic parameters were reassessed. Posterior wall thickness and LV mass index were significantly higher in OSA and hypertensive groups compared with healthy. Systolic S velocity was reduced in OSA and hypertensive compared with healthy control subjects (P<0.05). Diastolic function (E/A, IVRT, and E/E') was impaired in both OSA and hypertensive groups. On 3DE, mean LAVI was significantly greater in OSA and hypertensive compared with healthy. In OSA patients, continuous positive airway pressure therapy resulted in reduction of the posterior wall thickness (P=0.02) and improvement in LV ejection fraction (P<0.05), systolic S velocity (P<0.05), and diastolic LV impairment parameters. CONCLUSIONS: Moderate to severe OSA causes structural and functional changes in V function and are comparable to that seen in hypertension. These abnormalities significantly improve after CPAP therapy.

Myocardial perfusion by myocardial contrast echocardiography and endothelial dysfunction in obstructive sleep apnea.

Obstructive sleep apnea is associated with increased cardiovascular morbidity and mortality. We investigated myocardial perfusion using real-time quantitative myocardial contrast echocardiography with concurrent assessment of macrovascular and microvascular endothelial dysfunction in normotensive subjects with moderate-to-severe obstructive sleep apnea, who were compared with hypertensive and healthy subjects, as well as the impact of continuous positive airway pressure treatment on obstructive sleep apnea subjects. We measured flow (hyperemia)-mediated dilation and response to glyceryl trinitrate of brachial artery (ultrasound), cutaneous perfusion responses to acetylcholine and sodium nitroprusside (laser Doppler), pulse wave velocity, and circulating endothelial and endothelial progenitor cells in a total of 108 subjects (n=36 each of matched obstructive sleep apnea, hypertension, and healthy cohorts). Subjects with obstructive sleep apnea and hypertension demonstrated abnormal myocardial perfusion (P<0.001 for both comparisons), attenuated brachial artery reactivity (P<0.001), and cutaneous perfusion responses (P<0.001) compared with healthy individuals. Both hypertensive and obstructive sleep apnea patients showed significant improvements in myocardial perfusion (P<0.01), brachial artery reactivity (P<0.001), and cutaneous perfusion responses (P<0.001) after 26 weeks of continuous positive airway pressure therapy. There were no significant differences in pulse wave velocity and endothelial cells across the 3 groups. Concomitant endothelial dysfunction and impaired myocardial perfusion are present in otherwise normal subjects with moderate-to-severe obstructive sleep apnea, and effective continuous positive airway pressure treatment reverses many of these macrovascular/microvascular abnormalities.