Sanja Jelic

Inflammation, Oxidative Stress, and Repair Capacity of the Vascular Endothelium in Obstructive Sleep Apnea

Background— Indirect evidence implicates endothelial dysfunction in the pathogenesis of vascular diseases associated with obstructive sleep apnea (OSA). We investigated directly whether dysfunction and inflammation occur in vivo in the vascular endothelium of patients with OSA. The effects of continuous positive airway pressure (CPAP) therapy on endothelial function and repair capacity were assessed. Methods and Results— Thirty-two patients with newly diagnosed OSA and 15 control subjects were studied. Proteins that regulate basal endothelial nitric oxide (NO) production (endothelial NO synthase [eNOS] and phosphorylated eNOS) and inflammation (cyclooxygenase-2 and inducible NOS) and markers of oxidative stress (nitrotyrosine) were quantified by immunofluorescence in freshly harvested venous endothelial cells before and after 4 weeks of CPAP therapy. Vascular reactivity was measured by flow-mediated dilation. Circulating endothelial progenitor cell levels were quantified to assess endothelial repair capacity. Baseline endothelial expression of eNOS and phosphorylated eNOS was reduced by 59% and 94%, respectively, in patients with OSA compared with control subjects. Expression of both nitrotyrosine and cyclooxygenase-2 was 5-fold greater in patients with OSA than in control subjects, whereas inducible NOS expression was 56% greater. Expression of eNOS and phosphorylated eNOS significantly increased, whereas expression of nitrotyrosine, cyclooxygenase-2, and inducible NOS significantly decreased in patients who adhered to CPAP ≥4 hours daily. Baseline flow-mediated dilation and endothelial progenitor cell levels were lower in patients than in control subjects, and both significantly increased in patients who adhered to CPAP ≥4 hours daily. Conclusions— OSA directly affects the vascular endothelium by promoting inflammation and oxidative stress while decreasing NO availability and repair capacity. Effective CPAP therapy is associated with the reversal of these alterations.

Vascular Inflammation in Obesity and Sleep Apnea

Background— Unrecognized obstructive sleep apnea (OSA) is highly prevalent in obesity. Both obesity and OSA are associated with vascular endothelial inflammation and increased risk for cardiovascular diseases. We investigated directly whether the endothelial alterations that are attributed commonly to obesity are in fact related to OSA. Methods and Results— Seventy-one subjects with a body mass index ranging from normal to obese underwent attended polysomnography. To assess vascular inflammation and oxidative stress directly, we quantified the expression of nuclear factor-&kgr;B and nitrotyrosine by immunofluorescence in freshly harvested venous endothelial cells. To evaluate basal endothelial nitric oxide (NO) production and activity, we quantified the expression of endothelial NO synthase (eNOS) and phosphorylated eNOS. Vascular reactivity was measured by brachial artery flow-mediated dilation. Expression of eNOS and phosphorylated eNOS and flow-mediated dilation were significantly lower, whereas expression of nitrotyrosine was significantly greater in OSA patients (n=38) than in OSA-free subjects (n=33) regardless of central adiposity. Expression of nuclear factor-&kgr;B was greater in obese OSA patients than in obese OSA-free subjects (P=0.004). Protein expression and flow-mediated dilation were not significantly affected by increasing body mass index or central obesity in OSA patients and in OSA-free subjects. After 4 weeks of continuous positive airway pressure therapy, flow-mediated dilation and expression of eNOS and phosphorylated eNOS significantly increased whereas expression of nitrotyrosine and nuclear factor-&kgr;B significantly decreased in OSA patients who adhered to continuous positive airway pressure ≥4 hours daily. Conclusions— Untreated OSA rather than obesity is a major determinant of vascular endothelial dysfunction, inflammation, and elevated oxidative stress in obese patients.

Inflammation, Oxidative Stress, and the Vascular Endothelium in Obstructive Sleep Apnea

Obstructive sleep apnea (OSA) affects 25% of the Western adult population. It is an independent but seldom-recognized risk factor for hypertension, myocardial infarction, stroke, and increased mortality. Patients with OSA experience repetitive episodes of hypoxia/reoxygenation during transient cessation of breathing that promote systemic oxidative stress and inflammation. Vascular endothelial inflammation and enhanced oxidative stress that are reversible with therapy for OSA were recently demonstrated directly in patients with OSA who were free of overt cardiovascular conditions. Vascular endothelial inflammation and enhanced oxidative stress may in part explain the accelerated progression of atherosclerosis in patients with untreated OSA. The present review will focus on indirect and direct evidence of vascular endothelial inflammation and enhanced oxidative stress in patients with OSA. The potential utility of venous endothelial biopsy technique in evaluating the mechanisms that mediate the effects of systemic conditions such as diabetes mellitus, sleep apnea, and obesity on the vascular endothelium will also be discussed.

Endothelial Function in Obstructive Sleep Apnea

Untreated obstructive sleep apnea (OSA) is an independent risk factor for hypertension, myocardial infarction, and stroke. The repetitive hypoxia/reoxygenation and sleep fragmentation associated with OSA impair endothelial function. Endothelial dysfunction, in turn, may mediate increased risk for cardiovascular diseases. Specifically, in OSA, endothelial nitric oxide availability and repair capacity are reduced, whereas oxidative stress and inflammation are enhanced. Treatment of OSA improves endothelial vasomotor tone and reduces inflammation. We review the evidence and possible mechanisms of endothelial dysfunction as well as the effect of treatment on endothelial function in OSA.

Mechanisms of endothelial dysfunction in obstructive sleep apnea

Endothelial activation and inflammation are important mediators of accelerated atherogenesis and consequent increased cardiovascular morbidity in obstructive sleep apnea (OSA). Repetitive episodes of hypoxia/reoxygenation associated with transient cessation of breathing during sleep in OSA resemble ischemia/reperfusion injury and may be the main culprit underlying endothelial dysfunction in OSA. Additional factors such as repetitive arousals resulting in sleep fragmentation and deprivation and individual genetic suseptibility to vascular manifestations of OSA contribute to impaired endothelial function in OSA. The present review focuses on possible mechanisms that underlie endothelial activation and inflammation in OSA.

Coexistent chronic obstructive pulmonary disease and heart failure in the elderly

The prevalence of chronic obstructive pulmonary disease (COPD) and chronic heart failure (CHF) increases substantially with age. The coexistence of COPD and CHF is common but often unrecognized in elderly patients. To avoid overlooking COPD in elderly patients with known CHF pulmonary function tests should be routinely obtained. Likewise, to avoid overlooking CHF in elderly patients with known COPD left ventricular (LV) function should be routinely assessed. Plasma brain natriuretic peptide levels are useful to differentiate COPD exacerbation from CHF decompensation in patients presenting with acute dyspnea. Aging exacerbates skeletal muscle alterations that occur in patients with CHF and COPD. Skeletal muscle metabolic alterations and atrophy and the resulting deterioration of functional capacity progress rapidly in elderly patients with COPD and CHF. Physical conditioning reverses rapidly progressing skeletal muscle metabolic alterations and atrophy and promotes independence and life quality in the elderly. Physical conditioning is clearly an essential component of the management of elderly patients with COPD and CHF. The pharmacological management of patients with coexistent COPD and CHF should focus on not depriving these patients from long-term beta adrenergic blockade. Long-term beta adrenergic blockade has been repeatedly shown to improve survival in elderly patients with CHF due to LV systolic dysfunction and, contrary to conventional belief, is well tolerated by patients with COPD.

Peripheral venous congestion causes inflammation, neurohormonal, and endothelial cell activation

AIMS Volume overload and venous congestion are typically viewed as a consequence of advanced and of acute heart failure (HF) and renal failure (RF) although it is possible that hypervolaemia itself might be a critical intermediate in the pathophysiology of these diseases. This study aimed at elucidating whether peripheral venous congestion is sufficient to promote changes in inflammatory, neurohormonal, and endothelial phenotype similar to those observed in HF and RF. METHODS To experimentally model peripheral venous congestion, we developed a new method (so-called venous stress test) and applied the methodology on 24 healthy subjects (14 men, age 35 ± 2 years). Venous arm pressure was increased to ∼30 mmHg above the baseline level by inflating a tourniquet cuff around the dominant arm (test arm). Blood and endothelial cells (ECs) were sampled from test and control arm (lacking an inflated cuff) before and after 75 min of venous congestion, using angiocatheters and endovascular wires. Magnetic beads coated with EC-specific antibodies were used for EC separation; amplified mRNA was analysed by Affymetrix HG-U133 Plus 2.0 Microarray. RESULTS Plasma interleukin-6 (IL-6), endothelin-1 (ET-1), angiotensin II (AII), vascular cell adhesion molecule-1 (VCAM-1), and chemokine (C-X-C motif) ligand 2 (CXCL2) were significantly increased in the congested arm. A total of 3437 mRNA probe sets were differentially expressed (P < 0.05) in venous ECs before vs. after testing, including ET-1, VCAM-1, and CXCL2. CONCLUSION Peripheral venous congestion causes release of inflammatory mediators, neurohormones, and activation of ECs. Overall, venous congestion mimicked, notable aspects of the phenotype typical of advanced and of acute HF and RF.

Endothelial repair capacity and apoptosis are inversely related in obstructive sleep apnea

Purpose: To investigate the impact of obstructive sleep apnea (OSA) on endothelial repair capacity and apoptosis in the absence of potentially confounding factors including obesity. Patients and methods: Sixteen patients with a body mass index <30 and newly diagnosed OSA and 16 controls were studied. Circulating levels of endothelial progenitor cells, a marker of endothelial repair capacity, and endothelial microparticles, a marker of endothelial apoptosis, were quantified before and after four-week therapy with continuous positive airway pressure (CPAP). Endothelial cell apoptotic rate was also quantified in freshly harvested venous endothelial cells. Vascular reactivity was measured by flow-mediated dilation. Results: Before treatment, endothelial microparticle levels were greater and endothelial progenitor cell levels were lower in patients with OSA than in controls (P < 0.001 for both). Levels of endothelial microparticles and progenitors cells were inversely related (r = −0.67, P < 0.001). Endothelial progenitor cell levels increased after effective treatment (P = 0.036). Conclusions: In the absence of any co-morbid conditions including obesity, OSA alone impairs endothelial repair capacity and promotes endothelial apoptosis. These early endothelial alterations may underlie accelerated atherosclerosis and increased cardiovascular risk in OSA.

Clinical review: Airway hygiene in the intensive care unit

Maintenance of airway secretion clearance, or airway hygiene, is important for the preservation of airway patency and the prevention of respiratory tract infection. Impaired airway clearance often prompts admission to the intensive care unit (ICU) and can be a cause and/or contributor to acute respiratory failure. Physical methods to augment airway clearance are often used in the ICU but few are substantiated by clinical data. This review focuses on the impact of oral hygiene, tracheal suctioning, bronchoscopy, mucus-controlling agents, and kinetic therapy on the incidence of hospital-acquired respiratory infections, length of stay in the hospital and the ICU, and mortality in critically ill patients. Available data are distilled into recommendations for the maintenance of airway hygiene in ICU patients.

The effect of ventilation on spectral analysis of heart rate and blood pressure variability during exercise.

Heart rate variability (HRV) and systolic blood pressure variability (BPV) during incremental exercise at 50, 75, and 100% of previously determined ventilatory threshold (VT) were compared to that of resting controlled breathing (CB) in 12 healthy subjects. CB was matched with exercise-associated respiratory rate, tidal volume, and end-tidal CO(2) for all stages of exercise. Power in the low frequency (LF, 0.04-0.15 Hz) and high frequency (HF, >0.15-0.4 Hz) for HRV and BPV were calculated, using time-frequency domain analysis, from beat-to-beat ECG and non-invasive radial artery blood pressure, respectively. During CB absolute and normalized power in the LF and HF of HRV and BPV were not significantly changed from baseline to maximal breathing. Conversely, during exercise HRV, LF and HF power significantly decreased from baseline to 100% VT while BPV, LF and HF power significantly increased for the same period. These findings suggest that the increases in ventilation associated with incremental exercise do not significantly affect spectral analysis of cardiovascular autonomic modulation in healthy subjects.