Sleep-disordered breathing and nocturnal hypoxemia in young adults with sickle cell disease.

Sleep-disordered breathing (SDB) is reported in up to 69% of adolescents and children with sickle cell disease (SCD) [1], but data regarding the prevalence of SDB in adults with SCD are limited. In order to obtain a preliminary assessment of the frequency and degree of sleep-related hypoxemia and potential associations with cardiovascular function in adults with SCD, we conducted overnight sleep studies, 6-min walk tests, echocardiograms, and hematologic and chemistry panels, calculated the Pittsburgh sleep quality index (PSQI), and conducted fatigue- and health-related quality-of-life measurement in 20 young adults with SCD visiting a sickle cell clinic for routine care. Sleep apnea, defined as an apnea-hypopnea index (AHI) > 5 events/h, was found in 50% of patients. Traditional clinical indicators, such as obesity, the presence of snoring, and reported sleep complaints, did not reliably differentiate them. The patients with AHI > 5 had higher mean systolic blood pressure (p = 0.03), evidence of impaired left ventricular diastolic function (i.e., increased mitral valve E/A ratio, p = 0.05), a trend toward higher reduction in 6-min walk distances (p = 0.06), and lower health-related quality-of-life scores (p ≤ 0.01). Three of nine patients with more severe anemia (total Hb < 9.0) showed nocturnal hypoxemia in the absence of sleep apnea. As prolonged and frequent hypoxemic episodes likely increase risks for vaso-occlusive, cardiovascular, and neurologic complications of SCD, these results suggest that the prevalence and severity of SDB should be investigated further in studies of larger patient populations. If confirmed, these findings could identify opportunities to prevent or reduce nocturnal hypoxia and improve outcomes.

Role of free radicals in the pathogenesis of acute chest syndrome in sickle cell disease.

Acute chest syndrome (ACS) of sickle cell disease (SCD) is characterized pathologically by vaso-occlusive processes that result from abnormal interactions between sickle red blood cells (RBCs), white blood cells (WBCs) and/or platelets, and the vascular endothelium. One potential mechanism of vascular damage in ACS is by generation of oxygen-related molecules, such as superoxide (O2-), hydrogen peroxide (H2O2), peroxynitrite (ONOO-), and the hydroxyl (*OH) radical. The present review summarizes the evidence for alterations in oxidant stress during ACS of SCD, and the potential contributions of RBCs, WBCs and the vascular endothelium to this process.

Current management of primary pulmonary hypertension.

Primary pulmonary hypertension (PPH) is a rare disorder with an annual incidence of 1 to 2 per million people. The aetiology of this disorder is unknown, but it appears to result from an abnormal interaction of environmental and genetic factors leading to a vasculopathy. The pulmonary arteries in these patients exhibit a spectrum of pathological lesions ranging from the early medial hypertrophy to the end-stage fibrotic plexiform lesions. This characteristic pathology is also observed in pulmonary hypertension resulting from connective tissue disease (particularly systemic sclerosis), HIV infection, portal hypertension and certain toxins. PPH is a condition that is difficult to diagnose and treat, with a median survival of 2.8 years in historical studies. One of the difficulties in treating patients with PHH is that the subacute nature of disease presentation often prevents an accurate diagnosis during the early stages of the illness. Progressive dyspnoea on exertion is the most common presenting symptom. Diagnostic evaluation should include electrocardiography, chest radiograph and echocardiography, and laboratory and other studies to evaluate for secondary causes (e.g. pulmonary function tests, chest computed tomography and ventilation/perfusion scans, pulmonary arteriogram, cardiopulmonary testing, right heart catherisation). PHH is a disorder for which there is no known cure. Current medical and surgical treatment options for patients with PHH include anticoagulation, vasodilators and transplantation. Calcium channel antagonists are currently the oral drugs of choice for the treatment of patients with New York Heart Association (NYHA) Class II disease. These agents, in particular the dihydropyridine compounds, have beneficial effects on haemodynamics and right ventricular function, and possibly increased survival. Epoprostenol is administered by intravenous infusion, and studies have demonstrated short- and long-term improvements in symptoms, haemodynamics and survival. It is well tolerated and has become the treatment of choice for patients with NYHA Class III and IV disease. Inotropic agents are used as a bridge to transplant, which is indicated in patients who do not respond to maximal medical therapy. Experience has shown that single lung, double lung and heart-lung transplantation are approximately of equal efficacy. Currently, single lung transplant appears to be the procedure of choice. Newer agents, such as sildenafil, beraprost and bosentan, are presently being evaluated for the treatment of this disorder. Future study should include elucidation of the pathogenic mechanisms in the development of this vasculopathy, which will hopefully lead to the development of improved treatment options for patients with PHH.

Increased F2 isoprostanes in the acute chest syndrome of sickle cell disease as a marker of oxidative stress.

Nitric oxide metabolism is altered during the acute chest syndrome of sickle cell disease. In the presence of oxygen and oxygen-related molecules, nitric oxide can preferentially form the powerful oxidants nitrite, nitrate, and peroxynitrite. We hypothesized that increased oxidative stress may contribute to the pathogenesis of acute chest syndrome and measured F2 isoprostanes, a nonenzymatically generated molecule resulting from free radical catalyzed lipid peroxidation in patients with sickle cell disease in various stages of disease. Plasma samples were obtained from nineteen patients with sickle cell disease during acute chest syndrome (pre- and postexchange transfusion), vasoocclusive crisis, and/or at baseline; 12 normal volunteers served as controls. F2 isoprostanes were measured by gas chromatography/mass spectrophotometry. There was a 9-fold increase in F2 isoprostanes in patients with acute chest syndrome as compared with normal volunteers. There was approximately a 50-60% decline in isoprostanes postexchange transfusion to a level similar to that of patients with sickle cell disease at baseline. There was no difference in isoprostanes between vasoocclusive crisis and patients with sickle cell disease at baseline. Increased oxidative stress, measured by generation of F2 isoprostanes, occurs during acute chest syndrome and may have an important role in the pathogenesis of this disease process.

Lipopolysaccharide binding protein potentiates airway reactivity in a murine model of allergic asthma.

The development of allergic asthma is influenced by both genetic and environmental factors. Epidemiologic data often show no clear relationship between the levels of allergen and clinical symptoms. Recent data suggest that bacterial LPS may be a risk factor related to asthma severity. Airborne LPS is typically present at levels that are insufficient to activate alveolar macrophages in the absence of the accessory molecule LPS binding protein (LBP). LBP levels are markedly elevated in bronchoalveolar lavage fluids obtained from asthmatic subjects compared with those in normal controls. We hypothesized that LBP present in the lung could augment the pulmonary inflammation and airway reactivity associated with allergic asthma by sensitizing alveolar macrophages to LPS or other bacterial products and triggering them to release proinflammatory mediators. We compared wild-type (WT) and LBP-deficient mice using a defined Ag immunization and aerosol challenge model of allergic asthma. Immunized LBP-deficient mice did not develop substantial Ag-induced airway reactivity, whereas WT mice developed marked bronchoconstriction following aerosol Ag sensitization and challenge with methacholine. Similarly, production of NO synthase 2 protein and the NO catabolite peroxynitrite was dramatically higher in the lungs of WT mice following challenge compared with that in LBP-deficient mice. Thus, NO production appears to correlate with airway reactivity. In contrast, both mice developed similar pulmonary inflammatory cell infiltrates and elevated mucin production. Thus, LBP appears to participate in the development of Ag-induced airway reactivity and peroxynitrite production, but does not seem to be required for the development of pulmonary inflammation.

Endothelial dysfunction in a murine model of mild hyperhomocyst(e)inemia.

Homocysteine is a risk factor for the development of atherosclerosis and its thrombotic complications. We have employed an animal model to explore the hypothesis that an increase in reactive oxygen species and a subsequent loss of nitric oxide bioactivity contribute to endothelial dysfunction in mild hyperhomocysteinemia. We examined endothelial function and in vivo oxidant burden in mice heterozygous for a deletion in the cystathionine beta-synthase (CBS) gene, by studying isolated, precontracted aortic rings and mesenteric arterioles in situ. CBS(-/+) mice demonstrated impaired acetylcholine-induced aortic relaxation and a paradoxical vasoconstriction of mesenteric microvessels in response to superfusion of methacholine and bradykinin. Cyclic GMP accumulation following acetylcholine treatment was also impaired in isolated aortic segments from CBS(-/+) mice, but aortic relaxation and mesenteric arteriolar dilation in response to sodium nitroprusside were similar to wild-type. Plasma levels of 8-epi-PGF(2alpha) (8-IP) were somewhat increased in CBS(-/+) mice, but liver levels of 8-IP and phospholipid hydroperoxides, another marker of oxidative stress, were normal. Aortic tissue from CBS(-/+) mice also demonstrated greater superoxide production and greater immunostaining for 3-nitrotyrosine, particularly on the endothelial surface. Importantly, endothelial dysfunction appears early in CBS(-/+) mice in the absence of structural arterial abnormalities. Hence, mild hyperhomocysteinemia due to reduced CBS expression impairs endothelium-dependent vasodilation, likely due to impaired nitric oxide bioactivity, and increased oxidative stress apparently contributes to inactivating nitric oxide in chronic, mild hyperhomocysteinemia.

Endothelial cell nitric oxide production in acute chest syndrome.

Acute chest syndrome (ACS) is the most common form of acute pulmonary disease associated with sickle cell disease. To investigate the possibility that alterations in endothelial cell (EC) production and metabolism of nitric oxide (NO) products might be contributory, we measured NO products from cultured pulmonary EC exposed to red blood cells and/or plasma from sickle cell patients during crisis. Exposure to plasma from patients with ACS caused a 5- to 10-fold increase in S-nitrosothiol (RSNO) and a 7- to 14-fold increase in total nitrogen oxide (NO(x)) production by both pulmonary arterial and microvascular EC. Increases occurred within 2 h of exposure to plasma in a concentration-dependent manner and were associated with increases in endothelial nitric oxide synthase (eNOS) protein and eNOS enzymatic activity, but not with changes in nitric oxide synthase (NOS) III or NOS II transcripts, inducible NOS (iNOS) protein nor iNOS enzymatic activity. RSNO and NO(x) increased whether plasma was obtained from patients with ACS or other forms of vasoocclusive crisis. Furthermore, an oxidative state occurred and oxidative metabolites of NO, particularly peroxynitrite, were produced. These findings suggest that altered NO production and metabolism to damaging oxidative molecules contribute to the pathogenesis of ACS.

Systemic sclerosis-associated pulmonary hypertension: short- and long-term effects of epoprostenol (prostacyclin).

OBJECTIVE: To evaluate the short- and long-term effects of intravenous epoprostenol in patients with pulmonary hypertension (PH) associated with systemic sclerosis (SSc). METHODS: Sixteen patients with SSc-associated PH and New York Heart Association (NYHA) class III or IV symptomatology underwent right heart catheterization for determination of baseline hemodynamic values. Vasoreactivity was assessed with either inhaled nitric oxide or intravenous adenosine. After a medication washout period, all patients received intravenous epoprostenol in incrementally increasing doses; tolerance was assessed according to symptoms and hemodynamic findings at each dose increment and at the conclusion of the medication trial. Once a stable medication regimen was established, patients were discharged and followed up as outpatients for assessment of symptoms and exercise tolerance as measured by change in the NYHA class. Repeat hemodynamic testing was performed in 4 patients at 1 year and in 2 patients at 2 years of treatment. RESULTS: Therapeutic response to epoprostenol, defined by a reduction in the pulmonary vascular resistance of > or =25%, was achieved in the short-term treatment period in 13 of 16 patients (81.3%). Improvement in symptoms and exercise tolerance occurred in all patients, and a significant short-term hemodynamic response was observed. Followup hemodynamic tests revealed persistent favorable responses in all 4 of the patients studied. CONCLUSION: Most patients with PH secondary to SSc manifest favorable hemodynamic responses to epoprostenol in the short term. Long-term epoprostenol was generally well tolerated and provides a potential therapeutic option for patients with PH secondary to SSc.