Loss of alveolar membrane diffusing capacity and pulmonary capillary blood volume in pulmonary arterial hypertension.

BACKGROUND: Reduced gas transfer in patients with pulmonary arterial hypertension (PAH) is traditionally attributed to remodeling and progressive loss of pulmonary arterial vasculature that results in decreased capillary blood volume available for gas exchange. METHODS: We tested this hypothesis by determination of lung diffusing capacity (DL) and its components, the alveolar capillary membrane diffusing capacity (D(m)) and lung capillary blood volume (V(c)) in 28 individuals with PAH in comparison to 41 healthy individuals, and in 19 PAH patients over time. Using single breath simultaneous measure of diffusion of carbon monoxide (DL(CO)) and nitric oxide (DL(NO)), DL and D(m) were respectively determined, and V(c) calculated. D(m) and V(c) were evaluated over time in relation to standard clinical indicators of disease severity, including brain natriuretic peptide (BNP), 6-minute walk distance (6MWD) and right ventricular systolic pressure (RVSP) by echocardiography. RESULTS: Both DL(CO) and DL(NO) were reduced in PAH as compared to controls and the lower DL in PAH was due to loss of both D(m) and V(c) (all p < 0.01). While DL(CO) of PAH patients did not change over time, DL(NO) decreased by 24 ml/min/mmHg/year (p = 0.01). Consequently, D(m) decreased and V(c) tended to increase over time, which led to deterioration of the D(m)/V(c) ratio, a measure of alveolar-capillary membrane functional efficiency without changes in clinical markers. CONCLUSIONS: The findings indicate that lower than normal gas transfer in PAH is due to loss of both D(m) and V(c), but that deterioration of D(m)/V(c) over time is related to worsening membrane diffusion.

Effects of the menstrual cycle on lung function variables in women with asthma.

RATIONALE: Angiogenesis is a defining pathologic feature of airway remodeling and contributes to asthma severity. Women experience changes in asthma control over the menstrual cycle, a time when vessels routinely form and regress under the control of angiogenic factors. One vital function modulated over the menstrual cycle in healthy women is gas transfer, and this has been related to angiogenesis and cyclic expansion of the pulmonary vascular bed. OBJECTIVES: We hypothesized that changes in gas transfer and the pulmonary vascular bed occur in women with asthma over the menstrual cycle and are associated with worsening airflow obstruction. METHODS: Twenty-three women, 13 with asthma and 10 healthy control subjects, were evaluated over the menstrual cycle with weekly measures of spirometry, gas transfer, nitric oxide, hemoglobin, factors affecting hemoglobin binding affinity, and proangiogenic factors. MEASUREMENTS AND MAIN RESULTS: Airflow and lung diffusing capacity varied over the menstrual cycle with peak levels during menses that subsequently declined to nadir in early luteal phase. In contrast to healthy women, changes in lung diffusing capacity (DL(CO)) were associated with changes in membrane diffusing capacity and DL(CO) was not related to proangiogenic factors. DL(CO) did not differ between the two groups, although methemoglobin and carboxyhemoglobin were higher in women with asthma than in healthy women. CONCLUSIONS: Women with asthma experience cyclic changes in airflow as well as gas transfer and membrane diffusing capacity supportive of a hormonal effect on lung function.

Pulmonary gas transfer related to markers of angiogenesis during the menstrual cycle.

Gas transfer in the female lung varies over the menstrual cycle in parallel with the cyclic angiogenesis that occurs in the uterine endometrium. Given that vessels form and regress in the uterus under the control of hormones, angiogenic factors, and proangiogenic circulating bone marrow-derived progenitor cells, we tested the possibility that variation in pulmonary gas transfer over the menstrual cycle is related to a systemic cyclic proangiogenic state that influences lung vascularity. Women were evaluated over the menstrual cycle with weekly measures of lung diffusing capacity and its components, the pulmonary vascular capillary bed and membrane diffusing capacity, and their relation to circulating CD34(+)CD133(+) progenitor cells, hemoglobin, factors affecting hemoglobin binding affinity, and proangiogenic factors. Lung diffusing capacity varied over the menstrual cycle, reaching a nadir during the follicular phase following menses. The decline in lung diffusing capacity was accounted for by approximately 25% decrease in pulmonary capillary blood volume. In parallel, circulating CD34(+)CD133(+) progenitor cells decreased by approximately 24% and were directly related to angiogenic factors and to lung diffusing capacity and pulmonary capillary blood volume. The finding of a greater number of lung microvessels in ovariectomized female mice receiving estrogen compared with placebo verified that pulmonary vascularity is influenced by hormonal changes. These findings suggest that angiogenesis in the lungs may participate in the cyclic changes in gas transfer that occur over the menstrual cycle.

Nitric oxide and cardiopulmonary hemodynamics in Tibetan highlanders.

When O2 availability is reduced unavoidably, as it is at high altitude, a potential mechanism to improve O2 delivery to tissues is an increase in blood flow. Nitric oxide (NO) regulates blood vessel diameter and can influence blood flow. This field study of intrapopulation variation at high altitude tested the hypothesis that the level of exhaled NO (a summary measure of pulmonary synthesis, consumption, and transfer from cells in the airway) is directly proportional to pulmonary, and thus systemic, blood flow. Twenty Tibetan male and 37 female healthy, nonsmoking, native residents at 4,200 m (13,900 ft), with an average O2 saturation of hemoglobin of 85%, participated in the study. The geometric mean partial pressure of NO exhaled at a flow of 17 ml/s was 23.4 nmHg, significantly lower than that of a sea-level reference group. However, the rate of NO transfer out of the airway wall was seven times higher than at sea level, which implied the potential for vasodilation of the pulmonary blood vessels. Mean pulmonary blood flow (measured by cardiac index) was 2.7 +/- 0.1 (SE) l/min, and mean pulmonary artery systolic pressure was 31.4 +/- 0.9 (SE) mmHg. Higher exhaled NO was associated with higher pulmonary blood flow; yet there was no associated increase in pulmonary artery systolic pressure. The results suggest that NO in the lung may play a key beneficial role in allowing Tibetans at 4,200 m to compensate for ambient hypoxia with higher pulmonary blood flow and O2 delivery without the consequences of higher pulmonary arterial pressure.

Nitric oxide and pulmonary arterial pressures in pulmonary hypertension.

Decreased production of vasodilator substances such as nitric oxide (NO) has been proposed as important in development of pulmonary arterial hypertension (PAH). We hypothesize that NO measured over time serves as a non invasive marker of severity of PAH and response to therapy. We prospectively and serially measured exhaled NO and carbon monoxide (CO), a vasodilator and anti-inflammatory product of heme oxygenases, in 17 PAH patients in conjunction with hemodynamic parameters over 2 years. Although pulmonary artery pressures and NO were similar in all patients at entry to the study, NO increased in the 12 individuals who survived to complete the study, and correlated with change in pulmonary artery pressures. In contrast, CO did not change or correlate with hemodynamic parameters. Investigation of NO-oxidant reaction products in PAH in comparison to controls suggests that NO synthesis is impaired in the lung and that reactive oxygen species may be involved in the pathophysiology of pulmonary hypertension. Endogenous NO is inversely related to pulmonary artery pressure in PAH, with successful therapy of PAH associated with increase in NO.

Dysregulation of endogenous carbon monoxide and nitric oxide production in patients with advanced ischemic or nonischemic cardiomyopathy.

Carbon monoxide (CO) and nitric oxide (NO) are endogenous vasoregulatory molecules whose role in heart failure is not fully known. Exhaled CO and NO measurement provide novel noninvasive assessment of their endogenous production. We compared exhaled CO and NO in 24 patients with advanced ischemic and nonischemic cardiomyopathy and in 13 control subjects without known cardiac disease at rest and at 1 and 5 minutes after exercise testing. Exhaled CO was lower in patients with cardiomyopathy at rest (1.66 +/- 0.2 vs 1.80 +/- 0.5 ppm, p = 0.02) and 1 minute after exercise (1.35 +/- 0.2 vs 1.81 +/- 0.5 ppm, p = 0.009), with a similar trend at 5 minutes after exercise (1.45 +/- 0.3 vs 1.81 +/- 0.5 ppm, p = 0.14). Exhaled CO decreased in patients with cardiomyopathy after exercise (p <0.001 and p = 0.02 at rest vs 1 and 5 minutes after exercise, respectively) but was maintained in controls. Exhaled NO did not differ between patients with cardiomyopathy and controls at rest (9.48 +/- 1.4 vs 9.68 +/- 1.5 ppb, p = NS) and after exercise (1 minute: 10.91 +/- 1.8 vs 9.19 +/- 1.2 ppb; 5 minutes: 10.52 +/- 1.5 vs 8.90 +/- 1.2 ppb, p = NS). Exhaled NO increased after exercise in patients with cardiomyopathy (p = 0.01 and p = 0.04 rest vs exercise at 1 and 5 minutes, respectively), but was maintained in controls. Exhaled CO and NO were not correlated with peak oxygen consumption in patients with cardiomyopathy. The differential responses in exhaled CO and NO at rest or with exercise between patients with cardiomyopathy and normal controls may point to dysregulation in endogenous CO and NO production.

Low levels of nitric oxide and carbon monoxide in alpha 1-antitrypsin deficiency.

Quantitations of exhaled nitric oxide (NO) and carbon monoxide (CO) have been proposed as noninvasive markers of airway inflammation. We hypothesized that exhaled CO is increased in individuals with alpha(1)-antitrypsin (AT) deficiency, who have lung inflammation and injury related to oxidative and proteolytic processes. Nineteen individuals with alpha(1)-AT deficiency, 22 healthy controls, and 12 patients with non-alpha(1)-AT-deficient chronic obstructive pulmonary disease (COPD) had NO, CO, CO(2), and O(2) measured in exhaled breath. Individuals with alpha(1)-AT deficiency had lower levels of NO and CO than control or COPD individuals. Alpha(1)-AT-deficient and COPD patients had lower exhaled CO(2) than controls, although only alpha(1)-AT-deficient patients had higher exhaled O(2) than healthy controls. NO was correlated inversely with exhaled O(2) and directly with exhaled CO(2), supporting a role for NO in regulation of gas exchange. Exhaled gases were not significantly related to corticosteroid use or lung function. Demonstration of lower than normal CO and NO levels may be useful as an additional noninvasive method to evaluate alpha(1)-AT deficiency in individuals with a severe, early onset of obstructive lung disease.

Long-term continuous positive airway pressure therapy normalizes high exhaled nitric oxide levels in obstructive sleep apnea.

STUDY OBJECTIVES: Upper airway inflammation and oxidative stress have been implicated in the pathogenesis of obstructive sleep apnea (OSA) and may be linked to cardiovascular consequences. We prospectively examined fraction of exhaled nitric oxide (FENO), a surrogate marker of upper airway inflammation using a portable nitric oxide analyzer (NIOX MINO). DESIGN: In consecutive adult nonsmokers with suspected OSA, FENO was measured immediately before and after polysomnographic studies, and within 1-3 months following continuous positive airway pressure (CPAP) therapy. MEASUREMENT AND RESULTS: FENO levels were increased in the 75 patients with OSA compared to the 29 controls, both before sleep (13.4 ± 6.5 ppb vs. 6.5 ± 3.5; p < 0.001) and after sleep (19.0 ± 7.7 ppb vs. 6.9 ± 3.7; p < 0.001). Furthermore, in patients with OSA, FENO levels were significantly higher post-sleep than pre-sleep (19.0 ± 7.7 ppb vs. 13.4 ± 6.5; p < 0.001), while there was no significant overnight change in patients without OSA. The rise in FENO correlated with the apnea-hypopnea index (r = 0.65, p < 0.001), nadir oxygen saturation (r = 0.54, p < 0.001), and arousal index (r = 0.52, p < 0.001). Thirty-seven of these patients underwent CPAP titration and treatment. Successful titration was associated with a lower overnight increase in FENO (7.2 ± 3.3 vs. 11.0 ± 4.3, p = 0.02). FENO levels declined after 1-3 months of CPAP therapy (11.7 ± 4.4 ppb, p < 0.001). CONCLUSIONS: FENO levels are elevated in OSA, correlate with severity, and decrease after positive pressure therapy. This study supports the role of upper airway inflammation in OSA pathogenesis and a possible role for FENO in monitoring CPAP therapy.

Nitric oxide in adaptation to altitude.

This review summarizes published information on the levels of nitric oxide gas (NO) in the lungs and NO-derived liquid-phase molecules in the acclimatization of visitors newly arrived at altitudes of 2500 m or more and adaptation of populations whose ancestors arrived thousands of years ago. Studies of acutely exposed visitors to high altitude focus on the first 24-48 h with just a few extending to days or weeks. Among healthy visitors, NO levels in the lung, plasma, and/or red blood cells fell within 2h, but then returned toward baseline or slightly higher by 48 h and increased above baseline by 5 days. Among visitors ill with high-altitude pulmonary edema at the time of the study or in the past, NO levels were lower than those of their healthy counterparts. As for highland populations, Tibetans had NO levels in the lung, plasma, and red blood cells that were at least double and in some cases orders of magnitude greater than other populations regardless of altitude. Red blood cell-associated nitrogen oxides were more than 200 times higher. Other highland populations had generally higher levels although not to the degree shown by Tibetans. Overall, responses of those acclimatized and those presumed to be adapted are in the same direction, although the Tibetans have much larger responses. Missing are long-term data on lowlanders at altitude showing how similar they become to the Tibetan phenotype. Also missing are data on Tibetans at low altitude to see the extent to which their phenotype is a response to the immediate environment or expressed constitutively. The mechanisms causing the visitors' and the Tibetans' high levels of NO and NO-derived molecules at altitude remain unknown. Limited data suggest processes including hypoxic upregulation of NO synthase gene expression, hemoglobin-NO reactions, and genetic variation. Gains in understanding will require integrating appropriate methods and measurement techniques with indicators of adaptive function under hypoxic stress.

A technical report on exhaled nitric oxide measurement: asthma monitoring in athletes.

Exhaled NO (FE(NO)) measurements have been utilized as a marker to diagnose asthma as well as a non-invasive tool for monitoring airway inflammation and the response to anti-inflammatory medications. One area where this non-invasive monitoring may be helpful is for asthmatic athletes as they train for competitive events. We hypothesized that in the course of training an asthmatic individual may experience worsening of lung inflammation reflected in FE(NO) levels that may be too subtle to detect by conventional methods like spirometry. Data were collected from an asthmatic patient (n = 1) over the course of endurance training using both the desktop (NIOX) and the portable NO (MINO) analyzers daily for eight weeks. We found that average NO levels measured in the desktop system correlated well with the two portable analyzers (r(2) =0.73, r(2) = 0.74 p < 0.0001); additionally, there was a strong correlation between the two MINO devices (r(2) = 0.88; p < 0.0001). A strong negative relationship existed between the number of miles run and NO, regardless of the device used. FEV(1) and PEF, however, did not change significantly as the miles run increased. Exercise training in asthmatics was associated with a decrease (improvement) in NO levels but no significant change in FEV(1) and PEF. This suggests that exhaled NO levels may be more sensitive to changes in the airway as a result of exercise than traditional pulmonary function testing.

Diagnosis of lung cancer by the analysis of exhaled breath with a colorimetric sensor array.

BACKGROUND: The pattern of volatile organic compounds (VOCs) in the exhaled breath of patients with lung cancer may be unique. New sensor systems that detect patterns of VOCs have been developed. One of these sensor systems, a colorimetric sensor array, has 36 spots composed of different chemically sensitive compounds impregnated on a disposable cartridge. The colours of these spots change based on the chemicals with which they come into contact. In this proof of principle study, the ability of this sensor system to detect a pattern of VOCs unique to lung cancer is assessed. METHODS: Individuals with lung cancer, those with other lung diseases and healthy controls performed tidal breathing of room air for 12 min while exhaling into a device designed to draw their breath across a colorimetric sensor array. The colour changes that occurred for each individual were converted into a numerical vector. The vectors were analysed statistically, using a random forests technique, to determine whether lung cancer could be predicted from the responses of the sensor. RESULTS: 143 individuals participated in the study: 49 with non-small cell lung cancer, 18 with chronic obstructive pulmonary disease 15 with idiopathic pulmonary fibrosis 20 with pulmonary arterial hypertension 20 with sarcoidosis and 21 controls. A prediction model was developed using observations from 70% of the subjects. This model was able to predict the presence of lung cancer in the remaining 30% of subjects with a sensitivity of 73.3% and a specificity of 72.4% (p = 0.01). CONCLUSIONS: The unique chemical signature of the breath of patients with lung cancer can be detected with moderate accuracy by a colorimetric sensor array.

Effect of dexamethasone on atrial fibrillation after cardiac surgery: prospective, randomized, double-blind, placebo-controlled trial.

OBJECTIVE: The purpose of this study was to assess the effect of preoperative dexamethasone (DEX) on the occurrence of postoperative atrial fibrillation (AF). DESIGN: Prospective, randomized, double-blind, placebo-controlled clinical trial. SETTING: Tertiary referral center. PARTICIPANTS: Seventy-eight adult patients undergoing combined valve and coronary artery bypass graft (CABG) surgery were randomized to receive either DEX or placebo. INTERVENTIONS: The DEX group received dexamethasone, 0.6 mg/kg, after induction of anesthesia, and the placebo group received an equal volume of normal saline. Interleukin (IL)-6, -8, and -10; tumor necrosis factor alpha; and endothelin (ET)-1 were measured preoperatively and on postoperative days (POD) 1, 2, and 3. Complement (C-4) and C-reactive protein (CRP) were measured preoperatively and on POD 2. Exhaled nitric oxide (NO) was measured preoperatively, 15 minutes after aortic unclamping, and 1 hour after intensive care unit admission. MEASUREMENTS AND MAIN RESULTS: No significant difference in the incidence of AF was found between the placebo (41%) and DEX groups (30%) (95% confidence interval [-11%, 34%); p = 0.31). DEX significantly reduced at least 1 postoperative level of IL-6, IL-8, IL-10, CRP, and exhaled NO. DEX did not affect ET-1 or C-4 levels. IL-10 on POD 3 was positively correlated with postoperative hospital length of stay (r = 0.30, p = 0.01). Increased levels of IL-8 and IL-10 on POD 1 were positively correlated with the intubation time (r = 0.31, p = 0.01; r = 0.30, p = 0.01, respectively). Conversely, C-4 on POD 2 was negatively correlated with the intubation time and intensive care unit length of stay (r = -0.32, p = 0.006; r = -0.30, p = 0.01, respectively). CONCLUSIONS: DEX did not affect the incidence of AF in patients undergoing combined CABG and valve surgery. However, it did modulate the release of several inflammatory and acute-phase response mediators that are associated with adverse outcomes.

Detection of lung cancer by sensor array analyses of exhaled breath.

RATIONALE: Electronic noses are successfully used in commercial applications, including detection and analysis of volatile organic compounds in the food industry. OBJECTIVES: We hypothesized that the electronic nose could identify and discriminate between lung diseases, especially bronchogenic carcinoma. METHODS: In a discovery and training phase, exhaled breath of 14 individuals with bronchogenic carcinoma and 45 healthy control subjects or control subjects without cancer was analyzed. Principal components and canonic discriminant analysis of the sensor data was used to determine whether exhaled gases could discriminate between cancer and noncancer. Discrimination between classes was performed using Mahalanobis distance. Support vector machine analysis was used to create and apply a cancer prediction model prospectively in a separate group of 76 individuals, 14 with and 62 without cancer. MAIN RESULTS: Principal components and canonic discriminant analysis demonstrated discrimination between samples from patients with lung cancer and those from other groups. In the validation study, the electronic nose had 71.4% sensitivity and 91.9% specificity for detecting lung cancer; positive and negative predictive values were 66.6 and 93.4%, respectively. In this population with a lung cancer prevalence of 18%, positive and negative predictive values were 66.6 and 94.5%, respectively. CONCLUSION: The exhaled breath of patients with lung cancer has distinct characteristics that can be identified with an electronic nose. The results provide feasibility to the concept of using the electronic nose for managing and detecting lung cancer.