Joost G. van den Aardweg

Expression of smooth muscle and extracellular matrix proteins in relation to airway function in asthma

BACKGROUNDnSmooth muscle content is increased within the airway wall in patients with asthma and is likely to play a role in airway hyperresponsiveness. However, smooth muscle cells express several contractile and structural proteins, and each of these proteins may influence airway function distinctly.nnnOBJECTIVEnWe examined the expression of contractile and structural proteins of smooth muscle cells, as well as extracellular matrix proteins, in bronchial biopsies of patients with asthma, and related these to lung function, airway hyperresponsiveness, and responses to deep inspiration.nnnMETHODSnThirteen patients with asthma (mild persistent, atopic, nonsmoking) participated in this cross-sectional study. FEV(1)% predicted, PC(20) methacholine, and resistance of the respiratory system by the forced oscillation technique during tidal breathing and deep breath were measured. Within 1 week, a bronchoscopy was performed to obtain 6 bronchial biopsies that were immunohistochemically stained for alpha-SM-actin, desmin, myosin light chain kinase (MLCK), myosin, calponin, vimentin, elastin, type III collagen, and fibronectin. The level of expression was determined by automated densitometry.nnnRESULTSnPC(20) methacholine was inversely related to the expression of alpha-smooth muscle actin (r = -0.62), desmin (r = -0.56), and elastin (r = -0.78). In addition, FEV(1)% predicted was positively related and deep inspiration-induced bronchodilation inversely related to desmin (r = -0.60), MLCK (r = -0.60), and calponin (r = -0.54) expression.nnnCONCLUSIONnAirway hyperresponsiveness, FEV(1)% predicted, and airway responses to deep inspiration are associated with selective expression of airway smooth muscle proteins and components of the extracellular matrix.

Prolonged cardiac recovery from exercise in asymptomatic adults late after atrial correction of transposition of the great arteries: evaluation with magnetic resonance flow mapping

After atrial correction of transposition of the great arteries (TGA), dysfunction of the systemic right ventricle at rest and during exercise has been reported. Information on changes in systemic right ventricular function during recovery from exercise is lacking. This study evaluates cardiac recovery from supine exercise using magnetic resonance (MR) imaging in patients with asymptomatic TGA after atrial correction. Flow in the ascending aorta, representing stroke volume of the systemic ventricle, was assessed with MR flow mapping in 10 asymptomatic patients with atrially corrected TGA and in 12 controls at rest during exercise and an 8-minute recovery period. In response to exercise, the patients had a smaller increase in heart rate, stroke volume, and cardiac output than did controls. After exercise, no significant difference in halftime of heart rate recovery was observed (patients, 48 +/- 7 seconds; controls, 39 +/- 4 seconds [p >0.05]). In the patients, the time course of stroke volume recovery was significantly different (p <0.001). Stroke volume in the patients, as a percent difference from rest, remained significantly elevated, from 2.5 minutes (+16 +/- 5% vs +7 +/- 6%; p <0.05) to 8 minutes (+4 +/- 7% vs -3 +/- 5%; p <0.05) after exercise. Subsequently, cardiac output remained significantly elevated, from 4.5 minutes (+27 +/- 13% vs +15 +/- 11%; p <0.05) to 7 minutes (+22 +/- 11% vs +12 +/- 12%; p <0.05) after exercise. We conclude that heart rate recovery is within normal limits in patients with atrially corrected TGA. Furthermore, cardiac recovery from exercise, assessed with MR flow mapping, is prolonged in patients with asymptomatic TGA after atrial correction. Abnormal recovery may reflect dysfunction of the systemic right ventricle and an altered metabolic response to exercise.

Enhanced airway dilation by positive-pressure inflation of the lungs compared with active deep inspiration in patients with asthma

Deep inspiration temporarily reduces induced airways obstruction in healthy subjects. This bronchodilatory effect of deep inspiration is impaired in asthma. Passive machine-assisted lung inflation may augment bronchodilation compared with an active deep inspiration in patients with asthma by either opening closed airways or by reducing fluid flux across the airway wall during deep inspiration, and thereby increasing the tethering forces on the airway wall. We recruited 24 patients with asthma [18-46 yr old, forced expiratory volume in 1 s (FEV(1)) > 70% predicted; provocative concentration of methacholine inducing a 20% fall in FEV(1) (PC(20)) < 8 mg/ml], with either an impaired (n = 12) or an intact (n = 12) bronchodilatory response to deep inspiration. Two methacholine challenges were performed on separate days. At a 50% increase in respiratory resistance (forced oscillation technique at 8 Hz), the change in resistance by a positive-pressure inflation (computer-driven syringe) or an active deep inspiration was measured in randomized order. The reduction in resistance by positive-pressure inflation was significantly greater than by active deep inspiration in the impaired deep inspiration response group (mean change +/- SE: -0.6 +/- 0.1 vs. -0.03 +/- 0.2 cmH(2)O.l(-1).s, P = 0.002). No significant difference was found between positive-pressure inflation and active deep inspiration in the intact deep inspiration response group (-0.6 +/- 0.2 vs. -1.0 +/- 0.3 cmH(2)O.l(-1).s, P = 0.18). Positive-pressure inflation of the lungs can significantly enhance deep inspiration-induced bronchodilation in patients with asthma.

Automatic negative evaluation of suffocation sensations in individuals with suffocation fear.

The current study tested whether suffocation sensations (respiratory loads) are automatically evaluated in a negative way by people fearing these sensations. It was found that, after having been primed with a slight respiratory load, participants with high suffocation fear (n=15) reacted more quickly to suffocation words and more slowly to positive words than participants with low suffocation fear (n=21). However, the effect was present only in participants who had noticed the primes. The findings are relevant to the cognitive model of panic disorder because automatic negative appraisal of sensations may play a role in initiating a panic attack.

Respiratory variability after opioids : see it happen

SHORT-TERM RESPIRATORY VARIABILITY can contain information on the control systems that continuously adapt the pulmonary ventilation to the needs of the body. This information comes spontaneously: all we have to do is to record changes in ventilation from breath to breath and to interpret the found patterns of variability. Is it really that simple? In this issue of the Journal of Applied Physiology, Mitsis et al. (6) make use of respiratory variability to gain insight into the influence of a short-acting opioid, remifentanil, on the action of the respiratory control system in healthy subjects. They describe how the variability changes under the influence of the drug and show how these changes can be understood using a simple chemoreflex model. The subjects received increasing doses of remifentanil in 15-min intervals, interrupted by 5-min periods of equilibration. The mean ventilation decreased (VT/TTOT, the ratio of tidal volume to breath duration) due to a longer expiration time (TE), while the mean end-tidal PCO2 (PETCO2) increased, all in a dose-dependent manner. The overall variability of PETCO2 and TE increased, while the variability of tidal volume (VT) remained largely unchanged. For clarity, the explaining chemoreflex model is shown in Fig. 1. The feedback loop consists of the influence of PETCO2 on VT/TTOT through the chemoreflexes (the “controller”) and the influence of VT/TTOT on PETCO2 through pulmonary gas exchange (the “plant”). To separate these influences, breath-tobreath values were fitted to two models. The controller model has PETCO2 as input and VT/TTOT as output (after removal of sighs, which are likely not due to chemoreflex activity). The residual noise in this model consists of “spontaneous” changes in VT/TTOT (noise 2). The plant model describes pulmonary gas exchange and has VT/TTOT as input and PETCO2 as output (including the sighs that are now considered as part of the input). Here the residual noise consists of “spontaneous” changes in PETCO2 (noise 1). Mitsis et al. (6) found that the effect of the controller was suppressed by remifentanil, which one would expect. This agrees with the well-known decreased chemosensitivity after opioids (7), where it should be noted that the peripheral chemoreflex was partly suppressed since end-tidal PO2 (PETO2) was artificially kept at 30 kPa. The drug had a stronger, and positive, effect on the plant part of the loop. As the authors point out, this is probably related to the higher mean PETCO2, since the expiratory CO2 fraction is the main determinant of ventilatory efficiency. This may in turn be related to the decreased ventilation, mainly because of an increased mean TE (almost twice as high at the highest dose). This implies that the chemoreflex operates at a higher mean PETCO2 and lower VT/TTOT. One may speculate that this is related to the rightshift of the CO2 response curve that has been found after opioids, in relation with a higher apneic threshold (9). The question rises to which extent the two components of the feedback loop are indeed separated by this approach. Assuming that sighs are not influenced by chemoreflex feedback, it is plausible that changes in PETCO2 at the end of a sigh and during the next few breaths are almost exclusively due to the “plant.” It can be expected, however, that these changes are modulated by the peripheral chemoreflex after a number of breaths. This agrees with the observations of Khoo and Marmarelis (5), who estimated the chemoreflex response from respiratory oscillations after spontaneous sighs in anesthetized dogs. In the present study, the relation between PETCO2 and VT/TTOT showed oscillatory behavior after changes in PETCO2 at baseline (with a cycle time of 14 breaths). These oscillations may be ascribed to the band-pass filter characteristics of the closed feedback loop (4, 11). It also seems plausible that the first changes in VT/TTOT after a change in PETCO2 are mainly due to the “controller” (after correction for the lung-to-chemoreceptor delay). Although the estimated relations were derived from a closed-loop situation, an interpretation of respiratory instability in terms of the “loop gain” is still possible. The authors used linear and nonlinear coefficients to estimate the components of the feedback loop. In the frequency domain, the linear coefficients yield the “controller gain” (the frequency-dependent amplification from PETCO2 to VT/TTOT) and the “plant gain” (the frequency-dependent amplification from VT/TTOT to PETCO2). In the closed-loop situation, the product of the controller gain times the plant gain equals the “double loop gain” (11). This is the loop gain for a system with two simulta-

Tight coupling between inspiration and expiration after the respiratory compensation point

Background: The respiratory compensation point (RCP) is the point at which arterial PCO2 starts to decline during heavy exercise. It has been interpreted as a ventilatory response to lactic acidosis. However, in incremental exercise-- there is often a delay between the onset of lactic acidosis and the RCP, which has been ascribed to buffering of the acid. Question: can analysis of respiratory variability provide more insight into the underlying mechanism? Methods: Ten healthy subjects underwent a maximal incremental cycling test. In nine subjects, an RCP was identified as the start of a decline in mean expiratory PCO2. Breath-to-breath variability of tidal volume (VT), inspiratory and expiratory time (TI and TE) were analysed with spectral analysis. Results: After the RCP, TI and TE became almost equal to each other (TE – TI = 0.01 ± 0.01 s, mean ± SD, after low-pass filtering). Subsequently, both TI and TE decreased linearly as a function of time (average r2 > 0.90). The variability of TI and TE decreased by 0.76 ± 0.19 and 0.99 ± 0.31 (expressed as logarithmic power;P 0.99 (for low frequencies). The gain from TI to TE decreased to 1.06 ± 0.106, meaning that changes in TI became virtually equal to changes in TE. Conclusion: After the RCP, a strong linear relation develops between TI and TE, while their variability decreases. The tight respiratory timing during heavy exercise is possibly explained by the action of the lung inflation reflex (Hering-Breuer), in a situation in which both the end-inspiratory lung volume and the respiratory drive are high.