The Pulmonary Vasculature.

The pulmonary circulation is a low-pressure, low-resistance circuit whose primary function is to deliver deoxygenated blood to, and oxygenated blood from, the pulmonary capillary bed enabling gas exchange. The distribution of pulmonary blood flow is regulated by several factors including effects of vascular branching structure, large-scale forces related to gravity, and finer scale factors related to local control. Hypoxic pulmonary vasoconstriction is one such important regulatory mechanism. In the face of local hypoxia, vascular smooth muscle constriction of precapillary arterioles increases local resistance by up to 250%. This has the effect of diverting blood toward better oxygenated regions of the lung and optimizing ventilation-perfusion matching. However, in the face of global hypoxia, the net effect is an increase in pulmonary arterial pressure and vascular resistance. Pulmonary vascular resistance describes the flow-resistive properties of the pulmonary circulation and arises from both precapillary and postcapillary resistances. The pulmonary circulation is also distensible in response to an increase in transmural pressure and this distention, in addition to recruitment, moderates pulmonary arterial pressure and vascular resistance. This article reviews the physiology of the pulmonary vasculature and briefly discusses how this physiology is altered by common circumstances.

Prone positioning redistributes gravitational stress in the lung in normal conditions and in simulations of oedema.

NEW FINDINGS: What is the central question of this study? How does the interaction between posture and gravity affect the stresses on the lung, particularly in highly inflated gravitationally non-dependent regions, which are potentially vulnerable to increased mechanical stress and injury? What is the main finding and its importance? Changes in stress attributable to gravity are not well characterized between postures. Using a new metric of gravitational stress, we show that regions of the lung near maximal inflation have the greatest gravitational stresses while supine, but not while prone. In simulations of increased lung weight consistent with severe pulmonary oedema, the prone lung has lower gravitational stress in vulnerable, non-dependent regions, potentially protecting them from overinflation and injury. ABSTRACT: Prone posture changes the gravitational vector, and potentially the stress induced by tissue deformation, because a larger lung volume is gravitationally dependent when supine, but non-dependent when prone. To evaluate this, 10 normal subjects (six male and four female; age, means ± SD = 27 ± 6 years; height, 171 ± 9 cm; weight, 69 ± 13 kg; forced expiratory volume in the first second/forced expiratory volume as a percentage of predicted, 93 ± 6%) were imaged at functional residual capacity, supine and prone, using magnetic resonance imaging, to quantify regional lung density. We defined regional gravitational stress as the cumulative weight, per unit area, of the column of lung tissue below each point. Gravitational stress was compared between regions of differing inflation to evaluate differences between highly stretched, and thus potentially vulnerable, regions and less stretched lung. Using reference density values for normal lungs at total lung capacity (0.10 ± 0.03 g/ml), regions were classified as highly inflated (density < 0.13 g/ml, i.e., close to total lung capacity), intermediate (0.13 ≤ density < 0.16 g/ml) or normally inflated (density ≥ 0.16 g/ml). Gravitational stress differed between inflation categories while supine (-1.6 ± 0.3 cmH2 O highly inflated; -1.4 ± 0.3 cmH2 O intermediate; -1.1 ± 0.1 cmH2 O normally inflated; P = 0.05) but not while prone (-1.4 ± 0.2 cmH2 O highly inflated; -1.3 ± 0.2 cmH2 O intermediate; -1.3 ± 0.1 cmH2 O normally inflated; P = 0.39), and increased more with height from dependent lung while supine (-0.24 ± 0.02 cmH2 O/cm supine; -0.18 ± 0.04 cmH2 O/cm prone; P = 0.05). In simulated severe pulmonary oedema, the gradient in gravitational stress increased in both postures (all P < 0.0001), was greater in the supine posture than when prone (-0.57 ± 0.21 cmH2 O/cm supine; -0.34 ± 0.16 cmH2 O/cm prone; P = 0.0004) and was similar to the gradient calculated from supine computed tomography images in a patient with acute respiratory distress syndrome (-0.51 cmH2 O/cm). The non-dependent lung has greater gravitational stress while supine and might be protected while prone, particularly in the presence of oedema.

Abnormal pulmonary perfusion heterogeneity in patients with Fontan circulation and pulmonary arterial hypertension.

KEY POINTS: The distribution of pulmonary perfusion is affected by gravity, vascular branching structure and active regulatory mechanisms, which may be disrupted by cardiopulmonary disease, but this is not well studied, particularly in rare conditions. We evaluated pulmonary perfusion in patients who had undergone Fontan procedure, patients with pulmonary arterial hypertension (PAH) and two groups of controls using a proton magnetic resonance imaging technique, arterial spin labelling to measure perfusion. Heterogeneity was assessed by the relative dispersion (SD/mean) and gravitational gradients. Gravitational gradients were similar between all groups, but heterogeneity was significantly increased in both patient groups compared to controls and persisted after removing contributions from large blood vessels and gravitational gradients. Patients with Fontan physiology and patients with PAH have increased pulmonary perfusion heterogeneity that is not explainable by differences in mean perfusion, gravitational gradients, or large vessel anatomy. This probably reflects vascular remodelling in PAH and possibly in Fontan physiology. ABSTRACT: Many factors affect the distribution of pulmonary perfusion, which may be disrupted by cardiopulmonary disease, but this is not well studied, particularly in rare conditions. An example is following the Fontan procedure, where pulmonary perfusion is passive, and heterogeneity may be increased because of the underlying pathophysiology leading to Fontan palliation, remodelling, or increased gravitational gradients from low flow. Another is pulmonary arterial hypertension (PAH), where gravitational gradients may be reduced secondary to high pressures, but remodelling may increase perfusion heterogeneity. We evaluated regional pulmonary perfusion in Fontan patients (n = 5), healthy young controls (Fontan control, n = 5), patients with PAH (n = 6) and healthy older controls (PAH control) using proton magnetic resonance imaging. Regional perfusion was measured using arterial spin labelling. Heterogeneity was assessed by the relative dispersion (SD/mean) and gravitational gradients. Mean perfusion was similar (Fontan = 2.50 ± 1.02 ml min-1  ml-1 ; Fontan control = 3.09 ± 0.58, PAH = 3.63 ± 1.95; PAH control = 3.98 ± 0.91, P = 0.26), and the slopes of gravitational gradients were not different (Fontan = -0.23 ± 0.09 ml min-1  ml-1  cm-1 ; Fontan control = -0.29 ± 0.23, PAH = -0.27 ± 0.09, PAH control = -0.25 ± 0.18, P = 0.91) between groups. Perfusion relative dispersion was greater in both Fontan and PAH than controls (Fontan = 1.46 ± 0.18; Fontan control = 0.99 ± 0.21, P = 0.005; PAH = 1.22 ± 0.27, PAH control = 0.91 ± 0.12, P = 0.02) but similar between patient groups (P = 0.13). These findings persisted after removing contributions from large blood vessels and gravitational gradients (all P < 0.05). We conclude that patients with Fontan physiology and PAH have increased pulmonary perfusion heterogeneity that is not explained by differences in mean perfusion, gravitational gradients, or large vessel anatomy. This probably reflects the effects of remodelling in PAH and possibly in Fontan physiology.

Peripheral chemoresponsiveness during exercise in male athletes with exercise-induced arterial hypoxaemia.

NEW FINDINGS: What is the central question of this study? Do highly trained male endurance athletes who develop exercise-induced arterial hypoxaemia (EIAH) demonstrate reduced peripheral chemoresponsiveness during exercise? What is the main finding and its importance? Those with the lowest arterial saturation during exercise have a smaller ventilatory response to hypercapnia during exercise. There was no significant relationship between the hyperoxic ventilatory response and EIAH. The findings suggest that peripheral chemoresponsiveness to hypercapnia during exercise could play a role in the development of EIAH. The findings improve our understanding of the mechanisms that contribute to EIAH. ABSTRACT: Exercise-induced arterial hypoxaemia (EIAH) is characterized by a decrease in arterial oxygen tension and/or saturation during whole-body exercise, which may in part result from inadequate alveolar ventilation. However, the role of peripheral chemoresponsiveness in the development of EIAH is not well established. We hypothesized that those with the most severe EIAH would have an attenuated ventilatory response to hyperoxia and hypercapnia during exercise. To evaluate this, on separate days, we measured ventilatory sensitivity to hyperoxia and separately hypercapnia at rest and during three different exercise intensities (25, 50% of V̇O2max and ventilatory threshold (∼67% of V̇O2max )) in 12 males cyclists ( V̇O2max  = 66.6 ± 4.7 ml kg-1  min-1 ). Subjects were divided into two groups based on their end-exercise arterial oxygen saturation (ear oximetry, SpO2 ): a normal oxyhaemoglobin saturation group (NOS, SpO2  = 93.4 ± 0.4%, n = 5) and a low oxyhaemoglobin saturation group (LOS, SpO2  = 89.9 ± 0.9%, n = 7). There was no difference in V̇O2max (66.4 ± 2.9 vs. 66.8 ± 6.0 ml kg-1  min-1 , respectively, P = 0.9), peak ventilation during maximal exercise (182 ± 15 vs. 197 ± 32 l min-1 , respectively, P = 0.36) or ventilatory response to hyperoxia (P = 0.98) at any exercise intensity between NOS and LOS groups. However, those in the LOS group had a significantly lower ventilatory response to hypercapnia (P = 0.004, (η2  = 0.18). There was also a significant relationship between the mean hypercapnic response and end-exercise SpO2 (r = 0.75, P = 0.009) but not between the mean hyperoxic response and end-exercise SpO2 (r = 0.21, P = 0.51). A blunted hypercapnic ventilatory response may contribute to EIAH in highly trained men due to a failure to increase ventilation sufficiently to offset exercise-induced gas exchange impairments.

Precapillary pulmonary gas exchange is similar for oxygen and inert gases.

KEY POINTS: Precapillary gas exchange for oxygen has been documented in both humans and animals. It has been suggested that, if precapillary gas exchange occurs to a greater extent for inert gases than for oxygen, shunt and its effects on arterial oxygenation may be underestimated by the multiple inert gas elimination technique (MIGET). We evaluated fractional precapillary gas exchange in canines for O2 and two inert gases, sulphur hexafluoride and ethane, by measuring these gases in the proximal pulmonary artery, distal pulmonary artery (1 cm proximal to the wedge position) and systemic artery. Some 12-19% of pulmonary gas exchange occurred within small (1.7 mm in diameter or larger) pulmonary arteries and this was quantitatively similar for oxygen, sulphur hexafluoride and ethane. Under these experimental conditions, this suggests only minor effects of precapillary gas exchange on the magnitude of calculated shunt and the associated effect on pulmonary gas exchange estimated by MIGET. ABSTRACT: Some pulmonary gas exchange is known to occur proximal to the pulmonary capillary, although the magnitude of this gas exchange is uncertain, and it is unclear whether oxygen and inert gases are similarly affected. This has implications for measuring shunt and associated gas exchange consequences. By measuring respiratory and inert gas levels in the proximal pulmonary artery (P), a distal pulmonary artery 1 cm proximal to the wedge position (using a 5-F catheter) (D) and a systemic artery (A), we evaluated precapillary gas exchange in 27 paired samples from seven anaesthetized, ventilated canines. Fractional precapillary gas exchange (F) was quantified for each gas as F = (P - D)/(P - A). The lowest solubility inert gases, sulphur hexafluoride (SF6 ) and ethane were used because, with higher solubility gases, the P-A difference is sufficiently small that experimental error prevents accurate assessment of F. Distal samples (n = 12) with oxygen (O2 ) saturation values that were (within experimental error) equal to or above systemic arterial values, suggestive of retrograde capillary blood aspiration, were discarded, leaving 15 for analysis. D was significantly lower than P for SF6 (D/P = 88.6 ± 18.1%; P = 0.03) and ethane (D/P = 90.6 ± 16.0%; P = 0.04), indicating partial excretion of inert gas across small pulmonary arteries. Distal pulmonary arterial O2 saturation was significantly higher than proximal (74.1 ± 6.8% vs. 69.0 ± 4.9%; P = 0.03). Fractional precapillary gas exchange was similar for SF6 , ethane and O2 (0.12 ± 0.19, 0.12 ± 0.20 and 0.19 ± 0.26, respectively; P = 0.54). Under these experimental conditions, 12-19% of pulmonary gas exchange occurs within the small pulmonary arteries and the extent is similar between oxygen and inert gases.

Intra-pulmonary arteriovenous anastomoses and pulmonary gas exchange: evaluation by microspheres, contrast echocardiography and inert gas elimination.

KEY POINTS: Imaging techniques such as contrast echocardiography suggest that anatomical intra-pulmonary arteriovenous anastomoses (IPAVAs) are present at rest and are recruited to a greater extent in conditions such as exercise. IPAVAs have the potential to act as a shunt, although gas exchange methods have not demonstrated significant shunt in the normal lung. To evaluate this discrepancy, we compared anatomical shunt with 25-µm microspheres to contrast echocardiography, and gas exchange shunt measured by the multiple inert gas elimination technique (MIGET). Intra-pulmonary shunt measured by 25-µm microspheres was not significantly different from gas exchange shunt determined by MIGET, suggesting that MIGET does not underestimate the gas exchange consequences of anatomical shunt. A positive agitated saline contrast echocardiography score was associated with anatomical shunt measured by microspheres. Agitated saline contrast echocardiography had high sensitivity but low specificity to detect a ≥1% anatomical shunt, frequently detecting small shunts inconsequential for gas exchange. ABSTRACT: The echocardiographic visualization of transpulmonary agitated saline microbubbles suggests that anatomical intra-pulmonary arteriovenous anastomoses are recruited during exercise, in hypoxia, and when cardiac output is increased pharmacologically. However, the multiple inert gas elimination technique (MIGET) shows insignificant right-to-left gas exchange shunt in normal humans and canines. To evaluate this discrepancy, we measured anatomical shunt with 25-µm microspheres and compared the results to contrast echocardiography and MIGET-determined gas exchange shunt in nine anaesthetized, ventilated canines. Data were acquired under the following conditions: (1) at baseline, (2) 2 µg kg-1  min-1 i.v. dopamine, (3) 10 µg kg-1  min-1 i.v. dobutamine, and (4) following creation of an intra-atrial shunt (in four animals). Right to left anatomical shunt was quantified by the number of 25-µm microspheres recovered in systemic arterial blood. Ventilation-perfusion mismatch and gas exchange shunt were quantified by MIGET and cardiac output by direct Fick. Left ventricular contrast scores were assessed by agitated saline bubble counts, and separately by appearance of 25-µm microspheres. Across all conditions, anatomical shunt measured by 25-µm microspheres was not different from gas exchange shunt measured by MIGET (microspheres: 2.3 ± 7.4%; MIGET: 2.6 ± 6.1%, P = 0.64). Saline contrast bubble score was associated with microsphere shunt (ρ = 0.60, P < 0.001). Agitated saline contrast score had high sensitivity (100%) to detect a ≥1% shunt, but low specificity (22-48%). Gas exchange shunt by MIGET does not underestimate anatomical shunt measured using 25-µm microspheres. Contrast echocardiography is extremely sensitive, but not specific, often detecting small anatomical shunts which are inconsequential for gas exchange.

Sleep Hygiene for Optimizing Recovery in Athletes: Review and Recommendations.

For elite athletes who exercise at a high level, sleep is critical to overall health. Many studies have documented the effects of sleep deprivation in the general population, but few studies exist regarding specific effects in the athlete. This review summarizes the effects of sleep deprivation and sleep extension on athletic performance, including reaction time, accuracy, strength and endurance, and cognitive function. There are clear negative effects of sleep deprivation on performance, including reaction time, accuracy, vigor, submaximal strength, and endurance. Cognitive functions such as judgment and decision-making also suffer. Sleep extension can positively affect reaction times, mood, sprint times, tennis serve accuracy, swim turns, kick stroke efficiency, and increased free throw and 3-point accuracy. Banking sleep (sleep extension prior to night of intentional sleep deprivation before sporting event) is a new concept that may also improve performance. For sports medicine providers, the negative effects of sleep deprivation cannot be overstated to athletes. To battle sleep deprivation, athletes may seek supplements with potentially serious side effects; improving sleep quality however is simple and effective, benefiting not only athlete health but also athletic performance.

The effect of lung deformation on the spatial distribution of pulmonary blood flow.

KEY POINTS: Pulmonary perfusion measurement using magnetic resonance imaging combined with deformable image registration enabled us to quantify the change in the spatial distribution of pulmonary perfusion at different lung volumes. The current study elucidated the effects of tidal volume lung inflation [functional residual capacity (FRC) + 500 ml and FRC + 1 litre] on the change in pulmonary perfusion distribution. Changes in hydrostatic pressure distribution as well as transmural pressure distribution due to the change in lung height with tidal volume inflation are probably bigger contributors to the redistribution of pulmonary perfusion than the changes in pulmonary vasculature resistance caused by lung tissue stretch. ABSTRACT: Tidal volume lung inflation results in structural changes in the pulmonary circulation, potentially affecting pulmonary perfusion. We hypothesized that perfusion is recruited to regions receiving the greatest deformation from a tidal breath, thus ensuring ventilation-perfusion matching. Density-normalized perfusion (DNP) magnetic resonance imaging data were obtained in healthy subjects (n = 7) in the right lung at functional residual capacity (FRC), FRC+500 ml, and FRC+1.0 l. Using deformable image registration, the displacement of a sagittal lung slice acquired at FRC to the larger volumes was calculated. Registered DNP images were normalized by the mean to estimate perfusion redistribution (nDNP). Data were evaluated across gravitational regions (dependent, middle, non-dependent) and by lobes (upper, RUL; middle, RML; lower, RLL). Lung inflation did not alter mean DNP within the slice (P = 0.10). The greatest expansion was seen in the dependent region (P < 0.0001: dependent vs non-dependent, P < 0.0001: dependent vs middle) and RLL (P = 0.0015: RLL vs RUL, P < 0.0001: RLL vs RML). Neither nDNP recruitment to RLL [+500 ml = -0.047(0.145), +1 litre = 0.018(0.096)] nor to dependent lung [+500 ml = -0.058(0.126), +1 litre = -0.023(0.106)] were found. Instead, redistribution was seen in decreased nDNP in the non-dependent [+500 ml = -0.075(0.152), +1 litre = -0.137(0.167)) and increased nDNP in the gravitational middle lung [+500 ml = 0.098(0.058), +1 litre = 0.093(0.081)] (P = 0.01). However, there was no significant lobar redistribution (P < 0.89). Contrary to our hypothesis, based on the comparison between gravitational and lobar perfusion data, perfusion was not redistributed to the regions of the most inflation. This suggests that either changes in hydrostatic pressure or transmural pressure distribution in the gravitational direction are implicated in the redistribution of perfusion away from the non-dependent lung.

A statistical clustering approach to discriminating perfusion from conduit vessel signal contributions in a pulmonary ASL MR image.

The measurement of pulmonary perfusion (blood delivered to the capillary bed within a voxel) using arterial spin labeling (ASL) magnetic resonance imaging is often complicated by signal artifacts from conduit vessels that carry blood destined for voxels at a distant location in the lung. One approach to dealing with conduit vessel contributions involves the application of an absolute threshold on the ASL signal. While useful for identifying a subset of the most dominant high signal conduit image features, signal thresholding cannot discriminate between perfusion and conduit vessel contributions at intermediate and low signal. As an alternative, this article discusses a data-driven statistical approach based on statistical clustering for characterizing and discriminating between capillary perfusion and conduit vessel contributions over the full signal spectrum. An ASL flow image is constructed from the difference between a pair of tagged magnetic resonance images. However, when viewed as a bivariate projection that treats the image pair as independent measures (rather than the univariate quantity that results from the subtraction of the two images), the signal associated with capillary perfusion contributions is observed to cluster independently of the signal associated with conduit vessel contributions. Analyzing the observed clusters using a Gaussian mixture model makes it possible to discriminate between conduit vessel and capillary-perfusion-dominated signal contributions over the full signal spectrum of the ASL image. As a demonstration of feasibility, this study compares the proposed clustering approach with the standard absolute signal threshold strategy in a small number of test images.

Advances in functional and structural imaging of the human lung using proton MRI.

The field of proton lung MRI is advancing on a variety of fronts. In the realm of functional imaging, it is now possible to use arterial spin labeling (ASL) and oxygen-enhanced imaging techniques to quantify regional perfusion and ventilation, respectively, in standard units of measurement. By combining these techniques into a single scan, it is also possible to quantify the local ventilation-perfusion ratio, which is the most important determinant of gas-exchange efficiency in the lung. To demonstrate potential for accurate and meaningful measurements of lung function, this technique was used to study gravitational gradients of ventilation, perfusion, and ventilation-perfusion ratio in healthy subjects, yielding quantitative results consistent with expected regional variations. Such techniques can also be applied in the time domain, providing new tools for studying temporal dynamics of lung function. Temporal ASL measurements showed increased spatial-temporal heterogeneity of pulmonary blood flow in healthy subjects exposed to hypoxia, suggesting sensitivity to active control mechanisms such as hypoxic pulmonary vasoconstriction, and illustrating that to fully examine the factors that govern lung function it is necessary to consider temporal as well as spatial variability. Further development to increase spatial coverage and improve robustness would enhance the clinical applicability of these new functional imaging tools. In the realm of structural imaging, pulse sequence techniques such as ultrashort echo-time radial k-space acquisition, ultrafast steady-state free precession, and imaging-based diaphragm triggering can be combined to overcome the significant challenges associated with proton MRI in the lung, enabling high-quality three-dimensional imaging of the whole lung in a clinically reasonable scan time. Images of healthy and cystic fibrosis subjects using these techniques demonstrate substantial promise for non-contrast pulmonary angiography and detailed depiction of airway disease. Although there is opportunity for further optimization, such approaches to structural lung imaging are ready for clinical testing.

Assessing the pulmonary vascular responsiveness to oxygen with proton MRI.

Ventilation-perfusion matching occurs passively and is also actively regulated through hypoxic pulmonary vasoconstriction (HPV). The extent of HPV activity in humans, particularly normal subjects, is uncertain. Current evaluation of HPV assesses changes in ventilation-perfusion relationships/pulmonary vascular resistance with hypoxia and is invasive, or unsuitable for patients because of safety concerns. We used a noninvasive imaging-based approach to quantify the pulmonary vascular response to oxygen as a metric of HPV by measuring perfusion changes between breathing 21% and 30%O2 using arterial spin labeling (ASL) MRI. We hypothesized that the differences between 21% and 30%O2 images reflecting HPV release would be 1) significantly greater than the differences without [Formula: see text] changes (e.g., 21-21% and 30-30%O2) and 2) negatively associated with ventilation-perfusion mismatch. Perfusion was quantified in the right lung in normoxia (baseline), after 15 min of 30% O2 breathing (hyperoxia) and 15 min normoxic recovery (recovery) in healthy subjects (7 M, 7 F; age = 41.4 ± 19.6 yr). Normalized, smoothed, and registered pairs of perfusion images were subtracted and the mean square difference (MSD) was calculated. Separately, regional alveolar ventilation and perfusion were quantified from specific ventilation, proton density, and ASL imaging; the spatial variance of ventilation-perfusion (σ2V̇a/Q̇) distributions was calculated. The O2-responsive MSD was reproducible (R2 = 0.94, P < 0.0001) and greater (0.16 ± 0.06, P < 0.0001) than that from subtracted images collected under the same [Formula: see text] (baseline = 0.09 ± 0.04, hyperoxia = 0.08 ± 0.04, recovery = 0.08 ± 0.03), which were not different from one another (P = 0.2). The O2-responsive MSD was correlated with σ2V̇a/Q̇ (R2 = 0.47, P = 0.007). These data suggest that active HPV optimizes ventilation-perfusion matching in normal subjects. This noninvasive approach could be applied to patients with different disease phenotypes to assess HPV and ventilation-perfusion mismatch.NEW & NOTEWORTHY We developed a new proton MRI method to noninvasively quantify the pulmonary vascular response to oxygen. Using a hyperoxic stimulus to release HPV, we quantified the resulting redistribution of perfusion. The differences between normoxic and hyperoxic images were greater than those between images without [Formula: see text] changes and negatively correlated with ventilation-perfusion mismatch. This suggests that active HPV optimizes ventilation-perfusion matching in normal subjects. This approach is suitable for assessing patients with different disease phenotypes.

Luminance contrast of a visual stimulus modulates the BOLD response more than the cerebral blood flow response in the human brain.

The blood oxygenation level dependent (BOLD) response measured with functional magnetic resonance imaging (fMRI) depends on the evoked changes in cerebral blood flow (CBF) and cerebral metabolic rate of oxygen (CMRO(2)) in response to changes in neural activity. This response is strongly modulated by the CBF/CMRO(2) coupling relationship with activation, defined as n, the ratio of the fractional changes. The reliability of the BOLD signal as a quantitative reflection of underlying physiological changes depends on the stability of n in response to different stimuli. The effect of visual stimulus contrast on this coupling ratio was tested in 9 healthy human subjects, measuring CBF and BOLD responses to a flickering checkerboard at four visual contrast levels. The theory of the BOLD effect makes a robust prediction-independent of details of the model-that if the CBF/CMRO(2) coupling ratio n remains constant, then the response ratio between the lowest and highest contrast levels should be higher for the BOLD response than the CBF response because of the ceiling effect on the BOLD response. Instead, this response ratio was significantly lower for the BOLD response (BOLD response: 0.23 ± 0.13, mean ± SD; CBF response: 0.42 ± 0.18; p=0.0054). This data is consistent with a reduced dynamic range (strongest/weakest response ratio) of the CMRO(2) response (~1.7-fold) compared to that of the CBF response (~2.4-fold) as luminance contrast increases, corresponding to an increase of n from 1.7 at the lowest contrast level to 2.3 at the highest contrast level. The implication of these results for fMRI studies is that the magnitude of the BOLD response does not accurately reflect the magnitude of underlying physiological processes.

Is the Lung Built for Exercise? Advances and Unresolved Questions.

ABSTRACT: Nearly 40 yr ago, Professor Dempsey delivered the 1985 ACSM Joseph B. Wolffe Memorial Lecture titled: "Is the lung built for exercise?" Since then, much experimental work has been directed at enhancing our understanding of the functional capacity of the respiratory system by applying complex methodologies to the study of exercise. This review summarizes a symposium entitled: "Revisiting 'Is the lung built for exercise?'" presented at the 2022 American College of Sports Medicine annual meeting, highlighting the progress made in the last three-plus decades and acknowledging new research questions that have arisen. We have chosen to subdivide our topic into four areas of active study: (i) the adaptability of lung structure to exercise training, (ii) the utilization of airway imaging to better understand how airway anatomy relates to exercising lung mechanics, (iii) measurement techniques of pulmonary gas exchange and their importance, and (iv) the interactions of the respiratory and cardiovascular system during exercise. Each of the four sections highlights gaps in our knowledge of the exercising lung. Addressing these areas that would benefit from further study will help us comprehend the intricacies of the lung that allow it to meet and adapt to the acute and chronic demands of exercise in health, aging, and disease.

The spatial-temporal dynamics of pulmonary blood flow are altered in pulmonary arterial hypertension.

Global fluctuation dispersion (FDglobal), a spatial-temporal metric derived from serial images of the pulmonary perfusion obtained with MRI-arterial spin labeling, describes temporal fluctuations in the spatial distribution of perfusion. In healthy subjects, FDglobal is increased by hyperoxia, hypoxia, and inhaled nitric oxide. We evaluated patients with pulmonary arterial hypertension (PAH, 4F, aged 47 ± 15, mean pulmonary artery pressure 48 ± 7 mmHg) and healthy controls (CON, 7F, aged 47 ± 12) to test the hypothesis that FDglobal is increased in PAH. Images were acquired at ∼4-5 s intervals during voluntary respiratory gating, inspected for quality, registered using a deformable registration algorithm, and normalized. Spatial relative dispersion (RD = SD/mean) and the percent of the lung image with no measurable perfusion signal (%NMP) were also assessed. FDglobal was significantly increased in PAH (PAH = 0.40 ± 0.17, CON = 0.17 ± 0.02, P = 0.006, a 135% increase) with no overlap in values between the two groups, consistent with altered vascular regulation. Both spatial RD and %NMP were also markedly greater in PAH vs. CON (PAH RD = 1.46 ± 0.24, CON = 0.90 ± 0.10, P = 0.0004; PAH NMP = 13.4 ± 6.1%; CON = 2.3 ± 1.4%, P = 0.001 respectively) consistent with vascular remodeling resulting in poorly perfused regions of lung and increased spatial heterogeneity. The difference in FDglobal between normal subjects and patients with PAH in this small cohort suggests that spatial-temporal imaging of perfusion may be useful in the evaluation of patients with PAH. Since this MR imaging technique uses no injected contrast agents and has no ionizing radiation it may be suitable for use in diverse patient populations.NEW & NOTEWORTHY Using proton MRI-arterial spin labeling to obtain serial images of pulmonary perfusion, we show that global fluctuation dispersion (FDglobal), a metric of temporal fluctuations in the spatial distribution of perfusion, was significantly increased in female patients with pulmonary arterial hypertension (PAH) compared with healthy controls. This potentially indicates pulmonary vascular dysregulation. Dynamic measures using proton MRI may provide new tools for evaluating individuals at risk of PAH or for monitoring therapy in patients with PAH.

Quantitative Imaging Metrics for the Assessment of Pulmonary Pathophysiology: An Official American Thoracic Society and Fleischner Society Joint Workshop Report.

Multiple thoracic imaging modalities have been developed to link structure to function in the diagnosis and monitoring of lung disease. Volumetric computed tomography (CT) renders three-dimensional maps of lung structures and may be combined with positron emission tomography (PET) to obtain dynamic physiological data. Magnetic resonance imaging (MRI) using ultrashort-echo time (UTE) sequences has improved signal detection from lung parenchyma; contrast agents are used to deduce airway function, ventilation-perfusion-diffusion, and mechanics. Proton MRI can measure regional ventilation-perfusion ratio. Quantitative imaging (QI)-derived endpoints have been developed to identify structure-function phenotypes, including air-blood-tissue volume partition, bronchovascular remodeling, emphysema, fibrosis, and textural patterns indicating architectural alteration. Coregistered landmarks on paired images obtained at different lung volumes are used to infer airway caliber, air trapping, gas and blood transport, compliance, and deformation. This document summarizes fundamental "good practice" stereological principles in QI study design and analysis; evaluates technical capabilities and limitations of common imaging modalities; and assesses major QI endpoints regarding underlying assumptions and limitations, ability to detect and stratify heterogeneous, overlapping pathophysiology, and monitor disease progression and therapeutic response, correlated with and complementary to, functional indices. The goal is to promote unbiased quantification and interpretation of in vivo imaging data, compare metrics obtained using different QI modalities to ensure accurate and reproducible metric derivation, and avoid misrepresentation of inferred physiological processes. The role of imaging-based computational modeling in advancing these goals is emphasized. Fundamental principles outlined herein are critical for all forms of QI irrespective of acquisition modality or disease entity.

A novel nonlinear analysis of blood flow dynamics applied to the human lung.

The spatial/temporal dynamics of blood flow in the human lung can be measured noninvasively with magnetic resonance imaging (MRI) using arterial spin labeling (ASL). We report a novel data analysis method using nonlinear prediction to identify dynamic interactions between blood flow units (image voxels), potentially providing a probe of underlying vascular control mechanisms. The approach first estimates the linear relationship (predictability) of one voxel time series with another using correlation analysis, and after removing the linear component, it estimates the nonlinear relationship with a numerical mutual information approach. Dimensionless global metrics for linear prediction (FL) and nonlinear prediction (FNL) represent the average amplitude of fluctuations in one voxel estimated by another voxel, as a percentage of the global average voxel flow. A proof-of-principle test of this approach analyzed experimental data from a study of high-altitude pulmonary edema (HAPE), providing two groups exhibiting known differences in vascular reactivity. Subjects were mountaineers divided into HAPE-susceptible (S, n = 4) and HAPE-resistant (R, n = 5) groups based on prior history at high altitudes. Dynamic ASL measurements in the lung in normoxia (N, [Formula: see text] = 0.21) and hypoxia (H, [Formula: see text] = 0.13 ± 0.01) were compared. The nonlinear prediction metric FNL decreased with hypoxia [7.4 ± 1.3 (N) vs. 6.3 ± 0.7 (H), P = 0.03] and was significantly different between groups [7.4 ± 1.2 (R) vs. 6.2 ± 14.1 (S), P = 0.03]. This proof-of-principle test demonstrates that this nonlinear analysis approach applied to ASL data is sensitive to physiological effects even in small subject cohorts, and it potentially can be used in a wide range of studies in health and disease in the lung and other organs.NEW & NOTEWORTHY Pulmonary blood flow varies both spatially and temporally. We describe a novel technique to uncover nonlinear interactions in dynamic images of pulmonary blood flow measured using MRI, based on mutual information between the flow fluctuations in different imaging voxels. In a proof-of-principle study, we show that the proposed metric of nonlinear interactions was sufficiently sensitive to detect a difference between small cohorts of subjects susceptible to high-altitude pulmonary edema (HAPE) and subjects resistant to HAPE.

Measuring lung water: ex vivo validation of multi-image gradient echo MRI.

PURPOSE: To validate a fast gradient echo sequence for rapid (9 s) quantitative imaging of lung water. MATERIALS AND METHODS: Eleven excised pig lungs were imaged with a fast GRE sequence in triplicate, in the sagittal plane at 2 levels of inflation pressure (5 and 15 cm H(2) O), an intervention that alters T(2) *, but not total lung water. Images were acquired alternating between two closely-spaced echoes and data were fit (voxel-by-voxel) to a single exponential to determine T(2) * and water content, and compared with gravimetric measurements of total water. RESULTS: T(2) * averaged 1.08 ± 0.02 ms at 5 cm H(2) O and 1.02 ± 0.02 ms at 15 cm H(2) O (P < 0.05). The measure was reliable (R(2) = 0.99), with an average mean error of 1.8%. There was a significant linear relationship between the two measures of water content: The regression equations for the relationship were y = 0.92x + 19 (R(2) = 0.94), and y = 1.04x + 4 (R(2) = 0.96), for 5 and 15 cm H(2) O inflation pressure respectively. Y-intercepts were not statistically different from zero (P = 0.86). CONCLUSION: The multi-echo GRE sequence is a reliable and valid technique to assess water content in the lung. This technique enables rapid assessment of lung water, which is advantageous for in vivo studies.

Vaping disrupts ventilation-perfusion matching in asymptomatic users.

Inhalation of e-cigarette's aerosols (vaping) has the potential to disrupt pulmonary gas exchange, but the effects in asymptomatic users are unknown. We assessed ventilation-perfusion (V̇A/Q̇) mismatch in asymptomatic e-cigarette users, using magnetic resonance imaging (MRI). We hypothesized that vaping induces V̇A/Q̇ mismatch through alterations in both ventilation and perfusion distributions. Nine young, asymptomatic "Vapers" with >1-yr vaping history, and no history of cardiopulmonary disease, were imaged supine using proton MRI, to assess the right lung at baseline and immediately after vaping. Seven young "Controls" were imaged at baseline only. Relative dispersion (SD/means) was used to quantify the heterogeneity of the individual ventilation and perfusion distributions. V̇A/Q̇ mismatch was quantified using the second moments of the ventilation and perfusion versus V̇A/Q̇ ratio distributions, log scale, LogSDV̇, and LogSDQ̇, respectively, analogous to the multiple inert gas elimination technique. Spirometry was normal in both groups. Ventilation heterogeneity was similar between groups at baseline (Vapers, 0.43 ± 0.13; Controls, 0.51 ± 0.11; P = 0.13) but increased after vaping (to 0.57 ± 0.17; P = 0.03). Perfusion heterogeneity was greater (P = 0.04) in Vapers at baseline (0.53 ± 0.06) compared with Controls (0.44 ± 0.10) but decreased after vaping (to 0.42 ± 0.07; P = 0.005). Vapers had greater (P = 0.01) V̇A/Q̇ mismatch at baseline compared with Controls (LogSDQ̇ = 0.61 ± 0.12 vs. 0.43 ± 0.12), which was increased after vaping (LogSDQ̇ = 0.73 ± 0.16; P = 0.03). V̇A/Q̇ mismatch is greater in Vapers and worsens after vaping. This suggests subclinical alterations in lung function not detected by spirometry.NEW & NOTEWORTHY This research provides evidence of vaping-induced disruptions in ventilation-perfusion matching in young, healthy, asymptomatic adults with normal spirometry who habitually vape. The changes in ventilation and perfusion distributions, both at baseline and acutely after vaping, and the potential implications on hypoxic vasoconstriction are particularly relevant in understanding the pathogenesis of vaping-induced dysfunction. Our imaging-based approach provides evidence of potential subclinical alterations in lung function below thresholds of detection using spirometry.

Impact of obstructive sleep apnea on cardiopulmonary performance, endothelial dysfunction, and pulmonary hypertension during exercise.

RATIONALE: OSA has been associated with reduced exercise capacity. Endothelial dysfunction and exercise-induced pulmonary hypertension (ePH) may be mediators of this impairment. We hypothesized that OSA severity would be associated with impaired exercise performance, endothelial dysfunction, and ePH. METHODS: Subjects with untreated OSA were recruited. Subjects underwent endothelial function, and cardiopulmonary exercise testing with an echocardiogram immediately before and following exercise. RESULTS: 22 subjects were recruited with mean age 56 ± 8 years, 74 % male, BMI 29 ± 3 kg/m2, and AHI 22 ± 12 events/hr. Peak V˙O2 did not differ from normal (99.7 ± 17.3 % predicted; p = 0.93). There was no significant association between OSA severity (as AHI, ODI) and exercise capacity, endothelial function, or pulmonary artery pressure. However, ODI, marker of RV diastolic dysfunction, and BMI together explained 59.3 % of the variability of exercise performance (p < 0.001) via our exploratory analyses. CONCLUSIONS: Exercise capacity was not impaired in this OSA cohort. Further work is needed to elucidate mechanisms linking sleep apnea, obesity, endothelial dysfunction and exercise impairment.