Timothy D. Mickleborough

Normalization of flow-mediated dilation to shear stress area under the curve eliminates the impact of variable hyperemic stimulus

BackgroundNormalization of brachial artery flow-mediated dilation (FMD) to individual shear stress area under the curve (peak FMD:SSAUC ratio) has recently been proposed as an approach to control for the large inter-subject variability in reactive hyperemia-induced shear stress; however, the adoption of this approach among researchers has been slow. The present study was designed to further examine the efficacy of FMD normalization to shear stress in reducing measurement variability.MethodsFive different magnitudes of reactive hyperemia-induced shear stress were applied to 20 healthy, physically active young adults (25.3 ± 0. 6 yrs; 10 men, 10 women) by manipulating forearm cuff occlusion duration: 1, 2, 3, 4, and 5 min, in a randomized order. A venous blood draw was performed for determination of baseline whole blood viscosity and hematocrit. The magnitude of occlusion-induced forearm ischemia was quantified by dual-wavelength near-infrared spectrometry (NIRS). Brachial artery diameters and velocities were obtained via high-resolution ultrasound. The SSAUC was individually calculated for the duration of time-to-peak dilation.ResultsOne-way repeated measures ANOVA demonstrated distinct magnitudes of occlusion-induced ischemia (volume and peak), hyperemic shear stress, and peak FMD responses (all p < 0.0001) across forearm occlusion durations. Differences in peak FMD were abolished when normalizing FMD to SSAUC (p = 0.785).ConclusionOur data confirm that normalization of FMD to SSAUC eliminates the influences of variable shear stress and solidifies the utility of FMD:SSAUC ratio as an index of endothelial function.

Adjusting flow-mediated dilation for shear stress stimulus allows demonstration of endothelial dysfunction in a population with moderate cardiovascular risk

Background/Aims: Although normalization of brachial artery flow-mediated dilation (FMD) to individual shear stress (FMD:shear stress ratio) has been proposed to improve this measure of endothelial function, the clinical utility of FMD normalization has not yet been demonstrated. We tested (1) whether following conventional 5-min forearm occlusion, the FMD:shear stress ratio would discriminate a population with moderate cardiovascular risk (MR) from a low-risk (LR) population, and (2) whether the dose-response profile relating shear stress to FMD would be different between the 2 populations. Methods: Five different magnitudes of reactive hyperemia-induced shear stress were applied to 20 MR and 20 LR subjects by manipulating forearm cuff occlusion duration. Brachial artery diameters and velocities were measured via high-resolution ultrasound. To quantify the hyperemic stimulus, shear stress area under the curve was individually calculated for the duration of time-to-peak dilation. Results: Following 5-min of forearm occlusion, FMD:shear stress ratio (p = 0.041), but not FMD (p = 0.286), discriminated MR from LR. The slope of the shear stress-FMD regression line was lower in MR compared to the LR (p <0.001). Conclusion: The FMD:shear stress ratio distinguished reduced endothelial function in a population with MR. The dose-response profile of the shear stress-FMD relationship appears to differ between populations of distinct cardiovascular risk.

Characteristics of the control of human thermoregulatory behavior

The aim of this study was to characterize several of the thermal input(s) that influence thermo-behavior in humans. Eight male subjects completed two trials in which they were free to initiate an exit from a hot chamber (45 degrees C) to a cold chamber (10 degrees C; H-->C) or from a cold chamber to a hot chamber (C-->H). Upon initiating an exit from the chamber, mean skin temperature (T(Sk)), rectal temperature (T(Rectal)), subjective thermal comfort, and time in the climate chambers prior to exit were recorded. Thermo-behavior was defined as the initiation of exit. All variables were similar (P> or =0.05) between the two trials. T(Sk) and thermal comfort at H-->C were significantly (P</=0.05) higher (34.0+/-1.1 degrees C, and 7.3+/-0.6, respectively) than at C-->H (29.4+/-0.9 degrees C, and 3.0+/-0.6, respectively). No significant differences (P> or =0.05) were found between H-->C and C-->H for T(Rectal) (H-->C: 37.0+/-0.2 degrees C vs. C-->H: 37.0+/-0.2 degrees C) or time prior to exit (H-->C: 3.9+/-2.3 min vs. C-->H: 3.9+/-1.7 min). The frequency distributions and the probability of the initiation of exit curves at H-->C and C-->H for both T(Sk) and thermal comfort were significantly negatively skewed (P< or =0.05) and normally distributed, respectively (P>/=0.05). Skin temperature appears to be an important thermal input mediating thermo-behavioral responses. This behavioral response appears to be more precise when exposed to hot temperatures compared to cold temperatures.

Eicosapentaenoic acid is more effective than docosahexaenoic acid in inhibiting proinflammatory mediator production and transcription from LPS-induced human asthmatic alveolar macrophage cells

BACKGROUND & AIMS The purpose of the study was to determine which of the active constituents of fish oil, eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA), is most effective in suppressing proinflammatory mediator generation and cytokine expression from LPS-stimulated human asthmatic alveolar macrophages (AMphi). METHODS The AMphi were obtained from twenty-one asthmatic adults using fiberoptic bronchoscopy. Cells were pretreated with DMEM, pure EPA, an EPA-rich media (45% EPA/10% DHA), pure DHA, a DHA-rich media (10% EPA/50% DHA) or Lipovenos (n-6 PUFA), and then exposed to Dulbeccos Modified Eagles Medium (DMEM) (-) or LPS (+). Supernatants were analyzed for leukotriene (LT)B(4), prostaglandin (PG)D(2), tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta production. Detection of TNF-alpha and IL-1beta mRNA expression levels was quantified by reverse transcriptase polymerase chain reaction. RESULTS 120 microM pure EPA and EPA-rich media significantly (p<0.05) suppressed TNF-alpha and IL-1beta mRNA expression and the production of LTB(4), PGD(2) and TNF-alpha and IL-1beta in LPS-stimulated primary AMphi cells obtained from asthmatic patients to a much greater extent than 120 microM pure DHA and DHA-rich media respectively. CONCLUSIONS This study has shown for the first time that EPA is a more potent inhibitor than DHA of inflammatory responses in human asthmatic AMphi cells.

Dietary salt restriction improves pulmonary function in exercise-induced asthma.

PURPOSE Exercise-induced asthma (EIA) occurs in approximately 90% of persons with asthma. The mechanism has not been delineated. Epidemiological studies have suggested that dietary salt may play a role in airway responsiveness. Therefore, the purpose of this study was to determine the influence of both elevated and restricted salt diets on pulmonary function in subjects with EIA. METHODS Eight subjects with EIA and eight subjects without EIA (control) participated in a double-blind crossover study. Pulmonary function was determined pre- and post-exercise challenge before and after 2 wk on a normal salt, sodium chloride, diet (NSD), a low salt diet (LSD), and a high salt diet (HSD). A 1-wk washout occurred between diets. RESULTS Diet had no effect on preexercise pulmonary function values in either group and had no effect on postexercise pulmonary function values in control subjects. However, LSD improved and HSD worsened postexercise pulmonary function values in EIA subjects. Forced expiratory volume in 1 s (FEV1) decreased by at least 10% in EIA subjects with exercise. In EIA subjects, FEV1 decreased by 14+/-6% on LSD, 20+/-7% on NSD, and 24+/-6% on HSD at 15 min postexercise. Similar patterns were observed for forced vital capacity and peak expiratory flow rates. Although LSD did not normalize pulmonary function in EIA, it did improve it. CONCLUSIONS These data suggest that individuals with EIA might benefit from lower salt diets.

The oxygen uptake response running to exhaustion at peak treadmill speed

PURPOSE Peak treadmill speed (V(max)), which is the final speed reached and sustained for a minute during a speed-incremented continuous maximal oxygen uptake ([OV0312]O(2max)) test, is an effective predictor of endurance performance. This study assesses the reliability of V(max) and [OV0312]O(2max), and examines the oxygen uptake response while running to exhaustion at V(max). METHODS Eleven recreationally active runners completed two speed-incremented [OV0312]O(2max) tests (test 1 and test 2) to determine [OV0312]O(2max) and V(max). In addition, the subjects completed a constant speed test (test 3) at V(max) to determine time to exhaustion (T(max)). RESULTS No significant differences existed between test 1 and test 2 for [OV0312]O(2max) (P = 0.68) and V(max) (P = 0.10). Means (+/- SD) for [OV0312]O(2max) and V(max) were 51.1 +/- 5.8 mL.kg-1.min-1 and 17.4 +/- 1.3 km.h-1, respectively; 95% limits of agreement for V(max) were -0.1 +/- 1.4 km.h-1. However, as heteroscedasticity was present in the [OV0312]O(2max) test data, 95% ratio limits of agreement were reported (1.01 *// 1.08). During test 3, 6 of the 11 subjects attained an oxygen uptake equivalent to their previously recorded [OV0312]O(2max). The time to attain [OV0312]O(2max) was 155.0 +/- 48.0 s, which represented 66.5% of T(max) (237.0 +/- 35.0 s). Although 5 of the 11 subjects did not attain an oxygen uptake response equivalent to that previously recorded, no significant difference existed between the oxygen uptakes for the three tests (P = 0.52). CONCLUSION The results of this study indicate that V(max) and [OV0312]O(2max) attained during a speed incremented maximal oxygen uptake test were reliable. However, while running at V(max), not all the subjects attained an oxygen uptake response equivalent to that previously recorded during incremental tests 1 and 2.

Effect of inspiratory muscle training on exercise tolerance in asthmatic individuals.

PURPOSE The aim of this study was to determine the effects of inspiratory muscle training (IMT) on exercise tolerance, inspiratory muscle fatigue, and the perception of dyspnea in asthmatic individuals. METHODS Using a matched double-blind placebo-controlled design, 15 clinically diagnosed asthmatic individuals underwent either 6 wk of IMT (n = 7) consisting of 30 breaths twice daily at 50% maximum inspiratory pressure (PI max) or sham-IMT (placebo; PLA, n = 8) consisting of 60 breaths daily at 15% PI max. Time to the limit of exercise tolerance (Tlim) was assessed using constant-power output (70% peak power) cycle ergometry. Inspiratory muscle fatigue was determined by comparing the pre- to postexercise reduction in PI max. Dyspnea during the Tlim test was evaluated at 2-min intervals using the Borg CR-10 scale. RESULTS There were no significant changes (P > 0.05) in Tlim, inspiratory muscle fatigue, or perception of dyspnea in the PLA group after the intervention. In contrast, in the IMT group, PI max increased by 28%, and Tlim increased by 16% (P < 0.05). Dyspnea during exercise was also reduced significantly by 16% (P < 0.05). The exercise-induced fall in PI max was reduced from 10% before IMT to 6% after IMT (P < 0.05), despite the longer Tlim. Pulmonary function remained unchanged in both the IMT and PLA groups. CONCLUSIONS These data suggest that IMT attenuates inspiratory muscle fatigue, reduces the perception of dyspnea, and increases exercise tolerance. These findings suggest that IMT may be a helpful adjunct to asthma management that has the potential to improve participation and adherence to exercise training in this group. However, the perception of breathlessness is also an important signal of bronchoconstriction, and thus, caution should be exercised if this symptom is abnormally low.

Inspiratory muscle training lowers the oxygen cost of voluntary hyperpnea

The purpose of this study was to determine if inspiratory muscle training (IMT) alters the oxygen cost of breathing (Vo(2RM)) during voluntary hyperpnea. Sixteen male cyclists completed 6 wk of IMT using an inspiratory load of 50% (IMT) or 15% placebo (CON) of maximal inspiratory pressure (Pi(max)). Prior to training, a maximal incremental cycle ergometer test was performed to determine Vo(2) and ventilation (V(E)) at multiple workloads. Pre- and post-training, subjects performed three separate 4-min bouts of voluntary eucapnic hyperpnea (mimic), matching V(E) that occurred at 50, 75, and 100% of Vo(2 max). Pi(max) was significantly increased (P < 0.05) by 22.5 ± 8.7% from pre- to post-IMT and remained unchanged in the CON group. The Vo(2RM) required during the mimic trial corresponded to 5.1 ± 2.5, 5.7 ± 1.4, and 11.7% ± 2.5% of the total Vo(2) (Vo(2T)) at ventilatory workloads equivalent to 50, 75, and 100% of Vo(2 max), respectively. Following IMT, the Vo(2RM) requirement significantly decreased (P < 0.05) by 1.5% (4.2 ± 1.4% of Vo(2T)) at 75% Vo(2 max) and 3.4% (8.1 ± 3.5% of Vo(2T)) at 100% Vo(2 max). No significant changes were shown in the CON group. IMT significantly reduced the O(2) cost of voluntary hyperpnea, which suggests that a reduction in the O(2) requirement of the respiratory muscles following a period of IMT may facilitate increased O(2) availability to the active muscles during exercise. These data suggest that IMT may reduce the O(2) cost of ventilation during exercise, providing an insight into mechanism(s) underpinning the reported improvements in whole body endurance performance; however, this awaits further investigation.

Randomized Controlled Trial of Fish Oil and Montelukast and Their Combination on Airway Inflammation and Hyperpnea-Induced Bronchoconstriction

Background Both fish oil and montelukast have been shown to reduce the severity of exercise-induced bronchoconstriction (EIB). The purpose of this study was to compare the effects of fish oil and montelukast, alone and in combination, on airway inflammation and bronchoconstriction induced by eucapnic voluntary hyperpnea (EVH) in asthmatics. Methods In this model of EIB, twenty asthmatic subjects with documented hyperpnea-induced bronchoconstriction (HIB) entered a randomized double-blind trial. All subjects entered on their usual diet (pre-treatment, n = 20) and then were randomly assigned to receive either one active 10 mg montelukast tablet and 10 placebo fish oil capsules (n = 10) or one placebo montelukast tablet and 10 active fish oil capsules totaling 3.2 g EPA and 2.0 g DHA (n = 10) taken daily for 3-wk. Thereafter, all subjects (combination treatment; n = 20) underwent another 3-wk treatment period consisting of a 10 mg active montelukast tablet or 10 active fish oil capsules taken daily. Results While HIB was significantly inhibited (p<0.05) by montelukast, fish oil and combination treatment compared to pre-treatment, there was no significant difference (p>0.017) between treatment groups; percent fall in forced expiratory volume in 1-sec was −18.4±2.1%, −9.3±2.8%, −11.6±2.8% and −10.8±1.7% on usual diet (pre-treatment), fish oil, montelukast and combination treatment respectively. All three treatments were associated with a significant reduction (p<0.05) in FENO, exhaled breathe condensate pH and cysteinyl-leukotrienes, while the fish oil and combination treatment significantly reduced (p<0.05) urinary 9α, 11β-prostaglandin F2 after EVH compared to the usual diet; however, there was no significant difference (p>0.017) in these biomarkers between treatments. Conclusion While fish oil and montelukast are both effective in attenuating airway inflammation and HIB, combining fish oil with montelukast did not confer a greater protective effect than either intervention alone. Fish oil supplementation should be considered as an alternative treatment for EIB. Trial Registration ClinicalTrials.gov NCT00676468

Dietary salt alters pulmonary function during exercise in exercise-induced asthmatics

Epidemiological and experimental studies have suggested that dietary salt may play a role in airway responsiveness. We have previously shown that a low salt diet improves and a high salt diet exacerbates post-exercise pulmonary function in individuals with exercise-induced asthma. The aim of this study was to determine the influence of both elevated and restricted salt diets on pulmonary function during exercise in individuals with exercise-induced asthma. Nine men and six women participated in this double-blind, crossover study. The participants entered the study on their normal salt diet and were placed on either a low or high salt diet for 2 weeks. Each diet was randomized, with a 1 week washout period between diets before crossing over to the alternative diet for 2 weeks. The participants underwent treadmill testing at 85% of their age-predicted heart rate on the normal salt diet and at the end of each treatment period. Pulmonary function was assessed during exercise by arterial saturation (ear oximetry) and indirect calorimetry. Twenty-four hour urine collections confirmed compliance with the diets. Arterial saturation was reduced on the high and improved on the low salt diet at higher exercise intensities. Tidal volume and frequency selection during exercise varied with the diets, with a higher tidal volume and lower frequency on the high salt diet, but a lower tidal volume and higher frequency on the low salt diet. This suggested greater airway resistance during the high salt diet. In conclusion, the low salt diet improved and the high salt diet exacerbated pulmonary function during exercise in individuals with exercise-induced asthma. The mechanism of action remains unclear.