Courtney M. Wheatley

Sex differences in cardiovascular function during submaximal exercise in humans

Differences in cardiovascular function between sexes have been documented at rest and maximal exercise. The purpose of this study was to examine the sex differences in cardiovascular function during submaximal constant-load exercise, which is not well understood.Thirty-one male and 33 female subjects completed nine minutes moderate and nine minutes vigorous intensity submaximal exercise (40 and 75% of peak watts determined by maximal exercise test). Measurements included: intra-arterial blood pressure (SBP and DBP), cardiac index (QI), heart rate (HR), oxygen consumption (VO2) and arterial catecholamines (epinephrineu2009=u2009EPI and norepinephrineu2009=u2009NE), and blood gases. Mean arterial pressure (MAP), stroke volume index (SVI), systemic vascular resistance index (SVRI), arterial oxygen content (CaO2), arterial to venous O2 difference (AVO2) and systemic oxygen transport (SOT) were calculated.At rest and during submaximal exercise QI, SVI, SBP, MAP, NE, CaO2, and SOT were lower in females compared to males. VO2, AVO2, EPI were lower in females throughout exercise. When corrected for wattage, females had a higher Q, HR, SV, VO2 and AVO2 despite lower energy expenditure and higher mechanical efficiency.This study demonstrates sex differences in the cardiovascular response to constant-load submaximal exercise. Specifically, females presented limitations in cardiac performance in which they are unable to compensate for reductions in stroke volume through increases in HR, potentially a consequence of a female’s blunted sympathetic response and higher vasodilatory state. Females demonstrated greater cardiac work needed to meet the same external work demand, and relied on increased peripheral oxygen extraction, lower energy expenditure and improvements in mechanical efficiency as compensatory mechanisms.

Impaired cardiac and peripheral hemodynamic responses to inhaled β 2 -agonist in cystic fibrosis

BackgroundPulmonary system dysfunction is a hallmark of cystic fibrosis (CF) disease. In addition to impaired cystic fibrosis transmembrane conductance regulator protein, dysfunctional β2-adrenergic receptors (β2AR) contribute to low airway function in CF. Recent observations suggest CF may also be associated with impaired cardiac function that is demonstrated by attenuated cardiac output (Q), stroke volume (SV), and cardiac power (CP) at both rest and during exercise. However, β2AR regulation of cardiac and peripheral vascular tissue, in-vivo, is unknown in CF. We have previously demonstrated that the administration of an inhaled β-agonist increases SV and Q while also decreasing SVR in healthy individuals. Therefore, we aimed to assess cardiac and peripheral hemodynamic responses to the selective β2AR agonist albuterol in individuals with CF.Methods18 CF and 30 control (CTL) subjects participated (ages 22u2009±u20092 versus 27u2009±u20092 and BSAu2009=u20091.7u2009±u20090.1 versus 1.8u2009±u20090.0 m2, both pu2009<u20090.05). We assessed the following at baseline and at 30- and 60-minutes following nebulized albuterol (2.5mg diluted in 3.0mL of normal saline) inhalation: 12-lead ECG for HR, manual sphygmomanometry for systolic and diastolic blood pressure (SBP and DBP, respectively), acetylene rebreathe for Q and SV. We calculated MAPu2009=u2009DBPu2009+u20091/3(SBP–DBP); systemic vascular resistance (SVR)u2009=u2009(MAP/Q)•80; CPu2009=u2009Q•MAP; stroke work (SW)u2009=u2009SV•MAP; reserve (%change baseline to 30- or 60-minutes). Hemodynamics were indexed to BSA (QI, SVI, SWI, CPI, SVRI).ResultsAt baseline, CF demonstrated lower SV, SVI, SW, and SWI but higher HR than CTL (pu2009<u20090.05); other measures did not differ. At 30-minutes, CF demonstrated higher HR and SVRI, but lower Q, SV, SVI, CP, CPI, SW, and SWI versus CTL (pu2009<u20090.05). At 60-minutes, CF demonstrated higher HR, SVR, and SVRI, whereas all cardiac hemodynamics were lower than CTL (pu2009<u20090.05). Reserves of CP, SW, and SVR were lower in CF versus CTL at both 30 and 60-minutes (pu2009<u20090.05).ConclusionsCardiac and peripheral hemodynamic responsiveness to acute β2AR stimulation via albuterol is attenuated in individuals with CF, suggesting β2AR located in cardiac and peripheral vascular tissue may be dysfunctional in this population.

A systems biology approach to investigating the influence of exercise and fitness on the composition of leukocytes in peripheral blood

BackgroundExercise immunology has become a growing field in the past 20 years, with an emphasis on understanding how different forms of exercise affect immune function. Mechanistic studies are beginning to shed light on how exercise may impair the development of cancer or be used to augment cancer treatment. The beneficial effects of exercise on the immune system may be exploited to improve patient responses to cancer immunotherapy.MethodsWe investigated the effects of acute exercise on the composition of peripheral blood leukocytes over time in a male population of varying fitness. Subjects performed a brief maximal intensity cycling regimen and a longer less intense cycling regimen at separate visits. Leukocytes were measured by multi-parameter flow cytometry of more than 50 immunophenotypes for each collection sample.ResultsWe found a differential induction of leukocytosis dependent on exercise intensity and duration. Cytotoxic natural killer cells demonstrated the greatest increase (average of 5.6 fold) immediately post-maximal exercise whereas CD15+ granulocytes demonstrated the largest increase at 3 h post-maximal exercise (1.6 fold). The longer, less intense endurance exercise resulted in an attenuated leukocytosis. Induction of leukocytosis did not differ in our limited study of active (nu2009=u200910) and sedentary (nu2009=u20095) subjects to exercise although we found that in baseline samples, sedentary individuals had elevated percentages of CD45RO+ memory CD4+ T cells and elevated proportions of CD4+ T cells expressing the negative immune regulator programmed death-1 (PD-1). Finally, we identified several leukocytes whose presence correlated with obesity related fitness parameters.ConclusionsOur data suggests that leukocytes subsets are differentially mobilized into the peripheral blood and dependent on the intensity and duration of exercise. Pre-existing compositional differences of leukocytes were associated with various fitness parameters.

Commentaries on Viewpoint: Can elite athletes benefit from dietary nitrate supplementation?

Commentaries on Viewpoint : Can elite athletes benefit from dietary nitrate supplementation?

Effect of β2-adrenergic receptor stimulation on lung fluid in stable heart failure patients

BACKGROUNDnThe purpose of this study was to determine: (1) whether stable heart failure patients with reduced ejection fraction (HFrEF) have elevated extravascular lung water (EVLW) when compared with healthy control subjects; and (2) the effect of acute β2-adrenergic receptor (β2AR) agonist inhalation on lung fluid balance.nnnMETHODSnTwenty-two stable HFrEF patients and 18 age- and gender-matched healthy subjects were studied. Lung diffusing capacity for carbon monoxide (DLCO), alveolar-capillary membrane conductance (DmCO), pulmonary capillary blood volume (Vc) (via re-breathe) and lung tissue volume (Vtis) (via computed tomography) were assessed before and within 30 minutes after administration of nebulized albuterol. EVLW was derived as Vtis - Vc.nnnRESULTSnBefore administration of albuterol, Vtis and EVLW were higher in HFrEF vs control (998 ± 200 vs 884 ± 123 ml, p = 0.041; and 943 ± 202 vs 802 ± 133 ml, p = 0.015, respectively). Albuterol decreased Vtis and EVLW in HFrEF patients (-4.6 ± 7.8%, p = 0.010; -4.6 ± 8.8%, p = 0.018) and control subjects (-2.8 ± 4.9%, p = 0.029; -3.0 ± 5.7%, p = 0.045). There was an inverse relationship between pre-albuterol values and pre- to post-albuterol change for EVLW (r2 = -0.264, p = 0.015) and DmCO (r2 = -0.343, p = 0.004) in HFrEF only.nnnCONCLUSIONnLung fluid is elevated in stable HFrEF patients relative to healthy subjects. Stimulation of β2ARs may cause fluid removal in HFrEF, especially in patients with greater evidence of increased lung water at baseline.

The relationship between cardiac hemodynamics and exercise tolerance in cystic fibrosis

BACKGROUNDnIndividuals with cystic fibrosis (CF) have reduced pulmonary function and exercise tolerance. Additionally, these individuals may develop abnormal cardiac function. The implications of abnormal cardiac function on exercise tolerance are unclear in CF.nnnOBJECTIVEnStudy relationships between exercise cardiac hemodynamics and exercise tolerance in CF.nnnMETHODSn17 CF and 25 controls participated in cardiopulmonary exercise testing to measure exercise duration and peak workload (PW). Cardiac index (QI) was measured using acetylene rebreathe and oxygen uptake (VO2) breath-by-breath. Forced expiratory volume in 1-second (FEV1) was performed at rest.nnnRESULTSnPeak QI was 6.7xa0±xa00.5 vs. 9.1xa0±xa00.3xa0mL/min/m(2), CF vs. controls, respectively (Pxa0<xa00.05). Linear regressions between QI (R(2)xa0=xa00.63 and 0.51) and exercise duration or PW were stronger than VO2 (R(2)xa0=xa00.35 and 0.37) or FEV1 (R(2)xa0=xa00.34 and 0.36) in CF, respectively (Pxa0<xa00.05).nnnCONCLUSIONnThese data are clinically relevant suggesting attenuated cardiac function in addition to low airway function relate to exercise tolerance in CF.

Moderate intensity exercise mediates comparable increases in exhaled chloride as albuterol in individuals with cystic fibrosis

RATIONALEnDespite the demonstrated advantageous systemic changes in response to regular exercise for individuals with cystic fibrosis (CF), exercise is still viewed as an elective rather than a vital component of therapy, and it is likely that these benefits extend to and are partially mediated by exercise-induced changes in ion regulation.nnnOBJECTIVEnWe sought to determine if exercise could provide comparable improvements in ion regulation in the CF lung as albuterol, measured using exhaled breath condensate (EBC) collection and nasal potential difference (NPD).nnnMETHODSnFourteen CF (13-42xa0yrs.) and sixteen healthy (18-42xa0yrs.) subjects completed a randomized crossover study of albuterol and submaximal exercise. EBC was collected at baseline, 30- and 60-min post-albuterol administration, and at baseline and during three separate 15xa0min cycling exercise bouts at low, moderate, and vigorous intensity (25, 50 and 65% of the maximum workload, respectively). NPD was performed at 30- and 80-min post albuterol or following moderate and vigorous intensity exercise.nnnRESULTSnCF subjects had lower EBC Cl(-), but no difference in EBC Na(+) at baseline when compared to healthy subjects. EBC Cl(-) increased four-fold with moderate exercise which was similar to that seen 60-min post albuterol administration for CF subjects. Neither exercise nor albuterol altered EBC Na(+). The change in NPD voltage with amiloride (ΔAmil) was greater and there was minimal Cl(-) secretion (ΔTCC) seen at baseline in the CF compared to the healthy subjects. ΔAmil was greater with both albuterol and exercise when compared to baseline within both CF and healthy groups, but there was no significant difference in the ΔTCC response with either treatment.nnnCONCLUSIONnBoth exercise and albuterol can alter ion regulation increasing Cl(-) secretion to a significant and similar degree in individuals with CF.

Effects of exercise intensity compared to albuterol in individuals with cystic fibrosis

BACKGROUNDnAlthough exercise is a vital component of the therapy prescribed to individuals with cystic fibrosis (CF), it is not a priority due to a finite amount of treatment time and the view that exercise is not as beneficial as pharmacological treatments by many individuals with CF. We sought to compare the therapeutic benefits of exercise and their prescribed bronchodilator albuterol.nnnMETHODSnCF (nxa0=xa014) and healthy (nxa0=xa016) subjects completed three visits, a baseline screening with VO2 max test and two treatment visits. On the two treatment visits, subjects completed spirometry and diffusing capacity of the lungs for nitric oxide (DLNO) maneuvers either at baseline, 60, and 110xa0minxa0post-albuterol administration, or at baseline and the midway point of three separate 15xa0min exercise bouts at low, moderate and vigorous intensity (25, 50 and 65% of the maximum workload, respectively).nnnRESULTSnWith moderate exercise the increase in DLNO was double (39xa0±xa08 vs 15xa0xa0±xa06% change) and the level of bronchodilation similar (23% change) when compared to 110xa0min post-albuterol in individuals with CF. During exercise FVC became reduced (-309xa0±xa066xa0mL with moderate exercise) and the increase in FEV1 was attenuated (103xa0±xa039 vs 236xa0±xa058xa0mL, exercise vs. albuterol) when compared with the response to albuterol in individuals with CF. Epinephrine (EPI) release increased 39, 72 and 144% change with low, moderate and vigorous intensity exercise respectively for individuals with CF, but this increase was blunted when compared to healthy subjects.nnnCONCLUSIONnOur results suggest that moderate intensity exercise is the optimal intensity for individuals with CF, as low intensity exercise increases EPI less than 50% and vigorous intensity exercise is over taxing, such that airflow can be restricted. Although the duration of the beneficial effect is uncertain, exercise can promote greater improvements in gas diffusion and comparable bronchodilation when compared to albuterol.

Impact of chronic systolic heart failure on lung structure–function relationships in large airways

Heart failure (HF) is often associated with pulmonary congestion, reduced lung function, abnormal gas exchange, and dyspnea. We tested whether pulmonary congestion is associated with expanded vascular beds or an actual increase in extravascular lung water (EVLW) and how airway caliber is affected in stable HF. Subsequently we assessed the influence of an inhaled short acting beta agonist (SABA). Thirty‐one HF (7F; age, 62 ± 11 years; ht. 175 ± 9 cm; wt. 91 ± 17 kg; LVEF, 28 ± 15%) and 29 controls (11F; age; 56 ± 11 years; ht. 174 ± 8 cm; wt. 77 ± 14 kg) completed the study. Subjects performed PFTs and a chest computed tomography (CT) scan before and after SABA. CT measures of attenuation, skew, and kurtosis were obtained from areas of lung tissue to assess EVLW. Airway luminal areas and wall thicknesses were also measured. CT tissue density suggested increased EVLW in HF without differences in the ratio of airway wall thickness to luminal area or luminal area to TLC (skew: 2.85 ± 1.08 vs. 2.11 ± 0.79, P < 0.01; Kurtosis: 15.5 ± 9.5 vs. 9.3 ± 5.5 P < 0.01; control vs. HF). PFTs were decreased in HF at baseline (% predicted FVC:101 ± 15% vs. 83 ± 18%, P < 0.01;FEV1:103 ± 15% vs. 82 ± 19%, P < 0.01;FEF25–75: 118 ± 36% vs. 86 ± 36%, P < 0.01; control vs. HF). Airway luminal areas, but not CT measures, were correlated with PFTs at baseline. The SABA cleared EVLW and decreased airway wall thickness but did not change luminal area. Patients with HF had evidence of increased EVLW, but not an expanded bronchial circulation. Airway caliber was maintained relative to controls, despite reductions in lung volume and flow rates. SABA improved lung function, primarily by reducing EVLW.

Alveolar-Capillary reserve during exercise in patients with chronic obstructive pulmonary disease

Background Factors limiting exercise in patients with COPD are complex. With evidence for accelerated pulmonary vascular aging, destruction of alveolar–capillary bed, and hypoxic pulmonary vasoconstriction, the ability to functionally expand surface area during exercise may become a primary limitation. Purpose To quantify measures of alveolar–capillary recruitment during exercise and the relationship to exercise capacity in a cohort of COPD patients. Methods Thirty-two subjects gave consent (53% male, with mean ± standard deviation age 66±9 years, smoking 35±29 pack-years, and Global Initiative for Chronic Obstructive Lung Disease (GOLD) classification of 0–4: 2.3±0.8), filled out the St George’s Respiratory Questionnaire (SGRQ) to measure quality of life, had a complete blood count drawn, and underwent spirometry. The intrabreath (IB) technique for lung diffusing capacity for carbon monoxide (IBDLCO) and pulmonary blood flow (IBQc, at rest) was also performed. Subsequently, they completed a cycle ergometry test to exhaustion with measures of oxygen saturation and expired gases. Results Baseline average measures were 44±21 for SGRQ score and 58±11 for FEV1/FVC. Peak oxygen consumption (VO2) was 11.4±3.1 mL/kg/min (49% predicted). The mean resting IBDLCO was 9.7±5.4 mL/min/mmHg and IBQc was 4.7±0.9 L/min. At the first workload, heart rate (HR) increased to 92±11 bpm, VO2 was 8.3±1.4 mL/kg/min, and IBDLCO and IBQc increased by 46% and 43%, respectively, compared to resting values (p,0.01). The IBDLCO/Qc ratio averaged 2.0±1.1 at rest and remained constant during exercise with marked variation across subjects (range: 0.8–4.8). Ventilatory efficiency plateaued at 37±5 during exercise, partial pressure of mix expired CO2/partial pressure of end tidal CO2 ratio ranged from 0.63 to 0.67, while a noninvasive index of pulmonary capacitance, O2 pulse × PetCO2 (GxCap) rose to 138%. The exercise IBDLCO/Qc ratio was related to O2 pulse (VO2/HR, r=0.58, p<0.01), and subjects with the highest exercise IBDLCO/Qc ratio or the greatest rise from rest had the highest peak VO2 values (r=0.65 and 0.51, respectively, p<0.05). Of the noninvasive gas exchange measures of pulmonary vascular function, GxCap was most closely associated with DLCO, DLCO/Qc, and VO2 peak. Conclusion COPD patients who can expand gas exchange surface area as assessed with DLCO during exercise relative to pulmonary blood flow have a more preserved exercise capacity.