Does estrogen fluctuation throughout the menstrual cycle impact flow-mediated dilation during exercise in healthy premenopausal women?

The endothelium is the inner most layer of cells that lines all arteries. A primary function of endothelial cells is to regulate responses to increased blood flow and the resulting frictional forces or shear stress by producing factors such as nitric oxide that mediate arterial dilation (flow mediated dilation (FMD)). Menstrual cycle variations in estrogen (E2) have been shown to influence brachial artery (BA) FMD in response to transient increases in shear stress brought about by the release of a brief forearm occlusion (reactive hyperemia (RH)). FMD can also be assessed in response to a sustained shear stress stimulus such as that created with handgrip exercise (HGEX), and studies have shown that RH- and HGEX stimulated FMD provide unique information regarding endothelial function. However, the impact of menstrual phase on HGEX-FMD is unknown. Therefore, the purpose of this study was to determine the impact of cyclical changes in E2 levels on HGEX-FMD over two discrete phases of the menstrual cycle. FMD was assessed via ultrasound. 12 subjects (21 ± 2yrs) completed two experimental visits: (1) low estrogen phase (early follicular) and (2) High estrogen phase (late follicular). In each visit both RH- and HGEX-FMD (6 min handgrip exercise) were assessed. Results are mean ± SD. E2 increased from the low to the high estrogen phase of the menstrual cycle (low: 34 ± 8, high: 161 ± 113pg/mL, p = 0.004). There was no change in mean FMD between phases (RH-FMD: 7.7 ± 4.3% vs. 6.4 ± 3.1%, p = 0.139; HGEX-FMD: 4.8 ± 2.8% vs. 4.8 ± 2.3%, p = 0.979). The observation that both RH- and HGEX-FMD did not differ between phases indicates that menstrual cycle fluctuations in estrogen may not universally impact endothelial function in young, healthy premenopausal women. Further research is needed to improve our understanding of the mechanisms that underlie variability in the impact of menstrual phase on both transient and sustained FMD responses.

STRUCTURAL AND FUNCTIONAL CORRELATES OF EXERCISE VENTILATORY INEFFICIENCY IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE PATIENTS WITH MILD-TO-MODERATE SPIROMETRIC ABNORMALITIES

Background: Individuals with chronic obstructive pulmonary disease (COPD) have higher than normal ventilatory equivalents for carbon dioxide (VE/VCO2) during exercise. There is growing evidence that emphysema on thoracic computed tomography (CT) scans is associated with poor exercise capacity in COPD patients with only mild-to-moderate airflow obstruction. We hypothesized that emphysema is an underlying cause of microvascular dysfunction and ventilatory inefficiency, which in turn contributes to reduced exercise capacity. We expected ventilatory inefficiency to be associated with a) the extent of emphysema; b) lower diffusing capacity for carbon monoxide; c) a reduced pulmonary blood flow response to exercise; and d) reduced exercise capacity. Methods: In a cross-sectional study, 19 subjects with mild-to-moderate COPD (mean ± SD FEV1= 82 ± 13% predicted, 12 GOLD grade 1) and 26 age-, sex-, and activity-matched controls underwent a ramp-incremental symptom-limited exercise test on a cycle ergometer. Ventilatory inefficiency was assessed by the minimum VE/VCO2 value (nadir). A subset of subjects also completed repeated constant work rate exercise bouts with non-invasive measurements of pulmonary blood flow. Emphysema was quantified as the percentage of attenuation areas below -950 Housefield Units on CT scans. An electronic scoresheet was used to keep track of emphysema sub-types. Results: COPD subjects typically had centrilobular emphysema (76.8 ± 10.1% of total emphysema) in the upper lobes (upper/lower lobe ratio= 0.82 ± 0.04). They had lower peak oxygen uptake (VO2), higher VE/VCO2 nadir and greater dyspnea scores than controls (p<0.05). Lower peak O2 and worse dyspnea were found in COPD subjects with VE/VCO2 nadirs ≥ 30. COPD subjects had blunted increases in pulmonary blood flow from rest to iso-VO2 exercise (p<0.05). Higher VE/VCO2 nadir in COPD subjects correlated with emphysema severity (r= 0.63), which in turn correlated with reduced lung diffusing capacity (r= -0.72) and blunted changes in pulmonary blood flow from rest to exercise (r= -0.69) (p<0.01). Conclusions: Ventilation “wasted” in emphysematous areas is associated with reduced exercise ventilatory efficiency in mild-to-moderate COPD. Exercise ventilatory inefficiency links structure (emphysema) and function (gas transfer) to a key clinical outcome (reduced exercise capacity) in COPD patients with modest spirometric abnormalities.