Cerebrovascular responses to submaximal exercise in women with COPD

The regulation of cerebral blood flow (CBF) is imperative for adequate delivery of O₂ and energy supply to the brain. During cerebral activation and increased metabolism, cerebral arterioles dilate, thereby increasing CBF, and ultimately O₂ delivery. This process of neurovascular coupling (i.e., neural activation coupled with an adequate increase in blood flow) is challenged during dynamic exercise. Factors such as age and physical fitness have been suggested to play an important role in this regulatory process both at rest [1], and during exercise [2].

The reduction of physical activity levels and exercise capacity in COPD patients [3‐5] may pose a risk to patients’ cerebrovascular health. Even in the early stages of COPD, patients with mild and moderate obstruction are reported to have reduced exercise capacity [6]. Evidence suggests that patients with moderate COPD are already at an increased risk of cardiovascular disease and stroke, thereby suggesting an underlying vascular pathology. We have previously reported decreased CBF responsiveness to CO₂ in women with COPD, suggesting reduced cerebral dilatory function [7].

Cycle ergometry testing offers a functional and translational tool to test integrated responses during exercise. COPD patients may exhibit arterial hypercapnia [8] and hypoxemia, exaggerated vasopressor response [9], and ventilatory limitations [10] during exercise – which all have implications on the regulation of CBF. Furthermore, greater distribution of cardiac output to respiratory or peripheral muscles could impact the blood flow delivery to the brain. Presently, few studies have focused on the cerebrovascular response of COPD patients during exercise [11, 12], and of these studies, focus has been on exercise limitations. It is currently unknown if the cerebrovascular response to exercise in COPD patients differs from that of a healthy control group.

We therefore tested the hypothesis that women with mild-moderate COPD would have reduced cerebral blood flow during exercise, secondary to reduced physical fitness. Women were of particular interest in this study due to a shift in the disease burden from men to women [13], and comparatively, women report worse symptoms for a similar severity of disease to men, and for any given age, have lower aerobic capacity. Additionally, we chose to focus on patients with mild-moderate COPD because this demographic represents approximately half of all cases of COPD [14].

Two COPD patients were not able to complete the EX2 protocol; however, their data from EX1 was included in the study analysis. One control participant was excluded due to lack of a suitable CBF signal. We therefore compared the exercise responses between 11 COPD and 11 control participants in EX1, and 9 COPD and 11 control participants in EX2.

Our main findings are that 1) when patients with mild to moderate COPD exercise at the same intensity to healthy controls, the CBF response is similar; and 2) when comparing CBF at a matched O₂ demand (i.e., 30 Watts), CBF is elevated in this cohort of COPD patients. From these results, it is apparent that COPD does not have a detrimental effect on cerebral blood flow during moderate intensity exercise. The mechanisms underlying the increased CBF in COPD at higher workloads needs to be investigated further.

Cerebral blood flow velocity has consistently been shown to increase in healthy individuals during mild to moderate exercise intensity [16, 21‐23], and seems to be intensity dependent [24]. Although mechanisms are not fully elucidated [25], important regulators of the exercise-induced CBF response include: cortical activation [26], arterial blood pressure [27], cardiac output [21], and blood gases (particularly P a C O 2) [28]. Comparative studies are particularly lacking in the area of ageing and disease. Consequential alterations of CBF are apparent with age, however, physical fitness has been shown to offset these changes [1, 15]. Aerobic capacity appears to be an important determinant in cerebrovascular health with ageing, as it has been shown to be positively correlated with cerebrovascular CO₂ reactivity [29], and better cognitive outcomes [15]. Current opinion suggests that COPD represents a case of advanced ageing [30], which may make these patients particularly susceptible to alterations in cerebrovascular responses.

We reasoned that the known vascular consequences associated with COPD, including endothelial dysfunction [31], and increased arterial stiffness [32] would play a detrimental role in the CBF response to exercise. A recent study suggests that physical fitness (i.e., 6MWD) has a favorable effect on endothelial function in COPD patients [33]. We have furthermore shown that women with moderate COPD exhibit a nearly two-fold reduction in the expected CBF response to CO₂[7]. It is likely that during a more modest cerebrovascular challenge (e.g., submaximal exercise versus hypercapnia), the cerebrovascular response remains intact, despite underlying vascular pathologies that may exist.

We found patients to have decreases in Sao ₂ during exercise in response to maximal and submaximal exercise. As hypoxia is known to stimulate blood flow, it is interesting that we did not find a relationship between individuals with lower Sao ₂ during exercise and increased CBF. However, it is possible that increased CBF, as seen in COPD during more intense exercise (e.g., EX2), could be partially driven by decreased Sao ₂, in a regulatory effort to increase cerebral oxygen delivery.

Results from a study investigating cerebral hemodynamics in severe COPD during exhaustive exercise suggest increased frontal cortex O₂ delivery at the end of exhaustive normoxic exercise, in conjunction with increased CBF, despite exercise induced hypoxemia [11]. These results would suggest a regulatory difference, as it has alternatively been shown in healthy hypoxemic individuals that CBF is decreased (from rest) during exhaustive exercise [34]. The differences between these studies was explained by the lack of hyperventilation in COPD which maintained (and even increased) P a C O 2, causing a vasodilatory response. However, caution is warranted as this study does not allow for an accurate comparison with an age-matched control group. The “normal” hyperventilation-induced hypocapnia evident during high-intensity exercise as been shown to be blunted in healthy older individuals, which in turn leads to maintenance of P a C O 2, and CBF [35]. In patients with terminal lung disease, Jensen et al. [12] has shown continuous increases in CBF, with a slight reduction in cerebral oxygenation at end-exercise in room air, without changes in P a C O 2. It is therefore likely, that the CBF response in COPD depends on several aspects, such as disease severity, blood gases, exercise intensity, and physical fitness. We are hesitant to draw conclusions based on P a C O 2, as this variable was not measured in our study. However, COPD patients continue to increase V ˙ E in EX2, which would not support the hypoventilation/increased P a C O 2 theory.

Cardio-pulmonary interactions during exercise in COPD have the potential to have an adverse influence on CBF. Increased expiratory loading and dynamic hyperinflation (DH) during exercise may impair venous return, and consequently lead to a reduction in right heart preload, and ultimately stroke volume. O₂ pulse is commonly used as a surrogate measure of stroke volume (and cardiac efficiency). Studies have shown DH to be negatively correlated with O₂ Pulse during incremental exercise in COPD [36, 37]. Furthermore, resting hyperinflation (IC/TLC) was associated with a reduction of O₂ pulse at peak exercise. We did not find a difference in O₂ pulse at peak exercise between COPD patients and controls (Table 2), and take this to indicate that cardiac function was not impaired in our patients. Despite COPD patients in this study having significantly lower IC/TLC ratio at rest (37% versus 49%), this level of hyperinflation is noticeably less when compared to results of the aforementioned studies which reported DH during exercise. Furthermore, the role of DH in mild-moderate COPD remains to be clearly defined. Lastly, although cardiac output remains an important determinant in cerebrovascular regulation, reductions in cardiac output (by lower body negative pressure) reduce CBF, but seem to be less important during exercise compared to the resting state, which has been explained as a counter-regulatory activation of the sympathetic nervous system [38]. Overall, we speculate, that DH is not a major contributor to the determinants of CBF in our sample population. As this remains beyond the scope of this study, it should be considered in future studies.

One strength of our study is that it includes data comparing the physiological response during both as exercise challenge that is a fixed percentage of each person’s maximal workload, and an absolute workload - which represents a value that may be a more realistic occurrence in activities of daily living. Although we found that patients with mild and moderate COPD have a normal CBF response at 50% V ˙ O 2 peak, it is important to highlight that this workload is equivalent to ~2.9 METS, which would equate to light housework such as self care, washing dishes, and walking to a parking lot [39]. When physical demands are slightly increased to 30 Watts (~3.2 METS), these COPD patients further increase CBF. The importance of absolute requirements are highlighted by Paterson et al. [40] who report that a relative V ˙ O 2 of ~15 mL O₂·kg^-1·min^-1 is required for independent living in the aging population. During moderate activities (e.g., vigorous cleaning, sweeping, etc.), COPD patients would be exposed to increased aerobic demand, which may have cerebrovascular implications, including a reduced cerebrovascular reserve capacity compared to healthy controls. This remains highly speculative, and the implications of this are unclear at this time. Although we do not have measures of habitual activity, we have previously shown a significant, positive agreement between self-reported physical and V ˙ O 2 max in healthy, older women [41]. In this same study, fitness was correlated with better vascular outcomes during exercise [15]. We therefore suspect that individuals in the present study who have a higher V ˙ O 2 max are also more physically active, although this needs to be confirmed in future research. Conversely, it is possible that frequent increases in CBF may pose a vascular benefit to COPD patients, whereby increases in CBF result in shear stress on the vascular endothelium, thus providing beneficial adaptations through the up-regulation of nitric oxide synthase [42]. In contrast, modest activities increase CBF in COPD and may limit the supply of blood flow available for additional challenges, such as cognitive tasks.

Our selection of mild – moderate COPD patients includes 9 of 11 patients with GOLD II, moderate COPD. Of these 11 patients, 2 could not complete a 6-minute workload of 30 Watts. We believe that more severe patients would have further difficulty completing 2×6-min bouts of cycling exercise. Further, our selected cohort of COPD patients represents the patients that are most likely either still physically active, or still have the potential to become more active, and we would therefore gain the greatest insight into studying this population. Women in particular have lower V ˙ O 2 max, smaller lung volumes, and exhibit greater dyspnea at a similar V ˙ O 2 compared to men [43]. Finally, a homogeneous sample of women reduces additional heterogeneity between subjects, and is particularly important in this smaller sample size.

Cerebral blood flow responsiveness appears to be normal in patients with mild to moderate COPD compared to healthy controls when exercising at a moderate intensity (50% V ˙ O 2 max), but not when exercising at a slightly greater, matched workload (i.e., 30 Watts). It is likely that decreased physical fitness contribute to this. These results have implications for normal activities of daily living such as household activities in which COPD patients would likely experience greater increases in CBF, thereby decreasing the cerebral vascular reserve.