Experimental Gerontology 61 (2015) 92–97
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Experimental Gerontology journal homepage: www.elsevier.com/locate/expgero
Arterial stiffness is higher in older adults with increased perceived fatigue and fatigability during walking Joaquin U. Gonzales a,⁎, Matthew Wiberg a, Elizabeth Defferari a, David N. Proctor b a b
Department of Health, Exercise and Sport Sciences, Texas Tech University, Lubbock, TX, United States Department of Kinesiology, Pennsylvania State University, University Park, PA, United States
a r t i c l e
i n f o
Article history: Received 5 September 2014 Received in revised form 21 October 2014 Accepted 3 December 2014 Available online 4 December 2014 Editor: Christiaan Leeuwenburgh Keywords: Aging Arterial stiffness Fatigue Feeling of tiredness Femoral artery Walking
a b s t r a c t We investigated whether central and/or peripheral arterial stiffness contributes to increased perceived fatigue during walking in mobility-intact older adults. Arterial stiffness of the common carotid artery and superficial femoral artery (SFA) was measured using Doppler-ultrasound in 45 community-dwelling women and men (60–78 yrs). The change in perceived fatigue was measured after a fast-pace 400 meter walk test. Adults that rated feeling more tired after walking (n = 10) had higher SFA stiffness (p b 0.01), but not carotid artery stiffness, than adults that reported feeling more energetic after walking (n = 22). The change in perceived fatigue rating was normalized to energy expenditure during walking to determine perceived fatigability. Adults were divided into lower and higher perceived fatigability groups (n = 22 per group). Carotid artery stiffness was not different between perceived fatigability groups after adjusting for age, sex, body fat, systolic blood pressure, fasting blood glucose, daily physical activity levels, and resting diameter. However, SFA stiffness was significantly elevated in the higher as compared to lower perceived fatigability group (β-index: 20.7 ± 1.3 vs. 15.3 ± 1.4 U; p = 0.02) after adjusting for the abovementioned variables. Moreover, stepwise regression identified SFA β-index to be an independent predictor of perceived fatigability (r2 = 0.38, p b 0.01). These results suggest that peripheral arterial stiffness is independently associated with perceived fatigue and fatigability in older adults. © 2014 Elsevier Inc. All rights reserved.
1. Introduction Feeling of tiredness or perceived fatigue negatively impacts daily ambulatory activity (Simonsick et al., 1999) and walking speed in older adults (Vestergaard et al., 2009). Some, but not all, studies report greater perceived fatigue in older as compared to younger adults (Eldadah, 2010). One factor thought to contribute to this discrepancy is energy expenditure. It is postulated that older adults may lower physical activity patterns to limit feelings of tiredness within a tolerable range, thus showing similar perceived fatigue as compared to younger adults (Alexander et al., 2010; Eldadah, 2010). This limitation can be addressed by normalizing perceived fatigue to energy expenditure which allows for the examination of fatigability (Buchowski et al., 2011; Eldadah, 2010). An older adult with increased fatigability would be one that reports elevated perceived fatigue but expends a low amount of energy. Additionally, an older adult reporting average perceived fatigue, but has low energy expenditure would have increased fatigability. Using this approach to normalize perceived fatigue to work, others have
⁎ Corresponding author at: Department of Health, Exercise and Sport Sciences, Texas Tech University, Box 43011, Lubbock, TX 79409-3011, United States. E-mail addresses: [email protected] (J.U. Gonzales), [email protected] (M. Wiberg), [email protected] (E. Defferari), [email protected] (D.N. Proctor).
http://dx.doi.org/10.1016/j.exger.2014.12.005 0531-5565/© 2014 Elsevier Inc. All rights reserved.
shown that increased perceived fatigability during walking is negatively associated with daily physical activity and preferred walking speed in older adults (Schnelle et al., 2012). Recently, large artery elasticity was found to associate with perceived fatigue measured at rest in older women without cardiovascular disease (Hunter et al., 2014). The method used to assess arterial elasticity was pulse contour analysis, an indirect technique that estimates elasticity from cardiac output derived from an algorithm and diastolic pressure decay from a radial artery pulse wave (Mackenzie et al., 2002). A more direct assessment of regional arterial structure can be made using Doppler ultrasound imaging. Ultrasound-derived carotid artery stiffness has previously been shown to increase with age (Kawasaki et al., 1987), relate to depressed cognitive function (Tarumi et al., 2013), and negatively associate with walking speed in healthy older adults (Gonzales, 2013). Moreover, ultrasound allows for measurement of peripheral arterial stiffness (e.g., femoral artery in the leg) that may be more relevant to perceived fatigability during physical activity due to its relationship with muscle perfusion (Kizu et al., 2003) and energy expenditure during exercise (Ferreira et al., 2002). Therefore, the purpose of this study was to test the hypothesis that central (carotid artery) and peripheral (superficial femoral artery) arterial stiffness would associate with perceived fatigability during walking in older adults. Because daily physical activity is associated with perceived fatigability (Schnelle et al., 2012), we further hypothesized that the
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association between arterial stiffness and perceived fatigability would be independent of daily physical activity patterns. 2. Methods 2.1. Participants Twenty-five women and twenty men (N = 45) between the ages of 60–78 yrs took part in this study after giving informed consent to participate. Participants were recruited from the community via local city newspaper advertisements and electronic announcements sent to the university community. Participants self-reported no history of cardiovascular disease, diabetes, pulmonary disease, and none were taking medications for high blood pressure, cholesterol, or hormone replacement. All participants were non-smokers and non-obese based on a body mass index b 30 kg/m2. Participants were included if resting seated brachial blood pressure was b159/99 mm Hg and fasted blood glucose b115 mg/dL as measured by finger prick (Accu-Chek Active, Roche Diagnostics) following 8–12 h of fasting. Including hypertensive and glucose impaired ranges allowed for a spread of arterial stiffness values between participants. The Human Research Protection Program at Texas Tech University provided ethics approval for this study. 2.2. Arterial stiffness parameters Participants rested in the supine position for at least 10 min before vascular measurements. Carotid-femoral pulse wave velocity (PWV) was measured using applanation tonometry (SphygmoCor, Atcor Medical, Sydney, Australia) at the right radial artery. The average of two measurements was used for analysis. One researcher measured PWV in all participants with a test–retest coefficient of variation of 4% (Gonzales, 2013). Arterial diameter was measured in the right common carotid artery and the right superficial femoral artery (SFA) using Doppler ultrasound (Vivid 7) in 2D mode with a 5–13 MHz linear transducer probe. Measurements were taken ~ 1–2 cm proximal (carotid artery) and distal (SFA) to their respective bifurcations. A 20 s clip of the diameter pulses was saved and analyzed offline using an automated edge detection system (Brachial Analyzer, Medical Imaging Applications, Coralville, IA, USA) for the change in diameter throughout the cardiac cycle. From the average diastolic (Dd) and systolic (Ds) diameter, the following arterial stiffness parameter was calculated:
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2.3. Walking exercise Participants completed a 400 m walk test. Two traffic cones were placed 65.5 ft apart in a long flat-surfaced hallway. Participants were instructed to “select a pace that you can comfortably maintain for 10 laps but you feel that you can complete in your best time.” No participants needed a break period during the test. Walking speed (m/s) was calculated from the time to complete 400 m. Heart rate was recorded during the last lap of the walk test using a Polar monitor to calculate relative exercise intensity based on age-predicted maximum heart rate [208 − (0.7 × age)] (Tanaka et al., 2001). 2.4. Energy expenditure during walking Participants wore a tri-axial accelerometer (model GT3X+, ActiGraph, Pensacola, FL, USA) at their right hip with an elastic belt during the 400 m walk test. The accelerometer measured accelerations in the range of 0.05 g–2.0 g. The acceleration data was reduced to 1 s intervals, called epochs, to generate activity counts. Raw activity counts from the vertical axis were used to estimate energy expenditure using the equation: kcal/min = 3.28 + (0.0009 × counts per min) (Hall et al., 2013). The kcal/min expression was converted to oxygen uptake (mL/kg/min) using a standard equation: ((kcal/min/5) × 1000) / body weight. This conversion step was necessary in order to normalize energy expenditure to body weight. 2.5. Perceived fatigability A 7-item fatigue scale was used before and after walking exercise as previously described (Buchowski et al., 2011; Schnelle et al., 2012). Prior to walking exercise, participants were asked to rate their resting fatigue state as extremely energetic (rating = 1), somewhat energetic (rating = 2), a little energetic (rating = 3), neither tired or energetic (rating = 4), a little tired (rating = 5), somewhat tired (rating = 6), and extremely tired (rating = 7). Immediately after completing the 400 m walk test, participants were asked to rate their change in fatigue as extremely more energetic (rating = 1), somewhat more energetic (rating = 2), a little more energetic (rating = 3), neither more tired or energetic (rating = 4), a little more tired (rating = 5), somewhat more tired (rating = 6), and extremely more tired (rating = 7). The post-exercise fatigue rating was divided by the average energy expenditure (oxygen uptake) during the 400 m walk test to calculate a fatigability score (Buchowski et al., 2011).
β‐index ¼ ln ðSBP=DBPÞ=½ðDs –Dd Þ=Dd 2.6. Daily physical activity (Liao et al., 1999) −3 −1 mm Hg arterial distensibility 10 ¼ ½2 ðDs −Dd Þ=Dd =ðSBP−DBPÞ (Reneman et al., 2005). Data obtained from at least five simultaneous blood pressure (systolic, SBP; diastolic, DBP) and diameter waveforms were used in the analysis. Blood pressure on the left arm was measured continuously during diameter measurements using an automated device (CNAP monitor, CNSystems, Graz, Austria). Brachial pressure was used to calibrate the carotid waveform measured using applanation tonometry to derive local pressure used for calculating carotid artery stiffness. For the SFA, brachial pressure was used as a surrogate since i) the SFA is not superficial to the skin thus making it hard to get a high quality or reliable signal, and ii) brachial pulse pressure has been shown to be comparable to femoral pressure derived from tonometry (Benetos et al., 1993). Blood velocity (30 s sample) and diameter (20 s clip) were used to calculate blood flow by multiplying the cross-sectional area (πr2) of the carotid artery and the SFA with mean blood velocity.
Participants wore a triaxial accelerometer (Actigraph model GT3X+, Pensacola, FL, USA) on the right hip for 7 consecutive days. Participants were asked to take it off during bathing, swimming, and sleeping. The accelerometers collected data at a sampling rate of 30 Hz. Raw acceleration data were integrated to 60 s epochs without low-frequency extension. The integrated file underwent wear time validation using automated software (ActiLife v6, Pensacola, FL, USA). Recommended nonwear time criteria was used (Choi et al., 2011) including the criterion that a day must have ≥10 h of wear time to be considered valid. All non-wear time was excluded from further analysis. Steps per day were averaged across all valid days for each adult, and 30-min peak stepping cadence was calculated as the average steps per min for the 30 highest minutes in a day (but not necessarily consecutive minutes) for each adult (Tudor-Locke et al., 2012). 2.7. Statistical analysis Group comparisons were made using a one-way analysis of variance (ANOVA) for normally distributed data. A Kruskal–Wallis one-way ANOVA on ranks was used for comparing groups for asymmetrically
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distributed data. Tukey and Dunn's post-hoc testing, respectively, was used for pairwise comparisons if significance was met. Analysis of covariance (ANCOVA) adjusting for age, sex, body composition, fasting blood glucose, resting systolic blood pressure, daily ambulatory activity, and resting diameter was used to test for differences in arterial stiffness parameters between groups divided by the median fatigability score (0.178). Lastly, stepwise (forward and backward method) regression was used to identify independent predictors of fatigability using an alpha of 0.1 for entry and removal. Significance was considered p ≤ 0.05.
3. Results 3.1. Change in perceived fatigue following walking Table 1 presents the comparison between adults reporting feeling more tired, no change, or more energetic after the 400 m walk test. Ten adults (22%) reported feeling more tired (5.2 ± 0.4 avg. rating), thirteen adults (28%) reported no change in their feeling of being tired or energetic (4 rating by all), and twenty-two adults (48%) reported feeling more energetic after walking (2.5 ± 0.5 avg. rating). The group with increased feeling of tiredness after walking had similar (p N 0.05) age, body composition, resting blood pressure, fasting blood glucose, daily physical activity patterns, and walking performance (speed and intensity) than the other groups. Carotidfemoral pulse wave velocity and carotid artery stiffness was not different (p N 0.05) between adults that reported feeling more tired as compared to adults that reported feeling more energetic after walking. In contrast, SFA stiffness was higher (p b 0.05) in adults reporting feeling more tired than those feeling more energetic after walking. This group difference remained significant (β-index: 15.7 ± 1.2 vs. 21.8 ± 1.6 × 10− 3 mm Hg − 1; distensibility: 1.7 ± 0.12 vs. 1.0 ± 0.16 × 10− 3 mm Hg− 1; p = 0.01) after adjusting for age, sex, mean blood pressure, and SFA diameter using ANCOVA. Moreover, SFA β-index (Fig. 1A) and distensibility (r = − 0.59, p b 0.01) were significantly correlated with the change in perceived fatigue rating.
Fig. 1. Relationship between superficial femoral artery (SFA) β-stiffness index and the change in perceived fatigue rating (A) and perceived fatigability score (B) after performing a fast-pace 400 m walk test in older adults.
Table 1 Comparison between groups based on change in perceived fatigue following 400 m walk. Variable
More energetic (rating b 4)
No Change (rating = 4)
More tired (rating N 4)
Sample size (women/men) Age (yrs) Body mass index (kg/m2) Waist circumference (cm) Systolic blood pressure (mm Hg)a Diastolic blood pressure (mm Hg)a Fasting blood glucose (mg/dL) Daily physical activity Avg. steps per day Avg. peak cadence (steps per min) Walking performance variables 400 m walking speed (m/s) Relative intensity (%HRmax) Avg. energy expenditure (kcal/min) Central arterial stiffness parameters Carotid-femoral PWV (m/s) Carotid β-index Carotid distensibility (×10−3 mm Hg−1) Carotid diameter (cm) Carotid blood flow (mL/min) Peripheral arterial stiffness parameters SFA β-index SFA distensibility (×10−3 mm Hg−1) SFA diameter (cm) SFA blood flow (mL/min)
22 (16/6) 65.3 ± 3.9 23.0 ± 2.5 80.9 ± 8.4 117.8 ± 17.2 67.4 ± 8.6 94.0 ± 6.0
13 (5/8) 69.1 ± 4.8 23.8 ± 2.5 85.3 ± 13.4 127.7 ± 10.5 74.3 ± 5.8b 95.2 ± 8.9
10 (4/6) 67.6 ± 6.7 22.9 ± 2.3 83.8 ± 8.9 121.3 ± 10.3 69.6 ± 7.8 94.3 ± 5.7
0.03 0.62 0.45 0.15 0.04 0.87
7836 ± 2221 84.9 ± 22.6
6934 ± 3223 73.3 ± 28.3
5677 ± 2741 68.0 ± 33.4
0.11 0.22
1.50 ± 0.17 67.1 ± 10.4 6.7 ± 1.2
1.43 ± 0.14 69.6 ± 14.6 6.4 ± 1.2
1.40 ± 0.17 67.9 ± 12.0 6.1 ± 0.9
0.17 0.84 0.42
7.8 (7.3–10.4) 8.2 (6.9–11.5) 2.6 (1.7–3.4) 0.73 ± 0.07 590 ± 167
10.6 (8.5–11.4)b 9.3 (8.5–11.8) 2.0 (1.7–2.5) 0.77 ± 0.11 642 ± 157
9.3 (7.6–10.2) 8.4 (7.2–14.5) 2.5 (1.5–3.4) 0.74 ± 0.04 597 ± 151
0.04 0.43 0.41 0.31 0.64
14.2 ± 5.2 2.0 (1.0–2.3) 0.64 ± 0.08 126 ± 42
20.1 ± 5.2b 1.1 (0.8–1.2)b 0.73 ± 0.09b 148 ± 61
22.4 ± 5.7b 1.0 (0.8–1.2)b 0.71 ± 0.12 130 ± 57
b0.01 b0.01 0.02 0.44
Values are mean ± sd for normally distributed data, median (interquartile range) for asymmetrically distributed data. a Supine resting brachial blood pressure. HR, heart rate; PWV, pulse wave velocity; SFA, superficial femoral artery. b Different from the more energetic group.
p-Value
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3.2. Comparison based on perceived fatigability score Participants were divided into groups based on the median perceived fatigability score (0.178). Table 2 presents the comparison for demographic, walking performance, and perceived fatigue variables. Adults with increased perceived fatigability were older, had higher resting blood pressure, higher body mass index, higher fasting blood glucose, lower daily physical activity, slower walking speed, lower energy expenditure during walking, and a greater change in perceived fatigue rating following the 400 m walk test as compared to adults with lower perceived fatigability (p b 0.05). Interestingly, perceived fatigue measured at rest (prior to walking) was not different (p N 0.05) between fatigability groups. 3.3. Arterial stiffness and perceived fatigability Carotid-femoral pulse wave velocity, carotid artery stiffness, and SFA stiffness were higher (p ≤ 0.05) for adults with a greater perceived fatigability (Table 2). After adjusting for age, sex, body mass index, fasting blood glucose, waist circumference, resting systolic blood pressure, average steps per day, peak stepping cadence, and resting diameter it was found that carotid-femoral PWV and carotid artery stiffness were no longer significantly different between perceived fatigability groups (Figs. 2 and 3). However, adults with higher perceived fatigability still had elevated SFA β-index and lower SFA distensibility as compared to adults with lower perceived fatigability (p b 0.05; Fig. 3) after adjusting for the aforementioned variables. Stepwise regression was used to determine the best set of independent predictors for perceived fatigabilty. In order to reduce multicollinearity, only age, sex, body mass index, fasting blood glucose, resting systolic and pulse blood pressure (included separately), peak stepping cadence, resting diameter, and SFA β-index were
Fig. 2. Comparison of carotid-femoral pulse wave velocity (PWV) between groups with lower and higher perceived fatigability. Analysis of covariance was used to adjust for age and sex alone; followed by full adjustment with age, sex, body mass index, fasting blood glucose, systolic blood pressure, average steps per day, and 30-min peak stepping cadence.
included in the model. Three variables were identified to explain a total of 55% of the variance in perceived fatigability (p b 0.01). These independent predictors included body mass index, peak stepping cadence, and SFA β-index individually explaining 6%, 13% and 36% of the variance in perceived fatigability; respectively. Indeed, SFA β-index (Fig. 1B) and distensibility (r = − 0.62, p b 0.01) were significantly correlated with the perceived fatigability score.
Table 2 Comparison of older adults with lower and higher perceived fatigability. Variable
Lower fatigability
Higher fatigability
p-Value
Sample size (women/men) Age (yrs) Body mass index (kg/m2) Waist circumference (cm) Systolic blood pressure (mm Hg)a Diastolic blood pressure (mm Hg)a Fasting blood glucose (mg/dL) Carotid diameter (cm) SFA diameter (cm) Daily physical activity Avg. steps per day Avg. peak cadence (steps per min) Walking performance variables 400 m walking speed (m/s) Relative intensity (%HRmax) Avg. energy expenditure (kcal/min) Perceived fatigue Resting perceived fatigue rating Change in perceived fatigue rating Fatigability score Arterial stiffness parameters Carotid-femoral PWV Carotid β-index Carotid distensibility (×10−3 mm Hg−1) Carotid blood flow (mL/min) SFA β-index SFA distensibility (×10−3 mm Hg−1) SFA blood flow (mL/min)
22 (15/7) 65.1 ± 3.8 22.4 ± 2.3 80.2 ± 8.1 115.0 ± 13.6 66.5 ± 7.4 92.6 ± 5.3 0.71 ± 0.07 0.65 ± 0.09
22 (10/12) 69.4 ± 5.6 23.9 ± 2.4 85.6 ± 11.7 127.4 ± 13.2 73.1 ± 7.7 96.5 ± 7.5 0.77 ± 0.08 0.71 ± 0.10
b0.01 0.04 0.08 b0.01 b0.01 0.05 0.01 0.07
8273 ± 2597 90.6 ± 23.5
5956 ± 2461 65.5 ± 25.9
b0.01 b0.01
1.54 ± 0.10 68.6 ± 9.8 7.0 ± 1.2
1.37 ± 0.16 68.1 ± 13.9 6.0 ± 0.9
b0.01 0.89 b0.01
3.9 ± 1.3 2.6 ± 0.7 0.12 ± 0.03
3.8 ± 0.9 4.4 ± 0.8 0.25 ± 0.04
0.79 b0.01 b0.01
8.4 ± 2.0 8.0 (6.7–10.8) 2.7 ± 0.8
10.3 ± 2.1 9.5 (8.1–13.8) 2.1 ± 0.7
b0.01 0.04 0.01
592 ± 173 14.2 ± 5.3 2.0 (1.0–2.3) 130 ± 41
627 ± 149 21.2 ± 5.5 1.0 (0.8–1.2) 138 ± 60
0.47 b0.01 b0.01 0.63
Values are mean ± sd for normally distributed data, median (interquartile range) for asymmetrically distributed data. SFA, superficial femoral artery. PWV, pulse wave velocity. a Supine resting brachial blood pressure.
Fig. 3. Comparison of arterial stiffness parameters for the carotid artery and superficial femoral artery (SFA) between groups with lower and higher perceived fatigability. Analysis of covariance was used to adjust for age, sex, body mass index, fasting blood glucose, systolic blood pressure, average steps per day, 30-min peak stepping cadence, and resting diameter. *, significant difference between groups (p ≤ 0.05).
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4. Discussion The present study evaluated perceived fatigability during walking and its association with arterial stiffness in healthy communitydwelling older adults. Consistent with our first hypothesis, adults with increased perceived fatigability following a 400 m walk test had higher arterial stiffness in the peripheral (SFA) region of the body. Adjusting for age and other confounding variables (sex, systolic blood pressure, physical activity levels) did not alter the difference in peripheral arterial stiffness between perceived fatigability groups. Older adults with increased fatigability had higher SFA stiffness and lower SFA distensibility than adults with less fatigability. This novel finding suggests that peripheral vascular structure and/or function may contribute to feeling of tiredness and perceived fatigue during walking in older adults. The difference in SFA stiffness between perceived fatigability groups remained even after adjusting for steps per day and daily 30-min peak stepping cadence. This finding supports our second hypothesis that the relationship between arterial stiffness and fatigability is independent of the participants' daily physical activity patterns. Physical activity behavior is an important consideration as previous studies find higher amounts of daily physical activity is associated with lower perceived fatigability (Schnelle et al., 2012). While others have reported a lower likelihood of walking at least 8 blocks per week in older adults with increased perceived fatigue (Simonsick et al., 1999), the present study is the first to relate the volume (steps per day) and intensity (peak stepping cadence) of daily ambulatory activity to perceived fatigability. Adults with increased fatigability had lower average steps per day and 30-min peak stepping cadence than adults with less fatigability. In addition, average steps per day (r = − 0.39, p = 0.009) and 30-min peak stepping cadence (r = −0.41, p = 0.007) were significantly correlated with perceived fatigability during walking when the sample was pooled together. We cannot decipher the causality underlying this relationship. It is possible that older adults more prone to feelings of tiredness may reduce their daily physical activity levels in order to lower sensations of fatigue within a tolerable range (Alexander et al., 2010; Eldadah, 2010). Conversely, it is possible that a less active lifestyle (i.e., more sedentary behavior) promotes biological and physiological processes that augment perceived fatigue (Avlund, 2010). Irrespective of the nature of this relationship, daily physical activity did not explain the significant difference in SFA stiffness between fatigability groups in the present study. Thus, mechanisms associated with peripheral arterial stiffness other than physical activity levels were largely responsible for the association between SFA stiffness and perceived fatigability. The finding that peripheral arterial stiffness is associated with perceived fatigue and fatigability in older adults supports a physiological explanation for feeling of tiredness during physical activity in older adults. This relationship was not disease-based since participants in this study had no history of cardiovascular disease, not taking blood pressure or cholesterol medications, and on average were normotensive. In addition, since SFA stiffness does not significantly increase with age (Kawasaki et al., 1987) the observed relationship is not simply reflecting greater overall age-related loss in tissue elasticity (Sherratt, 2009). Rather, we contend that higher SFA stiffness in older adults may contribute to a decrement in vascular function during walking that augments perceived fatigue and fatigability. This may be related to the influence of SFA stiffness on blood flow and/or energy expenditure during exercise. In older diabetics without peripheral artery disease, femoral artery stiffness (β-index) has been shown to negatively correlate with perfusion to the foot during treadmill exercise (Kizu et al., 2003). In middle-aged adults, femoral artery compliance is positively associated with the maximal rate of oxygen consumption during treadmill exercise (Ferreira et al., 2002). Similarly, in the present study, SFA distensibility was positively associated with energy expenditure during walking (kcal/min: r = 0.30, p = 0.04). This suggests that elevated SFA stiffness may contribute to a lower capacity to consume energy (via reduced blood flow) during walking, thereby promoting increased
fatigability in older adults. However, more research is warranted to test this hypothesis using a more objective method of assessing energy expenditure during exercise (calorimetry). An alternative interpretation of the present results is that elevated SFA stiffness is serving as an early marker of generalized atherosclerosis (i.e., subclinical disease). If this is the case, it could be argued that the older adults with increased perceived fatigue in the present study had greater underlying cardiovascular risk making them more susceptible to cerebral ischemic events like stroke. The fact that peripheral, but not central, arterial stiffness was independently related to perceived fatigability in the present study does not discount this possibility. Arterial stiffness in the leg has been shown to have a stronger association with the presence of brain β-amyloid plaques than central arterial stiffness in older non-demented adults (Hughes et al., 2013). Deposition of βamyloid plaques is a pathologic feature of cognitive disorders like Alzheimer disease. Thus, it is possible that SFA stiffness is serving as a marker of atherosclerosis that may be directly or indirectly involved in the etiological pathway leading to increased perceived fatigability in older adults. Our method to study perceived fatigability included a novel approach of using accelerometer-derived energy expenditure during walking to normalize ratings of perceived fatigue to work performed. The accelerometer equation recently developed by Hall et al. (2013) was used in the present study because it was derived from objectively measured energy expenditure using indirect calorimetry while older adults walked at different intensities on a treadmill and above ground on a flat surface like the conditions of the present study. The average energy expenditure estimated in the present study (6.5 kcal/min for avg. walking speed of 1.45 m/s) is similar to directly measured values reported by Hall et al. (2013) for similar walking speeds (6.2 kcal/min for walking speed N 1.4 m/s). Thus, we believe that our accelerometer estimates of energy expenditure during the 400 m walk test was largely accurate, and served its purpose to normalize the self-reported perceived fatigue rating to the effort given during walking in order to assess perceived fatigability between individuals. This study had limitations. Due to a small sample size, we were unable to make sex comparisons in perceived fatigue and fatigability. Women are reported to experience greater feeling of tiredness at rest (Vestergaard et al., 2009) and perceived fatigue during daily activities (Avlund, 2010), although studies that report these findings often include an older population (~ 75 yrs) and adults with disability and/or frailty. In the present study of highly-functional, relatively young older adults (avg. age = 67 yrs), there was no significant sex difference in the perceived fatigue rating taken at rest (women, 4.08 ± 1.1 vs. men, 3.65 ± 1.09, p = 0.20) or the change in perceived fatigue rating recorded after walking (women, 3.28 ± 1.1 vs. men, 3.90 ± 1.12, p = 0.08). The reason for more women were categorized in the lower perceived fatigability group than men is due to women having slightly higher energy expenditure normalized to body weight (oxygen uptake) as compared to men (21.2 ± 4.8 vs. 18.7 ± 4.1 mL/kg/min; p = 0.06). This estimate of energy expenditure was used to normalize the change in perceived fatigue rating to work, thus resulting in lower fatigability scores for some women. Another limitation of this study is our analysis of resting arterial stiffness. It may be more informative to measure arterial stiffness after walking to determine if older adults with increased perceived fatigability have an impaired ability to decrease arterial stiffness during exercise. Campbell et al. (2011) has shown that the ability to decrease femoral artery stiffness following maximal cycling exercise is partially mediated by endothelial production of the vasodilator nitric oxide which is known to decrease with age. Lastly, we examined fast pace walking during the 400 m walk test as previously described (Simonsick et al., 2001) in order to stress the vascular system and improve the likelihood of increasing perceived fatigue after walking. We acknowledge, however, that fast pace walking may represent a small portion of daily ambulatory activity, particularly in
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older adults (Ayabe et al., 2011), thus our results may not be generalized to less strenuous daily activities. 5. Conclusion In conclusion, leg arterial stiffness is associated with greater perceived fatigue and fatigability following a clinically relevant walking test (400 m) in healthy mobility-intact older adults. Future studies should assess possible mechanisms by which leg vascular structure and function might affect perceived fatigability in older adults. Acknowledgment The authors would like to the participants for their time and effort. We also thank Ramona Harwell for her valuable administrative assistance. This study was funded by institutional startup funds. References Alexander, N.B., Taffet, G.E., Horne, F.M., Eldadah, B.A., Ferrucci, L., Nayfield, S., Studenski, S., 2010. Bedside-to-Bench Conference: Research Agenda for Idiopathic Fatigue and Aging. J. Am. Geriatr. Soc. 58, 967–975. Avlund, K., 2010. Fatigue in older adults: an early indicator of the aging process? Aging Clin. Exp. Res. 22, 100–115. Ayabe, M., Aoki, J., Kumahara, H., Tanaka, H., 2011. Assessment of minute-by-minute stepping rate of physical activity under free-living conditions in female adults. Gait Posture 34, 292–294. Benetos, A., Laurent, S., Hoeks, A.P., Boutouyrie, P.H., Safar, M.E., 1993. Arterial alterations with aging and high blood pressure. A noninvasive study of carotid and femoral arteries. Arterioscler. Thromb. 13, 90–97. Buchowski, M., Simmons, S., Whitaker, L., Powers, J., Beuscher, L., Choi, L., Ikizler, T., Chen, K., Shnelle, J., 2011. Fatigability as a function of physical activity energy expenditure in older adults. AGE 1–9. Campbell, R., Fisher, J.P., Sharman, J.E., McDonnell, B.J., Frenneaux, M.P., 2011. Contribution of nitric oxide to the blood pressure and arterial responses to exercise in humans. J. Hum. Hypertens. 25, 262–270. Choi, L., Liu, Z., Matthews, C.E., Buchowski, M.S., 2011. Validation of accelerometer wear and nonwear time classification algorithm. Med. Sci. Sports Exerc. 43, 357–364. Eldadah, B.A., 2010. Fatigue and fatigability in older adults. PM R 2, 406–413. Ferreira, I., Twisk, J.W.R., van Mechelen, W., Kemper, H.C.G., Stehouwer, C.D.A., 2002. Current and adolescent levels of cardiopulmonary fitness are related to large artery properties at age 36: the Amsterdam Growth and Health Longitudinal Study. Eur. J. Clin. Invest. 32, 723–731. Gonzales, J.U., 2013. Gait performance in relation to aortic pulse wave velocity, carotid artery elasticity, and peripheral perfusion in healthy older adults. Clin. Physiol. Funct. Imaging 33, 245–251.
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Hall, K.S., Howe, C.A., Rana, S.R., Martin, C.L., Morey, M.C., 2013. METs and accelerometry of walking in older adults: standard versus measured energy cost. Med. Sci. Sports Exerc. 45, 574–582. Hughes, T.M., Kuller, L.H., Barinas-Mitchell, E.J.M., Mackey, R.H., McDade, E.M., Klunk, W.E., Aizenstein, H.J., Cohen, A.D., Snitz, B.E., Mathis, C.A., DeKosky, S.T., Lopez, O.L., 2013. Pulse wave velocity is associated with β-amyloid deposition in the brains of very elderly adults. Neurology 81, 1711–1718. Hunter, G.R., Neumeier, W.H., Bickel, C.S., Mccarthy, J.P., Fisher, G., Chandler-Laney, P.C., Glasser, S.P., 2014. Arterial elasticity, strength fatigue, and endurance in older women. BioMed. Res. Int. 2014, 1–8. Kawasaki, T., Sasayama, S., Yagi, S., Asakawa, T., Hirai, T., 1987. Non-invasive assessment of age related changes in stiffness of major branches of the human arteries. Cardiovasc. Res. 21, 678–687. Kizu, A., Koyama, H., Tanaka, S., Maeno, T., Komatsu, M., Fukumoto, S., Emoto, M., Shoji, T., Inaba, M., Shioi, A., Miki, T., Nishizawa, Y., 2003. Arterial wall stiffness is associated with peripheral circulation in patients with type 2 diabetes. Atherosclerosis 170, 87–91. Liao, D., Arnett, D.K., Tyroler, H.A., Riley, W.A., Chambless, L.E., Szklo, M., Heiss, G., 1999. Arterial stiffness and the development of hypertension: the ARIC study. Hypertension 34, 201–206. Mackenzie, I.S., Wilkinson, I.B., Cockcroft, J.R., 2002. Assessment of arterial stiffness in clinical practice. Q. J. Med. 95, 67–74. Reneman, R.S., Meinders, J.M., Hoeks, A.P.G., 2005. Non-invasive ultrasound in arterial wall dynamics in humans: what have we learned and what remains to be solved. Eur. Heart J. 26, 960–966. Schnelle, J.F., Buchowski, M.S., Ikizler, T.A., Durkin, D.W., Beuscher, L., Simmons, S.F., 2012. Evaluation of two fatigability severity measures in elderly adults. J. Am. Geriatr. Soc. 60, 1527–1533. Sherratt, M.J., 2009. Tissue elasticity and the ageing elastic fibre. AGE 31, 305–325. Simonsick, E.M., Guralnik, J.M., Fried, L.P., 1999. Who walks? Factors associated with walking behavior in disabled older women with and without self-reported walking difficulty. J. Am. Geriatr. Soc. 47, 672–680. Simonsick, E.M., Newman, A.B., Nevitt, M.C., kritchevsky, S.B., Ferrucci, L., Guralnik, J.M., Harris, T., 2001. Measuring higher level physical function in well-functioning older adults: expanding familiar approaches in the Health ABC Study. J. Gerontol. Med. Sci. 56A, M644–M649. Tanaka, H., Monahan, K.D., Seals, D.R., 2001. Age-predicted maximal heart rate revisited. J. Am. Coll. Cardiol. 37, 153–156. Tarumi, T., Gonzales, M.M., Fallow, B., Nualnim, N., Pyron, M., Tanaka, H., Haley, A.P., 2013. Central artery stiffness, neuropsychological function, and cerebral perfusion in sedentary and endurance-trained middle-aged adults. J. Hypertens. 31, 2400–2409. Tudor-Locke, C., Brashear, M.M., Katzmarzyk, P.T., Johnson, W.D., 2012. Peak stepping cadence in free-living adults: 2005–2006 NHANES. J. Phys. Act. Health 9, 1125–1129. Vestergaard, S., Nayfield, S.G., Patel, K.V., Eldadah, B., Cesari, M., Ferrucci, L., Ceresini, G., Guralnik, J.M., 2009. Fatigue in a representative population of older persons and its association with functional impairment, functional limitation, and disability. J. Gerontol. A: Biol. Med. Sci. 64A, 76–82.
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Experimental Gerontology journal homepage: www.elsevier.com/locate/expgero
Arterial stiffness is higher in older adults with increased perceived fatigue and fatigability during walking Joaquin U. Gonzales a,⁎, Matthew Wiberg a, Elizabeth Defferari a, David N. Proctor b a b
Department of Health, Exercise and Sport Sciences, Texas Tech University, Lubbock, TX, United States Department of Kinesiology, Pennsylvania State University, University Park, PA, United States
a r t i c l e
i n f o
Article history: Received 5 September 2014 Received in revised form 21 October 2014 Accepted 3 December 2014 Available online 4 December 2014 Editor: Christiaan Leeuwenburgh Keywords: Aging Arterial stiffness Fatigue Feeling of tiredness Femoral artery Walking
a b s t r a c t We investigated whether central and/or peripheral arterial stiffness contributes to increased perceived fatigue during walking in mobility-intact older adults. Arterial stiffness of the common carotid artery and superficial femoral artery (SFA) was measured using Doppler-ultrasound in 45 community-dwelling women and men (60–78 yrs). The change in perceived fatigue was measured after a fast-pace 400 meter walk test. Adults that rated feeling more tired after walking (n = 10) had higher SFA stiffness (p b 0.01), but not carotid artery stiffness, than adults that reported feeling more energetic after walking (n = 22). The change in perceived fatigue rating was normalized to energy expenditure during walking to determine perceived fatigability. Adults were divided into lower and higher perceived fatigability groups (n = 22 per group). Carotid artery stiffness was not different between perceived fatigability groups after adjusting for age, sex, body fat, systolic blood pressure, fasting blood glucose, daily physical activity levels, and resting diameter. However, SFA stiffness was significantly elevated in the higher as compared to lower perceived fatigability group (β-index: 20.7 ± 1.3 vs. 15.3 ± 1.4 U; p = 0.02) after adjusting for the abovementioned variables. Moreover, stepwise regression identified SFA β-index to be an independent predictor of perceived fatigability (r2 = 0.38, p b 0.01). These results suggest that peripheral arterial stiffness is independently associated with perceived fatigue and fatigability in older adults. © 2014 Elsevier Inc. All rights reserved.
1. Introduction Feeling of tiredness or perceived fatigue negatively impacts daily ambulatory activity (Simonsick et al., 1999) and walking speed in older adults (Vestergaard et al., 2009). Some, but not all, studies report greater perceived fatigue in older as compared to younger adults (Eldadah, 2010). One factor thought to contribute to this discrepancy is energy expenditure. It is postulated that older adults may lower physical activity patterns to limit feelings of tiredness within a tolerable range, thus showing similar perceived fatigue as compared to younger adults (Alexander et al., 2010; Eldadah, 2010). This limitation can be addressed by normalizing perceived fatigue to energy expenditure which allows for the examination of fatigability (Buchowski et al., 2011; Eldadah, 2010). An older adult with increased fatigability would be one that reports elevated perceived fatigue but expends a low amount of energy. Additionally, an older adult reporting average perceived fatigue, but has low energy expenditure would have increased fatigability. Using this approach to normalize perceived fatigue to work, others have
⁎ Corresponding author at: Department of Health, Exercise and Sport Sciences, Texas Tech University, Box 43011, Lubbock, TX 79409-3011, United States. E-mail addresses: [email protected] (J.U. Gonzales), [email protected] (M. Wiberg), [email protected] (E. Defferari), [email protected] (D.N. Proctor).
http://dx.doi.org/10.1016/j.exger.2014.12.005 0531-5565/© 2014 Elsevier Inc. All rights reserved.
shown that increased perceived fatigability during walking is negatively associated with daily physical activity and preferred walking speed in older adults (Schnelle et al., 2012). Recently, large artery elasticity was found to associate with perceived fatigue measured at rest in older women without cardiovascular disease (Hunter et al., 2014). The method used to assess arterial elasticity was pulse contour analysis, an indirect technique that estimates elasticity from cardiac output derived from an algorithm and diastolic pressure decay from a radial artery pulse wave (Mackenzie et al., 2002). A more direct assessment of regional arterial structure can be made using Doppler ultrasound imaging. Ultrasound-derived carotid artery stiffness has previously been shown to increase with age (Kawasaki et al., 1987), relate to depressed cognitive function (Tarumi et al., 2013), and negatively associate with walking speed in healthy older adults (Gonzales, 2013). Moreover, ultrasound allows for measurement of peripheral arterial stiffness (e.g., femoral artery in the leg) that may be more relevant to perceived fatigability during physical activity due to its relationship with muscle perfusion (Kizu et al., 2003) and energy expenditure during exercise (Ferreira et al., 2002). Therefore, the purpose of this study was to test the hypothesis that central (carotid artery) and peripheral (superficial femoral artery) arterial stiffness would associate with perceived fatigability during walking in older adults. Because daily physical activity is associated with perceived fatigability (Schnelle et al., 2012), we further hypothesized that the
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association between arterial stiffness and perceived fatigability would be independent of daily physical activity patterns. 2. Methods 2.1. Participants Twenty-five women and twenty men (N = 45) between the ages of 60–78 yrs took part in this study after giving informed consent to participate. Participants were recruited from the community via local city newspaper advertisements and electronic announcements sent to the university community. Participants self-reported no history of cardiovascular disease, diabetes, pulmonary disease, and none were taking medications for high blood pressure, cholesterol, or hormone replacement. All participants were non-smokers and non-obese based on a body mass index b 30 kg/m2. Participants were included if resting seated brachial blood pressure was b159/99 mm Hg and fasted blood glucose b115 mg/dL as measured by finger prick (Accu-Chek Active, Roche Diagnostics) following 8–12 h of fasting. Including hypertensive and glucose impaired ranges allowed for a spread of arterial stiffness values between participants. The Human Research Protection Program at Texas Tech University provided ethics approval for this study. 2.2. Arterial stiffness parameters Participants rested in the supine position for at least 10 min before vascular measurements. Carotid-femoral pulse wave velocity (PWV) was measured using applanation tonometry (SphygmoCor, Atcor Medical, Sydney, Australia) at the right radial artery. The average of two measurements was used for analysis. One researcher measured PWV in all participants with a test–retest coefficient of variation of 4% (Gonzales, 2013). Arterial diameter was measured in the right common carotid artery and the right superficial femoral artery (SFA) using Doppler ultrasound (Vivid 7) in 2D mode with a 5–13 MHz linear transducer probe. Measurements were taken ~ 1–2 cm proximal (carotid artery) and distal (SFA) to their respective bifurcations. A 20 s clip of the diameter pulses was saved and analyzed offline using an automated edge detection system (Brachial Analyzer, Medical Imaging Applications, Coralville, IA, USA) for the change in diameter throughout the cardiac cycle. From the average diastolic (Dd) and systolic (Ds) diameter, the following arterial stiffness parameter was calculated:
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2.3. Walking exercise Participants completed a 400 m walk test. Two traffic cones were placed 65.5 ft apart in a long flat-surfaced hallway. Participants were instructed to “select a pace that you can comfortably maintain for 10 laps but you feel that you can complete in your best time.” No participants needed a break period during the test. Walking speed (m/s) was calculated from the time to complete 400 m. Heart rate was recorded during the last lap of the walk test using a Polar monitor to calculate relative exercise intensity based on age-predicted maximum heart rate [208 − (0.7 × age)] (Tanaka et al., 2001). 2.4. Energy expenditure during walking Participants wore a tri-axial accelerometer (model GT3X+, ActiGraph, Pensacola, FL, USA) at their right hip with an elastic belt during the 400 m walk test. The accelerometer measured accelerations in the range of 0.05 g–2.0 g. The acceleration data was reduced to 1 s intervals, called epochs, to generate activity counts. Raw activity counts from the vertical axis were used to estimate energy expenditure using the equation: kcal/min = 3.28 + (0.0009 × counts per min) (Hall et al., 2013). The kcal/min expression was converted to oxygen uptake (mL/kg/min) using a standard equation: ((kcal/min/5) × 1000) / body weight. This conversion step was necessary in order to normalize energy expenditure to body weight. 2.5. Perceived fatigability A 7-item fatigue scale was used before and after walking exercise as previously described (Buchowski et al., 2011; Schnelle et al., 2012). Prior to walking exercise, participants were asked to rate their resting fatigue state as extremely energetic (rating = 1), somewhat energetic (rating = 2), a little energetic (rating = 3), neither tired or energetic (rating = 4), a little tired (rating = 5), somewhat tired (rating = 6), and extremely tired (rating = 7). Immediately after completing the 400 m walk test, participants were asked to rate their change in fatigue as extremely more energetic (rating = 1), somewhat more energetic (rating = 2), a little more energetic (rating = 3), neither more tired or energetic (rating = 4), a little more tired (rating = 5), somewhat more tired (rating = 6), and extremely more tired (rating = 7). The post-exercise fatigue rating was divided by the average energy expenditure (oxygen uptake) during the 400 m walk test to calculate a fatigability score (Buchowski et al., 2011).
β‐index ¼ ln ðSBP=DBPÞ=½ðDs –Dd Þ=Dd 2.6. Daily physical activity (Liao et al., 1999) −3 −1 mm Hg arterial distensibility 10 ¼ ½2 ðDs −Dd Þ=Dd =ðSBP−DBPÞ (Reneman et al., 2005). Data obtained from at least five simultaneous blood pressure (systolic, SBP; diastolic, DBP) and diameter waveforms were used in the analysis. Blood pressure on the left arm was measured continuously during diameter measurements using an automated device (CNAP monitor, CNSystems, Graz, Austria). Brachial pressure was used to calibrate the carotid waveform measured using applanation tonometry to derive local pressure used for calculating carotid artery stiffness. For the SFA, brachial pressure was used as a surrogate since i) the SFA is not superficial to the skin thus making it hard to get a high quality or reliable signal, and ii) brachial pulse pressure has been shown to be comparable to femoral pressure derived from tonometry (Benetos et al., 1993). Blood velocity (30 s sample) and diameter (20 s clip) were used to calculate blood flow by multiplying the cross-sectional area (πr2) of the carotid artery and the SFA with mean blood velocity.
Participants wore a triaxial accelerometer (Actigraph model GT3X+, Pensacola, FL, USA) on the right hip for 7 consecutive days. Participants were asked to take it off during bathing, swimming, and sleeping. The accelerometers collected data at a sampling rate of 30 Hz. Raw acceleration data were integrated to 60 s epochs without low-frequency extension. The integrated file underwent wear time validation using automated software (ActiLife v6, Pensacola, FL, USA). Recommended nonwear time criteria was used (Choi et al., 2011) including the criterion that a day must have ≥10 h of wear time to be considered valid. All non-wear time was excluded from further analysis. Steps per day were averaged across all valid days for each adult, and 30-min peak stepping cadence was calculated as the average steps per min for the 30 highest minutes in a day (but not necessarily consecutive minutes) for each adult (Tudor-Locke et al., 2012). 2.7. Statistical analysis Group comparisons were made using a one-way analysis of variance (ANOVA) for normally distributed data. A Kruskal–Wallis one-way ANOVA on ranks was used for comparing groups for asymmetrically
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distributed data. Tukey and Dunn's post-hoc testing, respectively, was used for pairwise comparisons if significance was met. Analysis of covariance (ANCOVA) adjusting for age, sex, body composition, fasting blood glucose, resting systolic blood pressure, daily ambulatory activity, and resting diameter was used to test for differences in arterial stiffness parameters between groups divided by the median fatigability score (0.178). Lastly, stepwise (forward and backward method) regression was used to identify independent predictors of fatigability using an alpha of 0.1 for entry and removal. Significance was considered p ≤ 0.05.
3. Results 3.1. Change in perceived fatigue following walking Table 1 presents the comparison between adults reporting feeling more tired, no change, or more energetic after the 400 m walk test. Ten adults (22%) reported feeling more tired (5.2 ± 0.4 avg. rating), thirteen adults (28%) reported no change in their feeling of being tired or energetic (4 rating by all), and twenty-two adults (48%) reported feeling more energetic after walking (2.5 ± 0.5 avg. rating). The group with increased feeling of tiredness after walking had similar (p N 0.05) age, body composition, resting blood pressure, fasting blood glucose, daily physical activity patterns, and walking performance (speed and intensity) than the other groups. Carotidfemoral pulse wave velocity and carotid artery stiffness was not different (p N 0.05) between adults that reported feeling more tired as compared to adults that reported feeling more energetic after walking. In contrast, SFA stiffness was higher (p b 0.05) in adults reporting feeling more tired than those feeling more energetic after walking. This group difference remained significant (β-index: 15.7 ± 1.2 vs. 21.8 ± 1.6 × 10− 3 mm Hg − 1; distensibility: 1.7 ± 0.12 vs. 1.0 ± 0.16 × 10− 3 mm Hg− 1; p = 0.01) after adjusting for age, sex, mean blood pressure, and SFA diameter using ANCOVA. Moreover, SFA β-index (Fig. 1A) and distensibility (r = − 0.59, p b 0.01) were significantly correlated with the change in perceived fatigue rating.
Fig. 1. Relationship between superficial femoral artery (SFA) β-stiffness index and the change in perceived fatigue rating (A) and perceived fatigability score (B) after performing a fast-pace 400 m walk test in older adults.
Table 1 Comparison between groups based on change in perceived fatigue following 400 m walk. Variable
More energetic (rating b 4)
No Change (rating = 4)
More tired (rating N 4)
Sample size (women/men) Age (yrs) Body mass index (kg/m2) Waist circumference (cm) Systolic blood pressure (mm Hg)a Diastolic blood pressure (mm Hg)a Fasting blood glucose (mg/dL) Daily physical activity Avg. steps per day Avg. peak cadence (steps per min) Walking performance variables 400 m walking speed (m/s) Relative intensity (%HRmax) Avg. energy expenditure (kcal/min) Central arterial stiffness parameters Carotid-femoral PWV (m/s) Carotid β-index Carotid distensibility (×10−3 mm Hg−1) Carotid diameter (cm) Carotid blood flow (mL/min) Peripheral arterial stiffness parameters SFA β-index SFA distensibility (×10−3 mm Hg−1) SFA diameter (cm) SFA blood flow (mL/min)
22 (16/6) 65.3 ± 3.9 23.0 ± 2.5 80.9 ± 8.4 117.8 ± 17.2 67.4 ± 8.6 94.0 ± 6.0
13 (5/8) 69.1 ± 4.8 23.8 ± 2.5 85.3 ± 13.4 127.7 ± 10.5 74.3 ± 5.8b 95.2 ± 8.9
10 (4/6) 67.6 ± 6.7 22.9 ± 2.3 83.8 ± 8.9 121.3 ± 10.3 69.6 ± 7.8 94.3 ± 5.7
0.03 0.62 0.45 0.15 0.04 0.87
7836 ± 2221 84.9 ± 22.6
6934 ± 3223 73.3 ± 28.3
5677 ± 2741 68.0 ± 33.4
0.11 0.22
1.50 ± 0.17 67.1 ± 10.4 6.7 ± 1.2
1.43 ± 0.14 69.6 ± 14.6 6.4 ± 1.2
1.40 ± 0.17 67.9 ± 12.0 6.1 ± 0.9
0.17 0.84 0.42
7.8 (7.3–10.4) 8.2 (6.9–11.5) 2.6 (1.7–3.4) 0.73 ± 0.07 590 ± 167
10.6 (8.5–11.4)b 9.3 (8.5–11.8) 2.0 (1.7–2.5) 0.77 ± 0.11 642 ± 157
9.3 (7.6–10.2) 8.4 (7.2–14.5) 2.5 (1.5–3.4) 0.74 ± 0.04 597 ± 151
0.04 0.43 0.41 0.31 0.64
14.2 ± 5.2 2.0 (1.0–2.3) 0.64 ± 0.08 126 ± 42
20.1 ± 5.2b 1.1 (0.8–1.2)b 0.73 ± 0.09b 148 ± 61
22.4 ± 5.7b 1.0 (0.8–1.2)b 0.71 ± 0.12 130 ± 57
b0.01 b0.01 0.02 0.44
Values are mean ± sd for normally distributed data, median (interquartile range) for asymmetrically distributed data. a Supine resting brachial blood pressure. HR, heart rate; PWV, pulse wave velocity; SFA, superficial femoral artery. b Different from the more energetic group.
p-Value
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3.2. Comparison based on perceived fatigability score Participants were divided into groups based on the median perceived fatigability score (0.178). Table 2 presents the comparison for demographic, walking performance, and perceived fatigue variables. Adults with increased perceived fatigability were older, had higher resting blood pressure, higher body mass index, higher fasting blood glucose, lower daily physical activity, slower walking speed, lower energy expenditure during walking, and a greater change in perceived fatigue rating following the 400 m walk test as compared to adults with lower perceived fatigability (p b 0.05). Interestingly, perceived fatigue measured at rest (prior to walking) was not different (p N 0.05) between fatigability groups. 3.3. Arterial stiffness and perceived fatigability Carotid-femoral pulse wave velocity, carotid artery stiffness, and SFA stiffness were higher (p ≤ 0.05) for adults with a greater perceived fatigability (Table 2). After adjusting for age, sex, body mass index, fasting blood glucose, waist circumference, resting systolic blood pressure, average steps per day, peak stepping cadence, and resting diameter it was found that carotid-femoral PWV and carotid artery stiffness were no longer significantly different between perceived fatigability groups (Figs. 2 and 3). However, adults with higher perceived fatigability still had elevated SFA β-index and lower SFA distensibility as compared to adults with lower perceived fatigability (p b 0.05; Fig. 3) after adjusting for the aforementioned variables. Stepwise regression was used to determine the best set of independent predictors for perceived fatigabilty. In order to reduce multicollinearity, only age, sex, body mass index, fasting blood glucose, resting systolic and pulse blood pressure (included separately), peak stepping cadence, resting diameter, and SFA β-index were
Fig. 2. Comparison of carotid-femoral pulse wave velocity (PWV) between groups with lower and higher perceived fatigability. Analysis of covariance was used to adjust for age and sex alone; followed by full adjustment with age, sex, body mass index, fasting blood glucose, systolic blood pressure, average steps per day, and 30-min peak stepping cadence.
included in the model. Three variables were identified to explain a total of 55% of the variance in perceived fatigability (p b 0.01). These independent predictors included body mass index, peak stepping cadence, and SFA β-index individually explaining 6%, 13% and 36% of the variance in perceived fatigability; respectively. Indeed, SFA β-index (Fig. 1B) and distensibility (r = − 0.62, p b 0.01) were significantly correlated with the perceived fatigability score.
Table 2 Comparison of older adults with lower and higher perceived fatigability. Variable
Lower fatigability
Higher fatigability
p-Value
Sample size (women/men) Age (yrs) Body mass index (kg/m2) Waist circumference (cm) Systolic blood pressure (mm Hg)a Diastolic blood pressure (mm Hg)a Fasting blood glucose (mg/dL) Carotid diameter (cm) SFA diameter (cm) Daily physical activity Avg. steps per day Avg. peak cadence (steps per min) Walking performance variables 400 m walking speed (m/s) Relative intensity (%HRmax) Avg. energy expenditure (kcal/min) Perceived fatigue Resting perceived fatigue rating Change in perceived fatigue rating Fatigability score Arterial stiffness parameters Carotid-femoral PWV Carotid β-index Carotid distensibility (×10−3 mm Hg−1) Carotid blood flow (mL/min) SFA β-index SFA distensibility (×10−3 mm Hg−1) SFA blood flow (mL/min)
22 (15/7) 65.1 ± 3.8 22.4 ± 2.3 80.2 ± 8.1 115.0 ± 13.6 66.5 ± 7.4 92.6 ± 5.3 0.71 ± 0.07 0.65 ± 0.09
22 (10/12) 69.4 ± 5.6 23.9 ± 2.4 85.6 ± 11.7 127.4 ± 13.2 73.1 ± 7.7 96.5 ± 7.5 0.77 ± 0.08 0.71 ± 0.10
b0.01 0.04 0.08 b0.01 b0.01 0.05 0.01 0.07
8273 ± 2597 90.6 ± 23.5
5956 ± 2461 65.5 ± 25.9
b0.01 b0.01
1.54 ± 0.10 68.6 ± 9.8 7.0 ± 1.2
1.37 ± 0.16 68.1 ± 13.9 6.0 ± 0.9
b0.01 0.89 b0.01
3.9 ± 1.3 2.6 ± 0.7 0.12 ± 0.03
3.8 ± 0.9 4.4 ± 0.8 0.25 ± 0.04
0.79 b0.01 b0.01
8.4 ± 2.0 8.0 (6.7–10.8) 2.7 ± 0.8
10.3 ± 2.1 9.5 (8.1–13.8) 2.1 ± 0.7
b0.01 0.04 0.01
592 ± 173 14.2 ± 5.3 2.0 (1.0–2.3) 130 ± 41
627 ± 149 21.2 ± 5.5 1.0 (0.8–1.2) 138 ± 60
0.47 b0.01 b0.01 0.63
Values are mean ± sd for normally distributed data, median (interquartile range) for asymmetrically distributed data. SFA, superficial femoral artery. PWV, pulse wave velocity. a Supine resting brachial blood pressure.
Fig. 3. Comparison of arterial stiffness parameters for the carotid artery and superficial femoral artery (SFA) between groups with lower and higher perceived fatigability. Analysis of covariance was used to adjust for age, sex, body mass index, fasting blood glucose, systolic blood pressure, average steps per day, 30-min peak stepping cadence, and resting diameter. *, significant difference between groups (p ≤ 0.05).
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4. Discussion The present study evaluated perceived fatigability during walking and its association with arterial stiffness in healthy communitydwelling older adults. Consistent with our first hypothesis, adults with increased perceived fatigability following a 400 m walk test had higher arterial stiffness in the peripheral (SFA) region of the body. Adjusting for age and other confounding variables (sex, systolic blood pressure, physical activity levels) did not alter the difference in peripheral arterial stiffness between perceived fatigability groups. Older adults with increased fatigability had higher SFA stiffness and lower SFA distensibility than adults with less fatigability. This novel finding suggests that peripheral vascular structure and/or function may contribute to feeling of tiredness and perceived fatigue during walking in older adults. The difference in SFA stiffness between perceived fatigability groups remained even after adjusting for steps per day and daily 30-min peak stepping cadence. This finding supports our second hypothesis that the relationship between arterial stiffness and fatigability is independent of the participants' daily physical activity patterns. Physical activity behavior is an important consideration as previous studies find higher amounts of daily physical activity is associated with lower perceived fatigability (Schnelle et al., 2012). While others have reported a lower likelihood of walking at least 8 blocks per week in older adults with increased perceived fatigue (Simonsick et al., 1999), the present study is the first to relate the volume (steps per day) and intensity (peak stepping cadence) of daily ambulatory activity to perceived fatigability. Adults with increased fatigability had lower average steps per day and 30-min peak stepping cadence than adults with less fatigability. In addition, average steps per day (r = − 0.39, p = 0.009) and 30-min peak stepping cadence (r = −0.41, p = 0.007) were significantly correlated with perceived fatigability during walking when the sample was pooled together. We cannot decipher the causality underlying this relationship. It is possible that older adults more prone to feelings of tiredness may reduce their daily physical activity levels in order to lower sensations of fatigue within a tolerable range (Alexander et al., 2010; Eldadah, 2010). Conversely, it is possible that a less active lifestyle (i.e., more sedentary behavior) promotes biological and physiological processes that augment perceived fatigue (Avlund, 2010). Irrespective of the nature of this relationship, daily physical activity did not explain the significant difference in SFA stiffness between fatigability groups in the present study. Thus, mechanisms associated with peripheral arterial stiffness other than physical activity levels were largely responsible for the association between SFA stiffness and perceived fatigability. The finding that peripheral arterial stiffness is associated with perceived fatigue and fatigability in older adults supports a physiological explanation for feeling of tiredness during physical activity in older adults. This relationship was not disease-based since participants in this study had no history of cardiovascular disease, not taking blood pressure or cholesterol medications, and on average were normotensive. In addition, since SFA stiffness does not significantly increase with age (Kawasaki et al., 1987) the observed relationship is not simply reflecting greater overall age-related loss in tissue elasticity (Sherratt, 2009). Rather, we contend that higher SFA stiffness in older adults may contribute to a decrement in vascular function during walking that augments perceived fatigue and fatigability. This may be related to the influence of SFA stiffness on blood flow and/or energy expenditure during exercise. In older diabetics without peripheral artery disease, femoral artery stiffness (β-index) has been shown to negatively correlate with perfusion to the foot during treadmill exercise (Kizu et al., 2003). In middle-aged adults, femoral artery compliance is positively associated with the maximal rate of oxygen consumption during treadmill exercise (Ferreira et al., 2002). Similarly, in the present study, SFA distensibility was positively associated with energy expenditure during walking (kcal/min: r = 0.30, p = 0.04). This suggests that elevated SFA stiffness may contribute to a lower capacity to consume energy (via reduced blood flow) during walking, thereby promoting increased
fatigability in older adults. However, more research is warranted to test this hypothesis using a more objective method of assessing energy expenditure during exercise (calorimetry). An alternative interpretation of the present results is that elevated SFA stiffness is serving as an early marker of generalized atherosclerosis (i.e., subclinical disease). If this is the case, it could be argued that the older adults with increased perceived fatigue in the present study had greater underlying cardiovascular risk making them more susceptible to cerebral ischemic events like stroke. The fact that peripheral, but not central, arterial stiffness was independently related to perceived fatigability in the present study does not discount this possibility. Arterial stiffness in the leg has been shown to have a stronger association with the presence of brain β-amyloid plaques than central arterial stiffness in older non-demented adults (Hughes et al., 2013). Deposition of βamyloid plaques is a pathologic feature of cognitive disorders like Alzheimer disease. Thus, it is possible that SFA stiffness is serving as a marker of atherosclerosis that may be directly or indirectly involved in the etiological pathway leading to increased perceived fatigability in older adults. Our method to study perceived fatigability included a novel approach of using accelerometer-derived energy expenditure during walking to normalize ratings of perceived fatigue to work performed. The accelerometer equation recently developed by Hall et al. (2013) was used in the present study because it was derived from objectively measured energy expenditure using indirect calorimetry while older adults walked at different intensities on a treadmill and above ground on a flat surface like the conditions of the present study. The average energy expenditure estimated in the present study (6.5 kcal/min for avg. walking speed of 1.45 m/s) is similar to directly measured values reported by Hall et al. (2013) for similar walking speeds (6.2 kcal/min for walking speed N 1.4 m/s). Thus, we believe that our accelerometer estimates of energy expenditure during the 400 m walk test was largely accurate, and served its purpose to normalize the self-reported perceived fatigue rating to the effort given during walking in order to assess perceived fatigability between individuals. This study had limitations. Due to a small sample size, we were unable to make sex comparisons in perceived fatigue and fatigability. Women are reported to experience greater feeling of tiredness at rest (Vestergaard et al., 2009) and perceived fatigue during daily activities (Avlund, 2010), although studies that report these findings often include an older population (~ 75 yrs) and adults with disability and/or frailty. In the present study of highly-functional, relatively young older adults (avg. age = 67 yrs), there was no significant sex difference in the perceived fatigue rating taken at rest (women, 4.08 ± 1.1 vs. men, 3.65 ± 1.09, p = 0.20) or the change in perceived fatigue rating recorded after walking (women, 3.28 ± 1.1 vs. men, 3.90 ± 1.12, p = 0.08). The reason for more women were categorized in the lower perceived fatigability group than men is due to women having slightly higher energy expenditure normalized to body weight (oxygen uptake) as compared to men (21.2 ± 4.8 vs. 18.7 ± 4.1 mL/kg/min; p = 0.06). This estimate of energy expenditure was used to normalize the change in perceived fatigue rating to work, thus resulting in lower fatigability scores for some women. Another limitation of this study is our analysis of resting arterial stiffness. It may be more informative to measure arterial stiffness after walking to determine if older adults with increased perceived fatigability have an impaired ability to decrease arterial stiffness during exercise. Campbell et al. (2011) has shown that the ability to decrease femoral artery stiffness following maximal cycling exercise is partially mediated by endothelial production of the vasodilator nitric oxide which is known to decrease with age. Lastly, we examined fast pace walking during the 400 m walk test as previously described (Simonsick et al., 2001) in order to stress the vascular system and improve the likelihood of increasing perceived fatigue after walking. We acknowledge, however, that fast pace walking may represent a small portion of daily ambulatory activity, particularly in
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older adults (Ayabe et al., 2011), thus our results may not be generalized to less strenuous daily activities. 5. Conclusion In conclusion, leg arterial stiffness is associated with greater perceived fatigue and fatigability following a clinically relevant walking test (400 m) in healthy mobility-intact older adults. Future studies should assess possible mechanisms by which leg vascular structure and function might affect perceived fatigability in older adults. Acknowledgment The authors would like to the participants for their time and effort. We also thank Ramona Harwell for her valuable administrative assistance. This study was funded by institutional startup funds. References Alexander, N.B., Taffet, G.E., Horne, F.M., Eldadah, B.A., Ferrucci, L., Nayfield, S., Studenski, S., 2010. Bedside-to-Bench Conference: Research Agenda for Idiopathic Fatigue and Aging. J. Am. Geriatr. Soc. 58, 967–975. Avlund, K., 2010. Fatigue in older adults: an early indicator of the aging process? Aging Clin. Exp. Res. 22, 100–115. Ayabe, M., Aoki, J., Kumahara, H., Tanaka, H., 2011. Assessment of minute-by-minute stepping rate of physical activity under free-living conditions in female adults. Gait Posture 34, 292–294. Benetos, A., Laurent, S., Hoeks, A.P., Boutouyrie, P.H., Safar, M.E., 1993. Arterial alterations with aging and high blood pressure. A noninvasive study of carotid and femoral arteries. Arterioscler. Thromb. 13, 90–97. Buchowski, M., Simmons, S., Whitaker, L., Powers, J., Beuscher, L., Choi, L., Ikizler, T., Chen, K., Shnelle, J., 2011. Fatigability as a function of physical activity energy expenditure in older adults. AGE 1–9. Campbell, R., Fisher, J.P., Sharman, J.E., McDonnell, B.J., Frenneaux, M.P., 2011. Contribution of nitric oxide to the blood pressure and arterial responses to exercise in humans. J. Hum. Hypertens. 25, 262–270. Choi, L., Liu, Z., Matthews, C.E., Buchowski, M.S., 2011. Validation of accelerometer wear and nonwear time classification algorithm. Med. Sci. Sports Exerc. 43, 357–364. Eldadah, B.A., 2010. Fatigue and fatigability in older adults. PM R 2, 406–413. Ferreira, I., Twisk, J.W.R., van Mechelen, W., Kemper, H.C.G., Stehouwer, C.D.A., 2002. Current and adolescent levels of cardiopulmonary fitness are related to large artery properties at age 36: the Amsterdam Growth and Health Longitudinal Study. Eur. J. Clin. Invest. 32, 723–731. Gonzales, J.U., 2013. Gait performance in relation to aortic pulse wave velocity, carotid artery elasticity, and peripheral perfusion in healthy older adults. Clin. Physiol. Funct. Imaging 33, 245–251.
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