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Arterial stiffness is associated with age-related differences in cerebrovascular conductance
Arterial stiffness is associated with age-related differences in cerebrovascular conductance Tussana Jaruchart, Nijasri C. Suwanwela, Hirofumi Tanaka, Daroonwan Suksom PII: DOI: Reference:
S0531-5565(15)30084-X doi: 10.1016/j.exger.2015.11.006 EXG 9733
To appear in:
Experimental Gerontology
Received date: Revised date: Accepted date:
17 June 2015 31 October 2015 10 November 2015
Please cite this article as: Jaruchart, Tussana, Suwanwela, Nijasri C., Tanaka, Hirofumi, Suksom, Daroonwan, Arterial stiffness is associated with age-related differences in cerebrovascular conductance, Experimental Gerontology (2015), doi: 10.1016/j.exger.2015.11.006
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ACCEPTED MANUSCRIPT Arterial Stiffness is Associated with Age-Related Differences in
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Cerebrovascular Conductance
Faculty of Sports Science and bFaculty of Medicine, Chulalongkorn University, Pathumwan,
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a
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Tussana Jaruchart a, Nijasri C. Suwanwela b, Hirofumi Tanaka c, Daroonwan Suksom a,*
Bangkok 10330, Thailand Department of Kinesiology and Health Education, University of Texas at Austin, Austin, TX
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c
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78712, USA
Running Head: Aging, Arterial stiffness, Cerebrovascular reactivity
Correspondence: Daroonwan Suksom, Ph.D. Faculty of Sports Science Chulalongkorn University Rama 1 Rd, Pathumwan, Bangkok, 10330 Thailand Phone: 66-81-341-5736 Fax: 66-2-218-1035 E-mail: [email protected]
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ABSTRACT To determine if arterial stiffness is associated with age-related differences in cerebrovascular
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conductance and reactivity, twenty-eight apparently healthy sedentary young (25±1 years; n=15) and older (67±1 years; n=13) adults were studied. Brachial-ankle pulse wave velocity (baPWV)
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was measured as an index of arterial stiffness. Cerebrovascular reactivity was determined by
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measuring changes in mean blood velocity in the middle cerebral artery under normocapnic,
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hypocapnic and hypercapnic conditions. Mean baPWV was greater (p<0.05) in older compared with young adults. At baseline, mean cerebral blood flow velocity and cerebrovascular
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conductance index were lower (p<0.05) in older compared with young adults under normocapnic, hypocapnic and hypercapnic conditions.
There were no significant group differences in
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cerebrovascular reactivity when they were adjusted for stimuli (i.e., end-tidal CO2 concentrations)
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in most perturbation conditions except for the normocapnia to hypercapnia condition. baPWV
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was negatively associated with cerebrovascular conductance index at all conditions (all p<0.05). We concluded that arterial stiffness was associated with age-related differences in cerebrovascular conductance and that there were no apparent age-associated differences in cerebrovascular reactivity.
Keywords: Aging, pulse wave velocity, transcranial Doppler, cerebral vasomotor reactivity
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1. Introduction Cerebral blood flow and vascular conductance are tightly regulated to deliver and
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distribute oxygen and nutrients to active regions of the brain. Cerebrovascular reactivity (CVR) reflects the vasodilatory capacity of the cerebral arteries. Reductions in CVR can result in a
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decrease in perfusion in response to global vasodilatory stimuli. Assessment of the
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cerebrovascular response as measured by changes in middle cerebral artery velocity to alterations
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in arterial carbon dioxide is a well-established method to estimate the physiological reserve of cerebral perfusion (Ainsile and Duffin, 2009). CVR has been associated with subcortical
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infarctions and stroke (Cupini et al., 2001) and linked with cognitive declines and is impaired in patients with dementia and Alzheimer’s disease (Silvestrini et al., 2006). While it has been
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consistently reported that aging is associated with reduced cerebral vascular conductance (Fisher
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et al. 2013; Toda, 2012; Kamper et al., 2004), the effect of aging on CVR, however, remains
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unclear. Previous studies reported a reduced (Yamamoto et al., 1980; Reich, 1989) or maintained (Kastrup et al., 1998; Ito et al., 2002; Schwertfeger et al., 2006; Galvin et al., 2010) CVR to hypercapnia with aging. For CVR to hypocapnic stimuli, studies have reported unchanged (Ito et al., 2002), decreased (Yamaguchi et al., 1979; Tsuda, 1989; Zhu et al. 2013), and even elevated (Galvin et al., 2010) CVR with increasing age. Advancing age is associated with alterations in structure and function of blood vessel walls, resulting in decreased vascular distensibility (Mattace-Raso et al., 2006). Microvasculature in the brain is constantly exposed to pulsatile hemodynamic strain because the brain is a high flow, low impedance organ. Stiffening of arterial walls and the resulting failure to properly buffer cardiac pulsations could lead to barotrauma, elevated cerebrovascular resistance, and reduced perfusion. Age-associated alteration in large arteries (primarily arterial stiffening) and the progressive mismatch of their “cross-talk” or impedance with small cerebral arteries may induce microvascular brain damage (Scuteri et al., 2011). Indeed cerebrovascular reactivity has been
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associated with increased arterial stiffness in patients with coronary heart disease (Rucka et al., 2014). Arterial stiffness is significantly and inversely associated with cerebral perfusion in deep
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subcortical frontal white matter of middle-age adults (Tarumi et al., 2011). However, the number of studies that address the association of arterial stiffness with CVR and/or cerebral vascular
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conductance is very limited. Currently, there is no existing evidence that demonstrates the
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association of arterial stiffness and global cerebrovascular reactivity in relation to primary aging.
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Accordingly, the primary purpose of the present study was to determine the association between arterial stiffness and middle cerebral artery vascular conductance and reactivity in
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apparently healthy young and older adult subjects. In order to be more comprehensive in the analyses, CVR was assessed during normocapnic, hypocapnic and hypercapnic conditions. We
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hypothesized that older adults would exhibit increased arterial stiffness and compromised
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cerebrovascular conductance and CVR compared with young adults and that arterial stiffness
2. Methods
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would be significantly associated with cerebrovascular conductance as well as CVR.
2.1. Subjects
A total of forty-five subjects were screened (young n=22, older adults n=23). Individuals with a history of diabetes, cardiovascular diseases, neurological disorders, respiratory diseases, brain disorders, and chronic smoking were excluded from the study participation. Subjects with no window at temporal bone of skull for ultrasound assessment were excluded. Fifteen young (aged 19-35 years) and thirteen older (aged 61-70 years) adults were studied. All the older subjects completed the Mini-Mental State Examination and found to be normal. All subjects gave written informed consent prior to participation in the study. The study was approved by the institutional review board at Chulalongkorn University.
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2.2. Study protocol All experiments were performed in an environmentally-controlled laboratory with an
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ambient temperature of 25 °C. Subjects refrained from caffeinated beverages and alcohol at least 12 hours before the test. After providing written informed consent for participation, study
2.2.1 General physiological characteristics
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volunteers underwent a series of measurements described below.
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Body composition was evaluated using body composition analyzer (Whole Body
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Bioelectrical Impedance Analysis, ioi 353, JAWON, Korea). Blood pressure and heart rate at rest were measured with semi-automated blood pressure device (CARESCAPE V100, GE Dinamap,
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USA).
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2.2.2 Arterial Stiffness
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Brachial-ankle pulse wave velocity (baPWV) was measured using a noninvasive vascular screening device (Omron, Collin VP-1000 plus, Kyoto, Japan). Measurements were performed after at least 10 minutes of supine rest. Blood pressure and electrocardiogram were simultaneously measured with the vascular screening device. Waveforms were obtained from plethysmographic sensors in cuffs on both arms and ankles. Pulse wave velocity is calculated from the distance between two arterial recording sites divided by transit time. Transit time was determined from time delay between the proximal and distal foot waveforms (Sugawara et al., 2005). 2.2.3 Cerebrovascular reactivity test Cerebral blood flow velocity (CBFV) was measured on the middle cerebral artery (MCA) by ultrasound machine (CX50, Philips, USA). MCA was insonated from the left posterior temporal window using 1.8 MHz transcranial Doppler probe. Subjects were asked to wear nose clips and breathed only through a mouthpiece, with one end open to room air and the other end
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connected to gas mixture line. After at least 10 minutes of rest in supine position, baseline recordings were taken during spontaneous breathing of room air. Heart rate and blood pressure
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were recorded simultaneously using semi-automated blood pressure device (CARESCAPE V100, GE Dinamap, USA). End-tidal CO2 (EtCO2), an estimate of arterial CO2 level, was measured from
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expired air and analyzed by the gas analyzer (Vmax Encore 29 system, yorba Linda, CA, USA).
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Ventilatory expired gases were continuously measured and acquired via breath-by-breath using
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flow sensor. During these measurements, subjects were instructed to breathe normally and avoid body movement or Valsava maneuvers. After baseline data collection, subjects underwent 1
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minute of maximal voluntary hyperventilation to induce a period of hypocapnia. Heart rate and blood pressure were obtained during the first 10 seconds of hyperventilation while cerebral blood
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flow in MCA was recorded during the last 20 seconds of hyperventilation. Following
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hyperventilation, a 5-minute recovery period was provided allowing cerebral hemodynamics to
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restore to the baseline level. Then, subjects breathed air containing a gas mixture of 5% CO2 and 21% O2 balanced with nitrogen spontaneously for 3 minutes to induce hypercapnia. The data were recorded during the last minute of hypercapnia. Pulsatility index (PI) was calculated as the difference between systolic and diastolic flow velocity divided by mean flow velocity (Alexandrov, 2011).
Cerebrovascular reactivity was calculated as a percent change in MCA-CBFV over an absolute change in EtCO2. The change in cerebrovascular reactivity was calculated from the three different ranges of end-tidal CO2 levels; normocapnia to hypocapnia, normocapnia to hypercapnia, and hypocapnia to hypercapnia. Additionally, cerebrovascular conductance index (CVCi) was calculated in order to account for the effect of blood pressure on MCA-BFV. In an attempt to reduce variability associated with CVR measures, an average of 5-10 values were used
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to represent CVR responses in each subject. The equations used to estimate the cerebrovascular reactivity and cerebrovascular conductance index were shown below.
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Cerebrovascular reactivity index (%/mmHg) = % ∆ Middle cerebral artery blood flow velocity/ ∆ End tidal carbon dioxide
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Cerebrovascular conductance index (cm/sec*mmHg) = Middle cerebral artery blood flow
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velocity/ Mean arterial pressure
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Cerebrovascular conductance index (%/mmHg) = % ∆ middle cerebral artery vascular conductance/ ∆ End tidal carbon dioxide
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2.3 Statistical Analyses
All data were analyzed using SPSS statistical software (SPSS version 17.0, SPSS Inc.,
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Chicago, IL). Prior to the parametric tests, the tests for normal distribution were performed and verified. Independent-samples t-tests were used to compare group differences in demographic
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characteristics and magnitude of changes in arterial stiffness and hemodynamic variables during normocapnia, hypocapnia, and hypercapnia. Bivariate correlation (Pearson’s correlation) analyses were used to examine the relations between arterial stiffness and hemodynamic measures of middle cerebral artery during cerebrovascular reactivity test. Descriptive data are expressed as mean ± SEM. An α-level of 0.05 was considered the statistical significance. 3. Results The general characteristics of the participants are shown in Table 1. Height was lower (all p<0.05) in older compared with young adults. Systolic, mean, and diastolic blood pressure values were higher (all p<0.05) in older than in young adults. Body mass was not different but BMI and % body fat were higher in older than in young adults. As shown in Figure 1, baPWV at baseline were greater (p<0.05) in older compared with young adults. Representative data of middle cerebral artery blood flow velocity and
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cerebrovascular reactivity during normocapnic, hypocapnic, and hypercapnic conditions are presented in Table 2. Mean cerebral blood flow velocity and cerebrovascular conductance index
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were lower (p<0.05) in older compared with young adults under normocapnic, hypocapnic and hypercapnic conditions. Pulsatility index was not significantly difference between older and
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young subjects during all conditions and was not associated with baPWV. Cerebral vasodilatory
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response (∆CBFV/∆EtCO2) at normocapnia to hypercapnia was lower in older than in young
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adults. There were no significant differences in ∆CBFV/∆EtCO2 and ∆CVCi/∆EtCO2 between the groups at normocapnic to hypocapnic and hypocapnic to hypercapnic conditions.
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The associations between arterial stiffness and cerebral hemodynamics are shown in Figures 2. baPWV was negatively associated cerebrovascular conductance index and mean blood
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pressure in all conditions (all p<0.05). There were no significant correlations between baPWV and
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4. Discussion
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cerebrovascular reactivity (∆CBFV/∆EtCO2 or ∆CVCi/∆EtCO2) in all conditions.
The main findings of the present study are as follows. First, arterial stiffness as measured by brachial-ankle pulse wave velocity was higher in older than in young adults. Second, cerebral blood flow velocity and conductance were significantly reduced in apparently healthy older adults compared with young adults. Third, there were no apparent age-associated differences in cerebrovascular reactivity in most perturbation conditions (normocapnia, hypocapnia and hypercapnia) examined in the present study. Fourth, arterial stiffness was significantly and inversely associated with cerebral blood flow velocity and cerebrovascular conductance. These results are consistent with the idea that arterial stiffness plays a role, at least in part, in decreasing cerebrovascular conductance. Brachial-ankle pulse wave velocity (baPWV) was used as a measure of arterial stiffness in the present study. Similar to carotid-femoral pulse wave velocity (cfPWV), this measure of
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arterial stiffness has been shown to be an important predictor and prognosis of cardiovascular disease and has been correlated with cfPWV (Sugawara et al., 2005; Sugawara and Tanaka 2015).
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baPWV was greater in older compared with young adults, reflecting age-associated arterial stiffening even in apparently healthy adult populations (Sugawara and Tanaka 2015). Age-
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associated arterial stiffening has attributed to alterations in structure and function within the
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arterial wall, in particular degeneration or disorganization in the medial layer (Nosaka et al.,
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2003). These changes are important mechanisms underlying age-dependent progressive increases in systolic blood pressure and pulse pressure (Mattace-Raso et al., 2006; Boutouyrie, 2008).
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Stiffer systemic arterial system (as indicated by higher PWV) is accompanied by an increased pulsatility with consequent inward remodeling and rarefaction in the entire microcirculation. In
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the brain, these microvascular changes make an older subject more susceptible to intermittent
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hypotension leading to the age-associated decline in cognitive function (Scuteri et al., 2013).
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The effect of age on cerebral blood flow has been investigated in the past. Most studies have reported that cerebral blood flow undergoes a gradual and significant decline with advancing age (Toda, 2012; Kamper et al., 2004; Fisher et al., 2013; Leenders et al., 1990). Consistent with this, cerebral blood flow in the middle cerebral artery was lowering in older than in young adults. In addition, cerebrovascular conductance index (CVCi), calculated in order to account for the effect of blood pressure, was also lower in older vs. young adults.
In an attempt to gain
mechanistic insight into age-associated reductions in cerebrovascular blood flow and conductance, pulsatility index was derived as it represents the resistance to flow in cerebrovascular circulation (Alexandrov, 2011; Wijnhoud et al., 2006). Pulsatility index was significantly elevated in older than in young adults in the present study. Pulsatility index has been correlated with the National Institutes of Health Stroke Scale and is a predicting factor for functional and clinical outcomes after thrombotic therapy in acute ischemic stroke (Uzuner, 2013). The results of the present study showed that cerebrovascular blood flow velocity and vascular conductance are reduced even in
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healthy older adults and that these subclinical changes could lead to elevated risks of cerebrovascular diseases in older adults possibly via increases in cerebrovascular resistance.
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Our present results showed that blood flow velocity and conductance index in older adults were significantly lower in normocapnic, hypocapnic, and hypercapnic conditions compared with
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young adults. For the cerebrovascular reactivity tests, cerebral CO2 reactivity (∆CBFV/∆EtCO2)
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from the normocapnia to hypercapnia in older adults were lower than young adults while it did not
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show significant age-associated difference from the normocapnia to hypocapnia or hypocapnia to hypercapnia. These lower CVR to hypercapnia in older adults indicate that cerebrovascular
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reactivity was attenuated with advancing age. Our results are consistent with previous findings that cerebral blood flow responses to hypercapnia decrease with aging (Fisher et al., 2013; Fluck
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et al., 2014; Jennings et al., 2013). However, as described above, other studies reported no change
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in cerebral vascular reactivity to hypercapnia (Schwertfeger et al., 2006; Galvin et al., 2010) and
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one study even reporting a greater reactivity to hypercapnia with sedentary aging (Zhu et al., 2013). Clearly, more studies are warranted to determine the influence of age on cerebrovascular reactivity.
Arterial stiffness as measured by baPWV was negatively associated with mean cerebral blood flow velocity and cerebrovascular conductance index at normocapnic, hypocapnic and hypercapnic conditions. Our present findings are consistent with previous studies emphasizing a role of arterial stiffness in the pathogenesis of cerebrovascular dysfunction in older adults. Xu et al. (2012) previously reported a significant correlation between MCA and systemic arterial stiffness. Additionally, reduced hypercapnia-mediated cerebral blood flow responses through the MCA in older adults were associated with increased vascular stiffness (Fluck et al., 2014). Moreover, the elevation in arterial stiffness was inversely associated with cerebrovascular reactivity by breath holding index (BHI) in patients with coronary heart disease (Rucka et al., 2014). Furthermore, Tarumi et al. (2011) using the arterial spin labeling (ASL) technique reported
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that central artery stiffness is associated with cerebral perfusion in deep subcortical frontal white matter among middle-aged men and women. In the present study, the negative association
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between arterial stiffness and mean cerebral blood flow velocity and conductance index was observed without affecting cerebral vascular reactivity. There are a number of ways that arterial
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stiffness could affect cerebral conductance independent of cerebral reactivity. For example, a
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failure to control perfusion pressure via impaired baroreflex sensitivity can cause chronic brain
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hypoperfusion as we have recently demonstrated (Laosiripisan et al., 2015). Increasing stiffness in the systemic circulation reduces arterial baroreflex sensitivity (Laosiripisan et al., 2015) and
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influences the flow pattern in the cerebral artery via widening of pulse pressure (Xu et al., 2012). There are a number of limitations in the present study that should be emphasized. First, the
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present study utilizes a cross-sectional study design. Accordingly, a cause and effect relationship
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cannot be determined. Second, the number of participants studied was relatively small, and the
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results should be interpreted with caution. Third, the menstrual cycle of young female subjects were not controlled for during the measurements. However, the number of young female subjects was very small, and the sun-group results based only on young men were consistent with the results obtained with the entire young adults. Fourth, it is possible that CO2 in the breathing air during the hypercapnic condition could elevate arterial blood pressure via chemoreceptor stimulation. However, blood pressure was not different between different conditions as has been demonstrated in the previous study (Turner et al. 1996). In summary, we observed that arterial stiffness was elevated in healthy sedentary elderly compared with young subjects. Such arterial stiffening with age was negatively associated with cerebral blood flow and cerebrovascular conductance index. But when the cerebrovascular reactivity was adjusted for stimuli, age-associated differences in cerebrovascular reactivity were abolished in most perturbation conditions. Considering the important role that cerebrovascular reactivity plays in the age-associated increases in cerebrovascular disease and Alzheimer’s
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disease, there is no question that more studies, especially longitudinal studies, are warranted in the future.
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Acknowledgments
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This study was supported by Government Research Budget Chulalongkorn University
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2015 and The 90th Anniversary Research Fund, Chulalongkorn University, Thailand.
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Yamaguchi, F., Meyer J.S., Sakai, F., Yamamoto, M., 1979. Normal human aging and cerebral
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vasoconstrictive responses to hypocapnia. J Neurol Sci. 44 (1), 87-94.
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Yamamoto, M., Meyer, J.S., Sakai, F., Yamaguchi, F., 1980. Aging and cerebral vasodilatior
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responses to hypercarbia: responses in normal aging and in persons with risk factors for stroke. Arch Neurol. 37 (8), 489-496. http://dx.doi.org/10.1001/archneur.1980.00500570037005. Zhu, Y.S., Tarumi, T., Tseng, B.Y., Palmer, D.M., Levine, B.D., Zhang, R., 2013. Cerebral vasomotor reactivity during hypo- and hypercapnia in sedentary elderly and masters athletes. J Cerebral Blood Flow Metab. 33 (8), 1190-1196. http://dx.doi.org/10.1038/jcbfm.2013.66.
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Figure Legends Figure 1. Arterial stiffness as measured by brachial-ankle pulse wave velocity (baPWV) in young
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and older adults.
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Data are mean ± SEM. *P < 0.05 vs. young group.
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Figure 2. Associations between arterial stiffness as measured by brachial-ankle pulse wave
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velocity (baPWV) and cerebrovascular conductance index.
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Table 1. Selected characteristics of subjects. Group Variables
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Male/female (n)
Older adults
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Young
9/4
25.2 ± 1.2
66.9 ± 0.9*
Body mass (kg)
62.7 ± 2.8
63.7 ± 2.4
171 ± 2
162 ± 2*
21.3 ± 0.8
24.1 ± 0.7*
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Age (years)
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Height (cm)
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BMI (kg • m-2) Body Fat (%)
19 ± 2
24 ± 2*
69 ± 3
72 ± 3
113 ± 3
130 ± 5*
Diastolic BP (mmHg)
74 ± 2
83 ± 3*
Mean BP (mmHg)
82 ± 2
95 ± 4*
Obesity, (n)
0
5
Blood pressure lowering drug, (n)
0
3
Cholesterol lowering drug, (n)
0
7
MMSE score (unit)
-
28.6 ± 0.6
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Systolic BP (mmHg)
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Heart Rate (bpm)
Data are mean ± SEM. BMI = Body mass index; BP = Blood pressure; MMSE = Mini Mental State Examination (Thai version). *P<0.05 vs. young group.
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Table 2. Hemodynamic measures of middle cerebral artery during cerebrovascular reactivity test. Group
(mmHg)
Mean CBFV
78.1 ± 1.6
93.5 ± 3.1*
Hypocapnic
78.3 ± 2.2
93.6 ± 2.3*
Hypercapnic
81.9 ± 1.8
97.9 ± 3.0*
Normocapnic
(cm/sec)
58.6 ± 2.4
50.2 ± 2.3*
40.1 ± 2.4†
32.4 ± 2.0*, †
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Hypocapnic
69.0 ± 2.5†, §
54.1 ± 2.7*, §
Normocapnic
39.3 ± 1.0
37.9 ± 1.4
Hypocapnic
29.3 ± 0.8†
27.5 ± 0.8†
Hypercapnic
44.7 ± 1.0†,§
42.0 ± 0.6*, †, §
Normocapnic
0.87 ± 0.49
0.93 ± 0.64
Hypocapnic
1.29 ± 0.09†
1.21 ± 0.07†
Hypercapnic
0.73 ± 0.03§
0.84 ± 0.05§
Normocapnic
0.76 ± 0.04
0.54 ± 0.03*
Hypocapnic
0.54 ± 0.04†
0.35 ± 0.02*, †
condition
0.94 ± 0.07§
0.56 ± 0.04*, §
Normocapnic to
3.95 ± 0.90
3.72 ± 0.51
condition
3.49 ± 0.79
3.79 ± 0.58
Normocapnic to
3.87 ± 0.49
1.74 ± 0.88*
condition
4.00 ± 1.04
3.53 ± 0.49
Hypocapnic to
5.34 ± 0.72
4.98 ± 0.63
5.57 ± 1.04
4.44 ± 0.53
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Hypercapnic EtCO2
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MCA PI
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(mmHg)
CVCi
(cm/sec *mmHg)
∆CBFV/∆EtCO2
(% cm/sec*mmHg-1) ∆CVCi/∆EtCO2 (% cm/sec) ∆CBFV/∆EtCO2 (% cm/sec*mmHg-1) ∆CVCi/∆EtCO2 (% cm/sec) ∆CBFV/∆EtCO2 (% cm/sec*mmHg-1) ∆CVCi/∆EtCO2 (% cm/sec)
Older adults
Normocapnic
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MAP
Young
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Conditions
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Variables
Hypocapnic
Hypercapnic
Hypercapnic condition
ACCEPTED MANUSCRIPT 21 Data are mean ± SEM. CBFV = Cerebral blood flow velocity; EtCO2 = End-tidal CO2; MAP = Mean arterial pressure; PI = Pulsatility index; MCA = Middle cerebral artery; CVCi = Cerebrovascular
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conductance index. *P<0.05 vs young group. †P<0.05 vs normocapnic, §P<0.05 vs hypocapnic
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Figure 1
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*
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Figure 2
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Arterial Stiffness is Associated with Age-Related Differences in Cerebrovascular Conductance
Arterial stiffness is elevated in healthy sedentary elderly compared with young adults.
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Highlights
Cerebral blood flow velocity and conductance are reduced in healthy older adults compared with young adults.
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Arterial stiffness was significantly and inversely associated with cerebral blood flow velocity and cerebrovascular conductance.
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There are no apparent age-associated differences in cerebrovascular reactivity in apparently healthy older adults.
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S0531-5565(15)30084-X doi: 10.1016/j.exger.2015.11.006 EXG 9733
To appear in:
Experimental Gerontology
Received date: Revised date: Accepted date:
17 June 2015 31 October 2015 10 November 2015
Please cite this article as: Jaruchart, Tussana, Suwanwela, Nijasri C., Tanaka, Hirofumi, Suksom, Daroonwan, Arterial stiffness is associated with age-related differences in cerebrovascular conductance, Experimental Gerontology (2015), doi: 10.1016/j.exger.2015.11.006
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Arterial Stiffness is Associated with Age-Related Differences in
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Cerebrovascular Conductance
Faculty of Sports Science and bFaculty of Medicine, Chulalongkorn University, Pathumwan,
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a
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Tussana Jaruchart a, Nijasri C. Suwanwela b, Hirofumi Tanaka c, Daroonwan Suksom a,*
Bangkok 10330, Thailand Department of Kinesiology and Health Education, University of Texas at Austin, Austin, TX
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c
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78712, USA
Running Head: Aging, Arterial stiffness, Cerebrovascular reactivity
Correspondence: Daroonwan Suksom, Ph.D. Faculty of Sports Science Chulalongkorn University Rama 1 Rd, Pathumwan, Bangkok, 10330 Thailand Phone: 66-81-341-5736 Fax: 66-2-218-1035 E-mail: [email protected]
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ABSTRACT To determine if arterial stiffness is associated with age-related differences in cerebrovascular
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conductance and reactivity, twenty-eight apparently healthy sedentary young (25±1 years; n=15) and older (67±1 years; n=13) adults were studied. Brachial-ankle pulse wave velocity (baPWV)
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was measured as an index of arterial stiffness. Cerebrovascular reactivity was determined by
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measuring changes in mean blood velocity in the middle cerebral artery under normocapnic,
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hypocapnic and hypercapnic conditions. Mean baPWV was greater (p<0.05) in older compared with young adults. At baseline, mean cerebral blood flow velocity and cerebrovascular
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conductance index were lower (p<0.05) in older compared with young adults under normocapnic, hypocapnic and hypercapnic conditions.
There were no significant group differences in
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cerebrovascular reactivity when they were adjusted for stimuli (i.e., end-tidal CO2 concentrations)
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in most perturbation conditions except for the normocapnia to hypercapnia condition. baPWV
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was negatively associated with cerebrovascular conductance index at all conditions (all p<0.05). We concluded that arterial stiffness was associated with age-related differences in cerebrovascular conductance and that there were no apparent age-associated differences in cerebrovascular reactivity.
Keywords: Aging, pulse wave velocity, transcranial Doppler, cerebral vasomotor reactivity
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1. Introduction Cerebral blood flow and vascular conductance are tightly regulated to deliver and
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distribute oxygen and nutrients to active regions of the brain. Cerebrovascular reactivity (CVR) reflects the vasodilatory capacity of the cerebral arteries. Reductions in CVR can result in a
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decrease in perfusion in response to global vasodilatory stimuli. Assessment of the
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cerebrovascular response as measured by changes in middle cerebral artery velocity to alterations
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in arterial carbon dioxide is a well-established method to estimate the physiological reserve of cerebral perfusion (Ainsile and Duffin, 2009). CVR has been associated with subcortical
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infarctions and stroke (Cupini et al., 2001) and linked with cognitive declines and is impaired in patients with dementia and Alzheimer’s disease (Silvestrini et al., 2006). While it has been
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consistently reported that aging is associated with reduced cerebral vascular conductance (Fisher
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et al. 2013; Toda, 2012; Kamper et al., 2004), the effect of aging on CVR, however, remains
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unclear. Previous studies reported a reduced (Yamamoto et al., 1980; Reich, 1989) or maintained (Kastrup et al., 1998; Ito et al., 2002; Schwertfeger et al., 2006; Galvin et al., 2010) CVR to hypercapnia with aging. For CVR to hypocapnic stimuli, studies have reported unchanged (Ito et al., 2002), decreased (Yamaguchi et al., 1979; Tsuda, 1989; Zhu et al. 2013), and even elevated (Galvin et al., 2010) CVR with increasing age. Advancing age is associated with alterations in structure and function of blood vessel walls, resulting in decreased vascular distensibility (Mattace-Raso et al., 2006). Microvasculature in the brain is constantly exposed to pulsatile hemodynamic strain because the brain is a high flow, low impedance organ. Stiffening of arterial walls and the resulting failure to properly buffer cardiac pulsations could lead to barotrauma, elevated cerebrovascular resistance, and reduced perfusion. Age-associated alteration in large arteries (primarily arterial stiffening) and the progressive mismatch of their “cross-talk” or impedance with small cerebral arteries may induce microvascular brain damage (Scuteri et al., 2011). Indeed cerebrovascular reactivity has been
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associated with increased arterial stiffness in patients with coronary heart disease (Rucka et al., 2014). Arterial stiffness is significantly and inversely associated with cerebral perfusion in deep
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subcortical frontal white matter of middle-age adults (Tarumi et al., 2011). However, the number of studies that address the association of arterial stiffness with CVR and/or cerebral vascular
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conductance is very limited. Currently, there is no existing evidence that demonstrates the
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association of arterial stiffness and global cerebrovascular reactivity in relation to primary aging.
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Accordingly, the primary purpose of the present study was to determine the association between arterial stiffness and middle cerebral artery vascular conductance and reactivity in
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apparently healthy young and older adult subjects. In order to be more comprehensive in the analyses, CVR was assessed during normocapnic, hypocapnic and hypercapnic conditions. We
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hypothesized that older adults would exhibit increased arterial stiffness and compromised
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cerebrovascular conductance and CVR compared with young adults and that arterial stiffness
2. Methods
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would be significantly associated with cerebrovascular conductance as well as CVR.
2.1. Subjects
A total of forty-five subjects were screened (young n=22, older adults n=23). Individuals with a history of diabetes, cardiovascular diseases, neurological disorders, respiratory diseases, brain disorders, and chronic smoking were excluded from the study participation. Subjects with no window at temporal bone of skull for ultrasound assessment were excluded. Fifteen young (aged 19-35 years) and thirteen older (aged 61-70 years) adults were studied. All the older subjects completed the Mini-Mental State Examination and found to be normal. All subjects gave written informed consent prior to participation in the study. The study was approved by the institutional review board at Chulalongkorn University.
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2.2. Study protocol All experiments were performed in an environmentally-controlled laboratory with an
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ambient temperature of 25 °C. Subjects refrained from caffeinated beverages and alcohol at least 12 hours before the test. After providing written informed consent for participation, study
2.2.1 General physiological characteristics
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volunteers underwent a series of measurements described below.
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Body composition was evaluated using body composition analyzer (Whole Body
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Bioelectrical Impedance Analysis, ioi 353, JAWON, Korea). Blood pressure and heart rate at rest were measured with semi-automated blood pressure device (CARESCAPE V100, GE Dinamap,
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USA).
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2.2.2 Arterial Stiffness
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Brachial-ankle pulse wave velocity (baPWV) was measured using a noninvasive vascular screening device (Omron, Collin VP-1000 plus, Kyoto, Japan). Measurements were performed after at least 10 minutes of supine rest. Blood pressure and electrocardiogram were simultaneously measured with the vascular screening device. Waveforms were obtained from plethysmographic sensors in cuffs on both arms and ankles. Pulse wave velocity is calculated from the distance between two arterial recording sites divided by transit time. Transit time was determined from time delay between the proximal and distal foot waveforms (Sugawara et al., 2005). 2.2.3 Cerebrovascular reactivity test Cerebral blood flow velocity (CBFV) was measured on the middle cerebral artery (MCA) by ultrasound machine (CX50, Philips, USA). MCA was insonated from the left posterior temporal window using 1.8 MHz transcranial Doppler probe. Subjects were asked to wear nose clips and breathed only through a mouthpiece, with one end open to room air and the other end
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connected to gas mixture line. After at least 10 minutes of rest in supine position, baseline recordings were taken during spontaneous breathing of room air. Heart rate and blood pressure
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were recorded simultaneously using semi-automated blood pressure device (CARESCAPE V100, GE Dinamap, USA). End-tidal CO2 (EtCO2), an estimate of arterial CO2 level, was measured from
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expired air and analyzed by the gas analyzer (Vmax Encore 29 system, yorba Linda, CA, USA).
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Ventilatory expired gases were continuously measured and acquired via breath-by-breath using
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flow sensor. During these measurements, subjects were instructed to breathe normally and avoid body movement or Valsava maneuvers. After baseline data collection, subjects underwent 1
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minute of maximal voluntary hyperventilation to induce a period of hypocapnia. Heart rate and blood pressure were obtained during the first 10 seconds of hyperventilation while cerebral blood
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flow in MCA was recorded during the last 20 seconds of hyperventilation. Following
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hyperventilation, a 5-minute recovery period was provided allowing cerebral hemodynamics to
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restore to the baseline level. Then, subjects breathed air containing a gas mixture of 5% CO2 and 21% O2 balanced with nitrogen spontaneously for 3 minutes to induce hypercapnia. The data were recorded during the last minute of hypercapnia. Pulsatility index (PI) was calculated as the difference between systolic and diastolic flow velocity divided by mean flow velocity (Alexandrov, 2011).
Cerebrovascular reactivity was calculated as a percent change in MCA-CBFV over an absolute change in EtCO2. The change in cerebrovascular reactivity was calculated from the three different ranges of end-tidal CO2 levels; normocapnia to hypocapnia, normocapnia to hypercapnia, and hypocapnia to hypercapnia. Additionally, cerebrovascular conductance index (CVCi) was calculated in order to account for the effect of blood pressure on MCA-BFV. In an attempt to reduce variability associated with CVR measures, an average of 5-10 values were used
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to represent CVR responses in each subject. The equations used to estimate the cerebrovascular reactivity and cerebrovascular conductance index were shown below.
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Cerebrovascular reactivity index (%/mmHg) = % ∆ Middle cerebral artery blood flow velocity/ ∆ End tidal carbon dioxide
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Cerebrovascular conductance index (cm/sec*mmHg) = Middle cerebral artery blood flow
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velocity/ Mean arterial pressure
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Cerebrovascular conductance index (%/mmHg) = % ∆ middle cerebral artery vascular conductance/ ∆ End tidal carbon dioxide
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2.3 Statistical Analyses
All data were analyzed using SPSS statistical software (SPSS version 17.0, SPSS Inc.,
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Chicago, IL). Prior to the parametric tests, the tests for normal distribution were performed and verified. Independent-samples t-tests were used to compare group differences in demographic
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characteristics and magnitude of changes in arterial stiffness and hemodynamic variables during normocapnia, hypocapnia, and hypercapnia. Bivariate correlation (Pearson’s correlation) analyses were used to examine the relations between arterial stiffness and hemodynamic measures of middle cerebral artery during cerebrovascular reactivity test. Descriptive data are expressed as mean ± SEM. An α-level of 0.05 was considered the statistical significance. 3. Results The general characteristics of the participants are shown in Table 1. Height was lower (all p<0.05) in older compared with young adults. Systolic, mean, and diastolic blood pressure values were higher (all p<0.05) in older than in young adults. Body mass was not different but BMI and % body fat were higher in older than in young adults. As shown in Figure 1, baPWV at baseline were greater (p<0.05) in older compared with young adults. Representative data of middle cerebral artery blood flow velocity and
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cerebrovascular reactivity during normocapnic, hypocapnic, and hypercapnic conditions are presented in Table 2. Mean cerebral blood flow velocity and cerebrovascular conductance index
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were lower (p<0.05) in older compared with young adults under normocapnic, hypocapnic and hypercapnic conditions. Pulsatility index was not significantly difference between older and
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young subjects during all conditions and was not associated with baPWV. Cerebral vasodilatory
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response (∆CBFV/∆EtCO2) at normocapnia to hypercapnia was lower in older than in young
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adults. There were no significant differences in ∆CBFV/∆EtCO2 and ∆CVCi/∆EtCO2 between the groups at normocapnic to hypocapnic and hypocapnic to hypercapnic conditions.
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The associations between arterial stiffness and cerebral hemodynamics are shown in Figures 2. baPWV was negatively associated cerebrovascular conductance index and mean blood
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pressure in all conditions (all p<0.05). There were no significant correlations between baPWV and
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4. Discussion
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cerebrovascular reactivity (∆CBFV/∆EtCO2 or ∆CVCi/∆EtCO2) in all conditions.
The main findings of the present study are as follows. First, arterial stiffness as measured by brachial-ankle pulse wave velocity was higher in older than in young adults. Second, cerebral blood flow velocity and conductance were significantly reduced in apparently healthy older adults compared with young adults. Third, there were no apparent age-associated differences in cerebrovascular reactivity in most perturbation conditions (normocapnia, hypocapnia and hypercapnia) examined in the present study. Fourth, arterial stiffness was significantly and inversely associated with cerebral blood flow velocity and cerebrovascular conductance. These results are consistent with the idea that arterial stiffness plays a role, at least in part, in decreasing cerebrovascular conductance. Brachial-ankle pulse wave velocity (baPWV) was used as a measure of arterial stiffness in the present study. Similar to carotid-femoral pulse wave velocity (cfPWV), this measure of
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arterial stiffness has been shown to be an important predictor and prognosis of cardiovascular disease and has been correlated with cfPWV (Sugawara et al., 2005; Sugawara and Tanaka 2015).
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baPWV was greater in older compared with young adults, reflecting age-associated arterial stiffening even in apparently healthy adult populations (Sugawara and Tanaka 2015). Age-
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associated arterial stiffening has attributed to alterations in structure and function within the
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arterial wall, in particular degeneration or disorganization in the medial layer (Nosaka et al.,
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2003). These changes are important mechanisms underlying age-dependent progressive increases in systolic blood pressure and pulse pressure (Mattace-Raso et al., 2006; Boutouyrie, 2008).
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Stiffer systemic arterial system (as indicated by higher PWV) is accompanied by an increased pulsatility with consequent inward remodeling and rarefaction in the entire microcirculation. In
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the brain, these microvascular changes make an older subject more susceptible to intermittent
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hypotension leading to the age-associated decline in cognitive function (Scuteri et al., 2013).
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The effect of age on cerebral blood flow has been investigated in the past. Most studies have reported that cerebral blood flow undergoes a gradual and significant decline with advancing age (Toda, 2012; Kamper et al., 2004; Fisher et al., 2013; Leenders et al., 1990). Consistent with this, cerebral blood flow in the middle cerebral artery was lowering in older than in young adults. In addition, cerebrovascular conductance index (CVCi), calculated in order to account for the effect of blood pressure, was also lower in older vs. young adults.
In an attempt to gain
mechanistic insight into age-associated reductions in cerebrovascular blood flow and conductance, pulsatility index was derived as it represents the resistance to flow in cerebrovascular circulation (Alexandrov, 2011; Wijnhoud et al., 2006). Pulsatility index was significantly elevated in older than in young adults in the present study. Pulsatility index has been correlated with the National Institutes of Health Stroke Scale and is a predicting factor for functional and clinical outcomes after thrombotic therapy in acute ischemic stroke (Uzuner, 2013). The results of the present study showed that cerebrovascular blood flow velocity and vascular conductance are reduced even in
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healthy older adults and that these subclinical changes could lead to elevated risks of cerebrovascular diseases in older adults possibly via increases in cerebrovascular resistance.
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Our present results showed that blood flow velocity and conductance index in older adults were significantly lower in normocapnic, hypocapnic, and hypercapnic conditions compared with
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young adults. For the cerebrovascular reactivity tests, cerebral CO2 reactivity (∆CBFV/∆EtCO2)
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from the normocapnia to hypercapnia in older adults were lower than young adults while it did not
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show significant age-associated difference from the normocapnia to hypocapnia or hypocapnia to hypercapnia. These lower CVR to hypercapnia in older adults indicate that cerebrovascular
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reactivity was attenuated with advancing age. Our results are consistent with previous findings that cerebral blood flow responses to hypercapnia decrease with aging (Fisher et al., 2013; Fluck
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et al., 2014; Jennings et al., 2013). However, as described above, other studies reported no change
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in cerebral vascular reactivity to hypercapnia (Schwertfeger et al., 2006; Galvin et al., 2010) and
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one study even reporting a greater reactivity to hypercapnia with sedentary aging (Zhu et al., 2013). Clearly, more studies are warranted to determine the influence of age on cerebrovascular reactivity.
Arterial stiffness as measured by baPWV was negatively associated with mean cerebral blood flow velocity and cerebrovascular conductance index at normocapnic, hypocapnic and hypercapnic conditions. Our present findings are consistent with previous studies emphasizing a role of arterial stiffness in the pathogenesis of cerebrovascular dysfunction in older adults. Xu et al. (2012) previously reported a significant correlation between MCA and systemic arterial stiffness. Additionally, reduced hypercapnia-mediated cerebral blood flow responses through the MCA in older adults were associated with increased vascular stiffness (Fluck et al., 2014). Moreover, the elevation in arterial stiffness was inversely associated with cerebrovascular reactivity by breath holding index (BHI) in patients with coronary heart disease (Rucka et al., 2014). Furthermore, Tarumi et al. (2011) using the arterial spin labeling (ASL) technique reported
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that central artery stiffness is associated with cerebral perfusion in deep subcortical frontal white matter among middle-aged men and women. In the present study, the negative association
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between arterial stiffness and mean cerebral blood flow velocity and conductance index was observed without affecting cerebral vascular reactivity. There are a number of ways that arterial
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stiffness could affect cerebral conductance independent of cerebral reactivity. For example, a
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failure to control perfusion pressure via impaired baroreflex sensitivity can cause chronic brain
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hypoperfusion as we have recently demonstrated (Laosiripisan et al., 2015). Increasing stiffness in the systemic circulation reduces arterial baroreflex sensitivity (Laosiripisan et al., 2015) and
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influences the flow pattern in the cerebral artery via widening of pulse pressure (Xu et al., 2012). There are a number of limitations in the present study that should be emphasized. First, the
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present study utilizes a cross-sectional study design. Accordingly, a cause and effect relationship
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cannot be determined. Second, the number of participants studied was relatively small, and the
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results should be interpreted with caution. Third, the menstrual cycle of young female subjects were not controlled for during the measurements. However, the number of young female subjects was very small, and the sun-group results based only on young men were consistent with the results obtained with the entire young adults. Fourth, it is possible that CO2 in the breathing air during the hypercapnic condition could elevate arterial blood pressure via chemoreceptor stimulation. However, blood pressure was not different between different conditions as has been demonstrated in the previous study (Turner et al. 1996). In summary, we observed that arterial stiffness was elevated in healthy sedentary elderly compared with young subjects. Such arterial stiffening with age was negatively associated with cerebral blood flow and cerebrovascular conductance index. But when the cerebrovascular reactivity was adjusted for stimuli, age-associated differences in cerebrovascular reactivity were abolished in most perturbation conditions. Considering the important role that cerebrovascular reactivity plays in the age-associated increases in cerebrovascular disease and Alzheimer’s
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disease, there is no question that more studies, especially longitudinal studies, are warranted in the future.
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Acknowledgments
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This study was supported by Government Research Budget Chulalongkorn University
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2015 and The 90th Anniversary Research Fund, Chulalongkorn University, Thailand.
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Mattace-Raso, F.U.S., van der Cammen, T.J.M., Hofman, A., van Popele, N.M., Bos, M.L., Schalekamp, M.A.D.H., Asmar, R., Reneman, R.S., Hoeks, A.P.G., Breteler, M.M.B.,
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Figure Legends Figure 1. Arterial stiffness as measured by brachial-ankle pulse wave velocity (baPWV) in young
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and older adults.
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Data are mean ± SEM. *P < 0.05 vs. young group.
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Figure 2. Associations between arterial stiffness as measured by brachial-ankle pulse wave
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velocity (baPWV) and cerebrovascular conductance index.
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Table 1. Selected characteristics of subjects. Group Variables
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Male/female (n)
Older adults
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Young
9/4
25.2 ± 1.2
66.9 ± 0.9*
Body mass (kg)
62.7 ± 2.8
63.7 ± 2.4
171 ± 2
162 ± 2*
21.3 ± 0.8
24.1 ± 0.7*
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Age (years)
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Height (cm)
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BMI (kg • m-2) Body Fat (%)
19 ± 2
24 ± 2*
69 ± 3
72 ± 3
113 ± 3
130 ± 5*
Diastolic BP (mmHg)
74 ± 2
83 ± 3*
Mean BP (mmHg)
82 ± 2
95 ± 4*
Obesity, (n)
0
5
Blood pressure lowering drug, (n)
0
3
Cholesterol lowering drug, (n)
0
7
MMSE score (unit)
-
28.6 ± 0.6
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Systolic BP (mmHg)
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Heart Rate (bpm)
Data are mean ± SEM. BMI = Body mass index; BP = Blood pressure; MMSE = Mini Mental State Examination (Thai version). *P<0.05 vs. young group.
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Table 2. Hemodynamic measures of middle cerebral artery during cerebrovascular reactivity test. Group
(mmHg)
Mean CBFV
78.1 ± 1.6
93.5 ± 3.1*
Hypocapnic
78.3 ± 2.2
93.6 ± 2.3*
Hypercapnic
81.9 ± 1.8
97.9 ± 3.0*
Normocapnic
(cm/sec)
58.6 ± 2.4
50.2 ± 2.3*
40.1 ± 2.4†
32.4 ± 2.0*, †
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Hypocapnic
69.0 ± 2.5†, §
54.1 ± 2.7*, §
Normocapnic
39.3 ± 1.0
37.9 ± 1.4
Hypocapnic
29.3 ± 0.8†
27.5 ± 0.8†
Hypercapnic
44.7 ± 1.0†,§
42.0 ± 0.6*, †, §
Normocapnic
0.87 ± 0.49
0.93 ± 0.64
Hypocapnic
1.29 ± 0.09†
1.21 ± 0.07†
Hypercapnic
0.73 ± 0.03§
0.84 ± 0.05§
Normocapnic
0.76 ± 0.04
0.54 ± 0.03*
Hypocapnic
0.54 ± 0.04†
0.35 ± 0.02*, †
condition
0.94 ± 0.07§
0.56 ± 0.04*, §
Normocapnic to
3.95 ± 0.90
3.72 ± 0.51
condition
3.49 ± 0.79
3.79 ± 0.58
Normocapnic to
3.87 ± 0.49
1.74 ± 0.88*
condition
4.00 ± 1.04
3.53 ± 0.49
Hypocapnic to
5.34 ± 0.72
4.98 ± 0.63
5.57 ± 1.04
4.44 ± 0.53
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Hypercapnic EtCO2
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MCA PI
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(mmHg)
CVCi
(cm/sec *mmHg)
∆CBFV/∆EtCO2
(% cm/sec*mmHg-1) ∆CVCi/∆EtCO2 (% cm/sec) ∆CBFV/∆EtCO2 (% cm/sec*mmHg-1) ∆CVCi/∆EtCO2 (% cm/sec) ∆CBFV/∆EtCO2 (% cm/sec*mmHg-1) ∆CVCi/∆EtCO2 (% cm/sec)
Older adults
Normocapnic
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MAP
Young
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Conditions
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Variables
Hypocapnic
Hypercapnic
Hypercapnic condition
ACCEPTED MANUSCRIPT 21 Data are mean ± SEM. CBFV = Cerebral blood flow velocity; EtCO2 = End-tidal CO2; MAP = Mean arterial pressure; PI = Pulsatility index; MCA = Middle cerebral artery; CVCi = Cerebrovascular
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conductance index. *P<0.05 vs young group. †P<0.05 vs normocapnic, §P<0.05 vs hypocapnic
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Figure 1
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Figure 2
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Arterial Stiffness is Associated with Age-Related Differences in Cerebrovascular Conductance
Arterial stiffness is elevated in healthy sedentary elderly compared with young adults.
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Highlights
Cerebral blood flow velocity and conductance are reduced in healthy older adults compared with young adults.
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Arterial stiffness was significantly and inversely associated with cerebral blood flow velocity and cerebrovascular conductance.
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There are no apparent age-associated differences in cerebrovascular reactivity in apparently healthy older adults.
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