In elderly subjects, heart rate responses to postural change are attenuated, whereas their vascular responses are augmented. Altered strategy in maintaining blood pressure homeostasis during upright position may result from various cardiovascular changes, including age-related cardiovascular autonomic dysfunction. This exploratory study was conducted to evaluate impact of age on cardiovascular autonomic responses to head-up tilt (HUT) in healthy subjects covering a wide age range. The study population consisted of 63 healthy, normal-weight, nonsmoking subjects aged 23–77 yr. Five-minute electrocardiogram and finger blood pressure recordings were performed in the supine position and in the upright position 5 min after 70° HUT. Stroke volume was assessed from noninvasive blood pressure signals by the arterial pulse contour method. Heart rate variability (HRV) and systolic blood pressure variability (SBPV) were analyzed by using spectral analysis, and baroreflex sensitivity (BRS) was assessed by using sequence and cross-spectral methods. Cardiovascular autonomic activation during HUT consisted of decreases in HRV and BRS and an increase in SBPV. These changes became attenuated with aging. Age correlated significantly with amplitude of HUT-stimulated response of the high-frequency component (r = -0.61, P < 0.001) and the ratio of low-frequency to high-frequency power of HRV (r = -0.31, P < 0.05) and indexes of BRS (local BRS: r = -0.62, P < 0.001; cross-spectral baroreflex sensitivity in the low-frequency range: r = -0.38, P < 0.01). Blood pressure in the upright position was maintained well irrespective of age. However, the HUT-induced increase in heart rate was more pronounced in the younger subjects, whereas the increase in peripheral resistance was predominantly observed in the older subjects. Thus it is likely that whereas the dynamic capacity of cardiac autonomic regulation decreases, vascular responses related to vasoactive mechanisms and vascular sympathetic regulation become augmented with increasing age.
- autonomic nervous system
- baroreflex sensitivity
- blood pressure variability
- heart rate variability
circulatory lability and orthostatic hypotension are common in elderly subjects (15, 26, 29, 47). In particular, cardiovascular autonomic dysfunction in elderly people is likely to contribute to the hemodynamic impairment in the upright position.
The impact of age on the autonomic neuraxis occurs at multiple levels and in a heterogeneous manner (2, 9, 28). With increasing age, indexes related to sympathetic activity, such as muscle sympathetic nerve activity (20, 22, 35) and norepinephrine spillover (14, 22), increase, whereas the indexes related to parasympathetic activity, such as heart rate variability (HRV) (4, 6, 11, 23, 58) and cardiovagal baroreflex sensitivity (BRS) (10, 23, 44, 51), decrease with aging. So far, most of the reports about aging and cardiovascular autonomic regulation have referred to the recordings at rest, whereas the knowledge on the age dependency of integrative cardiovascular autonomic responses to different stimuli is less well characterized. Head-up tilt (HUT) test is a standardized, physiological, and clinically relevant stimulus that challenges the cardiovascular regulation. By the performance of HUT, it is possible to assess the dynamic capacity of the regulatory systems.
In elderly subjects, heart rate responses to postural change are attenuated, whereas, in contrast, their vascular responses are augmented (50, 53, 54). Altered strategy in maintaining blood pressure homeostasis during the upright position may result from age-related cardiovascular autonomic dysfunction. Previously, our laboratory has reported that in elderly men, plasma norepinephrine concentration at rest was increased and norepinephrine response to HUT was augmented, whereas blood pressure responses to HUT were comparable to those of younger subjects (16). Our laboratory has also shown that decreased BRS in elderly people is associated with increased blood pressure variability, bringing additional evidence of cardiovascular autonomic impairment with aging (24). In the present study, we investigated the effect of aging on the functional capacity of the cardiovascular autonomic regulatory systems during HUT in the same population of healthy subjects.
Subjects. Originally, 109 subjects were studied according to a HUT protocol. Forty-six subjects experienced presyncopal symptoms related to cardioneurogenic reflex mechanism and had to be returned to the supine position before the end of scheduled HUT. The population of this study consisted of 63 healthy subjects, 29 men and 34 women, who tolerated HUT without cardioneurogenic reflex syncope. They were divided according to age into three age groups representing young (23–39 yr, n = 20), middle-aged (40–59 yr, n = 18), and elderly (60–77 yr, n = 25) subjects. The subjects were evaluated with a detailed history, physical examination, routine laboratory tests, and clinical exercise test. All subjects were free of hypertension and other systemic diseases. None was taking any cardiovascular medication or smoked. All subjects were requested to abstain from beverages including caffeine for 12 h before the experiment. The subjects came to the laboratory between 7:30 and 9:00 AM, 45 min after ingestion of a light breakfast. Subjects gave a fully informed consent, and the Ethics Committee of Kuopio University Hospital approved the study protocol.
Assessment of exercise capacity. Maximal exercise testing was performed with an electrically braked bicycle ergometer (model 380, Siemens Elema, Solna, Sweden) in sitting position until exhaustion. The initial workload was 20 W with subsequent increments of 20 W/min. During the test, perceived exertion, subjective symptoms and blood pressure were recorded. In addition, heart rate, 12-lead electrocardiogram (ECG) and working time were recorded continuously with a computerized system (Marquette Centra, Milwaukee, WI). Maximum oxygen uptake was measured as previously described (34).
Recordings. Electrodes were placed for ECG recording. Continuous blood pressure recording was performed from the middle finger of the right hand with a Finapres digital plethysmograph (Ohmeda, Englewood, CO). The Finapres device's self-adjustment was performed just before the recordings, and it was disconnected during the recordings. ECG and blood pressure signals were recorded for period of 5 min after 3 h of bed rest in the supine position and for another 5 min on the tilt table in the upright position 5 min after the 70° HUT. During the recordings, the subjects were asked to breathe according to a metronome at 0.2-Hz frequency with their normal tidal volume. Note that, during the first 5 min in the upright position, the subjects were breathing spontaneously, but the actual recordings were performed during the subsequent 5 min when the subjects were breathing according to the metronome. Recorded signals were analog-to-digital converted with temporal resolution of 200 Hz/channel and amplitude resolution of 12 bits (56). We were not able to get reliable blood pressure signal in two cases in the supine position and in one case in the upright position. Data acquisition was performed with an IBM/PC-compatible microcomputer with CAFTS software (Medikro, Kuopio, Finland).
Study protocol. The subjects lay down on a pneumatically driven tilt table (Läätek, Kaarina, Finland) and were maintained in the horizontal position for 3 h in the supine position. Thereafter, the tilt table was inclined within 5 s to 70° head-up for 13 min, and then it was returned back to the horizontal position.
Analyses. Data analyses were performed with an IBM/PC-compatible microcomputer with WINCPRS software (Absolute Aliens Oy, Turku, Finland). All analyses were performed from stationary regions with the duration between 2.5 and 5 min and free of ectopic beats and technical artifacts.
Assessment of hemodynamics. Stroke volume was assessed from the noninvasive blood pressure signal by using the arterial pulse contour method, which is modified from the model flow method (60). Cardiac output was calculated from the equation cardiac output = heart rate · stroke volume, and peripheral resistance was calculated as total peripheral resistance = mean arterial pressure/cardiac output. Vascular compliance was calculated from the equation vascular compliance = stroke volume/pulse pressure.
Assessment of HRV and blood pressure variability. Fast Fourier transform method was used to obtain power spectral estimates of HRV and systolic blood pressure variability (SBPV). Original time series were unevenly resampled at a rate of 5 Hz. Spectrums were computed up to 0.50 Hz. The computed Fast Fourier transform spectrum was smoothed by using triangular averaging functions. Total power (TP) in the frequency range from 0 to 0.40 Hz was divided into low-frequency (LF; 0.04–0.15 Hz) and high-frequency (HF; 0.15–0.40 Hz) bands. Signal powers of each band were calculated as integrals under the respective power spectral density functions and expressed in absolute units (ms2 or mmHg2). In addition, the ratio between LF power and HF power (LF/HF ratio) of HRV and SBPV were calculated without any normalization.
Assessment of BRS. We also characterized spontaneous vagal cardiac baroreflex gain in two ways. Recordings were scanned for concordant systolic pressure and R-R-interval sequences (19, 46). We defined a spontaneous sequence as a ramp of three or more consecutive cardiac cycles with increasing systolic pressures of at least 1 mmHg/heartbeat. Each systolic pressure was correlated with the R-R interval of the next heartbeat. Data were pooled, and averaged data were used as up-up sequences to calculate local BRS. A criterion for valid up-up sequence was correlation at minimum level of 0.9. Second, we estimated vagal-cardiac baroreflex gain with a method based on the modulus of cross-spectral analysis of systolic pressures and R-R intervals (12, 45, 46). We estimated baroreflex gain as αLF with the square root of ratios of systolic pressure and R-R interval powers in the LF (0.04–0.15 Hz) band, over ranges with coherence 0.50.
Statistical analyses. Because of skewed distribution, HRV and SBPV were analyzed after logarithmic transformation and their changes during HUT after rank transformation. One-way ANOVA with Tukey's test was used to test the significance of differences between the age groups. The ANOVA test with age as a covariate was used to test the significance of difference between genders. Univariate correlations were calculated by using Pearson's correlation analysis. A P value <0.05 was considered statistically significant. All values are presented as means ± SE. Statistical analyses were performed by using a statistical program, SPSS for Windows (version 10.1.3; SPSS, Chicago, IL).
Clinical characteristics. Table 1 shows the clinical characteristics of the study population in relation to age. Systolic and diastolic blood pressure at rest increased and maximum oxygen uptake decreased with aging (P < 0.001 for all).
Hemodynamics and HUT. Circulatory responses to HUT are shown in Fig. 1. At rest, all hemodynamic measures were comparable between the age groups. However, in the upright position, there were marked differences between the groups; for example, cardiac output was lower in the elderly and the middle-aged subjects than in the young subjects (P < 0.001 vs. elderly and P < 0.05 vs. middle-aged subjects), and total peripheral resistance was higher in the elderly subjects compared with the young subjects (P < 0.001). In response to HUT, elderly subjects had a smaller increase in heart rate (P < 0.05), a larger decrease in cardiac output (P < 0.05), and a larger increase in total peripheral resistance (P < 0.001) compared with young subjects. Despite the differences in other circulatory responses, the increase in mean blood pressure was comparable in all groups. Vascular compliance in the supine position tended to become decreased with increasing age (group I: 1.16 ± 0.08, group II: 1.13 ± 0.08, group III: 0.94 ± 0.06 ml/mmHg; P = 0.051) and in the upright position it was significantly (P < 0.01) lower in the elderly subjects than in the young subjects (group I: 0.83 ± 0.06, group II: 0.74 ± 0.05, group III: 0.61 ± 0.04 ml/mmHg; P < 0.01).
HRV and HUT. HRV responses to HUT are shown in Fig. 2. Compared with the young subjects, the middle-aged and the elderly subjects had significantly lower TP (P < 0.001 vs. elderly and P < 0.01 vs. middle-aged subjects), LF power (P < 0.001 vs. elderly and P < 0.05 vs. middle-aged subjects) and HF power of HRV (P < 0.001 for both) in the supine position. On the contrary, LF/HF ratio of HRV was higher in the group of the middle-aged subjects compared with the young subjects (P < 0.01). During HUT also, compared with the young subjects, the elderly and the middle-aged subjects had significantly lower TP (P < 0.001 vs. elderly and P < 0.05 vs. middle-aged subjects), LF (P < 0.001 for both), and HF power (P < 0.001 vs. elderly and P < 0.01 vs. middle-aged subjects). Furthermore, the elderly subjects had the lowest LF/HF ratio in the upright position, and the difference between the elderly and young subjects reached statistical significance (P < 0.05). In response to HUT, the decrease in HF power and the increase in LF/HF ratio were significantly smaller in the elderly subjects compared with the young subjects (P < 0.01 for both).
SBPV and HUT. SBPV responses to HUT are shown in Fig. 3. With the subjects at rest in the supine position, TP of SBPV was slightly higher in the elderly subjects compared with the young and middle-aged subjects, but this difference was not statistically significant (P = 0.22). However, we found that HF power of SBPV was higher (P < 0.001) and LF/HF ratio of SBPV was lower (P < 0.05) in the elderly subjects than in the young subjects. SBPV in the upright position and its responses to HUT between the age groups did not differ from each other. The increase in LF power of SBPV was the smallest (although not significant) in the elderly subjects.
BRS and HUT. BRS responses to HUT are shown in Fig. 4. Compared with the young subjects, the middle-aged and the elderly subjects had significantly lower local BRS (P < 0.001 for both) and αLF (P < 0.001 vs. elderly and P < 0.05 vs. middle-aged subjects) in the supine position. In the upright position also, the elderly subjects had lower local BRS (P < 0.01) and αLF (P < 0.01), compared with the young subjects. However, the decrease in local BRS in response to HUT was smaller in the elderly and the middle-aged subjects than in the young subjects (P < 0.001 for both), and the decrease in αLF was significantly smaller in the elderly subjects compared with young subject (P < 0.05).
Age dependency of cardiovascular autonomic responses to HUT. Univariate correlations between age and cardiovascular autonomic responses to HUT are presented in Table 2. Statistically significant age dependency was seen in all HUT-induced responses of HRV, SBPV, and BRS responses except for LF power of HRV and HF power of SBPV.
Gender dependency of blood pressure and cardiovascular autonomic responses to HUT. Women had lower mean arterial blood pressure in the supine position than men (83 ± 3 vs. 96 ± 3 mmHg; P < 0.01). Moreover, in response to HUT, they had a little higher increase in mean arterial pressure compared with men (12 ± 2 vs. 5 ± 3 mmHg; P < 0.05). There was also age-gender interaction in the mean arterial pressure (P < 0.05). In women, the increase in the mean arterial pressure in response to HUT tended to become augmented in the oldest group (23–39 yr: 11 ± 2 mmHg; 40–59 yr: 9 ± 3 mmHg; 60–77 yr: 15 ± 4 mmHg). In contrast, in men, the mean arterial increased in response to HUT only in the two younger groups, and such a response was not seen in the oldest group (23–39 yr: 9 ± 2 mmHg; 40–59 yr: 10 ± 3 mmHg; 60–77 yr: 0 ± 5 mmHg). Gender-related differences were also found in some hemodynamic parameters, which were associated with body size and vascular compliance such as stroke volume, cardiac output, vascular resistance, and compliance (data not shown).
Except for the higher LF/HF ratio of SBPV in the supine position (P < 0.01) and smaller response in αLF during HUT (P < 0.05) in women than in men, all parameters reflecting cardiovascular variability and regulatory responses to HUT were comparable in men and women (Table 3).
Aging is associated with changes in the cardiovascular autonomic regulation both under resting and stimulated conditions. At rest, elderly subjects show increased sympathetic and decreased parasympathetic activity as well as impaired arterial baroreflex function (4, 6, 10, 11, 14, 20, 22, 23, 35, 44, 51, 58). In response to postural changes, young subjects rely essentially on cardiac adaptations, i.e., a marked increase in heart rate and myocardial contractility whereby cardiac output and mean arterial pressure are maintained. In contrast, elderly subjects maintain their blood pressure in the upright position essentially through increased peripheral resistance, whereas they increase their heart rate less than the young, showing a lesser ability to withdraw from vagal influence and/or decreased arterial baroreflex responses (50, 53, 54). In this context, the main finding of the present study is that aging has a significant impact on several measures of cardiovascular variability and BRS not only at rest but also during 70° HUT, indicating that cardiovascular autonomic responses to an orthostatic challenge are markedly age dependent. Influence of gender on these age-related changes in cardiovascular autonomic responses to HUT is minor.
Under an unstimulated condition, i.e., at rest, we confirm the occurrence of the following with aging. 1) There was a decrease in HRV (4, 6, 11, 40, 58), linked to an age-related decline in parasympathetic regulation (39). 2) An increase in SBPV occurred. The few studies that investigated the age dependency of short-term SBPV under resting condition (24, 38, 59) suggested a slight increase of baseline SBPV with aging, especially in the HF range, which is in agreement with the present study. SBPV is closely associated with LF/HF ratio of HRV, and therefore it may reflect changes in sympathovagal balance (24). 3) There was a decrease in BRS. Because baroreflex constitutes the main buffer mechanism against the changes in blood pressure, decreased BRS with aging may account for the increased SBPV and also the risk of orthostatic hypotension in the elderly.
Under a stimulated condition, i.e., in response to an orthostatic challenge, the typical response linked to parasympathetic deactivation at the cardiac level and a general increase in sympathetic activity is characterized by a decrease in HRV (1, 5, 8, 11, 18, 32, 33, 42), an increase in SBPV (5, 8, 18, 33, 59), as well as a decrease in cardiovagal baroreflex sensitivity (8, 17, 21, 25, 41, 55, 57).
These autonomic responses to HUT were clearly characterized by an age-related attenuation. Consistent with previous findings, we found a marked decrease in HF power of HRV in response to HUT in the young subjects (3, 48, 61). This suggests that parasympathetic deactivation of cardiac control during HUT is a very important adaptive mechanism in the young subjects. In contrast, in the elderly subjects, HF power of HRV was markedly depressed already at rest in the supine position and the additional reduction in HF power of HRV related to HUT was only modest, indicating that parasympathetic regulatory reserve becomes limited with aging. Especially in the young subjects, an increase in LF/HF ratio of HRV in response to HUT was associated predominantly with a marked decrease in HF power of HRV. This suggests that an increase in LF/HF ratio of HRV in this context probably depends largely on parasympathetic deactivation, and thus LF/HF ratio of HRV as a complex parameter is not a plain sympathetic index.
The former studies, which have addressed the influence of aging on short-term SBPV during an orthostatic stress, have shown upright posture to induce a significant increase in the LF band of SBPV in all age groups but a lesser increase in the older subjects (3, 59). Our data are consistent with these findings, even though the lesser increase in LF power of SBPV in our older subjects did not reach statistical significance. As suggested by Barnett and coworkers (3), this decrease in LF power of SBPV [which is believed to represent the baroreflexmediated sympathetic outflow to the vasculature (37)] that they observed both with healthy aging and in the female gender (from data adjusted for gender and age, respectively) in response to orthostasis, appears to be due to different mechanisms in the two cases (3). Our laboratory's previous data are in line with theirs, because our laboratory has shown in the same subjects as those dealt with in the present study that 1) older women (>50 yr old), in addition to having lower baseline plasma norepinephrine concentration than men, had also lower norepinephrine response to HUT than their male counterparts and 2) aging had a significant effect on plasma norepinephrine only in men, because aging men (>50 yr old) had higher plasma norepinephrine at baseline as well as in the upright posture than all women and, moreover, than younger men (16). However, in this study, we could not confirm observation of gender differences in the LF power of SBPV.
There may exist an important link connecting age-related vascular and regulatory changes. Monahan and coworkers (31) have shown that age-associated changes in vascular compliance of arteries in which baroreceptors are located are closely related with a decrease in cardiovagal baroreflex (31). We found that vascular compliance decreased with increasing age, and it is possible that, in the elderly subjects, decreased vascular compliance may lead up to secondary changes in cardiovascular regulation; in particular, it may result in a decrease in BRS. In the young subjects, the BRS response was pronounced, which was clearly linked to their high BRS at rest. Because it is well known that baroreflex control of heart rate is under strong parasympathetic modulation (13), this response was expected and is in line with the HRV responses indicating marked parasympathetic deactivation in the young subjects. Although also sympathetic activation is known to play an important role in a decrease in BRS (21, 55), we found that the elderly subjects with augmented sympathetic response to HUT had an attenuated BRS response.
The maintaining of blood pressure at an appropriate level during HUT was achieved by markedly divergent patterns of cardiovascular regulation in different age groups. In the elderly subjects, peripheral resistance was increased, especially in the upright position. It is possible that augmented vascular response in the elderly subjects may be appropriate response to maintain blood pressure homeostasis in the upright position, but such vascular changes may also have some other detrimental influences, especially if they lead to permanent increase in vascular compliance. Changes in cardiac autonomic responses to HUT were attenuated with advancing age, reflecting lower regulatory reserve in elderly subjects. Therefore, the altered cardiovascular autonomic regulation in the elderly subjects may be more vulnerable to the influences of orthostatic stress factors, and this may contribute to high prevalence of orthostatic hypotension in elderly people.
An interesting observation in this study was that older female subjects demonstrated greater increase in mean arterial pressure than older male subjects, although they have been previously shown to have smaller plasma norepinephrine response to HUT and lower plasma norepinephrine levels in the upright position (16). In addition, we did not find age dependency in peripheral vascular resistance in the supine position, although our laboratory has shown that plasma norepinephrine becomes increased with increasing age, at least in men (16). These findings may indicate that norepinephrine action is impaired in elderly men.
It is uncertain whether circulatory lability commonly seen in elderly subjects is due to aging per se or rather due to age-associated concomitant disorders. Clinically significant orthostatic hypotension may develop postprandially (27), after bed rest for more than a few days (7), or because of use of drugs with vasoactive properties (30). It is noteworthy that the elderly subjects of our study were healthy and had no drug therapies. Thus it is not surprising that they did not have orthostatic hypotension and that the differences in blood pressure responses during HUT between the age groups were not statistically significant. On the other hand, in 46 excluded cases of 109 originally studied subjects, the HUT was prematurely interrupted because of signs and symptoms of cardioneurogenic reflex syncope. Relatively high frequency of cardioneurogenic syncope was likely to be explained by the fact that upright posture was produced by using a tilt table after 3-h recumbency, and, in addition, the subjects performed a controlled breathing test while standing. It is possible that postural hypocapnia was an important mechanism responsible for the occurrence of orthostatic intolerance (49). There is evidence to suggest that mild alterations in arterial CO2 modulate HRV (43) as well as sympathetic postural response and peripheral vascular resistance (52). Furthermore, arterial hypocapnia has been linked to orthostatic intolerance (36). A limitation in our study is that end-tidal or arterial CO2 was not measured, and thus we are not able to assess the possible effects of hypocapnia induced by postural change and fixed-pace breathing.
In conclusion, in healthy subjects blood pressure was well maintained during acute orthostasis irrespective of age. Analysis of cardiovascular variability brought additional evidence to the known differences in the mechanisms of blood pressure adjustment during orthostasis between the young, who rely essentially on an increase in heart rate and myocardial contractility, and the elderly, who rely more on an increase in peripheral resistance, and contributed to the view that whereas the dynamic capacity of cardiac autonomic regulation decreases, the vascular responses related to vasoactive mechanisms and vascular sympathetic regulation become more important with increasing age.
This work was financially supported by Helena Vuorenmies Foundation, Uulo Arhio Foundation, and Kuopio University Hospital (EVO 403010).
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