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a Hebrew Rehabilitation Center for Aged Research and Training Institute, Beth Israel/Deaconess Medical Center Department of Medicine and Harvard Medical School, Boston, Massachusetts
b Quest Diagnostics Nichols Institute, San Juan Capistrano, California
Lewis A. Lipsitz, Hebrew Rehabilitation Center for Aged, 1200 Centre Street, Boston, MA 02131 E-mail: lipsitz{at}mail.hrca.harvard.edu.
Decision Editor: William B. Ershler, MD
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Abstract |
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Methods. We measured hemodynamic (blood pressure, heart rate, and forearm vascular resistance), autonomic (power spectral analysis of heart rate and blood pressure variability), and neurohumoral (plasma norepinephrine, renin, aldosterone, and endothelin) responses to a mixed 425 kilocalorie (kcal) meal in 89 rigorously screened healthy subjects aged 20–39, 40–59, and 60–83 years.
Results. After the meal, supine mean arterial blood pressure fell significantly only in the middle-aged group by 5.4 ± 7.9 mm Hg at 30 minutes 
p 
. Forearm vascular resistance fell after the meal in all age groups 
. Older groups had higher plasma norepinephrine p , lower heart rate p 
, lower cardiovagal activity p 
, and lower sympathetic vasomotor p activity, but there was no difference in the response of these variables to a meal.
Conclusion. Healthy aging, in the absence of blood pressure elevation, alters the level of autonomic activity without further impairing the ability to maintain blood pressure during meal digestion. Hemodynamic, autonomic, and neurohumoral responses to meal ingestion remain unchanged in very healthy, normotensive elderly adults.
POSTPRANDIAL hypotension (PPH) is a common and potentially dangerous abnormality in blood pressure regulation in elderly patients that may result from impaired peripheral vascular adaptation to splanchnic blood pooling during meal digestion (1). Previous studies have shown that PPH is highly prevalent among nursing home residents (2)(3)(4)(5), community-dwelling elderly adults (6)(7)(8), and patients with hypertension (9) or autonomic failure (10)(11). Although PPH has been reported in apparently healthy community-dwelling elderly subjects (6)(7)(12), these reports are limited by the potential confounding effect of blood pressure elevation in elderly subjects and by the lack of rigorous subject screening to exclude occult cardiovascular diseases that may affect postprandial autonomic and neurohumoral responses. Moreover, comparison and interpretation of these studies are difficult because of differences in subject characteristics, meal composition, experimental protocol, and lack of simultaneous measurements of postprandial hemodynamic, neurohumoral, and autonomic nervous system responses. Currently, it is not known whether normative age-related changes in levels of autonomic and neurohumoral activity in the absence of blood pressure elevation predispose elderly people to PPH, or whether PPH is a consequence of additional impairments caused by occult cardiovascular or other diseases. Therefore, we performed this cross-sectional study to determine the hemodynamic, autonomic, and neurohumoral responses to meal digestion in normotensive healthy people aged 20 to 83 years who were free of cardiovascular disease. Autonomic control of cardiovascular function was assessed using power spectral analysis of blood pressure and heart rate variability, and neurohumoral control was evaluated by measuring circulating vasoactive peptide levels at intervals coinciding with hemodynamic measures before and after meal ingestion.
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Methods |
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, or were obese (body mass index > 30 kg/m2) or hypertensive (systolic blood pressure [BP] > 140). A total of 34 potential subjects were deemed ineligible after screening, and 15 decided not to participate in the experimental protocol, leaving 95 subjects who completed the study. Six of these subjects were excluded during data analysis because of frequent atrial or ventricular ectopy during prolonged cardiac monitoring. Therefore, the final sample included 89 healthy subjects (48 women and 41 men, aged 20–83 years). The institutional review board of the HRCA approved the study, and all subjects provided written informed consent.
Instrumentation
Subjects underwent meal studies in the cardiovascular research laboratory at the HRCA at 10:00 AM after fasting overnight. Because the meal study was part of a larger investigation of cardiovascular dynamics in aging, it was preceded by a 45-minute head-up tilt protocol (13) followed by a 30-minute supine recovery period. The tilt results are reported elsewhere (13). Premenopausal women were studied between days 7 and 14 of their menstrual cycle. An intravenous catheter was placed in the right antecubital vein, 2 hours before the meal, for blood sampling during the study. Electrodes were attached to the chest for continuous recording of the electrocardiographic (ECG) signal. The right arm was kept level with the right atrium at all times during the study, and a noninvasive tonometric arterial pressure transducer, connected to a Colin Electronics BP monitor (San Antonio, TX), was strapped over the right radial artery. The sphygmomanometric cuff of an oscillometric BP recording device, used for calibration of the tonometric transducer, was attached to the upper right arm. Forearm blood flow was determined on the other arm by venous occlusion plethysmography using a Hokanson plethysmograph and the procedure of Whitney (14). Vascular resistance was calculated from the mean arterial pressure divided by forearm blood flow.
To monitor and control respiration during the study, a continuous respiration signal was recorded by an inductive plethysmograph (Respitrace, Ambulatory Monitoring, Ardsley, NY) from two elastic respiratory transducer bands, one around the midchest and the other around the abdomen. The Respitrace output was calibrated according to the procedure of Sackner and colleagues (15) by having subjects exhale and inhale to fill and empty an 800-cc spirometer bag. Minute ventilation was calculated during 3 minutes of spontaneous breathing during the pre-meal supine rest and subsequently was held constant during periods of paced breathing by having the subject adjust his or her depth of respiratory excursion according to a marker on an oscilloscope screen. During paced breathing, respiratory frequency was controlled at 15 breaths per minute (0.25 Hz) by having subjects follow a tape-recorded auditory signal and line on the oscilloscope screen.
Experimental Protocol
Following equipment attachment and calibration, subjects rested supine for 30 minutes to reach equilibrium. Next, subjects sat in a semirecumbent position for 10 minutes to consume a standardized test meal. The meal consisted of a Nestle Carnation Instant Breakfast French Vanilla drink (55 g), Moducal (Mead Johnson and Co., Evansville, IN) (25.25 g), and Promod (Ross Laboratories, Columbus, OH) (7.0 g) mixed with 168 ml of lactose-free skim milk and 72 ml of lactose-free 1% milk (424.98 kcal, 20.77 g of protein, 2.85 g of fat, and 78.13 g of carbohydrates). This meal composition represents that of a mixed breakfast and, in previous studies, has been shown to evoke a hypotensive response. Following the meal, subjects returned to a supine position for a follow-up period of 70 minutes. Continuous ECG and BP data segments were collected during 10-minute periods of paced breathing, as described previously, prior to the meal and at 30–40 and 60–70 minutes after the start of the meal. Forearm blood flow measurements were taken every 10 minutes before and after the meal. Blood samples were obtained prior to the meal and at 30 and 60 minutes after the start of the meal.
Vasoactive Hormone and Peptide Assays
Plasma was collected in tubes containing glutathione for the norepinephrine assay, and EDTA and Trasylol (Bayer Corporation, Charlotte, NC) for measurements of endothelin, renin (renin peptide and plasma renin activity), and aldosterone. Plasma was stored at -70°C until assayed. All assays were performed at Quest Diagnostics Nichols Institute (13).
Autonomic Assessment
Power spectral analysis of beat-to-beat BP and RR interval variability was used as a noninvasive method to assess the influence of sympathetic nervous system activity on vasomotor oscillations (low-frequency BP power in the range of 0.04–0.15 Hz) and vagal activity on cardiac interval oscillations (high-frequency RR interval power in the range of 0.15–0.50 Hz). To control for potential effects of varying respiratory rates on our results, breathing was paced at 15 breaths/minute (0.25 Hz) during measurement periods, as described previously.
Data Processing
ECG, BP, and respiratory data were digitized at 250 Hz and displayed in real time using commercially available data acquisition software (Windaq, Dataq Instruments, Akron, OH) on a personal computer. Continuous ECG and BP data segments before and after the meal were visually inspected and edited offline for artifact and ectopy, using an automated arrhythmia detection program for the ECG and manual editing for BP. Eight-minute data segments during paced breathing, pre- and postmeal, were used for the analysis.
Beat-to-beat RR intervals were determined from the R-wave of the electrocardiogram, and beat-to-beat systolic and diastolic pressures were derived from the maximum and minimum of the arterial pressure waveform. Each RR interval, systolic and diastolic blood pressure time series was interpolated by cubic spline function and resampled at 2 Hz to obtain equidistant time intervals. The resampled series were analyzed using a fast Fourier transform algorithm as previously described (16). The areas under the power spectra in the low-frequency BP (0.04–0.15 Hz) and high-frequency RR interval (0.15–0.50 Hz) were integrated and used for statistical comparisons. Heart rate was calculated as the reciprocal of the RR interval (in seconds) multiplied by 60. Blood pressure and RR interval data were examined for each subject over the entire study period but are reported here as the means of 8-minute data segments during paced breathing at baseline and at 30 and 60 minutes after the meal. These time points span the usual range over which blood pressure reaches its nadir in patients with PPH and coincide with periods of paced breathing and the collection of other hemodynamic and neurohumoral data.
Statistical Analysis
Subjects were stratified into three age groups: 20–39, 40–59, and 60+ years. Separate analyses were also conducted stratified by gender. Baseline characteristics of groups of subjects were compared using analysis of covariance, controlling for either age or gender (17). Pre- and postmeal cardiovascular variables and spectral powers were compared between the groups using two-way (group and time) repeated measures analysis of covariance with interaction terms. Multiple linear regression was used to determine factors independently associated with changes in blood pressure power after the meal. For statistical analyses, all spectral data were natural log transformed to normalize their distributions. Data are expressed as untransformed mean values ± SE. An alpha level of 0.05 was used to determine statistical significance.
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Results |
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p 
and plasma norepinephrine levels p 
were greater in the older subjects compared with young subjects, and low-frequency diastolic BP oscillations, a measure of sympathetic modulation of beat-to-beat vasomotor activity, was significantly lower in the older group compared with the young subjects p 
. High-frequency RR interval variability, representing vagal input to the sinus node, was also significantly lower as a function of age (p 
, old vs middle-aged and young groups). There were no significant age group differences in other supine hemodynamic variables, systolic BP power, or vasoactive peptide levels. There were also no baseline differences by gender (data not shown).
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Meal ingestion was associated with a small (2–5 mm Hg) decline in supine mean arterial BP for all age groups combined (time effect, 
); however, within groups, the change was statistically significant only in the middle-aged subjects (-5.4 ± 7.9 mm Hg, 
). There was no significant age difference in the mean arterial BP decline (Fig. 1). Heart rate (HR) was consistently lower in the older age group throughout the study (group effect, 
), but meal ingestion was associated with a similar increase in HR in all age groups (time effect, 
; group and time interaction, 
) (Fig. 1). The FVR was consistently higher in the middle-aged and elderly groups (group effect, 
), but it fell to a similar extent after meal ingestion in all age groups (time effect, 
; group and time interaction, 
). However, within groups, the postprandial change in FVR was statistically significant only in the young p 
and elderly 
subjects (Fig. 1). Although plasma norepinephrine levels were higher as a function of age (group effect, ), meal digestion was associated with a similar increase in norepinephrine levels in all age groups (time effect, ; group and time interaction, 
) (Fig. 1).
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; time effect, ; group and time interaction, p > .25) (Fig. 2 and Fig. 2). In contrast, aldosterone levels fell after meal ingestion (time effect, ), and there were no differences in response as a function of age (group effect, 
; group and time interaction, 
) (Fig. 2). Thirty minutes after the meal, endothelin levels had fallen in the middle-aged 
and elderly groups 
but not in the young group (group and time interaction, ). However, by 60 minutes, endothelin had continued to decline in the elderly group, whereas the levels had increased significantly in young subjects and had not changed further in middle-aged subjects (Fig. 2).
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), but meal ingestion was associated with a similar decline in high-frequency RR power in all age groups (time effect, ; group and time interaction, 
) (Fig. 3). There were no significant differences in the effect of a meal on low-frequency diastolic or systolic BP power for these age groups (Fig. 3 and Fig. 3).
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Discussion |
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Our findings confirm previous studies showing that high carbohydrate meal digestion in healthy young subjects is associated with no or relatively small changes in blood pressure, as well as increases in HR, plasma norepinephrine levels (11)(18), and plasma renin activity (6)(19). Although we (8)(11) and others (7)(9) have reported significant postprandial declines in BP following a high carbohydrate mixed meal or glucose ingestion in asymptomatic, "healthy," elderly persons, these subjects were not as carefully screened with exercise stress tests to exclude the possibility of occult cardiovascular disease. Moreover, in some of these studies (11), the healthy elderly group had higher baseline blood pressures compared with the young group. Postprandial hypotension is now well known to be associated with supine BP elevation (8). This study suggests that healthy aging, in the absence of blood pressure elevation, is not associated with a clinically significant impairment in postprandial BP regulation under quiet supine laboratory conditions. However, there are subtle alterations in autonomic nervous system activity that may impair adaptation to more stressful perturbations.
The results of this study also provide several insights into the neuroendocrine regulation of the peripheral vasculature and its changes with healthy aging. We found a significant postprandial elevation in plasma norepinephrine levels that achieved greater values in the elderly subjects compared with the young subjects, yet a reduction in FVR and no change in beat-to-beat systolic or diastolic BP oscillations at the frequency thought to coincide with sympathetic outflow to the vasculature (20). These findings suggest that sympathetic transduction into vascular resistance may be reduced after the meal.
Previous studies of healthy elderly subjects have shown an impaired alpha-1 adrenergic response to intraarterial norepinephrine infusion (21) or sympathetic activation induced by lower body negative pressure (22). However, in our study, all age groups showed a reduction in postprandial FVR. The forearm vasoconstrictor response to the orthostatic stress of lower body negative pressure has been shown to be attenuated by high carbohydrate meal ingestion in healthy young subjects (23). This may be caused by the vasodilatory effect of high insulin levels after the meal (24). Insulin is known to oppose the effects of norepinephrine on vasoconstriction (25). Other factors that may also attenuate vasoconstriction after the meal include the observed reduction in circulating endothelin and aldosterone, both of which are potent vasoconstrictors.
The dissociation between plasma norepinephrine and low-frequency BP power may also be related to decreased sympathetic transduction. Alternatively, because circulating plasma norepinephrine concentrations are influenced by norepinephrine release, reuptake, clearance, and other factors, they may not accurately represent sympathetic nervous system activity at the level of the vasculature.
Our results also show an interesting dissociation between the renin and aldosterone response to meal ingestion. Renin peptide levels and renin enzyme activity both increase after the meal, although aldosterone levels fall. It is likely that renin rises in response to increased sympathetic nervous system activity or translocation of blood flow from the renal arteries to the splanchnic circulation (19). Although one might expect a rise in renin to be accompanied by an elevation in aldosterone, food intake has been shown to increase the metabolic clearance rate of aldosterone, thereby reducing its plasma concentration after a meal (26). Postprandial increases in plasma norepinephrine might also suppress aldosterone secretion (14).
Finally, the observed postprandial reduction in high-frequency RR interval variability challenges the notion that meal digestion is a potent stimulus to vasovagal reflexes. Although the act of swallowing and gastric distention may invoke reflex cardiovagal activity (27), the more delayed digestive response to a meal appears to be associated with vagal withdrawal.
Limitations
There are several limitations to the current study. First, the study was conducted with subjects in the supine position to exclude the possible effects of upright posture on physiologic responses to the meal. As a result, we do not know whether postprandial BP declines would have been greater if subjects had been sitting. Second, the meal study followed a tilt study. However, in other experimental situations, people stand upright for an indeterminant period of time before coming to the laboratory and starting a study. To enable our subjects to reach equilibrium, the meal study followed a 30-minute supine rest period. Therefore, we do not believe that the tilt study affected our results. Third, the current study lacked measures of systemic vascular resistance and cardiac output. We were unable to control for volume status, which could have affected hemodynamic responses to the meal. However, all of our subjects were studied under the same conditions. Finally, because our subjects were carefully screened to exclude blood pressure elevation or cardiovascular disease, they may not have been typical of people from the general population.
Conclusion
This study suggests that healthy aging influences the setpoint, and possibly the adaptive capacity, of the autonomic nervous system but is not a state of autonomic failure. This notion is supported by our previous study of hemodynamic responses to head-up tilt in healthy subjects, which showed no age-related changes in the blood pressure response to orthostatic stress (13). Accordingly, it appears that the development of clinically significant postprandial hypotension probably results from the combined effect of age-related changes in autonomic cardiovascular control compounded by additional adverse effects of concomitant diseases. Future studies need to take careful account of the heterogeneity of the elderly population and distinguish effects of healthy aging from those of hypertension or occult age-associated diseases.
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Acknowledgments |
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Received September 1, 1999
Accepted December 29, 1999
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This article has been cited by other articles:
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  J. E. Morley Editorial: Postprandial Hypotension--The Ultimate Big Mac Attack J. Gerontol. A Biol. Sci. Med. Sci., December 1, 2001; 56(12): M741 - 743. [Full Text] [PDF]
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