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J Am Coll Cardiol, 2002; 40:1290-1297 © 2002 by the American College of Cardiology Foundation |
* Laboratory of Cardiovascular Science, Gerontology Research Center, National Institute on Aging, National Institutes of Health, Baltimore, Maryland, USA
Division of Cardiology, Johns Hopkins Hospital, Baltimore, Maryland, USA
Manuscript received July 18, 2001; revised manuscript received May 7, 2002, accepted June 27, 2002.
* Reprint requests and correspondence: Dr. Jerome L. Fleg, National Heart, Lung, and Blood Institute, DECA, Rockledge 2, Room 8112, 6701 Rockledge Drive, MSC 7936, Bethesda, Maryland 20892, USA.
flegj{at}nhlbi.nih.gov
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Abstract |
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BACKGROUND: Reductions in peak work rate, heart rate (HR), and left ventricular (LV) emptying but higher blood pressure (BP) and systemic vascular resistance occur in healthy older versus younger humans during short bursts of graded maximal aerobic exercise. However, the effect of aging on the cardiovascular response to prolonged exercise at submaximal work rates typical of daily aerobic activities remains unknown.
METHODS: We evaluated cardiovascular performance throughout prolonged submaximal upright cycle ergometry in 40 carefully screened healthy untrained volunteers, 8 men and 12 women <50 years old, mean = 37 ± 8 years (younger), and 10 men and 10 women 
50 years old, mean = 66 ± 9 years (older), during upright cycle exercise at 70% of peak cycle oxygen consumption (VO2) to exhaustion or a maximum of 120 min. Cardiac volumes were acquired by gated blood pool scans with 99mTc at rest and every 10 min throughout exercise.
RESULTS: Duration of exercise was similar in younger ([81 ± 28 min] versus older [71± 29 min] subjects, p = NS). At 10 min of exercise in the steady state, older subjects demonstrated lower VO2 (1.1 ± 0.2 l/min vs. 1.3 ± 0.3 l/min) and lower HR (118 ± 17 vs. 135 ± 11 beats/min, p < 0.001) but larger end-diastolic (80 ± 11 ml/m2 vs. 73 ± 8 ml/m2, p = 0.03) and end-systolic volume index (ESVI) 20 ± 6 ml/m2 vs. 17 ± 4 ml/m2, p < 0.05) than younger ones. Between 10 min and exercise termination, with VO2 held constant in both groups, increases in HR (14.0 ± 12.4 beats/min vs. 5.9 ± 11.5 beats/min, p = 0.04), cardiac index (1.6 ± 1.0 l/min/m2 vs. 0.8 ± 1.1 l/min/m2, p = 0.03), and LV ejection fraction (7.1 ± 4.0% vs. 2.9 ± 4.4%, p = 0.003) were greater in younger than older subjects, respectively, as was the reduction in ESVI (–5.1 ± 3.0 ml/m2 vs. –1.8 ± 3.3 ml/m2, p = 0.002), despite similar declines in systolic BP (–12.3 ± 6.3 mm Hg vs. –12.1 ± 15.0 mm Hg, p = NS).
CONCLUSIONS: Thus, age-associated deficits in chronotropic and LV systolic reserve performance occur during prolonged submaximal upright cycle ergometry, analogous to those observed during graded maximal exercise.
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20 min of exercise at a work level between 50% and 70% of maximal oxygen consumption (VO2max). It is noteworthy, however, that relatively little is known regarding the hemodynamic response to such routine bouts of sustained submaximal exercise, and the effect of age on this response. Age dramatically affects the cardiovascular response to maximal aerobic exercise, with reduced exercise capacity, cardiac output, heart rate (HR), and ejection fraction (EF) and higher end-systolic and diastolic cardiac volumes, blood pressure (BP), and systemic vascular resistance typically observed in older versus younger subjects (1–5). These age-associated differences in cardiovascular performance involve, in part, a reduction in beta-adrenergic responsiveness (5,6). The greater increase in BP observed in older versus younger subjects during maximal exercise may also contribute to the blunted left ventricular (LV) emptying that occurs. In contrast, prolonged bouts of submaximal exercise are typically accompanied by a decline, rather than an increase, in BP (7–9). Whether age, per se, affects the cardiovascular response to prolonged submaximal exercise (PSE) similarly to its effect during graded maximal protocols is not known. This study was designed to evaluate the changes in cardiovascular performance induced by PSE, using radionuclide ventriculography, in carefully screened healthy, but untrained, younger versus older volunteers.
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40 years, using standard methodology (12). Individuals who engaged in vigorous aerobic exercise 20 min at least three times per week, combined with a VO2max >1 SD above the age-adjusted mean for BLSA participants, were excluded.
Exercise protocol
The protocol was approved by the Joint Committee on Clinical Investigation of the Johns Hopkins Medical Institutions and by the BLSA Steering Committee. Initially, each subject underwent graded maximal treadmill exercise for determination of treadmill VO2max. Criteria for achieving VO2max included at least two of the following: 1) 90% of maximal HR predicted by age; 2) respiratory exchange ratio 1.10; and 3) an increase of oxygen consumption (VO2) 
2.0 ml/kg from the penultimate exercise stage. Two days later, after informed consent, upright cycle exercise was performed in the Nuclear Cardiology Laboratory of Johns Hopkins Hospital at a constant workload equivalent to 70% of the peak predicted cycle VO2. The calculation of peak cycle VO2 was based on the relation between treadmill VO2max and peak cycle VO2 previously derived from 40 men and 33 women from the BLSA. In men: cycle peak VO2 (ml/kg–1min–1) = (treadmill VO2max x 0.81) – 2.6; for women: cycle peak VO2 (ml/kg–1min–1) = (treadmill VO2max x 0.66) + 4.3. These relations are independent of age (4).
Upright cycle exercise on an electronically controlled cycle ergometer was begun at 25 W. Workload was increased by 12.5 W every 90 s until the measured cycle VO2 reached 70% of predicted peak cycle VO2. Steady-state VO2 was uniformly achieved within 10 min and maintained throughout the duration of the test by minor adjustments of external work rate, if needed. With the feedback of a visible tachometer, subjects maintained a constant pedal speed of 60 rpm throughout exercise and pedaled until unable to continue, or until 120 min had elapsed. A 12-lead electrocardiogram and manual measurements of brachial arterial cuff pressure were performed at rest and every 5 min during exercise. Cardiac volumes were acquired by gated radionuclide ventriculography with 99mTc before exercise and every 10 min during exercise, all in the seated upright position. Expired O2 and CO2 concentrations were measured continuously and O2 consumption, CO2 production, and respiratory exchange ratio calculated every 30 s using a metabolic cart (Medgraphics CPX, St. Paul, Minnesota). In the final 10 subjects, peripheral venous hematocrit was measured both before exercise and 10 min into recovery.
Gated blood pool scans
After subjects gave informed consent, in vitro labeling of red blood cells was performed with 99mTc (12 mCi/m2 body surface area), as previously described (13). The camera was placed in a position to best define the interventricular septum, usually the 40° left anterior oblique view. Gated cardiac images were acquired at seated rest and during the final 3 min of each 10 min of exercise, using a high-sensitivity parallel-hole collimator attached to a standard Anger camera interfaced with a commercial Nuclear Medicine computer system. Data were acquired on a magnetic disk (64 x 64 matrix, 1.9 zoom) for subsequent off-line analysis.
Measurement of LV volumes
Left ventricular volumes were determined using standard methods (13) by a single technician who was unaware of the study purpose. Briefly, end-diastolic count rate was obtained from a large manually drawn region of interest and corrected for background activity with the use of a separate region of interest drawn lateral and inferior to the left ventricle in the end-systolic frame. A blood sample was drawn at the end of exercise, counted with the same camera-collimator system used for the scintigraphic study, and corrected for time delay between the scintigram and the blood sample counting. Left ventricular end-diastolic volume (EDV) was obtained from the ratio of attenuation-corrected end-diastolic count rate from the gated study to the count rate per milliliter from the sample of venous blood drawn 5 to 10 min after the completion of exercise. Ejection fraction was calculated by a semiautomated algorithm after background subtraction. End-systolic volume (ESV) and stroke volume (SV) were calculated from the measured EF and EDV. Left ventricular volumes were normalized per m2 of body surface area.
Statistical analysis
The effect of age on the hemodynamic response to PSE was examined by stratifying the sample into subsets older versus younger than the median age. The following cardiovascular variables were examined: total body oxygen consumption (VO2 in l/min); arteriovenous oxygen difference (a-vO2) defined as (VO2 in ml/min ÷ cardiac output in ml/min) x 100; HR in beats/min; systolic blood pressure (SBP) and diastolic blood pressures (DBP) in mm Hg; mean blood pressure (MBP), calculated as (SBP + 2 DBP) ÷ 3; cardiac index (CI), stroke volume index (SVI), end-diastolic volume index (EDVI), and end-systolic volume index (ESVI), defined respectively as cardiac output, SV, EDV, and ESV ÷ body surface area in m2; EF, contractility index (CNTR) (defined as SBP/ESVI), total systemic vascular resistance (TSVR), calculated from MBP in mm Hg ÷ cardiac output in l/min; and arterial elastance index (EAI), an index of arterial load defined by the ratio of end-systolic pressure (estimated by [{2 SBP + DBP}] ÷ 3) ÷ SVI (14). Two-way repeated measures analysis of variance (i.e., age group and exercise time point) was used to compare VO2 and cardiovascular parameters every 10 min during exercise, once a steady-state VO2 was achieved. In addition, Student unpaired t test was used to compare baseline characteristics, seated hemodynamics, and cardiovascular responses between 10 min of exercise and exhaustion in older versus younger subgroups. Within group changes between these points were assessed by paired t test. Simple linear regression analysis was utilized to assess correlations between continuous variables. Values are expressed as means ± SD unless otherwise noted. For all analyses a two-tailed p 0.05 indicates statistical significance.
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6 metabolic equivalents) were similar in younger and older subsets (169 ± 185 metabolic equivalent-min/day vs. 230 ± 475 metabolic equivalent-min/day, respectively, p = NS). Hemodynamic comparison of older versus younger subjects in the seated position before exercise revealed no significant differences in BP, SVI, CI, or TSVR. The older subset, however, demonstrated lower seated HR (68 ± 10 beats/min vs. 76 ± 10 beats/min, p < 0.02), EF (65 ± 6 vs. 70 ± 6; p < 0.02), and SBP/ESVI (5.1 ± 1.4 mm Hg/ml/m2 vs. 6.2 ± 1.5 mm Hg/ml/m2, p < 0.03) and larger EDVI (77 ± 7 ml/m2 vs. 69 ± 9 ml/m2, p < 0.003) and ESVI (27 ± 5 ml/m2 vs. 21 ± 6 ml/m2, p < 0.002) than the younger subset.
Hemodynamic changes from rest to steady-state exercise at 70% of peak cycle VO2
During the initial 10 min of exercise, in the overall sample there was a 109% increase in CI, from 3.5 ± 0.5 l/min/m2 to 7.3 ± 1.3 l/min/m2, mediated by a 70% increase in HR from 72 ± 11 beats/min to 126 ± 17 beats/min and a 22% increase in SVI from 49 ± 7 ml/m2 to 58 ± 8 ml/m2. The latter was achieved by a 6% increase in EDVI (from 73 ± 9 ml/m2 to 77 ± 10 ml/m2) and 24% decrease in ESVI (from 24 ± 6 ml/m2 to 18 ± 5 ml/m2), reflecting both utilization of the Frank-Starling mechanism and enhancement of LV systolic performance. The subset younger than 50 years demonstrated larger increases in VO2 (1.04 ± 0.27 l/min vs. 0.83 ± 0.21 l/min, p < 0.01), and a-vO2 difference (5.2 ± 1.0 ml/100 ml blood vs. 4.3 ± 1.0 ml/100 ml blood, p < 0.02) from rest to 10 min of exercise, reflecting their higher absolute work rates. The increase in HR was also greater in younger subjects (60 ± 14 beats/min vs. 49 ± 19 beats/min, p < 0.05); however, no significant age differences were observed in the changes of any other hemodynamic variables between rest and 10 min of exercise.
Hemodynamic changes during PSE
The mean exercise duration for the overall sample was 76 ± 29 min (range, 25 to 120 min). Eight subjects (five young and three older, three men and five women) exercised for the entire 120 min, whereas 32 stopped earlier due to exhaustion (n = 28) or orthopedic reasons (n = 4). No significant relation was observed between submaximal exercise duration and treadmill VO2max (r = 0.18, p = NS). The median level of perceived exertion was 15, that is, hard, as measured by the Borg scale, and did not differ by age group or gender. Mean cycle VO2 at exercise termination was 1.18 ± 0.2 l/min (16.7 ± 3.2 ml/kg/min), corresponding to 72% of estimated cycle peak VO2 or approximately 55% of treadmill VO2max. Respiratory gas exchange ratio decreased significantly across exercise, from 1.00 ± 0.09 at 10 min of exercise to 0.91 ± 0.05 at exercise termination, p < 0.001, representing metabolic adaptation to the constant work rate. No ischemic electrocardiographic changes, significant arrhythmias, or other complications occurred in these carefully screened subjects.
Despite a constant VO2 throughout PSE, there was an 11% increase of CI from 7.3 ± 1.3 l/min/m2 at 10 min of exercise to 8.1 ± 1.5 l/min/m2 at exercise termination, p < 0.001, whereas a-vO2 difference decreased reciprocally (p < 0.001). The augmentation in CI from 10 min to end-exercise was achieved by a 3% increase in HR and a 6.3% increase in SVI (p < 0.001 for both). The SVI increase was achieved by a 14.7% decrease in ESVI (p < 0.001), whereas EDVI remained unchanged throughout exercise. Significant increases in EF (5.4%) and SBP/ESVI (11.7%) occurred between 10 min and termination of exercise, each p < 0.001, indicating an enhancement of systolic LV performance. No significant correlation was observed between any of the hemodynamic variables and exercise duration. In addition, SBP and DBP decreased significantly (7.4% and 12.2%, respectively, each p < 0.001), resulting in a 20% reduction in calculated TSVR and a 12.4% decline in EAI.
Effect of age on exercise response
The effects of age on the response to PSE between 10 min of exercise and exhaustion are shown in Table 1 and Figures 1 to 3. Whereas Table 1 compares the absolute change in each variable between 10 min and exhaustion, the p value in Figures 1 to 3 is derived from a repeated measures analysis of variance from 10 min through 40 min of exercise. Concordance between these analyses was very high. Because VO2 was held constant between these two points, any associated hemodynamics changes should be minimally influenced by age-associated differences in absolute work rates or VO2. Exercise duration was similar in younger versus older subjects (80.6 ± 27.8 min vs. 71.0 ± 29.3 min, respectively, p = 0.29). Furthermore, VO2 remained unchanged throughout exercise in both groups by study design. As shown in Table 1 and Figure 1, a smaller increase in CI occurred between 10 min and end-exercise in older subjects, mediated by a lesser acceleration of HR. However, SVI increased similarly in both age groups. An age-associated deficit in pump function between these points was manifested by lesser augmentation of EF and CNTR and a smaller reduction of ESVI in older versus younger subjects (Fig. 2). Similar results were obtained when the hemodynamic changes from 10 min to exercise termination were regressed on age as a continuous variable. Specifically, increases in HR (p = 0.09), EF (p = 0.04), and CNTR (p = 0.01), and the decline in ESVI (p = 0.03) between these time points varied inversely with age. Although no significant age group difference in EDVI response was evident between 10 min of exercise and exhaustion (Table 1), repeated measures analysis of variance between 10 min and 40 min revealed consistently larger EDVI in older than younger subjects across these time points (Fig. 2A). These age differences in hemodynamics were not explicable by differences in BP responses or derived indexes of ventricular afterload (Fig. 3), which declined similarly in both groups over time. Between 10 min of exercise and exhaustion and across exercise time points between 10 and 40 min, no gender difference in VO2, a-vO2 difference, or any hemodynamic variable was detected.
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Prior radionuclide evaluations of LV performance during PSE
Few prior studies have employed radionuclide ventriculography to examine LV performance during PSE. Upton et al. (15) measured LV volumes by the first pass technique at 10 and 60 min of a 110-min bout of upright cycle ergometry at 70% of maximal work rate in nine well-conditioned men age 20 to 32 years. Their major findings generally paralleled our own. Cardiac output increased 10% between 10 and 60 min of exercise, due to a 7% increase in HR and a 3% rise in SV. Ejection fraction rose from 79% to 83% between these points, while EDV remained essentially constant. Another ventriculogram obtained at 120 min, after 10 min of near maximal effort, demonstrated a further 21% rise in cardiac output from the 60-min value. However, VO2 was not monitored during exercise, and cardiac function data was not obtained during the final 50 min of submaximal exercise. Furthermore, the youth and excellent conditioning status of their subjects limit the generalizability of these findings to sedentary older individuals and to women. Similarly, in 10 young men, Foster et al. (16) reported that EF during steady-state upright cycling at approximately 75% of VO2max increased from 73% to 79% between 10 and 30 min of exercise, paralleling an 11 beats/min rise in HR. In a subsequent study by these authors using the same exercise protocol, no significant change in EF was observed between these time points in patients with coronary heart disease (17).
Reduced cardiovascular reserve with age during both PSE and graded maximal exercise
The salient finding of the present study was a blunted increase in HR, CI, EF, and SBP/ESVI between 10 min and exercise termination in older versus younger subjects. In addition, EDVI remained higher in older than younger subjects throughout exercise, analogous to the LV response to graded maximal cycle ergometry (1–5). Because no change in exercise intensity occurred in either group between these time points, this age difference in hemodynamic response is not explicable by the higher absolute work rate in younger subjects. It is noteworthy that the same variables demonstrating age-associated deficits during graded maximal exercise, that is, HR, CI, and LV pump performance (1–4), also showed blunted responses to PSE. Because both younger and older groups exercised at an identical percent of their treadmill VO2max by study design, the blunted hemodynamic response in the latter group is not explicable by a lesser relative effort or a saturation of reserve capacity. Given that a similar decline in BP, TSVR, and EAI occurred between 10 min and end-exercise in the two age groups, it is unlikely that the blunted LV emptying in older subjects was secondary to a lesser decline in afterload. Thus, the present study extends the concept of an age-associated reduction in cardiac performance reserve to PSE typical of everyday aerobic activities.
Study limitations
Certain limitations of the present study should be recognized. Exercise in a thermoneutral laboratory setting may not reproduce the hemodynamic effects of prolonged exercise in extreme heat or cold or high humidity. Such extreme conditions may elicit deterioration of SVI, CI, and LV systolic performance not observed in the present study. Although correction for the nonsignificant increase in hematocrit that occurred between rest and exhaustion would slightly attenuate the increases in SVI and CI between these points, calculations of EF would not be affected. Left ventricular afterload was approximated by TSVR and EAI. A better assessment of afterload would be provided by aortic characteristic impedance (18), which did not change significantly during incremental exercise in young beagle dogs but increased markedly in older ones; SV rose progressively in young dogs but increased minimally in older animals (18). If a similar age-associated differential change in impedance occurred during exercise in the present study, this could help to explain the blunted LV systolic emptying in older subjects; however, it would not explain their attenuated cardioacceleratory response. Finally, our failure to monitor plasma catecholamines during exercise does not allow us to determine whether the blunted HR and LV systolic performance in older adults is mediated by a reduced responsiveness to endogenous cathecholamines, as seen during graded maximal aerobic exercise (6), or to an attenuated rise in plasma norepinephrine during PSE, as observed by others (8,9,19,20).
Conclusions
In summary, prolonged submaximal cycle exercise up to 2 h in a thermoneutral environment elicited progressive increases in cardiac performance throughout exercise in healthy volunteers. However, older subjects demonstrated lesser augmentation of HR and systolic LV performance between 10 min and exercise termination than younger ones, analogous to findings during traditional graded maximal exercise protocols.
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