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(Circulation. 1999;100:1085-1094.)
© 1999 American Heart Association, Inc.

Clinical Investigation and Reports

Aerobic Exercise Training Can Reverse Age-Related Peripheral Circulatory Changes in Healthy Older Men

Polly A. Beere, MD, PhD; Stuart D. Russell, MD; Miriam C. Morey, PhD; Dalane W. Kitzman, MD; Michael B. Higginbotham, MB

From the Department of Medicine, Divisions of Cardiology and Geriatrics, Center for the Study of Aging and Human Development, Duke University Medical Center and the Geriatric Research, Education, and Clinical Center, Veterans Affairs Medical Center, Durham, NC. Dr Beere is now at Merck, Bluebell, Pa, and Dr Kitzman is at the Bowman Gray School of Medicine, Winston-Salem, NC.

Correspondence to M. Higginbotham, MB, Duke University Medical Center, Box 31219, Durham, NC 27710.

	Abstract

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Background—The age-related decline in maximal oxygen consumption is attenuated by habitual aerobic exercise. However, the relative effects of training on central and peripheral responses to exercise in older subjects are not known. The present study assessed the contribution of central and peripheral responses to the age-associated decline in peak oxygen consumption and compared the effect of exercise training in healthy older and younger subjects.

Methods and Results—Ten older and 13 younger men underwent invasive measurement of central and peripheral cardiovascular responses during an upright, staged cycle exercise test before and after a 3-month period of exercise training with cycle ergometry. At baseline, cardiac output and AV oxygen difference during exercise were significantly lower in older subjects. With training, the older and younger groups increased maximal oxygen consumption by 17.8% and 20.2%, respectively. Peak cardiac output was unchanged in both groups. Systemic AV oxygen difference increased 14.4% in the older group and 14.3% in the younger group and accounted for changes in peak oxygen consumption. Peak leg blood flow increased by 50% in older subjects, whereas the younger group showed no significant change. There was no change in peak leg oxygen extraction in the older group, but in the younger group, leg AV oxygen difference increased by 15.4%.

Conclusions—These findings suggest that the age-related decline in maximal oxygen consumption results from a reversible deconditioning effect on the distribution of cardiac output to exercising muscle and an age-related reduction in cardiac output reserve.

Key Words: aging • blood flow • cardiac output • exercise • physiology

	Introduction

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Adecline in maximal oxygen consumption of 10% per decade after 30 years of age has been observed in studies of healthy populations.^{1 2} This decline is proportional to a decreased cardiac output reserve, peak heart rate, and peak stroke volume in older subjects.^{3 4 5 6} The age-associated decline in maximal oxygen consumption can be attenuated by habitual aerobic exercise, although the mechanism is unclear.^{7 8 9 10 11} Although it has been shown that exercise training can augment both cardiac output and the AV oxygen difference in younger subjects,^{12 13} these components have not been measured in older subjects before and after exercise intervention.

The purpose of the present study was to examine the relative contribution of central and peripheral factors to the age-associated decline in peak oxygen consumption and to determine age-related differences in the response of each to dynamic exercise training.

	Methods

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Study Population
Healthy older male subjects ranging from 60 to 80 years of age were recruited by local advertisement and by letters to potential subjects obtained from the Duke Aging Registry. A healthy control group, 20 to 40 years of age, was recruited by newspaper advertisement.

Before participating in the study, consenting subjects underwent evaluation by physical examination, echocardiography, pulmonary function testing, laboratory studies, and a "screening" cycle exercise test with radionuclide angiography and expired-gas analysis. Abnormalities in any of these studies excluded a subject from further participation.

Ten older subjects 61 to 74 years of age (mean, 66±4.4 years) and 13 younger subjects 21 to 39 years of age (mean, 28±6.7 years) met eligibility criteria and completed the study. The protocol was approved by the Institutional Review Boards of Duke University and Durham Veterans Affairs Medical Centers.

Testing Protocol
Exercise Testing
All exercise testing was conducted in subjects in the postabsorptive state. Subjects were tested on a mechanically braked upright isokinetic cycle ergometer (Fitron, Lumex), starting at 25 W (150 kilopond-meters per minute [kpm]) and advancing 25 W every 3 minutes until maximal effort was reached. Continuous ECG monitoring was performed, and standard 12-lead ECGs were made during the last minute of each workload. During the screening study, cuff blood pressure was measured at each workload.

Radionuclide Angiography
After in vivo labeling of red blood cells with 30 mCi ^99mTc, gated equilibrium radionuclide studies, performed at supine and upright rest and at sequential workloads, were obtained at 40° left anterior oblique with a Searle LEM single-crystal gamma camera with a high-sensitivity 30°-slant-hole collimator interfaced with an A² computer (Medical Data Systems). Ejection fraction was computed from standard computer algorithms. The level of the right atrium was determined from a radioactive point source marked on the subject's chest and recorded for future reference.

Hemodynamic Studies
Subjects returned on another morning to undergo exercise testing with oxygen consumption, hemodynamic, and metabolic measurements. Under fluoroscopic guidance, a 7F thermodilution catheter was introduced through an antecubital vein, and the distal tip was positioned in the proximal pulmonary artery. A 5F thermodilution catheter was introduced through the femoral vein and advanced into the iliac vein to measure leg blood flow. A radiopaque marker was positioned opposite the iliac crest to mark the location of the distal tip of the catheter. A 3-in, 16-gauge catheter was inserted adjacent to this for sampling of femoral venous blood. An 18-gauge arterial catheter was placed in the brachial artery to measure blood pressure and to obtain arterial blood samples. Oxygen content and saturation were measured on a calibrated Instruments Laboratory 282 cooximeter.

After a 30-minute equilibration period, resting measurements were made in the supine and upright positions. Exercise measurements were made during the third minute of each workload by use of an exercise protocol identical to that of the screening study.

Systemic and pulmonary artery pressures were recorded continuously, and a single concurrent ECG lead was measured with Hewlett Packard transducers, amplifiers, and recorders as previously described.¹⁴

With the use of methods developed by Jorfeldt and Wahren¹⁵ and more recently adapted by others,^{14 16} leg blood flow was measured with a thermodilution catheter (model 93 1 105, Edwards Laboratory) positioned as described above and interfaced with a Gould Statham SP 1435 cardiac output computer. Bolus injections of 1 to 5 mL iced or room temperature saline were used to obtain an average of 3 blood flow measurements at rest and during the last 90 seconds of each workload.

Breath-by-breath analysis of expired gases was performed during the invasive hemodynamic studies with a commercially available (Sensormedics) system.¹⁷

Exercise Training
One week after the hemodynamic study, the subject began a "wash-in" period with either an Air-Dyne or a BioDyne cycle (Schwinn), which combines arm and leg exercise. Each exercise period was preceded and followed by 5-minute warm-up and cooldown periods. Exercise intensity was gradually increased over a 2- to 4-week period until the subject could sustain a continuous 30-minute period of exercise at 75% to 85% of maximal heart rate. Once achieved, a 3-month training period was begun, consisting of three 30-minute exercise sessions per week of exercise on an Air-Dyne or BioDyne for 2 days and a cycle ergometer for 1 day. Approximately every 2 weeks, the workload was increased to maintain a training heart rate at 75% to 90% of the maximal range.

Posttraining Evaluation
During the week after the training period, repeated exercise testing with expired-gas analysis, radionuclide angiography, and hemodynamic measurements was performed. This was followed by an invasive hemodynamic exercise study 2 days later. The methods used for these studies were identical to those for the pretraining evaluations.

Statistical Analysis
Group data for each variable at rest and peak exercise are expressed as mean±SD. Between-group comparisons were made with the use of unpaired t tests for resting and peak exercise measurements. Within-group pretraining and posttraining comparisons were made by use of a paired t test. Within-group submaximal exercise pretraining and posttraining comparisons were made with a paired t test at the prespecified workload of 300 kpm in the older group and 450 kpm in the younger group.

	Results

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Baseline Studies
At peak exercise, the younger subjects attained an average of 99% of their maximum age-predicted heart rate; the older subjects reached an average of 93%. The mean peak workload achieved at baseline was 630±198 and 807±115 kpm for the older and younger groups, respectively. All subjects achieved respiratory exchange ratio values >1.15 at peak exercise. Serum lactate at peak exercise was 9.8±2.7 and 12.7±3.1 mmol/L in the older and younger groups, respectively (P=0.03).

Rest and peak hemodynamic and metabolic measurements, the primary determinants of maximal exercise capacity, are shown in Table 1 and Figures 1 and 2. Although oxygen consumption was slightly lower in the older group at rest, other resting measurements were similar. At peak exercise, older subjects had lower oxygen consumption, cardiac output, heart rate, and central AV oxygen difference than the younger group.

View this table: [in this window] [in a new window]   Table 1. Primary Hemodynamic and Metabolic Measurements Before Exercise Training

View larger version (12K): [in this window] [in a new window]   Figure 1. Pretraining oxygen consumption, cardiac output, and systemic leg AV oxygen difference (AVO2) difference at supine rest (SR) and upright rest (UR) and during exercise in younger and older groups. Values are mean±SD. *P<0.05; P<0.01.

View larger version (13K): [in this window] [in a new window]   Figure 2. Pretraining peripheral hemodynamics, including leg blood flow, leg AV oxygen difference (AVO2), and leg oxygen consumption, in younger and older groups at supine rest (SR) and upright rest (UR) and with exercise. P<0.01.

Although leg blood flow was similar at rest, it was lower in the older group at peak exercise. Leg AV oxygen difference was similar in both groups at rest and during exercise. Calculated leg oxygen consumption was 33% lower in the older subjects at peak exercise.

Resting and peak values of secondary hemodynamic measures are shown in Table 2. Mean arterial pressure was slightly higher for the older group at rest but not at peak exercise. Systemic vascular resistance was significantly higher at rest and at peak exercise in the older group. There were no other significant group differences.

View this table: [in this window] [in a new window]   Table 2. Secondary Hemodynamic Measurements Before Exercise Training

Effects of Exercise Training
The older group reached 97% of their maximal predicted heart rate after training compared with 93% before training. In comparison, the younger subjects achieved 99% of their maximal age-predicted heart rate both before and after training.

Primary hemodynamic and metabolic responses to training are shown in Table 3 and Figures 3, 4, and 5. Maximal oxygen consumption increased to a similar degree in both groups, by 17.8% and 20.2% in the older and younger groups, respectively. The increase in peak oxygen consumption with exercise training was accounted for by changes in systemic AV oxygen difference in both groups. The older group showed no training effect on heart rate during submaximal exercise, whereas the younger group did show a trend toward lower heart rate at submaximal workloads. Heart rate at peak exercise was significantly increased in the older group.

View this table: [in this window] [in a new window]   Table 3. Primary Hemodynamic and Metabolic Measurements Before and After Exercise Training

View larger version (26K): [in this window] [in a new window]   Figure 3. Comparison of response to training for oxygen consumption, cardiac output, and systemic AV oxygen (AVO2) difference in older and younger groups. SR indicates supine rest; UR, upright rest. P<0.01; P<0.001.

View larger version (27K): [in this window] [in a new window]   Figure 4. Peripheral hemodynamic response to training in older and younger groups, including leg blood flow, leg AV oxygen (AVO2) difference, and leg oxygen consumption. Abbreviations as in Figure 3. *P<0.05.

View larger version (19K): [in this window] [in a new window]   Figure 5. Relationship of limb blood flow to cardiac output in older group before and after training at supine rest (SR) and upright rest (UR) and with exercise. *P<0.05.

Both submaximal and peak leg blood flow increased in the older group. Peak leg oxygen extraction, reflected by the increase in leg AV oxygen difference, was increased in the younger group but was unchanged in older subjects. Calculated peak leg oxygen consumption increased by 42.0% in the older group and tended to increase (by 31.1%) in the young group. The ratio between leg blood flow and cardiac output was increased with exercise training in the older group (Figure 5).

Secondary hemodynamic measurements are shown in Table 4. Systemic blood pressure did not change in either group at rest. Peak exercise diastolic blood pressure in the younger group was significantly decreased by training. Systemic vascular resistance was not affected by training in either group. Right atrial pressure was increased at peak exercise after training in the older group. Both groups had a significant decrease in resting pulmonary systolic pressures; the older group had posttraining increases in peak pulmonary systolic and mean pulmonary pressures. Mean pulmonary capillary wedge pressure was decreased in the older group at rest. Additionally, there was a significant though modest increase in peak ejection fraction in the older group after exercise training, with no change in the younger group.

View this table: [in this window] [in a new window]   Table 4. Secondary Hemodynamic Measurements After Exercise Training

	Discussion

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Baseline Findings
A number of differences were observed between the responses of men 20 to 40 and 60 to 72 years of age in upright rest and dynamic exercise. Lower peak oxygen consumption in the older group resulted from lower peak cardiac output and, to a lesser extent, AV oxygen difference. The lower peak cardiac output was associated with a lower peak heart rate, without a significant age-related difference in stroke volume. Notably, there was no evidence of a compensatory increase in stroke volume to augment cardiac output in the presence of the lower heart rate. These results are consistent with previous findings in our laboratory and others, which have correlated the age-related decline in peak oxygen consumption with a lower cardiac output reserve.^{4 5 6 18} The higher pulmonary capillary wedge pressure at submaximal and peak exercise in the older group supports a relative inability to use the Frank-Starling mechanism to augment stroke volume in older subjects.

In addition to differences in the central component of the cardiovascular response to exercise, the older subjects also had a lower peak central AV oxygen difference. In the only previous exercise study in which the AV oxygen difference was directly measured, we found no age-related differences; however, that study included only subjects who were <50 years of age and exercised regularly.³ Although other investigators have inferred an age-related difference in the peripheral circulatory response to exercise, they have used an estimated systemic AV oxygen difference that was based on oxygen consumption and measured or derived cardiac output.^{6 9 19 20 21}

The lower peak systemic AV oxygen difference in the older subjects appears to result from a less efficient redistribution of blood flow to the exercising limbs rather than a deficiency in peripheral oxygen extraction. There was a trend toward a lower ratio of limb blood flow to cardiac output in the older subjects. Furthermore, the femoral venous oxygen content was as low as that seen in the younger subjects, and hemoglobin concentration was not significantly different. Our study is consistent with that of Wahren et al,²² who demonstrated that leg blood flow was diminished in an older healthy group of men at higher levels of exercise.

Although the precise mechanisms underlying the observed age-related differences in central and peripheral exercise responses could not be ascertained with certainty from this study, a decrease in adrenergic responsiveness is a possible explanation. Diminished adrenergic responsiveness in older subjects may also be responsible for the smaller increases in heart rate and blood pressure, limited ability of stroke volume to compensate for the lower exercise heart rate, and relatively inefficient distribution of cardiac output during exercise.

It is also possible that noncirculatory peripheral factors may contribute to the age-related decline in maximal oxygen consumption. During aging, muscle mass decreases, there is a change in the ratio of type I to type II fibers, and oxidative enzyme activity is reduced²³ ; many of these changes are similar to those of deconditioning.²⁴ However, our finding that regional limb blood flow rather than oxygen extraction accounted for the age-related differences in oxygen uptake suggests that, at least in our study population, the circulation was more important than skeletal muscle in this regard.

Exercise Training
With training, both age groups increased peak oxygen consumption to an extent similar to that observed in other studies of comparable duration, methods, and intensity.^{9 11 12 25 26} This study showed that younger subjects increased their peak oxygen consumption primarily by increasing their leg oxygen extraction. There was a trend toward higher leg blood flow at peak exercise, but this was not statistically significant. Cardiac output at peak exercise was unchanged.

In contrast, the older subjects increased their peak oxygen consumption by a redistribution of cardiac output to the exercising limbs, resulting in a proportional increase in systemic AV oxygen difference without a change in peripheral oxygen extraction. The increase in leg blood flow in the older group was observed at both submaximal and peak workloads and resulted in values that were nearly identical to those seen in the younger group at baseline.

Ejection fraction also increased after training in the older group, similar to the finding of Ehsani and colleagues,²⁶ and is supportive of an increase in contractile reserve. However, the relationship between stroke volume and pulmonary capillary wedge pressure did not change, suggesting no significant effect of exercise training on the ability to use the Frank-Starling mechanism.

Previous reports on the effect of training on cardiac output reserve have varied. Consistent with our findings, Seals et al²⁷ failed to demonstrate an increase in maximal cardiac output despite effective exercise training in subjects averaging 63 years of age. This contrasts with the findings of several previous longitudinal studies in young^{6 13 28 29} and old^{6 29} subjects. Differences in selection and screening of normal subjects, training methods, and measurement techniques offer plausible explanations for these discrepancies.

Our findings suggest that some but not all of the age-related differences observed in the baseline comparisons were reversed by training. Both adaptations to exercise training observed in this study, namely enhanced oxygen extraction in the younger group and greater leg blood flow in the older group, represent peripheral changes and have been shown previously.³⁰ Other studies in which the effects of exercise training on systemic AV oxygen difference were addressed have been inconsistent.^{9 12 19 22 31}

We suspect that the change in blood flow in the older group was most likely due to an alteration in the relationship between regional vasodilator and vasoconstrictor mechanisms. Although improved adrenergic responsiveness is a conceivable mechanism by which exercise training may change this balance, a study by Stratton et al³² did not find any training effect on the response to graded isoproterenol infusion in young or old subjects.

Study Limitations
In contrast to some published studies, our older subjects increased their peak heart rate after exercise training. This may represent a greater tolerance of strenuous effort on the bicycle ergometer after habituation with intense exercise training. However, the high pretraining and posttraining measurements of the respiratory exchange ratio and blood lactate levels and the low leg oxygen contents of the older group suggest that there were no differences in effort between the 2 groups. Furthermore, changes in maximal leg blood flow and systemic AV oxygen difference were accompanied by submaximal changes that could not have resulted from a difference in effort.

Although this study demonstrates differences between old and young subjects and a specific change after exercise training, we may have overlooked other factors that can change with exercise training of a different type, duration, or intensity.

Conclusions
Our findings suggest that the decline in maximal oxygen consumption in older subjects results from a deconditioning effect on the distribution of cardiac output to exercising muscle and an age-related reduction in cardiac output reserve.

	Acknowledgments

 
This study was supported in part by NHLBI grant HL-17670 from the NIH and by Claude D. Pepper GRTC grant 5P30AG09463 and OAIC grant 1P60AG11268 from the NIH/NIA, Bethesda, Md. Dr Beere was supported by NIH NRSA grant 2T32-HL-07101. We are grateful to Patrick Shaw, NMT, Barbara Kuzil, RN, and Roger Page, PAC, for assistance with exercise testing; the staff of GEROFIT at the Durham VA Medical Center for sharing their facilities and assisting with exercise training; and the Duke University Aging Registry for use of their listings.

Received October 29, 1998; revision received June 4, 1999; accepted June 16, 1999.

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