Cardiovascular responses from the onset of exercise to maximal output have been elucidated in detail in patients with a variety of cardiovascular diseases (3,11,17). However, little is known about the cardiovascular responses during recovery from exercise. Rapidity of the recovery of cardiovascular function may be profoundly influenced by the severity of left ventricular dysfunction in patients with cardiovascular disease.
We recently found that the rapidity of the decrease in oxygen uptake during recovery from exercise was associated with exercise capacity in normal subjects and in patients with cardiovascular disease(14). The kinetics of the decrease in oxygen uptake during recovery were slowed in subjects with decreased peak oxygen uptake(14). Because the oxygen uptake is determined by the cardiac output (stroke volume × heart rate) and the arterial-venous oxygen difference, slowed recovery of oxygen uptake may be a reflection of delayed recovery of cardiovascular responses. However, the mechanism of delayed kinetics of oxygen uptake during recovery from exercise has not been clarified.
We investigated the kinetics of oxygen uptake and heart rate during recovery from exercise performed at a moderate, constant work rate by patients with left ventricular dysfunction. Our primary aim was to evaluate the relation between the kinetics of oxygen uptake and the kinetics of heart rate. A secondary aim was to evaluate the influence of resting cardiac function on the kinetics of oxygen uptake and heart rate during recovery in these patients. We hypothesized that the kinetics of oxygen uptake and heart rate during exercise recovery would be slowed, according to the severity of heart disease, in patients with left ventricular dysfunction.
The patient population and the exercise testing protocol have been described in the initial report from this investigation(10). We enrolled 40 consecutive patients with a history of prior myocardial infarction (Table 1). No patient had had a myocardial infarction in the month preceding enrollment in the study. All subjects were sedentary and had not participated in a regular exercise program during the past year. At the time of the study, they were clinically stable and in sinus rhythm. All medications were withheld for at least 24 h before initiation of the study protocol. No patient had received aβ-adrenergic blocking agent during the week before the study. The nature and purpose of the study as well as its risks were explained to the patients. Written informed consent was obtained before their enrollment. The study was approved by the institutional committee on human research.
On the study day before exercise testing, the resting left ventricular ejection fraction was calculated by a radionuclide technique with a cadmium telluride detector (RRG-607, Aloka Co. Ltd., Tokyo, Japan)(8,10,11). To assess the effect of resting cardiac function on the kinetics of heart rate and oxygen uptake during recovery from exercise, subjects were classified into groups based on whether their ejection fractions were ≥ 35% (group 1) or < 35% (group 2).
Exercise protocol. Exercise testing was performed in an upright position on an electromagnetically braked cycle ergometer (Siemens-Elema 930(Siemens Elema AB, Sweden) or WLP-400 (Lode, The Netherlands)). Before the study day, the patients performed a symptom-limited incremental exercise test increased by 1 W every 6 s to determine their gas exchange thresholds using the V-slope method (1,9,13). On the day of the study, after resting for several minutes, patients performed 6 min of constant work-rate exercise followed by a 6-min recovery period. During recovery, patients remained in the upright position on the ergometer without cooling down. The work intensity level corresponded to the work rate obtained at 80% of the patient's gas exchange threshold determined from the symptom-limited incremental exercise test.
Breath-by-breath oxygen uptake was measured throughout the test and 6 min of recovery using a Respiromonitor RM-300 (Minato Medical Science, Osaka, Japan) (10,19). This system consists of a microcomputer, a hot-wire flow meter, and oxygen and carbon dioxide gas analyzers (zirconium element-based oxygen analyzer and infrared carbon dioxide analyzer). The system was carefully calibrated before each study. A 12-lead electrocardiogram was monitored continuously (system ML-8000, Fukuda Denshi Co., Ltd., Tokyo, Japan) and recorded breath-by-breath, simultaneously with the measurement of oxygen uptake, using a personal computer (NEC PC-9801). Cuff blood pressures were obtained every minute with an indirect automatic manometer (STBP-680F, Collin Denshi, Aichi, Japan)(15).
Data analysis. The 6-min (end-exercise) values for heart rate and oxygen uptake during the exercise protocol were defined as the average of values obtained from 330 to 360 s during exercise. The 6-min recovery values were also determined as the average values obtained from 330 to 360 s of the recovery period. A 5-point moving average of the breath-by-breath data was used to evaluate the kinetics of heart rate and oxygen uptake.
The time constant of heart rate kinetics during recovery was determined by fitting a monoexponential function to the heart rate response, using the value at the end of exercise (6 min) as the baseline (Fig. 1) (12,14,20). The general form of this equation can be written as Y(t) = Y(b) +A(e -t/τ - 1), whereY(t) is the heart rate at time t, Y(b) is the heart rate at the end of exercise, A is the amplitude of the response during recovery, and τ is the time constant. A andτ were derived by nonlinear regression analysis using least-squares and iterative techniques (12,14,20) with a BMDP statistical software package (5). The time constant of oxygen uptake kinetics was determined by the same method.
Statistical analysis. Data are presented as the mean ± SD. Between-group differences were analyzed by unpaired t-tests. Linear regression analysis was used to determine the correlations between the ejection fraction and the time constant of oxygen uptake and the time constant of heart rate. Differences were considered statistically significant when theP value was <0.05.
There were no significant differences in age, height, body weight, or peak oxygen uptake between groups (Table 1). Although there were no differences in blood pressures or oxygen uptake between groups, heart rate was consistently higher in group 2 than in group 1(Table 2).
Hemodynamic variables during exercise. There was no significant difference in the intensity of the work rate between groups(Table 2). No patient experienced chest pain during the constant work-rate exercise test. Blood pressures and oxygen uptake at the end of exercise did not differ between groups (Table 2). However, the end-exercise heart rate was significantly higher in group 2 than in group 1.
Kinetics of heart rate and oxygen uptake during recovery from exercise. The time constants of heart rate and oxygen uptake during exercise recovery were prolonged in association with a decreased left ventricular ejection fraction (Fig. 2). There was a significant positive correlation between the time constant of oxygen uptake and the time constant of heart rate (r = 0.38, P = 0.008). The time constants of heart rate and oxygen uptake during exercise recovery were significantly prolonged in group 2 compared with group 1.
Blood pressure during recovery from exercise. Although systolic blood pressure tended to be lower in group 2, there was no significant difference in systolic or diastolic blood pressure during recovery from exercise between groups (Fig. 3).
In the initial report from this investigation (10), we reported that the kinetics of the increase in oxygen uptake and heart rate at the onset of exercise were delayed in patients with lower left ventricular ejection fractions (10). In this report(10), the time constant of oxygen uptake at the onset of exercise was found to be slower in the patients with lower ejection fractions(58.0 ± 7.6 s) compared with those with preserved ejection fractions(45.8 ± 10.5 s, P = 0.0002) despite similar oxygen uptake at the end of exercise. A delay in the kinetics of oxygen uptake at the onset of exercise indicates decreased cumulative oxygen consumption, i.e., greater oxygen deficit. However, if patients with relatively high and relatively low ejection fractions perform exercise at equal levels of intensity, the total energy used during exercise should, theoretically, be the same, irrespective of the difference in cumulative oxygen consumption or the difference in cardiac function. Thus, decreased cumulative oxygen consumption during exercise in patients with left ventricular dysfunction seems to result from the use of stored oxygen in tissues and blood and preformed chemical energy stores in muscle cells and the formation of ATP by nonoxidative metabolism of carbohydrate substrates (4,20,21).
In the present study there was a greater delay in recovery of oxygen uptake in patients with lower left ventricular ejection fractions. These patients showed an increase in the cumulative oxygen consumption, i.e., an increased oxygen requirement during recovery from exercise, because of the delayed decrease in oxygen uptake and the same (or slightly higher) oxygen uptake both at the end of exercise and at 6 min of recovery (Fig. 4). An increased oxygen requirement during recovery probably results from a compensatory mechanism in response to phe excessive use of stored oxygen or preformed chemical energy stores at the onset of exercise, that is, the greater oxygen deficit developed during exercise is repaid during recovery.
Stroke volume during exercise and recovery was likely to have been decreased in patients with lower left ventricular ejection fractions(10,16). Presumably because of the increased oxygen requirement during recovery despite the decreased stroke volume, heart rate was consistently higher, and its kinetics were significantly delayed in these patients.
Heart rate is controlled by both the sympathetic and parasympathetic components of the autonomic nervous system (6). Administration of atropine slows recovery of heart rate after exercise in normal subjects (18). Imai et al. (7) recently reported that the kinetics of heart rate during recovery after exercise were prolonged by parasympathetic blockade but were independent of sympathetic blockade in normal subjects. Therefore, the slowed kinetics of heart rate in patients with lower ejection fractions in the present study may have resulted primarily from their slower vagal reactivation during recovery from exercise. Blood pressure during recovery in group 2 was similar to that in group 1, or even lower, providing further support for this hypothesis. If sympathetic activity had been primarily responsible for the increased heart rate and its delayed kinetics in patients with lower ejection fractions, blood pressure would have been increased in these patients.
The oxygen uptake during recovery from exercise is known to decrease exponentially (2). Thus, we used a single exponential equation to determine not only the kinetics (time constant) of oxygen uptake but also those of heart rate. The large overlap of the time constants for groups 1 and 2 might be partly a result of the relatively low work rate(approximately 40 W). The overlap might also be due to a small difference(10%) in left ventricular ejection fraction between the 2 groups.
In the present study, we found that the kinetics of oxygen uptake and heart rate during exercise recovery were positively correlated and were delayed in patients with lower left ventricular ejection fractions. The increased cumulative oxygen consumption during exercise recovery in patients with lower ejection fractions, which must result from increased oxygen deficit during the onset of exercise, was probably attained primarily by the higher heart rate and its delayed recovery. An increased heart rate and its delayed recovery must generate an additional work load for the diseased heart by increasing myocardial oxygen consumption in these patients. Although the main therapeutic objective in patients with cardiovascular disease has been to increase exercise capacity during daily life activities, shortening the recovery of cardiovascular function after exercise may also be beneficial for improving the quality of life in these patients.
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