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Oxygen pulse during exercise is related to resting systolic and diastolic left ventricular function in older persons with mild hypertension
Oxygen pulse during exercise is related to resting systolic and diastolic left ventricular function in older persons with mild hypertension Jimmy G. Lim, MD, Timothy J. McAveney, MD, Jerome L. Fleg, MD, Edward P. Shapiro, MD, Katherine L. Turner, MS, Anita C. Bacher, MSN, MPH, Pamela Ouyang, MD, and Kerry J. Stewart, EdD Baltimore, Md
Background The mechanisms responsible for impaired cardiovascular hemodynamics during exercise among persons with milder forms of hypertension are not well documented. We examined the relationship of oxygen pulse during exercise, a correlate of stroke volume, with echocardiographic indices of resting left ventricular function to determine whether abnormal contractility and relaxation are related to abnormal cardiovascular dynamics during exercise among such persons. Methods Subjects were 44 men and 55 women ages 55 to 75 years with mild hypertension but who were otherwise healthy. Resting left ventricular systolic and diastolic functions were assessed with 2-dimensional Doppler echocardiography and tissue Doppler imaging. Oxygen pulse (millimeters per beat) at rest and during multistage treadmill testing was derived from measurements of oxygen consumption and heart rate. The slope of oxygen pulse between successive exercise stages was calculated. Results
After a steep rise in oxygen pulse from rest to stage 1 of exercise, a markedly diminished oxygen pulse slope was seen between subsequent exercise stages. In stepwise regression analysis, the increase in the slope of oxygen pulse from rest to stage 1 was explained by a greater lean body mass (57%, P b .001) and a larger left atrial size (2%, P b .001). After exercise stage 1, the increase in the slope of oxygen pulse was explained by sex (24%, P b .001), higher mitral E/A ratio (6%, P b .001), and higher mitral annular systolic velocity (6%, P b .001).
Conclusions
These results suggest that a blunted oxygen pulse response to exercise among older persons with milder forms of hypertension may reflect impaired left ventricular stroke volume changes during exercise secondary to subtle abnormalities in both systolic and diastolic left ventricular functions. (Am Heart J 2005;150:941 - 6.)
Hypertension affects approximately 50 million individuals in the United States. It is estimated that 90% of middle-aged individuals will develop hypertension in their lifetime.1 Hypertension is associated with adverse changes in left ventricular geometry and myocardial tissue composition,2 and abnormal systolic and diastolic functions. Aging is also associated with abnormalities in cardiovascular structure and function, including delayed early diastolic filling,3 decreased chronotropic response to catecholamines,4 and increased vascular stiffness with abnormal ventricular-vascular coupling.5 The combinaFrom the Division of Cardiology, Department of Medicine, Johns Hopkins Bayview Medical Center, Johns Hopkins University, School of Medicine, Baltimore, Md. This study was supported by a grant from the National Institutes of Health, R01HL59164 (K.J.S.) and the Johns Hopkins Bayview General Clinical Research Center (M01-RR-02719). Submitted February 23, 2004; accepted December 12, 2004. Reprint requests: Kerry J. Stewart, EdD, Johns Hopkins Bayview Medical Center, 4940 Eastern Avenue, Baltimore, MD 21224. E-mail: [email protected] 0002-8703/$ - see front matter n 2005, Mosby, Inc. All rights reserved. doi:10.1016/j.ahj.2004.12.021
tion of hypertension and aging can lead to abnormal cardiovascular responses to exercise. Whereas abnormalities in resting left ventricular diastolic function have been shown to adversely affect the cardiovascular response to exercise, less is known about these relationships in persons with milder forms of hypertension.6 -10 The relationship of resting systolic function to cardiovascular hemodynamics during exercise also remains controversial. This may be caused by the use of left ventricular ejection fraction, a relatively insensitive index of myocardial contractility, for this purpose.11,12 Tissue Doppler imaging of the mitral annulus has been shown to be complementary to conventional echocardiographic measures in assessing both systolic and diastolic functional abnormalities among persons with hypertension.13 -17 This methodology may also be able to detect early systolic abnormalities even among persons with normal left ventricular ejection fraction.18 Oxygen pulse, which normalizes oxygen consumption for heart rate, has been used as a surrogate for changes in stroke volume during exercise19 -21 and correlates with stroke volume obtained by multigated radionuclide testing.19 -22 Its value as a marker of cardiac performance
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942 Lim et al
Figure 1
Table I. Baseline characteristics
Oxygen Pulse (mlO2/beat)
18
Variable
14
10 Pattern A 6
Pattern B
2 Pre
1
2
3
4
5
Exercise Stages
White (%) Age (y) Body mass index (kg/m2) Lean body mass (kg) Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Pulse pressure (mm Hg) Mean arterial pressure (mm Hg) Percentage with BP V139 (prehypertension) Resting heart rate (beat/min)
Men (N = 44)
Women (N = 55)
P
91 62.7 F 5.8 29.3 F 3.3
84 64.8 F 5.6 29.6 F 5.0
.25 .08 .70
58.9 F 7.3
38.9 F 4.4
b.01
140 F 8
140 F 8
.99
81 F 6
73 F 8
b.01
60 F 7 101 F 6
67 F 9 96 F 7
b.01 b.01
53%
43%
.35
71 F 8
72 F 9
.60
Changes in oxygen pulse across exercise treadmill stages.
is supported by studies which have demonstrated impairment in oxygen pulse among patients with ischemic heart disease,22,23 mitral valve disease,24 and congestive heart failure.25 This study examined the relationship of echocardiographic and tissue Doppler-derived parameters of resting left ventricular systolic and diastolic function with oxygen pulse response to exercise among older persons with milder forms of hypertension. We hypothesized that tissue Doppler indices of left ventricular function would be more likely to demonstrate such a relationship than conventional echocardiographic measurements.
Methods Subjects Previously sedentary men and women, aged 55 to 75 years, with untreated forms of mild hypertension but who were otherwise healthy were recruited from the community for a study of exercise training. Exclusions were diabetes mellitus (fasting serum glucose N126 mg/dL), a history of smoking in the past 6 months, ischemic heart disease, congestive heart failure, and regular aerobic exercise more than 3 metabolic equivalents for 90 minutes per week.26 A screening exercise test also excluded subjects with exercise-induced ischemic electrocardiographic (ECG) changes (horizontal or downsloping ST-segment depression N1 mm), complex arrhythmias, or ischemic symptoms.
Blood pressure eligibility Participants not using antihypertensive medication entered blood pressure screening without delay. With their physician approval, participants using a single antihypertensive medication entered blood pressure screening 2 weeks after stopping the medication. To be eligible for this study, participants were required to have systolic blood pressure between 130 and
159 mm Hg and/or diastolic blood pressure between 85 and 99 mm Hg during 2 consecutive weekly visits and an average blood pressure in this range over 4 weekly visits. These levels correspond to prehypertension to stage 1 hypertension by the Joint National Committee for Detection, Evaluation, and Treatment of High Blood Pressure 7 guidelines. Informed consent was obtained from all subjects, and the protocol was approved by the Johns Hopkins School of Medicine institutional review board.
Echocardiographic measurements Standard echocardiographic views were obtained in the left lateral decubitus position using an Agilent Technologies Sonos 5500 or Hewlett-Packard Sonos 2500 system. Measurements were made off-line with a Microsonics Image-Vue analysis system or a Philips viewpoint system. Two-dimensional, M mode, and Doppler examinations were performed with a 2.5-MHz transducer. Left ventricular internal dimension and ventricular septal thickness were each measured at end systole and end diastole in accordance with established guidelines.27 Transmitral Doppler flows were recorded at the leaflet tips. Tracings for isovolumic relaxation time (IVRT) were recorded using continuous wave Doppler, and IVRT was measured as the interval between the aortic valve closure click and the onset of transmitral flow. Tissue Doppler imaging of the mitral annulus was obtained from the apical 4-chamber view. A fixed 5-mm sample volume was placed at the lateral aspect of the mitral annulus. Measurements were taken of the peak systolic myocardial velocity (Sm), and early (Em) and late (Am) diastolic velocity. Three measurements were made for each parameter and averaged. Left ventricular mass was calculated from end-diastolic left ventricular dimensions and wall thickness according to the Devereux formula,28 and it was indexed to body surface area (g/m2). Relative wall thickness was defined as twice the posterior wall thickness divided by the left ventricular internal radius, both measured in end diastole. Ejection fraction was determined by the method of Quinones and Reduto.29
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Lim et al 943
Table II. Resting echocardiographic measurements Variable
Men
Women
Table III. Cardiopulmonary exercise tests results by sex P value Variable
Peak E velocity (cm/s) Peak A velocity (cm/s) E/A ratio Deceleration time (ms) IVRT (ms) VSd (cm) LVId (cm) RWT LA (cm) LVMI (g/m2) LVEF (%) Sm (cm/s) Em (cm/s) Am (cm/s) Em/Am ratio
71 F 12 78 F 14 0.93 F 0.21 227 F 56 91 F 16 1.09 F 0.11 4.76 F 0.42 0.46 F 0.06 3.92 F 0.46 103.6 F 18.8 53 F 8 10.8 F 2.7 11.0 F 2.0 13.3 F 2.9 0.85 F 0.19
78 F 12 87 F 16 0.91 F 0.17 215 F 38 92 F 14 1.01 F 0.11 4.39 F 0.34 0.46 F 0.07 3.60 F 0.42 93.3 F 17 56 F 8 9.2 F 2.0 10.0 F 2.2 13.4 F 3.1 0.79 F0.25
b.01 b.01 .66 .21 .78 b.01 b.01 .91 b.01 b.01 .02 b.01 .02 .86 .16
Values are mean values F SD. VSd, Ventricular septum thickness measured in diastole; LVId, left ventricular internal dimension in diastole; RWT, relative wall thickness; LA, left atrial size; LVEF, left ventricular ejection fraction; LVMI, left ventricular mass index; Em, peak mitral annular early diastolic velocity; Am, peak mitral annular late diastolic velocity during atrial contraction; Sm, peak mitral annular systolic velocity.
Preexercise V˙o2 (mL/min/kg) Preexercise O2P (mL/beat) Peak V˙o2 (mL/min/kg) Peak O2P (mL/beat) RER at peak Time on treadmill (s) Max HR (beat/min) Max SBP (mm Hg) Max DBP (mm Hg) DO2P initial (mL/beat/stage) DO2P continued exercise (mL/beat/stage)
Men (N = 44)
Women (N = 55)
P value
3.8 F 0.9
3.4 F 0.8
.02
4.5 F 1.3
3.2 F 1.0
b.01
27.9 F 4.5
20.8 F 3.1
b.01
15.5 1.11 989 166 230 98 7.7
9.7 1.12 670 163 216 97 4.9
b.01 .44 b.01 .18 b.01 .59 b.01
F F F F F F F
2.6 0.06 216 13 19 9 2.0
0.56 F 0.1
F F F F F F F
2.1 0.08 187 12 17 14 1.7
0.24 F 0.1
b.01
Values are mean values F SD. O 2 P, Oxygen pulse; SBP, systolic blood pressure; DBP, diastolic blood pressure; PP, pulse pressure; HR, heart rate; RER, respiratory exchange ratio; DO 2 P initial, oxygen pulse at the end of stage 1 preexercise oxygen pulse; DO 2 P continued exercise, (max oxygen pulse stage 1 oxygen pulse)/number of stages.
Anthropometric measures Weight was measured with minimal clothing on a calibrated digital scale, and height was measured on a stadiometer. Body mass index was calculated as weight in kilograms divided by the square of the height in meters. Lean body mass was measured by dual energy x-ray absorptiometry performed on a General Electric Lunar Prodigy system (GE medical systems, Fairfield, Conn).
Exercise testing Exercise was performed on a treadmill integrated with a SensorMedics Vmax229 Metabolic and ECG system (SensorMedics, Inc, Yorba Linda, Calif). Subjects performed a modified Balke protocol, beginning at 3 mph with 0% grade and increasing 2.5% grade every 3 minutes until maximal volitional fatigue was reached. A 12-lead ECG was monitored continuously. Exercise blood pressure was measured during the last 30 seconds of each stage using a mercury column sphygmomanometer according to the guidelines of the American College of Sports Medicine.30 Exercise systolic blood pressure was measured at phase I of the Korotkoff sounds, and diastolic blood pressure was measured between phases IV and V. As needed, the subjects rested their hand on the examiner’s shoulder to minimize movement artifact. The Rating of Perceived Exertion using the Borg 6-to-20 scale31 was obtained during each stage, and a rating z18 was an indicator of maximal effort. The breath-by-breath signals during exercise testing were integrated to yield 10-second averages of oxygen consumption ˙o2 (mL/kg/min), respiratory exchange ratio, heart rate, and V ˙o2/heart rate expressed as mL O2/beat). Oxygen oxygen pulse (V pulse plots were generated by using the mean oxygen pulse values during the last 30 seconds of each stage versus exercise stage. Figure 1 shows the overall patterns in the oxygen pulse response during exercise. After an initial sharp rise at the start of exercise, there is a less steep rise in oxygen pulse during continued exercise. Two patterns of the oxygen pulse responses
to exercise that are often seen are labeled as patterns A and B. In pattern A, after an initial rise of oxygen pulse during the first stage of exercise, there is a continued increase in oxygen pulse with each successive stage. In pattern B, after an initial rise during the first stage of exercise, there is a plateau or markedly diminished rise in oxygen pulse with continued exercise. The slope of oxygen pulse during initial exercise and continued exercise was analyzed separately. The slope of oxygen pulse during initial exercise was calculated by subtracting the oxygen pulse at the end of stage 1 from preexercise standing oxygen pulse (mL O2/beat). The slope of oxygen pulse during continued exercise was the difference between oxygen pulse obtained at the last stage of exercise and oxygen pulse at the end of stage 1 divided by the number of exercise stages (mL O2/beat/stage).
Statistical analysis Data are expressed as the mean value F SD. Because of potential sex differences in left ventricular structure and exercise capacity, these relationships were also examined by sex, and comparisons were made with Student t tests. Stepwise regression was used to determine the independent contribution of each parameter that showed a significant bivariate correla˙o2, or exercise oxygen tion with peak oxygen pulse, peak V pulse responses for early and continued exercise separately. Sm velocity was skewed and was normalized with a logarithmic transformation. No other variables required transformation. The 2-tailed level of statistical significance was set at P b .05. All statistical analyses were done using JMP 5.0 (SAS, Cary, NC).
Results Forty-four men and 55 women were studied. Their baseline characteristics (Table I) were similar except for a lower lean body mass, a lower resting diastolic blood
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944 Lim et al
Table IV. Bivariate correlations between demographic and echocardiographic variables and cardiopulmonary exercise test results
Peak V˙o2 Peak O2P Slope O2P initial Slope O2P continued exercise
Age
Sex (male)
LBM (kg)
LA size (cm)
LVId (cm)
E/A ratio
Sm (cm/s)
Em (cm/s)
MAP (mm Hg)
DBP (mm Hg)
EF (%)
0.18 0.25y 0.15 0.14
0.69T 0.78T 0.61T 0.47T
0.56T 0.86T 0.75T 0.43T
0.15 0.57T 0.55T 0.17
0.29T 0.55T 0.52T 0.12
0.18 0.10 0.03 0.27T
0.27 T 0.37 T 0.19 0.36T
0.22y 0.29T 0.19 0.16
0.21y 0.32T 0.23y 0.23y
0.33T 0.42T 0.28T 0.33T
0.00 0.08 0.09 0.09
LBM, Lean body mass; LA, left atrium; Sm, tissue Dopple imaging-derived peak systolic velocity; Em, tissue Dopple imaging-derived peak diastolic velocity; MAP, mean arterial pressure; EF, ejection fraction. TP b .01. yPb .05.
pressure, a lower mean arterial pressure, and a larger pulse pressure among the women compared with the men (all P b .01). Fifty-three percent of our male patients and 43% of our female patients would be classified as having prehypertension. Baseline echocardiographic variables are shown in Table II. All subjects had a normal left ventricular ejection fraction, defined as N45%. Left atrial size, left ventricular dimensions, ventricular septal thickness, and left ventricular mass index were smaller among women than in men (all P b .01). Women had a lower Em velocity ( P = .02) and a lower Sm velocity ( P b .01) despite having a higher ejection fraction than the men ( P = .02). Women had a higher mitral peak E and peak A velocity than men (both P b .01), but the E/A ratio was similar. Men exercised longer on the treadmill and had higher ˙o2, peak oxygen pulse, and maximal systolic peak V blood pressure than the women (all P b .01) (Table III). Men also had greater increases in oxygen pulse during initial exercise and with continued exercise (each P b .01). The mean peak V˙o2 achieved for both sexes was within the predicted range for sedentary individuals in this age range.32 Table IV shows bivariate correlations of baseline demographics and resting echocardiographic variables with exercise test parameters. Left ventricular mass index and body mass index did not correlate with any of the exercise parameters (data not shown). The slope of oxygen pulse during continued exercise correlated with Sm velocity (R = 0.36, P b .01) but not with ejection fraction (R = 0.09, P = NS). There was no change in the relationships found when subjects with prehypertension or grade I hypertension were analyzed separately (analysis not shown). In stepwise regression models, male sex was the ˙o2, explaining 47% of only predictor of a higher peak V the variance. A higher peak oxygen pulse was predicted by higher lean body mass, which accounted for 74% of the variance, with an additional 2% explained by larger left atrial size and 2% by male sex. A higher initial slope of oxygen pulse correlated with higher lean body mass, which explained 57% of the variance, with an additional 2% explained by larger left
atrial size. With continued exercise, a higher slope of oxygen pulse correlated with male sex, which accounted for 24% of the variance, and a higher mitral E/A ratio and higher Sm velocity each explaining an additional 6% of the variance.
Discussion The novel finding of our study is the association of both systolic and diastolic function with the slope of oxygen pulse during exercise. Specifically, a lower resting mitral E/A ratio, a reflection of impaired diastolic function, and a lower Sm velocity, an indicator of reduced long-axis contractility, were associated with an attenuated rise in oxygen pulse after the first stage of exercise. Such an attenuated oxygen pulse slope over time suggests an impaired stroke volume response during sustained exercise. The normal increase in the slope of oxygen pulse later in exercise reflects an augmentation of stroke volume to meet the need for more cardiac output and consequently represents a greater demand on the left ventricle. This could explain why echocardiographic signs of early systolic or diastolic dysfunction were associated with an attenuated slope in oxygen pulse later in exercise, rather than in early exercise, when the demand for cardiac output is lower. Left ventricular diastolic filling during exercise plays an important role in determining exercise tolerance.33 - 35 Our finding that a lower mitral E/A ratio was associated with a diminished oxygen pulse slope is in agreement with previous studies among patients with moderate to severe hypertension.6-10 Among our older subjects with milder forms of hypertension, exercise testing may be revealing subtle abnormalities in diastolic functional reserve. Impaired resting left ventricular systolic function may be associated with impaired contractile reserve, leading to reduced left ventricular contractility despite increasing catecholamine levels during exercise. Increased afterload from increased systolic blood pressure during exercise36 may further reduce left ventricular performance. Hence, subjects with
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impaired resting left ventricular function may be expected to have some degree of stroke volume impairment during exercise. We found that decreased long-axis systolic function, but not ejection fraction, was associated with a decreased oxygen pulse slope during continued exercise. The lack of a correlation between ejection fraction and changes in oxygen pulse could be explained by the fact that ejection fraction reflects geometric left ventricular chamber function rather than actual myocardial function.11 The assessment of long-axis function may be a more sensitive early marker of left ventricular systolic dysfunction as demonstrated in a variety of conditions such as mitral regurgitation,37 cardiac amyloidosis,38 diabetes,39 and hypertension.40 We found that an attenuated rise of oxygen pulse during exercise was associated with lower long-axis resting systolic function, although the ejection fraction was normal. Thus, even subtle changes in myocardial contractility at rest may compromise the ability of the left ventricle to eject against rising pressure as seen with continued exercise. Kim et al41 found that whereas resting diastolic velocity by tissue Doppler was predictive of exercise time, systolic velocity at rest was not. That study may be limited by their measurement of exercise time only rather than cardiorespiratory responses to exercise. To our knowledge, our findings are the first to show a relationship between reduced left ventricular systolic function at rest and impaired cardiorespiratory response during exercise. As expected, men had higher values for oxygen pulse ˙o2max than women, which is likely caused by men and V ˙o2 extraction.9 having a greater stroke volume and AV Despite these differences, the relationships of systolic and diastolic function with the oxygen pulse response during exercise did not differ by sex.
Limitations The narrow age range, sedentary lifestyle, and similarities in baseline demographics among our subjects would serve to mask correlations among variables. For example, no indices of left ventricular function were ˙o2, which may be in independent predictors of peak V part caused by the narrow range of values for these measures. Despite these limitations, we found relationships between resting left ventricular function and the slope of oxygen pulse during exercise. The relative contribution of left ventricular function in cardiorespiratory response during exercise may be greater among older persons. The rise in cardiac output during exercise results from an increase in both stroke volume and heart rate. Among younger sedentary individuals, stroke volume typically peaks at approxi˙o2, and any further rise in cardiac mately 40% of peak V output is mainly attributable to increases in heart rate.42,43 Normal aging is associated with an attenuated heart rate response during exercise; therefore, the
Lim et al 945
relative contribution of stroke volume to cardiac output during exercise increases as individuals get older.44,45 Therefore, our findings may not apply to younger persons. Further studies to confirm these results should be done in populations with broader ranges in age, blood pressure, and left ventricular function. The response of oxygen pulse to exercise is also influ˙o2 extraction and not merely to enced by differences in AV stroke volume changes. Although we did not measure cardiac output and stroke volume directly, we found no correlation between changes in oxygen pulse during the later stages of exercise with lean body mass, a parameter ˙o2 extraction. Hence, the that should influence AV correlation between measures of left ventricular function and the slope of oxygen pulse would suggest that these associations are likely caused by the stroke volume ˙o2 changes during exercise. changes rather than AV We excluded patients during screening if they had a positive exercise test to rule out clinical ischemic heart disease. However, it remains possible that our subjects may have subclinical cardiac ischemia that could result in an abnormal oxygen pulse response during exercise.
Conclusion A lower tissue Doppler-derived resting long-axis systolic (Sm) velocity was associated with an attenuation of the oxygen pulse response to exercise, suggesting impaired exercise stroke volume. Reduced echocardiography-derived early left ventricular filling was also associated with attenuated oxygen pulse slope during exercise. Thus, early abnormalities in both systolic and diastolic left ventricular function may adversely affect cardiopulmonary response to exercise among older adults with milder forms of hypertension.
References 1. Vasan RS, Beiser A, Seshadri S, et al. Residual lifetime risk for developing hypertension in middle-aged women and men: the Framingham Heart Study. JAMA 2002;287:1003 - 10. 2. Motz W, Scheler S, Schwartzkopff B, et al. Evaluation of cardiac damage in hypertension. J Cardiovasc Risk 1995;2:16 - 26. 3. Lakatta EG, Gerstenblith G, Angell CS, et al. Prolonged contraction duration in aged myocardium. J Clin Invest 1975;55:61 - 8. 4. Lakatta EG, Gerstenblith G, Angell CS, et al. Diminished inotropic response of aged myocardium to catecholamines. Circ Res 1975;36: 262 - 9. 5. Najjar SS, Schulman SP, Gerstenblith G, et al. Age and gender affect ventricular-vascular coupling during aerobic exercise. J Am Coll Cardiol 2004;44:611 - 7. 6. Olsen MH, Wachtell K, Hermann KL, et al. Maximal exercise capacity is related to cardiovascular structure in patients with longstanding hypertension. A LIFE substudy. Losartan intervention for endpointreduction in hypertension. Am J Hypertens 2001;14:1205 - 10. 7. Goodman JM, McLaughlin PR, Plyley MJ, et al. Impaired cardiopulmonary response to exercise in moderate hypertension. Can J Cardiol 1992;8:363 - 71.
946 Lim et al
8. Modesti PA, Olivo G, Carrabba N, et al. Early impairment of the cardiopulmonary exercise capacity of hypertensive patients. Int J Cardiol 1994;44:163 - 9. 9. Reybrouck T, Fagard R. Gender differences in the oxygen transport system during maximal exercise in hypertensive subjects. Chest 1999; 115:788 - 92. 10. Missault L, Duprez D, de Buyzere M, et al. Decreased exercise capacity in mild essential hypertension: non-invasive indicators of limiting factors. J Hum Hypertens 1992;6:151 - 5. 11. Aurigemma GP, Silver KH, Priest MA, et al. Geometric changes allow normal ejection fraction despite depressed myocardial shortening in hypertensive left ventricular hypertrophy. J Am Coll Cardiol 1995;26:195 - 202. 12. Bing OH, Matsushita S, Fanburg BL, et al. Mechanical properties of rat cardiac muscle during experimental hypertrophy. Circ Res 1971; 28:234 - 45. 13. Oki T, Tabata T, Yamada H, et al. Left ventricular diastolic properties of hypertensive patients measured by pulsed tissue Doppler imaging. J Am Soc Echocardiogr 1998;11:1106 - 12. 14. Pai RG, Gill KS. Amplitudes, durations, and timings of apically directed left ventricular myocardial velocities: II. Systolic and diastolic asynchrony in patients with left ventricular hypertrophy. J Am Soc Echocardiogr 1998;11:112 - 8. 15. Naqvi TZ, Neyman G, Broyde A, et al. Comparison of myocardial tissue Doppler with transmitral flow Doppler in left ventricular hypertrophy. J Am Soc Echocardiogr 2001;14:1153 - 60. 16. Rodriguez L, Garcia M, Ares M, et al. Assessment of mitral annular dynamics during diastole by Doppler tissue imaging: Comparison with mitral Doppler inflow in subjects without heart disease and in patients with left ventricular hypertrophy. Am Heart J 1996;131: 982 - 7. 17. Pela G, Bruschi G, Cavatorta A, et al. Doppler tissue echocardiography: myocardial wall motion velocities in essential hypertension. Eur J Echocardiogr 2001;2:108 - 17. 18. Yu CM, Lin H, Yang H, et al. Progression of systolic abnormalities in patients with bisolatedQ diastolic heart failure and diastolic dysfunction. Circulation 2002;105:1195 - 201. 19. Whipp BJ, Higgenbotham MB, Cobb FC. Estimating exercise stroke volume from asymptotic oxygen pulse in humans. J Appl Physiol 1996;81:2674 - 9. 20. Jones S, Elliott PM, Sharma S, et al. Cardiopulmonary responses to exercise in patients with hypertrophic cardiomyopathy. Heart 1998; 80:60 - 7. 21. Hsi WL, Wong PL, Lai JS. Submaximal oxygen pulse divided by body weight during incremental exercise test. Am J Phys Med Rehabil 1997;76:297 - 303. 22. Klainman E, Fink G, Lebzelter J, et al. The relationship between left ventricular function assessed by multigated radionuclide test and cardiopulmonary exercise test in patients with ischemic heart disease. Chest 2002;121:841 - 5. 23. Klainman E, Fink G, Lebzelter J, et al. Assessment of functional results after percutaneous transluminal coronary angioplasty by cardiopulmonary exercise test. Cardiology 1998;89:257 - 62. 24. Nery LE, Wasserman K, French W, et al. Contrasting cardiovascular and respiratory responses to exercise in mitral valve and chronic obstructive pulmonary diseases. Chest 1983;83:446 - 53. 25. Wait J. Cardiopulmonary stress testing. A review of noninvasive approaches. Chest 1986;90:504 - 10. 26. Pate RR, Pratt M, Blair SN, et al. Physical activity and public health. A recommendation from the Centers for Disease Control and Prevention and the American College of Sports Medicine. JAMA 1995;273:402 - 7.
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27. Schiller NB, Shah PM, Crawford M, et al. Recommendations for quantitation of the left ventricle by two-dimensional echocardiography. American Society of Echocardiography Committee on Standards, subcommittee on quantitation of two-dimensional echocardiograms. J Am Soc Echocardiogr 1989;2:358 - 67. 28. Devereux RB, Alonso DR, Lutas EM, et al. Echocardiographic assessment of left ventricular hypertrophy: comparison to necropsy findings. Am J Cardiol 1986;57:450 - 8. 29. Quinones MAWA, Reduto LA. A new, simplified and accurate method for determining ejection fraction with two-dimensional echocardiography. Circulation 1981;64:744 - 53. 30. ACSM’s guidelines for exercise testing and prescription. Franklin B, Whaley MH, Howley ET, editors. 6th ed. Baltimore: Lippincott Williams and Wilkins; 2000. 31. Borg G. Simple ratings for estimation of perceived exertion. Physical work and effort. New York (NY): Pergamon Press; 39 - 46. 32. Wasserman K, Hansen JE, Sue DY, et al. Principles of exercise testing and interpretation. 3rd ed. Baltimore: Lippincott Williams & Wilkins; 1999. 33. Kitzman DW, Higginbotham MB, Cobb FR, et al. Exercise intolerance in patients with heart failure and preserved left ventricular systolic function: failure of the Frank-Starling mechanism. J Am Coll Cardiol 1991;17:1065 - 72. 34. Vanoverschelde JJ, Essamri B, Vanbutsele R, et al. Contribution of left ventricular diastolic function to exercise capacity in normal subjects. J Appl Physiol 1993;74:2225 - 33. 35. Marabotti C, Genovesi Ebert A, Palombo C, et al. Relationship of Doppler indexes of left ventricular filling and exertion tolerance. G Ital Cardiol 1992;22:1151 - 6. 36. Poliner LR, Dehmer GJ, Lewis SE, et al. Left ventricular performance in normal subjects: A comparison of the responses to exercise in the upright and supine positions. Circulation 1980;62:528 - 34. 37. Nazli C, Kinay O, Ergene O, et al. Use of tissue Doppler echocardiography in early detection of left ventricular systolic dysfunction in patients with mitral regurgitation. Int J Cardiovasc Imaging 2003;19:199 - 209. 38. Koyama J, Ray-Sequin PA, Falk RH. Longitudinal myocardial function assessed by tissue velocity, strain, and strain rate tissue Doppler echocardiography in patients with AL (primary) cardiac amyloidosis. Circulation 2003;107:2446 - 52. 39. Fang ZY, Najos-Valencia O, Leano R, et al. Patients with early diabetic heart disease demonstrate a normal myocardial response to dobutamine. J Am Coll Cardiol 2003;42:446 - 53. 40. Kobayashi T, Tamano K, Takahashi M, et al. Myocardial systolic function of the left ventricle along the long axis in patients with essential hypertension: A study by pulsed tissue Doppler imaging. J Cardiol 2003;41:175 - 82. 41. Kim HK, Kim YJ, Cho YS, et al. Determinants of exercise capacity in hypertensive patients: new insights from tissue Doppler echocardiography. Am J Hypertens 2003;16:564 - 9. 42. Ekblom B, Hermansen L. Cardiac output in athletes. J Appl Physiol 1968;25:619 - 25. 43. Zhou B, Conlee RK, Jensen R, et al. Stroke volume does not plateau during graded exercise in elite male distance runners. Med Sci Sports Exerc 2001;33:1849 - 54. 44. Fleg JL, O’Connor F, Gerstenblith G, et al. Impact of age on the cardiovascular response to dynamic upright exercise in healthy men and women. J Appl Physiol 1995;78:890 - 900. 45. Rodeheffer RJ, Gerstenblith G, Becker LC, et al. Exercise cardiac output is maintained with advancing age in healthy human subjects: cardiac dilatation and increased stroke volume compensate for a diminished heart rate. Circulation 1984;69:203 - 13.
Background The mechanisms responsible for impaired cardiovascular hemodynamics during exercise among persons with milder forms of hypertension are not well documented. We examined the relationship of oxygen pulse during exercise, a correlate of stroke volume, with echocardiographic indices of resting left ventricular function to determine whether abnormal contractility and relaxation are related to abnormal cardiovascular dynamics during exercise among such persons. Methods Subjects were 44 men and 55 women ages 55 to 75 years with mild hypertension but who were otherwise healthy. Resting left ventricular systolic and diastolic functions were assessed with 2-dimensional Doppler echocardiography and tissue Doppler imaging. Oxygen pulse (millimeters per beat) at rest and during multistage treadmill testing was derived from measurements of oxygen consumption and heart rate. The slope of oxygen pulse between successive exercise stages was calculated. Results
After a steep rise in oxygen pulse from rest to stage 1 of exercise, a markedly diminished oxygen pulse slope was seen between subsequent exercise stages. In stepwise regression analysis, the increase in the slope of oxygen pulse from rest to stage 1 was explained by a greater lean body mass (57%, P b .001) and a larger left atrial size (2%, P b .001). After exercise stage 1, the increase in the slope of oxygen pulse was explained by sex (24%, P b .001), higher mitral E/A ratio (6%, P b .001), and higher mitral annular systolic velocity (6%, P b .001).
Conclusions
These results suggest that a blunted oxygen pulse response to exercise among older persons with milder forms of hypertension may reflect impaired left ventricular stroke volume changes during exercise secondary to subtle abnormalities in both systolic and diastolic left ventricular functions. (Am Heart J 2005;150:941 - 6.)
Hypertension affects approximately 50 million individuals in the United States. It is estimated that 90% of middle-aged individuals will develop hypertension in their lifetime.1 Hypertension is associated with adverse changes in left ventricular geometry and myocardial tissue composition,2 and abnormal systolic and diastolic functions. Aging is also associated with abnormalities in cardiovascular structure and function, including delayed early diastolic filling,3 decreased chronotropic response to catecholamines,4 and increased vascular stiffness with abnormal ventricular-vascular coupling.5 The combinaFrom the Division of Cardiology, Department of Medicine, Johns Hopkins Bayview Medical Center, Johns Hopkins University, School of Medicine, Baltimore, Md. This study was supported by a grant from the National Institutes of Health, R01HL59164 (K.J.S.) and the Johns Hopkins Bayview General Clinical Research Center (M01-RR-02719). Submitted February 23, 2004; accepted December 12, 2004. Reprint requests: Kerry J. Stewart, EdD, Johns Hopkins Bayview Medical Center, 4940 Eastern Avenue, Baltimore, MD 21224. E-mail: [email protected] 0002-8703/$ - see front matter n 2005, Mosby, Inc. All rights reserved. doi:10.1016/j.ahj.2004.12.021
tion of hypertension and aging can lead to abnormal cardiovascular responses to exercise. Whereas abnormalities in resting left ventricular diastolic function have been shown to adversely affect the cardiovascular response to exercise, less is known about these relationships in persons with milder forms of hypertension.6 -10 The relationship of resting systolic function to cardiovascular hemodynamics during exercise also remains controversial. This may be caused by the use of left ventricular ejection fraction, a relatively insensitive index of myocardial contractility, for this purpose.11,12 Tissue Doppler imaging of the mitral annulus has been shown to be complementary to conventional echocardiographic measures in assessing both systolic and diastolic functional abnormalities among persons with hypertension.13 -17 This methodology may also be able to detect early systolic abnormalities even among persons with normal left ventricular ejection fraction.18 Oxygen pulse, which normalizes oxygen consumption for heart rate, has been used as a surrogate for changes in stroke volume during exercise19 -21 and correlates with stroke volume obtained by multigated radionuclide testing.19 -22 Its value as a marker of cardiac performance
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942 Lim et al
Figure 1
Table I. Baseline characteristics
Oxygen Pulse (mlO2/beat)
18
Variable
14
10 Pattern A 6
Pattern B
2 Pre
1
2
3
4
5
Exercise Stages
White (%) Age (y) Body mass index (kg/m2) Lean body mass (kg) Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Pulse pressure (mm Hg) Mean arterial pressure (mm Hg) Percentage with BP V139 (prehypertension) Resting heart rate (beat/min)
Men (N = 44)
Women (N = 55)
P
91 62.7 F 5.8 29.3 F 3.3
84 64.8 F 5.6 29.6 F 5.0
.25 .08 .70
58.9 F 7.3
38.9 F 4.4
b.01
140 F 8
140 F 8
.99
81 F 6
73 F 8
b.01
60 F 7 101 F 6
67 F 9 96 F 7
b.01 b.01
53%
43%
.35
71 F 8
72 F 9
.60
Changes in oxygen pulse across exercise treadmill stages.
is supported by studies which have demonstrated impairment in oxygen pulse among patients with ischemic heart disease,22,23 mitral valve disease,24 and congestive heart failure.25 This study examined the relationship of echocardiographic and tissue Doppler-derived parameters of resting left ventricular systolic and diastolic function with oxygen pulse response to exercise among older persons with milder forms of hypertension. We hypothesized that tissue Doppler indices of left ventricular function would be more likely to demonstrate such a relationship than conventional echocardiographic measurements.
Methods Subjects Previously sedentary men and women, aged 55 to 75 years, with untreated forms of mild hypertension but who were otherwise healthy were recruited from the community for a study of exercise training. Exclusions were diabetes mellitus (fasting serum glucose N126 mg/dL), a history of smoking in the past 6 months, ischemic heart disease, congestive heart failure, and regular aerobic exercise more than 3 metabolic equivalents for 90 minutes per week.26 A screening exercise test also excluded subjects with exercise-induced ischemic electrocardiographic (ECG) changes (horizontal or downsloping ST-segment depression N1 mm), complex arrhythmias, or ischemic symptoms.
Blood pressure eligibility Participants not using antihypertensive medication entered blood pressure screening without delay. With their physician approval, participants using a single antihypertensive medication entered blood pressure screening 2 weeks after stopping the medication. To be eligible for this study, participants were required to have systolic blood pressure between 130 and
159 mm Hg and/or diastolic blood pressure between 85 and 99 mm Hg during 2 consecutive weekly visits and an average blood pressure in this range over 4 weekly visits. These levels correspond to prehypertension to stage 1 hypertension by the Joint National Committee for Detection, Evaluation, and Treatment of High Blood Pressure 7 guidelines. Informed consent was obtained from all subjects, and the protocol was approved by the Johns Hopkins School of Medicine institutional review board.
Echocardiographic measurements Standard echocardiographic views were obtained in the left lateral decubitus position using an Agilent Technologies Sonos 5500 or Hewlett-Packard Sonos 2500 system. Measurements were made off-line with a Microsonics Image-Vue analysis system or a Philips viewpoint system. Two-dimensional, M mode, and Doppler examinations were performed with a 2.5-MHz transducer. Left ventricular internal dimension and ventricular septal thickness were each measured at end systole and end diastole in accordance with established guidelines.27 Transmitral Doppler flows were recorded at the leaflet tips. Tracings for isovolumic relaxation time (IVRT) were recorded using continuous wave Doppler, and IVRT was measured as the interval between the aortic valve closure click and the onset of transmitral flow. Tissue Doppler imaging of the mitral annulus was obtained from the apical 4-chamber view. A fixed 5-mm sample volume was placed at the lateral aspect of the mitral annulus. Measurements were taken of the peak systolic myocardial velocity (Sm), and early (Em) and late (Am) diastolic velocity. Three measurements were made for each parameter and averaged. Left ventricular mass was calculated from end-diastolic left ventricular dimensions and wall thickness according to the Devereux formula,28 and it was indexed to body surface area (g/m2). Relative wall thickness was defined as twice the posterior wall thickness divided by the left ventricular internal radius, both measured in end diastole. Ejection fraction was determined by the method of Quinones and Reduto.29
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Lim et al 943
Table II. Resting echocardiographic measurements Variable
Men
Women
Table III. Cardiopulmonary exercise tests results by sex P value Variable
Peak E velocity (cm/s) Peak A velocity (cm/s) E/A ratio Deceleration time (ms) IVRT (ms) VSd (cm) LVId (cm) RWT LA (cm) LVMI (g/m2) LVEF (%) Sm (cm/s) Em (cm/s) Am (cm/s) Em/Am ratio
71 F 12 78 F 14 0.93 F 0.21 227 F 56 91 F 16 1.09 F 0.11 4.76 F 0.42 0.46 F 0.06 3.92 F 0.46 103.6 F 18.8 53 F 8 10.8 F 2.7 11.0 F 2.0 13.3 F 2.9 0.85 F 0.19
78 F 12 87 F 16 0.91 F 0.17 215 F 38 92 F 14 1.01 F 0.11 4.39 F 0.34 0.46 F 0.07 3.60 F 0.42 93.3 F 17 56 F 8 9.2 F 2.0 10.0 F 2.2 13.4 F 3.1 0.79 F0.25
b.01 b.01 .66 .21 .78 b.01 b.01 .91 b.01 b.01 .02 b.01 .02 .86 .16
Values are mean values F SD. VSd, Ventricular septum thickness measured in diastole; LVId, left ventricular internal dimension in diastole; RWT, relative wall thickness; LA, left atrial size; LVEF, left ventricular ejection fraction; LVMI, left ventricular mass index; Em, peak mitral annular early diastolic velocity; Am, peak mitral annular late diastolic velocity during atrial contraction; Sm, peak mitral annular systolic velocity.
Preexercise V˙o2 (mL/min/kg) Preexercise O2P (mL/beat) Peak V˙o2 (mL/min/kg) Peak O2P (mL/beat) RER at peak Time on treadmill (s) Max HR (beat/min) Max SBP (mm Hg) Max DBP (mm Hg) DO2P initial (mL/beat/stage) DO2P continued exercise (mL/beat/stage)
Men (N = 44)
Women (N = 55)
P value
3.8 F 0.9
3.4 F 0.8
.02
4.5 F 1.3
3.2 F 1.0
b.01
27.9 F 4.5
20.8 F 3.1
b.01
15.5 1.11 989 166 230 98 7.7
9.7 1.12 670 163 216 97 4.9
b.01 .44 b.01 .18 b.01 .59 b.01
F F F F F F F
2.6 0.06 216 13 19 9 2.0
0.56 F 0.1
F F F F F F F
2.1 0.08 187 12 17 14 1.7
0.24 F 0.1
b.01
Values are mean values F SD. O 2 P, Oxygen pulse; SBP, systolic blood pressure; DBP, diastolic blood pressure; PP, pulse pressure; HR, heart rate; RER, respiratory exchange ratio; DO 2 P initial, oxygen pulse at the end of stage 1 preexercise oxygen pulse; DO 2 P continued exercise, (max oxygen pulse stage 1 oxygen pulse)/number of stages.
Anthropometric measures Weight was measured with minimal clothing on a calibrated digital scale, and height was measured on a stadiometer. Body mass index was calculated as weight in kilograms divided by the square of the height in meters. Lean body mass was measured by dual energy x-ray absorptiometry performed on a General Electric Lunar Prodigy system (GE medical systems, Fairfield, Conn).
Exercise testing Exercise was performed on a treadmill integrated with a SensorMedics Vmax229 Metabolic and ECG system (SensorMedics, Inc, Yorba Linda, Calif). Subjects performed a modified Balke protocol, beginning at 3 mph with 0% grade and increasing 2.5% grade every 3 minutes until maximal volitional fatigue was reached. A 12-lead ECG was monitored continuously. Exercise blood pressure was measured during the last 30 seconds of each stage using a mercury column sphygmomanometer according to the guidelines of the American College of Sports Medicine.30 Exercise systolic blood pressure was measured at phase I of the Korotkoff sounds, and diastolic blood pressure was measured between phases IV and V. As needed, the subjects rested their hand on the examiner’s shoulder to minimize movement artifact. The Rating of Perceived Exertion using the Borg 6-to-20 scale31 was obtained during each stage, and a rating z18 was an indicator of maximal effort. The breath-by-breath signals during exercise testing were integrated to yield 10-second averages of oxygen consumption ˙o2 (mL/kg/min), respiratory exchange ratio, heart rate, and V ˙o2/heart rate expressed as mL O2/beat). Oxygen oxygen pulse (V pulse plots were generated by using the mean oxygen pulse values during the last 30 seconds of each stage versus exercise stage. Figure 1 shows the overall patterns in the oxygen pulse response during exercise. After an initial sharp rise at the start of exercise, there is a less steep rise in oxygen pulse during continued exercise. Two patterns of the oxygen pulse responses
to exercise that are often seen are labeled as patterns A and B. In pattern A, after an initial rise of oxygen pulse during the first stage of exercise, there is a continued increase in oxygen pulse with each successive stage. In pattern B, after an initial rise during the first stage of exercise, there is a plateau or markedly diminished rise in oxygen pulse with continued exercise. The slope of oxygen pulse during initial exercise and continued exercise was analyzed separately. The slope of oxygen pulse during initial exercise was calculated by subtracting the oxygen pulse at the end of stage 1 from preexercise standing oxygen pulse (mL O2/beat). The slope of oxygen pulse during continued exercise was the difference between oxygen pulse obtained at the last stage of exercise and oxygen pulse at the end of stage 1 divided by the number of exercise stages (mL O2/beat/stage).
Statistical analysis Data are expressed as the mean value F SD. Because of potential sex differences in left ventricular structure and exercise capacity, these relationships were also examined by sex, and comparisons were made with Student t tests. Stepwise regression was used to determine the independent contribution of each parameter that showed a significant bivariate correla˙o2, or exercise oxygen tion with peak oxygen pulse, peak V pulse responses for early and continued exercise separately. Sm velocity was skewed and was normalized with a logarithmic transformation. No other variables required transformation. The 2-tailed level of statistical significance was set at P b .05. All statistical analyses were done using JMP 5.0 (SAS, Cary, NC).
Results Forty-four men and 55 women were studied. Their baseline characteristics (Table I) were similar except for a lower lean body mass, a lower resting diastolic blood
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944 Lim et al
Table IV. Bivariate correlations between demographic and echocardiographic variables and cardiopulmonary exercise test results
Peak V˙o2 Peak O2P Slope O2P initial Slope O2P continued exercise
Age
Sex (male)
LBM (kg)
LA size (cm)
LVId (cm)
E/A ratio
Sm (cm/s)
Em (cm/s)
MAP (mm Hg)
DBP (mm Hg)
EF (%)
0.18 0.25y 0.15 0.14
0.69T 0.78T 0.61T 0.47T
0.56T 0.86T 0.75T 0.43T
0.15 0.57T 0.55T 0.17
0.29T 0.55T 0.52T 0.12
0.18 0.10 0.03 0.27T
0.27 T 0.37 T 0.19 0.36T
0.22y 0.29T 0.19 0.16
0.21y 0.32T 0.23y 0.23y
0.33T 0.42T 0.28T 0.33T
0.00 0.08 0.09 0.09
LBM, Lean body mass; LA, left atrium; Sm, tissue Dopple imaging-derived peak systolic velocity; Em, tissue Dopple imaging-derived peak diastolic velocity; MAP, mean arterial pressure; EF, ejection fraction. TP b .01. yPb .05.
pressure, a lower mean arterial pressure, and a larger pulse pressure among the women compared with the men (all P b .01). Fifty-three percent of our male patients and 43% of our female patients would be classified as having prehypertension. Baseline echocardiographic variables are shown in Table II. All subjects had a normal left ventricular ejection fraction, defined as N45%. Left atrial size, left ventricular dimensions, ventricular septal thickness, and left ventricular mass index were smaller among women than in men (all P b .01). Women had a lower Em velocity ( P = .02) and a lower Sm velocity ( P b .01) despite having a higher ejection fraction than the men ( P = .02). Women had a higher mitral peak E and peak A velocity than men (both P b .01), but the E/A ratio was similar. Men exercised longer on the treadmill and had higher ˙o2, peak oxygen pulse, and maximal systolic peak V blood pressure than the women (all P b .01) (Table III). Men also had greater increases in oxygen pulse during initial exercise and with continued exercise (each P b .01). The mean peak V˙o2 achieved for both sexes was within the predicted range for sedentary individuals in this age range.32 Table IV shows bivariate correlations of baseline demographics and resting echocardiographic variables with exercise test parameters. Left ventricular mass index and body mass index did not correlate with any of the exercise parameters (data not shown). The slope of oxygen pulse during continued exercise correlated with Sm velocity (R = 0.36, P b .01) but not with ejection fraction (R = 0.09, P = NS). There was no change in the relationships found when subjects with prehypertension or grade I hypertension were analyzed separately (analysis not shown). In stepwise regression models, male sex was the ˙o2, explaining 47% of only predictor of a higher peak V the variance. A higher peak oxygen pulse was predicted by higher lean body mass, which accounted for 74% of the variance, with an additional 2% explained by larger left atrial size and 2% by male sex. A higher initial slope of oxygen pulse correlated with higher lean body mass, which explained 57% of the variance, with an additional 2% explained by larger left
atrial size. With continued exercise, a higher slope of oxygen pulse correlated with male sex, which accounted for 24% of the variance, and a higher mitral E/A ratio and higher Sm velocity each explaining an additional 6% of the variance.
Discussion The novel finding of our study is the association of both systolic and diastolic function with the slope of oxygen pulse during exercise. Specifically, a lower resting mitral E/A ratio, a reflection of impaired diastolic function, and a lower Sm velocity, an indicator of reduced long-axis contractility, were associated with an attenuated rise in oxygen pulse after the first stage of exercise. Such an attenuated oxygen pulse slope over time suggests an impaired stroke volume response during sustained exercise. The normal increase in the slope of oxygen pulse later in exercise reflects an augmentation of stroke volume to meet the need for more cardiac output and consequently represents a greater demand on the left ventricle. This could explain why echocardiographic signs of early systolic or diastolic dysfunction were associated with an attenuated slope in oxygen pulse later in exercise, rather than in early exercise, when the demand for cardiac output is lower. Left ventricular diastolic filling during exercise plays an important role in determining exercise tolerance.33 - 35 Our finding that a lower mitral E/A ratio was associated with a diminished oxygen pulse slope is in agreement with previous studies among patients with moderate to severe hypertension.6-10 Among our older subjects with milder forms of hypertension, exercise testing may be revealing subtle abnormalities in diastolic functional reserve. Impaired resting left ventricular systolic function may be associated with impaired contractile reserve, leading to reduced left ventricular contractility despite increasing catecholamine levels during exercise. Increased afterload from increased systolic blood pressure during exercise36 may further reduce left ventricular performance. Hence, subjects with
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impaired resting left ventricular function may be expected to have some degree of stroke volume impairment during exercise. We found that decreased long-axis systolic function, but not ejection fraction, was associated with a decreased oxygen pulse slope during continued exercise. The lack of a correlation between ejection fraction and changes in oxygen pulse could be explained by the fact that ejection fraction reflects geometric left ventricular chamber function rather than actual myocardial function.11 The assessment of long-axis function may be a more sensitive early marker of left ventricular systolic dysfunction as demonstrated in a variety of conditions such as mitral regurgitation,37 cardiac amyloidosis,38 diabetes,39 and hypertension.40 We found that an attenuated rise of oxygen pulse during exercise was associated with lower long-axis resting systolic function, although the ejection fraction was normal. Thus, even subtle changes in myocardial contractility at rest may compromise the ability of the left ventricle to eject against rising pressure as seen with continued exercise. Kim et al41 found that whereas resting diastolic velocity by tissue Doppler was predictive of exercise time, systolic velocity at rest was not. That study may be limited by their measurement of exercise time only rather than cardiorespiratory responses to exercise. To our knowledge, our findings are the first to show a relationship between reduced left ventricular systolic function at rest and impaired cardiorespiratory response during exercise. As expected, men had higher values for oxygen pulse ˙o2max than women, which is likely caused by men and V ˙o2 extraction.9 having a greater stroke volume and AV Despite these differences, the relationships of systolic and diastolic function with the oxygen pulse response during exercise did not differ by sex.
Limitations The narrow age range, sedentary lifestyle, and similarities in baseline demographics among our subjects would serve to mask correlations among variables. For example, no indices of left ventricular function were ˙o2, which may be in independent predictors of peak V part caused by the narrow range of values for these measures. Despite these limitations, we found relationships between resting left ventricular function and the slope of oxygen pulse during exercise. The relative contribution of left ventricular function in cardiorespiratory response during exercise may be greater among older persons. The rise in cardiac output during exercise results from an increase in both stroke volume and heart rate. Among younger sedentary individuals, stroke volume typically peaks at approxi˙o2, and any further rise in cardiac mately 40% of peak V output is mainly attributable to increases in heart rate.42,43 Normal aging is associated with an attenuated heart rate response during exercise; therefore, the
Lim et al 945
relative contribution of stroke volume to cardiac output during exercise increases as individuals get older.44,45 Therefore, our findings may not apply to younger persons. Further studies to confirm these results should be done in populations with broader ranges in age, blood pressure, and left ventricular function. The response of oxygen pulse to exercise is also influ˙o2 extraction and not merely to enced by differences in AV stroke volume changes. Although we did not measure cardiac output and stroke volume directly, we found no correlation between changes in oxygen pulse during the later stages of exercise with lean body mass, a parameter ˙o2 extraction. Hence, the that should influence AV correlation between measures of left ventricular function and the slope of oxygen pulse would suggest that these associations are likely caused by the stroke volume ˙o2 changes during exercise. changes rather than AV We excluded patients during screening if they had a positive exercise test to rule out clinical ischemic heart disease. However, it remains possible that our subjects may have subclinical cardiac ischemia that could result in an abnormal oxygen pulse response during exercise.
Conclusion A lower tissue Doppler-derived resting long-axis systolic (Sm) velocity was associated with an attenuation of the oxygen pulse response to exercise, suggesting impaired exercise stroke volume. Reduced echocardiography-derived early left ventricular filling was also associated with attenuated oxygen pulse slope during exercise. Thus, early abnormalities in both systolic and diastolic left ventricular function may adversely affect cardiopulmonary response to exercise among older adults with milder forms of hypertension.
References 1. Vasan RS, Beiser A, Seshadri S, et al. Residual lifetime risk for developing hypertension in middle-aged women and men: the Framingham Heart Study. JAMA 2002;287:1003 - 10. 2. Motz W, Scheler S, Schwartzkopff B, et al. Evaluation of cardiac damage in hypertension. J Cardiovasc Risk 1995;2:16 - 26. 3. Lakatta EG, Gerstenblith G, Angell CS, et al. Prolonged contraction duration in aged myocardium. J Clin Invest 1975;55:61 - 8. 4. Lakatta EG, Gerstenblith G, Angell CS, et al. Diminished inotropic response of aged myocardium to catecholamines. Circ Res 1975;36: 262 - 9. 5. Najjar SS, Schulman SP, Gerstenblith G, et al. Age and gender affect ventricular-vascular coupling during aerobic exercise. J Am Coll Cardiol 2004;44:611 - 7. 6. Olsen MH, Wachtell K, Hermann KL, et al. Maximal exercise capacity is related to cardiovascular structure in patients with longstanding hypertension. A LIFE substudy. Losartan intervention for endpointreduction in hypertension. Am J Hypertens 2001;14:1205 - 10. 7. Goodman JM, McLaughlin PR, Plyley MJ, et al. Impaired cardiopulmonary response to exercise in moderate hypertension. Can J Cardiol 1992;8:363 - 71.
946 Lim et al
8. Modesti PA, Olivo G, Carrabba N, et al. Early impairment of the cardiopulmonary exercise capacity of hypertensive patients. Int J Cardiol 1994;44:163 - 9. 9. Reybrouck T, Fagard R. Gender differences in the oxygen transport system during maximal exercise in hypertensive subjects. Chest 1999; 115:788 - 92. 10. Missault L, Duprez D, de Buyzere M, et al. Decreased exercise capacity in mild essential hypertension: non-invasive indicators of limiting factors. J Hum Hypertens 1992;6:151 - 5. 11. Aurigemma GP, Silver KH, Priest MA, et al. Geometric changes allow normal ejection fraction despite depressed myocardial shortening in hypertensive left ventricular hypertrophy. J Am Coll Cardiol 1995;26:195 - 202. 12. Bing OH, Matsushita S, Fanburg BL, et al. Mechanical properties of rat cardiac muscle during experimental hypertrophy. Circ Res 1971; 28:234 - 45. 13. Oki T, Tabata T, Yamada H, et al. Left ventricular diastolic properties of hypertensive patients measured by pulsed tissue Doppler imaging. J Am Soc Echocardiogr 1998;11:1106 - 12. 14. Pai RG, Gill KS. Amplitudes, durations, and timings of apically directed left ventricular myocardial velocities: II. Systolic and diastolic asynchrony in patients with left ventricular hypertrophy. J Am Soc Echocardiogr 1998;11:112 - 8. 15. Naqvi TZ, Neyman G, Broyde A, et al. Comparison of myocardial tissue Doppler with transmitral flow Doppler in left ventricular hypertrophy. J Am Soc Echocardiogr 2001;14:1153 - 60. 16. Rodriguez L, Garcia M, Ares M, et al. Assessment of mitral annular dynamics during diastole by Doppler tissue imaging: Comparison with mitral Doppler inflow in subjects without heart disease and in patients with left ventricular hypertrophy. Am Heart J 1996;131: 982 - 7. 17. Pela G, Bruschi G, Cavatorta A, et al. Doppler tissue echocardiography: myocardial wall motion velocities in essential hypertension. Eur J Echocardiogr 2001;2:108 - 17. 18. Yu CM, Lin H, Yang H, et al. Progression of systolic abnormalities in patients with bisolatedQ diastolic heart failure and diastolic dysfunction. Circulation 2002;105:1195 - 201. 19. Whipp BJ, Higgenbotham MB, Cobb FC. Estimating exercise stroke volume from asymptotic oxygen pulse in humans. J Appl Physiol 1996;81:2674 - 9. 20. Jones S, Elliott PM, Sharma S, et al. Cardiopulmonary responses to exercise in patients with hypertrophic cardiomyopathy. Heart 1998; 80:60 - 7. 21. Hsi WL, Wong PL, Lai JS. Submaximal oxygen pulse divided by body weight during incremental exercise test. Am J Phys Med Rehabil 1997;76:297 - 303. 22. Klainman E, Fink G, Lebzelter J, et al. The relationship between left ventricular function assessed by multigated radionuclide test and cardiopulmonary exercise test in patients with ischemic heart disease. Chest 2002;121:841 - 5. 23. Klainman E, Fink G, Lebzelter J, et al. Assessment of functional results after percutaneous transluminal coronary angioplasty by cardiopulmonary exercise test. Cardiology 1998;89:257 - 62. 24. Nery LE, Wasserman K, French W, et al. Contrasting cardiovascular and respiratory responses to exercise in mitral valve and chronic obstructive pulmonary diseases. Chest 1983;83:446 - 53. 25. Wait J. Cardiopulmonary stress testing. A review of noninvasive approaches. Chest 1986;90:504 - 10. 26. Pate RR, Pratt M, Blair SN, et al. Physical activity and public health. A recommendation from the Centers for Disease Control and Prevention and the American College of Sports Medicine. JAMA 1995;273:402 - 7.
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27. Schiller NB, Shah PM, Crawford M, et al. Recommendations for quantitation of the left ventricle by two-dimensional echocardiography. American Society of Echocardiography Committee on Standards, subcommittee on quantitation of two-dimensional echocardiograms. J Am Soc Echocardiogr 1989;2:358 - 67. 28. Devereux RB, Alonso DR, Lutas EM, et al. Echocardiographic assessment of left ventricular hypertrophy: comparison to necropsy findings. Am J Cardiol 1986;57:450 - 8. 29. Quinones MAWA, Reduto LA. A new, simplified and accurate method for determining ejection fraction with two-dimensional echocardiography. Circulation 1981;64:744 - 53. 30. ACSM’s guidelines for exercise testing and prescription. Franklin B, Whaley MH, Howley ET, editors. 6th ed. Baltimore: Lippincott Williams and Wilkins; 2000. 31. Borg G. Simple ratings for estimation of perceived exertion. Physical work and effort. New York (NY): Pergamon Press; 39 - 46. 32. Wasserman K, Hansen JE, Sue DY, et al. Principles of exercise testing and interpretation. 3rd ed. Baltimore: Lippincott Williams & Wilkins; 1999. 33. Kitzman DW, Higginbotham MB, Cobb FR, et al. Exercise intolerance in patients with heart failure and preserved left ventricular systolic function: failure of the Frank-Starling mechanism. J Am Coll Cardiol 1991;17:1065 - 72. 34. Vanoverschelde JJ, Essamri B, Vanbutsele R, et al. Contribution of left ventricular diastolic function to exercise capacity in normal subjects. J Appl Physiol 1993;74:2225 - 33. 35. Marabotti C, Genovesi Ebert A, Palombo C, et al. Relationship of Doppler indexes of left ventricular filling and exertion tolerance. G Ital Cardiol 1992;22:1151 - 6. 36. Poliner LR, Dehmer GJ, Lewis SE, et al. Left ventricular performance in normal subjects: A comparison of the responses to exercise in the upright and supine positions. Circulation 1980;62:528 - 34. 37. Nazli C, Kinay O, Ergene O, et al. Use of tissue Doppler echocardiography in early detection of left ventricular systolic dysfunction in patients with mitral regurgitation. Int J Cardiovasc Imaging 2003;19:199 - 209. 38. Koyama J, Ray-Sequin PA, Falk RH. Longitudinal myocardial function assessed by tissue velocity, strain, and strain rate tissue Doppler echocardiography in patients with AL (primary) cardiac amyloidosis. Circulation 2003;107:2446 - 52. 39. Fang ZY, Najos-Valencia O, Leano R, et al. Patients with early diabetic heart disease demonstrate a normal myocardial response to dobutamine. J Am Coll Cardiol 2003;42:446 - 53. 40. Kobayashi T, Tamano K, Takahashi M, et al. Myocardial systolic function of the left ventricle along the long axis in patients with essential hypertension: A study by pulsed tissue Doppler imaging. J Cardiol 2003;41:175 - 82. 41. Kim HK, Kim YJ, Cho YS, et al. Determinants of exercise capacity in hypertensive patients: new insights from tissue Doppler echocardiography. Am J Hypertens 2003;16:564 - 9. 42. Ekblom B, Hermansen L. Cardiac output in athletes. J Appl Physiol 1968;25:619 - 25. 43. Zhou B, Conlee RK, Jensen R, et al. Stroke volume does not plateau during graded exercise in elite male distance runners. Med Sci Sports Exerc 2001;33:1849 - 54. 44. Fleg JL, O’Connor F, Gerstenblith G, et al. Impact of age on the cardiovascular response to dynamic upright exercise in healthy men and women. J Appl Physiol 1995;78:890 - 900. 45. Rodeheffer RJ, Gerstenblith G, Becker LC, et al. Exercise cardiac output is maintained with advancing age in healthy human subjects: cardiac dilatation and increased stroke volume compensate for a diminished heart rate. Circulation 1984;69:203 - 13.