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Protective effect of high diastolic blood pressure during exercise against exercise-induced myocardial ischemia
Protective effect of high diastolic blood pressure during exercise against exercise-induced myocardial ischemia Hiroyuki Yamagishi, MD, Minoru Yoshiyama, MD, Naoya Shirai, MD, Kaname Akioka, MD, Kazuhide Takeuchi, MD, and Junichi Yoshikawa, MD Osaka, Japan
Background Hypertension is one of the risk factors for coronary artery disease. However, because most coronary blood flow to the left ventricle occurs during diastole, high diastolic blood pressure during exercise may have a protective effect against exercise-induced myocardial ischemia. The aim of the present study was to test this hypothesis. Methods and Results We identified 469 patients with sinus rhythm and known or suspected coronary artery disease who underwent exercise thallium-201 myocardial single-photon emission computed tomography and coronary arteriography. High diastolic blood pressure during exercise was defined as diastolic blood pressure at peak exercise z90 mm Hg. There was no significant difference in medications, number of diseased vessels, or Gensini score between patients with high (n = 228) and normal (n = 241) diastolic blood pressure during exercise, whereas patients with high diastolic blood pressure during exercise exhibited a higher pressure-rate product during exercise than patients with normal diastolic blood pressure during exercise. The reversibility score on thallium-201 myocardial scan was significantly smaller in patients with high diastolic blood pressure during exercise than in patients with normal diastolic blood pressure during exercise ( P = .021). Conclusions High diastolic blood pressure during exercise has a potential protective effect against exercise-induced ischemia, although the mechanism of such effects remains to be determined. (Am Heart J 2005;150:790 - 5.) Exercise-induced myocardial ischemia in patients with coronary artery disease (CAD) occurs because of imbalance between myocardial oxygen demand and supply. Myocardial oxygen demand is determined by myocardial wall tension, myocardial contractility, and heart rate. Systolic blood pressure and heart rate increase progressively with exercise, mediated through circulating catecholamines and sympathetic innervation of the sinoatrial node. The systolic blood pressure–heart rate (pressure-rate) product increases progressively with exercise and is closely correlated to myocardial oxygen demand.1 Myocardial oxygen supply is determined by coronary perfusion pressure and coronary vascular resistance without anemia or hypoxemia. In patients with organic stenosis of epicardial coronary arteries, the severity of coronary artery stenosis determines coronary vascular resistance. Most coronary blood flow to the left ventricle occurs during diastole, because coronary perFrom the Department of Internal Medicine and Cardiology, Osaka City University Graduate School of Medicine, Osaka, Japan. Submitted February 17, 2004; accepted November 21, 2004. Reprint requests: Hiroyuki Yamagishi, MD, Department of Internal Medicine and Cardiology, Osaka City University Graduate School of Medicine, 1-4-3 Asahi-Machi, Abeno-Ku, Osaka, 545-8585, Japan. E-mail: [email protected] 0002-8703/$ - see front matter n 2005, Mosby, Inc. All rights reserved. doi:10.1016/j.ahj.2004.11.007
fusion pressure drops during systole markedly because of systolic compression of the coronary vessels coursing through the myocardium. Therefore, high diastolic blood pressure during exercise may have a protective effect against exercise-induced myocardial ischemia, although high systolic blood pressure during exercise aggravates exercise-induced myocardial ischemia. The aim of the present study was to investigate whether high diastolic blood pressure during exercise has a protective effect against exercise-induced myocardial ischemia.
Methods Patient population We identified 469 consecutive patients [374 men and 95 women; mean age 63 F 9 (SD) years, range 36 to 86 years] with sinus rhythm and known or suspected CAD who underwent exercise thallium-201 (201Tl) myocardial singlephoton emission computed tomography (SPECT) and coronary arteriography in our hospital between January 1999 and December 2002. The decision to perform exercise 201Tl myocardial SPECT and coronary arteriography was made by physicians on the basis of clinical findings of patients. Patients who had undergone coronary bypass grafting and those with significant valvular disease were excluded. Information about coronary risk factors elicited through questioning by the treating physician and laboratory data were reviewed retrospectively in medical records.
American Heart Journal Volume 150, Number 4
Hypertension was defined as resting casual systolic blood pressure z140 mm Hg, diastolic pressure z90 mm Hg, or treatment with antihypertensive agents. Hypercholesterolemia was defined as fasting serum total cholesterol z240 mg/dL or treatment with cholesterol-lowering agents. Obesity was defined as body mass index of z25 kg/m2. Diabetes mellitus was diagnosed based on the criteria of American Diabetes Association.2 High diastolic blood pressure during exercise was defined as diastolic blood pressure of z90 mm Hg at peak exercise.
Exercise thallium-201 myocardial single-photon emission computed tomography Each patient performed symptom-limited exercise on a bicycle ergometer. The workload was started at 25 or 50 W and increased by 25 W every 2 minutes until the end point of exercise was reached. Twelve-lead electrocardiograms and blood pressure measurements were obtained at rest and every minute during exercise. Blood pressure was measured by an automatic sphygmomanometer (STBP-780B, Colin Corporation, Aichi, Japan) based on a cuff-oscillometric method at the upper arm. The exercise end points included leg fatigue, dyspnea, moderate to severe angina, significant ST depression (N2.0 mm horizontal or down-sloping), or significant arrhythmia. At peak exercise, 201Tl (111 MBq for patients without previous myocardial infarction and 74 MBq for patients with previous myocardial infarction) was injected intravenously, and the patient was encouraged to exercise for an additional minute. Postexercise images were obtained immediately after the termination of exercise, and delayed images were obtained 4 hours later. In patients with previous myocardial infarction, an additional dose of 37 MBq of 201Tl was injected at rest immediately after the acquisition of delayed images, and reinjection images were obtained 20 minutes later. Single-photon emission computed tomography was performed with a 2-detector g-camera (VERTEX, ADAC Laboratories, Milpitas, Calif) equipped with low-energy, general-purpose collimators, with the detectors set to form a 908 angle. A total of 32 equidistant projections were acquired over 1808 in a 64 64 matrix from the 458 right anterior oblique to 458 left posterior oblique projection with 40 seconds per step, in 68 angular steps. A total of 8 frames per cardiac cycle electrocardiography-gated acquisition for assessment of left ventricular ejection fraction (LVEF) were performed at each projection. Nongated images for assessment of 201Tl uptake were obtained by summing all gated images. Transaxial slices of 4.7-mm pixel thickness were reconstructed using a Butterworth filter (order = 5.0, critical frequency = 0.35 cycles per pixel) and the filtered back-projection method (ramp filter) on a processing computer (Pegasys, ADAC Laboratories) with an automatic processing software program for SPECT (Cedars AutoSPECT; Cedars-Sinai Medical Center, Los Angeles, Calif).3
Scintigraphic image analysis Perfusion defects. An automated perfusion abnormality analysis software program (autoQUANT, ADAC Laboratories) was used for quantification of the severity of perfusion defects compared with a normal limit database, which included 36 patients with a low likelihood (b5%) of CAD.4 Severity score was calculated as the average of the number
Yamagishi et al 791
of SD below the normal mean. All pixels above normal were considered equal to zero. Reversibility score was calculated as the difference between the severity scores of delayed and initial images. Reversibility score b0 was considered equal to zero. Left ventricular ejection fraction. A completely automated left ventricular function analysis software program (Cedars Quantitative Gated SPECT; Cedars-Sinai Medical Center)5,6 was used for calculation of global LVEF. Rest LVEF was derived from delayed images in patients without reinjection images and from reinjection images in patients with reinjection images.
Coronary arteriography Coronary angioplasty was not performed between the scintigraphic study and coronary arteriography in any patient. Coronary artery narrowing was visually assessed and reported as percentage luminal diameter stenosis. Significant CAD was defined as z75% narrowing of the internal diameter of the left anterior descending artery, the left circumflex artery, the right coronary artery, or their major branches and z50% narrowing of the left main coronary artery. Thirty-eight of the 469 patients had significant left main CAD, which was considered equivalent to combined disease of the left anterior descending artery and the left circumflex artery. Of 131 patients without angiographically significant organic stenosis, 75 had a history of previous percutaneous coronary intervention, 14 had previous myocardial infarction without previous percutaneous coronary intervention, 11 was diagnosed with vasospastic angina, and 31 was diagnosed with chest pain syndrome. Gensini score7 was calculated to evaluate the severity of coronary atherosclerosis. All patients gave written informed consent.
Statistics Values are given as mean values F SD. Incidences of phenomena were compared with the m2 test. Continuous variables were compared with Student t test. Correlation coefficients were calculated by linear regression analysis. P values of b.05 were considered significant. These analyses were performed with SPSS version 10.0 (SPSS, Inc, Chicago, Ill).
Results Patient characteristics Of 469 patients, 228 patients exhibited high diastolic blood pressure during exercise, 55 (24%) patients of whom exhibited high diastolic blood pressure at rest, whereas 241 patients exhibited normal diastolic blood pressure during exercise, 11 (5%) patients of whom exhibited high diastolic blood pressure at rest. Baseline characteristics of patients with high and normal diastolic blood pressure during exercise are shown in Table I. Patients with high diastolic blood pressure exhibited younger age, less frequent diabetes mellitus, and more frequent hypertension than patients with normal diastolic blood pressure during exercise. However, there was no significant difference between these groups in sex, previous myocardial infarction, previous percuta-
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792 Yamagishi et al
Table I. Baseline characteristics of patients with high and normal diastolic blood pressure during exercise
Variable Age, y Men, n (%) Previous myocardial infarction, n (%) Previous percutaneous coronary intervention, n (%) Coronary risk factors, n (%) Current smoking Diabetes mellitus Family history of CAD Hypercholesterolemia Hypertension Obesity Medication, n (%) h-Blockers Calcium-channel blockers Nitrates ACEI or ARB No. diseased vessels, n (%) 0 1 2 3 Gensini score Rest LVEF, %
Table II. Exercise thallium-201 single-photon emission computed tomography data
High diastolic BP during exercise, n = 228
Normal diastolic BP during exercise, n = 241
61 F 9 180 (79) 70 (31)
65 F 9 194 (80) 92 (38)
b.001 .676 .089
125 (55)
123 (51)
.383
P
85 (37) 61 (27) 39 (17) 53 (23) 136 (60) 77 (34)
100 93 32 44 122 81
(41) (39) (13) (18) (51) (34)
.351 .006 .248 .183 .049 .970
130 (57) 92 (40)
124 (51) 88 (37)
.227 .393
152 (67) 73 (32)
158 (66) 80 (33)
.800 .786
69 (30) 75 (33) 48 (21) 36 (16) 20.6 F 23.1 56 F 12
62 (26) 72 (30) 60 (25) 47 (20) 24.2 F 27.0 55 F 14
.412
Variable At rest Heart rate (beat/min) Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Pressure-rate product (beat d mm Hg/min) At peak exercise Heart rate (beat/min) Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Pressure-rate product (beat d mm Hg/min) Chest pain, n (%) Positive ECG findings, n (%) Severity score Initial image Delayed image Reversibility score
High diastolic BP during exercise, n = 228
Normal diastolic BP during exercise, n = 241
P
73 F 15 144 F 22
72 F 14 140 F 24
.225 .033
83 F 11
74 F 10
b.001
10 575 F 2745
9943 F 2488
.009
134 F 19 211 F 27
122 F 20 189 F 30
b.001 b.001
104 F 11
77 F 10
b.001
28 497 F 6094
23 271 F 5760
b.001
38 (17) 43 (19)
49 (20) 52 (22)
.307 .464
1.18 F 0.85 0.84 F 0.60 0.38 F 0.43
1.35 F 0.99 0.92 F 0.70 0.48 F 0.51
.045 .192 .021
ECG, Electrocardiography.
.118 .444
ACEI, Angiotensin-converting enzyme inhibitors; ARB, angiotensin II receptor blockers; BP, blood pressure.
neous coronary intervention, medications, number of diseased vessels, Gensini score, or rest LVEF.
Heart rate and blood pressure Exercise 201Tl SPECT data are shown in Table II. There was no significant difference in heart rate at rest between patients with high and normal diastolic blood pressure during exercise, whereas patients with high diastolic blood pressure during exercise exhibited higher systolic and diastolic blood pressures and higher pressure-rate product at rest. Patients with high diastolic blood pressure during exercise exhibited significantly higher heart rate, higher systolic and diastolic blood pressures, and higher pressure-rate product during exercise than patients with normal diastolic blood pressure during exercise. There was no significant difference in either systolic (139 F 25 vs 142 F 23 mm Hg, P = .646) or diastolic (77 F 10 vs 79 F 12 mm Hg, P = .396) blood pressure at rest, systolic (200 F 30 vs 200 F 32 mm Hg, P = .984) or diastolic (94 F 15 vs 90 F 17 mm Hg, P = .178) blood
pressure during exercise or the increase in systolic blood pressure by exercise (61 F 38 vs 58 F 29 mm Hg, P = .707) between 29 patients treated with h-blocker alone and 171 patients treated with vasodilators (calciumchannel blockers, nitrates, angiotensin-converting enzyme inhibitors, and angiotensin II receptor blockers) alone. However, the increase in diastolic blood pressure by exercise was significantly greater in patients treated with h-blocker alone than in patients treated with vasodilators alone (18 F 16 vs 11 F 14 mm Hg, P = .022).
Perfusion abnormality Perfusion abnormality data are also shown in Table II. There was no significant difference in severity score of reinjection images between patients with high (n = 70) and normal (n = 92) diastolic blood pressure during exercise (0.60 F 0.62 vs 0.65 F 0.64, P = .759). There was no significant difference in reversibility score between patients with high (n = 66) and normal (n = 403) diastolic blood pressure at rest (0.38 F 0.41 vs 0.44 F 0.49, P = .339). Reversibility score was significantly smaller in patients with high diastolic blood pressure during exercise than in patients with normal diastolic blood pressure during exercise (0.38 F 0.43 vs 0.48 F 0.51, P = .021), although there was no significant
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difference in the number of diseased vessels by angiography between 2 groups. There was no significant correlation between the change in diastolic blood pressure by exercise and reversibility score, between diastolic blood pressure during exercise and reversibility score, or between pulse pressure during exercise and reversibility score. Reversibility scores adjusted for pressure-rate product at peak exercise (reversibility score/pressure-rate product 104 ) are shown in Figure 1. The adjusted reversibility score for all patients was significantly smaller in patients with high diastolic blood pressure during exercise than in patients with normal diastolic blood pressure during exercise. The adjusted reversibility score for patients with 1-vessel CAD was significantly smaller in patients with high diastolic blood pressure during exercise than in patients with normal diastolic blood pressure during exercise. The adjusted reversibility scores for patients with 0 -vessel, 2-vessel, or 3-vessel CAD tended to be smaller in patients with high diastolic blood pressure during exercise than in patients with normal diastolic blood pressure during exercise, but not to a statistically significant extent.
Discussion In our study, patients with high diastolic blood pressure during exercise had less severe exerciseinduced ischemia than patients with normal diastolic blood pressure during exercise, although the former had severity of coronary atherosclerosis equal to and higher pressure-rate product at peak exercise than the latter.
Possible mechanisms of effects of high diastolic blood pressure during exercise on exercise-induced ischemia Most coronary blood flow to the left ventricle occurs during diastole, because perfusion pressure drops markedly during systole because of systolic compression of the coronary vessels coursing through the myocardium. Kern et al8 reported that augmentation of diastolic blood pressure by intra-aortic balloon pumping did not increase coronary flow velocity beyond significant coronary stenosis. However, Flynn et al9 reported that intra-aortic balloon pumping augmented coronary collateral blood flow velocity. It has been postulated that high diastolic blood pressure during exercise may increase myocardial blood flow in ischemic areas during exercise via collateral channels. Augmentation of diastolic blood pressure by 35-hour treatment with enhanced external counterpulsation was reported to improve coronary flow reserve and to reduce exerciseinduced myocardial ischemia in patients with CAD.10,11 High diastolic blood pressure during exercise in daily life may have the same effects on myocardial ischemia as enhanced external counterpulsation. It has been also postulated that high diastolic blood pressure during
Yamagishi et al 793
Figure 1
Reversibility score according to number of diseased vessels adjusted for pressure-rate product at peak exercise (reversibility score/ pressure-rate product 104) in patients with high (open bars) and normal (hatched bars) diastolic blood pressure during exercise. PRP, Pressure-rate product.
exercise in daily life may open or enhance the development of collateral channels during exercise. However, evaluation of collateral blood flow during exercise is difficult in the clinical setting.
Factors influencing diastolic blood pressure during exercise The principal components of blood pressure consist of a steady-state component of peripheral arteriolar resistance, represented by mean arterial pressure, and a pulsatile component of impedance, represented by pulse pressure.12 -16 Pulse pressure is determined by cardiac output, heart rate, large central artery stiffness, and the effects of early wave reflection. Increased central artery stiffness in elderly subjects increases pulse pressure.12 -16 If peripheral arteriolar resistance increases greatly and there is a small increase in central arterial stiffness, diastolic blood pressure rises to at least 90 mm Hg, a condition classified as combined systolic/diastolic hypertension. If central arterial stiffness increases greatly and there is a small increase in peripheral arteriolar resistance, diastolic blood pressure remains normal or decreases below normal, a condition classified as isolated systolic hypertension. Patients with high diastolic blood pressure during exercise exhibited significantly higher diastolic blood pressure at rest than patients with normal diastolic blood pressure during exercise and were considered to have increased peripheral arteriolar resistance but slightly increased arterial stiffness at rest. An exaggerated diastolic blood pressure response to exercise was reported to predict new-onset hypertension in normotensive subjects17 and can be explained by increased
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794 Yamagishi et al
resting peripheral arteriolar resistance in the early stages of hypertension18 and impaired capacity for exerciseinduced vasodilation.19 -22 Therefore, patients with high diastolic blood pressure during exercise but not at rest might have increased peripheral arteriolar resistance and/or impaired capacity for exercise-induced vasodilation. Although increased peripheral arteriolar resistance and impaired capacity for exercise-induced vasodilation increase myocardial oxygen demand during exercise by increasing afterload, we found that high diastolic blood pressure during exercise, which is believed to be caused by increased peripheral arteriolar resistance and/or impaired capacity for exercise-induced vasodilation, may have the potential to decrease exercise-induced myocardial ischemia by increasing of myocardial blood flow.
Effects of medications on diastolic blood pressure and myocardial ischemia Antianginal drugs such as nitrates and calcium-channel blockers relax vascular smooth muscle and induce vasodilation of coronary arteries and peripheral arteries, resulting in lowered systolic and diastolic blood pressures. Our findings suggest that although lowered systolic blood pressure reduces myocardial oxygen demand, lowered diastolic blood pressure may worsen exercise-induced ischemia. Vascular h2 receptor blockade by h-blockers inhibits the vasodilating effects of catecholamines in peripheral blood vessels and leaves a-adrenergic receptors unopposed and thereby enhances vasoconstriction. We also found that the increase in diastolic blood pressure by exercise was significantly greater in patients treated with h-blockers alone than in patients treated with vasodilators (calcium-channel blockers, nitrates, angiotensin-converting enzyme inhibitors, and angiotensin II receptor blockers) alone. The vasoconstriction by h-blockers may also have protective effects against exercise-induced ischemia by raising diastolic blood pressure during exercise, although the principal mechanism of the anti-ischemic effects of h-blockers is attenuation of cardiac responses to adrenergic stimulation. Study limitations We identified 469 consecutive patients with sinus rhythm and known or suspected CAD who underwent exercise 201Tl myocardial SPECT and coronary arteriography in our hospital for this study. However, the decision to perform exercise 201Tl myocardial SPECT and coronary arteriography was made by physicians on the basis of clinical findings of patients. Therefore, the patient selection might be biased and thus influence the data. The present study was performed retrospectively, and 90% of patients were treated with antianginal or antihypertensive drugs. Although there was no difference in medications between the patients with high and normal diastolic blood pressure during exercise,
effects of medications on the exercise-induced ischemia cannot be neglected. To confirm our conclusion, prospective investigation of the degree of exercise-induced ischemia in untreated patients is needed.
Conclusion We demonstrated that patients with high diastolic blood pressure during exercise had less severe exerciseinduced ischemia than patients with normal diastolic blood pressure, although the former had severity of coronary atherosclerosis equal to and higher pressurerate product at peak exercise than the latter. These results provide new insights into potential protective effects against exercise-induced ischemia of high diastolic blood pressure during exercise, although the mechanism of such effects remains to be determined.
References 1. Rooke GA, Feigl EO, Rooke GA, et al. Work as a correlate of canine left ventricular oxygen consumption, and the problem of catecholamine oxygen wasting. Circ Res 1982;50:273 - 86. 2. The expert committee on the diagnosis and classification of diabetes mellitus. Report of the expert committee on the diagnosis and classification of diabetes mellitus. Diabetes Care 1997;20: 1183 - 97. 3. Germano G, Kavanagh PB, Su H, et al. Automatic reorientation of three-dimensional, transaxial myocardial perfusion SPECT images. J Nucl Med 1995;36:1107 - 14. 4. Diamond GA, Staniloff HM, Forrester JS, et al. Computer-assisted diagnosis in the noninvasive evaluation of patients with suspected coronary artery disease. J Am Coll Cardiol 1983;1:444 - 55. 5. Germano G, Kiat H, Kavanagh PB, et al. Automatic quantification of ejection fraction from gated myocardial perfusion SPECT. J Nucl Med 1995;36:2138 - 47. 6. Germano G, Erel J, Lewin H, et al. Automatic quantitation of regional myocardial wall motion and thickening from gated technetium-99m sestamibi myocardial perfusion single-photon emission computed tomography. J Am Coll Cardiol 1997;30:1360 - 7. 7. Gensini GG. A more meaningful scoring system for determining the severity of coronary heart disease. Am J Cardiol 1983;51:606. 8. Kern MJ, Abuirre F, Bach R, et al. Augmentation of coronary blood flow by intra-aortic balloon pumping in patients after coronary angioplasty. Circulation 1993;87:500 - 11. 9. Flynn MS, Kern MJ, Donohue TJ, et al. Alterations of coronary collateral blood flow velocity during intraaortic balloon pumping. Am J Cardiol 1993;71:1451 - 5. 10. Urano H, Ikeda H, Ueno T, et al. Enhanced external counterpulsation improves exercise tolerance, reduces exerciseinduced myocardial ischemia and improves left ventricular diastolic filling in patients with coronary artery disease. J Am Coll Cardiol 2001;37:93 - 9. 11. Masuda D, Nohara R, Hirai T, et al. Enhanced external counterpulsation improved myocardial perfusion and coronary flow reserve in patients with chronic stable angina; evaluation by (13)N-ammonia positron emission tomography. Eur Heart J 2001;22:1451 - 8.
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12. O’Rourke MF. Arterial function in health and disease. Churchil Livingstone: Edinburg; 1982. 13. Safer ME. Pulse pressure in essential hypertension. Clinical and therapeutic implications. J Hypertens 1989;7:769 - 76. 14. Nichols WW, O’Rourke MF. McDonald’s blood flow in arteries. 4th ed. London: Arnold Hodder Headline Group; 1998. 15. Berne RM, Levy MN. Cardiovascular physiology. St Louis: MosbyYear Book; 1992. p.135 -51. 16. Safar ME, Cloarec-Blauchard L, London GM. Arterial alterations in hypertension with a disproportionate increase in systolic over diastolic blood pressure. J Hypertens 1996;14 (Suppl 2):S103 - 9. 17. Singh JP, Larson MG, Manolio TA, et al. Blood pressure response during treadmill testing as a risk factor for new-onset hypertension. The Framingham heart study. Circulation 1999;99:1831 - 6.
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18. Julius S. Abnormalities of autonomic nervous control in human hypertension. Cardiovasc Drugs Ther 1994;8(Suppl 1):11 - 20. 19. Wilson MF, Sung BH, Pincomb GA, et al. Exaggerated pressure response to exercise in men at risk for systemic hypertension. Am J Cardiol 1990;66:731 - 6. 20. Franz IW. Exercise hypertension: its measurement and evaluation. Herz 1987;12:99 - 109. 21. Saitoh M, Miyakoda H, Kitamura H, et al. Cardiovascular and sympathetic nervous response to dynamic exercise in patients with essential hypertension. Intern Med 1992;31:606 - 10. 22. Ekstrand K, Nilsson JA, Lilja B, et al. Markers for development of hypertension in commercial flight aviators. Aviat Space Environ Med 1991;62:963 - 8.
Background Hypertension is one of the risk factors for coronary artery disease. However, because most coronary blood flow to the left ventricle occurs during diastole, high diastolic blood pressure during exercise may have a protective effect against exercise-induced myocardial ischemia. The aim of the present study was to test this hypothesis. Methods and Results We identified 469 patients with sinus rhythm and known or suspected coronary artery disease who underwent exercise thallium-201 myocardial single-photon emission computed tomography and coronary arteriography. High diastolic blood pressure during exercise was defined as diastolic blood pressure at peak exercise z90 mm Hg. There was no significant difference in medications, number of diseased vessels, or Gensini score between patients with high (n = 228) and normal (n = 241) diastolic blood pressure during exercise, whereas patients with high diastolic blood pressure during exercise exhibited a higher pressure-rate product during exercise than patients with normal diastolic blood pressure during exercise. The reversibility score on thallium-201 myocardial scan was significantly smaller in patients with high diastolic blood pressure during exercise than in patients with normal diastolic blood pressure during exercise ( P = .021). Conclusions High diastolic blood pressure during exercise has a potential protective effect against exercise-induced ischemia, although the mechanism of such effects remains to be determined. (Am Heart J 2005;150:790 - 5.) Exercise-induced myocardial ischemia in patients with coronary artery disease (CAD) occurs because of imbalance between myocardial oxygen demand and supply. Myocardial oxygen demand is determined by myocardial wall tension, myocardial contractility, and heart rate. Systolic blood pressure and heart rate increase progressively with exercise, mediated through circulating catecholamines and sympathetic innervation of the sinoatrial node. The systolic blood pressure–heart rate (pressure-rate) product increases progressively with exercise and is closely correlated to myocardial oxygen demand.1 Myocardial oxygen supply is determined by coronary perfusion pressure and coronary vascular resistance without anemia or hypoxemia. In patients with organic stenosis of epicardial coronary arteries, the severity of coronary artery stenosis determines coronary vascular resistance. Most coronary blood flow to the left ventricle occurs during diastole, because coronary perFrom the Department of Internal Medicine and Cardiology, Osaka City University Graduate School of Medicine, Osaka, Japan. Submitted February 17, 2004; accepted November 21, 2004. Reprint requests: Hiroyuki Yamagishi, MD, Department of Internal Medicine and Cardiology, Osaka City University Graduate School of Medicine, 1-4-3 Asahi-Machi, Abeno-Ku, Osaka, 545-8585, Japan. E-mail: [email protected] 0002-8703/$ - see front matter n 2005, Mosby, Inc. All rights reserved. doi:10.1016/j.ahj.2004.11.007
fusion pressure drops during systole markedly because of systolic compression of the coronary vessels coursing through the myocardium. Therefore, high diastolic blood pressure during exercise may have a protective effect against exercise-induced myocardial ischemia, although high systolic blood pressure during exercise aggravates exercise-induced myocardial ischemia. The aim of the present study was to investigate whether high diastolic blood pressure during exercise has a protective effect against exercise-induced myocardial ischemia.
Methods Patient population We identified 469 consecutive patients [374 men and 95 women; mean age 63 F 9 (SD) years, range 36 to 86 years] with sinus rhythm and known or suspected CAD who underwent exercise thallium-201 (201Tl) myocardial singlephoton emission computed tomography (SPECT) and coronary arteriography in our hospital between January 1999 and December 2002. The decision to perform exercise 201Tl myocardial SPECT and coronary arteriography was made by physicians on the basis of clinical findings of patients. Patients who had undergone coronary bypass grafting and those with significant valvular disease were excluded. Information about coronary risk factors elicited through questioning by the treating physician and laboratory data were reviewed retrospectively in medical records.
American Heart Journal Volume 150, Number 4
Hypertension was defined as resting casual systolic blood pressure z140 mm Hg, diastolic pressure z90 mm Hg, or treatment with antihypertensive agents. Hypercholesterolemia was defined as fasting serum total cholesterol z240 mg/dL or treatment with cholesterol-lowering agents. Obesity was defined as body mass index of z25 kg/m2. Diabetes mellitus was diagnosed based on the criteria of American Diabetes Association.2 High diastolic blood pressure during exercise was defined as diastolic blood pressure of z90 mm Hg at peak exercise.
Exercise thallium-201 myocardial single-photon emission computed tomography Each patient performed symptom-limited exercise on a bicycle ergometer. The workload was started at 25 or 50 W and increased by 25 W every 2 minutes until the end point of exercise was reached. Twelve-lead electrocardiograms and blood pressure measurements were obtained at rest and every minute during exercise. Blood pressure was measured by an automatic sphygmomanometer (STBP-780B, Colin Corporation, Aichi, Japan) based on a cuff-oscillometric method at the upper arm. The exercise end points included leg fatigue, dyspnea, moderate to severe angina, significant ST depression (N2.0 mm horizontal or down-sloping), or significant arrhythmia. At peak exercise, 201Tl (111 MBq for patients without previous myocardial infarction and 74 MBq for patients with previous myocardial infarction) was injected intravenously, and the patient was encouraged to exercise for an additional minute. Postexercise images were obtained immediately after the termination of exercise, and delayed images were obtained 4 hours later. In patients with previous myocardial infarction, an additional dose of 37 MBq of 201Tl was injected at rest immediately after the acquisition of delayed images, and reinjection images were obtained 20 minutes later. Single-photon emission computed tomography was performed with a 2-detector g-camera (VERTEX, ADAC Laboratories, Milpitas, Calif) equipped with low-energy, general-purpose collimators, with the detectors set to form a 908 angle. A total of 32 equidistant projections were acquired over 1808 in a 64 64 matrix from the 458 right anterior oblique to 458 left posterior oblique projection with 40 seconds per step, in 68 angular steps. A total of 8 frames per cardiac cycle electrocardiography-gated acquisition for assessment of left ventricular ejection fraction (LVEF) were performed at each projection. Nongated images for assessment of 201Tl uptake were obtained by summing all gated images. Transaxial slices of 4.7-mm pixel thickness were reconstructed using a Butterworth filter (order = 5.0, critical frequency = 0.35 cycles per pixel) and the filtered back-projection method (ramp filter) on a processing computer (Pegasys, ADAC Laboratories) with an automatic processing software program for SPECT (Cedars AutoSPECT; Cedars-Sinai Medical Center, Los Angeles, Calif).3
Scintigraphic image analysis Perfusion defects. An automated perfusion abnormality analysis software program (autoQUANT, ADAC Laboratories) was used for quantification of the severity of perfusion defects compared with a normal limit database, which included 36 patients with a low likelihood (b5%) of CAD.4 Severity score was calculated as the average of the number
Yamagishi et al 791
of SD below the normal mean. All pixels above normal were considered equal to zero. Reversibility score was calculated as the difference between the severity scores of delayed and initial images. Reversibility score b0 was considered equal to zero. Left ventricular ejection fraction. A completely automated left ventricular function analysis software program (Cedars Quantitative Gated SPECT; Cedars-Sinai Medical Center)5,6 was used for calculation of global LVEF. Rest LVEF was derived from delayed images in patients without reinjection images and from reinjection images in patients with reinjection images.
Coronary arteriography Coronary angioplasty was not performed between the scintigraphic study and coronary arteriography in any patient. Coronary artery narrowing was visually assessed and reported as percentage luminal diameter stenosis. Significant CAD was defined as z75% narrowing of the internal diameter of the left anterior descending artery, the left circumflex artery, the right coronary artery, or their major branches and z50% narrowing of the left main coronary artery. Thirty-eight of the 469 patients had significant left main CAD, which was considered equivalent to combined disease of the left anterior descending artery and the left circumflex artery. Of 131 patients without angiographically significant organic stenosis, 75 had a history of previous percutaneous coronary intervention, 14 had previous myocardial infarction without previous percutaneous coronary intervention, 11 was diagnosed with vasospastic angina, and 31 was diagnosed with chest pain syndrome. Gensini score7 was calculated to evaluate the severity of coronary atherosclerosis. All patients gave written informed consent.
Statistics Values are given as mean values F SD. Incidences of phenomena were compared with the m2 test. Continuous variables were compared with Student t test. Correlation coefficients were calculated by linear regression analysis. P values of b.05 were considered significant. These analyses were performed with SPSS version 10.0 (SPSS, Inc, Chicago, Ill).
Results Patient characteristics Of 469 patients, 228 patients exhibited high diastolic blood pressure during exercise, 55 (24%) patients of whom exhibited high diastolic blood pressure at rest, whereas 241 patients exhibited normal diastolic blood pressure during exercise, 11 (5%) patients of whom exhibited high diastolic blood pressure at rest. Baseline characteristics of patients with high and normal diastolic blood pressure during exercise are shown in Table I. Patients with high diastolic blood pressure exhibited younger age, less frequent diabetes mellitus, and more frequent hypertension than patients with normal diastolic blood pressure during exercise. However, there was no significant difference between these groups in sex, previous myocardial infarction, previous percuta-
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792 Yamagishi et al
Table I. Baseline characteristics of patients with high and normal diastolic blood pressure during exercise
Variable Age, y Men, n (%) Previous myocardial infarction, n (%) Previous percutaneous coronary intervention, n (%) Coronary risk factors, n (%) Current smoking Diabetes mellitus Family history of CAD Hypercholesterolemia Hypertension Obesity Medication, n (%) h-Blockers Calcium-channel blockers Nitrates ACEI or ARB No. diseased vessels, n (%) 0 1 2 3 Gensini score Rest LVEF, %
Table II. Exercise thallium-201 single-photon emission computed tomography data
High diastolic BP during exercise, n = 228
Normal diastolic BP during exercise, n = 241
61 F 9 180 (79) 70 (31)
65 F 9 194 (80) 92 (38)
b.001 .676 .089
125 (55)
123 (51)
.383
P
85 (37) 61 (27) 39 (17) 53 (23) 136 (60) 77 (34)
100 93 32 44 122 81
(41) (39) (13) (18) (51) (34)
.351 .006 .248 .183 .049 .970
130 (57) 92 (40)
124 (51) 88 (37)
.227 .393
152 (67) 73 (32)
158 (66) 80 (33)
.800 .786
69 (30) 75 (33) 48 (21) 36 (16) 20.6 F 23.1 56 F 12
62 (26) 72 (30) 60 (25) 47 (20) 24.2 F 27.0 55 F 14
.412
Variable At rest Heart rate (beat/min) Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Pressure-rate product (beat d mm Hg/min) At peak exercise Heart rate (beat/min) Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Pressure-rate product (beat d mm Hg/min) Chest pain, n (%) Positive ECG findings, n (%) Severity score Initial image Delayed image Reversibility score
High diastolic BP during exercise, n = 228
Normal diastolic BP during exercise, n = 241
P
73 F 15 144 F 22
72 F 14 140 F 24
.225 .033
83 F 11
74 F 10
b.001
10 575 F 2745
9943 F 2488
.009
134 F 19 211 F 27
122 F 20 189 F 30
b.001 b.001
104 F 11
77 F 10
b.001
28 497 F 6094
23 271 F 5760
b.001
38 (17) 43 (19)
49 (20) 52 (22)
.307 .464
1.18 F 0.85 0.84 F 0.60 0.38 F 0.43
1.35 F 0.99 0.92 F 0.70 0.48 F 0.51
.045 .192 .021
ECG, Electrocardiography.
.118 .444
ACEI, Angiotensin-converting enzyme inhibitors; ARB, angiotensin II receptor blockers; BP, blood pressure.
neous coronary intervention, medications, number of diseased vessels, Gensini score, or rest LVEF.
Heart rate and blood pressure Exercise 201Tl SPECT data are shown in Table II. There was no significant difference in heart rate at rest between patients with high and normal diastolic blood pressure during exercise, whereas patients with high diastolic blood pressure during exercise exhibited higher systolic and diastolic blood pressures and higher pressure-rate product at rest. Patients with high diastolic blood pressure during exercise exhibited significantly higher heart rate, higher systolic and diastolic blood pressures, and higher pressure-rate product during exercise than patients with normal diastolic blood pressure during exercise. There was no significant difference in either systolic (139 F 25 vs 142 F 23 mm Hg, P = .646) or diastolic (77 F 10 vs 79 F 12 mm Hg, P = .396) blood pressure at rest, systolic (200 F 30 vs 200 F 32 mm Hg, P = .984) or diastolic (94 F 15 vs 90 F 17 mm Hg, P = .178) blood
pressure during exercise or the increase in systolic blood pressure by exercise (61 F 38 vs 58 F 29 mm Hg, P = .707) between 29 patients treated with h-blocker alone and 171 patients treated with vasodilators (calciumchannel blockers, nitrates, angiotensin-converting enzyme inhibitors, and angiotensin II receptor blockers) alone. However, the increase in diastolic blood pressure by exercise was significantly greater in patients treated with h-blocker alone than in patients treated with vasodilators alone (18 F 16 vs 11 F 14 mm Hg, P = .022).
Perfusion abnormality Perfusion abnormality data are also shown in Table II. There was no significant difference in severity score of reinjection images between patients with high (n = 70) and normal (n = 92) diastolic blood pressure during exercise (0.60 F 0.62 vs 0.65 F 0.64, P = .759). There was no significant difference in reversibility score between patients with high (n = 66) and normal (n = 403) diastolic blood pressure at rest (0.38 F 0.41 vs 0.44 F 0.49, P = .339). Reversibility score was significantly smaller in patients with high diastolic blood pressure during exercise than in patients with normal diastolic blood pressure during exercise (0.38 F 0.43 vs 0.48 F 0.51, P = .021), although there was no significant
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difference in the number of diseased vessels by angiography between 2 groups. There was no significant correlation between the change in diastolic blood pressure by exercise and reversibility score, between diastolic blood pressure during exercise and reversibility score, or between pulse pressure during exercise and reversibility score. Reversibility scores adjusted for pressure-rate product at peak exercise (reversibility score/pressure-rate product 104 ) are shown in Figure 1. The adjusted reversibility score for all patients was significantly smaller in patients with high diastolic blood pressure during exercise than in patients with normal diastolic blood pressure during exercise. The adjusted reversibility score for patients with 1-vessel CAD was significantly smaller in patients with high diastolic blood pressure during exercise than in patients with normal diastolic blood pressure during exercise. The adjusted reversibility scores for patients with 0 -vessel, 2-vessel, or 3-vessel CAD tended to be smaller in patients with high diastolic blood pressure during exercise than in patients with normal diastolic blood pressure during exercise, but not to a statistically significant extent.
Discussion In our study, patients with high diastolic blood pressure during exercise had less severe exerciseinduced ischemia than patients with normal diastolic blood pressure during exercise, although the former had severity of coronary atherosclerosis equal to and higher pressure-rate product at peak exercise than the latter.
Possible mechanisms of effects of high diastolic blood pressure during exercise on exercise-induced ischemia Most coronary blood flow to the left ventricle occurs during diastole, because perfusion pressure drops markedly during systole because of systolic compression of the coronary vessels coursing through the myocardium. Kern et al8 reported that augmentation of diastolic blood pressure by intra-aortic balloon pumping did not increase coronary flow velocity beyond significant coronary stenosis. However, Flynn et al9 reported that intra-aortic balloon pumping augmented coronary collateral blood flow velocity. It has been postulated that high diastolic blood pressure during exercise may increase myocardial blood flow in ischemic areas during exercise via collateral channels. Augmentation of diastolic blood pressure by 35-hour treatment with enhanced external counterpulsation was reported to improve coronary flow reserve and to reduce exerciseinduced myocardial ischemia in patients with CAD.10,11 High diastolic blood pressure during exercise in daily life may have the same effects on myocardial ischemia as enhanced external counterpulsation. It has been also postulated that high diastolic blood pressure during
Yamagishi et al 793
Figure 1
Reversibility score according to number of diseased vessels adjusted for pressure-rate product at peak exercise (reversibility score/ pressure-rate product 104) in patients with high (open bars) and normal (hatched bars) diastolic blood pressure during exercise. PRP, Pressure-rate product.
exercise in daily life may open or enhance the development of collateral channels during exercise. However, evaluation of collateral blood flow during exercise is difficult in the clinical setting.
Factors influencing diastolic blood pressure during exercise The principal components of blood pressure consist of a steady-state component of peripheral arteriolar resistance, represented by mean arterial pressure, and a pulsatile component of impedance, represented by pulse pressure.12 -16 Pulse pressure is determined by cardiac output, heart rate, large central artery stiffness, and the effects of early wave reflection. Increased central artery stiffness in elderly subjects increases pulse pressure.12 -16 If peripheral arteriolar resistance increases greatly and there is a small increase in central arterial stiffness, diastolic blood pressure rises to at least 90 mm Hg, a condition classified as combined systolic/diastolic hypertension. If central arterial stiffness increases greatly and there is a small increase in peripheral arteriolar resistance, diastolic blood pressure remains normal or decreases below normal, a condition classified as isolated systolic hypertension. Patients with high diastolic blood pressure during exercise exhibited significantly higher diastolic blood pressure at rest than patients with normal diastolic blood pressure during exercise and were considered to have increased peripheral arteriolar resistance but slightly increased arterial stiffness at rest. An exaggerated diastolic blood pressure response to exercise was reported to predict new-onset hypertension in normotensive subjects17 and can be explained by increased
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794 Yamagishi et al
resting peripheral arteriolar resistance in the early stages of hypertension18 and impaired capacity for exerciseinduced vasodilation.19 -22 Therefore, patients with high diastolic blood pressure during exercise but not at rest might have increased peripheral arteriolar resistance and/or impaired capacity for exercise-induced vasodilation. Although increased peripheral arteriolar resistance and impaired capacity for exercise-induced vasodilation increase myocardial oxygen demand during exercise by increasing afterload, we found that high diastolic blood pressure during exercise, which is believed to be caused by increased peripheral arteriolar resistance and/or impaired capacity for exercise-induced vasodilation, may have the potential to decrease exercise-induced myocardial ischemia by increasing of myocardial blood flow.
Effects of medications on diastolic blood pressure and myocardial ischemia Antianginal drugs such as nitrates and calcium-channel blockers relax vascular smooth muscle and induce vasodilation of coronary arteries and peripheral arteries, resulting in lowered systolic and diastolic blood pressures. Our findings suggest that although lowered systolic blood pressure reduces myocardial oxygen demand, lowered diastolic blood pressure may worsen exercise-induced ischemia. Vascular h2 receptor blockade by h-blockers inhibits the vasodilating effects of catecholamines in peripheral blood vessels and leaves a-adrenergic receptors unopposed and thereby enhances vasoconstriction. We also found that the increase in diastolic blood pressure by exercise was significantly greater in patients treated with h-blockers alone than in patients treated with vasodilators (calcium-channel blockers, nitrates, angiotensin-converting enzyme inhibitors, and angiotensin II receptor blockers) alone. The vasoconstriction by h-blockers may also have protective effects against exercise-induced ischemia by raising diastolic blood pressure during exercise, although the principal mechanism of the anti-ischemic effects of h-blockers is attenuation of cardiac responses to adrenergic stimulation. Study limitations We identified 469 consecutive patients with sinus rhythm and known or suspected CAD who underwent exercise 201Tl myocardial SPECT and coronary arteriography in our hospital for this study. However, the decision to perform exercise 201Tl myocardial SPECT and coronary arteriography was made by physicians on the basis of clinical findings of patients. Therefore, the patient selection might be biased and thus influence the data. The present study was performed retrospectively, and 90% of patients were treated with antianginal or antihypertensive drugs. Although there was no difference in medications between the patients with high and normal diastolic blood pressure during exercise,
effects of medications on the exercise-induced ischemia cannot be neglected. To confirm our conclusion, prospective investigation of the degree of exercise-induced ischemia in untreated patients is needed.
Conclusion We demonstrated that patients with high diastolic blood pressure during exercise had less severe exerciseinduced ischemia than patients with normal diastolic blood pressure, although the former had severity of coronary atherosclerosis equal to and higher pressurerate product at peak exercise than the latter. These results provide new insights into potential protective effects against exercise-induced ischemia of high diastolic blood pressure during exercise, although the mechanism of such effects remains to be determined.
References 1. Rooke GA, Feigl EO, Rooke GA, et al. Work as a correlate of canine left ventricular oxygen consumption, and the problem of catecholamine oxygen wasting. Circ Res 1982;50:273 - 86. 2. The expert committee on the diagnosis and classification of diabetes mellitus. Report of the expert committee on the diagnosis and classification of diabetes mellitus. Diabetes Care 1997;20: 1183 - 97. 3. Germano G, Kavanagh PB, Su H, et al. Automatic reorientation of three-dimensional, transaxial myocardial perfusion SPECT images. J Nucl Med 1995;36:1107 - 14. 4. Diamond GA, Staniloff HM, Forrester JS, et al. Computer-assisted diagnosis in the noninvasive evaluation of patients with suspected coronary artery disease. J Am Coll Cardiol 1983;1:444 - 55. 5. Germano G, Kiat H, Kavanagh PB, et al. Automatic quantification of ejection fraction from gated myocardial perfusion SPECT. J Nucl Med 1995;36:2138 - 47. 6. Germano G, Erel J, Lewin H, et al. Automatic quantitation of regional myocardial wall motion and thickening from gated technetium-99m sestamibi myocardial perfusion single-photon emission computed tomography. J Am Coll Cardiol 1997;30:1360 - 7. 7. Gensini GG. A more meaningful scoring system for determining the severity of coronary heart disease. Am J Cardiol 1983;51:606. 8. Kern MJ, Abuirre F, Bach R, et al. Augmentation of coronary blood flow by intra-aortic balloon pumping in patients after coronary angioplasty. Circulation 1993;87:500 - 11. 9. Flynn MS, Kern MJ, Donohue TJ, et al. Alterations of coronary collateral blood flow velocity during intraaortic balloon pumping. Am J Cardiol 1993;71:1451 - 5. 10. Urano H, Ikeda H, Ueno T, et al. Enhanced external counterpulsation improves exercise tolerance, reduces exerciseinduced myocardial ischemia and improves left ventricular diastolic filling in patients with coronary artery disease. J Am Coll Cardiol 2001;37:93 - 9. 11. Masuda D, Nohara R, Hirai T, et al. Enhanced external counterpulsation improved myocardial perfusion and coronary flow reserve in patients with chronic stable angina; evaluation by (13)N-ammonia positron emission tomography. Eur Heart J 2001;22:1451 - 8.
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12. O’Rourke MF. Arterial function in health and disease. Churchil Livingstone: Edinburg; 1982. 13. Safer ME. Pulse pressure in essential hypertension. Clinical and therapeutic implications. J Hypertens 1989;7:769 - 76. 14. Nichols WW, O’Rourke MF. McDonald’s blood flow in arteries. 4th ed. London: Arnold Hodder Headline Group; 1998. 15. Berne RM, Levy MN. Cardiovascular physiology. St Louis: MosbyYear Book; 1992. p.135 -51. 16. Safar ME, Cloarec-Blauchard L, London GM. Arterial alterations in hypertension with a disproportionate increase in systolic over diastolic blood pressure. J Hypertens 1996;14 (Suppl 2):S103 - 9. 17. Singh JP, Larson MG, Manolio TA, et al. Blood pressure response during treadmill testing as a risk factor for new-onset hypertension. The Framingham heart study. Circulation 1999;99:1831 - 6.
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18. Julius S. Abnormalities of autonomic nervous control in human hypertension. Cardiovasc Drugs Ther 1994;8(Suppl 1):11 - 20. 19. Wilson MF, Sung BH, Pincomb GA, et al. Exaggerated pressure response to exercise in men at risk for systemic hypertension. Am J Cardiol 1990;66:731 - 6. 20. Franz IW. Exercise hypertension: its measurement and evaluation. Herz 1987;12:99 - 109. 21. Saitoh M, Miyakoda H, Kitamura H, et al. Cardiovascular and sympathetic nervous response to dynamic exercise in patients with essential hypertension. Intern Med 1992;31:606 - 10. 22. Ekstrand K, Nilsson JA, Lilja B, et al. Markers for development of hypertension in commercial flight aviators. Aviat Space Environ Med 1991;62:963 - 8.