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Association of Systolic Blood Pressure at Time of Myocardial Ischemia With Angina Pectoris During Exercise Testing
Association of Systolic Blood Pressure at Time of Myocardial Ischemia With Angina Pectoris During Exercise Testing Brian M. Go,
MD,
David Sheffield,
PhD,
Rungroj Krittayaphong, and David S. Sheps, MD
MD,
William Maixner,
DDS, PhD,
ince the introduction of electrocardiographic exercise testing, it has been recognized that patients S can have ST-segment depression without angina
ing electrocardiographic abnormalities that might influence test interpretation (left ventricular hypertrophy, Wolff-Parkinson-White syndrome, left bundle pectoris.1 What makes ischemia either silent or branch block, or remarkable intraventricular conducsymptomatic may be related to the degree of isch- tion defect); (4) ECG changes with posture or hyemia2,3 and/or how an individual perceives sensory perventilation; (5) age °35 years; (6) normal or noninput during ischemia.4,5 Increased blood pressure significant coronary artery disease (õ50% diameter (BP) has been strongly associated with decreased narrowing) from coronary arteriography; and (7) pain perception in both animals6,7 and humans.8 – 10 subsequent nuclear imaging study not suggestive of An important initial step in this association appears flow-limiting disease. to involve the stimulation of baroreceptors. Located Tests were performed using a standard Bruce proin the carotid sinus and aortic arch, these pressure tocol and a Marquette system. Baseline ST-segment receptors are stimulated by increases in arterial pres- analysis was established as the level of ST segment sure and possess central nervous system inhibitory observed in the standing position before the start of properties, including antinociception.11 Krittaya- exercise. Leads aVF, V3, and V5 were continuously phong and Sheps12 recently demonstrated that resting monitored. Twelve-lead electrocardiograms were reBP influences anginal indexes during exercise test- corded before exercise in the supine, standing, and ing in patients not taking antianginal medications. posthyperventilation conditions at 1-minute intervals In this study, we present data that systolic BP at during exercise and until at least 5 minutes into the the time of electrocardiographic (ECG) evident recovery phase or return to baseline. Blood pressure ischemia and the dynamic increase in systolic BP recorded by cuff sphygmomanometer was taken at are important factors in sensory perception of isch- rest before exercise, at 2 minutes into each stage of emia, regardless of medication status, smoking the protocol until at least 5 minutes into the recovery history, or baseline hypertension. These data sup- phase or return to the baseline level. In addition, 12port the hypothesis that an acute elevation in BP lead electrocardiograms and BP were obtained at the affects pain perception through activation of bar- time of onset of angina and at the time of onset of oreceptors. positive test, defined as ¢1 mm ST-segment depresjjj sion at 0.08 second after the J point for ¢3 consecWe reviewed 4,723 exercise treadmill tests per- utive beats. The end points were fatigue, progressive formed at the University of North Carolina Hospitals angina, ST-segment depression ¢3 mm, ¢3 consecduring the years 1990 to 1994. There were 1,144 utive ventricular premature complexes, or decrease positive tests (24%) defined as exercise-induced hor- in systolic BP by ¢10 mm Hg. Patients were inizontal or downsloping ST-segment depression of structed to inform the supervising physician imme¢1 mm measured 0.08 seconds after the J point. All diately of the onset and resolution of chest pain. The positive tests were confirmed by the same experi- following exercise variables were recorded in each enced cardiologist. For patients who had ¢2 positive patient: (1) heart rate, BP, and rate-pressure product tests, we selected only the first positive test for anal- at rest, onset of 1 mm ST-segment depression, onset ysis. We reviewed these tests and subjects were ex- of chest pain, and maximal exercise; (2) time at onset cluded for the following reasons: (1) conditions that of 1 mm ST-segment depression, at onset of chest might affect anginal pain perception (diabetes mel- pain, and total exercise time; (3) maximal ST-seglitus, postcoronary bypass surgery); (2) exercise ment depression and ECG leads in which ST-segprotocol other than standard Bruce protocol; (3) rest- ment depression was present; and (4) presence or absence of typical chest pain. From the Departments of Medicine and Endodontics, University of Continuous variables were described as mean { North Carolina Schools of Medicine and Dentistry, Chapel Hill, SE, and categorical variables were described with North Carolina. This study was supported by Grant 1-R01-HL-47477 frequencies and percentages. Differences between from the National Heart, Lung, and Blood Institute, Bethesda, Maryland, by General Clinical Research Center Grant RR00046 from the groups were compared with Student’s t test for conNational Institutes of Health, Bethesda, Maryland, and by Cooper- tinuous data, and chi-square test for categorical data. ative Agreement CR817643 from the Environmental Protection A p value °0.05 was considered statistically signifAgency, Washington, D.C. Dr. Sheps’ address is: 338 Burnett-Womicant. ack Building/CB# 7075, Chapel Hill, North Carolina 27599Three hundred six patients with positive exercise 7075. Manuscript received July 31, 1996; revised manuscript retests were included in these analyses; 100 (33%) had ceived and accepted November 12, 1996. 954
Q1997 by Excerpta Medica, Inc. All rights reserved.
/ 2w1e 0890 Mp
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Wednesday Mar 05 10:47 PM
0002-9149/97/$17.00 PII S0002-9149(97)00018-0
EL–AJC (v. 79, no. 7 ’97)
0890
silent ischemia. However, the time to onset of ST depression was greater in patients with silent ischMyocardial Ischemia emia, suggesting that they had less severe disease. Accordingly, the reSilent p Painful (n Å 206) Value (n Å 100) lation between hemodynamic parameters and the expression of ischAge (yr) 59 { 1 61 { 1 0.11 emia was examined after adjusting Men/women 77/23 (77%) 145/61 (70%) 0.23 Current smokers 23 (23%) 35 (17%) 0.21 for time to ST depression using loHistory of hypertension 45 (45%) 85 (41%) 0.54 gistic regression. Only systolic BP History of myocardial infarction 18 (18%) 52 (25%) 0.16 at onset of ST depression remained Underwent nuclear study 66 (66%) 115 (56%) 0.09 a significant predictor of silent ischUnderwent catheterization 57 (57%) 81 (39%) 0.003 emia (p Å 0.04). Similarly, when Number of coronary arteries narrowed ú50% in patients were matched for time to diameter* ST depression, systolic BP at onset 1 31 (23%) 17 (12%) of ST depression remained a signif2 22 (16%) 23 (17%) icant predictor of silent ischemia (p 3 27 (20%) 17 (12%) 0.27 b blockers (%) 29 (29%) 50 (24%) 0.38 Å 0.05). The same pattern of findCalcium antagonists (%) 28 (28%) 62 (30%) 0.71 ings was found in analyses of subLong-acting nitrates (%) 13 (13%) 26 (12%) 0.93 samples that (1) only included pa*137 of 306 cases. tients with documented disease (as indexed by positive catheterization, positive nuclear study, or history of painful ischemia. Table I lists demographic and dis- myocardial infarction); (2) only included patients ease characteristics of patients with and without an- with positive catheterization; and (3) included pagina. Patients with silent ischemia during exercise tients not taking medications. had a tendency to be older, and were less likely to jjj undergo radionuclide study or catheterization after The reasons why some patients with positive exexercise testing; no other differences emerged. ercise tests do not experience angina pectoris have Differences in exercise test characteristics be- not been fully elucidated. Factors such as degree of tween patients with painful and silent ischemia were ischemia,2,3 circulating b endorphins,13 personality then examined; Table II displays these data. Patients traits,14 and resting BP12 have been implicated. In this with silent ischemia during exercise had higher sys- study, we provide evidence that acute elevations in tolic BP and rate-pressure product at the onset of ST BP during exercise are related to painful ischemia. depression. Further, change in systolic BP from rest There is considerable evidence that BP influences to onset of ST depression was greater in patients with pain perception,6 – 10 but the mechanisms underlying TABLE I Demographic and Disease Characteristics of Patients With and Without Angina
TABLE II Exercise Test Characteristics of Patients With and Without Angina Myocardial Ischemia
Rest Systolic BP (mm Hg) Diastolic BP (mm Hg) HR (beats/min) Measures of ischemic threshold Time to 1 mm ST depression (s) Systolic BP at 1 mm ST depression (mm Hg) Change in systolic BP from rest to 1 mm ST depression (mm Hg) Diastolic BP at 1 mm ST depression (mm Hg) HR at 1 mm ST depression (beats/min) Rate-pressure product at 1 mm ST depression (beats/min 1 mm Hg) Number of leads with 1 mm ST depression Peak ST depression (mm) Duration of 1 mm ST depression (s) Measures of exercise performance Exercise duration (s) Peak systolic BP (mm Hg) Change in systolic BP from rest to peak exercise (mm Hg) Peak diastolic BP (mm Hg) Peak HR (beats/min) Peak rate-pressure product (beats/min 1 mm Hg)
Painful (n Å 100)
Silent (n Å 206)
134 { 2 82 { 1 75 { 1
137 { 1 82 { 1 74 { 1
p Value 0.35 0.76 0.59
268 164 29 83 127 20,800 4.0 1.3 406
{ 12 {3 {2 {1 {2 { 500 { 0.2 { 0.1 { 30
299 172 35 83 129 22,400 3.8 1.3 395
{9 {2 {2 {1 {2 { 400 { 0.1 { 0.0 { 17
0.05 0.01 0.04 0.85 0.29 0.03 0.38 0.81 0.73
353 170 36 83 135 23,100
{ 12 {3 {2 {2 {2 { 600
414 181 44 83 143 26,000
{ 10 {2 {2 {1 {2 { 400
0.001 0.002 0.003 0.85 0.003 0.001
BP Å blood pressure; HR Å heart rate.
BRIEF REPORTS
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Wednesday Mar 05 10:47 PM
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this relation are less clear. Further, it is questionable whether this association is due to chronic elevations in BP and elements inherent to the hypertensive state7 – 9,15 or if acute elevations play a role.6,11 Studies examining the relation between BP and pain perception in humans have demonstrated that hypoalgesia is associated with hypertension or borderline hypertension.8 – 10,12,15 For example, using graded electrical stimulation of the tooth pulp, Ghione et al10 showed higher sensory thresholds in subjects with borderline or established hypertension than in normotensive subjects. However, they found treating a subgroup of hypertensive subjects with antihypertensive medications with resulting BP reduction did not alter their pain sensitivity. Guasti et al8 found that 24-hour ambulatory BP recordings were a better predictor of pain perception than blood pressures taken before testing. They suggested that the influence of BP on pain sensitivity has less to do with dynamic pressure changes and more to do with chronic, longer-lasting trends. These studies are contrasted by reports of acute elevations in arterial BP influencing pain perception. Pressor agents peripherally administered to rats have been shown to induce hypoalgetic behaviors.6 Further, sympathomimetics have been used as analgesics in humans.16 The mechanistic explanation for these reports center on the stimulation of baroreceptors. Rats with surgically destroyed baroreceptors do not have the increased pain threshold seen in rats with intact baroreceptors during pharmacologically stimulated BP elevations.6 In humans, Dworkin et al17 demonstrated that acute baroreceptor stimulation in synchrony with the cardiac cycle produced postulated central nervous system inhibitory effects and decreased pain perception. Our results support the concept that acute baroreceptor stimulation caused by an exercise-induced elevation in BP decreases pain perception. We demonstrated that occurrence of painful ischemia is related to systolic BP at the time of ECG-evident ischemia in patients with positive treadmill tests, regardless of their medication status. In addition, a relation was found between angina pectoris and the increase in systolic BP from rest to time of ST-segment depression. In contrast, we found no relation between angina and resting BP or a history of hypertension. In our study, patients with silent ischemia had a greater time to ST-segment depression and achieved a higher workload than symptomatic patients; these differences could represent differing ischemic burdens between the groups.2,3,18 However, the relation between pain and systolic BP at the time of ST-segment depression remained after adjusting for the time of onset of ST-segment depression, suggesting that it was independent of disease severity. Additionally, there was no difference in the number of diseased vessels among patients who had cardiac catheterization performed; acute BP increases were
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related to anginal pain in patients with disease confirmed by catheterization (p Å 0.03). Some patients may also have had ST-segment depression without ischemia, although we excluded patients who had resting ECG abnormalities that could have influenced test interpretation, notably left ventricular hypertrophy and bundle branch block. Thus, although we cannot be certain that ST-segment depression was indicative of ischemia in all patients, our data strongly suggest that this is the most likely explanation. In conclusion, we present evidence that systolic BP at the time of ischemia and dynamic pressure changes during exercise are important factors in determining the presence or absence of angina pectoris during treadmill testing. These findings are consistent with acute activation of baroreceptors and resulting antinociception during an exerciseinduced elevation in BP. 1. Goldhammer S, Scherf D. Elektrokardiographische untersuchungen bei kranken mit angina pectoris (‘‘ambulatorischer’’ typus). Z Klin Med 1932;122: 134–151. 2. Nihoyannopoulos P, Marsonis A, Joshi J, Athanassopoulos G, Oakley CM. The magnitude of myocardial dysfunction is greater in painful than painless myocardial ischemia: an exercise echocardiographic study. J Am Coll Cardiol 1995;25:1507–1512. 3. Klein J, Chao SY, Berman DS, Rozanski A. Is ‘‘silent’’ myocardial ischemia really as severe as symptomatic ischemia? The analytical effect of patient selection biases. Circulation 1994;89:1958–1966. 4. Droste C, Roskamm H. Experimental pain measurement in patients with asymptomatic myocardial ischemia. J Am Coll Cardiol 1983;1:940–1945. 5. Sheps DS, Bragdon EE, Miller PF, Maixner W, Hinderliter AL, Light KC. The perception of pain in patients with myocardial ischemia. J Myocardial Ischemia 1980;1:29–38. 6. Dworkin BR, Filewich RJ, Miller NE, Craigmyle N. Baroreceptor activation reduces reactivity to noxious stimulation: implications for hypertension. Science 1979;205:1299–1301. 7. Sitsen JMA, de Jong W. Observations on pain perception and hypertension in spontaneously hypertensive rats. Clin Exp Hypertens [A] 1984;6:1345–1356. 8. Guasti L, Cattaneo R, Rinaldi O, Rossi MG, Bianchi L, Gaudio G, Grandi AM, Gorini G, Venco A. Twenty-four hour noninvasive blood pressure monitoring and pain perception. Hypertension 1995;25:1301–1305. 9. Rosa C, Vignocchi G, Panattoni E, Rossi B, Ghione S. Relationship between increased blood pressure and hypoalgesia: additional evidence for the existence of an abnormality of pain perception in arterial hypertension in humans. J Hum Hypertens 1994;8:119–126. 10. Ghione S, Rosa C, Mezzasalma L, Panattoni E. Arterial hypertension is associated with hypoalgesia in humans. Hypertension 1988;12:491–497. 11. Randich A, Maixner W. The role of sinoaortic and cardiopulmonary baroreceptor reflex arcs in nociception and stress-induced analgesia. Ann NY Acad Sci 1986;467:385–401. 12. Krittayaphong R, Sheps DS. Relation between resting blood pressure and perception of angina during exercise testing. Am J Cardiol 1996;77:1224–1226. 13. Miller PF, Light KC, Bragdon EE, Ballenger MN, Herbst MG, Maixner W, Hinderliter AL, Atkinson SS, Koch GG, Sheps, DS. Beta-endorphin response to exercise and mental stress in patients with ischemic heart disease. J Psychosomat Res 1993;37:455–465. 14. Light KC, Herbst MC, Bragdon EE, Hinderliter AL, Koch GG, Davis MR, Sheps, DS. Depression and type A behavior pattern in patients with coronary artery disease: relationships to painful versus silent myocardial ischemia and bendorphin responses during exercise. Psychosom Med 1991;53:669–683. 15. Sheps DS, Maixner W, Hinderliter AL, Herbst MC, Bragdon EE, Herdt J, Kropp S, Adams KF, Koch G, Ekelund LG. Relationship between systolic blood pressure, ventricular volume and ischemic pain perception in patients with angina pectoris: a potential role for baroreceptors. Isr J Med Sci 1989;25: 482–487. 16. Fellows EJ, Ullyot GE. Analgesics: aralkylamines. In: Suter CM, ed. Medicinal Chemistry, 1. New York: John Wiley, 1951:390–396. 17. Dworkin BR, Elbert T, Rau H, Birbaumer N, Pauli P, Droste C. Central effects of baroreceptor activation in humans: attenuation of skeletal reflexes and pain perception. Proc Natl Acad Sci USA 1994;91:6329–6333. 18. Gasperetti CM, Burwell LR, Beller GA. Prevalence of and variables associated with silent myocardial ischemia on exercise thallium-201 stress testing. J Am Coll Cardiol 1990;16:115–123.
APRIL 1, 1997
EL–AJC (v. 79, no. 7 ’97)
0890
MD,
David Sheffield,
PhD,
Rungroj Krittayaphong, and David S. Sheps, MD
MD,
William Maixner,
DDS, PhD,
ince the introduction of electrocardiographic exercise testing, it has been recognized that patients S can have ST-segment depression without angina
ing electrocardiographic abnormalities that might influence test interpretation (left ventricular hypertrophy, Wolff-Parkinson-White syndrome, left bundle pectoris.1 What makes ischemia either silent or branch block, or remarkable intraventricular conducsymptomatic may be related to the degree of isch- tion defect); (4) ECG changes with posture or hyemia2,3 and/or how an individual perceives sensory perventilation; (5) age °35 years; (6) normal or noninput during ischemia.4,5 Increased blood pressure significant coronary artery disease (õ50% diameter (BP) has been strongly associated with decreased narrowing) from coronary arteriography; and (7) pain perception in both animals6,7 and humans.8 – 10 subsequent nuclear imaging study not suggestive of An important initial step in this association appears flow-limiting disease. to involve the stimulation of baroreceptors. Located Tests were performed using a standard Bruce proin the carotid sinus and aortic arch, these pressure tocol and a Marquette system. Baseline ST-segment receptors are stimulated by increases in arterial pres- analysis was established as the level of ST segment sure and possess central nervous system inhibitory observed in the standing position before the start of properties, including antinociception.11 Krittaya- exercise. Leads aVF, V3, and V5 were continuously phong and Sheps12 recently demonstrated that resting monitored. Twelve-lead electrocardiograms were reBP influences anginal indexes during exercise test- corded before exercise in the supine, standing, and ing in patients not taking antianginal medications. posthyperventilation conditions at 1-minute intervals In this study, we present data that systolic BP at during exercise and until at least 5 minutes into the the time of electrocardiographic (ECG) evident recovery phase or return to baseline. Blood pressure ischemia and the dynamic increase in systolic BP recorded by cuff sphygmomanometer was taken at are important factors in sensory perception of isch- rest before exercise, at 2 minutes into each stage of emia, regardless of medication status, smoking the protocol until at least 5 minutes into the recovery history, or baseline hypertension. These data sup- phase or return to the baseline level. In addition, 12port the hypothesis that an acute elevation in BP lead electrocardiograms and BP were obtained at the affects pain perception through activation of bar- time of onset of angina and at the time of onset of oreceptors. positive test, defined as ¢1 mm ST-segment depresjjj sion at 0.08 second after the J point for ¢3 consecWe reviewed 4,723 exercise treadmill tests per- utive beats. The end points were fatigue, progressive formed at the University of North Carolina Hospitals angina, ST-segment depression ¢3 mm, ¢3 consecduring the years 1990 to 1994. There were 1,144 utive ventricular premature complexes, or decrease positive tests (24%) defined as exercise-induced hor- in systolic BP by ¢10 mm Hg. Patients were inizontal or downsloping ST-segment depression of structed to inform the supervising physician imme¢1 mm measured 0.08 seconds after the J point. All diately of the onset and resolution of chest pain. The positive tests were confirmed by the same experi- following exercise variables were recorded in each enced cardiologist. For patients who had ¢2 positive patient: (1) heart rate, BP, and rate-pressure product tests, we selected only the first positive test for anal- at rest, onset of 1 mm ST-segment depression, onset ysis. We reviewed these tests and subjects were ex- of chest pain, and maximal exercise; (2) time at onset cluded for the following reasons: (1) conditions that of 1 mm ST-segment depression, at onset of chest might affect anginal pain perception (diabetes mel- pain, and total exercise time; (3) maximal ST-seglitus, postcoronary bypass surgery); (2) exercise ment depression and ECG leads in which ST-segprotocol other than standard Bruce protocol; (3) rest- ment depression was present; and (4) presence or absence of typical chest pain. From the Departments of Medicine and Endodontics, University of Continuous variables were described as mean { North Carolina Schools of Medicine and Dentistry, Chapel Hill, SE, and categorical variables were described with North Carolina. This study was supported by Grant 1-R01-HL-47477 frequencies and percentages. Differences between from the National Heart, Lung, and Blood Institute, Bethesda, Maryland, by General Clinical Research Center Grant RR00046 from the groups were compared with Student’s t test for conNational Institutes of Health, Bethesda, Maryland, and by Cooper- tinuous data, and chi-square test for categorical data. ative Agreement CR817643 from the Environmental Protection A p value °0.05 was considered statistically signifAgency, Washington, D.C. Dr. Sheps’ address is: 338 Burnett-Womicant. ack Building/CB# 7075, Chapel Hill, North Carolina 27599Three hundred six patients with positive exercise 7075. Manuscript received July 31, 1996; revised manuscript retests were included in these analyses; 100 (33%) had ceived and accepted November 12, 1996. 954
Q1997 by Excerpta Medica, Inc. All rights reserved.
/ 2w1e 0890 Mp
954
Wednesday Mar 05 10:47 PM
0002-9149/97/$17.00 PII S0002-9149(97)00018-0
EL–AJC (v. 79, no. 7 ’97)
0890
silent ischemia. However, the time to onset of ST depression was greater in patients with silent ischMyocardial Ischemia emia, suggesting that they had less severe disease. Accordingly, the reSilent p Painful (n Å 206) Value (n Å 100) lation between hemodynamic parameters and the expression of ischAge (yr) 59 { 1 61 { 1 0.11 emia was examined after adjusting Men/women 77/23 (77%) 145/61 (70%) 0.23 Current smokers 23 (23%) 35 (17%) 0.21 for time to ST depression using loHistory of hypertension 45 (45%) 85 (41%) 0.54 gistic regression. Only systolic BP History of myocardial infarction 18 (18%) 52 (25%) 0.16 at onset of ST depression remained Underwent nuclear study 66 (66%) 115 (56%) 0.09 a significant predictor of silent ischUnderwent catheterization 57 (57%) 81 (39%) 0.003 emia (p Å 0.04). Similarly, when Number of coronary arteries narrowed ú50% in patients were matched for time to diameter* ST depression, systolic BP at onset 1 31 (23%) 17 (12%) of ST depression remained a signif2 22 (16%) 23 (17%) icant predictor of silent ischemia (p 3 27 (20%) 17 (12%) 0.27 b blockers (%) 29 (29%) 50 (24%) 0.38 Å 0.05). The same pattern of findCalcium antagonists (%) 28 (28%) 62 (30%) 0.71 ings was found in analyses of subLong-acting nitrates (%) 13 (13%) 26 (12%) 0.93 samples that (1) only included pa*137 of 306 cases. tients with documented disease (as indexed by positive catheterization, positive nuclear study, or history of painful ischemia. Table I lists demographic and dis- myocardial infarction); (2) only included patients ease characteristics of patients with and without an- with positive catheterization; and (3) included pagina. Patients with silent ischemia during exercise tients not taking medications. had a tendency to be older, and were less likely to jjj undergo radionuclide study or catheterization after The reasons why some patients with positive exexercise testing; no other differences emerged. ercise tests do not experience angina pectoris have Differences in exercise test characteristics be- not been fully elucidated. Factors such as degree of tween patients with painful and silent ischemia were ischemia,2,3 circulating b endorphins,13 personality then examined; Table II displays these data. Patients traits,14 and resting BP12 have been implicated. In this with silent ischemia during exercise had higher sys- study, we provide evidence that acute elevations in tolic BP and rate-pressure product at the onset of ST BP during exercise are related to painful ischemia. depression. Further, change in systolic BP from rest There is considerable evidence that BP influences to onset of ST depression was greater in patients with pain perception,6 – 10 but the mechanisms underlying TABLE I Demographic and Disease Characteristics of Patients With and Without Angina
TABLE II Exercise Test Characteristics of Patients With and Without Angina Myocardial Ischemia
Rest Systolic BP (mm Hg) Diastolic BP (mm Hg) HR (beats/min) Measures of ischemic threshold Time to 1 mm ST depression (s) Systolic BP at 1 mm ST depression (mm Hg) Change in systolic BP from rest to 1 mm ST depression (mm Hg) Diastolic BP at 1 mm ST depression (mm Hg) HR at 1 mm ST depression (beats/min) Rate-pressure product at 1 mm ST depression (beats/min 1 mm Hg) Number of leads with 1 mm ST depression Peak ST depression (mm) Duration of 1 mm ST depression (s) Measures of exercise performance Exercise duration (s) Peak systolic BP (mm Hg) Change in systolic BP from rest to peak exercise (mm Hg) Peak diastolic BP (mm Hg) Peak HR (beats/min) Peak rate-pressure product (beats/min 1 mm Hg)
Painful (n Å 100)
Silent (n Å 206)
134 { 2 82 { 1 75 { 1
137 { 1 82 { 1 74 { 1
p Value 0.35 0.76 0.59
268 164 29 83 127 20,800 4.0 1.3 406
{ 12 {3 {2 {1 {2 { 500 { 0.2 { 0.1 { 30
299 172 35 83 129 22,400 3.8 1.3 395
{9 {2 {2 {1 {2 { 400 { 0.1 { 0.0 { 17
0.05 0.01 0.04 0.85 0.29 0.03 0.38 0.81 0.73
353 170 36 83 135 23,100
{ 12 {3 {2 {2 {2 { 600
414 181 44 83 143 26,000
{ 10 {2 {2 {1 {2 { 400
0.001 0.002 0.003 0.85 0.003 0.001
BP Å blood pressure; HR Å heart rate.
BRIEF REPORTS
/ 2w1e 0890 Mp
955
Wednesday Mar 05 10:47 PM
EL–AJC (v. 79, no. 7 ’97)
0890
955
this relation are less clear. Further, it is questionable whether this association is due to chronic elevations in BP and elements inherent to the hypertensive state7 – 9,15 or if acute elevations play a role.6,11 Studies examining the relation between BP and pain perception in humans have demonstrated that hypoalgesia is associated with hypertension or borderline hypertension.8 – 10,12,15 For example, using graded electrical stimulation of the tooth pulp, Ghione et al10 showed higher sensory thresholds in subjects with borderline or established hypertension than in normotensive subjects. However, they found treating a subgroup of hypertensive subjects with antihypertensive medications with resulting BP reduction did not alter their pain sensitivity. Guasti et al8 found that 24-hour ambulatory BP recordings were a better predictor of pain perception than blood pressures taken before testing. They suggested that the influence of BP on pain sensitivity has less to do with dynamic pressure changes and more to do with chronic, longer-lasting trends. These studies are contrasted by reports of acute elevations in arterial BP influencing pain perception. Pressor agents peripherally administered to rats have been shown to induce hypoalgetic behaviors.6 Further, sympathomimetics have been used as analgesics in humans.16 The mechanistic explanation for these reports center on the stimulation of baroreceptors. Rats with surgically destroyed baroreceptors do not have the increased pain threshold seen in rats with intact baroreceptors during pharmacologically stimulated BP elevations.6 In humans, Dworkin et al17 demonstrated that acute baroreceptor stimulation in synchrony with the cardiac cycle produced postulated central nervous system inhibitory effects and decreased pain perception. Our results support the concept that acute baroreceptor stimulation caused by an exercise-induced elevation in BP decreases pain perception. We demonstrated that occurrence of painful ischemia is related to systolic BP at the time of ECG-evident ischemia in patients with positive treadmill tests, regardless of their medication status. In addition, a relation was found between angina pectoris and the increase in systolic BP from rest to time of ST-segment depression. In contrast, we found no relation between angina and resting BP or a history of hypertension. In our study, patients with silent ischemia had a greater time to ST-segment depression and achieved a higher workload than symptomatic patients; these differences could represent differing ischemic burdens between the groups.2,3,18 However, the relation between pain and systolic BP at the time of ST-segment depression remained after adjusting for the time of onset of ST-segment depression, suggesting that it was independent of disease severity. Additionally, there was no difference in the number of diseased vessels among patients who had cardiac catheterization performed; acute BP increases were
956
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956
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related to anginal pain in patients with disease confirmed by catheterization (p Å 0.03). Some patients may also have had ST-segment depression without ischemia, although we excluded patients who had resting ECG abnormalities that could have influenced test interpretation, notably left ventricular hypertrophy and bundle branch block. Thus, although we cannot be certain that ST-segment depression was indicative of ischemia in all patients, our data strongly suggest that this is the most likely explanation. In conclusion, we present evidence that systolic BP at the time of ischemia and dynamic pressure changes during exercise are important factors in determining the presence or absence of angina pectoris during treadmill testing. These findings are consistent with acute activation of baroreceptors and resulting antinociception during an exerciseinduced elevation in BP. 1. Goldhammer S, Scherf D. Elektrokardiographische untersuchungen bei kranken mit angina pectoris (‘‘ambulatorischer’’ typus). Z Klin Med 1932;122: 134–151. 2. Nihoyannopoulos P, Marsonis A, Joshi J, Athanassopoulos G, Oakley CM. The magnitude of myocardial dysfunction is greater in painful than painless myocardial ischemia: an exercise echocardiographic study. J Am Coll Cardiol 1995;25:1507–1512. 3. Klein J, Chao SY, Berman DS, Rozanski A. Is ‘‘silent’’ myocardial ischemia really as severe as symptomatic ischemia? The analytical effect of patient selection biases. Circulation 1994;89:1958–1966. 4. Droste C, Roskamm H. Experimental pain measurement in patients with asymptomatic myocardial ischemia. J Am Coll Cardiol 1983;1:940–1945. 5. Sheps DS, Bragdon EE, Miller PF, Maixner W, Hinderliter AL, Light KC. The perception of pain in patients with myocardial ischemia. J Myocardial Ischemia 1980;1:29–38. 6. Dworkin BR, Filewich RJ, Miller NE, Craigmyle N. Baroreceptor activation reduces reactivity to noxious stimulation: implications for hypertension. Science 1979;205:1299–1301. 7. Sitsen JMA, de Jong W. Observations on pain perception and hypertension in spontaneously hypertensive rats. Clin Exp Hypertens [A] 1984;6:1345–1356. 8. Guasti L, Cattaneo R, Rinaldi O, Rossi MG, Bianchi L, Gaudio G, Grandi AM, Gorini G, Venco A. Twenty-four hour noninvasive blood pressure monitoring and pain perception. Hypertension 1995;25:1301–1305. 9. Rosa C, Vignocchi G, Panattoni E, Rossi B, Ghione S. Relationship between increased blood pressure and hypoalgesia: additional evidence for the existence of an abnormality of pain perception in arterial hypertension in humans. J Hum Hypertens 1994;8:119–126. 10. Ghione S, Rosa C, Mezzasalma L, Panattoni E. Arterial hypertension is associated with hypoalgesia in humans. Hypertension 1988;12:491–497. 11. Randich A, Maixner W. The role of sinoaortic and cardiopulmonary baroreceptor reflex arcs in nociception and stress-induced analgesia. Ann NY Acad Sci 1986;467:385–401. 12. Krittayaphong R, Sheps DS. Relation between resting blood pressure and perception of angina during exercise testing. Am J Cardiol 1996;77:1224–1226. 13. Miller PF, Light KC, Bragdon EE, Ballenger MN, Herbst MG, Maixner W, Hinderliter AL, Atkinson SS, Koch GG, Sheps, DS. Beta-endorphin response to exercise and mental stress in patients with ischemic heart disease. J Psychosomat Res 1993;37:455–465. 14. Light KC, Herbst MC, Bragdon EE, Hinderliter AL, Koch GG, Davis MR, Sheps, DS. Depression and type A behavior pattern in patients with coronary artery disease: relationships to painful versus silent myocardial ischemia and bendorphin responses during exercise. Psychosom Med 1991;53:669–683. 15. Sheps DS, Maixner W, Hinderliter AL, Herbst MC, Bragdon EE, Herdt J, Kropp S, Adams KF, Koch G, Ekelund LG. Relationship between systolic blood pressure, ventricular volume and ischemic pain perception in patients with angina pectoris: a potential role for baroreceptors. Isr J Med Sci 1989;25: 482–487. 16. Fellows EJ, Ullyot GE. Analgesics: aralkylamines. In: Suter CM, ed. Medicinal Chemistry, 1. New York: John Wiley, 1951:390–396. 17. Dworkin BR, Elbert T, Rau H, Birbaumer N, Pauli P, Droste C. Central effects of baroreceptor activation in humans: attenuation of skeletal reflexes and pain perception. Proc Natl Acad Sci USA 1994;91:6329–6333. 18. Gasperetti CM, Burwell LR, Beller GA. Prevalence of and variables associated with silent myocardial ischemia on exercise thallium-201 stress testing. J Am Coll Cardiol 1990;16:115–123.
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