Usefulness of plasma beta-endorphin level, pain threshold and autonomic function in assessing silent myocardial ischemia in patients with and without diabetes mellitus

Usefulness of Plasma Beta-Endorphin Level, Pain Threshold and Autonomic Function in Assessing Silent Myocardial lschemia in Patients With and Without Diabetes Mellitus Hiroyuki Hikita, MD, Akira Kurita, MD, Bonpei Takase, MD, Hirokazu Nagayoshi, MD, Akimi Uehata, MD, Toshihiko Nishioka, MD, Hideki Mitani, MD, Kyoichi Mizuno, MD, and Haruo Nakamura, MD

A

lthough the mechanismsof silent myocardial ischemia remain unclear, it has been reported that patients with silent myocardial ischemia have a greaterpain threshold1T2 and that the endogenousopioids have some role.3-7 However, previous studies exciuded diabetic patients, and did not investigate the relation between the endogenousopioids and silent myocardial ischemia in patients with diabetesmellitus. Previous studies indicated that diabetic patients with coronary artery diseasehave more frequent episodesof silent myocardial ischemia.8*9Furthermore, some studies have indicated a relation betweenautonomic dysfunction and silent myocardial ischemia.lc13 Heart rate variability during ambulatory electrocardiographic monitoring was recently used as an index of the cardiac autonomic function, especially in patients manifesting congestive heart failure or diabetes mellitus.‘4-17 Computerized analysis of 24-hour ambulatory electrocardiographicrecordings can provide quantitative measurementsof heart rate variability, which has been shown to be more mproducible and sensitive than are conventional tests18 used to evaluate the cardiovascular reflexes.15,17 Based on the hypothesis that there may be somedifferencesin the mechanismsbetween diabetic and nondiabetic patients with silent myocardial ischemia, we investigatedthe plasma P-endorphin levels, pain threshold and autonomic functions in both types of patients, because these factors are known to have some role in the pathogenesisof silent myocardial ischemia.

The dii betben diabetic and nondiabetic patients with silent mykardial ischemia were irr vestigated. Used on the kesutts of previous exer cise testing, a total of ii0 patients (15 diabetic and 95 nondiabetic) with exercise-induced my* cardial ischemia 3vere divided into the following 3 @aups: 15 diabetics wRh silent myocardial ische mia, 49 nondiabetics with silent myocardial ischemia, and 45 nondcabetics with angina1 symptoms All patients underwent treadmill exercise testing and 244our ambulatory elecWcefdiogrephic re cording. Before and during exercise, blood samples from the antecubital vein were obtained to detemdne the plasma P+ndo#phin levels, and the pain threshold of eech patient wes measured with the electficai skin stimulation test. Furthennofe, with regard to the amtndatory electrocardii icreeordin&themeanofthe5Dsofallnormalsinus RR intervals during successive Sminute * cording periods over 24 hours was analyzed and autonomic function. consideredasanindexofthe The plasma P-in level during exercise was signiicantly greater in nandiabetic: petients with silent ischemia then in diabetic ones The SD mean was signkantly less in the diabetic &up then in the 2 nondiabetic ones. The findings suggestthattheroleofpendotphinindiabeticpa tients with silent myocardial ischemia may be less sighkant than in nondiabetic oneq therefbre, a diicneuropathythataffectstheaut-ic pain fibers that innervate the heart may be irr valved in the mechanism of silent myocardial is chemia in diabetics. (Am J Cardiol1993;72:140-143)

METHODS

From the Fit Department of Internal Medicine, National Defense Medical College, Tokorozawa, Saitama, Japan. Manuscript received March 30, 1992; revised manuscript received February 17, 1993, and accepted February 19. Address for reprints: Akira Kurita, MD, the First Department of Internal Medicine, National Defense Medical College, 3-2, Namiki Tokorozawa, Saitama 359, Japan.

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THE AMERICANJOURNALOF CARDIOLOGY VOLUME72

Study patien&: Between June 1989 and August 1991,we performed a study of consecutivepatients who fultilled the following criteria: (1) reproducible myocardial ischemia with or without anginal symptoms, which had been detectedby 2 previous exercisetreadmill tests 3 to 8 months before beginning the present testing protocol (1 test was accompaniedby thallium scintigraphy); (2) angiographically documentedcoronary artery disease (coronary angiography and left ventriculography were performed 13 months before the study); and (3) absence of unstable angina or myocardial infarction within the previous 6 months, and electrocardiographicabnormahties that prevented adequate interpretation of the exercise stress tests, such as left bundle branch block or paced rhythms. Patients receiving digitalis were excluded from the study. All patients gave informed consent. The study was approved by the institutional review board of the National Defense Medical College.

JULY 15,1993

One hundred ten patients (15 diabetic and 95 nondi- 1 TABLE I Clinical Characteristics of the Study Groups J abetic) were enrolled in the study. Patients were dividNondiabetic ed into 3 groups according to the results of previous Diabetic with with with treadmill testings. Of 110patients, 15 diabetics and 46 Painful Silent Silent nondiabetics had previous positive electrocardiographic Myocardial Myocardial Myocardial lschemia lschemia lschemia tindings during exercise without anginal symptoms, whereas49 nondiabetics had positive stresstests associPatients 15 49 46 ated with anginal symptoms. Furthermore, the 15 dia57 2 7 61 2 8 592 10 Mean age (years) Men/women 14/l 4019 40/6 betic patients were receiving oral hypoglycemic drugs, 9 28 24 BP 2 160/90 mm Hg but no insulin, and their condition was diagnosedan av(no.) erage of 8.9 + 3.3 years previously on the basis of fast5 16 17 Smoking history (no.) ing hyperglycemia. 4 9 10 History of myocardial Exercise stress test&i While in the fasting state, infarction (no.) Medications used (no.) all patients underwent symptom-limited exercise testing Nitrates 49 46 15 between 9 and 11 A.M., using the treadmill protocol Calcium antagonists 8 25 28 (Bruce19).A 1Zlead standardelectrocardiogramwas ob2 p blockers 8 tained, and blood pressure was measured with a stanVessel disease (no.) 9 30 27 1 dard sphygmomanometerat the following times: before 5 17 L 18 the test, every minute during the test, at the end of the 1 2 3 1 exercise regimen, and every minute during recovery. BP = blood pressure. Leads II, aVF, V5 and CM5 were continuously monitored throughout the test. During the test, patients were queried regarding the occurrence of chest pain or dis- was measuredaccording to the method of Martin et al,14 comfort, and a positive responsewas defined as being a which determines the mean f SD of the sinus RR inhorizontal or downsloping ST-segment depression 21 tervals for each 5-minute period during the recording pemm at 0.08 secondafter the J point. Exercise testing was riod. Thus, the mean SD of all normal sinus RR interstoppedwhen moderateto severeangina, dyspneaor ex- vals during successive5-minute recording periods over haustion, or a combination, were noted or when ST- 24 hours was used as an index of heart rate variability for each patient. segmentdepression22 mm occurred. Plasma betaendorphin levels: To determine the Calcium antagonistsand nitrates were suspended12 plasma p-endorphin levels, blood samples (7 ml) were hours before each test. The dose of p-adrenergic blockobtained from the antecubital vein of each patient 10 ers was gradually reduced and then discontinued 1 week minutes before (while comfortably resting) and at the before testing. Exercise data, p-endorphin levels, pain end of exercise. The samples were immediately centri- threshold and ambulatory electrocardiographic monitorfuged at 4°C. The plasma was aspirated and immedi- ing were analyzed in a blinded fashion. ately frozen at -20°C until assayed.The sampleswere StatWcal msisr All values are presented as analyzed by the ~-endorphin-i251-RIA.7The recovery mean f SD. Subjective assessmentsof each group were yield from each plasma sample, determined using inter- compared using the &i-square test or Fisher’s exact nal standards,ranges between 92 and 104%. probability test. A l-way analysis of variance was used Electdeal skln stlmulatlon: Pain was produced to compare the means of the 3 groups, after which the with a validated electrical skin stimulation technique.2T7 multiple-comparison procedure (Scheffe’s procedure20) Stimulation of the left forearm through electrodes was was performed to isolate differencesbetween the groups. begun at a current strength of 0.1 mA. The pain thresh- Differences between rest and exercise in 1 group were old was detined as the current intensity at which the sub- analyzedby Student’s t test for paired observations.Sigject reported the fist perception of electrical stimulation. nificance was establishedat the p co.05 level. Electrical skin stimulation of each patient was performed 3 times before exercise testing and 3 times at RESULTS the end of exercise, with the average of the 3 recorded Cllnlcal charactetidics: There were no significant values used for analysis. differencesamong patients in the 3 groups with respect Ambulatay m monltodm One to clinical characteristics(Table I). hour after the exercise regimen, each patient underwent Exemlse stmse tesU~@ All 15 diabetic and 49 non24-hour ambulatory electrocardiography that was per- diabetic patients had electrocardiographic signs of myoformed with a Marquette model 8500 AM 2-channel cardial ischemia without symptoms,whereasthe 46 nonrecorder. Usually, the bipolar CM5 and CCs leads were diabetic ones had evidence of myocardial ischemia with the exploring electrodes. During monitoring, patients anginal symptomsduring exercise.The data of the tmadwere instructed to perform their usual daily activities ex- mill stress testing are listed in Table II. No sign&ant cept for physical training. Each recording was analyzed differenceswere observed among the 3 groups with reby using a Marquette 8000 computerized Holter system spect to exercise data. that classities each beat according to its site of origin. Plasma beteenkrpNn levels (Fl@re 1): The plasThe beat classification was overread manually and cor- ma P-endorphin levels at rest in the 3 groups were not rected where necessary.Each RR interval during the 24- significantly different. However, the plasma @ndorphin hour period was determined, and heart rate variability level at the end of exercise in nondiabetic patients with SILENT MYOCARDIALISCHEMIAIN DIABETESMELLITUS 141

silent myocardial ischemia was significantly greater than in diabetics with silent myocardial ischemia and in nondiabetics with painful myocardial ischemia. Pain thre&oM resufts (Figure 2): The pain threshold at rest in the nondiabetic group with painful myocardial ischemia was significantly less than in the diabetic and nondiabetic groups with silent myocardial ischemia; the pain threshold after exercise was also significantly less in the nondiabetic group with painful

TABLE II Exercise Stress Testing Nondiabetic with Silent Myocardial lschemia

Nondiabetic with Painful Myocardial lschemia

395 k 112

424 A 117

392 r 107

138 ? 20

144 ‘- 15

139 + 14

183 + 20

188 f 26

184 + 26

Diabetic with Silent Myocardial lschemia Mean exercise time (set) Mean peak exercise heart rate (beats/ min) Mean peak exercise systolic blood pressure (mm Hg) Mean maximal ST depression (mm) Mean time to 1 mm ST depression (set)

lwh 20.

-2.2

+ 0.3

280 2 30

I

-2.2

2 0.4

-2.0

276 + 40

k 0.7

293 k 36

*

myocardial ischemia than in the other 2 groups. At the end of exercise,the pain thresholdswere significantly increased in the diabetic and nondiabetic groups with silent myocardial ischemia. -latoymml-oms~d patients, the mean SD of all normal sinus RR intervals during the successive5minute recording periods over 24 hours was measuredas an index of heart rate variability. The mean SD was 33 + 9 ms in diabetic patients with silent myocardial ischemia, 47 + 7 ms in nondiabetics with silent myocardial ischemia, and 50 f 14 ms in nondiabetics with painful myocardial ischemia. Thus, the mean SD was significantly less in diabetic than in nondiabetic patients. DISCUSSION Exerdseinduced

silent

myocardial

ischeda

in

Mnwliabetic patients: The results of this study revealed that the plasma P-endorphin level and pain threshold were greater in nondiabetic patients with silent myocardial ischemiathan in those with anginal symptomsat the end of exercise.In accordancewith other studies,1-7the present data suggestthat a greater pain threshold associated with a greaterplasma p-endorphin level has a role in silent myocardial ischemia. Exercisslnduced

silent

myoczdal

ischemia

in

diabetic patients This study also revealeda sign&ant difference in the plasma P-endorphin level during exer-

1.

A

iM9allfSD *p
Beta-endorphin

FIGURE 1. PIesme f3anWphin met and exedee.

10.

Rest Exercise Diabetic with silent myocardial iachamia

Rest Exercise Nondiabetic with silent myocardial ischamia

leads

at

Rest Exercise Nondiabetic with painful myocardial iachamia

mA

3.0

2.0 FlGuRE2.Painemme.

Pain threshold

142

Rest Exercise

Rest Exercise

Rest Exercise

Diabetic with silent myocardial iachemia

Nondabatic with silent myocardlal ischamia

Nondiabetic with painful myocardial iachemia

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JULY 15,1993

at rest and ex-

cise between diabetic and nondiabetic patients with 1. Dmste C, Roskamm H. Experimental pain measurement in patients with asymp myocardial ischemia. J Am CON Cardiol 1983;1:940-945. silent myocardial ischemia. Furthermore, a significant tomatic 2. Glazier JJ, Chierchia S, Brown MJ, Maseri A. Importance of generalized dedifference in heart rate variability was noted between fective perception of painful stimuli as a cause of silent myocardial ischemia in diabetic and nondiabetic patients, suggesting that the chronic stable angina pectoris. Am J Cardiol 1986;58:667672. DS, Adams KF, Hinderliter A, Price C, Bissette J, Orlando G, Margolis mechanisms of silent myocardial ischemia differ be- 3.B, Sheps Koch G. Endorphims are related to pain perception in coronary artery disease. tween diabetics and nondiabetics. The role of p endor- AmJ Car&/ 1987;59:52>527, phin in silent myocardial ischemia may be less signiti- 4. Falcone C, Specchia G, Rondanelli R, Guasti L, Corsica G, Ccdega S, Montemartini C. Correlation between beta-endorphii plasma levels and anginal symptoms cant than that of neuropathy in diabetic patients. in patients with coronary artery disease. J Am CON Cordial 1988;11:71~723. Some studies have shown lower P-endorphin con- 5. Sheps DS, Maimer W, Hinderliter AL. Mechanisms of pain perception in pawith silent myocardial ischemia. Am Heart J 1990; 1191983-987. centrations or content in the plasma, pituitary and hy- 6.dents Sheps DS, Hinderliter A, Bragdon EE, Adams KF, Herbst MC, Koch G. Enpothalamus of diabetic rats than of control rats.21,22 dorphins and pain perception in silent myocardial &hernia. Am J Cardiol 1988;61: Those studies stated that the diabetic condition may 3~4~. 7. Kurita A, Takase B, Uehata A, Sugahara H, Nishioka T, Mamyama T, Satocause a reduction in the central and peripheral endoge- mura K, Mizuno K, Nakamura H. Differences in plasma beta-endorphin and nous opiate levels. Diminished opiate levels indicate a bradykinin levels between patients with painless or with painful myocardial ischereduced tolerance to nociceptive stimulation.22-24How- mia. Am Heart J 1992;123:3C&309, Chiariello M, lndolti C, Cotecchia MR, Sifola C, Roman0 M, Condor& M. ever, many diabetic patients manifest silent myocardial 8.Asymptomatic transient ST changes during ambulatory ECG monitoring in diabetic ischemia. A diabetic neuropathy that affects the auto- patients. em HW J 1985; 110529-534. nomic pain fibers innervating the heart may be involved 9. Nesto RW, Phillips RT, Kett KG, Hill T, Perper E, Young E, Leland OS. Angina and exertional myocardial ischemia in diabetic and nondiabetic patients: assessin the mechanismsof silent myocardial ischemia. Some ment by exercise thallium scintigraphy. Ann Intern Med 1988:108:17&175. diabetic patients with coronary artery diseasehave angi- 10. Murray DP, O’Brien T, Mulmoney R, O’Sullivan DJ. Autonomic dysfunction and silent myocaniial ischemia on exercise testing in diabetes mellitos. Diabetic nal symptoms during exercise. However, the differences Med 1990;7:580-584. ktw=D

diabetic

Patients

With

Silent

and

Painful

mYO-

11. Ambepityia G, Kopelman PG, Ingram D, &ash

M, Mills PG, Timmis AD.

cardial ischemia were not assessedin this study. A re- Exertional myocardial ischemia in diabetes: a quantitative analysis of angina1 perthreshold and the influence of autonomic function. J Am CON Cwdiol 1990, cent study of diabetic patients with typical exertional ceptual 15~72-77. angina revealed an association between cardiac auto- 12. Langer A, Freeman MR, Jesse RG, Steiner G, Armstrong PW. Detection of nomic dysfunction and prolongation of the time of onset silent myocardial ischemia in diabetes mellitus. Am J Cardiol 1991;67:1073-1078. 13. Umachandran V, Ranjadayalao K, Ambepityia G, Marchant B, Kopelman PG, of angina during exercise testing.1* Autonomic dysfunc- Timmis AD. The perception of angina in diabetes: relation to somatic pain threshtion may lead to a high pain threshold. However, that old and autonomic function. Am Heart J 1991;121:1&19-1654. Martin GJ, Magid NM, Myers G, Bamett PS, Schaad JW, Weiss IS, Lesch study did not compare the results between diabetic pa- 14. M, Singer DH. Heart rate variability and sudden death secondary to coronary artery tientS with eXertiOnalangina and silent myocardial is- dIsease during ambulatory electrocardiographic monitoring. Am J Cardiol 1987:-W chemia. Further studies are neededto assessthe mecha- 8689. Hoogenhuyze DV, Weinstein N, Martin GJ, Weiss JS, Schaad JW, Sahyouni nisms of silent myocardial ischemia in diabetic patients. 15. XN, Fiitel D, Remme WJ, Singer DH. Reproducibility and relation to mean heart The present data regarding plasma P-endorphin ap- rate of heart rate variability in normal subjects and in patients with congestive heart pear to show lower values than in other studies,34,25but failure secondary to coronary artery disease. Am J Cardiol 1991;68:1668-1676. 16. Masaoka S, Lev-Ran A, Hill LR, Vakil G, Han EHG. Heut rate variability in this may be due to different methods used and a differ- diabetes: relationship to age and duration of the disease. Diabetes Care 1985:8:6&58. ent specificity of the antibody for cross-reactivitieswith 17. Ewing DJ, Neilson JMM, Shapiro CM, Stewart JA, Reid W. Twenty four hour heart rate variability: effects of posture, sleep, and time of day in healthy controls other products. and comparison with bedside tests of autonomic function in diabetic patients. Br study htitatim: The measurementof heart rate Heart variability that we used to evaluate autonomic function 16. Ewing DJ, Clarke BF. Diagnosis and management of diabetic autonomic neuropathy. BMJ 1982:285:91f&918. assessesefferent parasympatheticactivities, whereascar- 19. Bruce RA, McDonough JR. Stress testing in screening for cardiovascular disdisc pain perception is perceived in the afferent sym- ease. Bull N Y Acad Med 1%9;45:1288-1305, pathetic nerves.However, there are few methodsto eval- 20. Dawson-Saunders B, Trapp RG. Comparing thme or more means. In: Basic and Clinical Biostatistics. Nonvalk, Connecticut: Appleton &Lange, 1990:12&134. uate only the cardiac afferent sympathetic fibers nonin- 21. Forman W, Marquis DE, Stevens R, Adler R, Vasilenko P. Diabetes induced vasively, and many other studies have also used by streptozocin results in a decrease in immunoreactive beta-endorphin levels in the pituitary and hypothalamus of female rats. Diabetes 1985;34: 1104-l 107. autonomic function tests (such as heart rate variability 22. Forman W, Estilow S. Lewis M. Vasilenko P. Stxeptozocin diabetes alters immeasurement)to correlate autonomic dysfunction with monoreactive beta-endorphin levels and pain perception after 8 wk in female rats. silent myocardial ischemia and anginal perceptional Diabetes 1986;35:1309-1313. 23. Raz I, Hasdai D, Seltzer Z, Melmed RN. Effect of hyperglycemia on pain pertbreshold.‘@r3Therefore, we also used heart rate vari- ception and on efficacy of morphine analgesia in rats. Diabetes 1988;37:1253-1259. ability to evaluate the cardiac autonomic function and 24. Morley GK, Mooradian AD, Levine AS, Morley JE. Mechanism of pain in dithereby correlate silent myocardial ischemia in diabetes abetic peripheral neuropathy. Am J Med 19&1;77:7%82. H&x GV, Garber CE, Connolly MJ, Allen-Rowlands CF. Siconolti SF, Gano mellitus with the damage to the cardiac autonomic 21. DS, Carleton RA. Plasma beta-endolphin levels in silent myocardial ischemia innerves. duced by exercise. Am J Cardiol 198x59:735-739. J

i991;63:23s2M,

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