Detection of silent myocardial ischemia in diabetes mellitus

Detection of Silent Myocardial Diabetes Mellitus

lschemia in

Anatoly Langer, MD, Michael R. Freeman, MD, Robert G. Josse, MD, George Steiner, MD, and Paul W. Armstrong, MD

The prevalence of sitent myocardial ischemia and its relation to autonomic dysfunction and pain threshotd was studii in 58 men with diabetes mellitus and without cardiac symptoms. All patients underwent 4S-hour ambulatory ekctrocardiographii monitoring and exercise testing after assessment of thetr autonomic function and pain threshold. Qfent myocardial ischemia, defined as 1.1 mm of ST-segment depression on either exercise testbtg or ambulatory ekctrocardiographk monitorfng, was corroborated by exercise-induced reversfbk defect(s) on tomographii thallium scintigraphy. Autonomic function was aueered by heart rate response to: (1) Valsatva maneuver, (2) deep breathing, and (3) upright posture, as well as by diastogi Mood pressure response to sustainad handgrip and systolic blood pressure response to uprtght posture. Autonomk dysfunc&n was defined as 12 abnormai -8. Pain threshold measurements were performed using ekctrkal cutaneous stimulation of both forearms. Of the 58 diabetii patients, 21 were found to have autonomii dysfunctiin (36%). Silent myocardial ischemia was detected in 10 patients (17%), and was signftcantfy more frequent in patients with than without autonomic dysfunction (36 VI 5%, p = 0.003). There was no diince in the efectrkal pain threshold or toterance in subjects with and wtthout silent myocardial ischemia. It is conctuded that silent myocardial ischemia in asymptomatic diabetic men occurs frequently and in association with autonomic dysfunction, suggestbtg that diabetic neuropathy

From the Divisions of Cardiology and Endocrinology, St. Michael’s Hospital, the Division of Endocrinology, Toronto General Hospital, Toronto, Ontario, Canada, and the Department of Medicine, University of Toronto, Toronto, Ontario, Canada. This work was conducted while Dr. Langer was a ResearchFellow of the Canadian Heart Foundation, Ottawa, Ontario, and while Dr. Armstrong was a Career Investigator of the Ontario Heart and Stroke Foundation,Toronto, Ontario. Manuscript receivedOctober 31,199O;revisedmanuscriptreceivedand acceptedJanuary 4, 1991. Addressfor reprints: Anatoly Langer, MD, St. Michael’s Hospital, 30 Bond Street, Suite 701A, Toronto, Ontario, M5B 1W8 Canada.

may be implicated in the mechanism of silent myocardial ischemia. (Am J Cardid 1991;67:1073-1078)

oronary artery diseaseis the ultimate cause of death in more than half of diabetic patients and frequently manifests itself silently and prematurely. L* Previous studies among patients with known coronary artery diseaseindicate that those with diabetes have more frequent silent myocardial infarction and silent myocardial ischemia during exercise testing and ambulatory electrocardiographicmonitoring than nondiabetic patients.3-5 However, the mechanism responsiblefor this lack of symptoms remains unclear. Becausediabetics are predisposedto a higher incidence of coronary artery disease6and autonomic neuropathy,7v8they present a unique opportunity to study the pathophysiologyof silent myocardial ischemia. Diabetic autonomic neuropathy may involve the cardiacafferent sympathetic system,which is a part of the pain perception pathway from myocardial pain receptors to the cerebral cortex. It is possiblethat the development of myocardial ischemia in patients with such a neuropathy may be associated with more frequent silent myocardial ischemia. The prevalenceof silent myocardial ischemia and the pathophysiologic mechanismsinvolved have not been adequately investigated in an asymptomatic diabetic population without previously documented coronary artery disease. We therefore studied asymptomatic diabetic subjects to define the frequency of silent myocardial ischemia and to determine whether a relation exists among silent myocardial ischemia, autonomic dysfunction and an elevated pain threshold.

C

METHODS The study population comprised 58 male diabetic9 subjects,ranging in age from 35 to 75 years, who had no symptomsof angina or any other clinical evidenceof coronary artery disease.Subjectswere not receiving digoxin, and had normal 1Zlead electrocardiograms recorded at rest. Subjects were enrolled from 2 sources: 45 were consecutive subjects attending the Diabetic Clinic at St. Michael’s Hospital over a period of 18 SILENT MYOCARDIAL ISCHEMIA

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months, from September 1987 to February 1989; the remaining 13 were participants of the Hyperlipidemia in Diabetes study at the Toronto General Hospital who were approached in a random manner. All subjects who were approachedacceptedthe invitation to participate. Autonomic function tests: These are 5 simple, reproducible bedside maneuvers reported previously.to,’I (1) VALSALVA MANEUVER: The subject was askedto blow into a mouthpiece connectedto a blood pressuresphygmomanometer at a pressureof 40 mm Hg for 15 seconds. The ratio of the longest RR interval after the maneuver to the shortest RR interval during the maneuver was measured; the normal ratio is L 1.21. (2) DEEP BREATHING: The subject breathed deeply and evenly at 6 breaths/min. The mean difference during 3 successivebreathing cycles between maximal and minimal heart rate was measured the normal responseis a difference of > 15 beats/min. (3) RESPONSE TO STANDING: The ratio of the longest RR interval (usually around the 30th beat) to the shortest RR interval (usually around the 15th beat), or the so-called 30:15 ratio, was calculated after the subject moved quickly from a supine to upright posture; the normal ratio is >1.04. (4) BLOOD PRESSURE RESPONSE TO STANDING: The difference in systolic blood pressurewas measured with the subject supine and then immediately after the assumption of an upright posture; the normal responseis a decrease of 5 10 mm Hg. (5) SUSTAINED HANDGRIP: The difference in diastolic blood pressurewas measuredafter the subject was askedto maintain a handgrip at 30% of the maximal voluntary contraction with a handgrip dynamometer for a maximum of 5 minutes; the normal responseis an increase of > 16 mm Hg. Medications thought capable of interfering with assessmentof autonomic function or exercise tests, such as /3 blockers or diuretics, were held 48 hours before these tests; no patients were receiving sympatholytic medications. Based on previous studies,lo,lt autonomic dysfunction was defined as an abnormal responseto L2 of the 5 tests, which has been shown to occur in <1.6% of nondiabetic patients. To document further the relevance of autonomic dysfunction to diabetic subjects only, autonomic function tests were performed in 20 nondiabetic patients who had angiographically documented coronary artery disease(250% stenosisin 2 1 vessel) and stable angina; 1 of 20 patients (5%) had 2 abnormal responses.

current intensity at which the subject reported his first perception of electrical stimulation. Pain tolerance was defined as the current intensity at which the patient indicated that he did not wish to continue further because of the pain. Electrical skin stimulation was also performed in a control group of 10 nondiabetic volunteers of an age similar to the diabetic subjects. Exercise tort: A graded exercisetest was performed according to the Bruce protocol12in the postabsorptive state between 9 A.M. and 3 P.M. (0900 and 1300 hours) with a Marquette Case 12 system.Patients were exercised to their maximal predopt pagejcicted heart rate. Heart rate and QRS morphology were monitored continuously and a 1Zlead electrocardiogram was obtained every 30 secondsfor purposes of ST-segment analysis. Exercise was discontinued if target heart rate was achieved,if fatigue that prevented further exercise developed,or if systolic blood pressuredecreased> 10 mm from baseline. Significant ST-segment depressionon exercise testingwasdefinedas11mm(1mm=0.1mV)ofhorizontal or downsloping ST-segment depression measured 60 to 80 ms after the J point and present on L 1 lead. Ambulatory ekctrowrdiographic monitoring: A 2channel (leads Vs and aVF) AM monitor was used (Marquette Electronics) with a frequency responsein accordance with American Heart Association Standards.13Patients were monitored for 48 hours. Particular care was taken to prepare electrode sites with skin abrasion techniques. ST-segment responsesto postural changesand hyperventilation were evaluated to rule out spurious ST-segment depressionor elevation. Two patients exhibiting those responseswere excluded from further testing. A significant episodeof ST-segmentdepressionwas defined as 21 mm of horizontal or downsloping STsegment depressionoccurring 60 to 80 ms after the J point, lasting 2 1 minute and separatedfrom other episodesby Ll minute. Exercise thallium-201 scintigraphy: Subjects with ST-segment depression on either exercise testing or ambulatory electrocardiographic monitoring underwent exercisethallium scintigraphy for corroboration of the presenceof myocardial ischemia with an independent and sensitive test. At peak exercise, 3.0 mCi of thallium-201 was injected intravenously and exercise was continued for a further 60 seconds.Tomographic images were obtained with a previously described techPain threshold awl tolerance nwasurem onb: These were performed on the volar surface of both forearms. nique,t4 with total acquisition lasting 20 minutes. ReThe pulse frequency used was 20 Hz; the pulse width peat imaging was performed 4 hours after the thallium was 1.2 ms. Pain threshold (mA) was defined as the injection.

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Images were read by an independent experienced observer unaware of the results of autonomic function tests,exercisetesting or ambulatory electrocardiographic monitoring. Visual impression of a reversible defect had to be corroborated by quantitative analysis. Quantitative analysis was performed with polar maps (bulls-eye) of thallium activity using short-axis and vertical long-axis slices.This method has been validated in our laboratory by comparison with coronary angiography and visual interpretation. l5 The method involves the comparison of stress and delayed bulls’eyes to normal limits; a defect, defined as thallium uptake 22.5 standard deviations below the lower limits of normal, was expressed as a percentage of the total stressbull’s-eye and then quantitatively assessedas reversible or nonreversible in each vascular territory. An abnormality was consideredpresent if 2 1% of the pixels of the bulls-eye were <2.5 standard deviations from normal.15 For the purposes of this study, silent myocardial ischemia was defined as a reversible defect on visual and quantitative thallium scintigraphy in patients with documented ST-segment depressionon either exercise testing or ambulatory electrocardiographic monitoring. We previously reported a sensitivity of 90% and a specificity of 80% for detection of coronary stenosis > 50% with tomographic thallium scintigraphy.l 5 Statistical analysis: All values are presented as mean f standard deviation. Comparison between patients with and without autonomic dysfunction and those with and without silent myocardial &hernia was performed with an unpaired t test in the caseof continuous variables and with Fisher’s exact test in the caseof discrete variables. Correlation analysis was performed between the thallium defect size and the duration and extent of ST depression on ambulatory electrocardiographic monitoring and exercisetesting. Statistical significance was set at a p value <0.05. RESULTS Of the 58 diabetic subjectswho were enrolled in our study and who completed all stagesof the protocol, 10 ( 17%) were found to have silent myocardial ischemia as evidenced by reversible perfusion defect on exercise thallium tomographic scintigraphy. The mean defect size was 13% and ranged from 1 to 31%: 5 subjectshad anterior defects, 4 had inferior, and 1 had a lateral defect. Comparison between diabetic subjects with and without silent myocardial &hernia is summarized in Table I. No difference was detected in baseline clinical characteristics or exercise performance. None of the patients had symptoms of chest pain during exercise testing.

TABLE I Comparison of Diabetic Subjects With and Without Silent lschemia Silent lschemia (n = 10) Clinical data Age Ws) Height (cm) Weight (kg) Duration of diabetes (yrs) % subjects receiving insulin Family history of CAD (%) Hypertension* (%) Smoking (%) Neuropathyt (%) Nephropathyf (%) Total serum cholesterol (mmol/ liter) Serum triglycerides(mmol/liter) HB A& (mmol/liter) Exercise data Duration of exercise test (min) Resting heart rate (beats/min) Resting systolic blood pressure

5Of6 175*4

No Silent lschemia (n=48)

1

57*7

5.7 f 0.8

172f9 81.8& 13.5 a.3 f 7.4 42 33 23 19 33 2 6.1 f 1.2

2.4 f 0.8 0.07 f 0.01

2.9f 1.8 0.08 f 0.02

8.2 f 2.1 79*13 149f23

8.2f 1.9 82f14 136f21

154f 215f

151f20

82.7 f 11.4 llf6.8 40

20 30 20 20 0

(mm t-k) Maximal heart rate (beats/min) Maximal systolic blood pressure

11 36

199f34

(mm He9 * Systolic blood pressure t 1 XI mm Hg or diastolic blood pressure t2 examinations. ’ Absence of ankleferk deep tendon reflex. *Serum creatinine >200 mmol/liter. CAD = coronary artery disease: HB A& = acetylated hemoglobin.

295 mm Hg on

Of the 10 diabetic subjects with silent myccardial &hernia, 6 had ST depressionof 11 mm during exercise testing and ambulatory electrocardiographic monitoring. One of the remaining 4 subjects with a reversible thallium defect had ST depressiononly on ambulatory electrocardiographic monitoring and 3 had ST depressiononly during exercisetesting. In addition to the 10 diabetic subjectswith a reversible thallium defect, 6 subjects had ST depressionon the initial exercisetest but did not demonstrateany abnormality in myocardial perfusion. One additional subject had ST depressiononly on ambulatory electrocardiographic monitoring and did not exhibit ST depression or a reversible thallium defect during exercise. Ambulatory electrocardiographic monitoring revealed episodesof ST-segment depression in 8 of 58 diabetic subjects (14%) 7 of whom had a reversible thallium defect. The mean number of episodeswas 1.9 f 1.7, with a range from 1 to 5 episodes,and the mean duration of ST depression was 13.9 f 12.9 min/24 hours. The mean heart rate at ST depressionduring ambulatory electrocardiographic monitoring (94 f 12) was significantly lower than that during exercisetesting (128 f 21, p
SILENT MYOCARDIALISCHEMIA 1075

subjectswith and without autonomic dysfunction with respectto the clinical and laboratory variables listed in Table I. % Abnormal Pain Weshold and tokranee: Comparisonsof elecTest (n = 58) trical pain threshold and tolerance between patients Valsalva maneuver 34 with and without silent myocardial ischemia and beHeart rate response to deep breathing 50 Heart rate response to standing 26 tween patients with and without autonomic dysfunction Blood pressure response to standing 17 is summarized in Table III. No difference was observed Blood pressure response to sustained handgrip 9 22 abnormal tests between patients with and without silent myocardial (autonomic dysfunction) 36 ischemia, and the measurementswere similar to those observedin the control nondiabetic subjects. The only significant difference was a slight increase in pain toting may be complementary measures of ischemic threshold in subjects with autonomic dysfunction (Taburden, we performed a correlation analysis between ble III). these 2 variables in 7 subjects with silent myocardial ischemia on ambulatory electrocardiographic monitor- DISCUSSION ing and with a reversible thallium defect. This revealed The principal new findings of this study are ( 1) a a modest relation of borderline statistical significance (r 17% prevalenceof silent myocardial ischemia in a se= 0.61, p = 0.059). No associationwas found between lect cohort of asymptomatic diabetic men, and (2) a thallium defect size and exercise-derivedvariables, such significantly greater frequency of silent myocardial as duration of exercise,extent of ST depression,time to ischemia among subjectswith than without autonomic l-mm ST depression,and duration of ST depressionin dysfunction (36 vs 5%). The diagnosisof silent myocardial ischemia was basedon documentation of exercisethe recovery phase. Autonomk functkn tests (Table II): In 15 of 58 induced reversible perfusion defects on quantitative (26%) of diabetic subjects, autonomic function tests thallium scintigraphy after initial detection of ST-segwere normal; 22 of 58 (38%) had 1 abnormal response, ment depressionon exercisetesting or ambulatory elec7 of 58 (12%) had 2 abnormal responses,10 of 58 trocardiographic monitoring. There were 6 additional ( 17%) had 3 abnormal responses,and 4 of 58 (7%) had subjectswith ST depressionduring exerciseand 1 with 4 abnormal responses;nobody had 5 abnormal tests. ST-segment depression on ambulatory electrocardioTherefore, 2 1 of 58 diabetic subjects(36%) were found graphic monitoring who did not have a reversiblethallito have autonomic dysfunction (i.e., 12 abnormal um defect and who were therefore not thought to have tests), whereas 37 subjects had preserved autonomic silent myocardial ischemia. At least one-third of our subjectsdemonstratedevifunction. Of the 21 diabetic subjectswith autonomic dysfunc- dence of autonomic dysfunction; a similar proportion tion, 8 (36%) had silent myocardial ischemia, com- has been detected by others.16Previous studies have pared with 2 of 37 (5%) without autonomic dysfunction shown that diabetic autonomic neuropathy is not only a (p = 0.003). In the 10 diabetic subjects with silent frequent complication of diabetesmellitus, but also that myocardial ischemia, autonomic dysfunction was de- its presenceis associatedwith a grave prognosis.17-22 Our findings, which demonstratea relation between tected more frequently (80%), comparedto that among autonomic dysfunction and silent myocardial &hernia, 48 subjectswithout silent myocardial ischemia (27%, p = 0.003). There was no difference between diabetic are supported by the autopsy study of Faerman et a1,23 TABLE II Results of Autonomic Subjects

Function Tests in Diabetic

TABLE III Results of Pain Threshold and Tolerance Measurement (mA) Pain Threshold

Pain Tolerance

n

Right*

Left*

Right*

Left*

0.27 f0.04 0.27 f0.05 0.28f0.08 0.29hO.08 0.26dcO.07

Silent myocardial &hernia No silent ischemia

10 10

0.18ztO.03 0.18f0.03

0.18*0.03 0.17f0.03

0.27 f0.05 0.30f0.09

48

0.17f0.03

0.17 f0.03

0.29 f 0.09

Autonomicdysfunction No autonomic dysfunction

21

0.18 f 0.03+

0.18ztO.03’

0.30f0.10

37

0.16*0.02

0.16f0.03

0.27f0.08

Normal control subjects

* Right and left refer to forearms. 7 p <0.05 compared with subiects with no autonomic

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who found evidence of typical diabetic neuropathic changesinvolving afferent sympathetic and parasympathetic tracts in patients dying with silent but not symptomatic myocardial infarction. Although coronary angiography was not performed in our subjects,previous studies have shown that thalliurn scintigraphy identified 97% of asymptomatic subjects with abnormal electrocardiograms correctly regarding the presence or absence of coronary artery disease.24Furthermore, the presenceof an exercise-induced thallium defect in an asymptomatic population has been shown to identify subjects with a strikingly high incidence of subsequentcoronary events.2sMyocardial ischemia in diabetesmay be mediated by a variety of factors other than conventional epicardial coronary narrowings, such as small vessel disease,26abnormal myocardial capillaries,27 disordered vasoreactivity,28 endothelial dysfunction,29increasedplatelet aggregability, reduced red cell deformability,31 and hyperfibrinogenemia.30 Although previous studies have identified pain threshold and tolerance to be generally elevated in patients with, compared to those without, silent myocardial ischemia,32,33 such measurementswere previously unavailable in asymptomatic diabetics. Our study demonstrates a similar pain threshold and tolerance in patients with and without silent myocardial ischemia. Of interest, however,is that diabetics with, comparedwith those without, autonomic dysfunction had an elevated pain threshold, suggestingthat subclinical peripheral neuropathy may be present in patients with autonomic dysfunction. Given the electrical skin stimulation evidence for normal pain threshold and tolerance in our subjectson the one hand, and the significant relation betweenautonomic dysfunction and silent myocardial ischemia on the other, a diabetic neuropathy affecting autonomic pain fibers that innervate the heart may be implicated in the mechanism of silent myocardial ischemia. This hypothesis is supported by the recent work of Ambepityia et a134in diabetic patients with typical exertional angina. Using a third-order polynomial fit, these workers showed an association between an abnormal heart rate responseto the Valsalva maneuver and prolongation of the time of the onset of angina during exercise testing. Clinkal implkations: A lack of symptomsin diabetic men, especially those with autonomic dysfunction, is not an adequate guide for assessmentof the presenceof myocardial ischemia. The impact of silent myocardial ischemia on and the development of cardiovascular morbidity and mortality in diabetics requires further evaluation with respectto developmentof (1) symptom-

atic myocardial &hernia, (2) myocardial infarction, (3) congestiveheart failure, an important cause of cardiovascular mortality in diabetic patients,35which may be a result of frequent episodesof silent myocardial ischemia over a long period of time, and (4) suddencardiac death. We acknowledgethe expert technical support of the Department of Electrocardiography at St. Michael’s Hospital, the secretarial assistanceof Gail Karaim, and the help of Daphne Keene. Aeknowkdgment:

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