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275

Silent Myocardial Ischemia: Qemodynamic Changes During Dynamic Exercise in Patients With Proven Coronary Artery Disease Despite Absence of Angina Pectoris

HEINZ O. HIRZEL, MD, RUTH LEUTWYLER, HANS P. KRAYENBUEHL, MD

Zurich, Switzerland

The hemodynamic changes during exercise occurring in 36 patients with proven coronary artery disease (10 with­out and 26 with previous myocardial infarction) who tolerated the stress test without angina were analyzed aud compared with changes observed in a control group of 36 carefully matched patients whose exercise was lim­ited by angina. All patients were exercised to the same extent, reaching a similar rate-pressure product at the end of the stress test (19,508 ± 4,828 [SD] versus 19,247 ± 4,1l7 beats/min x mm ~g [NS] in the study and control groups without prior infarction, and 19,665 ± 3,950 versus 17,701 ± 4,600 beats/min x mm Hg [NS] in the respective groups with infarction). In all groups left ventricular end-diastolic pressure increased from rest to exercise (from 18 ± 4 to 36 ± II and from 13 ± 5 to 29 ± 9 mm Hg, respectively, in the study and control groups without prior infarction and from 17 ± 7 to 32 ± 13 and from 19 ± 7 to 36 ± 9 mm Hg in the respective groups with prior infarction). Left ventricular ejection

Angina pectoris is considered a sensitive marker of ischemic events. Indirect evidence, however, suggests that ischemia may also occur silently, without accompanying chest pain. Such evidence has been derived from exercise induced ST segment changes (1-6), clear-cut perfusion defects at stress scintigraphy (7,8) or typical ischemic electrocardiographic alterations during continuous ambulatory Holter monitoring (8-14) in asymptomatic patients with arteriographically proven coronary artery lesions and patients who later developed symptomatic coronary heart disease. Yet, the underlying pathophysiologic mechanisms of silent ischemia remain ob-

From the Department of Medicine. Medical Policlinic. Division of Cardiology. University Hospital. Zurich. Switzerland. This work was sup­ported in part by a grant of the EM DO-Foundation, Zurich. Switzerland. Manuscript received December 5. 1984; revised manuscript received March 12. 1985. accepted March 29. 1985.

Address for reprints: Heinz O. Hirzel, MD. Department of Medicine. Medical Policlinic. Division of Cardiology. University Hospital. CH-8091 Zurich. Switzerland.

© 1985 by the American College of Cardiology

fraction decreased (from 59 ± 7 to 50 ± 15 and from 60 ± 4 to 52 ± 9% in the study and control groups without prior infarction and from 54 ± 9 to 47 ± 10 and 55 ± 9 to 50 ± 4% in the respective groups with prior infarction). Whereas the changes from rest to ex­ercise were highly significant within each group, no sig­nificant differences were noted between the correspond­ing groups. Regional de novo hypokinesia appeared in all patients without prior infarction and in 25 and 22 patients, respectively, of the groups with prior infarction.

Thus, under similar physical stress conditions, com­parable hemodynamic changes indicative of ischemia are observed in patients with significant coronary artery le­sions with or without previous myocardial infarction ir­respective of the occurrence of angina. Therefore, an­gina pectoris cannot be considered a prerequisite for hemodynamically significant ischemia during exertion.

(J Am Coil Cardiol 1985;6:275-84)

scure and little is known about the hemodynamic changes associated with such attacks.

Whereas global and regional changes of left ventricular function in the anginal state induced by various stress tests are well studied (15-25), only a few reports (25-27) have dealt with alterations of function during dynamic exercise tolerated without angina despite significant coronary artery lesions. Thus, we examined the hemodynamic changes dur­ing exercise occurring in 36 of 258 consecutive patients with proven coronary artery disease who tolerated the stress test without symptoms.

Methods StuJly patients (Groups I and II). Of 258 consecutive

patients with arteriographically severe coronary artery le­sions who were evaluated by dynamic exercise during the invasive examination, 36 were angina-free on admission and had no anginal symptoms during a bicycle stress test con­ducted in the upright position on the day before cardiac

0735-1097/85/$3.30

276 HIRZEL ET AL. HEMODYNAMIC CHANGES IN SILENT ISCHEMIA

catheterization and at catheterization. All 36 patients had experienced one or more episodes of chest pain 4 to 8 months before admission and 26 patients had a history of myocardial infarction that dated back more than 6 months. The indi­cation for catheterization was posed at the time when symp­toms occurred or in the early recovery period after myo­cardial infarction and was determined on the basis of objective findings such as a positive exercise stress test or exercise­induced reversible perfusion defects in the thallium-20l scintigram, or both. All patients were male, ranging in age from 26 to 63 years (Table 1). Group I consisted of 10 patients without prior myocardial infarction and Group II of 26 patients with prior myocardial infarction.

Before hospital entry, 5 of the 10 patients without prior infarction in Group I were treated intermittently with beta­receptor blocking agents, and long-acting nitrates, 3 patients with beta-blocking agents, long-acting nitrates and calcium channel antagonists, 1 with beta-blocking agents and cal­cium antagonists and 1 with beta-blocking agents only. The 26 patients in Group II had received beta-blocking agents and long-acting nitrates prophylactically for 3 months fol­lowing hospital discharge after infarction. Because symp­toms did not reappear when discontinuing medication the majority of these patients had stopped medication several

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weeks before the present admission. Thus, at hospital entry, none of the patients was receiving appropriate antianginal therapy.

Control patients (Groups III and IV). The 36 patients without exercise-induced angina were matched with 36 pa­tients who were limited by angina at stress. These control patients were similar to the patients without stress-induced angina in age, number of diseased vessels, extent of ath­erosclerosis, left ventricular end-diastolic pressure at rest, ejection fraction and absence of site of prior myocardial infarction. The diagnosis of a previous myocardial infarction was based on the history of an appropriate event associated with electrocardiographic or enzymatic changes, or both, and circumscribed left ventricular asynergy in the angiogram at rest. Despite continued medical therapy, all control pa­tients continued to have effort-induced angina. To obtain the most precise information regarding the clinical relevance and severity of the disease, all medication with the excep­tion of short-acting nitrates was discontinued in all patients on admission. No withdrawal effects necessitated restoration of full antianginal therapy in any patient.

Clinical evaluation. All patients were examined clini­cally and by routine laboratory tests including a 12 lead standard electrocardiogram at rest and a continuous muIti-

Table 1. Characteristics of the Four Patient Groups With Proven Coronary Artery Disease

Patients Without MI Patients With MI

Patients (no.) Age (yr)

Mean Range

Levine vascularization index Number of diseased vessels

I vessel 2 vessels 3 vessels

Critically stenosed vessels (>70% narrowing) LAD LCx RCA

Site of infarction Anterior Posterior

Upright bicycle stress test work load attained (walls)

ST segm~nt depression (>0.1 mY)

ST segment elevation (>0.1 mV)

Angina pectoris

Group I (without AP)

10

52 ± 7 38 to 63

-1.7 ± 0.9

2 6 2

5 8 6

131 ± 21

3

o

o

Group III (with AP)

10

50 ± 6 39 to 63

-1.7 ± 0.8

2 6 2

6 7 6

98 ± 39*

6

o

Group II (without AP)

26

48 ± 9 26 to 61

-1.8 ± 0.9

8 5

13

21 II 17

II 15

129 ± 37

12

o

Group IV (with AP)

26

49 ± 8 33 to 60

-1.9 ± 0.8

6 7

13

24 11 17

II 15

97 ± 32t

13

26t

Values are expressed as mean values ± I SO. *p < 0.05 versus Group I; tp < 0.01 versus Group II; tp < 0.001 versus Groups I and II, respectively (unpaired t tests). AP = exercise-induced angina pectoris; LAD = left anterior descending coronary artery; LCx = left circumflex coronary artery; MI = myocardial infarction; RCA = right coronary artery.

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stage bicycle exercise test in the upright posture with re­cording of precordial leads V2 , V4 , and Vo. Exercise testing was performed according to a modified Bruce protocol (28). The target work load was determined from a nomogram that adjusted for age, sex and height (29). Exercise was started at about one third of the target work load; the work load was then increased stepwise every 3 minutes until chest pain, dyspnea, fatigue or muscle weakness forced interrup­tion of exertion.

Cardiac catheterization and angiography. Premed­ication consisted of chlordiazepoxide (Librium), 10 mg, given perorally I hour before the study. After left heart catheterization by the transfemoral arterial route, the feet of the supine patient were attached to the pedals of the bicycle ergometer, whose axis was 42 cm above the cath­eterization table. The left ventricular pressure was then re­corded at rest on an oscillograph (VR 12, Electronics for Medicine). Thereafter, biplane cineangiography at rest was performed in the right and left anterior oblique projections (Cardioskop-U, Siemens) by injecting an average volume of 44 ml of contrast medium (Urografin, 76%, Schering) by means of an electrocardiographically triggered power injector (Contrac, Siemens) at a flow rate of 13 mils (Fig. I). A 15 minute pause was allowed to restore hemodynamic baseline levels. Exercise was started at about half the work load tolerated during the upright stress test performed the day before. The work load was then increased stepwise every 2 to 3 minutes. At the highest work load tolerated or at the onset of angina and with the patient still pedaling, the left ventricular pressure was recorded again and cine­angiography repeated using an average volume of 72 ml of contrast agent injected at a flow rate of 16 mils (Fig. I). Selective coronary arteriography using the Judkins tech­nique was performed after cineangiography. During the en­tire examination the patients received 10,000 units of heparin.

Ventriculographic analysis. The left ventriculograms were recorded on 35 mm cinefilm exposed at 50 frames/so The left ventricular cavity silhouettes were drawn from end­diastolic and end-systolic frames in both the left and right anterior oblique projections (Vanguard projector). The cor­responding frames in end-diastole and end-systole were identified using a numerical code displayed on both the cine frames and the recording paper. The end-diastolic frame was chosen at the peak of the R wave in the electrocardio­gram and the end-systolic frame when the left ventricular area was smallest. The volumetric analysis was confined to contractions occurring during normal electrical depolari­zation; extrasystoles or postextrasystolic beats were ex­cluded from analysis. After correction for image magnifi­cation, volume estimates were made using the area-length method (30,31), and biplane ejection fraction was com­puted. In addition, rate-pressure product, as an estimate of myocardial oxygen consumption, and the increase in the rate-pressure product from rest to exercise were calculated.

HIRZEL ET AL. 277 HEMODYNAMIC CHANGES IN SILENT ISCHEMIA

Coronary angiography. The angiographic severity of coronary artery disease was assessed by the numerical score proposed by Levine et al. (32). Thus, fixed values were assigned to each obstructive lesion located in any of the three coronary vessels and their major side branches. Le­sions with less than 70% reduction in luminal diameter were considered hemodynamically insignificant and were as­signed the value O. A 70 to 90% stenosis was assigned the value - 0.5, and a more than 90% stenosis or occlusion of the vessel was given the value - 1.0. By summing the values calculated for each individual coronary artery system the vascularization index was established. The more neg­ative this vascularization index was, the more extensive the coronary artery alterations.

Ventricular hypokinesia. The appearance of de novo hy­pokinesia during exercise was evaluated in two ways: I) visual inspection of the biplane left ventricular angiograms by two independent observers; in all cases there was agree­ment; and 2) comparison of the fractional shortening of the six hemiaxes (23,33) in the right and left anterior oblique projections. Thereby, de novo hypokinesia was defined as a greater than 10% decrease in fractional shortening of one hemiaxis from rest to exercise without a concomitant in­crease in shortening of the corresponding opposite hemiaxis. Hypokinesia was considered present only if both methods yielded a positive result.

Statistics. The results were expressed as mean values ± I standard deviation. To evaluate statistical differences be­tween the data, paired and unpaired Student's t tests, anal­ysis of variance and the chi-square test with the continuity correction described by Yates for small sample sizes were used.

Results The results are summarized in Tables I to 3 and Figures

2 and 3. Clinical and coronary status of the study and control

groups. Because the study and control groups were care­fully matched, they did not differ in mean age, coronary status (including the number of diseased vessels), mean vascularization index or site of previous myocardial infarc­tion. However, at the stress test in the upright position the work load tolerated by the patients without exercise-induced angina (Groups I and II) was significantly higher than the work load at which the stress test had to be terminated because of angina in the respective control groups (Groups III and IV). In the groups without prior myocardial infarc­tion, the exercise electrocardiogram revealed an ST segment depression of greater than 0.1 mV in three patients without stress-induced angina (Group I) and six with angina (Group III) (NS). Among the patients with prior infarction, ST segment depression was found in 12 patients without angina (Group II) and 13 with angina (Group IV) (NS) and sig-

278 HIRZEL ET AL. HEMODYNAMIC CHANGES IN SILENT ISCHEMIA

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Figure 1. Cineangiograms obtained in the right anterior oblique projec­tion in end-diastole (above) and end­systole (below) at rest (left panels) and during exercise (right panels) at similar work loads in two patients with severe three vessel coronary ar­tery disease. A, Case I, a 63 year old man who tolerated the stress test without anginal symptoms. During exercise (for 3 minutes, to a work load of 80 watts), left ventricular ejection fraction decreased from 52 to 35% and end-diastolic pressure in­creased from 28 to 40 mm Hg. Fur­thermore, severe hypokinesia of the anterolateral wall developed (ar­rows). B, Case 2, a 47 year old man who was limited by severe angina at exercise. During exercise (for 2 min­utes to a work load of75 watts), left ventricular ejection fraction de­creased from 69 to 44% and end­diastolic pressure increased from 16 to 40 mm Hg. Again, marked de novo hypokinesia of the anterolateral, ap­ical and inferior portions of the left ventricle became apparent (arrows).

280 HIRZEL ET AL. HEMODYNAMIC CHANGES IN SILENT ISCHEMIA

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Table 3. Hemodynamic Changes During Exercise in the 52 Patients With Myocardial Infarction With and Without Angina Pectoris

Patients With Myocardial Infarction

p Group II Group IV (Group II versus

(without AP) (with AP) Group IV)

Work load attained (watts) 107 :+: 35 99 :+: 33 NS HR (beats/min)

Rest 78 :+: 13 71 :+: II <0.05 Exercise 127 :+: 18* 118 :+: 22* NS

LVEOP (mm Hg) Rest 17 :+: 7 19 :+: 7 NS Exercise 32 :+: 13* 36 :+: 9* NS

LVSP (mm Hg) Rest 130 :+: 22 135 :+: 15 NS Exercise 154 :+: 22* 149 :+: 23* NS

Rate-pressure product (beats/min x mm Hg) Rest 10,185 :+: 2,326 9,954 :+: 2,182 NS Exercise 19,665 :+: 3,950* 17,701 :+: 4,600* NS % increase 97 :+: 37 80 :+: 40 NS

EOVI (mllm2) Rest 121 :+: 37 III:+: 26 NS Exercise 130 :+: 39 125 :+: 25 NS

ESVI (ml/m2) Rest 58 :+: 30 50 :+: 18 NS Exercise 71 :+: 32* 64 :+: 24* NS

EF(%) Rest 54 :+: 9 55 :+: 9 NS Exercise 47 :+: 10* 50 :+: 14* NS

Regional de novo hypokinesia 25/26 22/26 NS

Values expressed as mean:+: SO. Symbols and abbreviations as in Table 2.

significantly between the groups, averaging 82 ± 30 and 98 ± 55%, respectively, of the value at rest for Groups I and III (without infarction), and 97 ± 37 and 80 ± 40% of the value at rest for Groups II and IV (with infarction). Correspondingly, the final values for heart rate and systolic left ventricular pressure achieved during exercise and their increase from rest to exercise were nearly the same in the respective study and control groups. The end-diastolic left ventricular pressure increased significantly in all four groups, reaching 36 ± 11 and 29 ± 9 mm Hg, respectively, in Groups I and III (without infarction) and 32 ± 13 and 36 ± 9 mm Hg in Groups II and IV (with infarction). Because end-diastolic and especially end-systolic left ven­tricular volumes also increased similarly, left ventricular ejection fraction decreased to the same extent in the cor­responding groups, that is, from 59 ± 7 to 50 ± 15% and 60 ± 4 to 52 ± 9%, respectively, in Groups I and III and from 54 ± 9 to 47 ± 10 and 55 ± 9 to 50 ± 14% in Groups II and IV. Although the values were significantly different within each group, they did not differ between the respective study and control groups.

Contraction abnormalities occurring during exercise, such as regional de novo hypokinesia, were detected in all patients without myocardial infarction (Groups I and III; Fig. 1) and 25 of 26 patients without angina (Group II) and in 22 of 26 patients with angina (Group IV) with infarction (Tables 2

and 3). In none of the patients was global hypokinesia noted. The de novo contraction abnormalities during exercise as assessed by analysis of the fractional shortening of the six hemiaxes in either of the two projections (see Methods) involved I to 3 of the 12 analyzed segments in 3 and 5 patients, respectively, in Groups I and III (without infarc­tion) and in 17 and 8 patients in Groups II and IV (with infarction). Four to six segments were hypokinetic in 5 and 3 patients, respectively, in Groups I and III and in 6 and II patients, respectively, in Groups II and IV. Finally, seven to nine hypokinetic segments were observed in nine patients; two each in Groups I and III and two and three, respectively, in Groups II and IV.

With re~pect to the appearance of regional contraction abnormalities. the decrease in ejection fraction and the increase in left ventricular end-diastolic pressure during exercise as indicators of ischemia, findings were similar in individual patients whether or not these hemodynamic changes were accompanied by angina (Fig. 2 and 3). Thus, in the two groups without myocardial infarction all three findings were present in seven patients without exercise-induced an­gina (Group I) and eight patients with angina (Group III), two findings were present in two patients of each group and only de novo hypokinesia developed in one patient in Group I. In the two groups with myocardial infarction, all three findings were observed in 16 patients in Group II (without

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HIRZEL ET AL. 279 HEMODYNAMIC CHANGES IN SILENT ISCHEMIA

Table 2. Hemodynamic Changes During Exercise in the 20 Patients Without Myocardial Infarction With and Without Exercise-Induced Angina Pectoris (AP)

p (Group I

Group I versus (without AP) Group III (with AP) Group III)

Work load attained (watts) HR (beats/min)

Rest

115 ± 31

77± 12

94 ± 28 NS

72± 13 NS Exercise 126 ± 19* 115 ± 16* NS

L VEOP (mm Hg) Rest 18 ± 4 13 ± 5 <0.02 Exercise 36 ± 11* 29 ± 9* NS

LVSP (mm Hg) Rest 138 ± 21 141 ± 18 NS Exercise 152 ± 19* 168 ± 25* NS

Rate-pressure product (beats/min x mm Hg) Rest 10,499 ± 1,410 10,208 ± 2,879 NS Exercise 19,508 ± 4,828* 19,247 ± 4,117* NS % increase 82 ± 30 98 ± 55 NS

100 ± 23 100 ± 18 NS EOVI (mllm2)

Rest Exercise

ESVI (mllm2) Rest Exercise

EF(%)

116 ± 18* 103 ± 14 NS

44 ± 14 39 ± 7 NS 59 ± 25* 50 ± 13* NS

59 ± 7 60 ± 4 NS Rest Exercise 50 ± 15* 52 ± 9* NS

Regional de novo hypokinesia 10/10 10/10 NS

Values are expressed as mean values ± SO. * P < 0.001 different from value at rest (paired and unpaired t tests, one-way analysis of variance). EOVI = left ventricular end-diastolic volume index; EF = left ventricular ejection fraction; ESVI = left ventricular end-systolic volume index; HR = heart rate; LVEOP = left ventricular end-diastolic pressure; LVSP = left ventricular systolic pressure.

nificant ST segment elevation in 1 patient in each of these two groups (Table 1).

In further analysis of the risk profiles of the four groups, no differences were detected. In the patients without myo­cardial infarction (Groups I and III) no patient was diabetic. Moderate hypertension was present in two patients without exercise-induced angina and one patient with angina. Hy­perlipidemia was found in five patients without angina and four with angina; serum cholesterol levels ranged from 6.7 to 8.6 mmollliter. Seven patients in Group I and seven in Group III were smokers ( > 20 cigarettes/day for more than 2 years). In Groups II and IV (patients with myocardial infarction), two patients without and three with exercise­induced angina had a modest elevation of blood glucose levels in the fasting state. In three patients without and four with angina, serum cholesterol levels were above 6.5 mmollliter. Two patients with and two without angina had hypertension. Thirteen patients without angina and 12 with angina were heavy smokers before myocardial infarction had occurred.

Baseline hemodynamics at rest. Baseline hemody­namic values at rest were also nearly identical except for

the somewhat higher mean left ventricular end-diastolic pressure in the angina-free patients without myocardial in­farction (Group I) and the higher mean heart rate in the asymptomatic patients with infarction (Group II). The rate­pressure product, as an estimate of basal oxygen consump­tion, however, was almost identical in all four groups (Ta­bles 2 and 3).

Hemodynamic and angiographic changes during ex­ercise. At the stress test during catheterization, the external work load tolerated was slightly higher in Groups I and II (patients without exercise-induced angina) than in Groups III and IV (patients with angina), averaging 115 ± 31 and 94 ± 28 watts (NS), respectively, in Groups I and III (patients without infarction) and 107 ± 35 and 99 ± 33 watts (NS) in Groups II and IV (patients with infarction). The rate-pressure products achieved during exercise, how­ever, were almost identical (19,508 ± 4,828 and 19,247 ± 4,117 beats/min X mm Hg [NS] for the groups without prior infarction and 19,665 ± 3,950 and 17,701 ± 4,600 beats/min x mm Hg [NS] for the groups with prior in­farction, respectively). Moreover, the relative increases in the rate-pressure product from rest to exercise did not differ

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ANGINA

HIRZEL ET AL. 281 HEMODYNAMIC CHANGES IN SILENT ISCHEMIA

20 ----------II ~ I I

Figure 2. Clinical, hemodynamic and angio­graphic characteristics during exercise in Groups I and III, 20 patients with proven coronary artery disease but without prior myocardial infarction. Ten patients (Group III) were limited by angina, 10 (Group I) tolerated the exercise test without anginal symp­toms. Both patient groups were carefully matched for extent and severity of coronary artery lesions. No differences in prevalence of either regional de novo hypokinesia, decrease of left ventricular ejec­tion fraction (EF) or increase in end-diastolic pres­sure (L VEDP) were noted between the two groups during exercise at comparable external work loads and rate-pressure products.

DE NOVO HYPOKINESIA /~ ~

~. ~ " ~ FALL OF EF

RISE OF LVEDP .. b .'0 .b II CD Group III (with AP)

Group I (without AP)

l1li FINDING PRESENT

angina) and 16 patients in Group IV (with angina), whereas two of these indicators were present in 8 patients in Group II and 6 patients in Group IV; only one indicator was present in 2 patients in Group II and in 4 patients in Group IV. These differences between subgroups were not statistically significant.

Discussion Markers and determinants of ischemia. The existence

of silent myocardial ischemia has been postulated for several years to explain asymptomatic episodes of ST segment changes in patients with coronary artery disease (1-8). Our knowl­edge remains sparse, however, about the patients prone to development of such attacks and the underlying pathophy­siologic mechanisms. Moreover, it is still unclear whether ischemia without angina is related to the degree or special dynamic properties of coronary artery lesions, or both, and to what extent it is accompanied by hemodynamic alterations characteristic of ischemic myocardium.

Figure 3. Clinical, hemodynamic and angiographic characteristics during ex­ercise in Groups II and IV, 52 patients with proven coronary artery disease and previous myocardial infarction. Twenty­six patients (Group IV) developed an­gina during the stress test and 26 pa­tients (Group II) tolerated the exercise test without anginal symptoms. Both pa­tient groups were carefully matched for extent and severity of coronary artery lesions and location of infarction. No differences in prevalence of either re­gional de novo hypokinesia, decrease of left ventricular ejection fraction (EF) or increase in end-diastolic pressure (L VEDP) were noted between the two

ANGINA

DE NOVO HYPOKINESIA

FALL OF EF

RISE OF LVEDP

groups during exercise at comparable • FINDING PRESENT

external work loads and rate-pressure products.

The prevalence of significant coronary artery lesions in asymptomatic patients has been estimated by various in­vestigators (34-36) to be roughly 4.5% on the basis of arteriographic and postmortem findings in large groups of patients who were either asymptomatic or not known to have had coronary heart disease before death. However, it remains an unresolved issue whether this group of asymp­tomatic patients exhibited attacks of so-called silent ischemia.

Even though the degree of coronary luminal obstruction that may lead to compromised myocardial perfusion is the­oretically well established (37), several additional factors influence the significance of a stenosis. Aside from the driv­ing pressure, the length (38), shape and dynamic properties of the stenosis, the magnitude of the supplied muscle mass, the autoregulatory capacity of the vascular bed and the num­ber and size of functioning collateral vessels (39) play an important role. Thus, in a given anatomic setting the an­giographic appearance of a stenosis cannot be viewed as the only indicator of its significance in relation to myocardial ischemia. More precise information is derived from isch­emia-provoking tests such as dynamic exercise.

Group I V (with AP)

Group I I (without AP)

282 HIRZEL ET AL. HEMODYNAMIC CHANGES IN SILENT ISCHEMIA

Thus, the development of contraction abnormalities lead­ing to a decrease in ejection fraction and the increase in left ventricular end-diastolic pressure during exercise clearly in­dicate left ventricular dysfunction. Such changes, however, are observed in a variety of pathologic conditions and do not necessarily imply that ischemia is the underlying path­ophysiologic cause. In patients who have valvular insuffi­ciency or cardiomyopathy of various origins with normal coronary arteries, it is tempting to attribute this phenomenon to myocardial failure due to either increased tissue fibrosis or disease-related biochemical changes at the cellular level than to inadequate blood flow, especially because the con­traction abnormalities are uniform. The exercise-induced appearance of regional wall motion abnormalities in patients with significant coronary artery lesions, however, may in­dicate more specifically localized impairment of myocardial perfusion.

Periods without angina in the course of coronary ar­tery disease. The present study focuses on 36 (14%) of 258 consecutive patients with severe coronary artery lesions who tolerated a dynamic exercise test during cardiac cath­eterization without angina pectoris despite pronounced hemodynamic changes indicative of exertion-induced isch­emia. Group I comprised J 0 (7.9%) of 127 patients in whom neither anamnestic, clinical nor angiographic data suggested the presence of previous myocardial infarction and Group II comprised 26 (19.8%) of 131 patients who had experi­enced such an event as proven by the existence of an akinetic region in the left ventriculogram. All patients, however, were limited by angina at the time the decision for invasive evaluation was made but became spontaneously angina-free thereafter. This observation suggests that: I) the incidence of ischemic attacks without angina may not be that small because 14% of our patient group exhibited such an event, and 2) that such attacks seem to occur significantly more frequently (p < 0.0 I) in patients after myocardial infarction. Moreover, it documents that the course of clinically manifest coronary heart disease is by no means uniform and may be interrupted at times by periods without angina despite con­tinued silent ischemic attacks during exertion. Therefore, the spontaneous disappearance of anginal pain in a patient with coronary heart disease has to be interpreted with caution because it may not necessarily reflect true improvement in terms of disappearance of myocardial ischemia.

In comparing the hemodynamic changes that occurred in these two groups without angina withthe changes observed in two carefully matched control groups of patients who developed angina at nearly identical exercise conditions (Groups III and IV), no significant differences were de­tected. Although a similar external work load is not nec­essarily indicative of similar myocardial oxygen demand, the comparable rate-pressure product as an estimate of myo­cardial oxygen consumption achieved during exercise by

lACC Vol. 6. No.2 August 1985:275-84

the different groups suggest that the internal work load of the heart may have been much the same. Thus, our study further demonstrates that in the absence of angina the hemo­dynamic alterations during exertion may be of a magnitude similar to that of changes accompanied by angina. There­fore, angina pectoris cannot be considered a prerequisite for hemodynamically significant ischemia during exertion in patients with coronary artery disease.

Similar conclusions were reached by Cecchi et al. (40) and Chierchia and coworkers (41). Using long-term am­bulatory Holter monitoring alone (40) or combined with left ventricular or pUlmonary and systemic arterial pressure mea­surements (41), these investigator~ observed spontaneous asymptomatic ischemic episodes similar in duration and se­verity in patients with either effort-induced angina or angina at rest. This finding again favors the view that neither du­ration nor severity of ischemia are the only factors respon­sible for the genesis of anginal pain. In addition, these studies do~ument that ischemic attacks with angina may occur side by side with attacks without anginq in the same patient.

Possible pathophysiologic mechanisms of painless ischemic episodes. There is uncertainty about the patho­physiologic mechanisms underlying this lack of sensitivity to pain, and it is tempting to attribute the phenomenon of silent ischemia to individual differences in pain threshold, as suggested by experimental pain measurements (42). In patients with prior myocardial infarction, the morphologic destruction of nociceptive pathways could render an alter­native explanation for lack of pain sensations in the ischemic state. However, observations made after aortocoronary by­pass surgery indicate that only subsequent to extremely rad­ical denervation procedures may measurable changes in ex­perienced pain occur (43). In addition, such effects would be expected to be present in the control group as well.

Finally, it might be argued that differences in risk profile account for variations in the perceptibility of ischemic pain. In our study no differences were detectable between patients with and without exercise-induced angina with regard to the prevalence of hypertension, high serum cholesterol levels and smoking habits. Among patients without angina, dia­betes was excluded in all 10 patients without prior myo­cardial infarction, whereas modest elevations of blood glu­cose levels in the fasting state were found in only 2 of the 26 patients with prior infarction. On the basis of anamnestic data, none of the 36 patients without angina had evidence of excessive alcohol consumption thus ruling out polyneu­ropathy as a possible cause of lowered pain threshold in this patient cohort.

Thus, even though the present study offers no explanation for the altered pathophysiologic mechanisms operating in silent forms of myocardial ischemia, it confirms the exis­tence of such events in an appreciable proportion of patients

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with coronary heart disease and, more important, it docu­ments that silent ischemic attacks may be accompanied by hemodynamic changes equal in severity to those observed in patients who experience angina.

We are grateful to Joerg Grimm. PhD for his help in performing the statistical evaluation of the data.

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