Exercise-induced prominent U waves as a marker of significant narrowing of the left circumflex or right coronary artery

the coronary care unit, but only 2, who arrived at the hospital within 6 hours of the onset of pain, received thrombolytic therapy. All patients had uneventful courses and were discharged within 12 days. Six patients underwent an exercise test before hospital discharge (results were positive, with angina), and coronary arteriography was carried out 2 to 5 days after the test. The remaining 6 patients developed exertional angina and underwent exercise testing within 6 weeks after hospital discharge. These patients had chest pain during moderate effort and a poor response to sublingual glyceryl trinitrate. The exercise test result was positive in all 6 patients. Coronary arteriograms recorded 1 to 6 months after the exercise test showed completely normal coronary arteries. Tests for coronary artery spasm (hyperventilation andlor ergonovine), per$ormed at the time of the coronary arteriography, yielded negative results in all patients. No patient had left ventricular hypertrophy as assessed by echocardiography. All patients underwent 24-hour ambulatory electrocardiographic monitoring, which showed transient ST-segment depression of >I mm in 8 patients. Dipyridamole thallium scintigraphy, pe$ormed 3 to 12 months after AM, showed$xed myocardial perfusion defects, consistent with the infarction, in all patients. Transient, reversible perfusion defects were observed in 9 patients. This study shows that syndrome X may develop after an AMI. Several mechanisms could have been responsible for AM1 in our patients but, irrespective of its cause, it is conceivable that coronary artery occlusion during AM1 resulted in ischemic damage to the microvascular endothelium, thus causing persistent coronary microvascular dysfunction. We postulate that an abnormality at the small intramyocardial vessels, those that cannot be visualized by coronary arteriography, is responsible for the angina1 syndrome that developed after AMI. Our hypothesis is based on the fact that the large epicardial vessels of our patients were normal at angiography and no patient had coronary artery spasm or other causes of microvascular angina such as hypertension, left ventricular hypertrophy, or cardiomyopathy.

Our findings substantiate suggestions by Penny et al7 and Kloner et al9 that a period of no-flow, followed by reperfusion, in 1 of the large coronary arteries could result in long-term impairment of small vessel dilator reserve in the territory supplied by this artery. It has been shown that microscopic foci of myocardial necrosis may result from multifocal microembolism in patients who have nonocclusive thrombi in major epicardial arteries. lo This could also have been the mechanism in our patients, in whom coronary thrombosis probably resulted in both AM1 and persistent microvascular endothelial damage which, in turn, led to syndrome X. Lysis of the coronary thrombus after AMI, whether spontaneous or pharmacologic, may explain the presence of normal coronary arteriograms. In conclusion, in selected patients, syndrome X may develop as a consequence of an AM1 but the mechanism remains speculative. Acknowledgment: We are grateful to Stefania Zoboli and Carole Hann for help in data collection. 1. Acute myocardial

infarction and angiographically normal coronary arteries. An unproven combination. Circularion 1976:53:39+%00. Editorial. 2. Kemp HG, Kromnal RA, Vlietstra RE, Frye RL, and Coronary Artery Surgery Study (CASS) Participants. Seven-year survival of patients with normal or near normal coronaty atteriograms. A CASS registly study.JAm Coil Car&l 1986;7:47%483. 3. Cannon RO, Camici PG, Epstein SE. Pathophysiological dilemma of syndrome X. Circulation 1992;85:883-892. 4. Egashira K, Inou T, Hirooka Y, Yamada A, Urabe Y, Takeshita A. Evidence of impaired endothelium-dependent coronary vascdilatation in patients with angina pectoris and normal coronary angiograms. N En@ J Med 1993;328:1659-1664. 5. Vrints CJM, Bult H, Hitter E, Herman AC, Snoeck JP. Impaired endotheliumdependent cholinergic coronary vasodilation in patients with angina and normal coronary aneriograms. J Am Co/l Cardiol 1992; 19:2 l-3 I. 6. Motz W, Vogt M, Rabenau 0. Scheler S, Luckhoff A, Strauer BE. Evidence of endothelial dysfunction in coronary resistance vessels in patients with angina pee toris and normal coronary angiograms. Am J Cardiol 1991:68:99~1CMl3. 7. Penny WJ, Tweddel AC, Martin W, Hendenon AH. Microvascular angina may be a legacy of coronary thrombolysis. Eur Heart J 199O;ll: 1049-1052. 6. Kloner RA, ¬e CE, Jennings RB. The “no-reflow” phenomenon after temporary coronary occlusion in the dog. J Clin Invest 1974;54: 14961508. 9. Kloner RA, Giacomelli F, Alker KJ, Hale SL, Matthews R, Bellows S. Influx of neutrophils into the walls of large epicardial coronary arteries in response to ischemiafreperfusion. Circularion 1991;84:1758-1772. 10. Falk E. Unstable angina with fatal outcome: dynamic coronary thrombosis leading to infarction and/or sudden death. Autopsy evidence of recurrent mural thrombosis with peripheral embolizatton culminating in total vascular occlusion. Circulation 1985;71:69%708.

ExercisHnduced Prominent U Waves as a Marker of Significant Narrowing of the Left Circumflex or Right Coronary Artery Taishiro Chikamori, MD, Mitsutoshi Yamada, MD, Jun Takata, MD, Takashi Furuno, MD, Fumiyasu Yamasaki, MD, and Yoshinori L. Doi, MD

E

xercise-induced U-wave inversion is established as a marker for anterior myocardial ischemia.’ Exercise-induced prominent U waves have recently been proposed as reciprocal changes for U-wave inversion in inferoposterior ischemia. 2,3 The present study was con-

From the Section of Cardiology, Department of Medicine and Geriatrics, Kochi Medical School, Kohasu, Oko-cho, Nankoku, Kochi 783, Japan. Manuscript received January 25, 1994; revised manuscript received March 14, 1994, and accepted March 17.

ducted to assessthe usefulness of this prominent Uwave in identifying significant narrowing of the left circumflex or right coronary artery in a large number of patients suspected of having coronary artery disease (CAD). Three hundred eleven consecutive patients (205 men and 106 women, aged 34 to 85 years [mean 621) with suspected CAD were studied. No patient with previous myocardial infarction was included. Patients with complete bundle branch block, Wolff-Parkinson-White syndrome, and atria1 fibrillation, and those receiving digiBRIEF REPORTS 495

TABLE

I Sites of U-Wave

Changes

U-Wave Leads I II III aVL aVF VI v2 v3 V.4 v5 v, Total

in 311 Patients

Increase WI

Prominent

5 (2) 65 (21) 56 (18)

3(l)

28 (9) 26 (8)

2(l) 70 (23) 120 (39) 101 (32) 50 (16) 12 (4)

1 (0.3) 24 (8) 3 (1) 53 (17) 78 (25) 55 (18) 17 (6) 5 (2)

552 (16)

293 (9)

65 (21)

6 (2)

(n = 3,421)

U Wave W

talis or class la antiarrhythmic agents were also excluded. Left main CAD was found in 26 patients, S-vessel CAD in 30, 2-vessel CAD in 44, and l-vessel CAD in 95; the remaining 116 patients had insignificant coronary artery narrowing. Treadmill exercise testing was pegormed with the patient off cardioactive medications using a modijied Bruce protocol! Chest pain, ST-segment depression, or submaximal heart rate (85% of the age-predicted maximal heart rate-s) was regarded as an indication for stopping exercise. Heart rate, blood pressure, 12-lead electrocardiogram, and symptoms at rest, during exercise, and for thejrst 5 minutes after exercise were recorded.6 The electrocardiographic leads were grouped as anterior (Vt to V,), lateral (V,, I, and aVL), and inferior (II, III, and aVF).7 Precordial leads were divided into right (Vr to Vs) and left (V4 to V6). Electrocardiography soon after exercise was compared with that performed at rest for the magnitude of ST-segment depression, which was measured at 80 ms after the J point. ST-segment depression of 20.1 mV was considered signtficant for myocardial ischemia. The magnitude of positive U waves was also measured, with T-P segment as the baseline. A prominent U wave was defined if the magnitude of a positive U wave increased 20.05 mV along with decreased height of the T wave compared with U waves seen on electrocardiography at rest.23 A typical case is shown in Figure 1.

at rest

soon after exercise

:....:.:..:

:.

Coronary angiography was per$ormed in multiple oblique projections by the Judkins or the Sones technique and was interpreted by 2 experienced angiographers unaware of the results of exercise testing, using the criteria proposed by the American Heart Association7 A significant stenosis of the coronary artery was defined as 275% diameter narrowing. Lef main CAD was considered equivalent to narrowings of both the left anterior descending and circumflex arteries. If the highest grade narrowing was present in only 1 of the 3 coronary arteries, identified by consensus agreement, we defined it as a culprit lesion. Results are expressed as mean f 1 SD. Student’s t test was used to compare means of the continuous variables, and contingency tables were analyzed using a chisquare test. The computations were performed using the SPSS-PC+ computer program. A significant increase in the magnitude of positive U waves was observed during exercise testing in 16% of the total leads analyzed, of which almost half had an associated decrease in the height of T waves (prominent U wave) (Table I). Prominent U waves were observed predominantly in leads V,, V,, and V,. All 18 patients with prominent U waves in leads V, or V, also had prominent U waves in leads V,, V,, or both. The association of increased magnitude of U waves with decreased height of T waves was more common in precordial than in limb leads (211 of 359 vs 82 of 193; p <0.0003). To clarify the association of U-wave changes with individual coronary artery narrowing, the prevalence of a U-wave increase and a prominent U wave in patients with 1 -vessel CAD or an insignificant lesion is shown in Figure 2. The prevalence of these U-wave changes in patients with an insignificant lesion and those with left anterior descending CAD was similar. Prominent U waves in the precordial leads were rarely found in patients with insignificant lesions and lef anterior descending CAD. In contrast, they were morefiequently observed in patients with lef circumflex CAD (IO of 21 vs 14 of 116, and 10 of 21 vs 7 of 60; p
1 min

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example of a prominent U wave in a patient with a-vessel cere nary artery disease. The narrowing in the left core nary artery was 7S%, in the &cumflex artery 7S%, and In the right coronary artey 99%.

TABLE

II

Sites

of Prominent

Sites of Prominent U Waves

U Waves

Sensitivity VW

Limb leads Right precordial leads Right and left precordial leads

in Detecting

Left Circumflex

Specificity w

or Right Coronary

Accuracy (“4

Artery

Narrowing

Predictive value VW

19 49

93 89

61 72

67 78

52

88

72

77

Accuracy = true test results/total number of tests performed: Predictive value = true positives/true + false positives: Sensitivity = number of true-positive detections/total number of positives in the group tested; Specificity = number of true-negative detections/total number of negatives in the group tested.

waves in the limb leads were similar in the 4 groups. When patients with multivessel CAD were included, the prevalence of prominent U waves in the precordial leads was 33% in patients with left anterior descending CAD, 52% in those with circumflex CAD, and 59% in those with right CAD. In all 311 patients, the incidence of prominent U waves in the precordial leads was higher in patients with than without left circumflex or right CAD (70 of 135 vs 21 of 176; p <0.00001). Predictability for left circumflex or right CAD according to the site of prominent U waves is shown in Table II. Prominent U waves had a specificity of approximately 90%. Overall predictability was similar whether prominent U waves in the right precordial leads or in the right and left precordial leads were used. Respective sensitivities and specificities of prominent U waves in the precordial leads were 55% and 85% in patients with and 25% and 92% in those without ST-segment depression of 20.1 rnK The incidence of left circumflex or right CAD was higher in patients with than without ischemic STsegment depression in the inferior leads (82 of 134 vs 53 of 177; p
61%; p = 0.01) in detecting left circumflex or right CAD, whereas sensitivity was similar (52% vs 61%; p = NS). Ninety-one patients (29%) had prominent U waves in the precordial leads during exercise. Findings of exercise testing in patients with and without these prominent U waves are detailed in Table III. A high-grade narrowing of 290% in the left circumflex or right coronary artery was found in 35% of the total patients, whereas it was observed in 70% of those with and in 20% of those without prominent U waves in the precordial leads (Figure 3). In 91 patients with prominent U waves in the precordial leads, a narrowing in the left circumflex or right coronary artery was culprit in 59%.

The present study demonstrates that exercise-induced prominent U waves in the precordial leads are assumed as reciprocal changes for U-wave inversion in inferoposterior myocardial ischemia and are useful as a marker of the narrowing of the left circumflex or right coronary artery. Although this U-wave change was not frequently observed, it had a high specificity of approximately 90%. Sensitivity of this marker depended on the presence or absence of ischemic ST-segment depression, whereas specificity remained high even in patients without ST-segment depression. Furthermore, in most patients with prominent U waves in the precordial leads,

(%) 100

FlBURE 2. Prevalence of Uwave increase and prominent U waves in all leads, and prominent U waves in the limb and precordial leads in patients with lvessel coronary artery disease or indgnificant lesion. LAD = left anterior descending artery; LC q left circumflex artery; RCA q right coronary artery.

u

Increased magnttude U waves in all leads

Ezlprominent all leads 0

50

of

U waves

In

promment U waves the limb leads

in

U waves in m prominent the precordial leads

Insignificant lesion (n=l16)

LAD (n=60)

RCA (n=14)

BRIEF REPORTS

497

TABLE U Waves

III Comparison in the Precordial

of Findings Leads

in Exercise

Age (years) (mean) Men/women Exercise duration (min) Chest pain HR at rest (beats/min) HR at peak exercise (beats/min) BP at rest (mm Hg) BP at peak exercise (mm Hg) Incidence of ischemic ST depression Anterior leads Lateral leads Inferior leads All leads Magnitude of the maximal ST depression (mV) BP = blood pressure;

With

Prominent U Wave (-) (n = 220)

63 k 8 65/26 4.6 + 1.8 57 (83%) 64 f 9 113&21

61 k9 140/80 5.2 f 2.1 95 (43%) 70fll 131 f 19

142fl9 173f29

143?22 180f31

74 (81) 73 (80) 51 (56) 80 (88) 0.20 +0.14

and Without

106 (48%) 95 (43) 83 (38) 130 (59) 0.11 fO.10

Promineni

p Value

NS NS

<0.00001 <0.00001 0.003 <0.00001
l-vessel CAD or an insignificant lesion, an increased magnitude of positive U waves during exercise alone showed a low specificity for the left circumflex or right CAD. If the height of T waves was not taken into account, approximately 40% of the patients with left anterior descending artery narrowing or an insignificant lesion had this U-wave change (Figure 2). Because myocardial ischemia is usually associated with ST-T changes, a decreased height in T waves may be regarded as reciprocal changes for such ST-T changes in the inferoposterior wall; it is important to improve the specificity of prominent U waves for inferoposterior ischemia. Because electrocardiographic tindings of reciprocal changes of inferoposterior wall myocardial ischemia usually localized in the right precordial leads, prominent U waves only in leads V, to V, were regarded as a marker of left circumflex or right CAD in previous studies.2*3 However, our results indicated that this meticulous approach did not help to better identify left circumflex or right CAD because overall predictability was similar whether prominent U waves in the right precordial leads or in the right and left precordial leads were used (Table II). Prominent U waves predominantly localized in leads V, to V, when they were observed as reciprocal changes for U-wave inversion in inferoposterior ischemia. In addition, no patient had prominent U waves solely in

50

(n=311)

Prominent precordial

U waves leads (-)

Prominent precordial

u waves in the leads (+) (n=91)

498

Patients

HR = heart rate.

0 patients

Between

Prominent U Wave (+) (n=91)

a high-grade narrowing of 290% in the left circumflex or right coronary artery was observed, and a left circumflex or right coronary arterial lesion was culprit. Hasegawa et al3 recently reported that prominent U waves had a sensitivity of 70% and a specificity of 98% in detecting left circumflex or right CAD in 84 patients with angina pectoris. Although the predictability of their study was higher than that of ours, the number of study patients was smaller and their electrocardiograms were recorded in different clinical settings: during Master’s test, treadmill exercise test, ergometer test, and spontaneous angina. However, despite these discrepancies in results, the present study conlirmed, by a large number of patients, the usefulness of this simple electrocardiographic marker in clinical practice. The percentage of patients excluded because of criteria mentioned previously, other than myocardial infarction, was ~10%. A larger number of patients with myocardial infarction were not evaluated in this study, and the usefulness of a prominent U wave in this patient subset remains to be clarified. The relation between U and T wave was not evaluated in recent studies.2,3 Our study revealed that although an exercise-induced increase in the magnitude of U ivaves was observed in both limb and precordial leads, an associated decrease in the height of T waves was predominantly found in the precordial leads. In patients with

Total

Testing

FIBURE 3. Severity left circumflex or relation te pmminent cordial leads.

in the (n=220)

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of the nmowing of the coremary artery In U waves in the pre

right

leads V, or V,. All of the patients with prominent U waves in V, or V, also had this U-wave change in V,, V,: or both, and this could indicate extensive inferopostenor myocardial ischemia. As an electrocardiographic marker localizing coronary artery narrowings, the site of ischemic ST-segment depression is widely applied in the clinical practice.*-lo However, recent reports revealed that ischemic ST-segment depression in the inferior leads was not specific for the narrowing of the left circumflex or right coronary artery.“-I4 The present study showed modest predictability of ischemic ST-segment depression in the inferior leads (sensitivity 61%, specificity 70%, predictive value 61%). In contrast, a higher specificity of 88% and a predictive value of 77% were seen with prominent U waves in the precordial leads. The fact that specificity increased without a significant loss of sensitivity using this type of marker is considerably important in clinical practice. Prominent U waves are obtained by standard exercise testing without any additional test, equipment, or cost, except for detailed and careful analysis of electrocardiography. In conclusion, a prominent U wave in the precordial leads induced by exercise testing is a specific marker for the narrowing of the left circumflex or right coronary artery. 1. Gerson MC, Phillips JF, Morris SN, McHemy PL. Exercise-induced U-wave inversion as a marker of stenosis of the left anterior descending coronary artay.

Circulation 1979;60:101~1020. 2. Hasegawa K, Nezuo S, Fujiwam T, Samukawa M, Tadaoka S, Nakao M, Nakamua T, Yoneda M, Kakumae S, Sawayama T. Transient positive U wave as a new marker of the critical left circumflex artery stenosis and postem-inferior &hernia (in Japanese). Heart 1988;20:269-275. 3. Hasegawa K, Fujiwara T, Sawayama T, Nezuo S, Nakao M, Tadaoka S, Nakamt~ra T, Kakumae S, Kawahara Y, Inoue S. Angina-induced transient positive U wave in right precordial leads: a marker of left circumflex artery/right coronary artery stenosis (in Japanese). Heart 1988;20: 1033-1039. 4. Bruce RA, McDonough JR. Stress testing for cardiovascular disease. Bull N Y Acad Med 1969;45:1288-1294. 5. Blackbum H. The exercise electrocardiogram. Technological, procedural and conceptual developments. In: Blackbum H, ed. Measurement in Exercise Electrocardiography. Springfield, Illinois: CC Thomas, 1969:220-258. 6. Chikamori T, Doi YL, Furuno T, Yonezawa Y, Ozawa T. Diagnostic significance of deep T-wave inversion induced by exercise testing in patients wtth suspected coronary artery disease. Am J Cardiol 1992;70:403406. 7. AHA Committee Report. A reponing system on patients evaluated for coronary artery disease. Circularion 1975:5 l(suppl):5-%0. 8. Ellestad MH. Stress Testing: Principles and Practice. Philadelphia: FA Davis, 1986:223-276. 9. Robertson D, Kostuk WJ, Ahuja SP. The localization of coronary artery stenoses by 12 lead ECG response to graded exercise test: support for intercoronary steal. Am Heart J 1976;91:437.444. 10. Fox KM, Selwyn A, Oakley D, Shillingford JP. Relation between the precordial projection of S-T segment changes after exercise and coronary angiographic findings. Am .I Cardiol 1979;4411068-1075. 11. Fuchs RM, Achuff SC, Gmnwald L, Yin FCP, Griffith LSC. Electrocardiographic localization of coronary artery narrowings: studies during myocardial ischemia and infarction in patients with one-vessel disease. Circulation 1982;ti 1168-l 176. 12. Kaul S, Kiess M, Liu P, Guiney TE, Pohost GM, Okada RD, Boucher CA. Comparison of exercise electrocardiography and quantitative thallium imaging for one-vessel coronary amy disease. Am J Cardiol 1985;56:257-261. 13. Fox RM, Hakki A, Iskandrian AS. Relation between electrocardiographic and scintigraphic location of myocardial ischemia during exercise in one-vessel cow nay artery disease. Am J Cardiol 1984;53:152%1531. 14. Mark DB, Hlatky MA, Lee KL, Harrell FE, Califf RM, Pryor DB. Localizing coronary artery obstructions with the exercise treadmill test. Ann Intern Med 1987;106:53-55.

Safety of Combined PravastatiwGemfibroziI

Therapy

Robert S. Rosenson, MD, and William A. Frauenheim, MD, MPH harmacotherapy for dyslipidemias in which lowP density lipoprotein cholesterol (LDL) elevations are accompanied by other lipid abnormalities may require

bined pravastatin-gemfibrozil therapy in a cohort of 32 hyperlipidemic patients with a mean follow-up of 53 weeks.

the use of multiple agents.’ Combined drug therapy with The cohort consisted of 32 hyperlipidemic patients lovastatin and either gemfibrozil or niacin enhances the with the following Fredrickson phenotypes: Ila (n = I), risk for the myopathic syndrome and its associated IIb (n = 24), III (n = I), IV (n = 2), and V (n = 4). Estabsequelae.2 The incidence of myositis with lovastatin lished coronary artery disease was present in 26 of the monotherapy is 0.1% to 0.3%; however, concomitant 32 patients. Prior adverse reactions to lipid-lowering administration of lovastatin with gemfibrozil enhances drugs requiring a change in medications occurred in 7 the risk of myositis to 5%. 2-4 Whether the lower inci- of the 32 patients. These reactions included I case of dence of myositis with pravastatin alone (4 times the upper limit of normal. In this report, we addressed the safety of com- fibrozil therapy. Both patients reported dtjiculty arising

From the Rush-Presbyterian-St. Luke’s Medical Center, 1653 West Congress Parkway, Chicago, Illinois 60612. Manuscript received December 28, 1993; revised manuscript received and accepted March 10, 1994.

from a chair, and 1 of the patients could not lift her arms above her head. The third patient had lower extremity pain and weakness that developed several weeks after combined therapy was initiated. None of the patients had concurrent viral illness, trauma, or change in physical BRIEF REPORTS 499