Variable threshold of angina during exercise: A clinical manifestation of some patients with vasospastic angina

Variable Threshold of Angina During Exercise : A Clinical Manifestation of Some Patients With Vasospastic Angina

STEFANO DE SERVI, MD GIUSEPPE SPECCHIA, MD MARIA TERESA CURTI, MD COLOMBA FALCONE, MD ANTONELLO GAVAZZI, MD EZIO BRAMUCCI, MD ANTONIO MUSSINI, MD LUIGI ANGOLI, MD JORGE SALERNO, MD PIERO BOBBA, MD

Two patients complained of chest pain while at rest and during physical activities . However there seemed to be no direct relation between exertional angina and an Increasing level of work performed, indicating that these patients had a variable threshold of angina during exercise . In one patient spontaneous chest pain was associated with transient S-T segment changes in precordial leads, and during coronary arteriography the administration of ergonovine Induced spasm of the left anterior descending coronary artery . The other patient showed S-T segment elevation in inferior leads during an ergonovine-induced anginal attack and coronary arteriography revealed a spontaneous spasm of the right coronary artery . In both patients repeated exercise tests yielded different results, because the chest pain and S-T segment depression occurred at different work loads with large differences in heart rate-systolic blood pressure product . It is concluded that a variable threshold of angina during exercise is a clinical manifestation In some patients with vasospastic angina and is probably due to the difference In coronary arterial tone at the onset of exercise .

Pavia, Italy

From the Division di Cardiologia, Policlinico S . Matteo, Pavia, Italy. Manuscript received September 10, 1980; revised manuscript received February 2, 1981, accepted February 11, 1981 . Address for reprints : Stefano de Servi, MD, Division dl Cardlologia, Policlinico S . Matteo, 27100 Pavia, Italy .

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Exertional angina is considered to be the result of increased mechanical work of a heart in which blood supply to certain areas of the myocardium is inadequate under stress .' However, the role of the changes in tone of the coronary arteries in classic angina pectoris remains to be elucidated . 2- t Experimental data have demonstrated that during exercise alpha adrenergic blockade causes a greater increase in coronary blood flow and a more profound decrease in coronary vascular resistance than those occurring in control conditions . This suggests that vasoconstriction occurs during physical activity s,7 In some patients with vasospastic anginas coronary spasm can be repeatedly induced during or just after exercise, 9-14 indicating a direct effect of exercise on coronary arterial tone. However, in other patients chest pain and subendocardial ischemia are provoked by coronary spasm at rest, whereas there is no evidence of coronary vasoconstriction during exercise . 75 In this paper we report on two patients who complained of chest pain occurring both at rest and during physical activity . However, exertional angina did not always occur at the same level of work and repeated exercise Iests induced both chest pain and myocardial ischemia at very different values of heart rate-systolic blood pressure product, an indirect index of myocardial oxygen consumption . This variable threshold of angina during exercise is a clinical manifestation of patients with vasospast.ic angina and is probably due to the difference in coronary arterial tone at the onset of exercise . Methods

Exercise testing : Two patients with spontaneous and exertional angina with no previous myocardial infarction were studied . In both patients three multistage

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tests induced chest pain with S-T depression in the precordial leads but at different work loads and variable values of ratepressure product (Fig . 1) . Furthermore S-T segment depression was more marked during the first exercise test, which was stopped at the least work load and rate-pressure product . The left ventriculogram revealed normal myocardial contractility . Selective coronary arteriography disclosed a 75 percent stenosis of luminal diameter of the left anterior descending artery after the second diagonal branch . The administration of 0 .2 mg of ergonovine maleate induced chest pain associated with S-T segment depression in the precordial leads, and at this time coronary arteriography showed more severe narrowing of the left anterior descending artery with slow filling of the distal portion of the vessel (Fig . 2) . The spasm subsided after sublingual administration of nitroglycerin . Case 2 : This patient was a 48 year old painter who was in good health until January 1980 when he first experienced angina pectoris while walking in the morning breathing cold air . He was asymptomatic during the day while performing his normal working activities . Each anginal attack was relieved in a few seconds by rest. Because he became free of pain after 15 days he did not consult a physician . During the following months he complained of only one episode of chest pain while he was carrying a heavy weight . He was hospitalized in July 1980 after chest pain reappeared, both during his usual activities and while he was sleeping, awakening him suddenly . Physical examination revealed a fit man with a normal blood pressure and cardiac findings . The only coronary risk factor was consumption of 1 pack a day of cigarettes. The control electrocardiogram was normal . During hospitalization he had no pain and a continuous ambulatory electrocardiographic recording did not reveal "silent" ischemic episodes ." The intravenous administration of 0 .15 mg of ergonovine maleate in the coronary care unit induced chest pain associated with a slight S-T segment elevation in leads 11, III and aVF . The three exercise tests yielded conflicting results (Fig. 3) . The first and the third tests induced chest pain associated with S -T segment depression in inferior leads, but at different work loads and values of rate-pressure product, whereas the

supine bicycle exercise tests were performed in the morning (8:30 to 11 a .m .) on different days with an initial work load of 50 watts and subsequent increases of 25 watts every 3 minutes . Exercise was stopped when typical anginal pain, dyspnea or exhaustion developed . Cuff blood pressure was measured at 3 minute intervals . The rate-pressure product was calculated as the product of heart rate and systolic arterial blood pressure and expressed in mm Hg/min X 10 -2 . Drug therapy, which included administration of nifedipine in both patients and of nitrates in only one patient, was discontinued 12 hours before the exercise tests . Selective coronary arteriography : This procedure was performed using the Sones technique . Multiple views of each vessel were routinely filmed . The left ventricle was opacified in the 30° right anterior oblique projection before coronary arteriography was performed . Coronary spasm was considered documented when the coronary segment was reduced in caliber or completely obstructed in comparison with the initial angiographic appearance . Ergonovine maleate was administered intravenously (0 .05 mg/min) and the injection stopped when S-T segment elevation or depression of 0 .1 mV or more occurred or when the maximal dose of 0 .4 mg of ergonovine had been reached. The drug was administered during coronary arteriography in one patient and in the coronary care unit in the other patient . 18-2° Informed consent was obtained from each patient . The procedures caused no complications . Case Reports Case 1 : This patient was a 54 year old electrician who for 1 month complained of substernal chest pains that occurred when he awoke in the morning and during his usual daily activities . The pains were not always related to the severity of exertion and might occur when he was walking on level ground but not during exertion at greater work loads . The pains were always relieved after a few minutes of rest . The patient had no history of hypertension or diabetes mellitus . Physical examination was normal . X-ray examination of the chest revealed a heart of normal size, and the control electrocardiogram was normal . The electrocardiogram taken when chest pain occurred at rest showed either S-T segment elevation or depression in leads V2 to V s . All three exercise

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FIGURE 2 . Case 1 . Coronary arteriogram . Left panel: During ergonovine-induced chest pain, the left anterior descending artery shows a severe spasm (arrow) with slow filling of the distal portion of the vessel . Rigid panel : After administration of nitroglycerin, the spasm is relieved and the left coronary arterlogram shows a 75 percent stenosis of the left anterior descending artery after the second diagonal branch .

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second test failed to induce either chest pain or electrocardiographic changes . The left t'entriculogram showed a normal pattern of ventricular contraction . Coronary arteriography showed normal coronary vessels . Spontaneous spasm of the right coronary artery appeared during the procedure but was not associated with chest pain or electrocardiographic changes and subsided after sublingual administration of nitroglycerin (Fig . 4) .

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FIGURE 3. Case 2. The first and third exercise tests induced chest pain associated with S-T segment depression In inferior leads at different work loads and rate-pressure products (PRP) . The second test is negative .

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The two patients complained of angina when at rest and during physical activity . However, angina of effort did not always occur at the same work load as would be expected when myocardial oxygen consumption increases in the presence of fixed coronary arterial obstructions . In these patients repeated exercise tests yielded different results because chest pain and S-T depression were induced at different work loads with widely changing values for rate-pressure product, indicating that the patients had a variable threshold of angina pectoris during exertion . Because they were susceptible to coronary spasm, demonstrated during coronary arteriography, we believe that spontaneous changes in coronary arterial tone might account for the clinical presentation and different response to repeated exercise tests . Exertional angina and coronary vasospasm: Classic exertional angina is secondary to increased myocardial oxygen consumption in the presence of organic obstruction of major coronary arteries . Because chest pain generally occurs at the same level of myocardial oxygen consumption, these patients have a fixed threshold of angina during exercise . However, in some



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FIGURE 4. Case 2 . Coronary arteriogmphy. Left panel : Right coronary arteriogram shows a spontaneous spasm of the proximal portion of the right coronary artery . Right panel: Coronary arterial spasm disappears after sublingual administration of nitroglycerin .

tolerate greater work loads because myocardial oxygen supply can be limited only by organic obstruction of the coronary arteries, but when coronary arterial tone is increased, oxygen supply is further reduced and even moderate physical activity can precipitate chest pain and myocardial ischemia . Clinical implications : The clinical recognition of patients with a variable threshold of angina during exercise arouses suspicion that coronary vasoconstriction could be implicated in the occurrence of the chest pain and myocardial ischemia . However, further studies are needed to establish the true incidence of this clinical finding in a population of patients with vasospastic angina . Furthermore, the variability of coronary arterial tone can account for the ischemic episodes recorded during usual daily activities with continuous ambulatory electrocardiographic monitoring . 21 Because exercise tests performed under control conditions can give different results, patients with a variable threshold of angina should not be included in studies assessing the effectiveness of antianginal drugs . However propranolol, which is the most effective treatment in patients with classic exertional angina, can be ineffective and even detrimental in patients in whom coronary arterial spasm plays an important role in determining the response to exercise .xo In such cases nifedipine, which prevents the -25 and reduces coronary occurrence of coronary spasm 23 vascular resistance, 26 should be the drug of choice.

patients with vasospastic angina exercise can provoke coronary spasm, 9-14 probably because of excessive sympathetic activity . In some studies, 10-12 coronary arteriography performed at the time of exercise-induced S-T segment elevation in patients with variant angina has shown severe spasms occluding major coronary vessels . Yasue et al ." demonstrated that exercise-induced coronary vasoconstriction occurs in the early morning and not in the afternoon, suggesting a circadian daily variation in the tone of the coronary arteries . Nevertheless, in some patients exercise-induced S-T segment elevation due to coronary arterial spasm can repeatedly occur in exercise tests performed at different hours of the day, thus indicating a fixed limitation of exercise capacity 22 In contrast, in our two patients the results of three exercise tests performed at the same hour of the day had different results, as chest pain and S-T segment depression occurred at different work loads and values for rate-pressure product . Moreover, in one patient with normal coronary arteries one of three exercise tests did not induce chest pain or ischemic electrocardiographic changes . Because of this wide variability of results a direct effect of exercise on coronary arterial tone seems unlikely. We believe that the variable threshold of angina during exertion is secondary to the difference in tone of the coronary arteries at the start of exercise . When coronary arterial tone is decreased, these patients can

Ref erences 1.

Gorlln

2.

Hillis LO, Braunwald E . Coronary-artery spasm . N Engl J Mad

3.

Maser) A, Sever) S, Do Nes M, et al . Variant angina : one aspect of a continuous spectrum of vasospastic myocardial ischemia . Pathogenetic mechanisms, estimated incidence and clinical and coronary arteriographic findings in 138 patients . Am J Cardiol

R. 138-48 .

Pathophysiology of cardiac pain . Circulation

1965 :32:

4.

5.

1978 ;299 :695-702 .

8.

1978;42:1019-35-

July

1981

Mudge GH Jr, Grossman W, Mile RM Jr, Leech M, Braunwald E. Reflex increase in coronary vascular resistance in patients with ischemlc heart disease . N Engl J Mod 1976 ;295 :1333-7. Gunther S, Green L, Muller JE, Mudge OH, Grossman W. Inappropriate coronary vasoconstriction In patients with coronary artery disease: a role for nifedipine? Am J Cardiol 1979 ;44:793-7 . Murray PA, Vatner SF . Alpha receptor attenuation of coronary vascular response to severe, spontaneous exercise (abstr) . Fed Proc 1978 :37:235 . The American Journal of CARDIOLOGY Volume

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7 . Heyndrlckx GR, Muylaert P. Mabllde C, Pannier JL. Role of coronary alpha receptors in the regulation of the coronary flow during exercise in dogs (abstr) . VIII European Congress of Cardiology . Paris, June 1980 :135 . 8 . Maserl A, Pesola A, Marzllll M, et al . Coronary vasospasm in angina pectoris . Lancet 1977 ;1 :713-7 . 9 . Waters DD, Chaitman BR, Dupree G, Th6roux P, Mlzgala HF . Coronary artery spasm during exercise in patients with variant angina . Circulation 1979 ;59 :580-5 . 10 . Yasue H, Orate S, Taklzawa A, Nagao M, Miwa K, Tanaka S . Exertlonal angina pectoris caused by coronary arterial spasm : effects of various drugs . Am J Cardiol 1979 ;43 :647-52 . 11 . Yasue H, Omote S, Taklzawa A, Nagao M, Mlwa K, Tanaka S . Circadian variation of exercise capacity in patients with Prinzmetal's variant angina : role of exercise-induced coronary arterial spasm . Circulation 1979 ;59 :938-48 . 12 . Specchla G, de Seal S, Falcons C, at al . Coronary arterial spasm as a cause of exercise-induced S-T segment elevation in patients with variant angina . Circulation 1979 ;59 :948-54 . 13. Welder DA, Schick EC, Hood WS, Ryan TJ . ST-segment elevation during recovery from exercise . A new manifestation of Prinzmetal's variant angina . Chest 1978;74 :133-8. 14 . Braustet JP, GrWo R, Series E, Guam P, Laylavolx F . Anger de Prinzmetal declenche par 1'arret de 1'effort . Arch Mal Coeur 1979 ;72:391-400 . 15 . de Servi 5, Specchla G, Ardissino 0, et al . Angiographlc demonstration of different pathogenetic mechanisms in patients with spontaneous and exertional angina associated with S-T segment depression . Am J Cardiol 1980 ;45 :1285-91 . 16. Heupler FA, Proudff WL, Razavl M, Shlrey EK, Greenstreet R, Sheldon WC. Ergonovine maleate provocative test for coronary arterial spasm . Am J Cardiol 1978 ;41 :631-40 . 17 . Schroeder JS, Solen JL, Quint RA, at al . Provocation of coronary

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spasm with ergonovine maleate. New test with results in 57 patients undergoing coronary arteriography . Am J Cardiol 1977 ; 40 :487-91 . 18. Curry RC, Peplne CJ, Saborn MB, Feklman RL, Christie LG, Cone CR. Effects of ergonovine in patients with and without coronary artery disease . Circulation 1977 ;56 :803-9 . 19. Speechla G, Angoll L, do Seal S, at al . Spasmo coronarico indotto delta somministrazione di ergonovina maleato in soggetti affetti do angina spontanea . G hat Cardiol 1976 ;6:1177-83 . 20 . do Servi S, Specchle G, Angell L, et al . Coronary arterial spasm in angina at rest associated with transient S-T segment changes . Clin Cardiol 1980 ;3 :54-60 . 21 . Schang SJ Jr, Peplne CJ . Transient asymptomatic S-T segment depression during daily activities . Am J Cardiol 1977 ;39 :396402 . 22 . Specchla G, de Servi 5, Falcone C, at al. Significance of exercise-Induced ST-segment elevation in patients without myocardial infarction . Circulation 1981 ;63 :46-54 . 23 . Heupler FA Jr, Proudtlt WL. Nifedipine therapy for refractory coronary arterial spasm . Am J Cardiol 1979 :44 :798-80324. Prevhall M, Salemo J, Tavazzl L, at al . Treatment of angina at rest with nifedipine . A short-time controlled study . Am J Cardiol 1980;45:825-30 . 25 . Amman E, Muller J, Goldberg 5, et al . Nifedipine therapy for coronary-artery spasm . Experience in 127 patients . N Engl J Med 1980 ;302 :1269-73 . 26. do Servi S, Mussinl A, Specchla G, at al . Effects of nifedipine on coronary blood flow and coronary resistance during cold pressor test and isometric exercise in patients with coronary artery disease . VIII European Congress of Cardiology . Satellite Workshop "New developments in calcium antagonists ." Eur Heart J 1980; 1 :Suppl B :43-7 .