use of thrombolytic agents or angioplasty in these pa- tients remains very limited.

This study reports our experience in patients after coronary artery bypass grafting in the setting of acute myocardial infarction. Although the number of patients available for review is small when compared to large scale clinical trials, it represents a large series of such patients reported to date. Furthermore, we report all such patients presenting to our institution regardless of whether or not an intervention was performed.

We noted a limited ability of the standard electrocar- diogram to corroborate acute myocardial infarction and aid in ability to determine the infarct area. The prepon- derance of non-Q-wave myocardial infarcts in our study probably relates to either the finding that the infarct- related vessel is less likely to be a main epicardial arterylo or to the presence of collaterals. Thus, such infarcts are usually smaller in postcoronary artery bypass surgery patients.” This observation may impede the ability to promptly intervene in these patients when they present with acute myocardial infarction.

Furthermore, even with angiography the infarct- related vessel could not be reliably identified in a fairly large proportion of our patients. This phenomenon was due to the presence of >l vessel occlusion or multiple discordant wall motion abnormalities. With our concern over patient safety intervention with direct angioplasty or intracoronary thrombolysis was not possible in this group.

However, in our patients in whom the infarct-related vessel could be ascertained and acute intervention was performed, the results as assessed by vessel patency com- pared less favorably with a cohort of patients who never had bypass surgery. Although the lesions encountered in these patients may have been somewhat more “resistant” to thrombolytic therapy or angioplasty, there was yet a high degree of success. We did not encounter overt angio- graphic evidence of embolic complications as reported by others.12 Furthermore, more definitive revascularization with redo surgery was then possible in many of these

patients at a later date. The limited number of patients in our study preclude recommendations as to the general treatment of such patients. However, based on this expe- rience acute intervention in this setting is a viable option, albeit with a decreased reperfusion success rate, but with a potentially positive impact on the prognosis of these patients. There appears to be no legitimate reason to exclude this important group of patients from prospective reperfusion trials.

1. White HD, Norris RM, Brown MA, Takayama M, Maslowski A, Bass NM, Ormiston JA, Whitlock T. Effect of intravenous streptokinase on left ventricular function and early survival after acute myocardial infarction. N Engl J Med 1987:317:850-855. 2. Gruppo Italian0 per lo Studio della Streptochinasi nell’lnfarto Miocardico (GISSI). Effectivenessofintravenous thrombolytic treatment in acutemyocardial infarction. Lancet 1986;1:397-401. 3. Pezzella AT, Svinarich JT, Davis RC, Jr, Ehrich D, Esente P. Successful early streptokinase thrombolysis of aortocoronary vein grafts. Ann Thorac Surg 1986;42:213-215. 4. Kleiman NS, Berman DA, Gaston WR, Cashion WR, Roberts R. Early intravenous thrombolytic therapy for acute myccardial infarction in patients with prior coronary artery bypass grafts. Am J Cardioi 1989,63:102-104. 5. Wiseman A, Waters DD, Walling A, Pelletier GB, Roy D, Theroux P. Long- term prognosis after myocardial infarction in patients with previous coronary artery bypass surgery. JACC 1988;12:873-880. 6. Topol EJ, Califf RM, George BS, Kereiakes DJ, Abbottsmith CW, Candela RJ, Lee KL, Pitt B, Stack RS, O’Neill WW, and the Thrombolysis and Angie- plasty in Myocardial Infarction Study Group. A randomized trial of immediate versus delayed elective angioplasty after intravenous tissue plasminogen activator in acute myocardial infarction. N Eng/ J Med 1987;317:581-588. 7. Loop FD, Lytle BW, Gill CC, Gelding LAR, &grove DM, Taylor PC. Trends in selection and results of coronary artery reoperations. Ann Thorac Surg 1983;36:380-38888. 8. Campeau L, Lespcrance J, Bourassa MG. Natural history of saphenous vein aortocoronary bypass grafts. Mod Concepts Cardiovasc Dis 1984;53:59-63. 9. Coronary Artery Surgery Study (CASS) Principal Investigators and Their Associates. A randomized trial of coronary artery bypass. Quality of life in patients randomly assigned to treatment groups. Circulation /983,68:951-956. 10. Crean PA, Waters DD, Bosch X, Pelletier GB, Roy D, Theroux P. Angio- graphic findings after myocardial infarction in patients with previous bypass surgery: explanations for smaller infarcts in this group compared with control patients. Circulation 1985:71:693-698. 11. Waters DD, Pelletier GB, Hache M, Theroux P, Campeau L. Myocardial infarction in patients with previous coronary artery bypass surgery. JACC 3984;3:909-915. 12. De Feyter PJ, Serruys P, van den Brand M, Meester H, Beatt K, Suryapran- ata H. Percutaneous transluminal angioplasty of a totally occluded venous bypass graft: a challenge that should be resisted. Am J Cardiol 1989;64;88-90.

Effects of Verapamil on the Anaerobic Threshold and Peak Oxygen Consumption in Effort Angina Pectoris Andrew Thomson, MB, PhD, FRACP, and David T. Kelly, MB, FRACP

T he anaerobic threshold is the submaximal level of exertion above which lactic acid progressively accu-

mulates in the blood and fatigue progressively increases during incremental exercise. lv2 The anaerobic threshold is a useful clinical measurement of submaximal exercise performance in normal subjects1-3 and in patients with congestive heart failure,4 angina pect0ri.G and valvular regurgitation,6 and has been used to assess drug interven- tions.’ In patients with effort angina, ST-segment depres-

From the Hallstrom Institute of Cardiology, Royal Prince Alfred Hos- pital, Sydney, and the Department of Cardiology, Royal Hobart Hospi- tal, GPO Box 1061L, Hobart 7001, Australia. This study was supported in part by the National Health and Medical Research Council of Australia, Canberra, ACT, Australia. Manuscript received July 20, 1989; revised manuscript received November 15, 1989, and accepted December 4.

926 THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 65

sion is reduced and exercise time increased after calcium antagonists.8y9 If relief of myocardial ischemia by verapa- mil allows an improvement in peak oxygen consumption (VO@&), there may also be an improvement in oxygen metabolism by exercising muscle and the anaerobic threshold may increase, delaying the onset of fatigue. This study determines whether verapamil alters the oxy- gen consumption (VO2) at the anaerobic threshold, or the perception of leg fatigue in patients with effort angina pectoris.

Sixteen patients with stable exertional angina pecto- ris and positive exercise tests (Bruce protocol with at least 1 -mm horizontal ST-segment depression) entered the stu@. No patient had chronic lung disease, valvular regurgitation, clinical heart failure or peripheral vascu- lar disease. All patients gave written informed consent

TABLE II Hemodynamic and ST-Segment Results TABLE I Rest and Exercise Oxygen Consumption and Lactate Results

Control Verapamll p Value Control Verapamil p Value

Rest HR BP RPP

Onset of angina Patients Time (s) HR BP

RPP Onset of l-mm STdepression

Patients Time (s) HR BP RPP

Maximum exercise HR BP

RPP

Rest

m Lactate

Anaerobic threshold Patients Time(s)

vo2 HR

Work (watts) Lactate

Maximum exercise Time

Vozpeak

Work (watts) LACTmax MAXlactate

74f3 135 f 4

10.1 f 0.5

68k3 123f4 8.3 f 0.5

<O.Ol

<O.Ol <O.ool

0.29 f 0.02 0.8fO.l

0.31 f 0.03 1.3fO.l

NS <O.OOl

14 751 f 47

1.03 f 0.07 113f4

60&5 1.8dzO.2

16 793 f 50

1.03f0.06 103f 5

58f4 2.2 f 0.2

NS NS

NS <0.05 NS <0.05

16 8 794 f 68 829 f 137

116f5 101 f 8 189 f 7 174f 11

22.2 f 1.7 18.1 f 2.3

11 1,041 f 76

118~~7 190f6

22.6 f 1.9

NS NS NS NS

16 897 f 77 119f 5 189 f 6

22.6 f 1.3

<0.05

NS NS NS

1,180 f 71

1.73f0.10 88f6

3.5 f 0.4 4.3 f 0.5

1,276 f 60

1.94f0.08 97 f 5

4.0 f 0.4 4.9 f 0.5

-co.02 <0.02 <0.05

-co.05 <0.05

139 f 6 202 f 6

28.2 f 1.8

133f6 197 f 6

26.2 f 1.5

NS NS NS

HR = heart rate (beats/min); LACTmax = lactate at maximum exercise (mmol/ liter); MAXlactate = maximum lactate including recovery period (mmol/liter); VOZ = oxygen consumption (Ilters/min); VO zpeak = peak oxygen consumpbon (liters/mln).

BP = SyStOliC blood pressure (mm Hg); HR = heart rate (beats/mln); RPP = rate pressure product (beats. min-’ m m Hg 103).

before entering the study. The mean age of patients was 57 years (range 40 to 75), mean weight was 78 kg (range 56 to 97) and mean height was I73 cm (range 163 to 183).

We familiarizedpatients with the exercise equipment and then asked them to cease all antianginal medications for at least 48 hours before testing; the exception was nitrates, which were ceased 12 hours before each test. On the first study day, patients performed an incremental exercise test without medication. Then they received ve- rapamil, 240 to 360 mglday, according to side effects, until the protocol was repeated a week later.

All studies were performed erect on a cycle ergometer (Siemens Elema 380B). After a rest period of 2 minutes, patients began unloaded pedaling for 4 minutes. The initial workload of 30 watts was then increased by I5 watts at the end of each 3-minute stage until the patient

J

was limited by symptoms. Patients remained erect on the ergometer for 2 recovery stages.

We used breath-by-breath respiratory gas analysis to measure rest, anaerobic threshold and peak gas ex- change parameters. At the end of each test the ratio of ventilation to oxygen consumption/breath (V, /VOz) and the end-tidal fraction of expired oxygen were plotted graphically. The anaerobic threshold was determined by 2 experienced blinded observers as thepoint above which there was a sustained increase in both V, IV02 and end- tidal fraction of expired oxygen in the absence of a change in the ratio of ventilation to carbon dioxide pro- duction.‘JO VO2 was calculated over 20 seconds and ex- pressed in literslmin. Venous blood for lactate analysis was sampled via an indwelling cannula in the cubital fossa. Patients were asked to rate angina and legfatigue on a simple 0 to 5 point scale with 0 being no discomfort and 5 being the maximum symptom tolerable.

251

I 0 CONTROL

2.0 q VERAPAMIL

* pco.05

ANGINA LEG FATIGUE

REST ANAEROBIC THRESHOLD P?ZAY%Y

EXERCISE LEVEL

FIGURE 1. Gxygen conswnptlonatrest,attheanasrobk th&oldandatmaxhwnexerclssbeforedaRer verapamll.

IGURE 2. Anglna and leg fatly ratings before and aRer

THE AMERICAN JOURNAL OF CARDIOLOGY APRIL 1. 1990 927

0 CONTROL q VERAPAMIL * pco.05

t f I -3’ * I

REST ONSET MAXIMUM ANGINA EXERCISE

EXERCISE STAGE

FlGURE3.ST-se~mentdepmssionatmt,atthe~of anglna and at maxlmum ex6fclee before and after verapamll.

Comparisons between control and verapamil results were performed using Student t tests. A value of p <0.05 was considered significant. Group data are expressed as the mean f standard error.

Rest VOz values were similarfor control and verapa- mil. Rest heart rate (p <O.Ol) and ratepressureproduct (p <O.OOl) were lower after verapamil. ST-segment lev- els were similar (Table I).

During the control study 2 patients were limited by chest pain before reaching their anaerobic threshold. The VOz (Figure 1) and work at the anaerobic threshold were not different after verapamil although lactate levels were slightly higher (p <0.05).

All 16 patients experienced angina in the control test while only 8 experienced angina after verapamil. Heart rate, blood pressure and rate pressure product at angina tended to be lower after verapamil (Table IT).

All patients had at least 1 -mm of ST-segment de- pression in the control study while only I I patients had at least I -mm ST depression after verapamil. There was no change in the time to 1 -mm ST depression, heart rate, blood pressure or rate pressure product at I -mm ST depression after verapamil.

The angina pain rating at maximum exercise was significantly reduced by verapamil (p <O.OOl), but in contrast the legfatigue rating was increased signt~cantly (p <O.OOl; Figure 2). VO~peak (p <0.02), lactate at maxi- mum exercise (p X0.05), peak lactate (including recov- ery) (p <0.05) and maximum work (p <0.05) were all significantly increased after verapamil, while maximum rate pressure product and ST-segment depression were signtj?cantly reduced (p KO.01; Figure 3).

This study shows that in these patients with effort angina and significant ST-segment depression, neither the VOz nor the work at the anaerobic threshold was changed by verapamil. In contrast, the VOzpeak, maxi- mum work and peak lactate were significantly increased after verapamil.

928 THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 65

While the order of testing may have contributed to the increased VOzpeak after verapamil, there was no change in the VO2 at the metabolic threshold, suggesting no change in peripheral oxygen metabolism at submaximal levels of exercise after this drug. Although vasodilators may im- prove the anaerobic threshold in patients with abnormal vasodilator reserves,7J 1 the calcium antagonists nifedi- pine and diltiazem do not alter the anaerobic threshold in normal subjects12 or in patients with atria1 fibrilla- tion.13 In patients with effort angina, nifedipine increases cardiac output at rest and during exercise, but there is no increase in exercising muscle blood flow and the excess cardiac output is redistributed to non-exercising tissues.14 Similarly, in this study, verapamil probably did not alter submaximal leg oxygen metabolism or blood flow, leav- ing the anaerobic threshold unchanged.

All patients experienced angina in the control test while only 8 patients were limited by chest pain in the verapamil test. The degree of angina rated by patients was significantly lower after verapamil and leg fatigue was significantly increased. The increased leg fatigue af- ter verapamil may be attributed to the higher maximal work level, the higher lactate and therefore the higher level of anaerobic metabolism achieved after this medica- tion rather than a change in the threshold for anaerobic metabolism. The anaerobic threshold was the same whether the patient was limited by angina or not.

The VOZp& and VO2 at the anaerobic threshold are both submaximal measurements of oxygen consumption as patients are limited by symptoms before a true plateau of maximal VO2 is reached. In these patients, the increase in voZFak after verapamil reflects improvement in limit- ing symptoms, whereas the lack of change in VOZ at the anaerobic threshold reflects no change in the exercising muscles’ supply of or ability to use oxygen. The measure- ment of the anaerobic threshold may be a useful submaxi- mal measurement of fitness in patients with angina pecto- ris, particularly as it does not appear to be changed by calcium antagonists, or altered by the presence or absence of angina. In contrast, the VO@& is subject to variable symptom relief.

1. Wasserman K, Whipp BJ, Koyal SN, Beaver WL. Anaerobic threshold and respiratory gas exchange during exercise. J Appl Physiol 1973;35:236-243. 2. Rusko H, Luhtanen P, Rahkila P, Viitasalo J, Rehunen S, Harkonen M. Muscle metabolism, blood lactate and oxygen uptake in steady state exercise at aerobic and anaerobic thresholds. Eur J Appl Physiol 1986;55:181-186. 3. Davis JA, Frank MH, Whipp BJ, Wasserman K. Anaerobic threshold alter- ations caused by endurance training in middle-aged men. J Appl Physiol 1979;46:1039-1046. 4. Wilson JR, Ferraro N, Weber KT. Respiratory gas analysis during exercise as a noninvasive measure of lactate concentration in chronic congestive heart failure. Am J Cardiol1983;51:1639-1643. 5. Coyle EF, Martin WH, Ehsani AA, Hagberg JM, Bloomfield SA, Sinacore DR. Holloszy JO. Blood lactate threshold in some well-trained ischemic heart disease patients. J Appi Physiol 1983;54:18-23. 6. Boucher CA, Kanarek DJ, Okada RD, Hutter AM, Strauss HW, Pohost GM. Exercise testing in aortic regurgitation: comparison of radionuclide left ventricular ejection fraction with exercise performance at the anaerobic threshold and peak exercise. Am J Cardiol 1983;52:801-808. 7. White HD, Rib&o JP, Hartley LH, Colucci WS. Immediate effects of mil- rinone on metabolic and sympathetic responses to exercise in severe congestive heart failure. Am J Cardiol 1985;56:93-98. 6. Subramanian VB, Bowles MJ, Davies AB, Raftery EB. Calcium channel blockade as primary therapy for stable angina pectoris. Am J Cardiol 1982; 50:1158-l 163.

9. Frishman WH, Klein NA, Strom JA, Willens H, LeJemtel TH, Siegel L, Klein P, Kirschen N, Silverman R, Pollack S, Doyle R, Kirstem E, Sonnenblick EH. Superiority of verapamil to propranolol in stable angina pectoris: a double blind randomized crossover trial. Circulazion 198/;65(suppl I):151-159. 10. Caiozzo VJ, Davis JA, Ellis JF. Azus JL, Vandagriff R, Prietto CA, McMas- ter WC. A comparison of gas exchange indices used to detect the anaerobic threshold. J Appl Physiol 1982;53:1184-1189. 11. Ribeiro JP, White HD, Arnold JMO, Hartley LH, Colucci WS. Exercise responses before and after long-term treatment with oral milrinone in patients with severe heart failure. Am J Med 1986;8/:759-764.

12. Chick TW. Halperin AK, Jackson JE, Van As A. The effect of nifedipine on cardiopulmonary responses during exercise in normal subjects. Chest 1986; 89:641-646. 13. Atwood JE, Meyers JN, Sullivan MJ, Forbes SM, Pewen WF, Froelicher VF. Diltiazem and exercise performance in patients with chronic atrial fibrillation. Chesr 1988,92:20-25. 14. Thomson A, Fletcher PJ, Harris PJ, Freedman B. Kelly DT. Regional distribution of cardiac output at rest and during exercise in patients with exertional angina pectoris before and after nifedipine therapy. JACC I988; ll:837-842.

Increase of Plasma Beta Endorphins in Vasodepressor Syncope Gian Piero Perna, MD, Umberto Ficola, MD, Mauro Pellegrino Salvatori, MD, Mario Stanislao, MD, Carlo Vigna, MD, Alessandro Villella, MD, Aldo Russo, MD, Raffaele Fanelli, MD, Pier Giuseppe Paleani Vettori, MD, and Francesco Loperfido, MD

V asodepressor syncope pathophysiology has not been definitively elucidated. Although it is common-

ly accepted that vasodepressor syncope is consequent to primary peripheral vasodilation, other factors, such as failure of reflex-mediated compensatory increases in car- diac rate and output, may also be involved.’ Beta endor- phins have an inhibitory effect on the sympathetic dis- charge.2-4 To investigate the role of endogenous opioid peptides in precipitating syncopal episodes, we assayed plasma /3 endorphin activity in patients with vasodepres- sor syncope.

Five patients were examined. There were 4 males and 1 female, with ages ranging from 12 to 31 years. All 5 patients were apparently healthy. Syncope had beenpre- cipitated by hunger in 2 subjects and occurred immedi- ately after a maximal graded bicycle stress test in the other 3. All syncopal episodes occurred between 8 A.M.

and 10 A.M. and lasted between 4 and I2 minutes. Brady- cardia was present in all patients during syncopal epi- sodes. Two blood samples were drawn the first was

From the Departments of Cardiology and Nuclear Medicine, Casa Sollievo della Sofferenza Hospital, 7 1013 San Giovanni Rotondo (FG), Italy, and the Department of Cardiology, Universitz? Cattolica de1 Sacro Cuore, Roma. Manuscript received April 26, 1989; revised manuscript received and accepted September 5, 1989.

obtained during fainting and the second in the resting state 24 hours later (basal value). As a control, we ex- amined 8 normal male volunteers, with ages ranging from 18 to 22 years. In these subjects, blood samples were drawn 3 minutes after a well-tolerated maximal bicycle stress test, performed at 9 A.M., and 24 hours later. Beta endorphins were assayed using a 2-step high- ly specific procedure (INCSTAR plasma /3 endorphin by radioimmunoassay). Thefirst step was chromatograph- ic extraction and concentration of 8 endorphin; the sec- ond was radioimmunoassay using an antibody with a high affinity for 8 endorphin and a cross-reactivity <5% for 8 lipotropin and <O.Ol% for other peptides. Beta endorphin levels are expressed in pmollliter. Results were analyzed by 1 -way analysis of variance for paired and unpaired data.

In the 5 study patients, plasma p endorphin activity was very high during syncopal episodes (46.32 f 11.74 pmollliter) compared with either basal activity in the same subjects (3.7 f 1.45 pmollliter; p <0.00004) or with plasma levels found immediately after exercise in control subjects (9.5 f 1 .lQpmol/liter;p <O.OOOl). Bas- al plasma p endorphin activity in control subjects was 3.94 f 1.2 pmollliter (difference not significant us basal value in patients with syncope) (Figure 1).

FIGURE 1.-B edorpMnactivityin

pdht9WRhVruO-

I Patients with rasodepressar syncope

(51 60

70.

60. 0

50' 00 0

40.

30 t

0

20

10 t

controls (81

- f&o 0

syncopc Basal Postexercise Basal

THE AMERICAN JOURNAL OF CARDIOLOGY APRIL 1. 1990 929