Ventricular arrhythmias during ergonovine-induced episodes of variant angina

Ventricular arrhythmias during ergonovine-induced episodes of variant

angina

Of 95 consecutive patients with active variant angina who underwent ergonovine testing in the coronary care unit while off treatment, 24 (25%) developed serious ventricular arrhythmias: ventricular tachycardia in eight, bigeminy in seven, pairs in five, and frequent ventricular extrasystoles in four. Ergonovine-induced arrhythmias were observed more often in patients with anterior than inferior ST segment elevation (p < 0.05). ST segment elevation was significantly higher (10.3 -t 8.1 vs 3.1 * 2.1 mm) in patients who developed arrhythmias. All ventricular arrhythmias began within 3 minutes after the onset of ST segment elevation. The intravenous administration of nitroglycerin eliminated arrhythmias in 22 of 24 cases; in only two patients did ventricular arrhythmias develop after the administration of nitroglycerin. Serious ventricular arrhythmias were found during spontaneous variant angina attacks in 14 of 24 patients with ergonovine-induced arrhythmias compared to 16 of 71 patients without ergonovine-induced arrhythmias (p < 0.001). We conclude that arrhythmias during ergonovine testing are most often caused by ischemia and not reperfusion. Patients with arrhythmias during ergonovine-induced attacks are more likely to have arrhythmias during spontaneous attacks. (AM HEART J 107:20, 1984.)

Jadwiga Szlachcic, M.D., David D. Waters, M.D., Douglas Miller, Pierre Theroux, M.D. Montreal, Quebec, Canada

In Prinzmetal’s original description of variant angina nearly half of his patients were noted to have arrhythmias, usually of ventricular origin, during ST segment elevation.’ A typical patient was described as follows: “During the severe attacks he had ventricular arrhythmias which became increasingly alarming as the pain intensified. At the peak of pain, runs of ventricular tachycardia appeared,” in association with marked ST-segment elevation. “During a moderate attack the ST segment was moderately appeared.“’ Serielevated, . . . and no arrhythmias ous ventricular arrhythmias and heart block occurring during spontaneous episodes of variant angina are of clinical importance because they predict subsequent sudden death.2-4 Because spontaneous episodes of variant angina occur unpredictably, a comprehensive analysis of arrhythmias during an attack is often difficult. However, the clinical and

Received accepted From the University Supported LBvesque

for publication .July 2, 1982. Department of Montreal

Jan.

2fi. 1982;

revision

of Medicine, Montreal Medical School.

in part by grants from Alcan Co., Foundation, and by Montreal Heart

received Heart

Jutw Institute.

Montreal, Institute

Reprint requests: David D. Waters, M.D., Montreal Heart East Belanger St., Montreal, Quebec, HlT. lC8. Canada.

20

19. 1982; and

the

and the J-Louis Research Funds. Institute,

5000

M.D., and

angiographic characteristics of spontaneous and ergonovine-induced attacks of variant angina have been shown to be similar.5 Therefore, this study was undertaken to examine the incidence, severity, and clinical correlates of ventricular arrhythmias during ergonovine-induced episodes of variant angina and to compare arrhythmias during spontaneous and induced attacks. METHODS Patient characteristics. For the purpose of this study, variant angina was defined as angina at rest with transient ST segment elevation, rapidly relieved by nitroglycerin without evidence of myocardial necrosis. The study population consisted of 95 consecutive patients with active variant angina, who underwent ergonovine testing in the coronary care unit, while receiving no treatment. All patients had previously undergone coronary arteriography. While in the coronary unit during the active phase of their disease, all patients were monitored for at least 3 days with an ECG lead where ST elevation had been recorded. Episodes of angina at rest during this period were analyzed for arrhythmias. Seventy-one were men and 24 women; their ages ranged from 32 to 71 (mean 50.4) years. Coronary arteriography. Selective coronary arteriography was performed via a percutaneous femoral approach with the use of preformed catheters, as previously described.“, ’ No attempt was made during catheterization

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1. An example of ventricular arrhythmias during an ergonovine-inducedepisodeof variant angina in a patient with two-vessel disease. The first two tracings on the upper panel, before ergonovine administration and 4 minutes after the 0.025mgdose,are normal. One minute later, ST-segmentelevation appears in the inferior ECG leads. The middle panel is a continuous strip recorded 30 secondslater, showingventricular tachycardia occurring coincident with nitroglycerin (NTG) administration. The lower panelswere recorded 30 seconds,2 minutes, and 3 minutes later, as ST-segment elevation decreasesand disappears,without a reappearanceof ventricular arrhythmias. All tracings are lead III except middle panel.

Fig.

to induce coronary spasmby administration of ergonovine. Nitroglycerin was not given before the initial injections; however, when a lesion was noted, the vessel was filmed again in several views, after nitroglycerin had been administered. All angiographic documents were routinely interpreted independently by an experiencedcardiovascular radiologist. The left ventricular angiogramwasfilmed in the 30-degree right anterior oblique view before the coronary arteriogram. Ergonovine testing. All ergonovine tests were performed in an identical fashion in the coronary care unit. Written informed consentwasobtained prior to testing in all cases.The test wasperformed only in patients who had recently undergone coronary arteriography; those with critical organic stenosesin two or more major coronary arteries, severeleft ventricular dysfunction, cerebrovascular disease,recent myocardial infarction, or episodesof myocardial ischemialasting longer than 10 minutes or not promptly relieved by nitroglycerin were excluded. The test protocol is describedin detail e1sewhere.8 Briefly, cuff blood pressure and a 12-lead ECG were recorded every minute beginning 2 minutes before the first drug doseand continuing for a minimum of 5 minutes after the last injection. A continuous ECG was recorded during all arrhythmias and when ST segment abnormalities were present, a complete tracing was obtained at 30-second intervals or more often. At &minute intervals a bolus of ergonovine was administered intravenously in the follow-

ing sequence:0.0125,0.025, 0.05, 0.1, 0.2, 0.3, and 0.4 mg. The criterion for a positive test was the appearanceof an ST segmentshift greater than 1 mm compared with the control tracing. An intravenous bolusinjection of 0.3 mg of nitroglycerin was administered as soon as a positive responsewas detected. The ST segmentelevation of each patient was measuredon the ECG, with the TP segment asthe isoelectric line. Of the ECG leadsreflecting myocardial ischemia, the one showing the highest ST segment elevation was used for statistical analysis. Our total experience with ergonovine testing in the coronary care unit comprises631 tests, of which 221 were positive. Seven serious complications occurred: Two patients had severe hypotension requiring intravenous metaraminol and three others had recurrent angina with ST segmentelevation relieved by nitroglycerin during the hour following the test. None of these u patients had permanent sequelae. However, two other patients had elevated cardiac enzymes,without Q wavesafter the test; subendocardial infarction was diagnosed. All complications were limited to patients with fixed lesionsin at least one coronary artery. Death, transmural myocardial infarction, ventricular fibrillation, complete heart block, or asystole did not occur in any of these patients as a complication of ergonovine testing. No patient required antiarrhythmic drug therapy or cardiac pacing. Data analysis. The unpaired t test wasusedto compare the mean values between two groups for continuous

22

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American

January, 1984 Heart Journal

I. Comparisonbetween patients with and without seriousarrhythmias during ergonovine-induced episodes variant angina Table

Group Z arrhythmias)

(with Total

patients

Meanage(yr) Male/female Abnormal control ECG Anterior ST elevation Maximum ST elevation (mm) Coronary arteriography No stenosis ~70% Stenosis z70? Artery to ischemic zone >70P, Abnormal left ventriculogram Arrhythmias during spontaneous attacks Maximum ergonovine dose (median for group) p = NS for all comparisons,

unless otherwise

(without

Group ZZ arrhythmias)

of

P

24 49.0 (32-67) 2212 11 (46%) 18 (75%) 10.3 + 8.1

71 51.8 (34-71) 49122 27 (38Oc) 35 (49%) 3.1 ?!I 2.1

<0.05
10 (42%) 14 (58”;) 12 (50%) 2 (8%) 14 (58%) 0.05 mg

37 (52%) 34 (48% ) 26 (37%) 13 (19%) 16 (22%) 0.1 mg


indicated.

variables, and the chi squareanalysiswasusedto compare the mean values between two groups for noncontinuous variables. RESULTS Ergonovine testing. The ergonovine test induced ST segment elevation in 93 patients, 69 of whom had coexisting angina; one patient had angina with ST segment depression and one had pseudonormalization of previously negative T waves. Ventricular arrhythmias developed during the test in 24 patients, all of whom had ST segment elevation. An example of one such patient is illustrated in Fig. 1. Eight patients had ventricular tachycardia which terminated spontaneously in less than 15 seconds in all cases. Five patients had ventricular pairs, seven had bigeminal rhythm, and four others had frequent ventricular extrasystoles. In patients with more than one arrhythmia, only the most severe was included in this tabulation. The remaining 71 patients had no ventricular arrhythmias or less than four ventricular extrasystoles during the test. Second-degree heart block occurred in only one patient coincident with ventricular bigeminy. No patient required antiarrhythmic drug therapy or cardiac pacing since no arrhythmia persisted after the resolution of ST elevation. With the exception of isolated ventricular extrasystoles, no patient exhibited arrhythmias in the absence of spontaneous or induced myocardial ischemia. The ergonovine dose level at which the test became positive was slightly lower (p < 0.02) in the group with arrhythmias (median 0.05 mg) compared to the others (median 0.1 mg). All ventricular arrhythmias began within 3 minutes of the onset of ST-segment elevation, usu-

ally much sooner. Intravenous nitroglycerin alone rapidly relieved ischemic chest pain and ST segment elevation in all cases and resolved arrhythmias in 22 of 24 patients. In eight of those patients arrhythmias continued without worsening for up to 2 minutes after nitroglycerin was administered. In only two patients did arrhythmias begin (bigeminy in one patient and ventricular extrasystoles in the other) after the administration of nitroglycerin and during normalization of ST segment elevation. Arrhythmias VI no arrhythmias. In Table I, the clinical and angiographic characteristics of the 24 patients with and the 71 patients without arrhythmias during the test are compared. The age, sex, coronary anatomy, left ventriculogram, presence of severe fixed lesion in the artery presumed to be perfusing the ischemic zone, and the control ECG did not differentiate patients who developed arrhythmias during ergonovine testing from those who did not. Two factors clearly separated patients who developed serious ventricular arrhythmias during ergonovine-induced episodes of variant angina. ST segments were higher Cp < 0.01) in patients with ventricular arrhythmias (10.3 mm + 8.1 SD) than in those without arrhythmias (3.1 mm +- 2.1). Ventricular arrhythmias occurred more often in patients with anterior compared to inferior ST segment elevation: 18 of 24 patients (75 % ) in the arrhythmia group had anterior ST segment elevation, while only 35 of 71 (49%) without arrhythmias during ergonovine testing had anterior ST segment changes (p < 0.05). Spontaneous vs ergonovine-induced arrhythmias. In Table II, arrhythmias are compared during sponta-

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II. Comparison of arrhythmias during spontaneous and ergonovine-induced variant angina attacks Spontaneous

Ergonouine-induced attacks None V Fib

V Tach V Bigeminy V Pairs V extrasystoles 2-3" AV block Totals Abbreviations:

V = ventricular;

None

VFib

V Tach

attacks

V Bigeminy

V pairs

V extrasystoles

2-3" AV

block

Totals

55 0 3 3 2 2

2 0 0

8 0 4

5 0 0

1

0

0

0 0

0 0

0

0 8

1

2

1

0

0

1 0

0 0

1 2

2 0

0 0

0 0

0 0

0

0

0

0

65

3

17

8

0 1

0 0

0 1

Fib = fibrillation;

Tach = tachycardia;

2-3” AV block = second- or third-degree

neous and ergonovine-induced attacks for the 95 variant angina patients in the study. When more than one spontaneous attack was documented, the episode with the worst arrhythmia was chosen for analysis. Fourteen of the 24 patients (58%) with arrhythmias during ergonovine-induced attacks also had arrhythmias during spontaneous attacks; only 16 of the 71 (23% ) without arrhythmias during ergonovine-induced attacks had arrhythmias during spontaneous attacks (p < 0.001). In general, the arrhythmias were more severe during spontaneous attacks. Ventricular fibrillation occurred during spontaneous attacks in three cases and high-degree AV block in one; these arrhythmias did not occur during ergonovine-induced attacks. Ventricular tachycardia developed during spontaneous attacks in 17 patients but with ergonovine in only eight cases. DISCUSSION

Serious ventricular arrhythmias occurred during ST segment elevation in 24 of 95 consecutive patients who underwent ergonovine testing in the coronary care unit. Eight patients had ventricular tachycardia, seven had bigeminy, five had ventricular pairs, and four others had frequent extrasystoles. Mechanisms. The mechanism producing serious arrhythmias during spontaneous attacks of variant angina is controversial. Some authorPsg suggest that arrhythmias correlate with the degree of myocardial ischemia as evidenced by ST segment elevation, while others10-12 argue that coronary reperfusion during resolution of spasm causes arrhythmias. Because the exact point at which reperfusion occurred was not documented in this study, our results cannot prove whether ventricular arrhythmias were caused by ischemia or reperfusion. The following points suggest that ischemia and not

atrioventricular

71

7 5 4 0 95

block.

reperfusion caused the arrhythmias observed during ergonovine testing. Ischemia-induced arrhythmias. Arrhythmias usually (22 of 24 cases) began before the administration of nitroglycerin and within 1 to 3 minutes after the onset of ST segment elevation. Experimentally produced reperfusion arrhythmias occur only after more prolonged periods of coronary occlusion.13 Although arrhythmias persisted during the short period between the administration and onset of action of intravenous nitroglycerin, they were all rapidly relieved by nitroglycerin alone without the need of antiarrhythmic drugs. In no case did arrhythmias worsen after nitroglycerin administration. Ergonovine-induced arrhythmias were observed most often in patients with anterior ST segment elevation and higher degrees of ST elevation, supporting the concept that extensive transmural ischemia is responsible for the majority of arrhythmias in patients with variant angina. In only 2 cases did arrhythmias begin after the administration of nitroglycerin, raising the possibility of reperfusion as their cause. Both patients in question had near-normal coronary arteries perfusing the ischemic zone. In animal studies a higher incidence of reperfusion arrhythmias occurs in the absence of fixed obstructive lesions.” The fact that the patients with arrhythmias had worse ischemia as reflected by higher peak ST segment elevation does not argue strongly in favor of ischemia as their cause because reperfusion arrhythmias are also favored by more severe ischemia.14 Reperfusion arrhythmias might be more likely to occur during spontaneous attacks, particularly if untreated, than in this study because nitroglycerin was always given at the onset of ischemic ST segment elevation; thus no attack lasted longer than 5 minutes. Spontaneous arrhythmias. As shown in Table II,

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most patients with ergonovine-induced arrhythmias also had serious arrhythmias documented during spontaneous episodes of variant angina. Similarly, Curry et a1.5 showed that the clinical and angiographic features of spontaneous and induced attacks of variant angina did not differ. Among seven patients that they studied, four had identical dysrhythmias during both attacks. In this study, the arrhythmias observed during ergonovine testing were less severe than those detected during spontaneous attacks in the same patients (Table II). Ventricular fibrillatic asystole, and complete heart block were not seen during ergonovine testing. No arrhythmia lasted longer than 15 seconds and no syncopal episode occurred. This difference between spontaneous and induced attacks may be explained by the immediate treatment of myocardial ischemia at the onset of ST segment elevation during ergonovine testing. When ergonovine-induced ischemia is allowed to persist for longer periods, serious complications, including death, may occur.‘” Therapeutic implications. The results of this study may have therapeutic implications. Sudden death in patients with variant angina, with or without fixed coronary lesions, presumably occurs when fatal arrhythmias are induced by severe transmural myocardial ischemia resulting from coronary artery spasm.2s” Spontaneous and ergonovine-induced arrhythmias are more common in patients with the most profound myocardial ischemia as reflected by the highest ST segment elevation.14s’6 Patients with life-threatening arrhythmias during attacks should be treated vigorously17 in an attempt to eliminate all attacks and not just to reduce their frequency. Because arrhythmias during induced attacks correlate with arrhythmias during spontaneous attacks, patients with arrhythmias during testing should probably be included in this high-risk subgroup, particularly if no or few spontaneous attacks have been recorded. The absence of arrhythmias during the test does not exclude the possibility of arrhythmias complicating spontaneous attacks; 16 of 71 patients without arrhythmias during the test had them detected during spontaneous episodes. Patients without arrhythmias during attacks are at a lower risk for sudden death.3 Such patients should also be treated with calcium antagonist drugs initially; however, in some of them it may be reasonable to eventually discontinue this treatment after long symptom-free periods. l8 It would be difficult to justify discontinuing treatment in patients who had life-threatening arrhythmias during attacks.

American

January, 1984 Heart Journal

REFERENCES

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