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ACC/AHA 2008 Performance Measures for Adults With ST-Elevation and Non–ST-Elevation Myocardial Infarction

ACC/AHA 2008 Guidelines for the Management of Adults With Congenital Heart Disease
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J Am Coll Cardiol, 2002; 40:1841-1847
© 2002 by the American College of Cardiology Foundation
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CLINICAL STUDY: ELECTROPHYSIOLOGIC DISORDERS

ST-segment elevation and ventricular fibrillation without coronary spasm by intracoronary injection of acetylcholine and/or ergonovine maleate in patients with Brugada syndrome

Takashi Noda, MD*, Wataru Shimizu, MD, PhD*,*, Atsushi Taguchi, MD*, Kazuhiro Satomi, MD*, Kazuhiro Suyama, MD, PhD*, Takashi Kurita, MD, PhD*, Naohiko Aihara, MD* and Shiro Kamakura, MD, PhD*

* Division of Cardiology, Department of Internal Medicine, National Cardiovascular Center, Suita, Japan

Manuscript received April 17, 2002; revised manuscript received June 24, 2002, accepted July 24, 2002.

* Reprint requests and correspondence: Dr. Wataru Shimizu, Division of Cardiology, Department of Internal Medicine, National Cardiovascular Center, 5-7-1 Fujishiro-dai, Suita, Osaka, 565-8565 Japan.
wshimizu{at}hsp.ncvc.go.jp


   Abstract
Top
 Abstract
Methods
 Results
 Discussion
 References
 
OBJECTIVES: The study examined whether patients with Brugada syndrome are sensitive to vagal stimulation or ischemia.

BACKGROUND: Experimental studies have suggested that a prominent transient outward current (Ito)-mediated action potential notch and a subsequent loss of the action potential dome in the epicardium, but not in the endocardium, give rise to ST-segment elevation and subsequent ventricular fibrillation (VF).

METHODS: We evaluated the frequency of coronary spasm, augmentation (≥0.1 mV) of ST-segment elevation in leads V1 to V3, and induction of VF by intracoronary injection of acetylcholine (ACh) and/or ergonovine maleate (EM) in 27 symptomatic patients with Brugada syndrome and 30 control subjects.

RESULTS: The coronary spasm was induced in 3 (11%) of the 27 patients with Brugada syndrome and in 13 (43%) of the 30 control subjects. ST-segment elevation was augmented by 11 (33%) of the 33 right coronary injections (ACh: 6/11 [55%]; EM: 5/22 [23%]), without coronary spasm, but not by any of the left coronary injections in patients with Brugada syndrome. Ventricular fibrillation was induced by 3 (9%) of the 33 right coronary injections (ACh: 2/11 [18%]; EM: 1/22 [5%]), but not by any of the left coronary injections. In contrast, neither ST-segment elevation nor VF was observed in any of the control subjects.

CONCLUSIONS: Our results support the hypothesis that mild ischemia and vagal influences act additively or synergistically with the substrate responsible for the Brugada syndrome to elevate the ST- segment and precipitate VF. These observations suggest that Brugada patients may be at a higher risk for ischemia-related sudden death.

Abbreviations and Acronyms
  ACh
  acetylcholine
  ECG
  electrocardiogram or electrocardiographic
  EM
  ergonovine maleate
  ICa
  calcium current
  IKATP
  adenosine triphosphate–sensitive potassium current
  INa
  sodium current
  Ito
  transient outward current
  RBBB
  right bundle branch block
  RVOT
  right ventricular outflow tract
  VF
  ventricular fibrillation

In 1992, Brugada and Brugada (1) reported eight patients with a distinct electrocardiographic (ECG) pattern, consisting of right bundle branch block (RBBB) with peculiar ST-segment elevation in the right precordial leads (V1 to V3) and sudden cardiac death in the absence of any structural heart disease. Patients with these peculiar ECG abnormalities and documented ventricular fibrillation (VF) have been recognized as a subgroup (i.e., Brugada syndrome), and their clinical manifestations have been described (2–5).

Vasospastic angina is another etiology of VF in patients without identifiable structural heart disease and should be excluded to confirm the diagnosis of Brugada syndrome (6–8). However, coexistence of Brugada syndrome and vasospastic angina has recently been reported in a couple of case reports (9–11).

Recent experimental studies have suggested that a prominent transient outward current (Ito)-mediated action potential notch and a subsequent loss of the action potential dome in epicardial cells, but not in endocardial cells, in the right ventricular outflow tract (RVOT), give rise to voltage gradients across the ventricular wall, resulting in ST-segment elevation in the right precordial leads and subsequent VF due to the mechanism of phase 2 reentry (12,13). Because the maintenance of the action potential dome is determined by the balance of inward and outward currents active at the end of phase 1 of the action potential, any agents that cause an outward shift (e.g., increase in Ito, increase in adenosine triphosphate–sensitive potassium current [IKATP], decrease in calcium current [ICa], decrease in fast sodium current [INa]) can increase the magnitude of the action potential notch, leading to the ST-segment elevation and VF in patients with Brugada syndrome (14). Therefore, we hypothesized that the increase in IKATP and/or decrease in ICa may enhance the ST-segment elevation in the right precordial leads and induce VF in patients with Brugada syndrome, secondary to ischemia or vagomimetic action by intracoronary injection of acetylcholine (ACh) and/or ergonovine maleate (EM), especially by injection to the right coronary artery, which perfuses to the RVOT.

The present study was designed to examine this hypothesis, as well as to systematically evaluate the frequency of coexistence of Brugada syndrome and vasospastic angina.


   Methods
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 Methods
Results
 Discussion
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Patient characteristics.   The study population included 27 consecutive patients affected with symptomatic Brugada syndrome who were admitted to the National Cardiovascular Center, Osaka, Japan, between 1992 and 2001. There were 26 men and 1 woman ranging in age from 21 to 63 years (mean 47 ± 13). All 27 patients had episodes of syncope without any prodrome, including chest pain, or a history of aborted cardiac arrest with or without documentation of VF. In all patients, a physical examination, chest roentgenogram, laboratory values, echocardiographic study with wall motion analysis and Doppler screening, and cardiac catheterization with left and right ventriculography were performed or obtained, and no structural heart disease was found. The patients also fulfilled the following criteria (15,16): 1) spontaneously documented persistent or transient ST-segment elevation (coved or saddle-back type) in the right precordial leads V1 to V3 with or without some degree of RBBB; and 2) a corrected QT interval <440 ms. The control group consisted of 30 randomly selected subjects; all were men ranging in age from 38 to 75 years (mean 60 ± 11) who had chest pain or chest discomfort and were suspected of having vasospastic angina. There were four patients with incomplete RBBB (QRS duration 100 to <120 ms) and two with complete RBBB (QRS duration ≥120 ms).

Coronary angiography and administration of ACh and/or EM
All protocols were reviewed and approved by our Ethical Review Committee, and written, informed consent was obtained from all patients. Before coronary angiography, all drugs, including nitroglycerin and Ca2+ antagonists, were discontinued for at least five half-lives of each drug. The patients were in the supine resting state and underwent coronary angiography by the Judkins technique. The left coronary angiograms in the right anterior oblique projection and the right coronary angiograms in the left anterior oblique projection were obtained in the baseline condition without injection of nitroglycerin, in a standard manner. An electrode catheter was positioned in the right ventricular apex and connected to a pacemaker for backup pacing (40 beats/min). We first injected ACh, which was diluted in 10 ml of 0.9% saline and was raised to 37°C, into the right coronary artery and then into the left coronary artery. Acetylcholine was injected over 20 s in incremental doses of 20 and 50 µg within a 2-min interval. We injected EM into the right coronary artery and then into the left coronary artery in incremental doses of 10, 20, and 40 µg in the same manner. The EM study was performed at least 10 min after the completion of the ACh injection. In the 27 patients with Brugada syndrome, ACh alone was injected in 6 patients, EM alone in 15 patients, and both ACh and EM in the remaining 6 patients (Patient # 22 to 27) (Table 1). In the 30 control subjects, ACh alone was injected 6 patients and EM alone in 24 patients. Arterial blood pressure and the 12-lead ECG were continuously monitored before and after injection of ACh or EM. Coronary angiography was performed to observe the presence or absence of coronary spasm and whether the patients had chest discomfort, the ST segment was elevated or depressed in any leads, or the injection of the maximal dose of ACh or EM to each coronary artery was complete. If coronary spasm was induced but was not resolved spontaneously, 200 µg nitroglycerin was injected into the coronary artery with spasm.


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  		Table 1 Clinical and Electrocardiographic Characteristics in the 27 Patients WithBrugada Syndrome

 
Analysis of parameters
We evaluated the frequency of induction of coronary artery spasm, augmentation of ST-segment elevation in the right precordial leads, and induction of VF. Coronary artery spasm was assessed at total or near-total occlusion focally. Augmentation of ST-segment elevation in leads V1 to V3 was defined as an increase of ≥0.1 mV in the amplitude of the ST segment 20 ms after the end of the QRS complex in lead V1, V2, or V3 after injection of ACh or EM.


   Results
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 Abstract
 Methods
 Results
Discussion
 References
 
Clinical characteristics.   Table 1 shows the clinical characteristics of the 27 patients with Brugada syndrome. In the baseline condition, 9 patients with Brugada syndrome showed a normal QRS duration, 10 patients had incomplete RBBB, and 8 patients exhibited complete RBBB. All patients had episodes of syncope, and 14 patients had a history of aborted cardiac arrest. Ventricular fibrillation was documented in 14 patients, and 4 patients had family members who died suddenly.

Induction of coronary artery spasm
There was no significant organic stenosis of the right and left coronary arteries in the baseline condition in both groups. Coronary spasm was induced in 3 (11%) of the 27 patients with Brugada syndrome. Right coronary spasm (segment no. 1, 100%) was induced by the right coronary injection of ACh in one patient. Left coronary spasm was induced by the left coronary injection of ACh in one patient (segment no. 7, 90%) and by the same injection of EM in the remaining one patient (segment no. 6, 99%). In contrast, coronary spasm was induced by 4 of 6 ACh injections and by 9 of 24 EM injections in the control subjects (Table 2).


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  		Table 2 Frequency of Induction of Coronary Spasm, Augmentation of ST-Segment Elevation, and Induction of Ventricular Fibrillation

 
Augmentation of ST-segment elevation in the right precordial leads
Figure 1 shows the 12-lead ECG before and after ACh injection into the right coronary artery in a patient with Brugada syndrome. The baseline ECG shows coved or saddle-back type ST-segment elevation in leads V1 and V2 (Fig. 1A). Injection of 50 µg ACh augmented the ST-segment elevation in leads V1 and V2, without any induction of coronary spasm (Fig. 1B), leading to spontaneously induced VF (Fig. 1C). Figure 2 illustrates the 12-lead ECG before and after EM injection into the right coronary artery in a control subject. In this case, injection of 40 µg EM produced spasm of the right coronary artery (segment no. 2, 75%; segment no. 4, 100%), associated with ST-segment elevation in leads II, III, and aVF. However, no ST-segment elevation was observed in leads V1 to V3, like that in the patient with Brugada syndrome (Fig. 2B). In the patients with Brugada syndrome, the ST-segment elevation in leads V1 to V3 was augmented by 6 (55%) of 11 right coronary injections of ACh and by 5 (23%) of 22 right coronary injections of EM, and this was not associated with any induction of coronary spasm. It is noteworthy that the augmentation of ST-segment elevation localized in leads V1 to V3 was never induced by the left coronary injection of ACh or EM. ST-segment elevation in leads V1 to V3 was not observed by either ACh or EM injection in any of the control subjects (Table 2).



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  		Figure 1 Twelve-lead electrocardiogram (ECG) in the baseline condition (A), after injection of 50 µg acetylcholine (ACh) into the right coronary artery (B), and after ventricular fibrillation (VF) induction by ACh (C) in a patient with Brugada syndrome. The baseline ECG shows coved or saddle-back type ST-segment elevation in leads V1 and V2. Injection of ACh augmented the ST-segment elevation in leads V1 and V2 (B, arrows), without any induction of coronary spasm, resulting in spontaneously induced VF.

 


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  		Figure 2 Twelve-lead electrocardiogram in the baseline condition (A) and after injection of 40 µg ergonovine maleate (EM) into the right coronary artery (B) in a control subject. Injection of EM produced right coronary spasm (segment no. 2, 75%; segment no. 4, 100%), associated with ST-segment elevation in leads II, III, and aVF (B, arrows). However, no ST-segment elevation was observed in leads V1 to V3, like that in patients with Brugada syndrome (B, arrows).

 
Induction of VF
In the patients with Brugada syndrome, VF was induced by 2 (18%) of the 11 right coronary injections of ACh and by 1 (5%) of 22 right coronary injections of EM, and this was not associated with any induction of coronary spasm. Ventricular fibrillation was not induced by the left coronary injection of ACh or EM. In contrast, VF did not occur in any of the control subjects (Table 2).

Acetylcholine versus EM
The frequency of augmentation of ST-segment elevation in leads V1 to V3 and VF induction was evaluated in six patients with Brugada syndrome in whom both ACh and EM were used. No coronary spasm was induced by either ACh or EM in these patients. Figure 3 shows the 12-lead ECG of a patient with Brugada syndrome with injection of both ACh and EM. The baseline ECG shows coved and saddle-back type ST-segment elevation in leads V1 and V2 (Fig. 3A). ST-segment elevation was augmented by the right coronary injection of 50 µg ACh, without any induction of coronary spasm (Fig. 3B), but not by the right coronary injection of 40 µg EM (Fig. 3C). Once again, the augmentation of ST-segment elevation in leads V1 to V3 was never induced by the left coronary injection of either ACh or EM. ST-segment elevation in leads V1 to V3 was augmented by four of six injections of ACh, but by only one of six injections of EM. Ventricular fibrillation was induced by one of six right coronary injections of ACh (Table 3).



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  		Figure 3 Twelve-lead electrocardiogram in the baseline condition (A), after injection of 50 µg acetylcholine (ACh) into the right coronary artery (B), and after injection of 40 µg ergonovine maleate (EM) into the right coronary artery (C) in a patient with Brugada syndrome. Injection of ACh augmented the ST-segment elevation in leads V1 and V2, without any induction of coronary spasm (B, arrows), whereas injection of EM did not change the ST-segment elevation.

 

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  		Table 3 Frequency of Induction of Coronary Spasm, Augmentation of ST-Segment Elevation, and Induction of Ventricular Fibrillation in Six Patients With Brugada Syndrome in Whom Both Acetylcholine and Ergonovine Maleate Were Injected

 

   Discussion
Top
 Abstract
 Methods
 Results
 Discussion
References
 
Brugada syndrome and vasospastic angina.   Brugada syndrome is characterized by a peculiar ST-segment elevation in leads V1 to V3 and an episode of VF in the absence of any structural heart disease (1–5). ST-segment elevation in any ECG lead reflecting the ischemic region and subsequent VF are also observed in patients with vasospastic angina but no structural heart disease (6–8). Therefore, vasospastic angina must be excluded to diagnose the patient with Brugada syndrome. However, some case reports have demonstrated the combination of Brugada syndrome and vasospastic angina simultaneously (9–11). The present study systematically evaluated the incidence of induced coronary spasm by injections of ACh and/or EM in symptomatic patients with Brugada syndrome. The data suggest that the coexistence of vasospastic angina was not rare (11%) in symptomatic patients with Brugada syndrome. The coexistence of Brugada syndrome and vasospastic angina is clinically important, especially from a therapeutic point of view. The first line of therapy for vasospastic angina is administration of calcium antagonists or nitrates, which also have a blocking action of ICa. The use of these agents in patients with vasospastic angina would be expected to attenuate ST-segment elevation in the right precordial leads and to induce VF as a result of ICa inhibition—that is, if the patients were associated with Brugada syndrome. Therefore, the coexistence of Brugada syndrome and vasospastic angina should always be taken into account for the management of both patients with Brugada syndrome and those with vasospastic angina.

Possible mechanism of augmentation of ST-segment elevation in the right precordial leads and VF by intracoronary injection of ACh and/or EM
Yan and Antzelevitch (12,13) developed an experimental model of Brugada syndrome by using arterially perfused canine right ventricular wedge preparations, and they suggested that heterogeneous repolarization across the ventricular wall of the RVOT was responsible for the ST-segment elevation and the genesis of VF in Brugada syndrome. They used several autonomic and anti-arrhythmic agents in their models and suggested that any agents that increase outward currents (Ito or IKATP) or decrease inward currents (ICa or fast INa) can increase the magnitude of the action potential notch, resulting in ST-segment elevation and VF in patients with Brugada syndrome. So far, this hypothesis most likely explains the clinical manifestation, such as responses to autonomic agonists (e.g., isoproterenol, ACh) and antagonists (e.g., beta-blockers, atropine) or sodium channel blockers in patients with Brugada syndrome (16–23). In the present study, ST-segment elevation in leads V1 to V3 was augmented by the right coronary injection of ACh or EM, without any visible coronary spasm in one-third of the symptomatic patients with Brugada syndrome, but not in any of the control subjects. Of note, the left coronary injection of ACh or EM could never attenuate the ST-segment elevation in leads V1 to V3, even in patients with Brugada syndrome. These findings suggest that the Ito-mediated phase 1 notch of the epicardial cells in the RVOT was sensitive to vagal stimulation (decrease in ICa) produced by ACh or to mild ischemia (increase in IKATP and/or decrease in ICa), which was induced by EM but was not able to cause visible coronary spasm, thus resulting in the augmentation of ST-segment elevation in the right precordial leads. Augmentation of ST-segment elevation was more easily induced by the right coronary injection of ACh versus EM (55% vs. 23%). Moreover, ST-segment elevation in leads V1 to V3 was augmented by four of six right coronary injections of ACh, but by only one of six right coronary injections of EM in six patients with Brugada syndrome in whom both ACh and EM were used. These data indicate that suppression of ICa by vagal stimulation with ACh played a more significant role in the mechanism of augmentation of ST-segment elevation in Brugada syndrome.

Ventricular fibrillation was induced after augmentation of ST-segment elevation in the right precordial leads by three right coronary injections of ACh or EM, but not by any left coronary injections. These results indicate a correlation between prominent ST-segment elevation and subsequent VF and support the hypothesis of VF due to phase 2 reentry (24,25).


   Footnotes
 
This study was supported in part by the Japanese Cardiovascular Research Foundation (W. S.), Vehicle Racing Commemorative Foundation (W. S.), Health Sciences Research Grants from the Ministry of Health, Labour and Welfare (W. S. and S. K.) and a Research Grant for Cardiovascular Diseases (13A-1) from the Ministry of Health, Labour and Welfare (S. K.), Japan. This study was also supported in part by the Program for Promotion of Fundamental Studies in Health Sciences of the Organization for Pharmaceutical Safety and Research of Japan.


   References
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