Clinical characteristics and possible mechanism of paroxysmal atrial fibrillation induced by intracoronary injection of acetylcholine

Atrial fibrillation (AF) is the most common cardiac arrhythmia and is associated with an increased morbidity and mortality. There is clinical evidence that an increasing number of cardiovascular and non-cardiovascular drugs, mainly anticancer drugs, can induce AF either in patients with or without pre-existing cardiac disorders, but drug-induced AF (DIAF) has not received the attention that it might deserve. In many cases DIAF is asymptomatic and paroxysmal and patients recover sinus rhythm spontaneously, but sometimes, DIAF persists, and it is necessary to perform a cardioversion. Furthermore, DIAF is not mentioned in clinical guidelines on the treatment of AF. The risk of DIAF increases in elderly and in patients treated with polypharmacy and with risk factors and comorbidities that commonly coexist with AF. This is the case of cancer patients. Under these circumstances ascribing causality of DIAF to a given drug often represents a clinical challenge. We review the incidence, the pathophysiological mechanisms, risk factors, clinical relevance, and treatment of DIAF. Because of the limited information presently available, further research is needed to obtain a deeper insight into DIAF. Meanwhile, it is important that clinicians are aware of the problem that DIAF represents, recognize which drugs may cause DIAF, and consider the possibility that a drug may be responsible for a new-onset AF episode.

Acetylcholine (ACh) was administered for 3 min in the ENCORE study, while the Japanese Circulation Society guidelines recommended the 20 s ACh injection as an ACh test.

We compared the ischemic findings between ACh administration for 3 min and ACh injection for 20 s in the same patients and in the same ACh doses without administration of nitrates in the left coronary artery.

We investigated 30 patients with ischemic heart disease (25 men, 67 ± 10 years, ACh 50 μg: 3, ACh 100 μg: 9, ACh 200 μg: 18) by the above two ACh injection procedures. Temporary pacemaker was inserted and set at the rate of 40/min. Positive provoked spasm was defined as transient ≥90% narrowing and typical chest symptoms or ischemic electrocardiographic (ECG) changes.

Provoked spasm was observed in 22 patients with ACh 20 s injection, while 10 patients had provoked spasm by ACh 3 min administration (73.3% vs. 33.3%, p < 0.05). Ischemic ECG changes (50.0% vs. 23.3%, p < 0.05) and chest symptoms (73.3% vs. 43.3%, p < 0.05) were significantly higher with ACh 20 s injection than ACh 3 min administration. Pacemaker rhythm was recognized in 19 patients with ACh 20 s injection, whereas 7 patients with ACh 3 min administration had a pacemaker rhythm (63.3% vs. 23.3%, p < 0.01). Maximal ST elevation by ACh 20 s injection was significantly higher than that by ACh 3 min administration (0.47 ± 0.94 vs. 0.13 ± 0.51, p < 0.05), while maximal ST depression was not different between the two procedures. Coronary artery diameter after ACh 20 s injection was significantly lower than that after ACh 3 min administration in the left anterior descending artery.

ACh administration procedures (3 min or 20 s injection) may influence the ischemic findings in spasm provocation testing.

Abnormal coronary response on acetylcholine test is observed in patients with early coronary atherosclerosis.

We analyzed retrospectively the abnormal response rate during 17 years of spasm provocation tests in 2093 consecutive patients.

We performed 2093 spasm provocation tests, consisting of 1198 acetylcholine tests and 895 ergonovine tests, between January 1991 and December 2007. Spasm provocation test was mainly performed in patients with ischemic heart disease. Abnormal response was defined as transient >90% luminal narrowing during spasm provocation tests. We classified these 17 years into two periods: former period from January 1991 to December 2000, and the latter period from January 2001 to December 2007. In the former period, 1300 spasm provocation tests were performed and 793 spasm provocation tests were done in the latter period.

The incidences of hypertension, dyslipidemia, and diabetes mellitus were significantly increased in the latter period. The values of total cholesterol, triglycerides, and fasting blood sugar were also significantly increased in the latter period. The frequency of abnormal response in the latter period was significantly higher than that in the former period (46.0% vs. 33.2%, p < 0.05). The frequency of abnormal coronary response to acetylcholine in the latter period was significantly higher than that in the former period (60.0% vs. 34.0%, p < 0.01), whereas there was no difference concerning abnormal response of ergonovine between the two periods (31.9% vs. 30.7%, ns).

In Japanese patients, abnormal coronary response to acetylcholine has increased and coronary endothelial dysfunction is suggested to have progressed.

We examined some recommendations for performing acetylcholine (ACh) tests safely.

We performed 1000 ACh tests from 1991 to December 2004. ACh was injected in incremental doses of 20/50/80 μg into the RCA and of 20/50/100 μg into the LCA. During these periods, we encountered various major/minor complications; 12 ventricular tachycardia (1.2%) necessary one dc, one ventricular fibrillation (0.1%) necessary dc, 3 shock like the left main stem spasm (0.3%), one cardiac tamponade necessary surgical drainage (0.1%), and 164 Paf (164/959:17.1%) necessary administration of antiarrhythmic agents to sinus rhythm in about one third patients (31.7%). We did not experience irreversible severe complications, such as acute myocardial infarction or death.

(1) Stand by direct current with pasting, (2) Thump version when ventricular tachycardia or fibrillation occurred, (3) Over infusion to avoid hypovolemia, (4) Perform angiography before complete spasm provocation if a severe spasm, (5) Drainage if cardiac tamponade occurred, (6) Cibenzoline or disopyramid administration when ACh induced paroxysmal atrial fibrillation, (7) Incremental ACh dose up should be performed, (8) Administer small amount of noradrenaline if shock observed and (9) Test shot should be performed before 1-min angiography.

We recommend STOP DCIAT for performing ACh tests safely.

Atrial fibrillation (AF) is the most common sustained rhythm disorder observed in clinical practice and predominantly associated with cardiovascular disorders such as coronary heart disease and hypertension. However, several classes of drugs may induce AF in patients without apparent heart disease or may precipitate the onset of AF in patients with preexisting heart disease. We reviewed the literature on drug-induced AF, using the PubMed/Medline and Micromedex databases and lateral references. Successively, we discuss the potential role in the onset of AF of cardiovascular drugs, respiratory system drugs, cytostatics, central nervous system drugs, genitourinary system drugs, and some miscellaneous agents. Drug-induced AF may play a role in only a minority of the patients presenting with AF. Nevertheless, it is important to recognize drugs or other agents as a potential cause, especially in the elderly, because increasing age is associated with multiple drug use and a high incidence of AF. This may contribute to timely diagnosis and management of drug-induced AF.