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Logo of thijTexas Heart Institute JournalSee also Cardiovascular Diseases Journal in PMCSubscribeSubmissionsTHI Journal Website
Tex Heart Inst J. 2010; 37(4): 476–479.
PMCID: PMC2929852

Syncope, Widened QRS Interval, and Left Ventricular Systolic Depression Coincident with Propafenone Therapy for Atrial Fibrillation


We report the case of a 46-year-old man who developed syncope, a widened QRS interval, and depressed left ventricular systolic function during propafenone therapy for atrial fibrillation. These acute findings may have been consequent to an increased dosage of propafenone combined with heavy alcohol consumption that led to decreased metabolism of propafenone. In addition, propafenone is known to interfere with liver function, although this patient's test results showed scant evidence of liver abnormalities. Yet another possible factor is the genetic spectrum in the metabolism of propafenone and other class I antiarrhythmic agents. When propafenone is prescribed, we recommend advising patients that alcohol consumption and interactions with other drugs can lead to increased levels of the antiarrhythmic agent, with resultant toxicity that can lead to adverse cardiovascular effects. Patients taking propafenone should also undergo periodic liver function testing. Finally, attention should be paid to voluntary or official recalls of specific antiarrhythmic medications that are of unreliable quality or potency.

Key words: Anti-arrhythmia agents/administration & dosage/adverse effects, atrial fibrillation/diagnosis/drug therapy/etiology/prevention & control, cytochrome P-450 CYP2D6/genetics, dose-response relationship, drug, heart/drug effects, liver/enzymology/metabolism, propafenone/administration & dosage/adverse effects/therapeutic use

Herein, we report the case of a patient with previously near-normal left ventricular (LV) systolic function and normal QRS duration who, while on propafenone therapy because of atrial fibrillation, developed syncope, marked QRS widening, and depressed LV systolic function. We describe our treatment of the patient, discuss mechanisms that could have contributed to the onset of the acute findings, and present recommendations.

Case Report

In July 2008, a 46-year-old man (body weight, 220 lb) underwent emergency treatment for an initial episode of atrial fibrillation. His medical history included hypertension, and he had undergone aortic valve replacement in the 1980s because of congenital aortic stenosis. An earlier baseline electrocardiogram (ECG) had shown sinus rhythm (Fig. 1). At this presentation, his LV ejection fraction was 0.50. The atrial fibrillation was successfully treated by means of transesophageal echocardiographic (TEE)-guided cardioversion. He was released from the hospital with instructions to take diltiazem, metoprolol, and simvastatin.

figure 18FF1
Fig. 1 Baseline electrocardiogram shows sinus rhythm.

In early January 2009, the patient experienced a recurrence of atrial fibrillation, for which he was prescribed 325 mg of propafenone twice daily. After 3 weeks, the dosage was increased to 425 mg twice daily. Coincident to the dosage increase, he experienced increasing exertional dyspnea, for which furosemide was prescribed.

In mid-February, 3 weeks into the new propafenone regimen, the patient drank 8 beers and 2 alcoholic mixed drinks at an evening party. Upon awakening in the morning, he was very short of breath, experienced syncope while standing, and fell, sustaining a subdural hematoma and a 3-cm laceration in the parietal scalp. At the emergency room, he was alert, oriented, and in no acute distress, with blood pressure of 106/84 mmHg and a pulse rate of 84 beats/min. Electrolyte levels and most laboratory values were within normal limits. Hepatic test results were total bilirubin, 1.1 mg/dL (normal range, 0.3–1.1 mg/dL); alanine aminotransferase, 29 U/L (normal range, 1–45 U/L); and aspartate aminotransferase, 46 U/L (normal range, 1–36 U/L). Propafenone levels were not determined, because the hospital's laboratory lacked the ability to perform this test. A 12-lead ECG showed sinus rhythm at 91 beats/min, a markedly widened QRS interval (360 msec), and left bundle branch block morphology (Fig. 2). A bedside echocardiogram showed severe LV systolic dysfunction (ejection fraction, 0.20). He was admitted to the cardiac care unit for observation. The propafenone was discontinued. On the 2nd day, monitoring revealed atrial flutter with variable contraction, LV hypertrophy, and left-axis deviation; in addition, the QRS interval gradually decreased to 142 msec (Fig. 3). On the 3rd day, the patient underwent TEE-guided cardioversion with successful conversion to sinus rhythm on ECG (Fig. 4). The next day, TEE showed moderate LV systolic dysfunction (ejection fraction, 0.35). An implantable defibrillator was not considered at this time, because the patient's heart function had improved considerably during the short hospital stay. However, because of an arrhythmogenic substrate, as evidenced by the extreme QRS widening while the patient was taking propafenone, an electrophysiologic study was recommended in order to rule out ventricular tachycardia inducibility. The patient declined the study and was discharged from the hospital with instructions not to take propafenone. A month later, at a follow-up examination, the patient had normal LV function and was doing well.

figure 18FF2
Fig. 2 Electrocardiogram shows sinus rhythm, a substantially widened QRS interval, and a left bundle branch block morphology.
figure 18FF3
Fig. 3 Electrocardiogram shows atrial flutter and decreased QRS interval after the discontinuation of propafenone.
figure 18FF4
Fig. 4 After echocardiographic-guided cardioversion, electrocardiogram shows sinus rhythm.


Our patient—with previously near-normal LV systolic function and a normal QRS interval—presented with syncope, widened QRS, and depressed LV systolic function during therapy with propafenone for atrial fibrillation. These findings may have been consequent to propafenone toxicity that resulted from the recently increased dosage of that drug, in conjunction with a decreased metabolism of propafenone. The patient reported drinking socially and no chronic alcohol abuse; however, he had slightly abnormal hepatic test results. This may have been due to alcohol toxicity or to a hepatotoxic effect of propafenone, a drug that is known to produce hepatocellular injury and acute cholestatic hepatitis due to an unknown mechanism.1,2 The patient's condition rapidly improved after the discontinuation of propafenone. Because his LV systolic function improved so quickly, tachycardia-induced cardiomyopathy was unlikely; furthermore, the patient had been mechanically monitoring his own heart rate daily and reported no reading faster than 80 beats/min.

The mechanism underlying the syncope in this patient is unclear. However, the depressed LV systolic function and the extremely widened QRS interval could have been the substrate for ventricular arrhythmia. Other possible causes of the syncope are propafenone-associated heart block or bradycardia, orthostatic hypotension, vasovagal syndrome (in the setting of heavy alcohol consumption), and 1:1 atrial flutter (heart rate, 250–350 beats/min). Because the patient had been taking 2 atrioventricular-nodal-blocking agents and his heart rate was normal, atrial flutter was not likely to be the cause of syncope.

This case suggests a rare manifestation of propafenone toxicity. The patient was taking the highest appropriate dosage of propafenone—425 mg twice daily—for his body weight. It is unclear whether it is necessary to test for a therapeutic range of propafenone.

Propafenone is a Class 1C antiarrhythmic drug that reduces the conduction velocity of the fast inward sodium current.3 The drug is metabolized in the liver by the cytochrome P-450 2D6 enzyme. Alcohol inhibits cytochrome P-450, thus reducing the metabolism of certain drugs, including propafenone.4 One day before being admitted to the hospital, our patient had consumed a substantial amount of alcohol, which could have caused a transient elevation in propafenone levels secondary to a decrease in the metabolism of propafenone through inhibition of the cytochrome P-450 system. Moreover, approximately 1% to 10% of the population lacks the CYP2D6 enzyme that is necessary for appropriate propafenone metabolism.5

There are 2 genetically determined patterns of propafenone metabolism. It has been shown that CYP2D6 genotypes play an important role in plasma levels and in the effects of propafenone.6 Patients with the homozygous mutant of CYP2D6*10 not only had a Cmax of propafenone twice as high as that in patients who had a wild-type genotype, but also showed a 2-fold higher inhibitory rate of ventricular premature contractions. In more than 90% of patients, the drug is rapidly and extensively metabolized (elimination half-life, 2–10 hr).7 In persons with slow metabolism, propafenone pharmacokinetics are linear. Plasma concentrations of propafenone differ substantially in slow versus extensive metabolism: at dosages of 675 to 900 mg/d, concentrations in slow metabolism are 1.5 to 2 times higher than those in extensive metabolism. At low dosages, the differences are greater: concentrations in slow metabolism are more than 5 times higher than those in extensive metabolism. Propafenone toxicity can cause substantial QRS widening and markedly abnormal ventricular activation patterns. Aberrant ventricular activation, upon resolution, produces persistent T-wave changes that have been called “cardiac memory.”8

Studies in human beings have shown that propafenone exerts a negative inotropic effect on the myocardium. The effect is also dose-dependent with worsening heart failure as the dose of propafenone increases.2 Cardiac catheterization studies using intravenous propafenone infusions in patients with moderately impaired ventricular function have shown significant increases in pulmonary capillary wedge pressure and in systemic and pulmonary vascular resistances, and depression of cardiac output and cardiac index. Furthermore, in a study by Baker and colleagues,9 a mean daily dosage of 879 mg of propafenone resulted in a statistically significant decrease (P <0.05) in resting LV ejection fraction, from 0.52 to 0.48.

We believe that our patient's acute condition resulted primarily from an increased dosage of propafenone in combination with heavy alcohol consumption that led to decreased metabolism of propafenone. Interaction between the alcohol, the increased propafenone dosage, and his other medications is also possible.4 Propafenone has been shown to interfere with liver function; however, the patient's test results showed no significant liver abnormalities. It is not inconceivable that the genetic spectrum in the metabolism of propafenone and other class I antiarrhythmic agents is another factor. Finally, in view of recent voluntary recalls10,11 and official recalls12 of medications due to irregularities during manufacturing, it is possible that our patient's dosage of this medication was higher than necessary.

We recommend advising patients who are prescribed propafenone that alcohol consumption and interactions with other drugs may cause an increase in propafenone levels, with resultant toxicity that can lead to adverse cardiovascular effects. Patients taking propafenone should undergo periodic liver function testing. Attention should also be paid to recalls of specific antiarrhythmic medications that have caused or may cause patients to experience adverse side effects.


Address for reprints: Rodney A. Samaan, MD, MPH, Cardiology Division, Richmond University Medical Center, 355 Bard Ave., Staten Island, NY 10310

E-mail: moc.liamg@naamas.yendoR


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