Brief report

N-Acetyl procainamide causing torsades de pointes

Many antiarrhythmic drugs inhibit potassium currents, particularly the rapid component of the delayed rectifier potassium current (I_Kr). Some antiarrhythmic drugs also inhibit other potassium channels, including the slow component of the delayed rectifier potassium current (I_Ks), the inward rectifier potassium current (I_K1) and the transient outward current (I_to). Inhibition of these currents delay ventricular repolarization, which can prolong the QT interval and increase the risk of torsades de pointes (TdP). In addition, some antiarrhythmic drugs also augment late sodium current (I_Na-L), which also prolongs ventricular repolarization and increases the risk of TdP. Antiarrhythmic agents that prolong the QT interval and are associated with an increased risk of TdP include Vaughan Williams class IA drugs (quinidine, procainamide, disopyramide), class IC agents (flecainide, propafenone), and class III drugs (ibutilide, dofetilide, sotalol, amiodarone, dronedarone).

A 65-year-old male on hemodialysis three times a week due to end-stage renal failure underwent cardiac surgery one year previously, and complained of breathlessness on exertion after surgery. Echocardiograms evidenced a significant obstruction in the left ventricular outflow with intraventricular pressure gradient of 62 mmHg, and the patient was started on beta-blocker. After a maximal dose of carvedilol was given, a class 1A antiarrhythmic drug of Na channel blocker, procainamide, was added because of insufficient relief of symptoms. Electrocardiogram (ECG) showed prolonged QT intervals (523 ms) on a regular visit one month after the administration of procainamide, and the dose of procainamide was decreased. On the next day, he was brought to our hospital due to cardiac pulmonary arrest. Initial rhythm was ventricular fibrillation and the corrected QT intervals (QTc) were prolonged (531 ms). Blood examination revealed that N-acetyl procainamide (NAPA), metabolite of procainamide, was significantly higher than the recommended threshold. NAPA was identified as the cause of prolonged QTc and procainamide was stopped. NAPA decreased under the recommended threshold on the seventh day and the QT intervals were normalized. This case report outlines the first case of long QT syndrome caused by NAPA in a hemodialysis patient.

<Learning objective: Administration of procainamide could be dangerous even in patients undergoing hemodialysis whose serum procainamide level is within normal limits. We should pay careful attention to it and must not forget to measure the concentrations of procainamide and NAPA. The measurement of QT intervals could help to avoid a fatal side effect.>

Long QT syndrome (LQTS) is characterized by abnormal prolongation of the QT interval on the surface electrocardiogram associated with risk of polymorphic ventricular arrhythmia, torsades de pointes (TdP), and sudden cardiac death. Causes of LQTS may be congenital (e.g. autosomal dominant Romano-Ward syndrome) or acquired upon exposure to environmental triggers such as particular medications. Increasing numbers of causative mutations for congenital LQTS have been identified. Drugs are the commonest cause of acquired LQTS and it is thought that there is also a significant heritable component to drug-induced LQTS. Over the years, several drugs have been withdrawn due to QT prolongation and arrhythmia.

Here we discuss LQTS, its public health implications, future directions and perspectives including pharmacogenomic studies and new drug development. More detailed characterization of the genetics of congenital and drug-induced LQTS will allow improved evaluation of personalized risk, and better inform patient management in the future.

Syncope is generally benign but when it is due to an underlying cardiovascular condition, the prognosis can be guarded. Patients with syncope may be at risk of dying suddenly from a ventricular arrhythmia especially if the collapse is caused by a poorly-tolerated, self-terminating, ventricular tachycardia (VT). If a similar VT recurs, and persists, it could initiate cardiac arrest, leading to sudden cardiac death. However, distinguishing which patient with syncope may benefit most from implantable cardioverter defibrillator (ICD) therapy, which can stop life-threatening and poorly tolerated VT, thereby preventing sudden cardiac death, remains an ongoing challenge. Careful assessment of the patient's underlying cardiovascular conditions, scrupulous attention to historical detail to assess potential causes for syncope, and risk stratification based upon clinical characteristics and short and long-term risks can help. This review focuses on the sudden death risk in patients with syncope and explores the role of the ICD to treat ventricular arrhythmias, prevent symptoms, and prevent death.

Drug-induced long QT syndrome is characterized by a prolonged corrected QT interval (QTc) and increased risk of a polymorphic ventricular tachycardia known as torsade de pointes (TdP). We review mechanisms, predispositions, culprit agents, and management of this potentially fatal phenomenon. Virtually all drugs that prolong QTc block the rapid component of the delayed rectifier current (I_kr). Some drugs prolong QTc in a dose-dependent manner, others do so at any dose. Most patients that develop drug-induced TdP have underlying risk factors. Female sex is the most common. Implicated drugs include class 1A and III antiarrhythmics, macrolide antibiotics, pentamidine, antimalarials, antipsychotics, arsenic trioxide, and methadone. Treatment for TdP includes immediate defibrillation for hemodynamic instability and intravenous magnesium sulfate. Potassium levels should be maintained in the high normal range, and all QT prolonging agents must be promptly discontinued.

Limitations in understanding of arrhythmias stem from lack of animal models which serve as surrogates for man. The purpose of this review is to discuss iatrogenic and naturally occurring animal models that are useful in our understanding of the mechanisms of ventricular arrhythmia and of antiarrhythmic and proarrhythmic agents. It is not surprising however that some information obtained from studies on infrahuman mammals may not be extrapolated to man. Need for anesthesia affects profoundly the electrophysiology of the heart, including autonomic affects. Most of the animal are modification of the Harris' 2-stage model. A model proposed by Schwartz, Billman and Stone has evolved as one that produces arguably the most information on the pathophysiology of arrhythmia production, including the role of the autonomic nervous system and the interaction with pharmacological agents. Intoxication with digitalis and escalating doses of epinephrine are commonly used models for production of ventricular arrhythmias. No matter what model of ventricular arrhythmias is used, programmed electrical stimulation can be useful to uncover increased tendency for arrhythmia, even if no arrhythmia occurs spontaneously. Models of spontaneous ventricular arrhythmia occur in German shepherd puppies, Boxer dogs, Doberman pinchers with dilated cardiomyopathy, and in large dogs with gastric dilatation or splenic torsion. Models are necessary because they allow for controlled studies and methods of exploration impossible, for legal and ethical reasons, in humans. Nonetheless, ethical considerations in using animal models are still important, and there is a continual search for non-animal models to explore ventricular arrhythmias.