ATRIAL FIBRILLATION

Atrial fibrillation is the most common persistent cardiac arrhythmia, with an estimated prevalence of 2.2 million patients in the United States, and approximately 160,000 new cases diagnosed in the United States each year. Atrial fibrillation is associated with aging, with approximately 9% of all individuals over the age of 80 affected by the disorder. There are two alternative treatment strategies for patients with atrial fibrillation: (i) control of the ventricular heart rate and anticoagulation; and (ii) restoration of the normal cardiac rhythm.



The first treatment strategy is directed at treating the complications of atrial fibrillation, primarily a rapid ventricular heart rate, decreased cardiac output and the risk of blood clot formation. Physicians use a variety of drugs, including beta blockers, calcium channel blockers and digitalis, to control the ventricular heart rate response to atrial fibrillation and improve cardiac output. These drugs are associated with a number of side effects, including lowered blood pressure, fatigue and depression. Because the underlying cardiac rhythm with these treatments remains atrial fibrillation, physicians must also use anticoagulants, such as warfarin, to prevent the formation of blood clots in the atria. The utility of this treatment approach is limited by (i) the risk of bleeding complications associated with anticoagulation therapy, which must therefore be closely monitored by blood tests, and (ii) suboptimal improvement in cardiac output.

An alternative treatment strategy is directed at restoration of the normal cardiac rhythm. If it can be accomplished safely, restoration of the normal cardiac rhythm is preferable to management through anticoagulation and control of the ventricular heart rate. Restoring normal rhythm avoids the risks associated with anticoagulation therapy and often results in a more significant improvement in cardiac output. Currently available antiarrhythmic drugs for the conversion of atrial fibrillation to the normal cardiac rhythm include dofetilide, amiodarone and sotalol. In addition, the normal cardiac rhythm can also be restored through the application of an electrical shock to the chest wall or directly to the heart, called electrical cardioversion.

Many currently available therapeutic options for restoring normal cardiac rhythm are associated with potentially serious side effects. Because many currently available antiarrhythmic drugs lack specificity for atrial myocytes, they may induce life-threatening arrhythmias in the ventricles, including torsade de pointes, which can occur in as many as 1 to 5% of patients treated with some of these medications. In addition, many of these drugs are also associated with other potentially serious side effects.

Together with our collaborator, Bristol-Myers Squibb, we have developed a small molecule ion channel inhibitor that targets a particular potassium channel located on the membrane of atrial but not ventricular cardiac cells to restore and maintain normal cardiac rhythm without inducing ventricular arrhythmias.



BMS is developing this compound, which is currently in preclinical studies for the chronic treatment of atrial fibrillation. The BMS atrial fibrillation compound is taken orally and is being developed for once-a-day or twice-a-day dosing.

In preclinical studies this compound:

• extended the refractory period in atrial myocytes in vitro without affecting that of ventricular myocytes;
• did not increase the incidence of life threatening ventricular arrhythmias; and
• demonstrated an acceptable safety and toxicity profile.