Calming Rogue Calcium Cycling Behind Ventricular Arrhythmias

New calcium inhibitors may turn the tide in structural heart disease.

About one in 10,000 people have catecholaminergic polymorphic ventricular tachycardia (CPVT), a genetic disease caused by mutations in cardiac calcium release channels, that makes them prone to ventricular fibrillation (V-fib) and sudden cardiac death. For these patients, flecainide, a calcium release channel inhibitor, is a life-saving drug.

For patients with structural heart disease from remodeling after a heart attack or cardiomyopathy, however, flecainide can be dangerous. Other drugs specific for normalizing calcium cycling in the heart offer new hope. Under an American Heart Association grant, researchers at Vanderbilt University Medical Center are exploring new therapeutics for CPVT and arrhythmias.

Bjorn Knollmann, M.D., professor of medicine at Vanderbilt and pioneer in calcium cycling research, is leading one arm of the research, testing a compound he developed specific for cardiac calcium handling. William Stevenson, M.D., a Vanderbilt specialist in arrhythmia and electrophysiology, is leading the other arm, a clinical trial of dantrolene, a drug approved for malignant hyperthermia in ablation patients.

Seeking a Treatment for Damaged Hearts

Arrhythmias in CPVT are caused by hyperactive calcium cycling, that causes heart muscle cells to depolarize independent of the normal conduction pathways. This can trigger ventricular tachycardia (V-tach), V-fib and sudden cardiac death.

Cellular studies of tissue from explanted human hearts indicate that similar aberrant calcium cycling occurs in patients at risk for V-tach/V-fib who do not have CPVT, but rather, whose hearts are damaged by disease. “We know that there is an association between abnormal calcium cycling and cardiac remodeling in structural heart disease,” Knollmann said. “We need to determine if a selective calcium release inhibitor can effectively treat ventricular arrhythmias in these patients.”

“We need to determine if a selective calcium release inhibitor can effectively treat ventricular arrhythmias in these patients.”

Flecainide, which helps CPVT patients, is not an answer for this population because it inhibits not only calcium release channels, but also sodium channels, causing arrhythmias. Dantrolene, which is not a sodium channel inhibitor, holds promise. However, since it acts systemically, its effects on the musculoskeletal and other systems need to be understood and weighed against the drug’s benefits.

The Ryanodine Receptor Study Arm

Knollmann’s compound is designed to selectively target abnormal calcium release in the heart without blocking sodium channels and without systemic impact. He is currently testing the compound in mouse models and also collaborating with researchers at George Washington University to run tests on explanted human hearts.

“Among the myriad of remodeling changes that occur in damaged human hearts, we have found that the calcium release channel called type 2 ryanodine receptor (RyR2) is hyperactive,” Knollmann said. “By testing this new selective RyR2 inhibitor, we want to learn whether or not RyR2 hyperactivity actually contributes to the arrhythmias in those patients.”

The Dantrolene Study Arm

Stevenson hypothesizes that dantrolene, an FDA-approved drug that inhibits calcium release channels in heart and skeletal muscle, will be effective in calming arrhythmias. Historically, dantrolene could only be administered intravenously with very large fluid volumes, preventing its potential use in heart failure. Recently, however, the FDA approved a new 15 milliliter nanosuspension, enabling Stevenson’s hypothesis to be tested in a clinical trial.

Stevenson plans to enroll 80 patients undergoing catheter ablation for ventricular arrhythmias. Study participants will receive either dantrolene or placebo.

“If we give the medication and it’s no longer provocable, that will be evidence supporting benefit.”

“Many of these patients have provocable V-tach. If we give the medication and it’s no longer provocable, that will be evidence supporting benefit,” Stevenson said. “We are also going to be assessing how dantrolene effects other electrical properties of the heart that can influence arrhythmias.”

Safe Inhibitors

Flecainide has enabled many young people with CPVT to lead more normal lives, either free of an implanted ventricular defibrillator or with a reduction in the number of shocks provoked by arrhythmias.

If dantrolene or the new compound are found effective and safe, the number of people who stand to benefit is enormous. About 100,000 people in the U.S. receive a ventricular defibrillator implant each year and most of them have structural heart disease. Without a current alternative, the stakes for new drug approval are high.