Under an American Heart Association grant, researchers at Vanderbilt University Medical Center are exploring a new therapeutic for patients with structural heart disease and ventricular tachycardia (V-tach) who cannot take class IC antiarrhythmic drugs, such as flecainide and propafenone.
William Stevenson, M.D., director of the Cardiac Arrhythmia Clinical Research Program at the Vanderbilt Heart and Vascular Institute, is leading the clinical trial on dantrolene – a drug FDA approved to treat malignant hyperthermia – for patients who undergo ablation procedures for V-tach. Benjamin Shoemaker, M.D., an electrophysiologist and assistant professor of medicine at Vanderbilt, will conduct the trial.
“Over 400,000 sudden cardiac deaths occur per year in the U.S. in patients with coronary artery or structural heart disease, but most of our antiarrhythmic drugs can’t be used in these patients,” Shoemaker said. “This study seeks to provide evidence for a new class of antiarrhythmic drugs to address this problem.”
“Over 400,000 sudden cardiac deaths occur per year in the U.S. in patients with coronary artery or structural heart disease, but most of our antiarrhythmic drugs can’t be used in these patients.”
The randomized, controlled trial will enroll a total of 82 patients. “To date, we have conducted a small pilot study of five patients to refine our protocol, demonstrate safety and confirm that the innovative data collection methods we are using are sound,” Shoemaker said.
Added Stevenson, “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. We are also going to be assessing how dantrolene affects other electrical properties of the heart that can influence arrhythmias.”
Dantrolene Spares Sodium Channels
Flecainide is a “go-to” medication for most patients with cardiac arrhythmias. However, for patients with cardiomyopathy or other structural heart disease, it can be dangerous.
Flecainide inhibits calcium channels, making it an effective therapy for patients with a rare genetic disorder called catecholaminergic polymorphic ventricular tachycardia, but as Shoemaker explained, since its primary effect is on sodium channel cycling, it raises risk of lethal arrhythmias for patients with structural heart disease. Dantrolene holds promise for these patients because it is not a sodium channel inhibitor.
Historically, dantrolene could only be administered intravenously with very large fluid volumes, preventing its potential use in heart failure. The FDA has now approved a new 15 milliliter nanosuspension, enabling the team to test their hypothesis in a clinical trial.
Learning Bonus for Anesthesiologists
Since dantrolene is normally used to treat a rare, genetically-based side effect of some anesthetics, the study has a side benefit.
“Anesthesiologists often get questions about dantrolene on their board exams, yet many go decades without ever needing to use the drug,” Shoemaker said. “Now, they are engaged in a substudy that enables them to analyze the effect of dantrolene on respiratory and skeletal muscle strength in real patients who are under anesthesia, but not acutely ill with malignant hyperthermia.”
Because it acts systemically, dantrolene’s effects on the musculoskeletal and other systems will need to be understood and weighed against the drug’s benefits. Addressing this potential downside for some patients, Bjorn Knollman, M.D., a professor of medicine and pharmacology at Vanderbilt, has developed an RyR2 inhibitor that selectively targets abnormal calcium release in the heart without blocking sodium channels or having a systemic impact.
Knollman is currently testing the compound in mouse models and collaborating with researchers at George Washington University to run tests on explanted human hearts.