A Clinical Trial Utilizing Dantrolene in Patients With Ventricular Arrhythmias.

A Randomized Controlled Trial of RyR2 Inhibition With Dantrolene and Susceptibility to Ventricular Arrhythmias in Patients With Structural Heart Disease.

This is a randomized, placebo controlled trial of Dantrolene (N= 84 participants) to demonstrate the feasibility of using I.V. dantrolene to study the effect of RyR2 inhibition on cardiac electrophysiology, hemodynamics and ventricular arrhythmia inducibility in patients with structural heart disease referred for VT ablation. The investigators will also explore the pharmacokinetic/pharmacodynamic relationship of I.V. dantrolene and it short-term effect on specific cardiac electrophysiologic and hemodynamic parameters.

The hypothesis to be tested is that RyR2 hyperactivity in patients with structural heart disease drives proarrhythmic changes in refractoriness and conduction, and decreases cardiac contractility, which promotes VT/VF. Dantrolene, a currently available drug that inhibits RyR2, but has no Na or K channel activity, will be used as a tool to study RyR2 modulation. The investigators propose a randomized controlled trial of dantrolene versus placebo in patients with structural heart disease referred for VT ablation to evaluate electrophysiologic, hemodynamic, and arrhythmia prevention endpoints. Dantrolene's inhibition of RyR1 will also be studied to define its effect on muscle and respiratory strength in this clinical population, which will be important if dantrolene is to be considered for repurposing as an antiarrhythmic drug. The two aims are: Aim 1: To conduct a randomized, placebo-controlled trial of dantrolene to study the effect of RyR inhibition on cardiac electrophysiology, hemodynamics, arrhythmia inducibility, muscle strength, and respiratory mechanics in patients with structural heart disease referred for VT ablation. Aim 2: To explore the pharmacokinetic/pharmacodynamic relationship of I.V. dantrolene and its short-term effect on cardiac electrophysiology, hemodynamics, and muscle and respiratory strength.

84 participants will be randomly assigned in a 2:1 ratio to treatment (dantrolene) or control (placebo). A computer-generated randomization list will be prepared by the study statistician using the stratified permuted block randomization, where block size varies randomly from 4 or 6 to ensure overall balance across treatment arms. Randomization will be stratified by 1) documented CAD with prior infarct, 2) amiodarone use within the past 21 days defined as chronic oral use or >5 grams cumulative, 3) LVEF <35%. Enrollment will be evenly distributed across the two study arms by the stratification factors

The study statistician will generate the allocation schedule but will remain blinded to the treatment assignment as well as the study staff physician's. The research clinician will not be blinded.

Dantrolene/Ryanodex; intravenous administration of dantrolene; 1 mg/ kg IV over 3 minute, one time dose

Post drug ventricular stimulation with RV ventricular catheter in the RV apex with increasing extra stimuli with planned decrement stimuli by 10 ms to ERP. Outcome is measured as Ventricular inducibility yes/no.

measured as ordinal variable for stage of ventricular stimulation protocol;specific step by step V-stim research protocol will be followed with single extra stimuli up to six extra stimuli added to VERP. What stage of Inducible VT will be recorded.

post drug infusion at 5 minutes,10 minutes,15 minutes, 20 minutes, 1-4 hours, 6-12 hours,16-24 hours and optional 28-36 hours

Post drug infusion at 5 minutes, 10 minutes, 15 minutes, 20 minutes, 1-4 hours, 6-12 hours,16-24 hours and optional 28-36 hours

Post drug infusion at 5 minutes, 10 minutes, 15 minutes, 20 minutes, 1-4 hours, 6-12 hours,16-24 hours and optional 28-36 hours

post drug infusion at 5 minutes, 10 minutes, 15 minutes, 20 minutes, 1-4 hours, 6-12 hours,16-24 hours and optional 28-36 hours

Train of four stimulation test measured as a % of the fourth stimulation compared to the first (unitless, % change)

Arterial blood concentrations of sodium, chloride, potassium, ionized calcium, bicarbonate, glucose, and lactate measured in SI ) international system of units.

Inclusion Criteria: Greater than or equal to 18 years of age Able to give written informed consent Referred for catheter-based VT ablation Structural heart disease (cardiomyopathy or RV/LV scar) Permanent pacemaker or implantable cardioverter defibrillator Exclusion Criteria: Mechanical ventricular support (e.g. LVAD, ECMO) NYHA class IV heart failure LVEF < 20% Morbid obesity (BMI > 40 kg/m2) Severe renal insufficiency (GFR<30 mL/min) Chronic liver disease (Child Pugh class A-C) Current use of calcium channel blockers Neuromuscular disorder (e.g. muscular dystrophy) Chronic obstructive pulmonary disease or restrictive lung disease requiring oxygen Therapy or history of intubation Pregnant or nursing History of dysphagia