Abstract 4135425: Add-on Therapy with Dantrolene, a RyR2 Stabilizer, Terminates Ventricular Tachycardia Storm refractory to Intravenous Amiodarone in Heart Failure.

Background: Aberrant diastolic Ca 2+ leak through the cardiac ryanodine receptor (RyR2) is an important cause of heart failure (HF) and lethal arrhythmia. Dantrolene (DAN) specifically binds to the Leu 601- Cys 620 of N terminal domain in RyR2 and stabilizes the tetrameric structure of RyR2, preventing the Ca 2+ leak through RyR2. Our previous study as a proof-of-concept showed that intravenous injection (i.v.) of DAN was effective in termination and prevention of refractory ventricular tachycardia (VT) storm in HF. Research Question: How much is loading dose of DAN i.v. to terminate VT storm in HF? We hypothesized that the optimal dose was within 3mg/kg from our previous study. Aim: This study aimed to verify that 3mg/kg DAN i.v. was optimal for the termination of amiodarone-resistant VT storm in HF. Methods: This was an open-label, uncontrolled, single-center study. The detail in the study design and methods is shown in Fig.1 . We studied patients with episodes of VT storm regardless of medications, such as amiodarone and beta-blockers, recommended by HF guidelines. DAN(3mg/kg) was intravenously added on the above guideline treatment. The acute anti-arrhythmic efficacy of DAN was assessed as follows: 1) proportion of patients whose VT storm was terminated by 3mg/kg DAN i.v., 2) incidence rate of VT storm within 24 hours before and after DAN i.v.. Results: The consecutive 7 patients with refractory VT storm were enrolled in this study (median age:72 years old, male/female: 4/3, median LVEF29%). Underlying heart disease included 3 ischemic cardiomyopathy, 3 acute myocardial infarction after successful percutaneous coronary intervention and 1 tachycardia-induced cardiomyopathy. 2 of 7 patients underwent mechanical circulatory support before DAN i.v. because of pulseless VT. All patients were classified as NYHA class III/IV. 3 mg/kg of DAN i.v. ceased VT storm within 60 min in 7/7 (100%) (Fig.2, left). The number of sustained VT within 24 h after DAN i.v. were significantly lower than those within 24 h prior to DAN administration (Fig 2, right) . A representative case is shown in Fig.3 The VT storms refractory to amiodarone and landiolol (beta-blocker) as well as sedation showed complete response to 3mg/kg DAN i.v.. Conclusions: DAN, a RyR2 stabilizer, was effective in the termination of VT storm in HF resistant to guideline directed medical treatment. This is the first study to evaluate the optimal dose of DAN i.v. against the refractory VT storm in HF.