Acute in vivo antiarrhythmic effects of cGMP-modifying drugs in the R2474S mouse model of catecholiminergic polymorphic ventricular tachycardia
Abstract
Abstract Background Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmia syndrome arising from mutations in cardiac calcium regulatory proteins. CPVT has a high mortality rate when left untreated. First-line treatments such as β-blockers have incomplete effectiveness and may be poorly tolerated by patients. Consequently, new effective, safe and targeted antiarrhythmic therapies are urgently required. In particular, recent data (1) has indicated that targeting the cGMP pathway offers an alternative strategy to prevent ventricular arrhythmias. Purpose Our objective is to evaluate in vivo efficacy of acutely-administered cGMP modulating sGC activators (cinaciguat 0.3mg/kg, runcaciguat 0.3mg/kg) and PDE5i (tadalafil 1.0mg/kg) for treating CPVT-associated arrhythmias in a preclinical mouse model. Methods RyR2 R2474S+/- mice were used because they replicate the human CPVT arrhythmia phenotype. All experiments were performed in accordance with UK ASPA regulations. Intra-abdominal implantation of a biopotential-recording telemetry device (ETA-F10: DSI, USA) was completed under isoflurane (2%) anaesthesia. ECG electrodes were fixed sub-cutaneously in lead II configuration. After 7-days recovery, mice underwent an electrophysiological assessment protocol: i) 30 minute baseline recording; ii) drug or vehicle control (DMSO) injection (IP); iii) 30 minute recording of arrhythmias induced by isoprenaline injection (20 mg/kg IP). 7 days later, the…
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