Acute in vivo antiarrhythmic effects of cGMP-modifying drugs in the R2474S mouse model of catecholiminergic polymorphic ventricular tachycardia

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 experiment was repeated so that each mouse received a drug and vehicle control, and therefore acted as its own control. We also evaluated the efficacy of nadalol (70 mg/kg) to facilitate comparison with an existing clinical treatment. Arrhythmia severity was manually scored according to a modified scoring system (2) and ECG parameters (heart rate, PR and QT intervals) were calculated using Ponemah software (DSI, USA). Results In all cases, cGMP modifying drugs reduced arrhythmia severity (Figure 1). sGC activators cinaciguat (N=19) and runcaciguat (N=17) caused a reduction in average arrhythmia score by 42.1% (P=0.012) and 30.4% (P=0.026), respectively, while heart rate and ECG parameters remained unaffected (P>0.05). PDE5i tadalafil (N=15) precipitated a 39.0% reduction (P=0.004) in arrhythmia score without effects on ECG parameters (P>0.05). The β-blocker nadalol (N=9) also reduced arrhythmia severity (49.2%; P=0.026) and blunted the heart rate increase after isoprenaline (DMSO: 9.25% increase vs. nadalol: 0.03% decrease; P=0.045), but had no effect on PR or QT intervals (P>0.05). Conclusion Our data demonstrated that acute administration of cGMP modifying drugs can offer targeted and effective alternative therapeutic approaches to treat arrhythmias in CPVT. Data on chronically administering these drugs in R2474S mice will provide further insight into clinical suitability for prevention of arrhythmias in patients.