LAUSR

Heart failure (HF) patients often suffer from lethal ventricular arrhythmias leading to sudden cardiac arrests. Phosphodiesterase 2 (PDE2), a cGMP activated enzyme hydrolyzing cAMP, is upregulated in HF. Cardiac-specific PDE2 overexpression revealed strong anti-arrhythmic and heart rate lowering effects of PDE2. Here, we validated the cardioprotective role of PDE2 upon modulating cardiac PDE2 activity, first, via assessing cardiac function of cardiac-specific PDE2-KO mice and second, via potentiating PDE2 mediated cGMP/cAMP crosstalk using natriuretic peptide type C (CNP), which are upstream of the cGMP/PDE2 axis. Cardiac function and arrhythmia susceptibility of PDE2-KO were assessed via echocardiography and ECG telemetry under basal conditions and after myocardial infarction (MI). Patch clamp technique was used to investigate CNP effects on action potentials and ion currents in WT isolated cardiomyocytes and in-vivo via ECG-telemetry. Already under basal conditions, PDE2-KO displayed severe irregularities in RR-intervals. 14 days post MI, PDE2-KO showed lower cardiac function and delayed increase in heart rate after arrhythmia provocation (double isoprenaline (ISO) injection (2 mg/kg i.p.) compared to WT controls, indicating diminished cardiac responsiveness. On the other hand, CNP treatment in WT displayed a PDE2-dependent antiarrhythmogenic effect. CNP (1 μM) significantly reduced the total number of delayed afterdepolarizations and spontaneous action potentials upon acute ISO (10 nM) stimulation. Furthermore, CNP significantly reduced the ISO-mediated increase of the L-type Ca 2+ and late Na + currents as well as SR Ca 2+ waves. These effects were reversed upon specific PDE2 inhibition with BAY 60-7550. Finally, in vivo, CNP (33 μg/g i.p.) significantly reduced the number of ventricular extrasystoles after arrhythmia provocation. This effect was significantly attenuated after PDE2 inhibition with BAY 60-7550. Here we provide evidence for acute antiarrhythmic effects of CNP upon downstream stimulation of cGMP-stimulated PDE2 and a critical role of PDE2 on heart rate regulation. Therefore, pharmacologically enhancing myocardial PDE2 activity may represent a novel cardioprotective strategy in cardiac arrhythmia and HF.