Abstract 2691: Persistent Atrial Fibrillation Causes Remodelling of Na Currents: Impact of INa Inhibition by Ranolazine on Arrhythmias and Contractility
Atrial fibrillation (AF) is the most common cardiac arrhythmia in clinical practice. It leads to electrical remodelling of several ion currents such as Ca and K currents and reduced action potential (AP) duration. It remains unclear whether Na currents (INa) are also altered in AF. For instance, the late component of INa (late INa), which persists throughout the whole AP and induces Na and Ca overload (via reverse mode Na/Ca exchanger, NCX) in heart failure and ischemia, has never been investigated. Thus, we studied changes in INa and potential beneficial effects of late INa inhibition using ranolazine (Ran) on arrhythmias and contractility in human atrial myocardium. We isolated human atrial myoyctes and trabeculae from 90 patients (SR vs. AF). Patch-clamp experiments revealed significantly reduced peak INa density by 16% in AF vs. SR which was accompanied by 26% lower expression of Nav1.5 (P<0.05). In contrast, late INa was significantly increased in myocytes from AF atria by 17%. Ran (10 μM) reduced the abnormally increased late INa in AF myocytes by 60% but only by 18% (P<0.05) in myocytes from SR atria. In SR myocytes, peak INa was concentration- and frequency-dependently inhibited (i.e. the higher the pacing rate the stronger peak INa inhibition) but only slightly in AF cells. Proarrhythmic activity was elicited in isometrically contracting atrial muscles exposed to 30 nM isoprenaline or 5 mM [Ca]o which was significantly reversed by Ran (8 out of 8 and 5 out of 6, respectively). Increasing pacing rates from 0.5 to 3 Hz were associated with increases in diastolic tension that could be significantly reduced by Ran (e.g. 3 Hz: Ran 3.2±0.6 vs. vehicle 4.6±0.9 mN/mm2) similar to our previous findings of reduced diastolic dysfunction by Ran in end-stage failing ventricular myocardium. In summary the results show that remodelling in AF also affects Na channels. Ran selectivity inhibited the abnormally increased late INa in AF, but caused a more pronounced inhibition of peak INa in SR. These effects had beneficial antiarrhythmic and contractile effects in multicellular atrial preparations. Therefore, Ran appears to be a promising new treatment option for patients with atrial rhythm disturbances and diastolic dysfunction and should be investigated in a clinical setting.