P106Loss of myocardial nNOS in human atrial fibrillation (AF) shortens action potential duration (APD) by increasing Ito: Implications for AF-induced electrical remodelling. (15th July 2014)

• Record Type: Journal Article
• Authors: Liu, X; Reilly, S; Carnicer, R; Recalde, A; Krasopoulos, G; Sayeed, R; Desilva, R; Casadei, B
• Is Part Of: Cardiovascular research. Volume 103(2014)Supplement 1
• Page Start: S18
• Page End: S18
• Publication Date: 2014-07-15
• Subjects: Cardiovascular system -- Diseases -- Periodicals; Cardiovascular system -- Periodicals; 616.1
• DOI: 10.1093/cvr/cvu082.47
• Languages: English
• ISSNs: 0008-6363

Abstract

Abstract: Purpose: Understanding the mechanism underlying atrial electrical remodelling in AF is of fundamental importance for the prevention and treatment of AF. We have recently found that neuronal nitric oxide synthase (nNOS) activity is dramatically reduced in atrial myocytes from patients with AF. Whether loss of nNOS activity contributes to AF-induced atrial electrical remodelling remains to be established. Methods: Whole-cell patch clamp was used to record action potentials (APs) and ion currents in human and murine right atrial myocytes. AF was induced in isoflurane anaesthetised mice by using trans-oesophageal electrical stimulation. N=number of patients or mice, n= number of myocytes. Results: Inhibition of nNOS by S-methylthiocitrulline (SMTC, 100 nM), induced a significant reduction in APD at 20 (38%), 50 (39%) and 90 (30%) percent of repolarization in atrial myocytes from patients in sinus rhythm (SR, N=8, n=38 control vs. N=8, n=31 in the presence SMTC, p<0.001) and suppressed APD rate-dependent adaptation (from 0.5 to 3 Hertz, N=6, n=24 control vs. N=6, n=17 cells with SMTC, p<0.05). In mice, nNOS inhibition or gene deletion reduced APD50 by 46% and 29%, respectively. (N=9, n=35 from nNOS-/- & N=6, n=11 WT plus SMTC vs. N=10, n=28 WT control, p<0.001 for the effect of nNOS dysruption). By contrast, SMTC had no effect on APD in atrial myocytes from patients with AF or nNOS-/- mice. In agreement with these findings, nNOS-/- mice displayed a 2-fold increase in AF inducibility in response to burst stimulation (p<0.05 vs. WT littermates, N=18 per genotype). Investigations of the ionic changes underlying the effect of nNOS dysruption on APD in RA myocytes from patients in SR (N=7, n=31 control vs. N=7, n=35 in SMTC) or WT mice with SMTC (N=9, n=19 control via N=6, n=9 in SMTC) showed an increase in Ito with SMTC in both species with no change in IK1 or IKr. Ito blockade with 4-AP (0.5 mM) significantly prolonged APD20 (by 19% in SR and by 153% in SMTC), APD50 (by 19% in SR and by 55% in SMTC) and, to a lesser extent, APD90 (by 7% in SR and by 13% in SMTC) in atrial myocytes from patients in SR. 4-AP also recovered the APD rate dependent adaptation that was suppressed by SMTC, confirming a role of Ito in the nNOS regulation of APD in human atrial myocytes. Conclusions: In mammalian atrial myocytes, nNOS-derived NO plays an important role in the regulation of APD and its rate-dependent adaptation by modulating Ito. These findings suggest that the marked loss of nNOS protein and activity in the fibrillating atrial myocardium has potentially important implication for AF-induced electrical remodelling.