What currents underlie pulmonary vein automaticity

The seminal studies of Haissaguerre and colleagues clearly identified the pivotal role of ectopy originating in the pulmonary vein region as a critical trigger for the onset of atrial fibrillation (AF) 1. In the years since, targeting of the pulmonary vein (PV) region using an array of ablation technologies has transformed the practice of clinical electrophysiology. While electrical isolation of the pulmonary veins has significantly impacted the burden of AF for many patients, many fundamental questions remain. What is it about the function of the pulmonary vein region that makes it such a potent trigger for AF? Why does AF typically only occur in older adults? In the current issue, Malecot and colleagues begin to address these questions 2. Using microelectrode techniques, they recorded action potentials from strips of the right superior pulmonary vein, superfused in an organ bath, and evaluated the impact of the adrenergic agonist norepinephrine (NE) on the evoked and spontaneous electrical activity. The authors showed that while NE elicited bursts of action potentials in the PV tissue (catecholaminergic automatic activity, CAA), NE exposure had no impact on activity on similar tissues from the left atrium (LA). They noted that the resting potential of the PVs was depolarized (~-70 mV) relative to that of the LA tissues (~-76 mV). Interestingly, exposure of the PV tissue to 10 μmol/L tetrodotoxin (TTX, a selective voltage gated sodium channel blocker) hyperpolarized the resting potential of PV but not LA tissue. This observation provides the somewhat surprising insight that differences in sodium channel activity contribute to the regional differences in automaticity. Why is this surprising? At a resting potential of -70 mV, relatively few sodium channels are available for activation, due to the marked steady-state inactivation of these channels at depolarized potentials. To directly evaluate the possibility of regional differences in sodium current properties, the authors performed comparative voltage clamp studies on myocytes enzymatically disaggregated from both the LA and from the PV regions. At first glance, the differences were not striking. The threshold for activating sodium current (INa) was slightly more negative in PV than LA myocytes, but there were no differences in peak current density, the voltage at which current density was maximal, or the sodium current reversal potential. There were no differences in sensitivity to TTX that could explain the differences on the basis of different alpha (pore) subunit expression. Considerable attention has been focused recently on the role of persistent (late) sodium current (INa,L) in cardiovascular disease and arrhythmogenesis 3. Malecot et al. evaluated INa from both the PV and LA regions and found little difference in the TTX-sensitive INa,L between regions, and no evidence of any sodium current remaining after 200 ms of depolarization. Ranolazine, a INa,L blocker, had effects that were quite similar to those of TTX. This suggests that INa,L does not underlie the intrinsic differences in automaticity between the PV and LA myocytes in this experimental model. If not INa,L, then what might account for the observed differences in automaticity? Analysis of the window current (the current that is present at potentials that span the overlap between the steady-state inactivation and activation curves) revealed that myocytes from the PV region has a wider range of potentials at which sodium current window currents can be elicited. They showed that treatment with TTX, ranolazine or quinidine (an older antiarrhythmic drug) could all suppress the sodium channel window current and suppress the CAA response to norepinephrine. In summary, subtle differences in sodium channel voltage-dependence can account for the baseline differences in the ectopic response to norepinephrine between LA and PV myocytes. Given the difference in embryologic origin of the PVs from the body of the LA4, it seems likely that while the pore subunit (Nav1.5) is identical between the PV and LA region, other components of the sodium channel macromolecular complex may have systematic regional differences. Future studies are needed to address this hypothesis. While the present studies were performed in young healthy rats, it is notable that young healthy individuals seldom develop AF. Conditions such as hypertension, valvular heart disease and heart failure significantly increase the risk of AF. Increased hemodynamic burden on the atria increases atrial oxidant production 5. Oxidant stress can cause persistent activation of calcium dependent calmodulin kinase (CaMKII), leading to activation of INa,L. While AF is not frequently evident or inducible in young, healthy animals, and INa,L is not evident in that setting, both might be more apparent in the presence of comorbidities that enhance oxidant production. Thus, it will be of great interest for future studies to compare the physiology of sodium currents from the PV and LA myocytes isolated from older animal models, and from those with risk factors for AF (hypertension, heart failure or valvular heart disease). Even better, though logistically more challenging, would be efforts to obtain these data from isolated human hearts. Malecot and colleagues have provided interesting insights into a topic that has the potential to significantly enhance our understanding of one of the fundamental enigmas of AF. What is unique about the PV region? By studying this question in depth, there is a potential to identify both the relevant pathophysiologic mechanisms, and to establish the groundwork for new treatments that might selectively suppress the ectopy that often initiates AF – perhaps without directly targeting the cardiac sodium channel. This might again transform the care of AF, with a shift in focus from the ablation of the atria to the suppression of atrial ectopy that precedes its onset.