Role of the Na(+)/H(+) exchanger in short-term atrial electrophysiological remodeling.

BACKGROUND: The pathophysiology underlying electrophysiological remodeling (ER) from rapid atrial rates is unknown. We tested the hypothesis that activation of the Na(+)/H(+) exchanger (NHE) by ischemia contributes to ER. METHODS AND RESULTS: Twenty-eight dogs were studied under autonomic blockade. In 15 closed-chest dogs, atrial fibrillation was simulated by right atrial pacing at 600 bpm over 5 hours. Of these, 9 (pace/NHEI) received HOE642, a selective inhibitor of the NHE, and 6 (pace/control) received saline. In pace/controls, atrial effective refractory period (AERP) at a drive cycle length (DCL) of 400 ms shortened from 143+/-7 to 118+/-5 ms (1 hour) and to 122+/-17 ms (5 hours). Shortening of AERP was prevented in the pace/NHEI group (P=0.02 compared with pace/controls). At baseline in all 15 dogs, pacing at shorter DCL resulted in shortening of AERP (physiological rate adaptation), which was lost at 5 hours in pace/controls. In pace/NHEI animals, rate adaptation was maintained despite 5 hours of pacing (P=0.02). In 13 other open-chest dogs, right atrial ERP was determined before and after occlusion of the right coronary artery. Five received HOE642 (ischemia/NHEI), 5 saline (ischemia/control), and 3 intravenous glibenclamide. In ischemia/controls, AERP(400) decreased (156+/-30 to 130+/-32 ms). Shortening of AERP was not prevented by glibenclamide (180+/-20 to 153+/-33 ms) but was prevented in ischemia/NHEI dogs (169+/-12 to 184+/-19 ms, P=0.001 compared with ischemia/controls and ischemia/glibenclamide). Rate adaptation was lost in ischemia/controls and preserved in ischemia/NHEI dogs (P=0. 02). CONCLUSIONS: Activation of the NHE is one mechanism underlying short-term ER.

Inhibition of the Na(+)/H(+) exchanger delays the development of rapid pacing-induced atrial contractile dysfunction.

BACKGROUND: Atrial mechanical stunning due to atrial fibrillation may persist after restoration of sinus rhythm. Although the mechanism of rapid rate-related contractile dysfunction remains unknown, ischemia, pH changes, and calcium overload have been postulated as potential mechanisms. We hypothesized that blockade of the Na(+)/H(+) exchanger (NHE) would alter atrial contractile dysfunction from rapid rates. METHODS AND RESULTS: Twenty-three anesthetized dogs were studied and subjected to 5 hours of rapid right atrial pacing. Ten received an inhibitor of the NHE, 10 received saline, and 3 received nifedipine. All animals underwent placement of 2 sonomicrometers on the left atrium, transesophageal echocardiography, and invasive hemodynamic monitoring. All measurements were made in sinus rhythm. Except for baseline and postdrug measurements, reduction in left atrial fractional shortening was significantly less at all time points in the NHEI group than in the control and nifedipine groups (P:=0.05). The percent change from baseline of left atrial function at all time intervals as assessed by left atrial appendage contraction velocity (LAACV) was significantly less in the NHEI group than in the control (P:=0.05) group. LAACV was significantly preserved at all time intervals (except 300 minutes) in the NHEI group compared with the nifedipine group (P:=0.05). The only significant difference in hemodynamics among the groups was between the control and the nifedipine groups at 30 minutes after drug (P:=0.05). CONCLUSIONS: Treatment with HOE642 significantly blunts the decline in left atrial mechanical function from rapid atrial rates compared with both control and nifedipine-treated groups.