Effects of inhibiting Na(+)/H(+)-exchange or angiotensin converting enzyme on atrial tachycardia-induced remodeling.
BACKGROUND
Inhibitors of the Na(+)/H(+)-exchanger (NHE1) and of angiotensin-converting enzyme (ACE) have been shown to reduce short-term (<6 h) tachycardia-induced atrial electrical remodeling. The role of NHE1 and ACE in longer-term electrical remodeling, as might occur with persistent AF, has not been studied.


METHODS
Dogs were subjected to atrial-tachypacing (400 bpm) for 7 days during treatment with 240 mg/day (standard clinical dose) of the NHE1 inhibitor cariporide (CariL, n=6), 1000 mg/day cariporide (CariH, n=6), 2 mg/kg/day of the ACE inhibitor enalapril (E, n=6), or no-drug controls (n=7). To ensure steady state concentrations at the onset of pacing, treatment began 3 days before the initiation of atrial tachypacing. Results were compared to those of unpaced dogs (n=9).


RESULTS
Atrial tachypacing reduced atrial effective refractory period (ERP), e.g. at a basic cycle length of 300 ms from 126+/-4 ms (unpaced, mean+/-S.E.) to 79+/-8 ms (no-drug controls, P<0.001). ERP abbreviation was unchanged by CariL (83+/-8 ms), CariH (80+/-7 ms), or E (76+/-5 ms). Atrial tachypacing increased mean duration of the longest AF episode in each dog (DAF) from 130+/-80 s (unpaced) similarly in all groups: 864+/-364 s, no-drug controls; 609+/-376 s, CariL; 709+/-353 s, CariH; 645+/-365 s, E (P=NS for differences among groups). Sustained AF requiring cardioversion for termination was induced in 0% of unpaced dogs vs. 33% of CariL, 33% of CariH, 33% of E, and 43% of control dogs. AF inducibility by single extrastimuli increased from 4+/-2% in unpaced dogs to 48+/-13% (P<0.01) in no-drug control dogs, an effect not changed by CariL (33+/-14%), CariH (35+/-17%) or E (48+/-16%).


CONCLUSIONS
In contrast to short-term (several-hour) atrial tachycardia-induced remodeling, remodeling by 7-day tachycardia is not affected by NHE1 or ACE inhibition. These results support the notion that short-term atrial tachycardia remodeling involves different mechanisms from longer-term remodeling, and urges caution in extrapolating results from studies of short-term remodeling to effects in longer-term remodeling as often occurs clinically.
Shinagawa
Kaori
K
Department of Medicine, University of Montreal, and Montreal Heart Institute Research Center, 5000 Belanger Street East, Quebec, Canada H1T 1C8.
Mitamura
Hideo
H
Ogawa
Satoshi
S
Nattel
Stanley
S
D000200:Action Potentials / Q000187:drug effects*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001281:Atrial Fibrillation / Q000188:drug therapy*; D002304:Cardiac Pacing, Artificial; D004285:Dogs; D004656:Enalapril / Q000494:pharmacology*; D006146:Guanidines / Q000627:therapeutic use*; D023421:Models, Animal; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors*; D013450:Sulfones / Q000627:therapeutic use*; D013997:Time Factors
D000806:Angiotensin-Converting Enzyme Inhibitors; D006146:Guanidines; D017923:Sodium-Hydrogen Exchangers; D013450:Sulfones; D004656:Enalapril; C093373:cariporide