Repolarization alternans reveals vulnerability to human atrial fibrillation

Abstract

Background: The substrates for human atrial fibrillation (AF) are poorly understood, but involve abnormal repolarization (action potential duration [APD]). We hypothesized that beat-to-beat oscillations in APD may explain AF substrates, and why vulnerability to AF forms a spectrum from control subjects without AF to patients with paroxysmal then persistent AF.

Methods and results: In 33 subjects (12 with persistent AF, 13 with paroxysmal AF, and 8 controls without AF), we recorded left (n=33) and right (n=6) atrial APD on pacing from cycle lengths 600 to 500 ms (100 to 120 bpm) up to the point where AF initiated. Action potential duration alternans required progressively faster rates for patients with persistent AF, patients with paroxysmal AF, and controls (cycle length 411±94 versus 372±72 versus 218±33 ms; P<0.01). In AF patients, APD alternans occurred at rates as slow as 100 to 120 bpm, unrelated to APD restitution (P>0.10). In this milieu, spontaneous ectopy initiated AF. At fast rates, APD alternans disorganized to complex oscillations en route to AF. Complex oscillations also arose at progressively faster rates for persistent AF, paroxysmal AF, and controls (cycle length: 316±99 versus 266±19 versus 177±16 ms; P=0.02). In paroxysmal AF, APD oscillations amplified before AF (P<0.001). In controls, APD alternans arose only at very fast rates (cycle length <250 ms; P<0.001 versus AF groups) just preceding AF. In 4 AF patients in whom rapid pacing did not initiate AF, APD alternans arose transiently then extinguished.

Conclusions: Atrial APD alternans reveals dynamic substrates for AF, arising most readily (at lower rates and higher magnitudes) in persistent AF then paroxysmal AF, and least readily in controls. APD alternans preceded all AF episodes and was absent when AF did not initiate. The cellular mechanisms for APD alternans near resting heart rates require definition.

Figure 1. Left Atrial Monophasic Action Potential (MAP) recording site

(A) Fluoroscopy (Left Anterior Oblique 30°) showing MAP catheter placed near the left superior PV (LSPV), and the coronary sinus (CS) catheter; (B) Digital Reconstruction of LA (NavX, St Jude Medical, CA). (C) Segmented 64-slice computed tomogram imported into NavX for positional reference.

Figure 2. APD Alternans At Slow Rates in Persistent AF, Disorganizing to Complex Oscillations Prior to AF

This man (LA diameter 44 mm, LVEF 44 %) showed substantial APD alternans at 500 ms, (A) CL 450 ms (mean ΔAPD=120 ms for 10 beats), (B) CL 400 ms during intermittent AV block, with a phase reversal (*), (C) CL 290 ms with multiple phase reversals, and (D) CL 260 ms, with complex oscillations then AF. (E) Maximum APD restitution slope <1. (Key: AP phases II and IV marked; A, Atrial; V, Ventricular signal).

Figure 3. Intermediate Rate Alternans in Paroxysmal AF, With Rate-Dependent Onset of Complex Oscillations Prior to AF

This 61 year old man (LA diameter 42 mm, LVEF 65 %), showed (A) No APD alternans at CL 500 ms, (B) APD alternans at CL 320 ms (LSL…) during 4:1, 2:1 AV ratios, that (C) exaggerated at CL 280 ms, with complex oscillations abruptly before AF onset. (D) APD restitution had maximum slope>1, but was <1 at time of APD alternans onset. (Key: as figure 2).

Figure 4. Amplification of Rate-Dependent APD Alternans in Paroxysmal AF Prior to AF

This patient (LA diameter 39 mm, LVEF 59 %) showed (A) No APD alternans at CL 500 ms; (B) APD alternans at CL 300 ms; (C) marked AP Alternans at CL 250 ms(phase II/III shape), during 3:1 AV conduction prior to AF initiation. Asterisk indicates far-field AF activation or an after-depolarization triggering AF. (D) APD restitution slope was >1 at its maximum, but <1 at APD alternans onset. (Key: as figure 2).

Figure 5. Control Subject with APD Alternans Only At Very Fast Rates Preceding AF

This 59 year old man (LA diameter 38 mm, LVEF 66%) showed no APD alternans at CL (A) 500 ms to (B) CL 240 ms. (C) APD alternans appeared at CL 210 ms during 1:1 and 2:1 AV conduction. (D) At CL=180 ms, APD alternans amplified to 6.5 % of APD immediately preceding AF initiation. (D) APD restitution slope=1 at the fast rates of APD alternans onset.(Key: as figure 2).

Figure 6. APD Dynamics

(A) APD-Cycle Length had an overall trend between AF groups of p=0.08, and differed significantly at CL indicated *; (B) APD Oscillation-Cycle Length. AF patients show marked APD oscillations (alternans at slow rates transitioning to complex oscillations at faster rate), while controls show APD alternans only at very short CL; (C) APD Oscillations as a Percentage of Mean APD. In paroxysmal AF, APD oscillations increased in magnitude with rate. In persistent AF, APD oscillations onset at slow rates had modest rate-dependence. In controls, APD oscillations arise only at very fast rates.

Figure 7

A. Spontaneous Premature Atrial Complex (PAC*) Initiates AF in the Milieu of APD Alternans at relatively slow rates. This happened multiple times in this patient at various rates. B. Failure to Initiate AF: APD Alternans Quenches that slowed atrial rate and prevented AF initiation.