Atrial cellular electrophysiological changes in patients with ventricular dysfunction may predispose to AF

Abstract

Background: Left ventricular systolic dysfunction (LVSD) is a risk factor for atrial fibrillation (AF), but the atrial cellular electrophysiological mechanisms in humans are unclear.

Objective: This study sought to investigate whether LVSD in patients who are in sinus rhythm (SR) is associated with atrial cellular electrophysiological changes that could predispose to AF.

Methods: Right atrial myocytes were obtained from 214 consenting patients in SR who were undergoing cardiac surgery. Action potentials or ion currents were measured using the whole-cell-patch clamp technique.

Results: The presence of moderate or severe LVSD was associated with a shortened atrial cellular effective refractory period (ERP) (209 +/- 8 ms; 52 cells, 18 patients vs 233 +/- 7 ms; 134 cells, 49 patients; P <0.05); confirmed by multiple linear regression analysis. The left ventricular ejection fraction (LVEF) was markedly lower in patients with moderate or severe LVSD (36% +/- 4%, n = 15) than in those without LVSD (62% +/- 2%, n = 31; P <0.05). In cells from patients with LVEF <or= 45%, the ERP and action potential duration at 90% repolarization were shorter than in those from patients with LVEF > 45%, by 24% and 18%, respectively. The LVEF and ERP were positively correlated (r = 0.65, P <0.05). The L-type calcium ion current, inward rectifier potassium ion current, and sustained outward ion current were unaffected by LVSD. The transient outward potassium ion current was decreased by 34%, with a positive shift in its activation voltage, and no change in its decay kinetics.

Conclusion: LVSD in patients in SR is independently associated with a shortening of the atrial cellular ERP, which may be expected to contribute to a predisposition to AF.

Figure 1. Change in ERP and capacity of atrial cells from patients with LVSD

A. Representative, superimposed action potentials stimulated by the 7^th and 8^th of a train of current pulses, S₁, followed by responses to a premature, S₂, in a cell from a patient with no LVSD (upper trace) and moderate/severe LVSD (lower). ERP (bar)=longest S₁-S₂ which failed () to produce an S₂ response of amplitude>80% of S₁. Mean±SE ERP (B) and capacity (C) of cells from patients with no LVSD (□; n=134 cells, 49 patients for ERP, and 535 cells, 135 patients for capacity) and moderate/severe LVSD (■; n=52 cells, 18 patients for ERP, and 152 cells, 38 patients for capacity). *=P<0.05 vs □.

Figure 2. Associations and correlations between LVEF, LVSD and atrial cellular electrophysiology

A. Mean±SE LVEF in patients with no LVSD (□; n=31) vs mild (n=12), moderate (n=11) and severe (n=4) LVSD (■). Comparison of APD at 50, 75 and 90% repolarisation (B), ERP (C) and dV/dtmax (D) between patients with LVEF>45% (horizontal stripes; n=27-38 cells, 10-13 patients) and ≤45% (diagonal stripes; n=22-26 cells, 7-8 patients). *=P<0.05; NS=not significant, vs LVEF>45%. E. Correlation between LVEF and ERP. Points are means of cell data from individual patients (n=49 cells, 17 patients).

Figure 3. Changes in atrial K⁺ currents associated with LVSD

I_TO recordings (A), peak density (B), current-voltage relationships (C), Vact₅₀ (D) and decay kinetics (E) in no LVSD (□; n=72-81 cells, 38-40 patients) and moderate/severe LVSD (■; n=11-12 cells, 5-6 patients). I_K1 recordings (F) and density at -120 mV (G) in no LVSD (□; n=99 cells, 40 patients) and moderate/severe LVSD (■; n=20 cells, 10 patients).

Figure 4. I_CaL characteristics in atrial cells from patients with and without LVSD

I_CaL recordings (A), peak density (B), current-voltage relations (C), Vact₅₀ (D) and decay kinetics (E) in no LVSD (□; n=167-222 cells, 61-73 patients) and moderate/severe LVSD (■; n=36-65 cells, 12-19 patients). Comparison of stimulatory effects on I_CaL of isoproterenol (ISO; 50 nM) (F) and 5-hydroxytryptamine (5-HT; 10 μM) (G) between no LVSD (□; n=45 cells, 19 patients for ISO; 37 cells, 23 patients for 5-HT) and moderate/severe LVSD (■; n=12 cells, 6 patients for ISO; 10 cells, 5 patients for 5-HT).