Post-operative atrial fibrillation is influenced by beta-blocker therapy but not by pre-operative atrial cellular electrophysiology

Abstract

Introduction: We investigated whether post-cardiac surgery (CS) new-onset atrial fibrillation (AF) is predicted by pre-CS atrial cellular electrophysiology, and whether the antiarrhythmic effect of beta-blocker therapy may involve pre-CS pharmacological remodeling.

Methods and results: Atrial myocytes were obtained from consenting patients in sinus rhythm, just prior to CS. Action potentials and ion currents were recorded using whole-cell patch-clamp technique. Post-CS AF occurred in 53 of 212 patients (25%). Those with post-CS AF were older than those without (67 +/- 2 vs 62 +/- 1 years, P = 0.005). In cells from patients with post-CS AF, the action potential duration at 50% and 90% repolarization, maximum upstroke velocity, and effective refractory period (ERP) were 13 +/- 4 ms, 217 +/- 16 ms, 185 +/- 10 V/s, and 216 +/- 14 ms, respectively (n = 30 cells, 11 patients). Peak L-type Ca(2+) current, transient outward and inward rectifier K(+) currents, and the sustained outward current were -5.0 +/- 0.5, 12.9 +/- 2.4, -4.1 +/- 0.4, and 9.7 +/- 1.0 pA/pF, respectively (13-62 cells, 7-19 patients). None of these values were significantly different in cells from patients without post-CS AF (P > 0.05 for each, 60-279 cells, 29-86 patients), confirmed by multiple and logistic regression. In patients treated >7 days with a beta-blocker pre-CS, the incidence of post-CS AF was lower than in non-beta-blocked patients (13% vs 27%, P = 0.038). Pre-CS beta-blockade was associated with a prolonged pre-CS atrial cellular ERP (P = 0.001), by a similar degree (approximately 20%) in those with and without post-CS AF.

Conclusion: Pre-CS human atrial cellular electrophysiology does not predict post-CS AF. Chronic beta-blocker therapy is associated with a reduced incidence of post-CS AF, unrelated to a pre-CS ERP-prolonging effect of this treatment.

Figure 1. Comparison of pre-CS Ca²⁺ current between patients without and with post-CS AF

A, Original, representative, L-type Ca²⁺ currents (I_CaL) recorded from atrial myocytes isolated just prior to cardiac surgery (CS), from a patient in post-CS sinus rhythm, SR (□) and from a patient in post (3 day)-CS AF (■). Superimposed currents shown were evoked by voltage pulses (100 ms, 0.33 Hz, −40 mV holding potential), increasing in 10 mV steps between −30 and +40 mV. B and C, Histograms of peak I_CaL density (at +10 mV) and increase in peak I_CaL density by 0.05 μM isoproterenol (ISO), respectively, in atrial myocytes from patients in post-CS sinus rhythm (P-CS SR, □) and post-CS AF (P-CS AF, ■). Values are mean±SE. In (B), n=279 cells, 86 patients for P-CS SR, and 62 cells, 19 patients for P-CS AF (3 day). In (C), n=56 cells, 22 patients for P-CS SR, and 23 cells, 12 patients for P-CS AF (7 day). NS=not significant.

Figure 2. Comparison of pre-CS K⁺ currents between patients without and with post-CS AF

A, Original transient outward K⁺ currents (I_TO) and sustained outward currents (I_SUS) in atrial cells from a patient in post-CS SR (□) and post-CS AF (■). Superimposed currents evoked by voltage pulses (100 ms, 0.33 Hz, −50 mV holding potential) increasing in 10 mV steps between −40 and +60 mV. B, Histograms of peak (at +60 mV) I_TO (left hand panel) and I_SUS (right hand panel) densities in cells from patients in post-CS SR (□, n=60-84 cells, 29-44 patients) and post-CS AF (■, n=13-21 cells, 7-9 patients). Values are means±SE. NS=not significant.

Figure 3. Comparison of pre-CS inward rectifier K⁺ current between patients without and with post-CS AF

A, Original currents recorded in response to a voltage ramp, increasing from −120 to +50 mV at 24 mV/s, in atrial cells from a patient in post-CS SR (□) and post-CS AF (■). B, Histogram of means±SE inward rectifier K⁺ current density (I_K1, measured at −120 mV) in cells from patients in post-CS SR (□, n=111 cells, 48 patients) and post (7 day)-CS AF (■, n=26 cells, 10 patients). NS=not significant.

Figure 4. Comparison of pre-CS action potential characteristics between patients without and with post-CS AF

A, Original, representative, action potentials recorded in atrial myocytes from a patient in post-CS SR (□) and post (3 day)-CS AF (■). Superimposed action potentials shown were stimulated by the 7th and 8th of a train of conditioning current pulses, S₁ (rate: 75 beats/min), followed by responses to an increasingly premature test pulse, S₂. The cell effective refractory period (ERP, solid bars) was the longest S₁-S₂ interval failing to elicit an S₂ response of amplitude >80% of the preceding S₁ action potential. In each case, the S₂ response used to measure this interval is labelled (↘). B, Histograms of action potential measurements in atrial cells from patients in post-CS SR (□, n=174-204 cells, 64-69 patients) and post (3 day)-CS AF (■, n=21-30 cells, 9-11 patients). APD₅₀ and APD₉₀=action potential duration at the levels of 50 and 90% repolarisation, respectively. V_max=action potential maximum phase 0 (upstroke) velocity. Values are means±SE. NS=not significant (P=0.65, 0.94, 0.78 and 0.23 for APD₅₀, APD₉₀, ERP and V_max, respectively).

Figure 5. Influence of pre-CS beta-blocker therapy on post-CS AF and pre-CS atrial refractory period

A, Comparison of incidence of post (3 day)-CS AF between patients not treated (, −BB, n=13/48) and treated (, +BB, n=13/99), respectively, for >7 days pre-CS with a beta-blocker. Asterisk denotes P<0.05 between groups. B, Comparison of magnitude of increase in mean pre-CS atrial cellular effective refractory period (ERP) associated with pre-CS treatment (>7 days) of patients with a beta-blocker, between those in post-CS sinus rhythm (□; patient n: −BB=21; +BB=43) and post (3 day)-CS AF (■; patient n: −BB=4; +BB=5). †s denote P<0.05 for the increase in ERP associated with pre-CS β-blockade within each group.