Title:
Effects of ventricular pacing protocol on electrical restitution assessments in guinea-pig heart.

Abstract:
The steep slope of the rate adaptation of ventricular action potential duration (APD) is thought to indicate profibrillatory tendency. In cardiac patients, APD restitution is commonly assessed by extrasystolic (S(1)-S(2)) stimulations rather than dynamic pacing, because the latter may provoke myocardial ischaemia. In this study, ventricular APD and effective refractory period (ERP) were measured in perfused guinea-pig hearts to determine whether S(1)-S(2) stimulations and dynamic pacing may have similar value in APD restitution assessments aimed to predict arrhythmic risk. The maximal restitution slope was greater upon S(1)-S(2) stimulation than dynamic pacing at the epicardium (S(1)-S(2), 1.2 ± 0.08; dynamic, 0.72 ± 0.06; P = 0.0004) and endocardium (S(1)-S(2), 1.45 ± 0.08; dynamic, 0.95 ± 0.06; P = 0.0003). This difference was partly accounted for by an effect of the previous pacing history, as evidenced by flattening of APD restitution upon reductions in the regular beating interval prior to S(2) application. Furthermore, shorter ERP than APD relationships enabled ventricular capture at shorter diastolic intervals during S(1)-S(2) stimulation than dynamic pacing at the epicardium (S(1)-S(2), -1 ± 3 ms; dynamic, 35 ± 3 ms; P < 0.0001) and endocardium (S(1)-S(2), -1 ± 7 ms; dynamic, 38 ± 3 ms; P < 0.0001), thereby contributing to greater maximal restitution slope values. Flecainide, a Na(+) channel blocker, increased the ERP-to-APD ratio and eliminated early premature beats (diastolic interval of ∼0 ms), thereby flattening the S(1)-S(2) restitution curve, but had no effect on dynamic restitution. In hypokalaemia-induced arrhythmogenicity, a reduction in ventricular fibrillation threshold was paralleled by increased steepness of dynamic APD restitution, while no change in the maximal restitution slope was revealed by S(1)-S(2) stimulations. In summary, changes in electrical restitution obtained from extrasystolic stimulations may dissociate from those revealed by dynamic pacing. These findings therefore challenge the value of electrical restitution assessments based on extrasystolic stimulation alone, as commonly performed in the clinical setting.