Restitution analysis of alternans and its relationship to arrhythmogenicity in hypokalaemic Langendorff-perfused murine hearts

Abstract

Alternans and arrhythmogenicity were studied in hypokalaemic (3.0 mM K + ) Langendorff-perfused murine hearts paced at high rates. Epicardial and endocardial monophasic action potentials were recorded and durations quantified at 90% repolarization. Alternans and arrhythmia occurred in hypokalaemic, but not normokalaemic (5.2 mM K + ) hearts (P<0.01): this was prevented by treatment with lidocaine (10 μM, P<0.01). Fourier analysis then confirmed transition from monomorphic to polymorphic waveforms for the first time in the murine heart. Alternans and arrhythmia were associated with increases in the slopes of restitution curves, obtained for the first time in the murine heart, while the anti-arrhythmic effect of lidocaine was associated with decreased slopes. Thus, hypokalaemia significantly increased (P<0.05) maximal gradients (from 0.55±0.14 to 2.35±0.67 in the epicardium and from 0.67±0.13 to 1.87±0.28 in the endocardium) and critical diastolic intervals (DIs) at which gradients equalled unity (from −2.14±0.52 ms to 50.93±14.45 ms in the epicardium and from 8.14±1.49 ms to 44.64±5 ms in the endocardium). While treatment of normokalaemic hearts with lidocaine had no significant effect (P>0.05) on either maximal gradients (0.78±0.27 in the epicardium and 0.83± 0.45 in the endocardium) or critical DIs (6.06±2.10 ms and 7.04±3.82 ms in the endocardium), treatment of hypokalaemic hearts with lidocaine reduced (P<0.05) both these parameters (1.05±0.30 in the epicardium and 0.89±0.36 in the endocardium and 30.38±8.88 ms in the epicardium and 31.65±4.78 ms in the endocardium, respectively). We thus demonstrate that alternans contributes a dynamic component to arrhythmic substrate during hypokalaemia, that restitution may furnish an underlying mechanism and that these phenomena are abolished by lidocaine, both recapitulating and clarifying clinical findings.

Epac activation, altered calcium homeostasis and ventricular arrhythmogenesis in the murine heart

“…We thus demonstrate, for the first time to our knowledge, the arrhythmogenic consequences of Epac activation in any whole heart preparation. In contrast to previous arrhythmogenic phenomena in murine models of LQTS [27, 45, 46, 51, 53], these phenomena were observed in the absence of evidence for reentrant mechanisms within the left ventricular free wall. Thus, alterations in transmural gradients of repolarisation, apico-basal gradients of repolarisation and action potential duration (APD) restitution were all absent.…”

“…The magnitude of MAP alternans, a clinical predictor of arrhythmogenicity [42], was given by the difference between odd and even numbered MAPs [45]. We observed a general trend towards increasing alternans magnitude as BCL decreased, in both control and 8-CPT-treated hearts (Fig.…”

“…Finally, we proceeded to investigate the effect of BCL on APD 90 with a dynamic pacing protocol as used recently in isolated perfused murine hearts [45, 46], whilst MAPs were recorded from the left ventricular basal epicardium. Hearts were paced for 100 stimuli at a BCL of 190 ms, with 5 ms decrements in the BCL every 100 stimuli until reaching the shortest BCL of 65 ms. Firstly, we examined the effect of BCL on the measured APD 90 over this range of stimulation rates.…”

“…In such experiments, hearts were initially perfused with 2 μM H-89 for 30 min, followed by 100 nM isoproterenol in the continued presence of H-89. In a separate study to investigate the effects of BCL on left ventricular epicardial APD 90 , hearts were paced with a dynamic pacing protocol [45]. This began with a series of 100 stimuli at a BCL of 190 ms, with the BCL reduced by 5 ms every 100 stimuli, until reaching a BCL of 65 ms.…”

Attenuated Ventricular β-Adrenergic Response and Reduced Repolarization Reserve in a Rabbit Model of Chronic Heart Failure

“…29 Animal studies show that the increased arrhythmogenicity seen in hypokalemia is most likely due to increase in repolarization duration, increase in dispersion of APD, and lengthening of the critical window for induction of early after-depolarizations. [30][31][32] This is FIGURE 5. Variability of APD 90 in ex vivo rabbit hearts.…”